HX641 35721 RC734 „0p3 1921 Epidemic respiratory RECAP PAULRHOEBER MEDICAL BOOKS 67-69 E. S9thSt..N Y 4&* <£ # Columbia Wtnitw&ttp mtljeCftpofJlrttigork College of ^fjpsficiansf anb burgeons ILibravp Digitized by the Internet Archive in 2010 with funding from Open Knowledge Commons http://www.archive.org/details/epidemicrespiratOOopie EPIDEMIC RESPIRATORY DISEASE EPIDEMIC RESPIRATORY DISEASE The Pneumonias and Other Infections of the Respiratory Tract Accompanying Influenza and Measles BY EUGENE L. OPIE, M.D. COLONEL, M. R. C, U. S. ARMY; PROFESSOR OF PATHOLOGY, WASHINGTON UNIVERSITY SCHOOL OF MEDICINE FRANCIS G. BLAKE, M.D. MAJOR, M. R. C, U. S. ARMY; ASSOCIATE MEMBER OF THE ROCKEFELLER INSTITUTE FOR MEDICAL RESEARCH JAMES C. SMALL, M.D. FORMERLY FIRST LIEUTENANT, M. C, U. S. ARMY; BACTERIOLOGIST, PHILADELPHIA GENERAL HOSPITAL THOMAS M. RIVERS, M.D. FORMERLY FIRST LIEUTENANT, M. C, U. S. ARMY; ASSOCIATE IN BACTERIOLOGY, JOHNS HOPKINS UNIVERSITY ILLUSTRATED ST. LOUIS C. V. MOSBY COMPANY 1921 Copyright, 1921, By C. V. Mosby Company Press of C. V. Mosby Company St. Louis, U. S. A. INTRODUCTION Death from lobar pneumonia, bronchopneumonia and measles, fatal with few exceptions in consequence of com- plicating pneumonia, constituted in 1916 approximately one- sixth (16.8 per cent) of the mortality in the army,' whereas in j 917 the same diseases were responsible for nearly two- thirds (61.7 per cent) of all deaths. During the first half of 1918 the incidence of pneumonia steadily increased and in some army camps there were extensive outbreaks of un- usually severe pneumonia. In July, 1918, the Surgeon General assigned a group of medical officers to the study of the pneumonias prevalent in the army and stationed them at Camp Funston, Kansas. At the base hospital of this camp all cases of pneumonia oc- curring among troops assembled in the camp were studied, but during the month of August there were few cases of pneumonia and these were of mild type. Pneumonia which occurred at Camp Funston during Au- gust was almost wholly limited to recently recruited colored troops from southern states (Louisiana, Mississippi). There was a low rate of mortality, and few complication?. This pneumonia exhibited a noteworthy difference in etiol- ogy from that usually seen in civil life, for it was' associated with a high incidence of those types of pneumococci which occur in the mouths of healthy men, namely, Pneumococcus atypical II, 2 Type III, and the group of. microorganisms represented by Type IV. Pneumococcus Type I was en- countered in only a few instances and Type II was not found, although these two microorganisms are responsible for two-thirds of the lobar pneumonia which occurs in civil life. ^•Report of the Surgeon General, U. S. Army to the Secretary of War, 1918, p. 44. 2 Stillman, F. G. : A Study of Atypical Type II Pneumococci, Jour. Exper. Med., 1919, xxix, 251. 11 12 INTRODUCTION During the investigation at ('amp Funston the Commis- sion had the courteous cooperation of Major Willard Stone, Director of Medical Service, and received much valuable assistance Prom Lieutenant A. McGlory, Registrar of the Base Hospital. A review el' the accurately compiled records of the base hospital was made in order to obtain a history of the pneu- monias and other respiratory diseases which had occurred throughout the existence of the camp, established in Sep- tember, 1917. It soon became evident that a disease recog- nized as influenza had been prevalent throughout this pe- riod and its incidence had shown a close parallel with that of acute bronchitis. At the same time there had been much pneumonia and a high death rate from this disease. The chart 3 which was constructed showed that the disease which had been designated influenza assumed epidemic propor- tions in March, 1918. Any doubt that may have been en- tertained concerning the nature of the disease is dispelled by the characters of this epidemic which, beginning at the end of February, reached its height on March 12 and rap- idly subsided; 1,127 men with influenza entered the base hospital between March 4 and March 29 and many more were treated in the infirmaries of the camp. In April there was a second wave of influenza and in May a third, each in large part limited to newly drafted men brought into the camp shortly before these outbreaks. Corresponding to the epidemic of influenza there was a great increase of pneumonia, reaching a maximum about one week after the height of the incidence of influenza; subsequently the incidence of pneumonia increased after each one of the sec- ondary waves of influenza. Pneumonia following measles occurred throughout the history of the camp ; in November and December, 1917, there was a severe outbreak of pneu- monia following measles and the mortalitv was high. Our 3 Opie, E. L., Freeman. A. \\\. Blake, F. G., Small, J. C Rivers, T. M. : Pneumonia at Camp Funston, Jour. Am. Med. Assn., 1919, lxxii, 108. INTRODUCTION 1 3 conclusions in regard to the pneumonias which occurred during the history of Camp Funston were as follows: 1. Pneumonia of a relatively stationary camp popula- tion, such as that which occurred among white troops dur- ing the period of our investigation, was in considerable part caused by Pneumococcus Types I and II and resembled the pneumonia of civil life. 2. Pneumonia of newly drafted colored troops from southern states during the period of our investigation was caused in great part by pneumococci of those types which occur in the mouths of healthy men, namely, Types IV, III and atypical II. 3. Pneumonia caused by influenza occurred after the epi- demic of influenza which we have described. The report states : "With the information available it is not possible to draw a sharp line between (1) the pneumonia of the stable camp population, (2) the pneumonia of the newly drafted southern troops, and (3) the pneumonia following influ- enza. It is possible that influenza, in greater or less degree, also acts as a predisposing factor in the production of the first and second varieties." 4. Pneumonia with measles was a frequent and unusu- ally fatal type of the disease. The most important causes of pneumonia during the history of the camp were influ- enza and measles. Evidence is not lacking that influenza occurred in epi- demic form in other widely separated camps in the United States during the spring of 1918. Vaughan and Palmer 4 state that a disease strongly resembling influenza became prevalent in the Oglethorpe camps about March 18, 1918, and continued three weeks; during this time the number sent to hospital or to quarters with this disease was 1,468 in a total strength of 28,586. Pneumonia, does not appear to have followed this epidemic. *Vaughan, V. C, and Palmer, G. T.: Communicable Diseases in the National Guard and National Army of the United States, Jour. Lab. and Clin. Med., 1918, iii, 635. 14 INTRODUCTION Miller and Lusk 5 found the ordinary type of pneu- monia prevalent at Camp Dodge, [owa, until March is to 20, L918, when abruptly the streptococcus type predomi- nated and there was a greal increase in the rate of mortal- ity. A mild tracheitis, they stale, was widespread in the camp during March. In March. 1918, one member of our commission saw an outbreak of influenza at Fort Sam Houston which was iden- tical in its clinical characters with the disease which ap- peared as a pandemic in the fall of 1918. The report of the Surgeon General 6 lor 1919 shows that there was a sharp increase of the incidence of influenza in the army during - March, reaching a maximum in April. The rate of influenza for 1,000 troops fell to its original level through May and June and finally rose to a great height in September and October. Influenza in epidemic form made its appearance in the army camps of the United States during March, 1918. The symptomatology of the disease associated with its peculiar epidemiology as seen at Camp Funston make its recogni- tion unquestionable. The disease had doubtless been pres- ent in this camp since its establishment in September, 1917, hut did not assume epidemic proportions until the spring of 1919. Pneumonia followed the epidemics of influenza which oc- curred in the spring of 1918 and exhibited characters sim- ilar to those of the pneumonias which followed the pan- demic of September and October, 1918. In both instances the height of the outbreak of pneumonia has been one week after the maximum incidence of influenza. Influenza became epidemic in Spain about the middle of May and in other countries received the name "Spanish influenza" which is not more applicable than the designa- tion "Russian influenza" often applied to the disease dur- ing the pandemic of 1889-90. •'.Miller, J. L., and Lusk, P. B. : Jour. Am. Med. Assn., 1918, Ixxi, 702. "Report of the Surgeon General to the Secretary of War, 1919, i, 637. INTRODUCTION 1 5 The studies of MacNeal 7 have shown that the first epi- demic of influenza in the American Expeditionary Force in France occurred about April 15, 1918, at a rest camp near Bordeaux, reached its height on April 22 and ceased May 5. The disease was of a mild character witli few complica- tions. Localized epidemics were reported from various camps and hospitals during May and June, when the dis- ease, MacNeal states, had become widespread in all sections of the American Expeditionary Force in France and in the French and British armies as well. Influenza had become epidemic in the Italian navy in the first two weeks of May. The belief that the disease was introduced from America, the author thinks, is " probably completely disproved by the fact that the epidemic was subsequently introduced in- to America in August and September and found there a most fertile soil for its spread." This view is disproved by the demonstration that influenza had appeared as scat- tered epidemics in the army camps in March, 1918. There is little reason to doubt that influenza in the American Ex- peditionary Force was brought from America. At the end of August our commission was transferred from Camp Funston to Camp Pike, where throughout the history of the encampment pneumonia had been so prev- alent that it had given the camp the rank of third in death rate from lobar pneumonia and fourth in death rate from bronchopneumonia among 32 camps established in this country. We arrived at Camp Pike September 5 and were stationed at the base hospital. Our work was facilitated by the hearty cooperation of the commanding officer, Major Morton R. Gibbons, who neglected no opportunity to pro- mote the investigation. Our work was cordially aided by Major Carl R. Comstock, Director of the Medical Service, and by Major Henry H. Lissner, who later occupied this po- sition. Work in the laboratory of the hospital received the valuable cooperation of Major Allen J. Smith, Director of 'MacNeal, W. J.: The Influenza Epidemic of 1918 in the American Expeditionary Forces in France and England, Arch. Int. Med., 1919, xxiii, 657. 16 [NTRODUCTION the Laboratory, who placed at our disposal every facility available. Lieutenant James R. Davis, who was for a time in charge of the laboratory, effectively assisted the work. The commission consisted of the following oi'licers: E. L. Opie, Colonel, M. R. C: Allen W. Freeman, Major, M. C; Francis Gr. Blake, Major. M. R. C, James C. Small, Lieu- tenant, M. C. and Thomas M. Rivers, Lieutenant, M. C. Major Freeman acted as epidemiologist and will publish a report upon the epidemiology of Influenza and pneumonia at Camp Pike. On October 11 the laboratory car "Lister" in charge of Lieutenant Warren II. Butz was assigned to the commission. Lieutenant Harry 1). Bailey was attached to the commission on October 14 and later assisted in its work. Valuable technical assistance was given by Ser- jeant Charles Behre, by Wm. E. Hoy, detailed from the Army Medical Museum, and by Thomas Payne. Study of the pathology of the lesions concerned was com- pleted in the Pathological Laboratory of Washington Uni- versity School of Medicine. The existence of an epidemic of influenza at Camp Pike was recognized on September 23, when 214 cases of influ- enza were admitted to the base hospital. Preceding this date and beginning September 1 there had been a gradual increase of the number of patients admitted with the diag- nosis of acute bronchitis. It is noteworthy that the dem- onstration of B. influenzae had been regarded as essential for a diagnosis of influenza and since this microorganism had not been found, instances of acute inflammation of the respiratory passages with the symptoms of influenza were classified under a variety of names. After September 2.') influenza was recognized by its symptoms. The number of cases increased with great rapid- ity and on September 27 reached over 1,000 per day; this number was approximately maintained during one week and after October 3 the epidemic gradually subsided. Among 52,551 men in the camp, including those who ar- INTRODUCTION 17 rived during October, 12,393 were attacked by influenza ; of these 1,499 suffered with pneumonia and 466 died. The height of the outbreak of pneumonia followed approxi- mately one week after that of influenza. The statistics from September 20 to October 14 collected by Major Freeman show that pneumonia following influenza, like the pneu- monia at Camp Funston during the interepidemic period, has a conspicuous tendency to select men who have been in the camp less than one month, designated in Table I as new recruits : Table I POPULA- TION INFLUENZA PNEUMONIA No. Per cent No. Per cent Men in camp more than one month NeAv recruits 27,782 23,769 4,462 7,263 15.6 30.6 493 1006 1.7 4.2 Total 51,551 11,725 22.7 1499 2.9 New recruits were nearly two and a half times as sus- ceptible to pneumonia as men who had been in camp more than one month. This statement does not take into con- sideration differences in the environment and mode of liv- ing of the new men. In view of the existing uncertainty concerning the bacte- riology of influenza and its associated pneumonias, the com- mission has availed itself of the opportunity afforded by the epidemic of influenza to determine what bacteria were present in the nasopharynx and sputum in these diseases. The examinations have been necessarily limited to a small proportion of the immense number of patients admitted to the hospital with influenza and pneumonia. Autopsies on those who have died with pneumonia have offered a more direct means of determining the relation of bacteria to in- flammation of the bronchi and lungs. An attempt has been made to classify the pneumonias following influenza and to determine their relation to the complex bacterial flora of the injured respiratory passages. These studies have shown very early the threatening prevalence of strepto- L8 [NTRODUCTION coccus pneumonia, and appropriate measures have been taken to combat the spread of this infection. No better il- lustration could be furnished to demonstrate the value of routine performance of autopsies as a means for the recog- nition of obscure epidemic disease. In view of the wide di I't'ereiiee of opinion concerning the pathology of influenzal pneumonia special study lias been given to the lesions of the disease, because the epidemic lias furnished the unique opportunity of examining all in- stances of pneumonia accurately referable to an epidemic of influenza attacking a Large but definitely defined group of individuals (50,000 troops). In a civil hospital there is often great difficulty in deciding, even in the presence of an epidemic, if death from pneumonia is the result of influ- enza, but at Camp Pike the relation of the heightened death rate to the epidemic lias excluded all save a trivial error in determining the relation of fatal pneumonia to influenza. At the direction of Col. F. F. Russell, who has promoted the work of the commission by unfailing aid, a special study has been made of the relation of hemolytic strepto- coccus to the complications of measles. During the later period of the investigation at Camp Pike experiments were performed on monkeys to determine the pathogenicity of B. influenza 1 and of microorganism isolated from the pneumonias following influenza. Typical lobar pneumonia was produced in monkeys by intratracheal in- jection of pneumococci. These experiments are described in an appendix. The Surgeon General lias approved the publication of this report but the authors alone are responsible for the views expressed. Eugene L. Opie. Washington University School of Medicine CONTENTS CHAPTER I page The Etiology of Influenza. (By Francis G. Blake, M.D. ; Thomas M. Rivers, M.D.; James C. Small, M.D.) 25 Discussion, 43; Conclusions, 49. CHAPTER II Clinical Features and Bacteriology of Infuuenza and Its Associ- ated Purulent Bronchitis and Pneumonia. (By Francis G. Blake, M.D., and Thomas M. Rivers, M.D.) 51 Influenza, 52; Purulent Bronchitis, 56; Pneumonia, 59; Hemolytic Streptococcus Pneumonia Following Influenza, 70; Bacillus Influenzas Pneumonia Following Influenza, 72; Summary, 73; Discussion, 76. CHAPTER III Secondary Infection in the Ward Treatment of Influenza and Pneumonia. (By Eugene L. Opie, M.D. ; Francis G. Blake, M.D. ; James C. Small, M.D. ; and Thomas M. Rivers, M.D.) . 83 Secondary Infection with S. Hemolyticus in Pneumonia, 84; Second- ary Infection with Pneumococcus in Pneumonia, 91 ; Secondary Con- tact Infection in Influenza, 95; Methods for the Prevention of Secondary Contact Infection in Influenza and Pneumonia, 98 ; Sum- mary, 106. CHAPTER IV The Pathology and Bacteriology of Pneumonia Following Influ- enza. (By E. L. Opie, M.D.; F. G. Blake, M.D.; and T. M. Rivers, M.D.) 107 Bronchitis, 142; Lobar Pneumonia, 154; Bronchopneumonia, 162; Peribronchial Hemorrhage and Pneumonia, 189 ; Suppurative Pneu- monia with Necrosis and Abscess Formation, 199; Interstitial Sup- purative Pneumonia, 209 ; Suppurative Pneumonia with Multiple Clus- tered Abscesses Caused by Staphylococci, 225; Empyema, Pericarditis and Peritonitis, 232; Bronchiectasis, 239; Unresolved Bronchopneumo- nia, 261. 19 L 1 !) CONTEXTS CHAPTER V i'akv Infection in the Ward Treatment of Measles. (By James C. Small, RID.) 282 Eemolytic Streptococci with Measles al Camp Pike, 297; Complica- tions of Measles, 303; Tlio Dissemination of Eemolytic Streptococci in Wards, 315; Carriers of Eemolytic Streptococci, 321. CHAPTEB VI The Pathology and Bacteriolog's of Pneumonia Following Measles. (By Eugene L. Opie, M.D.; Francis G. Blake, M.D.; James C. Small, M.D.; and Thomas M. Rivers, M.D.) 234 Changes in Bronchi, 336; Lobar Pneumonia, 337; Bronchopneumonia, 340; Suppurative Pneumonia, .'147; Pneumonia Associated with Acute Infectious Diseases other than Influenza and Measles, 353. CHAPTER VII Summary of the Investigation and Conclusions Reached. (By Eu- gene L. Opie. M.D.) ' 359 Lobar Pneumonia, 3(52; Bronchopneumonia, 363 ; Streptococcus Pneu- monia, 36.1; Staphylococcus Pneumonia, 3(56; Empyema, 366; Bron- chiectasis, 367; Unresolved Bronchopneumonia, 368; B. Influenza?, 369; Pneumococcus, 372; S. Hemolyticus, 374; Nonhemolytic Strep- tococci, 376; Staphylococci, 377; Pneumonia of Measles, 378; The Transmission of Streptococcus Pneumonia, 381; Transmission of Pneumococcus Pneumonia, 383; Prevention of the Transmission of Pneumonia, 3S3. APPENDIX Experimental Inoculation of Monkeys with Bacillus Influenzae and Microorganisms Isolated from the Pneumonias of In- fluenza. (By Eugene L. Opie, M.D. ; Allen W. Freeman, M.D. ; Francis G. Blake, M.D. ; James C. Small, M.D.; and Thomas M. Rivers, M.D.) 387 Inoculation of the Nose and Pharynx with B. Influenzas, 3S9 ; Intro- duction of Bacillus Influenza? into the Trachea, 391; Introduction of B. Influenza? and S. Hemolyticus into the Trachea, 392; Introduction of B. Influenza? and of Pneumococcus or of Pneumococcus Alone into the Trachea, 393. ILLUSTRATIONS CHARTS PAGE 1. The onset of cases of pneumonia shown by autopsy to be uncompli- cated by secondary infection with hemolytic streptococcus and of cases of streptococcus pneumonia 141 2. The date of onset of cases in which autopsy demonstrated lobar pneu- monia 161 3. Shows the relation of the epidemic of measles to that of influenza at Camp Pike, and the relations of the pneumonia following measles to both measles and influenza 293 4. Shows the time interval between the onset of measles and the onset of the subsequent pneumonia in the 56 cases of pneumonia follow- ing measles at Camp Pike 306 5. Shows the time relation between the identification of hemolytic strep- tococci in the throats and the development of otitis media in 27 cases shown to be due to hemolytic sti'eptococci 314 FIG. 1. Acute bronchitis showing engorgement of blood vessels of mucosa and elevation of epithelium by serum and blood 146 2. Acute bronchopneumonia with nodules of peribronchiolar consolidation and purulent bronchitis 167 3. Acute bronchopneumonia with peribronchiolar consolidation .... 169 4. Acute bronchopneumonia with peribronchiolar consolidation . . .170 5. Bronchopneumonia with hemorrhagic peribronchiolar consolidation . 174 6. Acute bronchopneumonia with confluent gray lobular consolidation in lower part of upper lobe and hemorrhagic peribronchiolar pneu- monia in lower lobe; purulent bronchitis ISO 7. Bronchopneumonia with purulent bronchitis and peribronchial hemor- rhage 190 8. Streptococcus pneumonia with massive necrosis 201 9. Abscess below pleura with perforation caused by hemolytic strep- tococci 202 10. Interstitial suppurative pneumonia; interstitial septa are the site of suppuration and lymphatics are distended with purulent fluid; empyema 211 11. Suppurative interstitial pneumonia 212 12. Suppurative interstitial pneumonia 216 13. Suppurative interstitial pneumonia showing a dilated lymphatic . . 217 21 22 ILLUSTRATIONS no. page ll. Endophlebitis occurring in association with suppurative pneumonia . 219 15. Abscesses in two clusters caused by S. aureus in upper part of right upper lobe 227 16. Abscesses in cluster caused by s. aureus ;it apex of right lulu' . . . 228 17. Acute bronchiectasis showing fissures penetrating into bronchial wall and at one place entering alveolar tissue 24(> IS. Acute bronchiectasis showing- fissures in the bronchial wall extending into neighboring alveoli which in zone about are filled with fibrin 247 19. Acute bronchiectasis; the bronchial wall indicated by engorged mucosa shows a varying degree of destruction, fissures extending into and through the bronchial wall 248 20. Acute bronchiectasis with destruction of bronchial wall exposing alve- oli filled with fibrin 249 21. Bronchiectasis with fissures extending through the bronchial wall into alveolar tissue which is site of fibrinous pneumonia 251 22. Regeneration of epithelium over fissures which have been formed in the wall of a bronchus 252 23. Squamous epithelium growing over the defect in the bronchial wall . 253 24. Acute bronchiectasis with fissures extending through bronchial wall which is marked by great engorgement of blood vessels . . . 25-1 25. Advanced bronchiectasis throughout lower left lobe 258 26. Unresolved bronchopneumonia with tubercle-like nodules of peribron- chiolar consolidation best seen in lower lobe ; bronchiectasis . . 2(iS 27. Unresolved pneumonia with peribronchial formation of fibrous tissue; bronchiectasis 270 28. Unresolved pneumonia with bronchiectasis showing new formation of fibrous tissue about a greatly dilated bronchus of which the epi- thelial lining has been lost 271 29. Lobar pneumonia following measles 338 30. Unresolved bronchopneumonia with measles showing new formation of fibrous tissue about a bronchus and in immediately adjacent alveolar walls 342 31. Unresolved bronchopneumonia with measles showing a nodule of chronic fibrous pneumonia surrounding a respiratory bronchiole . 343 32. Unresolved bronchopneumonia with measles showing chronic pneu- monia about a respiratory bronchiole and alveolar duct . . .344 33. Experimental lobar pneumonia in the stage of gray hepatization pro- duced by injection of Pneumococcus III into the trachea of a monkey 395 EPIDEMIC RESPIRATORY DISEASE EPIDEMIC RESPIRATORY DISEASE THE PNEUMONIAS AND OTHER INFECTIONS OF THE RESPIRATORY TRACT ACCOMPANYING INFLUENZA AND MEASLES CHAPTER I THE ETIOLOGY OF INFLUENZA Feancis G. Blake, M.D. ; Thomas M. Rivers, M.D. ; James C. Small, M.D. The bacteriologic investigation which will be described was made at Camp Pike, Arkansas, during the period of the influenza epidemic from September 6 to December 5, 1918. The data presented are limited to observations made during life in uncomplicated cases of influenza and to con- trol studies in normal individuals, and in cases of measles. Bacteriologic studies made at autopsy will be described in a subsequent part of this report. Because of the wide variations in opinion concerning the relationship of various bacteria to influenza that have arisen during the progress of the recent pandemic, a brief review of the salient features of the earlier literature seems advisable. In 1892 Pf eiffer 1 found a small, Gram-negative, hemophilic bacillus in all cases of influenza, often in almost pure culture, both during life and at autopsy. He stated that the organism was found only in cases of influenza or in those convalescent from the disease. Similar bacilli oc- casionally found in other conditions he classified as pseudo- influenza bacilli. He furthermore showed that freshly iso- lated cultures were pathogenic for monkeys, producing a disease not unlike influenza, though lacking in what he con- iPfeiffer: Ztschr. f. Hyg., 1893, xiii, 357. 25 26 PNEUMONIAS AND [NFECTIONS OF aESPIRATOR"X TRACT sidered the characteristic lung - lesions. [To therefore felt justified in claiining that this bacillus, which he designated I'). influenza 1 , was the cause of epidemic influenza. Pfeif- I'er's work^though hailed by many as unassailable, lias failed to stand the test of time in two respects. It has been definitely shown, by Wollstein 2 in particular, that there is no justification for recognizing a group of pseudoinfluenza bacilli, organisms so classified by Pfeiffer being indistin- guishable from B. influenza 1 . Furthermore, numerous in- vestigations have demonstrated that B. influenza} may fre- quently be found in a variety of diseases affecting the res- piratory tract and in a small proportion of normal individ- uals. Kretz 3 found it 47 times in 950 examinations, usually associated with disease of the respiratory tract. Siiss- wein, 4 Liebscher, 5 Jehle, G Wollstein, 2 Davis 7 and many others have demonstrated its presence in cases of measles. Lord s isolated B. influenzae in 30 per cent of 186 sputums from patients with acute and chronic infection of the res- piratory tract. Boggs 9 found it in frequent association with chronic bronchiectasis. Wollsteim 2 ' 10 showed that it was often present in the respiratory diseases of infants, and was not an infrequent cause of meningitis. Rosenthal 11 found that one in six of normal individuals harbors influ- enza bacilli and therefore considered it purely a sapro- phyte, a position, of course, thoroughly untenable in the face of indisputable evidence that it may be highly patho- genic. The widely accepted statement that B. influenzas is nonpathogenic for animals has apparently served in con- siderable degree to shake belief in its etiologic relationship to epidemic influenza. It would appear, however, that this opinion is not founded upon fact. Reference is again made : Wollstein: Jour. Exper. Med., 1916, viii. 681. •Kretz: Wien. klin. Wchnschr., 1897, x, 877. *Suss\vein: W T ien. klin. Wchnschr., 1901, xiv, 1149. ^Liebscher: Prag. med. Wchnschr.. 1903, xxviii, 85. "Jehle: Ztschr. f. Heilk., 1901, xx, n. s. 2, Int. Med. 7 Davis: Jour. Infect. Dis., 1906, iii. 1. 8 Lord: Boston Med. Sur. Jour., 1905, clii, 537, 574. "Boggs: Am. Jour. Med. Sc, 1905, cxxx, 902. "Wollstein: Am. Jour. Dis. Child., 1911, i, 42. "Rosenthal: Comp. rend. Soc. Biol., 1903, lv, 1500. ETIOLOGY OF I X FLU E X Z A 27 to the work of Wollstein 12 , who has shown that virulent strains of B. influenzae, when freshly isolated from the hu- man host, are highly pathogenic for rabbits and monkeys and that nearly all strains are more or less pathogenic for mice and guinea-pigs. None of these modifications of Pfeiffer's original work, however, would seem to constitute any valid reason for abandoning the conception of the etiologic importance of B. influenzae. On the contrary, they are quite in harmony with well-established facts concerning other bacteria which cause infections of the respiratory tract. Such bacteria are frequently found in normal individuals leading a sapro- phytic existence, are often associated with other disease conditions, and tend to show marked variations in viru- lence. Since the outbreak of scattered epidemics of influenza beginning in 1915-16, which finally culminated in the pan- demic of 1918-19, a vast amount of literature on the subject has appeared. No attempt has been made thoroughly to analyze this, because much of it is not available, much of it abounds in contradictions which it is difficult to harmo- nize at the present time, and much of it has been written on the basis of insufficient data gathered under the handicap of war conditions by men without sufficient time to under- take special investigation, or it is feared, in many instances, not sufficiently qualified by previous bacteriologic training. The sum and substance of opinion in 1918 would seem to be best summarized by quoting from the published report compiled by the British Medical Research Commission: 13 "Although Pfeiffer may yet furnish reasons why the ver- dict should not be pronounced, there is already sufficient material to shake the orthodox conception out of its high altar. Two facts stand out prominently : the generally ac- knowledged, or by some reluctantly admitted, absence of B. influenzae from organs on postmortem examinations, and "Wollstein: Tour. Exper. Med., 1915, xxii, 445. "Med. Sup. October 1, 1918 also Jour. Am. Med. Assn., 1918, lxxi, 1573. 28 PNEUMONIAS AND [NFEOTIONS OF RESPIRATORY TRACT the universally recorded findings of diplostreptococci, sin- gly or in association with the Pf eiffer bacillus. " Comment on this opinion will be made in the general discussion at the end of this paper. In undertaking a study of the bacteriology of influenza, it seemed essential to bear in mind certain clinical features of the disease which will be discussed in greater detail in a subsequent paper. It suffices to say for our present pur- pose that it is felt that influenza in itself should be regarded as a self-limited disease of short duration (two to five days in most instances), the most prominent local manifestation of which is a rapidly progressing attack upon the mucous membranes of the respiratory tract. Among the cases ob- served during the epidemic at Camp Pike uncomplicated influenza never proved fatal and death invariably was as- sociated with a complicating pneumonia. In a large ma- jority of cases pneumococci, S. hemolyticus, or less fre- quently other bacteria in addition to B. influenza? were asso- ciated with the pneumonia. 11 is 1'elt, therefore, that in any attempt to determine the primary cause of influenza bacteriologic studies made during life in early uncompli- cated cases of the disease are of primary importance and that the bacteriology of the sputum of patients with com- plicating pneumonia and the bacteriology of autopsies can only properly be used as valuable supplements to data so obtained. Since cultures from the respiratory tract must often of necessity contain many bacteria which play no part in the production of influenza, it is essential to have a working knowledge of the bacteria that may be encountered by the methods employed. It is also important that such knowl- edge as may have been gained in interepidemic periods be amplified by study of the bacterial flora present at various periods throughout the course of an epidemic, both in nor- mal individuals and in other disease conditions. These points have been borne in mind throughout the present ETIOLOGY OF INFLUENZA 29 study and such observations have formed an essenital part of the work. Methods. — In an investigation of this nature the culture methods employed should be suitably directed to determine primarily what bacteria are present and in what relative proportion they exist. The use of culture or animal inoc- ulation methods that are highly selective in character, en- hancing the growth of certain bacteria and retarding or in- hibiting the growth of others, are of great additional value, but can only properly be used secondarily in order to aug- ment the results obtained by nonselective culture methods. As the most suitable medium for the purpose in hand plain meat infusion agar, titrating 0.1 + to 0.3 + to phenolphtha- lein, to which 5 per cent of sterile defibrinated horse blood was added, was used. Since growth on freshly poured plates is greatly superior to that on plates that have been stored, the agar was melted as needed, the blood being- added when the medium had cooled to approximately 45° C. Cultures from the nose and throat were made by swab- bing the mucous membranes with a sterile applicator, touching the applicator to a small area on the surface of a blood agar plate, and spreading the inoculum over the sur- face of the medium with a platinum needle, insuring as wide a separation as possible. Direct cultures of selected and washed specimens of sputum were made when possi- ble. In many instances, of course, it was impossible to get sufficiently satisfactory specimens to permit of washing, especially when cultures were made very early in the dis- ease. To supplement direct culture of the sputum the mouse inoculation method as employed for the determina- tion of pneumococcus types was used. This is, of course, a highly selective method, of particular value in the detec- tion of pneumococcus and B. influenzae when they are pres- ent in relatively small numbers as compared with other bacteria. Plates were examined after twenty to twenty- 30 PNEUMONIAS AND [NFECTIONS OE RESPIRATOR'S TRACT four hours' incubation and again at the end of thirty-six in Forty-eight hours when necessary. In the presenl study, attention has been centered upon P>. influenzae, S. hemolyticus, and the various immunologic types of piit'uiiiococci, other organisms encountered having played no significant part in the cases studied except in rare instances. B. influenzae was identified by its morphologic, staining and cultural characteristics and conformed to the classical description given by Pfeiffer. S. hemolyticus was identified by its morphologic, staining, and cultural char- acteristics on blood agar, supplemented by a confirmatory hemolytic test with washed sheep corpuscles, and bile sol- ubility test. Pneumococci were identified by morphologic, staining and cultural characteristics, bile solubility test, and agglutination with specific antipneumococcus immune sera. Note was made in most instances of the presence of other organisms, such as members of the Gram-negative diploeoc- cus, staphylococcus, diphtheroid and streptococcus viridans groups, but no attempt was made further to isolate or iden- tify them. Bacillus Influenzae in Cases of Influenza. — On October 10, 1918, at the height of the epidemic at Camp Pike, search for B. influenza? was made in a group of 23 consecutive cases of uncomplicated influenza from one to six days after the on- set of the disease. From each individual simultaneous cul- tures on blood agar plates were made (a) from the nose, (b) from the throat, and (c) from the sputum, and the spu- tum from each case was injected into the peritoneal cavity of a white mouse. A similar study of 5 consecutive cases was made on November 19. The results are presented in Table II. By means of multiple cultures taken simultaneously from different portions of the respirator)' tract no difficulty was encountered in demonstrating B. influenzae in all these cases of uncomplicated influenza. Not only was B. influenzae found in all cases, but often in very large numbers predom- .ETIOLOGY OF INIO.UKNZA 31 mating over all other bacteria on at least one of the plates from each patient, and in occasional instances occurring in nearly pure culture. One culture made about two hours after onset of the initial coryza is of interest. There was at the time a profuse serous nasal discharge. One drop of Table II Presence op B. Influenzae in 28 Cases of Influenza SPUTUM DAY OF SPUTUM PASSED NO. DISEASE NOSE THROAT CULTURE THROUGH MOUSE 1 1 + + + + 2 4 - + + + 3 5 - - + - 4 4 - - + + 5 3 - - + + 6 4 - + + C 7 2 - + - c 8 4 + + + - 9 5 - + + + 10 2 + - - - 11 2 - + C + 12 3 C + + + 13 3 - _ _ + 14 o - - + + 15 3 c - - + 16 1 - + + + 17 3 - + - + 18 4 + + c + 19 6 - - + + 20 1 - + + + 21 2 - + - + 22 4 + _ + + 23 3 c - — + 24 2 + - _ _ 25 1 - - + + 26 5 - - + + 27 1 - + - + 28 1 - - + + 6 14 17 22 c indicates that the plate was contaminated. this allowed to fall on the surface of a blood agar plate gave a practically pure culture of B. influenza?. During the latter part of November and in early Decem- ber a small secondary wave of influenza occurred at Camp Pike. In a series of 48 consecutive cases, B. influenzae was readily found in all by means of combined throat cultures QO pneumonias and infections of inspiratory tract and mouse inoculation of the sputum, 33 times ((IS. 7 per cent) in the throat cultures, 39 times (81.3 per cent) in the sputum. These cases were cultured on admission to the receiving ward of the hospital within twenty-four to forty- eighl hours after onset and were all early cases of influenza without complications at the time the cultures were made. In 90 more consecutive cases in this series 62 or 68.9 per cent showed B. influenza in a single throat culture taken on admission. A summary of all cultures made in cases of uncomplicated influenza is presented in Table III. Of any single method used the intraperitoneal inocula- tion of a white mouse with a specimen of the patient's spu- Table hi Presence of B. Influenza in Cases of Influenza METHOD NUMBER OF CASES CULTURED B. INFLUENZA FOUND NUMBER PER CENT Xose culture 28 6 21.4 Throat culture 166 109 65.7 Sputum culture 28 17 60.7 Sputum (mouse passage) 76 61 80.3 Combined nose, throat and sputum cultures and sputum inoculation 28 28 100 Combined throat cultures and sputum inoculation 48 48 100 turn proved the most efficient in demonstrating the presence of B. influenzae. No single method served to demonstrate B. influenzae in all cases, but by simultaneous cultures from the nose, throat, and deeper air passages no difficulty was met in showing that B. influenzae was invariably present, usually in abundance somewhere in the respiratory tract during the acute stage of the disease. This result is not out of harmony with the rapidly progressive character of the attack upon the mucous membranes of the respiratory tract in influenza. Of interest in this connection are certain observations which suggest that the presence of B. influenzae in predomi- ETIOLOGY OF IXI'r/CKNXA 66 nant numbers at least is in many eases coincident with the acute stage of influenza and that the organisms show a tend- ency rapidly to diminish in abundance with the progress of the disease to recovery. In 82 cases of influenza cultured on the day of admission to the hospital, B. influenzae was present in 52 (63.4 per cent) of the throat cultures. Re- peated throat cultures in this group of cases from the fourth to the eighth day after admission when the temper- ature had fallen to normal, showed that B. influenzae was still present in demonstrable numbers in the throat of only 25 cases or 30.5 per cent. Not only was there a material reduction in the number of patients in whom B. influenzas could be demonstrated by the throat culture method, but the contrast in the predominance of B. influenzae on the plates made early in the disease with those made during convalescence was often very striking. It is only fair to say, however, that some cases continued to carry B. influ- enzae in their throats in large numbers throughout the pe- riod of observation. Presence of Pneumococcus in Cases of Influenza. — It seemed of some importance to determine the prevalence of pneumococcus in cases of influenza, not because of any pos- sibility that pneumococci might bear an etiologic relation- ship to the disease, but more by way of comparison with the prevalence of B. influenzae, since both organisms are found in the mouths of normal individuals and are also frequently found together in the pneumonias that complicate influenza. The results obtained in cases of influenza early in the disease before the development of either a purulent bron- chitis or of pneumonia are presented. The presence of pneumococcus was determined by the intraperitoneal inocu- lation of white mice with the saliva or sputum. Twenty-four cases examined on September 27 and 28 gave the results shown in Table IV. These patients had been in the hospital from two to five days at the time the determinations were made. PNEUMONIAS AND [NFECTIONS OF RESPIRATOR? TRACT T.Uil.r IV PNEUMOCOCCUS ix Casts OF [NFLUENZA Pneumococcus^ Type I Pneumococcus, Type II Pneumococcus, Atypical 1 1 Piunimoeoccus, Typi- I ! I Pneumococcus, Group I V No pneumococci found NUMBER PER CENT 8.3 15 62.5 7 29.2 From November 27 to December 1, the pneumococci pres- ent in 47 consecutive eases of influenza were determined. In this group specimens of sputum were collected shortly after admission of the patients to the receiving ward of the hospital. The results are shown in Table V. Table V Pneumococci in Cases of Influenza Pneumococcus, Type I Pneumococcus, Type II Pneumococcus, Atypical II Pneumococcus, Type III Pneumococcus, Group IV Mo pneumococci found. PER CENT 4.3 53.2 42.5 The results obtained show that pneumococci found in early uncomplicated cases of influenza, both early and late in the course of the epidemic, differ in no respect from those found in the mouths of normal individuals at any time. Similar studies of the prevalence of S. hemolyticus as determined by throat cultures in early cases of influenza are shown in Table VI. The only point of interest in these observations is the in- creased prevalence of S. hemolyticus in cases examined late in the epidemic of influenza as compared with that found early in the epidemic. The significance of this will be dis- cussed in other parts of this report. Presence of Bacillus Influenzae in Normal Men. — For comparison with the results obtained in cases of influenza ETIOLOGY OF INKI/UKXZA DO Table VI S. Hemolyticus in Cases of Influenza NUMBER OF S. IIEMOLYTI- CASES CULTURED CUS FOUND S. HEMOLYTI- PER CENT POSI- CUS NOT TIVE FOR S. FOUND HEMOLYTICUS Sept. 25-26 100 6 94 6 Nov. 27— Dec. 5 138 39 99 28.3 a fairly extensive study of the prevalence of B. influenzae in normal individuals lias been made at various times prior to and throughout the course of the epidemic. This was deemed of special importance, since it was obvious that the results obtained by previous workers during interepidemic periods would not in all probability coincide with those ob- tained in the presence of a widespread epidemic of influ- enza where the opportunity for the dissemination of B. in- fluenzae was almost unlimited. From the results obtained in the multiple cultures in cases of influenza it is obvious that only like methods can be compared. The results obtained in normal individuals have, therefore, been tabulated in groups dependent upon the culture method employed. These groups have been subdivided according to the time and the place of the study, such explanatory notes as seem necessary being added. (See Tables VII-IX.) The most striking feature of the figures presented in Table VII is the wide variation in the incidence of B. influ- enzae in different groups varying all the way from 11.1 to 68 per cent. Analysis of these differences brings out cer- tain points of great interest. It is apparent that the per- centage of cases carrying B. influenzae depended in large part upon the prevalence of respiratory diseases in the group from which the data were obtained. In the studies made at Camp Funs ton prior to the fall outbreak of influ- enza in epidemic proportions, it is noteworthy that "bron- chitis ' ' and pneumonia were prevalent throughout the sum- mer in those groups showing a relatively high incidence of B. influenzae. At the time these studies were made the pres- .ill PNEUMONIAS AND INFECTIONS OF R 'IRATORY TRACT Tabli VII Incidence of B. Influenzae ix Normal Men as Determined \-\ INTRA- PERITONEAL l\oi Tl.\TiON OF WHITE MlCE \\ III I SALIVA OR SPUTUM a v. o r- N V. O - - a g H - n ^ ~ -*, g X v. M ■a X V. - g g X I - - c . & 03 PER CENT POSITIVE FOR li. INFLUENZAE REM VRKS 1918 Aug. 13 i lamp Funston, 22 Prov. K.-uis. De- Colored bention Co. 104th Camp, Depot No. 2 Brigade 25 6 21 Bronchitis and pneumonia were prevalenl in this or- ganization of r e c e n t 1 y d i.-i £ted aegroes 'luring July and August, 15)18 Aug. 18 Camp Co. D. 3rd Punston, Dev. Bn. Kims. De- tention < lamp, No. 2 25 11 44 Recently drafted southern negroes not fit for full mili- tary duty. Bronchitis and pneumonia were prevalent in this organization during July and August, 1918 Aug. 20 Camp Funston, Kan. 70th Inf. 25 11 44 25 men presenting them- selves at sick call for vari- ous complaints; not Btrict- ly normal; respiratory dis- eases not prevalenl Aug. 22 Ft. Riley Kan. Quarters 4M M.O.T.C. 32 16 50 Recently drafted white men of 4 to 8 weeks' service. Pneumonia fairly prevalent in this organization Aug. 26 Camp Funston, Kan. 210th Eng. 27 3 11.1 About one mile distant from Camp Funston proper. No sickness in this organiza- tion Nov. 12 Hot Springs, Ark. Drafted men assembled to ''tit rain for camp 50 11 13 22 50 men selected from iso- lated farm communities; 12 gave a history of "influen- za" within the preceding 8 Weeks Nov. 25 Camp Pike Ark. Miscella- neous 26 50 12 of this group had influ- enza during the epidemic Dec. 10 Camp Pike Ark. Miscella- neous 25 17 68 12 of this group had influ- enza during the epidemic Summary: Normals Cases of influenza (for com- parison ) 235 76 88 61 37.4 80.3 ETIOLOGY OF INFLUENZA 37 ence of influenza in these organizations was not recognized, but in view of knowledge gained throng}) out the course of the epidemic at Camp Pike, it seems not improbable that influenza in mild form was present throughout the summer in certain organizations at Camp Funston. This would seem more likely in view of the fact that this commission has clearly demonstrated that a considerable epidemic of influenza swept through Camp Funston in March, 1918, and was followed by recurring smaller epidemics in April and May. 14 In contrast with these groups showing a high inci- dence of B. influenza) is that of the 210th Engineers, an or- ganization entirely free from respiratory diseases during the period of our study. On November 12 search was made for Bi. influenzae in 50 normal drafted men who had assembled at Hot Springs, Ark., on that date preparatory to entraining for Camp Pike. These men were all from isolated farming communi- ties where influenza was only moderately prevalent and where there was little opportunity for the wide dissemina- tion of B. influenzae such as occurs when large bodies of men are assembled in camps. Twelve of the 50 gave a his- tory of influenza within the preceding eight weeks. The cultures were made by the same methods as those used at Camp Pike, the laboratory car "Lister" being taken to Hot Springs for that purpose. The incidence of B. influ- enzae was only 22 per cent. In striking contrast with this figure are the figures of 50 and 68 per cent obtained in the last two groups studied at Camp Pike after the epidemic had swept through the camp: 24 of the 51 men in these groups had influenza during the epidemic. It is of interest to record that the incidence of pneumo- coccus in these cases was approximately the same in all groups and bore no relation to the prevalence of influenza, bronchitis, or pneumonia. 14 0pie, Freeman, Blake, Small, and Rivers: Jour. Am. Med. Assn., 1919, lxxii, 108. •> a PNEUMONIAS AND INFECTIONS OF RESPIRATORS TRACT Table VII] Incidence of r>. [npluenz2e in Normal Men as Determined ky Throat 1 1 n ki:s ox Hi.ook A<;ak Plates < c < - - ts; h S a - _ ?• < - X 3 s: V. § 1! SB g Efl . M 23 C- PEB CENT POSITIVE FOR B. INFLUENZAE REMARKS Sept. Oct. 5 Camp Pike, Ark. Med. De- 82 tachment, Base 11 os. ; personnel on measles wanls 14 17.1 82 throat cultures in 42 individuals Nov. 5-9 Camp Pike Ark. Miscella- 296 neous 71 23.9 Number among this group who had had influenza no! recorded Nov. 12 Hot Springs, Ark. Drafted 64 men assem- bled to en- train for camp Mi 'ii, in large part from isolated farm communi- ties; 13 gave a history of "influenza" within the preceding 8 weeks Nov. 25 Camp Pike Miscella- 26 neous 13 50 12 of this group had in- fluenza during the epi- demic Dee. 10 Camp Pike Miscella- neous 25 13 52 12 of this group had influ- enza, during the epidemic Summary Normals 493 Cases of in- fluenza (for comparison); 166 111 109 22.5 65.7 The results obtained by throat culture are quite similar to those obtained by the mouse inoculation method. The entire absence of B. influenzae in the group of 64 throat cul- tures made in the draft men assembled at Hot Springs as compared with the relatively high incidence in the last two groups examined at Camp Pike is very striking. In consideration of the figures presented in Table IX it is important to remember that the group of 50 men from Hot Springs were all from isolated farm communities, had not previously been assembled and had not been in continu- ous contact with a widespread epidemic of influenza. On the other hand, the two groups of normal men at Camp Pike were studied immediately after the epidemic had ETIOLOGY OK IXKLUKX/A 39 Table IX Incidence op B. Influenza in Normal Men Contrasted With That in Early Cases op Influenza as Determined by Multiple Cultures from Nose, Throat, and Sputum o P o O a H W £ M 5 P W PER CENT SHOWING B. INFLUENZA a w o "A o K SPUTUM DIRECT CULTURE SPUTUM MOUSE INOCULATION w 3 a- ^ w r « £ P 05 U Nov. Hot Normal 50 22 22 12 Springs, draft men (4 cul- tures only) (31 Ark. assembled cul- to entrain tures for camp only) Nov. Camp Pike Normal 26 38.6 50 34.6 50 80.8 25 men; 12 had influ- enza dur- ing the epi- demic Dec. Camp Pike Normal 25 48 52 24 68 88 10 men ; 12 had influ- enza dur- ing the epi- demic Oct, Camp Pike Patients 28 21.4 50 60.7 78.6 100 10 with influ- and enza in ' Nov. Base Hos. 19 •swept through the camp and had been constantly in contact with epidemic influenza for a period of three months, 24 of the 51 actually having had the disease during this period. The fact that in the group of men from Hot Springs, B. influenzae was found only by the mouse inoculation method is noteworthy, since it indicates that the organism was pres- ent in relatively small numbers and could be detected only by a highly selective method. Summary of the results obtained in normal men shows that the incidence of B. influenzae in normal individuals from isolated communities or in groups free from respira- tory diseases prior to the occurrence of the fall epidemic 40 PNEUMONIAS AND [NFECTIONS OF RESPIRATORY TRACT was relatively low, namely, 10 to 20 per cent; that in ob- servations made before the fall epidemic in groups in which "bronchitis" and pneumonia were fairly prevalent, B. in- fluenzae was found much more frequently, namely, in 25 to 50 per cent of the cases; and thai in groups studied at in- tervals during the epidemic the incidence of B. influenzae rapidly rose, peaching 85 per cent at the end of the epi- demic. In contrast with this. B. influenzae was found in 100 per cent of cases of influenza without reference to the time at which they occurred during the epidemic. It is obvious that the high percentage of normal men carrying B. influ- enzae found at the end of the epidemic can depend only on the wide dissemination of B. influenzae that must occur dur- ing epidemic times. Bacillus Influenzas in Measles. — Since the presence of B. influenzae in other diseases than influenza has been ad- vanced as an argument against its causal relationship to influenza, an extensive study of the incidence of B. influenzae in the throats of measles patients was made during the pe- riod of the epidemic of influenza at Camp Pike from Sep- tember 10 to October 20. In all a total of 830 throat cul- tures in 487 cases of measles were made, many cases being cultured repeatedly at weekly intervals. The results have been condensed as far as possible and are presented in Tables X, XI, XII. Table X Incidence of B. Influenzae in 400 Consecutive Casks of Measles as De- termined by Throat Culture at Time of Admission to the Base Hosimtal DATE NUMBER OF CASES B. INFLUENZAE FOUND NUMBER PEB CENT Sept. 16— Oct. 4 Oct. 4— Oct. 10 Oct. 10— Oct. 15 Oct. 15— Oct. 19 100 nm 100 100 27 32 32 48 27 32 32 48 The prevalence of B. influenza' in cases of measles during the period of the influenza epidemic corresponded very closelv with that found in normal individuals under similar ETIOLOGY OK INKU'KNXA 41 Table XI Incidence of B. Influenza in 830 Throat Cultures in 487 Cases of Mea- sles; Cultures Eepeated at Weekly Intervals NUMBER OF CULTURES B. INFLUENZAE FOUND NUMBER PER CENT Sept. 10-15 Sept. 16-29 Sept. 30— Oct. 6 Oct. 7-13 Oct. 14-20 47 106 122 235 320 15 33 38 96 157 31.9 31.1 31.1 40.8 49.1 Total 830 339 40.8 circumstances. The increasing proportion of cases carry- ing B. influenzae as the epidemic of influenza advanced is further evidence of the wide dissemination of the organism during the epidemic. Table XII Total Number of B. Influenza Carriers Among 223 Cases of Measles as Determined by Repeated Throat Cultures at Weekly Intervals after Admission to Hospital TOTAL CARRIERS IN times NUMBER NUMBER B. INFLUENZA FOUND ONE OR MORE CULTURED OF CASES OF CULTURES CULTURES NUMBER PER CENT NUMBER PER CENT 2 129 1st 2nd 37 63 28.7 48.8 82 63.6 3 69 1st 2nd 3rd 20 31 33 28.9 44.9 47.8 52 75.4 4 25 1st 2nd 3rd 4th 6 10 13 14 24 40 52 56 21 84.0 It is evident from the figures presented in Table XII that a large percentage of the measles cases studied were at one time or another carriers of B. influenza?. In consideration of this fact, it must be borne in mind that all these cases were cultured during the period when the influenza epi- demic was at its height and that many of these cases had in- fluenza while in the hospital for measles. Xo data are available as to the exact number, since a definite diagnosis of influenza could hardly be made during the acute stage of measles. It is probable that approximately 25 per cent 4'2 PNEUMONIAS AND [NFECTIONS OF RESPIRATOR? TRACT developed influenza, since that was the incidence of influ- enza in the total population of Camp Pike. The consistent increase in the percentage of influenza carriers clearly demonstrates that this was due to wide dissemination of B. influenzae with the progress of the epidemic. Another point of exceeding interest is that the percentage of meas- les cases carrying- B. influenzae in the throat was lowest dur- ing the acute stage of the disease and increased during con- valescence. This is in direct contrast with the results found in cases of influenza where the number of cases carrying B. influenzae in the throat Avas highest during the acute -stage and rapidly diminished in uncomplicated cases with the on- set of convalescence. Summary. — Multiple cultures made simultaneously from the nose, throat and lower respiratory tract showed that B. influenzae was invariably present in all cases of influenza from the onset of the disease. Not only was B. influenzae present in all cases, hut it was frequently present in pre- dominant numbers, sometimes in nearly pure culture. In the majority of cases that went on to rapid recovery with- out the development of an extensive bronchitis or compli- cating pneumonia, the predominance of B. influenzae over other organisms rapidly diminished coincident with onset of convalescence. Many cases, however, continued to carry B. influenza? in large numbers in the throat throughout con- valescence. Xo data on the possible duration of the carrier state have been obtained. By the culture methods em- ployed no other organism has been found that would sug- gest any etiologic relationship to the disease. The two organisms most frequently associated with B. influenzae in postinfluenzal pneumonias, pneumococcus and S. hemolyti- cus, have not differed in their incidence in early uncom- plicated cases of influenza from that found in normal in- dividuals. The incidence of B. influenzae in normal men, in different groups studied, has varied between 11.1 and 88 per cent. ETIOLOGY OF INFLUENZA 4d This wide variation has depended npon the prevalence of respiratory diseases, more particularly influenza, in the groups studied and the opportunity thereby offered for the wide dissemination of B. influenza. With the progress of the epidemic, the number of normal men carrying B. in- fluenzae has steadily increased until it reached its maximum at the end of the epidemic. The incidence of B. influenzae in cases of measles studied during the epidemic of influenza has been relatively high though never equaling that found in cases of influenza. As in normal men, the incidence in cases of measles has stead- ily increased during the period of the epidemic. Repeated throat cultures at weekly intervals in cases of measles have shown that approximately 80 per cent became temporary carriers of B. influenzae at one time or another during the period of the epidemic. Many of these cases had influenza during the time that they were in the hospital. The carrier state in cases of measles was found to bear no relation to the acute stage of the disease since the number of carriers at the time of admission to the hospital was considerably lower than that found during convalescence as determined by repeated cultures in the same cases. Discussion The bacteriologic studies in cases of influenza described in this report fully support Pfeiffer's claim that B. influ- enzae is invariably present in the disease. It is particularly important to note that these results were obtained in early uncomplicated cases of influenza and are not dependent upon cultures made from cases complicated by pneumonia or obtained at autopsy. In view of this fact the tendency so apparent in much of the recent literature to relegate B. influenzae to a place of secondary or minor importance in the disease seems hardly justifiable. It would seem that this tendency is largely dependent upon three factors : first, the failure of many to find B. influenza? either during life or 44 PNEUMONIAS AND INFECTIONS OF RESPIRATOR? TRACT a1 autopsy in any considerable proportion of cases; second, the frequenl failure to draw a clear distinction between in- fluenza itself and the pneumonia to which it predisposes with a consequent overemphasis upon autopsy bacteriology where a considerable variety of secondary organisms have attracted particular attention: and third, an incorrect in- terpretation of the undoubtedly Large number of B. influ- enzae carriers Pound among normal individuals and those with other diseases during the period of the epidemic and to less extent in interepideinic times. Since the majority of workers who are thoroughly fa- miliar with the technic of cultivating B. influenzal have en- countered little difficulty in finding it in a large majority of cases, it is felt that the considerable number of negative reports that have appeared can depend only upon the un- familiarity of those who have failed to find it with the proper bacteriologic methods. This is quite apparent in many of the reports that have been published, and is not surprising in the face of the excessive demand for well- trained bacteriologists occasioned by the war. One important feature in the successful isolation of B. influenzae from all cases that has been brought out in the course of the work here reported, is the necessity of making simultaneous cultures from all portions of the respiratory tract, since by no single culture method was it found possi- ble to find the organism in all cases. It has been pointed out that one of the most characteristic local phenomena of the disease is the rapidly progressing attack upon the mu- cous membranes of the respiratory tract. Tt seems quite possible that B. influenza' in predominant numbers at least may be found in many cases only at the crest of the wave, if we may speak of it as such. By way of analogy is the well-recognized fad that the successful isolation of strep- tococcus from eases of erysipelas often depends upon tak- ing cultures from the margin of the advancing lesion. While definite proof is lacking for this opinion, it would seem to ETIOLOGY OF IXKIJ'KX/A 45 receive some support from the observation that 15. influ- enzae rapidly disappears from the throat with the onset of convalescence in a considerable proportion of eases. It is felt that these observations, establishing the predominance of B. influenzae in the early acute stages of the disease, are of considerable significance, especially when exactly the re- verse condition was found in studying the incidence of the organism in cases of measles. In consideration of the primary cause of influenza, atten- tion has often been focused upon the many different bacteria found in autopsy cultures. The most prominent of these are the ill-defined cliplostreptococci of the European writ- ers, the various immunologic types of pneumococci, and S. hemolyticus. Other microorganisms less frequently found are staphylococci, M. catarrhalis, nonhemolytic strepto- cocci, and B. mucosus capsulatus. It is not within the scope of this paper to discuss their relation to the various types of pneumonia found at autopsy, but their very multiplicity would seem sufficient prima facie evidence that they bear no etiologic relationship to influenza and must be regarded only as secondary invaders. If any further support for this opinion were necessary, it may be found in the studies upon the incidence of pneumococcus and S. hemolyticus in early cases of influenza described in this report. Both were found to occur in the same proportions in which they may be found in normal individuals at any time. Although Pfeiffer maintained that B. influenzae was found only in true epidemic influenza, the incorrectness of this contention has been thoroughly established by many reliable investigators and it has been shown beyond ques- tion that influenza bacilli may always be found in a small proportion of normal individuals and are not infrequently found in other respiratory diseases. The fairly extensive study that has been made of the in- cidence of B. influenzae in normal men and in cases of mea- sles has clearly demonstrated that the proportion of car- 4l! PNEUMONIAS AND [NFECTIONS OF RESPIRATOR'S TRACT riers found in any group depends upon the prevalence of influenza in the group studied and thai with the progress of the epidemic the percentage of carriers has steadily in- creased. When one considers that the opportunity i'or the dissemination of B. influenzae by contact infection is almost unlimited during an epidemic of the proportions of that which has swept over the country, this is not at all surpris- ing. That such a large number of normal individuals be- came carriers of B. influenzae during the epidemic would seem to be sufficient evidence that actual dissemination does occur and to controvert the theory that in actual cases of influenza, conditions are established in the respiratory tract whereby B. influenzas, always present in small numbers, is enabled to "grow out" and become the predominant or- ganism. From a consideration of all the observations made as to the incidence of B. influenzae in various conditions it would appear that the carrier condition is quite analogous to that found with many other bacteria, and may be divided into three groups: (a) acute carriers, those having influ- enza, (b) contact carriers, those who during epidemic times become temporary carriers of the organism without con- tracting the disease, and (c) chronic carriers, the relatively small number of normal individuals or those with chronic respiratory conditions who carry B. influenzae over long periods of time. From the facts at hand this would seem to be the most probable explanation of the conditions found. It is certainly true that the established presence of pneu- mococcus, B. diphtheria?, meningococcus and many other organisms in a varying proportion of normal individuals is not regarded as sufficient evidence to exclude them as the etiologic agents of the diseases which they cause. It is quite obvious that if B. influenzae is to be regarded as the cause of epidemic influenza, it must change quite rapidly under certain circumstances from a relatively sap- rophytic organism to a relatively virulent pathogenic or- ganism, and conversely return to its avirulent state follow- ETIOLOGY OF I X KM 'K X/A 47 ing the passage of an epidemic Animal experimentation has taught us that virulence is acquired by the, rapid pas- sage of an organism 'from host to host. That an oppor- tunity for the rapid transference of B. influenza? from man to man was provided by the assembling of large groups of individuals relatively susceptible to respiratory diseases in our camps and cantonments is by no means impossible. It has been clearly shown by Vaughn and Palmer 15 that men from rural districts are very susceptible to respiratory diseases and that the camps in which such men were as- sembled suffered most heavily in this respect during the winter of 1917-18. This Commission has clearly demon- strated that an epidemic of influenza swept through Camp Funston 14 in the spring of 1918 and that a similar epidemic occurred at Camp Pike. Accumulating evidence will un- doubtedly show that like epidemics existed in many of our southern camps (Vaughn and Palmer, 15 Soper 16 ). It is of considerable interest that B. influenzae was found in almost one-half of the cases of bronchopneumonia 'studied by Cole and MacCallum 17 at Fort Sam Houston in February and March, 1918. This relation is especially noteworthy, since an epidemic of influenza was seen by one of us (Blake) among the troops at Kelly Field and Fort Sam Houston during these months. That similar conditions existed in European armies as early as 1916-17 is suggested by the reports of Hammond, Eolland, and. Shore 18 and of Abra- hams, Hallows, Eyre, and French 19 on epidemics of "pur- ulent bronchitis" with bronchopneumonia in the British army. B. influenzae was found abundantly in these cases. Theoretically, under the conditions outlined, above, ideal opportunities have been provided for B. influenzae to build up sufficient virulence to enable it to produce the pandemic of 1918-19. While it is thoroughly recognized that these 15 Vaughn and Palmer: Jour. Lab. and Clin. Med., 1918, iii, 635. 16 Soper: Jour. Am. Med. Assn., 1918, bcxi, 1899. 1T Cole and MacCallum: Jour. Am. Med. Assn., 1918, lxx, 1146. "Hammond, Rolland, and Shore: Lancet, London, 1917, ii, 41. 10 Abrahams, Hallows, Eyre, and French: Lancet, London, 1917, ii, 377. 4-S PNEUMONIAS AND INFECTIONS OF RESPIRATORS TRACT considerations are in the main hypothetical, it is felt that they are by bo means beyond the bounds of possibility, and for thai reason arc offered as suggestions worthy of l'ur- i her investigation. It is, of course, perfectly possible on the basis of the ob- servations presented still to regard B. influenzae as a sec- ondary invader which makes its appearance in all cases of influenza simultaneously with the onset of clinical symp- toms. Final proof of its causal relationship to the disease must depend upon the production of influenza by experi- mental inoculation. Results hitherto obtained in attempts to produce the disease experimentally have been contra- dictory. ri'eifl'er 1 claimed to have produced a disease in monkeys in some respects resembling influenza by the in- tratracheal injection of freshly isolated cultures of B. in- fluenzae. Wollstein, 12 in studies upon the pathogenicity of various strains, has shown that B. influenzae is generally pathogenic for mice and guinea-pigs without respect to source or virulence for man. Pathogenicity for rabbits and monkeys, on the other hand, was possessed only by strains that were highly virulent for man. She further- more pointed out that for successful animal experimenta- tion, it is imperative that inoculations be carried out im- mediately after the isolation of the bacilli because they rap- idly lose virulence by subculture on artificial media. It is felt that failure to appreciate these facts has been respon- sible for the often repeated statement that B. influenzae is not pathogenic for animals. In a series of animal experiments carried out by this com- mission recorded in an appendix to this report, sixteen- hour cultures of B. influenzae freshly isolated from early cases of influenza were demonstrated to be pathogenic for monkeys, both by inoculation of the nasal and pharyngeal mucosa and by intratracheal injection. Monkeys so inocu- lated developed coryza, epistaxis, tracheitis, bronchitis, and extreme prostration. Experiments with forty-eight-hour ETIOLOGY OF I NK'LUUXZA 41) cultures of strains preserved by subculture during from ten to fifteen days failed to demonstrate pathogenicity for mon- keys. Proof that these monkeys had influenza can depend only upon the demonstration that they suffered with a dis- ease having the clinical character and pathologic lesions of influenza. The reported failure to produce influenza in man by di- rect inoculation with freshly isolated cultures of B. influ- enzae in experiments conducted on volunteers by the United States Public Health Service 20 at Gallops Island, Boston, is interesting, but would seem to lack definite significance since attempts to transmit the disease from man to man by direct contact also failed. Since all the subjects of these experiments had been previously exposed to influenza dur- ing the epidemic, 30 per cent actually having contracted the disease, it would seem probable that the remaining 70 per cent were only very slightly if at all susceptible. It is note- worthy that the attack rate of influenza in most army groups was approximately 20 to 30 per cent during the epi- demic, the remaining 70 to 80 per cent failing to contract the disease though equally exposed. No other explanation presents itself except that influenza is no longer transmis- sible when clinical symptoms have appeared. Conclusions 1. Consideration of all the evidence available makes it seem highly probable that B. influenzae is the specific etio- logic agent of epidemic influenza, because (a) it is always present in early uncomplicated cases of influenza; (b) it is predominantly so during the acute stage of the disease in cases going on to rapid recovery without development of complications; (c) its presence in varying numbers in nor- mal individuals and in other diseases of the respiratory tract is not valid evidence against its etiologic relationship to influenza, but on the contrary is quite in harmony with ""Public Health Reports, U.S.P.H. Service, 1919, xxxiv, 33. 50 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT what should be expected from our knowledge of oilier bac- teria known to be the etiologie agents of various respira- tory diseases; (d) its vapidly increasing prevalence in nor- mal individuals simultaneously with the progress of the epidemic indicates that actual dissemination of B. influenzae readily occurs and is very widespread during pandemic times; (e) cultures of B. influenzas freshly isolated from early acute cases of influenza are pathogenic for animals, and may produce in monkeys a disease closely resembling influenza. 2. Final proof of the exact relationship of B. influenzae to influenza must depend upon (a) more definite knowledge of the immunology both of the organism and of the disease, and (b) knowledge of the pathologic lesions of influenza and the production of these lesions in animals by inocula- tion with B. influenzae. CHAPTER II CLINICAL FEATURES AND BACTERIOLOGY OF IN- FLUENZA AND ITS ASSOCIATED PURULENT BRONCHITIS AND PNEUMONIA Francis G. Blake, M.D., and Thomas M. Rivers, M.D. The material presented in this section of the report con- sists of clinical and bacteriologic observations made dur- ing the course of an investigation of influenza and its asso- ciated bronchitis and pneumonia at Camp Pike, Ark., be- tween September 6 and December 15, 1918, comprising part of a correlated study of the epidemiology, bacteriology, pathology, and clinical features of these diseases. The bac- teriologic studies are in the main limited to those made dur- ing life, those made at necropsy being reported in another section of this report. Methods. — All cases upon which the clinical and bacte- riologic data presented are based, were examined by the authors and our own clinical histories and physical exam- inations were recorded. This was considered of special im- portance, since in studying a group of diseases in which secondary infection of the respiratory tract might super- vene at any time, it was essential to determine as far as possible the exact clinical condition of the patient at the time when bacteriologic examinations were made. The bac- teriologic methods employed were the direct culture of nose and throat swabbings and of selected and washed specimens of sputum on the surface of 5 per cent defibri- nated horse blood agar plates, the intraperitoneal inocula- tion of white mice with specimens of sputum according to the method described by Blake 1 for the determination of VBlake: Jour. Exper. Med., 1917, xxvi, 67. 51 52 PNEUMONIAS AND INFECTIONS OF RESPIRATOR1' TRACT pneumococcus types, and in some cases the method of Awry.- B. influenzas pneumococci and hemolytic strep- tococci were identified by the methods described elsewhere. Note was made in most instances of the presence of other organisms such as members of the Gram-negative ftiplo- coccus group, staphylococci, diphtheroids, and members of the streptococcus viridans group, but no attempl was made to further isolate or identify them since they played no sig- nificant pari in the cases studied except in rare instances. Influenza The fall epidemic of influenza at Camp Pike began about September 1, 1918, and reached epidemic proportions on September 23 when 214- cases were admitted to the base hospital. The epidemic was at its height from September 27 to October 3, during which period there were in the neighborhood of 1,000 new cases daily. From this date un- til October 31 the number of new cases occurring daily steadily decreased and by the latter date the epidemic was over. Scattered cases continued to occur, however, through- out November, and during the last week of this month and the first week of December a second epidemic wave of rela- tively mild character occurred. From September 1 to Octo- ber 3] the total number of cases of influenza reporting sick was 12,393. During the same period there were 1,499 cases of pneumonia with 46(3 deaths. Influenza as observed at Camp Pike differed in no es- sential respects from that occurring elsewhere. In brief, it presented itself as a highly contagious, self -limited infec- tious disease of relatively short duration in most instances, the principal manifestations of which were sudden onset with high fever, profound prostration, severe aching pains in back and extremities, conjunctival injection, flushing of the face, neck, and upper thorax often amounting to a true erythema, and a rapidly progressing attack upon the mu- -Avcry: Jour. Am. Med. Assn., 191S, Ixx, 1". CLINICAL FEATURES AND BACTERIOLOGY OF I X KLI'KXZA .)■> cous membranes of the respiratory tract as manifested by coryza, pharyngitis, tracheitis and bronchitis with a marked tendency to hemorrhage; in itself it is rarely se- rious, but in reality serious because of the large number of individuals attacked and temporarily incapacitated and be- cause it predisposed to widespread and highly fatal sec- ondary infection of the lungs. Clinical Features. — A clinical study of 100 consecutive cases of influenza admitted during the height of the epi- demic was made. The onset was sudden, in most instances being initiated with marked sensations of chilliness in 82 cases. Although a severe chill was probably relatively uncommon, 44 of these patients considered the symptom of sufficient severity to describe it as such. This was accompanied by extreme gen- eral malaise with severe aching pains throughout the whole body. Intense backache was complained of in 40 cases, headache in 54 cases. A varying degree of prostration, sometimes leading to complete collapse, was almost uni- versal ; 5 patients complained of extreme asthenia and 2 of marked dizziness. At time of admission to the hospital the face, neck and upper chest exhibited a uniform eryth- ematous flush, never macular in appearance. The conjunc- tivae were deeply injected, but lacrimation was not notice- able and a true exudative conjunctivitis was not encoun- tered. Onset was accompanied by a sharp elevation of tem- perature ranging from 100°F. to 106° F., in most cases be- ing between 102° F. and 105° F., at the time of admission. No constant type of temperature curve was maintained. Excluding the 15 cases in this group that developed pneu- monia, the temperature was well sustained throughout the course of the disease in 46, irregular in 33, and definitely remittent in 6. The duration of the fever varied between one and seven days, the temperature having returned to normal in all but 19 of the 85 cases by the end of four days. The duration of fever was one dav in 18 cases, two days in 54 PNEUMONIAS AND INFECTIONS OF RESPIRATORS TRACT 12, three .lays in 19, four days in 17, five days in 10, six days in 4, and seven days in 5. Of the 4 cases with fever for six days, 2 had a fairly extensive bronchitis, 1 a laryn- gitis. Of the 5 eases with lexer of seven days' duration, 3 had signs of an extensive bronchitis, 2 of only a mild bron- chitis. The pulse was relatively slow in rate as compared with the degree of temperature elevation, running between 90 and 100 heats per minute in the large majority of cases. At the height of the disease it was full and easily com- pressed. No irregularities were noticed. With recovery it fell promptly to normal. The respiratory rate showed only moderate elevation, being between 20 and 26 in most cases. In a few instances a rate as high as 32 was recorded at time of admission to the hospital, but this promptly fell with rest in bed. A respiratory rate rising above 26 after the third or fourth day of the disease nearly always indi- cated a beginning pneumonia. With recovery the rate promptly fell to normal. Cyanosis did not occur in the absence of pneumonia. Aside from the manifestations of a profound toxemia, influenza was preeminently characterized by symptoms of respiratory tract infection. The appearance of respiratory symptoms occurred at varying intervals after the onset of the disease, being well developed by the end of twenty-four hours in most cases. A progressive attack upon the mu- cous membranes of the respiratory tract was universal, be- ginning with coryza and . pharyngitis and progressing to tracheitis or vice versa. Further extension of the infection to the bronchi, however, Mas by no means universal, 49 cases in the group studied recovering 1 without developing evidence of bronchitis. Sore throat was rarely complained of, and laryngitis, possibly due to secondary infection, oc- curred only once. The progress of the infection was marked subjectively by sensations of irritation, stinging, and a feel- ing of tightness. A profuse, thin, mucoid exudate appeared; CLINICAL FEATURES AND BACTEHIOLOG'X OF I XKU'KXXA 55 the pharyngeal walls and the soft palate showed a charac- teristic deep red granular appearance. The onset of tra- cheitis began with a sense of burning and tightness beneath the sternum accompanied by a harassing cough, at first non- productive, later with the outpouring of an exudate becom- ing productive. The sputum varied in character between a scanty, thin, mucoid sputum and a profuse, frankly puru- lent sputum in cases subsequently developing an extensive bronchitis. Hemorrhage from the mucous membranes was common. Epistaxis occurred in 12 per cent of the cases and was often profuse. The sputum contained fresh blood in varying amounts in 24 per cent of the cases ; 51 per cent of the cases developed signs of bronchitis. In 15 of these the bronchitis was mild, probably limited to the larger bronchi, physical examination showing only inconstant sibi- lant and musical rales. The sputum in these cases was neither profuse nor frankly purulent; 36 cases developed a fairly extensive purulent bronchitis as manifested by more or less diffusely scattered moist rales and by moderately copious mucopurulent or frankly purulent sputum. This bronchitis was not accompanied by an increase in the re- spiratory rate or by cyanosis unless pneumonia subse- quently developed. Gastrointestinal symptoms were insignificant : 8 patients complained of nausea early in the disease and 6 of them vomited. Diarrhea occurred in only 1 case, constipation being the rule. The spleen was palpable in 21 cases, but this is of doubtful significance, since nearly all the patients came from malarial regions. Jaundice was not noted. Aside from the profound depression, sometimes amounting to stupor, mental symptoms were not noted except in 1 case which showed a mild delirium. Influenza, although per se a self -limited disease of short duration, frequently leads to the development of serious complications, the most important of which are pneumonia and purulent bronchitis with a varying degree of bronchi- 56 PNEUMONIAS AND IMITATIONS OF RESPIRATOR? TRACT ectasis. In the group of UK) cases of influenza studied, pur- ulent bronchitis developed in 36 instances, pneumonia in 15; in 3 eases there was lobar pneumonia, in L2 broncho- pneumonia. Further dismission of these complications is reserved for the sections dealing with them in detail. Other complications were relatively rare, otitis media occurred in one ease and frontal sinusitis in one. No fatalities were observed among eases of uneonipl ieated influenza, the deaths that occurred being invariably associated with a secondary pneumonia due in nearly all instances to sec- ondary infection with pneumoeoeei or hemolytic strepto- cocci. Purulent Bronchitis It has been stated that a considerable number of cases of influenza developed a more or less extensive purulent bronchitis. This term is used as descriptive of a group of cases showing clinically evidence of a diffuse bronchitis as manifested by numerous medium and fine moist rales scat- tered throughout the chest and evidence of a definitely pu- rulent inflammatory reaction as indicated by the expectora- tion of fairly copious amounts of mucopurulent or frankly purulent sputum. This condition is regarded as quite dis- tinct, on the one hand, from the common type of mucoid bronchitis frequently associated with "common colds" and a fairly common feature of uncomplicated cases of influ- enza, in which physical examination of the chest reveals only transient sibilant and musical rales without evidence of extension to finer bronchi, and, on the other hand, from bronchopneumonia. Bacteriology. — Thirteen cases of purulent bronchitis fol- lowing influenza in none of which was there any evidence of pneumonia at the time cultures of the 'sputum were made nor later were subjected to careful bacteriologic study. Specimens of bronchial sputum were collected in sterile Petri dishes and selected portions thoroughly washed to remove surface contaminations before bacteriologic ex- CLINICAL FEATURES AND BACTERIOLOGY OF INFLUENZA :>( aminations were made. The results arc shown in Table XIII. Table XIII Bacteriology of the Sputum in Cases of Purulent Bronchitis Follow- ing Influenza CASE STAINED FILM OF SPUTUM DIRECT CULTURE ON BLOOD AGAR PLATE MOUSE INOCULATION GJ B. influenzae 4-4-4- B. influenzae 4-4-4-4- B. influenzae Gram + diplococci 4- Pneumococcus 4- J'licuinococcus (type undcterminfd ) WAL B. influenzas + 4- B. influenzae 4-4-4- — Gram + diplococci + 4- Pneumococcus IV 4- 4- TH B. influenzae 4-4-4- B. influenzae 4-4-4-4- — Gram + diplococci 4-4-4- Pneumococcus IV 4- 4- LH B. influenzae 4- B. influenzae 4-4- — Gram + diplococci 4- Pneumocoecus IV 4-4- FBD Gram + diplococci 4-4-4-4 Pneumococcus IV 4-4-4- Pneumococcus IV B. influenzae 4- B. influenzae Wa B. influenzae 4- 4- B. influenzae 4-4- — Gram 4- diplococci 4- 4- Pneumococcus IV 4- 4- Sh B. influenzae 4-4-4- B. influenzae 4-4- • — Gram 4- diplococci 4-4- Pneumococcus IV 4-4-4- Wal Gram 4- diplostrep 4 4-4- S. viridans 4-4- — B. influenzae 4- B. influenzae 4- 4- CLF B. influenzae 4-4-4-4-4- — B. influenzae Gram 4- diplococci 4- Pneumococcus IV NCC B. influenzae 4-4- B. influenzae 4-4-4- B. influenzae Gram - micrococcus 4- M. eatarrhalis 4-4- M. eatarrhalis Gram 4- diplostrep. 4- S. viridans 4-4- JCM B. influenzae 4-4-4- B. influenzae 4-4-4-4- B. influenzae Gram 4- streptococcus 4- S. hemolyticus 4- S. hemolyticus Gram — micrococcus 4- M. eatarrhalis 4- Pneumococcus IV Gram 4- diplococcus 4- Bl B. influenzae 4- — B. influenzae Gram 4- diplococcus 4- Pneumococcus Ila Bu B. influenzae 4-4-4-4- B. influenzae 4-4-4- B. influenzae Gram 4- diplococcus 4-4-4-4- Pneumococcus IV 4-4-4- Pneumococcus TV From the data presented in Table XIII it is evident that a mixed infection existed in all cases. The results obtained by stained sputum films and by direct culture on blood agar plates are of special significance. B. influenzae was present in all cases, being the predominant organism in 6 cases, abundantly present in others, and few in number in 2. Of other organisms the pneumococcus was most frequently found, occurring in 11 of the 13 cases, in all but 2 instances being present in considerable numbers. S. viridans was en- countered twice, once in association with a Gram-negative micrococcus resembling M. eatarrhalis culturally. S. hem- olyticus was found oner, together with M. eatarrhalis and a few pneumococci, Type IV, coming through in the mouse only and of doubtful significance. The stained sputum films and direct cultures always showed these organisms present in sufficient abundance to indicate that they were present in the bronchial sputum and wore not merely con- taminants from the buccal mucosa. It seems quite probable from these results that purulent bronchitis following influenza is, in most cases at least, due to mixed infection of the bronchi and should be looked upon as a complication of influenza. Whether the condition may be caused by infection with B. influenza? alone is difficult to say. No evidence that it may be caused by B. influenza 1 alone was obtained in the cases studied. It is not intended to enter here into a discussion as to whether B. influenza? should be regarded as a secondary invader or not; the other organisms encountered certainly are. It would seem most probable that purulent bronchitis is caused by the mixed infection of B. influenza? and various other organisms, com- monly the pneumococcus, but that the condition is initiated by the invasion of the bronchi by these other organisms in the presence of a preceding infection with B. influenza?. Clinical Features. — Purulent bronchitis following in- fluenza began insidiously without any prominent symptoms to mark its onset. About the third or fourth day of in- fluenza, when recovery from the primary disease might be looked for, the patient would begin to cough more fre- quently, raising increasing amounts of mucopurulent sputum. This sputum was yellowish green in color, copious in amount, and often somewhat nummular in character, sometimes streaked with blood. These symptoms were ac- companied by the appearance of coarse, medium and fine moist rales more or less diffusely scattered throughout the chest and usually most numerous over the lower lobes. The percussion note, breath and voice sounds, and vocal CLINICAL FEATURES AND BACTERIOLOGY OF I X FU'KNZA 59 and tactile fremitus remained normal. There was no increase in the respiratory rate or pulse rate, and cya- nosis did not develop in the absence of a beginning pneu- monia. Many such cases, of course, developed broncho- pneumonia; in this event areas showing 1 diminished reso- nance, suppressed breath sounds, and fine crepitant rales with the "close to the ear" quality would appear, the res- piratory rate would become increased and cyanosis would become evident. In those cases of purulent bronchitis not developing pneumonia, a moderate elevation of tem- perature, rarely above 101° F., and irregular in character usually occurred and persisted for a few days or a week. Many cases maintained a persistent cough, raising con- siderable amounts of sputum throughout the period of their convalescence in the hospital, which was often considerably prolonged when this complication of influenza occurred. Although no clinical data are available on such cases over a prolonged period of observation, it seems probable that some of them, at least, had developed some degree of bron- chiectasis. This would seem all the more probable, since many cases of pneumonia following influenza showed at autopsy extensive purulent bronchitis with well-developed bronchiectasis. Bronchiectasis will be discussed in greater detail in another section of this report. It is this group of cases with more or less permanent damage to the bron- chial tree that makes this type of bronchitis following in- fluenza a serious complication of the disease. PNEUMONIA The opportunity presented for a correlated study of the clinical features, bacteriology, and pathology of pneumonia following influenza throughout the period of the epidemic at Camp Pike from September 6, 1918, to December 15, 1918, made it evident that this pneumonia could be regarded as an entity in only one respect, namely, that influenza was the predisposing cause. Clinically, bacteriologically, and GO PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT pathologically ii presented a very diversified picture rang- ing all the way from pneumococcal lobar pneumonia to hemolytic streptococcus interstitial and suppurative pneu- monia with the picture modified to a varying extenl by the preceding or concomitant influenzal infection. One hundred and eleven consecutive eases in which care- ful clinical and bacteriologic studies were made form the basis of the material presented. Of these cases, 38 came to necropsy so that ample opportunity was presented to cor- relate the clinical and bacteriologic studies made during life with the pathology and bacteriology at necropsy. It has seemed advisable to group the eases primarily on an etiologic basis with secondary division according to clinical features in so far as this can be done. Bacteriologic studies showed that at the time of onset these pneumonias were either pneumococcus pneumonias or mixed pneumococcus and influenza bacillus pneumonias in nearly all instances. Certain of these cases later became complicated by a super- imposed hemolytic streptococcus or a staphylococcus in- fection. In a few instances hemolytic streptococcus pneumonia directly followed influenza Avithout an interven- ing pneumococcus infection. B. influenzre was present in varying numbers in nearly all cases. In only 2 instances however, was it found unassociated with pneumococci or hemolytic streptococci, once alone and once with S. viridans. Clinically the cases fell into four main groups : (1) Lobar pneumonia; (2) lobar pneumonia with purulent bronchitis; (3) bronchopneumonia (pneumococcus) ; (4) bronchopneu- monia (streptococcus). It should be borne in mind, how- ever, that the picture was a complex one and that cor- rect clinical interpretation was not always possible, since many cases did not conform sharply to any one type and superimposed infections during the course of the disease often modified the picture. Pneumococcus Pneumonia Following Influenza. —Bacte- riologic examination of selected and washed specimens of CLINICAL FEATUEES AND BACTERIOLOGY OF I X FL1 'KXZA ( i 1 sputum coughed from the lungs at time of onset of pneu- monia showed the various immunologic types of pneumo- coccus to be present in 105 cases. The incidence of the different types is shown in Table XIV. Tabli XIV Types of Pneumococcus in 105 Cases of Pneumococcus Pneumonia Fol- lowing Influenza lobar pneumonia BRONCHO- PNEUMONIA TOTAL PES CENT Pneumococcus, Type I 8 8 7:6 Pneumococcus, Type II 3 1 4 3.8 Pneumococcus, II atyp. 12 7 9 18.1 Pneumococcus, Type III 3 3 6 5.7 Pneumococcus, Group IV 32 36 68 64.8 The most noteworthy feature of the figures in Table XIV is the high proportion of pneumonias due to types of pneu- mococci found in the mouths of normal individuals, 93 cases or 88,6 per cent, being caused by Pneumococcus Types II atypical, III, and TV. This is in harmony with the results generally reported and is in all probability due to the fact that in patients with influenza pneumococci, which under normal conditions would fail to cause pneumonia, readily gain access to the respiratory tract and produce the disease. It is also of interest that with one exception the highly parasitic pneumococci of Types I and II were associated with pneumonias clinically lobar in type. Superimposed infection of the lungs with other types of pneumococci than those primarily responsible for the de- velopment of pneumonia occurred not infrequently in this group of cases either during the course of the disease or shortly after recovery from the first attack of pneumonia. Pneumococcus Type II infection was superimposed upon or shorth T followed pneumonia caused by Group IV pneu- mococci in 4 instances, by Pneumococcus II atypical in 1 instance. In 1 case pneumonia due to Pneumococcus II atypical occurred three days after recovery from a Pneu- mococcus Type I pneumonia, in another case Pneumococcus 62 PNEUMONIAS -VXD IXFECTIOXS OF RESPIRATORY TRACT Typo 111 infection was superimposed upon a pneumonia or- iginally due to a pneumococcus <>l' Group IV. Those cases are presented in detail in another section of this report, and in several instances were shown to ho directly due to contact infection from patients in neighboring beds. In a similar manner, superimposed infection with S. hemolyticus at some time during the course of the pneu- monia, occurred in 1',) cases in this group, with fatal result in all %ut one. Streptococcus infection occurred in pneu- monia duo to Pneumococcus II atypical once, to Pneumo- coccus Type III once, and to pneumococci of Group IV eleven times. Nine of these cases were free from hemo- lytic streptococci at the time of onset of the pneumonia, 4 showed a very few colonies of hemolytic streptococci in the first sputum culture made. B. influenzae was found in the sputum coughed from the deeper air passages in the majority of cases, being present in 80, or 76.2 per cent, of the 105 cases. In the 58 cases of lobar pneumonia it was found 41 times, or 70.7 per cent, in the 47 cases of bronchopneumonia 39 times, or 82.9 per cent. The abundance of B. influenza? in the sputum varied greatly in different cases. Microscopic examination of stained sputum films and direct culture of the sputum on blood agar plates showed that in general it was more abun- dant in the mucopurulent sputum from cases of broncho- pneumonia than in the mucoid rusty sputum from cases of lobar pneumonia. This was by no means an invariable rule, however, since in the former the bacilli were some- times very few in number, in the latter quite abundant. Whether B. influenza? shared in the production of the actual pneumonia in these cases is difficult to decide and cannot be stated on the basis of the bacteriologic and clinical ob- servations which have been made. Clinical Features. — One of the most striking aspects of pneumococcus pneumonia following influenza was the diversity of clinical pictures presented. These varied all CLINICAL FEATURES AND BACTERIOLOGY OF INFLUENZA 63 the way from the classical picture of lobar pneumonia to that of bronchopneumonia of all grades of severity from the rapidly fatal coalescing type to that of very mild char- acter with very slight signs of consolidation. For this reason it is questioned whether there is any real justifica- tion for speaking of a typical influenzal pneumonia, an opinion that seems well supported by the diversified picture found at the necropsy table. For purposes of presentation, pneumococcus pneumonia following influenza may be divided into three clinical groups: (1) Lobar pneumonia; (2) lobar pneumonia with purulent bronchitis; (3) bronchopneumonia. No accurate data are available as to the relative frequency with which these three types occurred at Camp Pike. In the group of 105 cases studied there were 58 cases of lobar pneumonia, 11 of which had purulent bronchitis, and 47 cases of broncho- pneumonia. The majority of these cases, however, oc- curred during the early days of the epidemic of influenza and probably show a considerably higher proportion of lobar pneumonias than actually occurred in the total num- ber of pneumonias throughout the epidemic. This is indi- cated by the fact that of 100 consecutive cases of influenza selected for observation at the height of the epidemic, 3 de- veloped clinical evidence of lobar pneumonia and 12 of bronchopneumonia. (1) Lobar pneumonia presenting the typical clinical pic- ture with sudden onset, tenacious rusty sputum, sustained temperature, and physical 'signs of complete consolidation of one or more lobes occurred in 47 cases ; 36 cases in this group definitely followed influenza. In 11 cases no certain clinical evidence of a preceding influenza was obtained, and it is probable that some of these represent cases of pneu- monia occurring independently of the epidemic of influenza. The onset of pneumonia in this group of cases occurred from four to nine claj^s after the onset of influenza and with few exceptions was ushered in b}^ a chill and pain in the 64 PNEUMONIAS AND [NFECTIONS OF RESPIRATORS TRACT chest. In several instances the patienl had apparently re- covered from influenza as evidenced by fall of temperature to normal. A Pter twenty-four to seventy-1 wo hours of nor- mal temperature the patient would have a chill and develop lobar pneumonia. In the majority of eases, however, lobar pneumonia developed while the patient was still sick with influenza. The course of the disease, symptomatology and physical signs were quite characteristic of lobar pneu- monia and require no special comment. Recovery by crisis occurred in 21 eases, by lysis in 8. Pneumococcus empyema developed in 3 cases, fibrinopurulenl pericarditis in 3 and all but 1 ol* these (! eases terminating fatally. In Table XV 5 fatal eases of lobar pneumonia, which illustrate some of the unusual features of the disease when it follows . influenza, have been summarized. The first 2 cases represent examples of recurring' attacks of pneu- monia which developed shortly after recovery from the first attack, in both instances being due to types of pneu- mococci different from those causing the first attack. The third case represents an example of superimposed infection of the lungs with hemolytic streptococci and staphylococci during the course of a pneumonia due to Pneumococcus IV and disappearance of the latter organism from the tissues so that it was not found at time of necropsy. The last 2 cases are examples of fulminating rapidly fatal cases of lobar pneumonia associated with mixed infections of pneu- mococci and hemolytic streptococci, the streptococci prob- ably being secondary in both cases. Cases like the few examples cited above, which occurred not infrequently throughout the epidemic of influenza, serve to illustrate the difficulties which may be met in attempting to corre- late the clinical, bacteriologic and pathologic features of pneumonia following influenza unless careful bacteriologic examinations are made both during life and at the necropsy table in the same group of cases. CLTNTCAL FEATURES AND BACTERIOLOGY OF I N FL1 1 KX/A 65 co. p., o 03 Q W 1* O O : HH M H O -1 oa + + + + + + + + + M M "g 1— 1 ft ft pq ft Wpq « + + Ph+ + + i?+ + + re + + + 4- + . re • re H=nH 9 • M M S HH S ft M fl " H . fl f * =j ft pq ft cocoft W pq « H.B. S. hem. Br. S. hem. + + + + Staph. + L.L. 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Cases !'i'. 99, L02, and L04 arc all examples of superimposed hemo- lytic streptococcus infection occurring in the presence of a Pneumococcus Type IV pneumonia, with the picture of in- terstitial suppuration, abscess formation, and empyema due to S. hemolyticus on the background of a pneumococcus lobular pneumonia found at necropsy. All showed abun- dant pneumococci and B. influenzas in the sputum and were free from hemolytic streptococci at time of onset of pneu- monia, except Case 92 which showed 2 colonies of S. hemo- lyticus in the first sputum culture made. At time of death the pneumococci had disappeared in all cases and were re- place. I by hemolytic streptococci. The eases cited in the preceding paragraph are illustra- tive examples from a series of over 250 necropsies which are described in another section of this report. They serve to indicate clearly the extent to which mixed and superim- posed infections of the lungs may occur in pneumonia following influenza and leave little doubt that a considerable proportion of the deaths from influenzal pneumonia are clue to this circumstance. Hemolytic Streptococcus Pneumonia Following- Influenza But 4 cases of hemolytic streptococcus pneumonia di- rectly following influenza without an intervening pneumo- coccus infection of the lungs occurred in the group of cases studied clinically. Superimposed infection with S. hemo- lyticus, however, occurred not infrequently during the course of pneumococcus pneumonia following influenza, as has been stated above. This occurred 3 times in lobar pneumonia and 10 times in bronchopneumonia, with fatal outcome in all but 1 case. CLINICAL FEATURES AN' I) BACTEEIOLOGY OF I X FL1 'EN'ZA 71 Bacteriology. — Bacteriologies examination of the sputum in the 4 cases of streptococcus pneumonia directly follow- ing influenza showed S. hemolyticus present in abundance. B. influenza was also present in largo numbers in 3 eases, but was not found in the fourth. In 1 ease a Gram-nega- tive micrococcus resembling M. catarrhalis was also pres- ent in large numbers in the sputum. Pneumococci were not found either by direct culture on blood agar plates or by inoculation of the sputum intraperitoneally in white mice. In the 13 cases of superimposed hemolytic streptococcus infection occurring during the course of pneumococcus pneumonia, bacteriologic examination of the sputum by di- rect culture and by mouse inoculation shortly after onset of the pneumonia showed Pneumococci (atypical II once, Type III once, Group IV eleven times) B. influenzae present in large numbers, and no hemolytic streptococci ex- cept in 4 instances in which a very few organisms were pres- ent. Subsequent invasion of the lower respiratory tract by S. hemolyticus was shown to occur by means of cultures of empyema fluids or by cultures made at necropsy. Clinical Features. — The 4 cases of hemolytic streptococ- cus pneumonia following influenza that occurred in this series resembled in all respects the secondary streptococcus pneumonias of the winter and spring of 1918 and presented no features requiring special comment. The onset re- sembled that of pneumococcus bronchopneumonia, the disease appearing to develop as a continuation of the pre- ceding influenza. The sputum was profuse and muco- purulent in 3 cases, mucoid and bloody in the other. Two cases ran a severe and rapid course with the development of empyema early in the disease and fatal outcome. The other 2 cases ran only moderately severe courses without developing empyema and recovered by lysis in twenty and fifteen days, respectively, after the onset of influenza. Clinical differentiation between streptococcus and pneumo- coccus bronchopneumonia following Influenza did not seem possible without bacteriologic examination of the sputum excepl in those cases of the streptococcus group which de- veloped an extensive pleural effusion early in the disease. The advent of superimposed hemolytic streptococcus in- fection of the lower respiratory trad during the course of pneumococcus pneumonia following influenza presented no clinical features tliat made diagnosis certain without bac- teriologic examination. The sudden occurrence of a pleu- ral exudate during the course of the disease seemed of par- ticular significance, especially since empyema in the bron- chopneumonias following influenza was exceedingly rare in the absence of hemolytic streptococcus infection. Other suggestive symptoms were a chill during the course of the disease, a sudden turn for the worse in cases apparently doing well, or the development of a cherry red cyanosis. None of these 1 features, however, was sufficiently constant or distinctive of streptococcus invasion to he depended upon and when they occurred, were merely indications for fur- ther bacteriologic examination. Bacillus Influenzae Pneumonia Following' Influenza Bacteriologic evidence that cases of pneumonia following influenza might be due to B. influenza 1 alone was very meager in the group of cases studied clinically at Camp Pike; in fact, no convincing evidence was obtained that such cases occurred. In one case B. influenzae alone was found in the sputum coughed from the deeper air passages, and in another case B. influenzae with a few colonies of S. v in dans was found. Both were cases of bronchopneu- monia, mild in character, and recovered promptly. They presented no clinical features by which they could he dis- tinguished from cases of pneumococcus bronchopneumonia. It has been previously stated that B. influenzae was found in all early uncomplicated cases of influenza somewhere in the respiratory trad; that it was present together with CLINICAL FEATURES AND BACTERIOLOGY OK I N KLI 'EX/A (■> other organisms, notably pneumococcus in the sputum from cases of purulent bronchitis following influenza; and that it was found in the sputum coughed from the lung in ap- proximately 80 per cent of cases of pneumonia compli- cating influenza. In 35 cases it was very abundant, often being the predominating organism. In all these cases, however, pneumococci or hemolytic streptococci were also present in considerable numbers at the time of onset of the pneumonia. It is impossible to say merely from the clin- ical and bacteriologic data under consideration what part B. influenza? played in the development of the actual pneu- monia in these cases. Discussion of this subject is there- fore reserved for the section of this report dealing with the pathology and bacteriology of pneumonia following in- fluenza, Summary Influenza as observed at Camp Pike presented itself as a highly contagious infectious disease, the principal clinical manifestations of which were, sudden onset with high fever, profound prostration with severe aching pains in the head, back and extremities, erythema of the face, neck and upper chest with injection of the conjunctivae, and a rapidly progressive attack upon the mucous mem- branes of the respiratory tract as evidenced by coryza, pharyngitis, tracheitis and bronchitis with their accom- panying symptoms. In the majority of cases it ran a short self -limited course, rarely of more than four days' dura- tion, and was never fatal in the absence of a complicating pneumonia. Bacteriologic examination in early uncomplicated cases of the disease showed the B. influenza? of Pfeiffer to be present in all cases, often in predominating numbers. It was found more abundantly present during the acute stage of the disease than during convalescence in uncomplicated cases. No other organisms of significance were encountered by the methods employed. i4 PNEUMONIAS AND [NFECTIONS OF RESP1 RAT( >i; V TRACT Purulent bronchitis of varying extenl developed in ap- proximately 35 per cenl of the eases and often prolonged the course of the illness to a considerable extent. Bacte- riologic studies showed thai it was invariably associated with a mixed infection of the bronchi with B. influenzae and other bacteria, in most instances the pneumococcus, and in- dicated that it should be regarded as a complication rather than as an essential part of influenza. Its clinical features consisted of a mild febrile reaction, Frequent cough with the raising of considerable amounts of purulent sputum, and the physical signs of a more or less diffuse bronchitis. It led to a varying degree of bronchiectasis in at least some instances. Pneumonia complicating influenza presented a very di- versified picture and appeared to have only one constant character, namely, that influenza was the predisposing cause. It may be best classified on an etiologic basis since the clinical features to some extent and the pathology to a much greater extent depended upon the infecting bacteria in a given case. Bacteriologic examination showed that a very large pro- portion of the cases was due to infection with the different immunologic types of pneumococci or to a mixed infection with B. influenza* and pneumococci. The types of pneumo- cocci commonly found in normal mouths, namely, II atypi- cal, III, and IV, comprised approximately 88 per cent of these, the highly parasitic Pneumococci Types I and II, but 12 per cent. A small number of cases were due to hemolytic streptococci or to mixed infection with B. influ- enza? and S. hemolyticus. No certain evidence was obtained that pneumonia was due to B. influenza? alone. This or- ganism was present in varying numbers, however, in approximately 80 per cent of the sputums examined, and it seems fairly certain that it must have played at least a part in the development of the pneumonia in many of the cases in which it was found. Superimposed infections CLINICAL FEATURES AND BACTERIOLOGY OE I X FL1 'KX/A 75 with other typos of pneumococci than those primarily re- sponsible for the development of pneumonia, with hemo- lytic streptococci and with Staphylococcus aureus occurred frequently in cases of pneumococcus or mixed pneumococcus and B. influenzae pneumonia and undoubtedly conl ributed to a considerable extent in increasing the number of deaths. Three clinical types of pneumococcus pneumonia follow- ing influenza occurred: lobar pneumonia, lobar pneumonia with purulent bronchitis, and bronchopneumonia. Lobar pneumonia was usually sudden in onset and ran the char- acteristic course of the primary disease. Lobar pneumonia with purulent bronchitis similarly ran the characteristic course of the primary disease but presented the unusual picture of lobar pneumonia with mucopurulent rather than rusty, tenacious sputum and numerous moist rales through- out the unconsolidated portions of the lungs. The cases of bronchopneumonia ran a very variable course from mild cases of a few days ' duration and meager signs of consoli- dation to rapidly progressive cases with signs of extensive pulmonary involvement. Purulent bronchitis was very frequently associated with bronchopneumonia. Hemolytic streptococcus pneumonia following influenza presented the clinical picture of bronchopneumonia and was not readily distinguished on clinical grounds from pneu- mococcus bronchopneumonia except in those cases which developed a pleural exudate early in the disease. The ad- vent of tertiary infection of the lower respiratory tract with hemolytic streptococci in cases of secondary pneumococcus pneumonia presented no symptoms sufficiently constant or certain to make clinical diagnosis easy. The development of empyema in pneumococcus bronchopneumonia usually meant streptococcus infection. Pure B. influenzae pneumonia, if such cases existed, pre- sented no diagnostic features by which it could be distin- guished from pneumococcus bronchopneumonia following influenza. It was impossible to determine on clinical and .1) PNEUMONIAS AX!) 1 X FECTN »XS OF RESPIRATORS TRACT bacteriologic grounds alone what part the prevalent in- fluenza bacilli played in the causation of the actual pneu- monia. Discussion That wide variations in the conception of influenza have arisen during the recent pandemic, even a hasty review of the literature makes clear. In its essence this divergence of opinion seems to depend upon whether pneumonia is considered an essential pari of influenza or a complica- tion due either to the primary cause of influenza or to secondary infection. One extreme is expressed by Dunn 8 who says "the so-called complication is the disease," the other by Fantus 4 who finds influenza a relatively mild disease with pneumonia a relatively infrequent and largely preventable complication. A similar divergence of opinion prevails with respect to the bacteriology of influenza. There is fairly general agreement that the members of the pneumococcus and streptococcus groups and to a less extent other organisms are responsible for a large proportion of the secondary pneumonias, and but few observers hold that they possess any etiologic relationship to influenza. No such uniform- ity of opinion exists, however, with respect to the relation of B. influenzae to influenza and to the complicating pneu- monia. By some it is considered the primary cause of influenza, by others it is regarded as a secondary invader responsible for a certain proportion of the secondary pneumonias, and by still others it is not considered to bear any relation either to influenza or its complications. A limited number of references to the extensive litera- ture of the recent pandemic will amply serve to illustrate the various points of view that have developed. Keegan 5 regards pneumonia as a complication and con- siders that B. influenza 1 , the probable cause of influenza, is 3 I)unn: Jour. Am. Med. Assn., 1918, lxxi, 2128. «Fantus: Jour. Am. Med. Assn., 1918. lxxi, 1736. 5 Keegan: Jour. Am. Med. Assn.. 191S, lx.xi, 1CS1. CLINICAL FEATURES AND BACTERIOLOGY OF [NFLTJENZA 77 the primary cause of the pneumonia which may or may not be still further complicated by pneumococcus or si reptococ- cus infection as a terminal event. Christian states thai epidemic influenza causes a clinically demonstrable bron- chitis and bronchopneumonia in the larger proportion of cases, and lays particular emphasis upon the fact that it is quite incorrect to consider fatalities in the epidemic as due to influenza uncomplicated by bronchopneumonia. Blanton and Irons 7 speak of influenza as an "antecedent respiratory infection" of undetermined etiology, and be- lieve that pneumonia when it occurs is due to autogenous infection by a variety of secondary invaders, principally of the pneumococcus and streptococcus groups. Hall, Stone, and Simpson 8 regard pneumonia strictly as a com- plication and quite distinct from influenza itself. Synnott and Clark 9 believe that the infection is characterized by a progressive intense exudative inflammation of the respira- tory tract often terminating in an aspiration pneumonia with a variety of conditions found at autopsy and a mul- tiplicity of secondary organisms responsible for the fatal termination. B. influenzae was usually found but always with other organisms. Friedlander and his collaborators 10 speak of a fulminating fatal type of influenza with acute inflammatory pulmonary edema, but regard true broncho- pneumonia as secondary, due to infection with pneumococ- cus or S. hemolyticus. B. influenzas was not found more frequently than under normal conditions. Brem 11 and his collaborators present a clear cut clinical picture both of influenza and the secondary pneumonia to which it predis- poses, regarding the latter as definitely due to secondary infection with pneumococcus, streptococcus or B. influenzae, the virus of influenza being unknown. Ely 12 and his col- °Christian: Jour. Am. Med. Assn., 1918, lxxi, 1565. 7 Blanton and Irons: Jour. Am. Med. Assn., 1918, lxxi. 19S8. 8 Hal1, Stone and Simpson., Jour. Am. Med. Assn., 1918, lxxi, 19S6. ;, Synnott and Clark: Jour. Am. Med. Assn., 1918, lxxi, 1816. 10 Friedlander, McCord, Sladen and Wheeler: Tour. Am. Med. Assn., 191S. lxxi, 1652. "Brem, Boiling and Casper: Jour. Am. Med., Assn., 1918, lxxi, 213S. 12 Ely, Lloyd, Hitchcock, and Nickson: Jour. Am. Med. Assn., 1919, lxxii, 24. (8 PNEUMONIAS AND [NFECTIONS OF RESPIRATOR? TRACT laborators make no distinction between influenza and pneu- monia, and apparently consider the epidemic due to a hemo- lytic streptococcus of indefinite and inconstant characters. The Camp Lewis Pneumonia Unit 13 slates "the process [influenza], whether mild or severe, is etiologically and pathologically the same; * : V B. influenza 1 was not found. In a report of The American Public Health Asso- ciation 1 ' it is stated that deaths resulting from influenza are commonly due to pneumonias resulting from an in- vasion of the lungs by one or more forms of streptococci, by one or more forms of pneumoeoeci, or by the so-called influenza bacillus. This invasion is apparently secondary to the initial attack. Wolbach 15 found B. influenzae in a high proportion of cases, not infrequently in pure culture in the lung, and believes that there is a true influenzal pneu- monia whether B. influenzae is the cause of the primary dis- ease or not. Spooner, Scott and Heath 16 isolated B. in- fluenzae in a high percentage of cases and consider it reasonable to suppose that it was the prime factor in the epidemic. Kinsella 17 found B. influenzae infrequently and regards it as a secondary invader. MacCallum ls regards B. influenzae as a secondary invader and believes that it is responsible for a form of purulent bronchitis and broncho- pneumonia following certain cases of influenza. Pritchett and Stillman 10 found B. influenzae in 93 per cent of cases of influenza and bronchopneumonia. Hirsch and McKinney 20 state that B. influenza^ played no role in the epidemic at Camp Grant and apparently consider it due to a specially virulent pneumococcus. Xo further references to the extensive literature of the recent pandemic seem necessary, since those cited above serve to illustrate the various points of view that exist. "Camp Lewis Pneumonia Unit: Jour. Am. Med. Assn., 1919, lxxii, 268. "Jour. Am. Med. Assn., 1918, lxxi, 2068. '•'•Wolbach : Hull. Johns Hopkins IIosp., 1919, xxx, 104. "Spooner, Scott and Heath: Jour. Am. Med. Assn., 1919, lxxii, 155. "Kinsella: Jour. Am. Med. Assn., 1919, lxxii, 717. "MacCalluin: Jour. Am. Med. Assn., 1919, lxxii, 720. lu Pritchett and Stillman: Jour. F.xper. Med., 1919, xxix, 259. -"Ilirsch and McKinney: Jour. Am. .Mid. Assn., 1918, lxxi, 1735. CLINICAL FEATURES AND BACTERIOLOGY OF IM'IJ'KXZA 79 A similar diversity of opinion may be found in the reports from foreign sources. It would appear that much of the divergence of opinion that has been formed has depended to a considerable ox- tent upon the conditions under which cases have been ob- served. This is clearly brought out by contrasting the experience of Fantus 4 dealing with private cases in civilian practice, where pneumonia was relatively uncommon, with that of others dealing only with cases in large hospitals, where those admitted have been in large part selected se- riously ill patients with a high incidence of pneumonia, the milder cases comprising from 60 to 90 per cent of those attacked by influenza never reaching the hospital. Varia- tions in opinion with respect to the bacteriology of the epidemic, especially in regard to B. influenzae, would appear to be due for the most part to differences in bacteriologic technic, in some degree to differences in interpretation. Accumulating evidence can leave little doubt that B. in- fluenzas was at least extraordinarily and universally preva- lent throughout the period of the epidemic and thereafter, and that earlier reports of failure to find it were due to the use of methods unsuitable for its detection and isolation. The opportunit} r afforded the commission at Camp Pike to devote their full time to a systematic and correlated group study of the epidemic simultaneously from many aspects throughout its whole course made it apparent that influenza per se is in the large majority of instances, in spite of the initial picture of profound prostration, a rela- tively mild disease which tends to rapid spontaneous re- covery. This opinion is supported by the fact that the disease during the first waves of the epidemic in this coun- try, which it is now recognized occurred pretty generally in the army camps during the spring of 1918, was so mild that it attracted only passing attention, since the disease ' at that time was not sufficiently virulent to predispose to any alarming amount of pneumonia. AVith the return of SO PNEUMONIAS A.ND [NFECTIONS <>!' RESPIRATOR'S TRACT the epidemic in the late summer and early fall, however, the disease had attained such a high degree of virulence thai it predisposed to an appalling amount of severe and often rapidly fatal pneumonia, which often detracted at- tention from the real nature of the preceding disease. Vet even during the fall epidemic Prom 60 to 90 per cent i^\' the cases of influenza proceeded to rapid recovery with- out developing complications. On this ground alone it would seem only logical to regard pneumonia strictly as a complication of influenza rather than as an essential part of the disease, irrespective of whether the pneumonia may be caused by the primary cause of influenza or not. The complexity of the clinical features, the bacteriology and pathology of the pneumonias following influenza lend fur- ther support to this opinion. It seems better, therefore, to consider influenza first as a disease by itself and subsequently to take up the question of pneumonia and the relation of influenza to it. The most str ikin g clinical features of influenza are its epidemic character, its involvement of the respiratory tract, its extremely prostrating effect, and the often sur- prising- rapidity with which the individual cures himself. These features strongly suggest that the etiologic agent of the disease is an organism subject to rapid changes in vir- ulence; that it is confined to the respiratory tract where it produces a superficial inflammatory reaction giving rise to the characteristic symptoms of coryza, pharyngitis and tracheitis; that it elaborates a poison, possibly a true toxin, readily absorbed by the lymphatics, the effect of which is manifested in the profound prostration, severe aching pains, erythema, and leucopenia; and that it may either disappear promptly from the respiratory mucous mem- brane at time of recovery or may persist, leading a rela- tively saprophytic existence for an indefinite period of time, being no longer harmful to the individual, at least more than locally, because of an acquired immunity*. Put* CLINICAL FEATURES AND BACTERIOLOGY 03? IN I-'Ll'KXZA 81 thermore, in our opinion, the very brief incubation period suggests that the disease is bacterial in origin, rather than that it is analogous to the exanthemata, the majority of which present a comparatively long, fairly constant, incu- bation period. B. influenzae has characteristics in accord with the clinical features of influenza. It is an organism of very labile viru- lence; it is always present in our experience on the mucous membranes of the respiratory tract in early uncomplicated cases of influenza, often in overwhelming numbers ; in only very exceptional instances, in adults at least, does it invade the body producing a general infection, as the numerous reports of negative blood cultures testify ; recent investiga- tions by Parker 21 and others indicate that it is capable of producing a toxin quickly fatal for rabbits ; it is predomi- nantly present in the respiratory tract during the active stage of the disease and disappears in a considerable pro- portion of cases at time of recovery, while in others, more particularly those that develop an extensive secondary bronchitis and bronchiectasis it may persist for an in- definite period of time. It is, of course, fully appreciated that the foregoing is in the main merely argumentative reasoning and it is put forth only to suggest that B. influenzae merits a much closer scrutiny with respect to its etiologic relationship to influ- enza than the trend of present opinion has awarded it. Although there remains some difference of opinion as to the relation of influenza to pneumonia, the majority of ob- servers concur in regarding pneumonia as a complication and this would seem to be the only logical interpretation of the facts available. The same may be said with respect to purulent bronchitis and bronchiectasis. It is of consider- able significance in this connection that pneumonia follow- ing influenza presents no uniform clinical picture, no uni- form bacteriology and no uniform pathology. "Whether the 21 Parker: Jour. Am. Med. Assn., 1919, lxxii, 476. ^L 1 PNEUMONIAS AND IX V ECTIONS OF RESPIRATORS TRACT predisposition of patients with influenza to contract pneu- monia is preponderantly due to lowering of general resist- ance to infection by the extremely prostrating effect of the disease and the inhibition of leucocytic defense, or to a de- struction of local resistance againsl bacterial invasion by reason of profound injury to the bronchia] mucosa, or to a combination of both factors, is difficult to say. It seems most probable that both are concerned. At any rate it seems clear that in the presence of influenza a considerable variety of organisms which under ordinary conditions do not find lodgement in the lungs are able to gain access to the lower respiratory tract and produce pneumonia. CHAPTER III SECONDARY INFECTION IN THE WARD TREAT- MENT OF INFLUENZA AND PNEUMONIA Eugene L. Opie, M.D. ; Francis G. Blake, M.D. ; James C. Small, M.D. ; and Thomas M. Rivers, M.D. One of the most pressing problems that presented itself in the care of influenza and pneumonia patients in the army cantonments during the recent epidemic was the danger of secondary contact infection because of the overcrowding of the base hospitals, nearly all of which were taxed far be- yond the limits of their capacity. That this danger was very real was fully demonstrated by certain studies in ward infection that this commission was able to make at Camp Pike 1 . It is the purpose of the present section of the re- port to present these studies and to discuss the means whereby this danger may be most successfully met. It is perhaps well, first to define exactly what is meant by secondary contact infection in influenza and pneumonia. In our experience at Camp Pike it was found that a very large percentage of the pneumonias following influenza were accompanied by secondary infection with pneumococ- cus, some few being caused by hemolytic streptococcus. The types of pneumococcus encountered were almost en- tirely those that are found normally in the mouths of healthy men, approximately 85 per cent being Types II atypical, III, and IV. It has been generally accepted that infection with these types of pneumococci is usually autog- enous — that is, that under the proper conditions of low- ered resistance an individual becomes infected with the pneumococcus that he carries in his own mouth. Many ob- 1 0pie, Freeman, Blake, Small and Rivers: Jour. Am. Med. Assn., 1919, Ixxii, 556. S3 ^4 PNEUMONIAS AND [NFECTIONS OF RESPIRATORY TRACT servations made during the course of the present work have suggested thai this is probably nol so in many in- stances and thai the influenza patienl may qo1 be so much in daimor Prom the pneumococcus thai be normally carries in his own mouth as he is from that carried by his neighbor, in other words, he is in danger from contact infection. The same considerations hold true with respect to hemolytic streptococcus infection. Secondary contact infection in eases of already existing pneumonia following influenza were round to occur frequently. These were for the most pail caused by hemolytic streptococcus infection superim- posed upon a pneumococcus pneumonia. Many instances of double pnonmococcns infection, however, either coinci- dent with or following one another were encountered. Secondary Infection with S. Hemolyticus in Pneumonia Pneumonia caused by streptococci was repeatedly ob- served 2 during the pandemic of influenza which occurred in 1889-90. With clearer recognition of the characters which distinguish varieties of streptococci several observers have shown that secondary infection with hemolytic streptococci may occur during the course of pneumonia and though defi- nite evidence lias been lacking have suggested that it may he acquired within hospital wards. That a similar second- ary infection with S. hemolyticus in pneumococcus pneu- monias following influenza occurred not infrequently at Camp Pike during the epidemic was shown by bacteriologic studies made during life and at autopsy in a considerable series of cases. During the early days of the epidemic of influenza, secondary streptococcus infection was almost entirely limited to certain wards which were opened for the care of the rapidly increasing number of patients with pneumonia. During this period these wards were overcrowded, organization was incomplete, and the op- portunities for transfer of infection from patient to pa- -S p < !z a, E 18.6 46.1 58.6 NUMBER OF PATIENTS ADMITTED TOTAL DEATHS CULTURES AT AUTOPSY AMONG PATIENTS ADMITTED DURING THE CORRESPOND- ING PERIOD 6 W Is 2 p H ""H -r J s q 5 > fH H ^ !8 W 2 O h NUMBER PER CENT 5 s c.eh Sept. 6-15 Sept. 16-25 Sept. 26— Oct. 5 11 52 23 3 16 8 27.2 30.7 34.7 3 13 5 1 1 2 2 During the period from September 6 to 15, just prior to the outbreak of influenza in epidemic proportions, the ward had an average population of 18.6 patients. The total number of new patients admitted was 11, of whom 3 died, a mortality of 27.2 per cent. All these cases were pneu- mococcus pneumonias as determined by bacteriologic ex- amination of the sputum at time of admission. The 3 fatal cases showed pneumococcus infection at autopsy. During the second period, from September 16 to 25, with the out- 86 PNEUMONIAS ANIi [NFECTIONS OF RESPIRATOR'S TRACT break of the epidemic of influenza, the ward rapidly filled with new cases of pneumonia, attaining an average popula- tion of 46J patients. Of the 52 new cases admitted 16 died, a mortality of .'50.7 per cent. Again all the cases ad- mitted during this period iii which bacteriologic examina- tion (if the sputum was made, were found to lie piienniococ- eus pneumonias with one exception. This case, admitted on September 21 and dying two days later, had a hemolytic streptococcus pneumonia. Fortunately, though quite by ac- cident, he was placed in a bed at one end of the porch and no transmission of streptococcus infection to other cases in the ward took place. At autopsy 13 cases showed pneu- mococcus infection; the foregoing case, hemolytic strepto- coccus. During the third period from September 2G to October 5 the ward became even more crowded, having an average of 58.6 patients; 23 new cases were admitted, 8 of whom died, a mortality of 34.7 per cent. Autopsy showed that 5 of these were pneumococcus pneumonias and 1 was caused by hemolytic streptococcus infection. It is note- worthy that the death rate from pneumonia gradually in- creased as the ward became more and more crowded. This may possibly be attributed in part to the increasing severity of the pneumonia during the early days of the influenza epidemic. That it was in part directly due to secondary contact infection with pneumococcus will be shown when the transmission of pneumococcus infection is discussed. In spite of the overcrowding- of the ward the introduction of 2 cases of streptococcus pneumonia did not cause an out- break of streptococcus infection. Whether this was due to precautions taken against the transfer of infection or was merely a matter of good luck is difficult to say, in view of the fact that a considerable amount of transfer of pneu- mococcus infection from one patient to another did occur. Ward 8 had long been used for the care of colored pa- tients with pneumonia. As in Ward 3 cubicles were in use SECONDARY INFECTION IN WAKI) TUKATMKNT 87 and ordinary precautions against the transfer of infection were used. The data are presented in Table XVIII. Table XVIII Pneumonia in Ward 8 AVERAGE NUMBER OF PATIENTS IN WARD NUMBER OF PATIENTS ADMITTED TOTAL DEATHS CULTURES AT AUTOPSY AMONG PATIENTS ADMITTED DURING THE CORRESPOND- ING PERIOD PNEUMO- COCCUS S. HEMO- LYTICUS UNDETER- MINED (NO AU- TOPSY ) NUMBER PER CENT Sept. 6-20 Sept. 21 —Oct. 5 25.5 46.1 18 59 2 20 11.1 33.9 2 10 1 9 During the period from September 6 to 20, prior to the outbreak of influenza in epidemic proportions among the colored troops, the ward had an average population of 25.5 patients ; 18 new cases of pneumonia were admitted during this period,, all of whom were pneumococcus pneumonias as determined by bacteriologic examination of the sputum at time of admission to the ward. Only 2 died, a mortality of 11.1 per cent, autopsy cultures showing pneumococcus in both cases. All these patients were treated on the porch of the ward while they were acutely sick. During the sec- ond period from September 21 to October 5, when the in- fluenza epidemic was at its height, the ward rapidly filled with active cases of pneumonia and became distinctly crowded. It contained an average of 46.1 patients, but had actually reached a population of 64 patients at the end of the period. Of the 59 new cases admitted, 20 died, a mortality of 33.9 per cent, 10 with pneumococcus pneu- monia, one with hemolytic streptococcus pneumonia. In 9 there was no autopsy. The conditions in Ward 8 were quite analogous to those in Ward 3. In spite of the over- crowding during the second period no outbreak of second- ary infection with S. hemolyticus occurred, but secondary pneumococcus infection did occur as will be shown below. ^ s PNEUMONIAS AND [NFECTIONS OF RESPIRAT0R1 TRACT lii contrasl with these two wards arc Wards 1 and 2 in which widespread secondary contacl infection with S. heniolyticus took place. Ward 2 was opened September 26, ai the beginning of the period when 20 new wards for pneumonia were organized. From September l!(> to Octo- ber 1 the cubicle system was net in use, the ward was crowded, organization was imperfect, ami few precautions were taken to prevent transfer of infection from one pa- tient to another. On October '2 the cubicle system was installed and precautions againsl transfer of infection were instituted. The data are shown in Table XIX. Table XIX I'XKI'.MOXIA IN W \i:i> - . TOTA L DEATHS CULTURES AT AUTOPSY AMONG PATIENTS o c NUMBER g PATIENTS IN WARD M NUMBER ° PATIENTS ADMITTED ADMITTED DURING THE CORRESPOND- ING PERIOD 6 p tn z, K P o o o o 2 p g _ w p DETER- INED NO AU- OPSY) NUMBER PER CENT P Sept. 26 Sept. 27 27 17 HO 27 67.5 23 4 Sept. 28 40 13 J Sept. 29 .11 121 Sept. 30 49 1 H7 6 35.3 o 2 Oct. 1 43 4J Oct. 2 47 61 Oct. 3 42 U0 4 40.0 2 1 1 Oct. 4 41 4J During- the first three days 40 patients with pneumonia were admitted to the ward. Of these 40 patients, Ti died, a mortality of 67.5 per cent. Cultures at autopsy showed that 23 of these died with hemolytic streptococcus infection, none of pneumococcus infection. In four there was no au- topsy. To appreciate the full significance of these figures it must be emphasized that these patients at time of ad- mission to the ward in no way differed from those admitted to Ward 3 during the corresponding period and were not in any sense selected cases. The type of infection in 9 of these patients had been determined by bacteriologic exami- SECONDARY INDUCTION IN" WARD TREATMENT 89 nation of tho sputum just prior to or immediately after ad- mission to the ward before opportunity for secondary eon- tact infection in this ward had occurred. All 9 were shown to have pneumococcus pneumonia free from hemolytic si rep- tococci at that time. All 9 died, 7 with secondary strepto- coccus infection as shown by cultures taken at autopsy, 1 with a secondarily acquired Pneumococcus Type III infec- tion — sputum showed a Pneumococcus Type IV on admis- sion — and in 1 there was no autopsy. In view of the fact that bacteriologic examination of the sputum in cases of pneumonia following influenza had shown that the large majority of them were due to pneumococcus infection, it is probable that most of the other cases of pneumonia ad- mitted to this ward were pneumococcus pneumonias at time of admission, and that they acquired the streptococcus in- fection after admission. During the next three days 17 new patients were admit- ted, of whom 6 died, a mortality of 35.3 per cent. Cultures at autopsy showed pneumococcus infection in 2, strepto- coccus in 2. It is noteworthy that the porch was first put into use on September 29. Of the 12 patients admitted on this date, 8 were treated throughout the acute stage of their illness on the porch. Of these 8 patients but one died, of a Pneumococcus T}^pe IV infection and none became in- fected with S. hemolyticus. From October 4 to October 6, 10 patients were admitted, of whom 4 died. Cultures at autopsy showed pneumococcus infection in 2, hemolytic streptococcus in 1. The widespread prevalence of hemolytic streptococcus infection in this ward as compared with its almost entire absence in Wards 3 and 8 is very striking. Cultures made during life and at autopsy have shown clearly that it was due to rapid spread of contagion throughout the ward. The almost unlimited opportunities for transfer of infection from patient to patient, during the first six days the ward was in use, undoubtedly greatly facilitated this spread. 90 PNEUMONIAS AND [UTECTIONS OF RESPIRATOR* TRACT Prom the data available it is impossible to stale exactly when and by which patients hemolytic streptococcus In- fection was introduced into the ward, but it must have been very early since the death rate was very high Prom the be- ginning, and the first 23 eases coming to autopsy died with streptococcus infection. Ward 1 was opened on September 24. Prom thai date until ( Ictober 2 no cubicles were in use and few precautions were taken against transfer of infection. On October 2 cubicles were installed and ordinary precautions to prevent transfer of infection were instituted. On October 6 the ward was closed to further admissions. The data pre- sented in Table XX are divided into two periods, because on September 29 and 30, 4 patients with streptococcus pneu- monia were admitted to the ward. Table XX Pneumonia in "Ward 1 AVERAGE NIW! BER OF PATIENTS l\ WARD NUMBER OP PATIENTS ADMITTED TOTAL DEATHS CULTURES AT AUTOPSY AMONG PATIENTS ADMITTED DURING THE CORRESPOND- ING PERIOD PNEUMO- COCCUS HI ^ S Q < s* S y. o £ B Z y - O NUMBER PER CENT D Sept. 24-29 Sept. 30 —Oct. 5 35.8 55.3 34 40 11 24 32.3 fiO.O 5 6 3 14 3 4 During tlie first period from September 24 to 29 the ward contained an average of 35.8 patients, being only mod- erately crowded; 34 cases of pneumonia were admitted, of whom 11 died, a mortality of 32.3 per cent. It is note- worthy that deaths among this group which occurred prior to September 30 were due to pneumococcus infection with one exception, a patient entering the ward on September 26 and dying the following day. Of the other 2 patients in this group who died Avitli hemolytic streptococcus pneu- monia, 1 was admitted to the ward on September 25, was SECONDARY INFECTION IN WARD TREATMENT 91 shown to be free from S. hemolyticus on September 30, and died on October 12 with a secondarily acquired streptococ- cus pneumonia and empyema; the other was admitted on September 29 with streptococcus pneumonia and died the following day. During the second period from September 30 to October 5 the ward contained an average of 55.3 patients, being very overcrowded; 40 new cases of pneumonia were ad- mitted of whom 24 died, a mortality of 60 per cent. Cul- tures taken at autopsy showed that 6 died of pneumococcus pneumonia, 14 with hemolytic streptococcus infection. As in Ward 2, patients admitted to this ward were in no way selected and were probably, as experience has shown, in large part pneumococcus pneumonias at time of admission. The widespread dissemination of hemolytic streptococcus and its fatal effect following the introduction of the organ- ism on September 29 and 30 is only too evident. Secondary Infection with Pneumococcus in Pneumonia The foregoing studies have shown that hemolytic strep- tococcus infection may spread by contagion throughout an entire ward with great rapidity. Other observations have demonstrated that pneumococcus infection may be trans- mitted in the same way. Only three instances of this nature will be cited. The first occurred in Ward 3 (Table XXI). Between September 6 and 16 no cases of pneumonia caused Table XXI Secondary Infection with Pneumococcus Type II BED OCCU- PIED ADMITTED PNEUMO- COCCUS IN SPUTUM ON ADMISSION SECONDARY INFECTION NAME DATE PNEUMO- COCCUS AT AUTOPSY Pvt. Wolfe Pvt. Pullam Pvt. Swain No. 6 No. 5 No. 3 Sept. 17 Sept. 9 Sept. 16 IV IV II Sept 23 Sept. 24 II* II 'Isolated by blood culture on Sept. 23. Patient recovered. 92 PNEUMONIAS AM' [NFECTIONS OF RESPIRATORS TRACT by Pneumococcus Type II had been admitted to the ward. (>n September L6 Pvt. Swain was admitted to the ward and placed in Bed .">. Bacteriologic examination of his sputum showed that his pneumonia was caused by Pneumococcus Type II. At this time Pvt. Pullam, who had been ad- mitted to the ward on September !• with a pneumococcus Type 1 V pneumonia, occupied Bed 5 separated from Bed 3 by one intervening bed. lie had had his crisis on Septem- ber 14 and was doing well, his temperature being normal. On September 24 lie developed a second attack of pneu- monia and died on September 30. Cultures at autopsy showed Pneumococcus Type II in heart's blood and lung, Pneumococcus Type II and B. influenzae in the right bron- chus. Pvt. Wolfe was admitted to the ward with broncho- pneumonia on September 17 and placed in Bed 6 next to Pvt. Pullam. Pneumococcus Type IV and B. influenza 1 were found in his sputum. Mis temperature had fallen to normal by lysis on September 21 and he was doing well. On September 23 his temperature suddenly rose and he developed a second attack of pneumonia. Pneumococcus Type II was isolated by blood culture on this date. He recovered. In both instances Pneumococcus Type II was acquired after the admission of a patient with a Pneumo- coccus Type II pneumonia, the opportunity for contact in- fection having been favored by the association of these patients in adjoining beds. The second instance is almost identical and occurred on the opposite side of Ward 3 at about the same time (Table XXT1). Pvt. Linehan was admitted on September 16 and placed in Bed 30. Pneumococcus Type IV was found in his sputum. Pvt. Thompson was admitted the following day with a Pneumococcus II atypical pneumonia and placed in Bed 28. The next day Pvt. Smith was admitted and placed in Bed 26. Pneumococcus Type IT was found in his sputum. On September 1!) Pvt. Thompson recovered by crisis and was doing well. On September 21 lie had a SECONDARY INFECTION IN WAIlli TUKATMKNT 93 Table XXII Secondary Infection with Pneumococcus Type II PNEUMO- SECONDARY INFECTION BED OCCU- PIED ADMITTED COCCUS IN SPUTUM NAME PNEUMO- ON ADMIS- DATE COCCUS SION AT AUTOPSY Fvt. Smith No. 26 Sept. 18 II II Pvt. Thompson No. 28 Sept. 17 Atyp. II Sept. 21 II Pvt. Linehan No. 30 Sept. 16 IV Sept. 26 II chill, his temperature rose to 104.4° F. and he developed a second attack of pneumonia. He died on September 29; cultures at autopsy showing Pneumococcus Type II in heart's blood and left pleural cavity, Pneumococcus Type II and B. influenza? in bronchus and lung. Pvt. Linehan had begun to improve on September 24 and his temperature was falling by lysis. On September 26 he became worse, developed signs of pericarditis and died on September 30. Cultures from lungs and bronchus at autopsy showed Pneu- mococcus Type II and B. influenzae. In both instances the fatal secondary infection with Pneumococcus Type II was undoubtedly acquired from Pvt. Smith in the nearby bed. The third instance occurred in Ward 8 (Table XXIII). Pvts. Lewis and Scott were admitted on September 21 and were placed in adjoining beds, 50 and 51. Lewis showed Pneumococcus Type I in his sputum, Scott Pneumococcus II atypical. The following day Pvts. Pighee, Jones, and Columbus were admitted and given Beds 48, 49 and 53 re- spectively. All showed Pneumococcus II atypical in the sputum. Pvt. Lewis with Pneumococcus Type I pneu- monia recovered by crisis on September 29. His tempera- ture remained normal until October 2 when it suddenly rose to 104.2° F. He developed a second attack of pneu- monia and died on October 8. Cultures at autopsy from heart's blood and lung showed Pneumococcus II atypical, from the bronchus Pneumococcus II atypical and B. influ- 94 PNEUMONIAS AND [NFECTIONS OF RESPIRATOR'S TRACT Tab] i Will - >\i>\::y Infection with Pneumococcus ii Atypical BED 0CC1 PIED ADMITTED PNEUMO- COCCUS 1\ SPUTUM SECONDARY INFECTION NAME I'NKl' MO- i>\ AMIS- DATE COCCUS SION AT Al TOPS'? Pvt. Pighee Pvt. Jones No. 48 No. 49 Sept. 22 Sept. 22 Atvp. II Atvp. ir Pvt. Lewis No. 50 Sept. 21 i Oct. 2 Atvp. II Pvt. Scotl No. 5 1 Sept. _'l Atvp. ir Pvt. • olumbus No. 53 Sept. 22 Atvp. 11 enzse. It is, of course, impossible to say from which one of his neighbors Pvt. Lewis acquired his second pneumo- coccus infection. It is noteworthy thai these instances of secondary con- tact infection with pneumococei occurred in wards where every precaution was supposedly taken to prevent trans- fer of infection from one patient to another. It is true however that the wards were greatly overcrowded al the time. Many other instances of secondary pneumococcus infection in cases of pneumonia following' influenza were encountered in which it was impossible to trace the source of infection, many combinations of different types of pneu- mococcus being found. There were two instances in which Pneumococcus Type IV was found in the sputum by inocu- lation of white mice shortly after onset of pneumonia, whereas secondary infection with other types was found at autopsy, one with Pneumococcus Type II, one with Pneu- mococcus Type III. In 2 cases by inoculation of white mice, two types of pneumococcus were round simultaneously in the sputum coughed from the lung, in one Pneumococ- cus Types III and I.Y, in the other Pneumococcus Types I and IV. There were 5 cases in which two types of pneu- mococcus were found in cultures at autopsy as shown in Table XXI Y. Combined pneumococcus infections of this nature are almost never encountered in pneumonia occur- SECONDARY INFECTION IN WARD TREATMENT 95 Table XXIV Mixed Pneumococcus Infections in P'nei vtonia CULTURES AT AUTOPSY heart's blood BRONCHUS LU: •' Pvt. Gal. Fn. Type III B. influenzae Staphylococcus Pn. Type III Pn. Type IV B. influenzas Pvt. Sug. Pn. Type III Pn. Type III Pn. Type IV B. influenzae Staphylococcus Pn. Type III Pn. Type IV B. influenzae Pvt. Hig. S. hemolytieus Pn. Type 1 1 Pn. Type IV S. hemolytieus Staph, aureus Pvt. Can. Pn. Type I — Fn. Type III S. hemolytieus Pvt. Fer. Sterile Pn. Type IV B. influenzas Staphylococcus Pn. Type I Pn. Type IV B. influenza? ring under normal conditions in the absence of epidemic in- fluenza. The foregoing data show that infection with one type of pneumococcus may readily be superimposed upon or closely follow infection with another type. Cases have been cited in which it was clearly demonstrated that this was due to contact infection. It is furthermore evident that pneumo- nia caused by one type of pneumococcus affords no relia- ble immunity against pneumonia caused by another type. The same conditions that favored the spread of hemolytic streptococcus infection also favored the transfer of pneu- mococcus infection from patient to patient. Secondary Contact Infection in Influenza The material so far presented has dealt with contact in- fection in cases of pneumonia following influenza. That a similar contact infection in cases of influenza treated in crowded hospital wards is responsible in considerable de- gree for the development of pneumonia in cases of influ- enza seems quite probable. It has already been stated that this pneumonia was found in large part to be caused by 96 PNEUMONIAS AND [NFECTIONS 01 RESPIRATOR'S TRACT infection with types of pneumococcus thai are found in the mouths of Dorma] individuals. Ii 1ms been fairly definitely established by Stillman 3 that Lobar pneumonia caused by pneumococcus Types 1 and II is in all probability due to contad infection, and definite instances of such infection by Pneumococcus Type 11 have been reported above. In a recent communication Stillman 4 has furthermore shown thai of the various groups of Pneumococcus II atypical those most frequently associated with pneumonia are rarely found in normal mouths, while those infrequently associated with pneumonia are more commonly found. Whether similar considerations will hold true for pneu- mococci of Group IV can only be determined by further investigation. It has been stated that certain observations made during the course of this work have suggested that cases of pneumonia which complicate influenza may be due to contact rather than to autogenous infection. The data available are far too limited to establish this fact and it would require a very extensive study to furnish conclusive evidence. Certain general observations have suggested this point of view. It is well recognized that the incidence of pneu- monia in patients with influenza has been much higher where overcrowding- has existed. It would seem probable that this has been in large part due to the greater oppor- tunity for the dissemination of organisms capable of pro- ducing pneumonia and the consequently increased oppor- tunity for secondary contact infection among patients treated under such conditions. The not infrequent occur- rence of influenzal pneumonia due to combined infections of the different types of pneumococci, hemolytic strepto- cocci, staphylococci, and other bacteria, instances of which have been cited, is in harmony with this view, especially since pneumonia under ordinary conditions is rarely found to be associated with mixed infections of this nature. It 'Stillman: Tour. Exper. Med., 1916. xxiv, 651. 4 Stillman: Jour. Exper. Med., 1919, xxix, 251. SECONDARY INFECTION IN WAI!I> TEEATMENT 97 is true that healthy individuals occasionally carry more than one type of pneumococcus simultaneously in the mouth, though, this is very infrequent, and autogenous in- fection occurring in such individuals might account in some instances for the mixed pneumococcus infections en- countered. By way of analogy it lias been clearly shown in other studies by the Commission on the relation of hem- olytic streptococcus carriers to the complications of mea- sles, that secondary infection of the respiratory tract with S. hemolyticus is in very large part due to contact infec- tion, the chronic carrier rarely developing complications due to this organism. To obtain further light on this question the type of pneu- mococcus present in the mouths of 46 consecutive cases of early uncomplicated influenza was determined by the mouse inoculation method at time of admission to the receiving ward of the hospital before the patients had been associ- ated, with the purpose of determining if cases among this group which subsequently developed pneumonia might be shown to have acquired a pneumococcus which they did not carry at time of admission. This group of patients was treated in a special ward set apart for the purpose. The patients were assigned to beds in rotation and confined in bed until thoroughly convalescent. Beds were well separ- ated and cubicles, masks and gowns were in use. Cultures were made from the ward personnel. By these procedures an accurate record was kept of all sources of pneumococcus infection. The types of pneumococcus found in the mouths of these patients at time of admission are shown in Table XXV. Only 1 patient in this group developed pneumonia. At time of admission he had no pneumococcus in his mouth as determined by inoculation of a white mouse with his spu- tum. Examination of the sputum by the same method at time of onset of pneumonia three days after admission showed Pneumococcus Tj^pe III. The only ascertainable 98 PNEUMONIAS AND INFECTIONS OF RESPIRATORS TRACT Table XXV Types op Pneumococci in the Mouths of Inpluenza Patients i'\ ii Mot on i s xi MBER PER CENT PneumocoecuS; Type I (l Pneumoeoccus, Tj pe 1 1 Pneumococcus, II atypical 1 .) o Pneumoeoccus, Type 1 1 1 Pneumococcus, Group I V 25 54.3 Xo pneunioeoeci found 20 43.5 source of infection in this case was our of the ward attend- ants who carried Pneumococcus Type III in his throat in sufficiently large numbers to be demonstrable by direct cul- ture and who frequently came in contact with the patient. In tins instance the development of pneumonia was prob- ably due to contact infection. An extensive study of this nature would be necessary to determine in what proportion of cases pneumonia following influenza is caused by second- ary contact infection and in what proportion to autogenous infection. It is at least evident that contact infection with a type of pneumococcus found in the mouth of normal indi- viduals may occur in influenza and be responsible for the development of pneumonia. Therefore every precaution should be taken to prevent it. Methods for the Prevention of Secondary Contact Infection in Influenza and Pneumonia The methods at present in vogue for preventing the spread of contagion in wards devoted to the care of patients with influenza and pneumonia may be briefly enumerated: The separation of patients by means of sheet or screen cubicles, the wearing of masks and gowns by the ward per- sonnel and to some extent by convalescent patients who are up and about the ward, and in some hospitals the separa- tion of streptococcus carriers from noncarriers as deter- mined by throat culture at time of admission. That these methods are of some value in preventing spread of infec- tion cannot be denied, and it is probable that they are fairly SECONDARY INFECTION IN WARD TREATMENT 99 effective under ordinary conditions when conscientiously carried out. That they inevitably break down in the pres- ence of an overwhelming epidemic when hospital wards become overcrowded is only too evident. Under such con- ditions the sheets hung between the beds are constantly be- ing displaced and are slight proof against a patient's curi- osity as to the identity and condition of the man in the; ad- joining bed; masks cannot be worn by patients seriously ill with pneumonia, during the very time when they are most dangerous and in greatest danger and those worn by the ward personnel are very rarely sufficiently well made to prevent spread of contagion by droplet infection as the studies of Haller and Colwell 5 and Doust and Lyon 6 have shown; the separation of streptococcus carriers from non- carriers as at present carried out cannot keep pace with the ever increasing influx of patients nor with the rapidity of the spread of the hemolytic streptococcus, in part because of the time required to make the bacteriologic diagnosis, in part because the amount of work involved cannot be accom- plished by the laboratory personnel available. That this is so will be shown in data presented below. Not only do these methods break down in the face of an epidemic, but they often provide a false sense of security. In searching for a solution of the problem it is essential to have the following considerations clearly in mind. Ev- ery patient with influenza must be considered a potential source of pneumococcus or hemolytic streptococcus infec- tion for his neighbor until he is proved otherwise by bac- teriologic examination. Every person engaged in the care of patients with respiratoiy diseases must also be regarded as a potential source of danger. Pneumonia cannot be re- garded as one disease but must be looked upon as a group of different diseases, with more or less similar physical signs and symptoms, it is true, but caused by a considerable variety of bacteria, infection with any one of which not E Haller and Colwell: Jour. Am. Med. Assn., 1918, lxxi, 1213. "Doust and Lyon: Jour. Am. Med. Assn., 1918, lxxi, 1216. 100 PNEUMONIAS AND [NFECTIONS OF RESPIRATORS TRACT only provides qo protection againsi infection with another, inn may even render the individual more susceptible to secondary infection. Therefore, every patienl with pneu- monia musl be regarded as an actual source of danger to his neighbor, at least until it is established that he has the same type of infection. All these considerations are espe- cially true iii the presence of influenza, for it has become evident thai many organisms readily gain access to the lung and produce pneumonia in patients with influenza which under ordinary circumstances fail to cause disease of t he respiratory organs. Since secondary infection in respiratory disease is un- doubtedly spread in large part by droplet and contact in- fection, the prevention of secondary infection must depend upon the elimination of these methods of transmission. Three solutions present themselves: (1) Ward treatment with absolute elimination of overcrowding and much wider separation of patients than has hitherto been deemed nec- essary; (2) segregation of patients according to type of bacterial infection; (3) effective individual isolation of every patient. It has been clearly shown that treatment of influenza and pneumonia in overcrowded wards even with the use of such precautions to prevent transfer of infection as cubicles, masking of attendants and patients, etc., is attended by se- rious danger of contact infection and that such infection will almost inevitably occur. This is not at all surprising when it is remembered that we are treating in the same ward, in the case of pneumonia, a group of what are in real- ity entirely different diseases, all of which may be trans- mitted from one patient to another, and in the case of in- fluenza a group of individuals who carry a variety of potentially pathogenic bacteria. No one would expect to treal cases of scarlet fever, measles, and diphtheria to- gether in a hospital ward without having contact infection result. Among patients ill with influenza and postinflu- SECONDARY INFECTION IN WAED TREATMENT 101 enzal pneumonia, certainly streptococcus pneumonia and to some extent pneumococcus pneumonia may be transmil ted quite as readily as any of these diseases. In view of these considerations it must be apparent if ward treatment of these diseases is to be continued without respect to type of bacterial infection, not only that overcrowding is abso- lutely contraindicated but also that much wider separation of patients than has hitherto been regarded as necessary is imperative. Furthermore, beds should be separated by permanent cubicles that cannot readily be displaced. Pa- tients should be confined to their cubicles until thoroughly convalescent and when up and about should not be allowed to enter cubicles occupied by patients still sick. Medical officers, nurses and attendants who come into contact with the patients should use the same rigid precautions that are used in the care of patients with typhoid or erysipelas or meningitis with the additional use of means to prevent droplet infection of the patients, always bearing in mind that the respiratory tract in patients with influenza or postinfluenzal pneumonia is as susceptible to secondary infection as the postpartum uterus or an open surgical wound. In other words, the most rigid aseptic technic should be maintained. The recognition of a case of strep- tococcus pneumonia in a ward should be an indication for immediate quarantine of the ward until it has been shown by bacteriologic examination that there is no longer danger of spread of streptococcus contagion. This is done in the case of meningitis or diphtheria, neither of which diseases is comparable with streptococcus pneumonia in rapidity of spread or in resulting fatality. Segregation of patients in wards according to type of bacterial infection while theoretically an improvement over the indiscriminate mixing of patients with many different types of infection presents many practical difficulties which make it impossible to carry out in the presence of an over- whelming epidemic. It is quite obvious that grouping of L02 PNEUMONIAS AN'h INFECTIONS OF RESPIRATOR'S TRACT influenzal patients on the basis of the types of pneumococci thai they carry in their mouths is impossible since the greal majority of mouth pneumococci belong to Group IV and comprise a heterologous immunologic group. The separa- tion of influenza patients who carry S. hemolyticus Iron) those who do nol would appear to offer a more hopeful field. since we cannot make an immediate distinction between streptococcus carriers and aoncarriers by inspection of the patient, this procedure requires the taking of throat cul- tures at time of admission to the hospital, the holding of patients for eighteen to twenty-four hours in receiving wards until the bacteriologic diagnosis lias been made, and their subsequent distribution to streptococcus and non- streptococcus wards. This is feasible when the admission rate is low and the aumber of streptococcus carriers found at time of admission is small. In the presence of an influ- enza epidemic it immediately becomes impossible to carry out in base hospitals as now constituted, since the demand for beds under such conditions at once converts a large part of the hospital into a group of receiving wards with little room remaining for subsequent separation of patients. The amount of bacteriologic work involved at once be- comes prohibitive and the time required to make the bac- teriologic diagnosis defeats its purpose since it allows the spread of hemolytic streptococcus to occur in the receiving- wards during the interval. The foregoing statements are based on results obtained in an attempt to separate streptococcus carriers from non- carriers in a limited group of cases of influenza at Camp Pike, the investigation being conducted during a secondary wave of influenza between November 27 and December 5. A special group of five wards consisting of one receiving ward and four distributing wards were set aside for the study. Cubicles, masks and gowns were in use and the wards were not crowded. The personnel on these wards did not carry S. hemolyticus in their throats. Patients entering SECONDARY INFECTION IN VVAIMJ TKKATMENT 1 0?> the receiving ward were assigned to beds in rotation. Throat cultures were made on blood agar plates at time of admission. The plates were examined promptly the next morning, the diagnosis of S. hemolyticus being made by the characteristic hemolytic colonies and microscopic examina- tion of stained smears. By this method a report reached the receiving ward at 9 :30 a.m. and patients were promptly evacuated to the streptococcus and nonstreptococcus wards, where they were again assigned to beds in rotation, re- maining confined in bed until convalescent. Confirmation of all strains of hemolytic streptococcus was subsequently carried out by isolation in pure culture, bile solubility test, and hemolytic test with washed sheep corpuscles. All cases free from hemolytic streptococci at time of admission who were sent to the " clean" wards were recultured daily throughout the period of study, those acquiring a hemo- lytic streptococcus being transferred to a streptococcus ward as soon as the bacteriologic diagnosis was made. The results are shown in Table XXVI. Table XXVI S. Hemolyticus in Cases of Influenza DATE PATIENTS ADMITTED TO RECEIV- ING WARD THROAT CULTURES ON ADMIS- SION. S. ' ' CLEAN ' 'CASES ACQUIR- ING S. HEMOLYTICUS IN THE HOSPITAL HEMOLY- TICUS : WHILE IN REC. "WARD "WHILE IN "CLEAN" WARD TOTAL + - Nov. 27 12 4 8 2 2 Nov. 28 8 2 6 1 1 Nov. 29 17 s 8 9 1 2 3 Nov. 30 11 9 9 3 3 Dec. 1 10 5 5 Dec. 2 37 16 21 1 1 2 Dec. 3 21 8 13 2 2 Dec. 4 32* 11 21 4 2 6 Dec. 5 17 10 7 5 5 Totals 165 66 99 14 10 24 *Held in receiving ward 40 hours because of admission of case of meningococcus meningitis to ward by mistake. One hundred and sixty-five cases were admitted to the receiving ward during the period of study as cases of influ- L04 PNEUMONIAS AND ENFECTIONS OF RESPIRATORS TRACT enza. Of these, L37 had infhienza; 4 of those with influenza had pneumonia at time of admission, 23 had acute follicular tonsillitis, •! epidemic cerebrospinal meningitis, 1 scarlel fever, and 1 Vincent's angina. Sixty-six cases (-10 per cent) showed hemolytic streptococcus in the throai at time of admission and were sent to the streptococcals wards; 99 cases (60 per cent) were negative for hemolytic streptococ- cus on admission, and of these 91 were sent to the "clean"' influenza wards. Twenty-four of these clean cases subse- quently became positive for S. hemolyticus. It is especially noteworthy that 14 of them acquired a hemolytic strepto- coccals during the short period that they were held in the receiving ward awaiting the report of the culture taken at time of admission, the first culture taken shortly after ad- mission to tin 1 "clean" wards being positive. This result was undoubtedly due to the fact that these cases were un- avoidably associated in the receiving ward with many car- riers of hemolytic streptococcus. It is evident that cases which were supposedly free from streptococci but which in reality had picked up the organism in the receiving ward were constantly being sent to the "clean" wards. It is furthermore evident that if the precaution had not been taken of reculturing all clean cases on day of admission to the "clean" wards and daily thereafter these wards would soon have become saturated with hemolytic strep- tococci. Even under these conditions, 10 cases, after vary- ing periods in the "clean" wards, acquired the organism in their throats. When it is stated that it required the full time of two men under very special conditions to carry out this work in a very limited number of cases and that it failed to keep "clean" wards free from hemolytic strepto- cocci, it is only too apparent that the efficient separation of carriers from noncarriers in the presence of an epidemic of influenza is an impossible task. The segregation of pneumococcus pneumonias following influenza according to type of infection is obviously impos- SECONDARY INFECTION IN WARD TREATMENT L05 sible, since they are caused by an almost unlimited variety of immunologic types as far as presenl knowledge goes. Even the efficient separation of streptococcus pneumo- nias from pneumococcus pneumonias would require a con- siderable team of workers and the closest cooperation be- tween laboratory and ward staffs, so that no case of pneu- monia would be sent to a pneumonia ward until the bacte- riologic diagnosis had been made. In our experience this is rarely considered feasible even under ordinary conditions, and in the presence of an epidemic is nearly impossible be- cause of the volume of work involved and the delay neces- sitated by bacteriologic methods. It is, nevertheless, abso- lutely essential if highly fatal ward epidemics of strepto- coccus pneumonia are to be prevented. In view of the considerations discussed above, it is be- lieved that the clear and most fundamental indication for the management of epidemic respiratory diseases in the army is to scatter patients as widely as possible instead of following the time-honored custom of concentrating them. In brief, abandon open ward treatment and adopt effective individual isolation of every case, maintaining as strict a quarantine as is demanded in other highly contagious and infectious diseases. The adoption of a strict aseptic tech- nic in the handling of these patients is an evident corollary. Only by this means can the serious and highly fatal second- ary hospital infections, which occur in influenza and pneu- monia when these diseases are present in epidemic form, be prevented. The prevention of secondary infection, prior to admis- sion to the hospital, is another and more difficult problem. That opportunity for secondary contact infection in cases of influenza before patients reach the hospital is great seems unquestionable, since many cases have already de- veloped these infections at time of admission. During the epidemic patients were crowded in regimental infirmaries, in ambulances, and in the receiving office of the hospital 106 PNEUMONIAS ANh INFECTIONS OF RESPIRATOR'S TRACT with every opportunity for droplel infection present. No study has been made of this question, hut it seems reason- able that the same methods of prevention should apply, namely, effective separation of patients. It is not within the scope of this paper to discuss details of method, hut anything that is possible becomes feasible as soon as suflicient evidence can be broughl to hear thai it is a necessity. In the present instance it would seem that any means that can be used to reduce materially the ter- rific toll taken by respiratory diseases is an absolute neces- sity. Summary 1. Secondary contact infection with pneumococci not in- frequently occurs in patients with pneumonia following in- fluenza when they are treated in hospital wards. 2. Secondary contact infection with S. hemolyticus read- ily occurs in patients with pneumonia and may spread rapidly throughout an entire ward with highly fatal results. 3. Secondary contact infection may be responsible for the development of pneumonia in patients with influenza. 4. Ward treatment of these diseases is fraught with se- rious danger which is greatly increased by overcrowding, by imperfect separation of patients by cubicles, and by imperfect aseptic technic of medical officers, nurses, and attendants. 5. It is probable that secondary contact infection can be effectively prevented only by individual isolation and strict quarantine of every patient. CHAPTER IV THE PATHOLOGY AND BACTERIOLOGY OF PNEU- MONIA FOLLOWING INFLUENZA E. L. Opie, M.D. ; F. G. Blake, M.D. ; and T.M. Rivers, M.D. Many observers have described isolated phases of the recent epidemic and of past epidemics of influenza. Few have had an opportunity to follow the pathology of influ- enza from the onset of an epidemic through a period of sev- eral months and to observe the succession of acute and chronic changes which occur in the lungs. Our commission arrived on September 5, 1918, at Camp Pike two weeks be- fore the outbreak of influenza. The commission had pre- viously made a careful study of the clinical course, the bac- teriology and to a limited extent the pathology of pneu- monia occurring at Camp Funston where there was little if any influenza. Study of the records preserved at the base hospital at Camp Funston had convinced us that this camp had passed through an epidemic of influenza dur- ing the spring of 1918, this epidemic being followed by a very severe outbreak of pneumonia. Our investigation at Camp Funston had brought to our attention those phases of pneumonia which with the facilities of a base hospital laboratory could be most profitably studied with a view to determining the causation, the epidemiology and the prevention of the pneumonias prevalent in the Amer- ican army. Study of pneumonia after death offers the only oppor- tunity of determining the relation of pulmonary lesions to the considerable variety of microorganism associated with them. Clinical diagnosis furnishes no certain crite- rion for distinguishing lobar and bronchopneumonia: sup- 107 L08 PNEUMONIAS ANIt [NFECTIONS OF RESPIRATORS TRACT purative pneumonia is rarely recognizable during life. The relation of pneumococci, streptococci, staphylococci or I), influenzas 1<> one or other t\ pe of pneumonia can be deter- mined with accuracy only after death; for the demonstra- tion of one or more of these micro organisms in material obtained Prom the upper respiratory passages in life, though of value, furnishes us no definite evidence thai the organism which lias been identified lias entered the lung and passed from the bronchi to produce pneumonia. Study of autopsies following examination of the sputum during life has shown that an individual primarily attacked by influenza may suffer with a succession of pneumonias, one microorganism having prepared the way Tor another. The complexity of the subject is much increased by the truth that pyogenic microorganisms, like the tubercle bacilli, are capable of producing a considerable variety of pulmonary lesions. Examination of the lungs of a large number of individuals who have died as the result of pneumonia following in- fluenza lias disclosed a succession of acute and chronic dis- eases. Immediately succeeding the height of the epidemic of influenza, death occurred with acute lobar pneumonia or with diffusely distributed hemorrhagic bronchopneumo- nia caused in the majority of instances by Pneumococcus IV in association with B. influenzae. Superimposed infec- tion with hemolytic streptococci increased in frequency and in individuals who had occupied certain wards was almost invariable. At a later period, from one to two months fol- lowing the maximum incidence of influenza chronic lesions, namely, bronchiectasis, unresolved pneumonia, and chronic empyema were common and often occurred as the result of influenza which had had its onset at 1 lie height of the epi- demic. When influenza attacked the encampment, about 50,000 troops were quartered in it, and for a considerable period no more troops were brought into the camp and none left PATHOLOGY AND BACTERIOLOGY FOLLOWING I N KM ' K.N'XA L09 it. All cases of pneumonia occurring anions those i coops were brought to the base hospital so that the autopsies which were studied were; ropresonljitivo of ;ill the pneu- monias following influenza in this limited group of men. It is noteworthy that autopsy disclosed no instance of fatal influenza unaccompanied by pneumonia. Pneumonia of Influenza, — Knowledge concerning the bac- teriology of the pneumonia of influenza dates from the study of the epidemic of 1889-90. The frequency with which Diplococcus lanceolatus occurred in association with influenzal pneumonia was well recognized, although several observers, notably Finkler 1 and Ribbert, 2 found Streptococ- cus pyogenes so often that they attributed the pneumonia of influenza to this microorganism. During a subsidiary outbreak of influenza occurring in 1891-92 Pfeiffer 3 discovered the microorganism which he believed was the cause of the disease. Pneumonia, he be- lieved, was caused by the invasion of this microorganism into the lung, and the pneumonia of influenza, if death oc- curred at the height of the disease, was characterized not only by the presence of the bacillus of influenza, but was recognizable by its anatomic peculiarities. He described lobular patches of consolidation which were separated from one another by air containing tissue or were confluent, so that, although the lobular character was still recognizable, whole lobes might be affected. The consolidated tissue was dark red and within each lobular area were small, yel- lowish gray spots varying in size from that of a pinhead to a pea. In the mucus of the larynx and trachea were nu- merous microorganisms, including diplococci and strepto- cocci, among which influenza bacilli were predominant ; in the larger bronchi, bacteria other than influenza bacilli were less abundant, whereas in the finer bronchi filled with 1 Finkler, D.: Infectionen der Lunge durch Streptococcen und Influenza Bacillen, Bonn, 1895. 2 Ribbert: Anatomische und bacteriologische Beobachtungen iiber Influenza. Deutsch. med. Wchnschr., 1890, xvi. 61, 301. 3 Pfeiffer: Die Aetiologie der Influenza, Ztschr. f. Hyg. 1893, xiii, 357. 110 PNEUMONIAS AND [NFECTIONS OF RESPIRATOR'S TRACT purulent fluid and in the lung tissue influenza bacilli had undivided sway. Pfeiffer slated that the changes de- scribed were found when death occurred at the height of the disease, whereas other pulmonary lesions might be sequelae of this typical influenzal pneumonia. Observations upon the pathology of influenzal pneumonia made during the epidemic of 1889-92 have been collected in the monograph of Leichtenstern 4 published in 1896. He combats the opinion held by some observers that pneumonia with influenza is always catarrhal and cites many writers to prove that lobar pneumonia not infrequently accom- panies the disease. Indeed, some have found "croupous" pneumonia more often than "catarrhal." Krannhals 8 at Riga found typical fibrinous pneumonia in 53 instances, doubtful forms in 22 and bronchopneumonia in 37. Cruick- shank 6 in England found croupous forms predominant. Among -A3 autopsies performed upon individuals dead with influenza Birch-Hirschfeld 7 found 11 instances of croupous lobar pneumonia, 8 instances of croupous lobular pneumo- nia and 24 instances of catarrhal pneumonia. Leichten- stern thinks that the atypical symptomatology of lobar pneumonia with influenza — for example, the purulent char- acter of the sputum — has led many physicians to believe that lobar pneumonia rarely occurs. It is equally true that many instances of confluent lobular pneumonia are mis- taken for lobar. There appears to be no comprehensive description of the pneumonias of influenza based upon the epidemics of 1889- i)2. Descriptions dating from this period are much ob- scured by attempts to separate croupous or fibrinous from catarrhal pneumonias. Croupous lobular pneumonia has been recognized, for example, by Birch-Hirschfeld. Leicht- onstern describes a form of pneumonia which he regards as 'Leichtenstern, O. : Influenza, Nothnagel's Specielle Pathologie und Tberapie, Wien, 1896, vol. ii, ;it. 2. "Krannhals: Quoted by Leichtenstern. °Cruickshank:"Brit. Med. Jour., 1S95, i, 360. T Birch-Hirschfeld: Schmidt's Jahrbiichcr, 1S90, ccxxvi, 110. PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 111 neither lobar nor lobular although it implicates whole lobes; the consolidated tissue is homogeneous and varies in color from fleshy red to bluish red ; it is tough arid elastic in consistency. The author thinks that it is an error to regard this lesion as a confluent lobular pneumonia. Kuskow 8 , who has discussed the pathology of influenza in considerable detail, has seldom seen lobar pneumonia but has almost invariably found, even when there is lobar dis- tribution of the lesion, lobular patches of consolidation in- volving groups of lobules, single lobules or only parts of lobules; the lung tissue has been hyperemia and in Traces edematous. Opinions concerning the pathology and bacteriology of the pneumonias of influenza, published since the recent epidemic, have varied almost as much as those just cited. Few observers have had the opportunity of making a con- siderable number of observations under conditions which determine the relation of the pulmonary lesions to the pri- mary disease. Keegan 9 has found with influenza a massive and conflu- ent bronchopneumonia, frequently resembling lobar pneu- monia but distinguishable particularly in its early stages when the cut section of the consolidated lung has a finely granular character and each bronchiole stands out as a grayish area with intervening dark red alveolar tissue. Symmers 10 states that the pneumonia of influenza is a confluent lobular exudative and hemorrhagic pneumonia which bears a close resemblance to the pneumonic variety of bubonic plague. Our commission 11 published a preliminary report on pneumonia following influenza observed at Camp Pike. The occurrence of purulent bronchitis, distention of lungs, s Kuskow, N.: Zur pathologischen Anatomie der Grippe, Virchow's Archiv., 1S95, cxxxix, 406. 9 Keegan, J. J..: The Prevailing Epidemic of Influenza, Jour. Am. Med. Assn., 1918, lxxi, 1051. 10 Symmers, D.: Pathologic Similarity between Pneumonia _ of Bubonic Plague and of Pandemic Influenza, Jour. Am. Med. Assn., 1918, lxxi, 1482. "Opie, E. L., Freeman, A. W., Blake, F. G., Small, J. C, Rivers, T. M.: Pneumonia Following Influenza, Jour. Am. Med. Assn., 1919, Ixxii, 536. L12 PNEUMONIAS AND [NFECTIONS OF RESPIRATOR'S TRACT peribronchial hemorrhage and bronchiectasis were de- scribed. I». influenzae was isolated from the bronchi in ap- proximately s "t per cent of instances of influenzal pneu- monia bul from the consolidated Lung in less than half this number of autopsies. Lobar pneumonia was present in a large proportion of autopsies bul was less frequent than bronchopneumonia. Bronchopneumonic consolidation is in pari red, lobular and confluent, in part nodular; pneumo- cocci have a predominant part in the production of these Lesions. Three types of suppurative pneumonia are de- scribed: (a) Abscess caused by hemolytic streptococci usually in contact with the pleura and accompanied by em- pyema; {!>) Suppuration of interstitial tissue of the lung caused by hemolytic streptococci and accompanied by em- pyema; (r) multiple foci of suppuration clustered about a bronchus of medium size and caused by staphylococci. We have expr< ssed the opinion that B. influenzas descends into the bronchi; pneumococci, usually Type IV, may enter the lung and produce either lobar or bronchopneumonia. Hemolytic streptococci may descend and infect the pneu- monic lung causing death often before suppuration has oc- curred. Epidemics of such superimposed streptococcus pneumonia in wards of the hospital were described. LeCount 12 says: "The pneumonia of influenza is com- monly referred to as bronchopneumonia. It may be so des- ignated, but it differs from other bronchopneumonias in its predilection Tor the periphery of the lungs and in the extent to which the inflammation is hemorrhagic. ' ' MacCallum 13 states that the following types of pneumo- nia following influenza may be recognized. 1. Pneumococcus pneumonia. The lobular character of the consolidation is in these cases well marked, although it tends to lose its definiteness through the confluence of adjacent areas. The cut surface of the lung shows in the more acute cases a j: LeCount, V.. R.: The Pathological Anatomy of Influenzal Bronchopneumonia, jour. Am. Med. Assn., 1919, Ixxii, 6S0. "MacCallum, W. (",.: Pathology "»' tin- Pneumonia Following Influenza, four. Am. Mid Assn., 1919, lxxii, 720. PATHOLOGY AND BACTERIOLOGY FOLLOWING I X I'M K.VZA 113 peculiar lobular or confluent consolidation which corre- sponds well with what is commonly written of the stage of engorgement in the description of lobar pneumonia. Later stages in the pneumonia show within these areas patches of rough gray consolidated tissue from which def- inite plugs of exudate project. 2. Staphylococcal pneumo- nia. 3. Streptococcal pneumonia. There is lobular pneu- monia, the interlobular septa are edematous and, micro- scopically, bronchi and alveoli are loaded with streptococci. Whole areas of lung, though retaining their form, are en- tirely necrotic. Lymphatics are distended with exudate containing streptococci in great numbers, but in none of these cases is interstitial bronchopneumonia found. 4. Pneumonia produced by B. influenzae of Pf eiffer. The lung is studded with palpable shot-like grayish yellow nodules ; the bronchi exude thick yellow pus, which contains in- fluenza bacilli. Microscopically, the walls of the bronchi are found to be thickened by mononuclear infiltration and new formation of connective tissue. The walls of the al- veoli are thickened and indurated and the alveoli often con- tain fibrin in process of organization. Absence of conspic- uous changes in lymphatics, absence of intense pleural in- fection and relatively scant numbers of polynuclear leuco- cytes in the exudate within the alveoli and bronchial walls are, MacCallum states, all that distinguish this pulmonary change from the interstitial bronchopneumonia caused by the hemolytic streptococcus and described by him in previous papers. Lyon 14 designates the pulmonary lesion following in- fluenza, hemmorrhagic pneumonitis, the lung tissue con- taining serous fluid loaded with red blood corpuscles; in many instances there was such scant consolidation that the process could not be regarded as a true pneumonia. In 35 instances the lesion was lobular in distribution and in 16 "Lyon, M. W.: Gross Pathology of Epidemic Influenza at Walter Reed Hospital, Toui. Am. Med. Assn., 1919, lxxii, 924. 114 PNEUMONIAS AXU [NFECTIONS OF RESPIRATORS TRACT bistances was sufficiently extensive to be designated Lobar, but it was not typical lobar pneumonia, and. often asso- ciated with lobular patches of consolidation, appeared t<> be a confluent lobular pneumonia. Goodpasture and Burnett 15 say: "The difficulties of ana- lyzing the pulmonary lesions in any group of influenza pneumonias as they have appeared in this epidemic, are very apparent to anyone who lias had an opportunity to ob- serve the bacteriology and pathology of this accompani- ment of the disease." There is an acute outflow of the fluid elements of the blood and of hemorrhage into the lung tissue filling the alveoli in lobular areas and not infre- quently in an entire lobe. By a special method of staining these authors have studied the distribution of Gram-nega- tive bacilli with the morphology of B. influenzae The fact that in certain very early cases demonstrable bacteria of any kind are scarce or not found at all, has lead them to believe "notwithstanding the demonstration of influenza bacilli in pure culture in the lung in all but one instance, that at this stage organisms are comparatively few within the alveoli, and the primary injury is due to a very potent toxic agent elaborated in and disseminated. jthrough the larger air passages. In the later stages or from the be- ginning, if the injury be slight, the infection focalizes about the bronchi or their terminations, so that the bronchial and lobular distribution becomes very conspicuous." Typical lobar pneumonia with "croupous" exudate within the al- veoli occurs in cases complicated by secondary pneumo- coccus infection. Wolbach 16 has found that two types of pneumonia are characteristic of influenza. In cases in which death has occurred within a few days after onset of pulmonary signs, the lung tissue is dark red and "meaty in consistency" and contains abundant blood-tinged serous fluid which drips '^Goodpasture, E. W. ami Burnett, F. T,.: The Pathology of Pneumonia Accompanying Influenza, I*. S. Naval Medical Hull.. 1919, xiii, No. J. ir Woll)ach: Comments on the Pathology ami Bacteriology of Fatal Influenza Cases as Observed at Camp Devens, Mass., Bull. Johns Hopkins IIosp. 1919, xxx, 104. PATHOLOGY AND BACTERIOLOGY FOLLOWING I X I'l.c KXZA 115 from the cut surface. The other type of Lesion is found in patients who have lived for ten days or more after onset of the disease; there is extensive bronchitis, bronchopneu- monia, discrete or confluent, and peribronchitis. The lungs are voluminous and the smaller bronchi are distended. Microscopically, there is peribronchitis with extensive in- filtration of the interlobular septa and organization in al- veoli and bronchioles. This lesion is that designated by MacCallum as "interstitial bronchopneumonia." Wolbach thinks that the two types of lesion represent different stages of the same process. He regards as distinctive of the pneumonias of influenza the presence of hyalin fibrin lining distended air spaces. With the two types of lesion which have been described, B. influenzae was the only or- ganism which could be cultivated, and the author associates these distinctive conditions with that microorganism. Streptococcus Pneumonia. — Finkler emphasized the im- portance of streptococcus pneumonia as a complication of influenza. In 1888 he described instances of acute primary streptococcus pneumonia observed in 1887 and 1889. This form of pneumonia, Finkler thought, occurred in Bonn in epidemic form before the influenza epidemic of 1889-90 and, he states, exhibited an astonishing similarity to the pneumonia of influenza. He thought that later there was in Bonn a mixed infection of influenza and primary strepto- coccus pneumonia. In one type of streptococcus pneumo- nia, described by Finkler, there was lobular consolidation which in multiple patches produced "pseudolobar" con- solidation; the consolidated lung was smooth and red, and similar to spleen, rather than hepatized. In another group of instances the lesion merited the name "erysipelas of the lung." The lesion was an acute interstitial pneumonia in some places, a cellular or occasionally fibrinous pneumo- nia with involvement of the interstitial tissue in other places. There was edematous swelling and accumulation of leucocvtes in the interstices between the alveoli and about 11(! PNEUMONIAS AND INFECTIONS OF RESPIRATOR! TRACT the blood vessels and bronchi. Finkler staled thai the sim- ilarity to erysipelas mighl suggesl thai the Lymphatics con- tain streptococci, bul this relation did qo1 exist although large lymphatic channels were occasionally Tilled with coag- u In i ) i. lie asserted thai the disease was contagions and ciied eases w liieli he believed had their origin in hospital wards. The widespread occurrence of streptococcus pneumonia in the army camps in this country attracted attention dur- ing the first months of 1018. Cummings, Spruit and Lynch 17 at Fort Sam Houston, Texas, recognized the prev- alence of streptococcus pneumonia, both as a complication of measles and in association with lobar pneumonia, and showed thai the microorganism concerned was a hemolytic streptococcus. In 7 autopsies upon individuals with lobar pneumonia, they found pneumococcus alone in 2 instances and pneumococcus and hemolytic streptococcus or hemo- lytic streptococcus alone in 5 instances. Hemolytic strep- tococcus was found in all of 24 instances of bronchopneumo- nia, three-fourths of which followed measles. They rec- ommend the bacteriologic examination of the throat of patients with measles and the segregation of those who harbor hemolytic streptococci. Cole and MacCallum 18 have published almost simul- taneously, with that just cited, a report upon the pneumonia which has occurred at Fort Sam Houston and have shown the importance of hemolytic streptococci in its causation. They have found two varieties of pneumonia, namely, acute lobar pneumonia which does not differ essentially from that which occurs elsewhere and bronchopneumonia which in most cases has followed measles and is caused by S. hemo- lyticus. They think this infection is usually acquired in the hospital. They believe that the pulmonary lesions are characteristic. In this publication and elsewhere Mac- l7 CummingS, J. 0., Spruit, C. B, and L/vnch, ('.: The Pneumonia-;: Streptococcus and Pneumococcus Groups, Jour. Am. Med. Assn., 1918, lxx, 106d. 1 i ole, R. and MacCallum, W. C Oh H-3 1— 1 C - > - > e Ck CO c Ph > — = - - :>v 11 m \ i>i:i.i..)\u - — - .= - pq* |_H «*H — = CQ - SfiHONOua \i \ iir.1.1.. >\5i - PQ . — . •— c - wnxrids ni viaaxova — ' - — = -• S2 - — — = - pc — a c"" Oh — 7. 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Lj -^co^d CO i CO CC-S coW PQ a • k • ^c -- >■ HJ 3 h-jCO « d *y Oh.S "o u CO | + 1 | | | + | + 1+ 1 + | |+ + |+ + + + W w w W H h| |h I ' 1 | | 1 + |+ j l + l + 1 + § -a + + 1 + + + + + + 1+ + + i + + + + + + l + 1 + + + ^ + § + + + 1+ 1+ 1 1+ 1+ JQ-f | Oh Oh Oh Oh Oh Oh Oh |0h |0h|0h Oh ffl CQ jjcQ |j CQ |-J J JPQ |cQ J g |pq|pQJj eq|j CQ + CO + CN + (M + 1— 1 + CO CO + co 1 (M C- J i—l i— 1 i— i r-H i— 1 i \eru co ko CM VC i-H ^ ^H (N t^ + co + r— 1 o >o i— 1 i— i + o CM CN + CM CO 1—1 o CO + C>J + co s s I— 1 s i— 1 s 1—1 r-H o 1— 1 s ^H ITS S H CO • CM S l-d <-* CM sis CO r-H s — s 1— ( o u * £ £ a £ O o|^ o £ ^ ^ ^ £ a £ to — ko in I-* LO CO in ON lO o i—i no CM X CO NO H "? LO NO X X "S CO ON i— i 134 PNEUMONIAS AND [NFECTIONS OF RESPIRATORY TRACT .1 h\:iii .;<> aoo'ia \i ^ laaxova - C2 _ - r CO — — / J3 CO CO 8 - o J3 CO :>\ I l M \ IHM.I i\:i > 7. J3 — i 20 . — . - — a /. - — co = _ / - a - 1- sa* ja co sniiDMoaa m viaaxova r. _■ . .5 - :. - 7 - ■ — i: - • u - ~ i - . — .-- r. ■ j. ■~~ - .- ~- CQco <-' 3 cs . -' ". - — T r co = - — — / a-sj _ _ i ~ i coco iv ixnds m viaaxova SIXIIIDMOUa OMIZINVOUO | + viNoivnav.ioirjNoaa L uMAiosauMn 1 — sisvxDaiiiDNioaa j+ r _ = vwaAdwa |w |w |a M C O — saax 1 -smo Nisassaosav aidixinro 1 1 III viMowaaiMd I awxvariddns r ivixixsaaxMi 1 1 l + > x a - ssaosav | + z Z NOIX -vanosMOD iviiiDNoaaniMd s < MoixvanosMOD uvinatn + 1+ 1+ 1 + NoixvanosiMOD avio | -niDNoaaiaad -jiuvHaaoivan 1 Moixva -nosMOD avioiHDMouaiua.i + § % + S vivoivriHMd avaoi 1 1 l + 1 sixniOMoaa xsiainand |oh |&, | |a, Oh |d. SISONOVId 1V3IMI13 p H m|m j|j « CQ ca vi.vownaMd ao Noixvaaa CI + — cq «*H .= - -d /. « a r-l CC ■^CO CO pa'-S « • ft u P c 2 .i-i CO " 1 l + 1 + | + + + w H w w H 1 | l + 1 + + |+ \z 1 s xi + + + 1 l + 1 ! + § ~ + - Ph Ph Ph «|t-i CQ J J PQ J pa o co U* CO i— i 1/5 CO no i— i i— 1 — r-l \o cc no + — — T3 -3 co M = lO s s co co £ O * £ £ £ £ 1 - CC — oo co ON CO "5? ON co ON <* o- o NO 136 PNKr.MoxiAS AND [NFECTIONS OF RESPIRATOR'S TRACT Included in the table is an instance (Autopsy 487) in which a definite attack of influenza preceded scarlet fever. In successive columns the table gives the autopsy num- ber, race, and length of military service. These factors have had an important influence upon the incidence of in- fluenza and pneumonia and have been discussed in a pre- liminary report. 23 The duration of illness (4tli column of table), counted Prom the date of onset of symptoms of influenza or in some instances, when the earliest symptoms were those of pneumonia, from onset of pneumonia, can usually be determined accurately. The duration of pneu- monia (5th column of table) is much more uncertain, be- cause its determination datos from the first recognition of the physical signs of pneumonia. Clinical Diagnosis. — The clinical diagnosis recorded upon the clinical history of the patient is given in column 6. Many clinicians have been impressed with tho difficulty of determining during life the type of pneumonia associated with influenza. The occurrence of purulent bronchitis, the frequent coexistence of lobar and bronchopneumonia and an atypical onset often make the recognition of lobar pneumonia more difficult than usual. The diffuse consoli- dation of confluent lobular pneumonia increases the diffi- culty of recognizing bronchopneumonia. In the table (col- umn 6) lobar pneumonia is indicated by L., bronchopneu- monia by B. Among 227 autopsies the clinical diagnosis agreed with the condition found at autopsy in 109 instances (48 per cent) ; in 35 instances (15.4 per cent) both lobar and bronchopneumonia were found at autopsy and a diagnosis of one or other was made during life. In 83 instances (36.6 per cent) the diagnosis made during life was incor- rect. Cases admitted to the base hospital at Camp Pike were as carefully studied as the conditions in a base hos- pital during an epidemic permitted and diagnosis of pneu- monia was doubtless as accurate as in other base hospitals. a Tour. Am. Mid. Assn., 1919, bcxii, 556, PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA L37 Statistics from military and other hospitals based upon clinical diagnosis of the pneumonias of influenza are prob- ably subject to an error of at least 1 in ?> cases, and conclu- sions based upon them are almost valueless. The inaccuracy of clinical diagnosis of the pneumonia of influenza is further illustrated by a consideration of lobar pneumonia. This diagnosis on the one hand was made 136 times and was correct 67 times and incorrect 69 times ; on the other hand, lobar pneumonia was found at autopsy 98 times and had been diagnosed in only 67 of these cases (68.4 per cent). Classification of the Pulmonary Lesions of Influenza.— Influenzal pneumonia exhibits the following noteworthy characters : 1. Acute bronchitis with injury or destruction of lining epithelium and accumulation of inflammatory exudate within the lumen. 2. Hemorrhagic pneumonia with accumulation of blood within the alveoli and within and about the bronchi. 3. Susceptibilny of bronchi and pulmonary tissue to sec- ondary pyogenic infection with necrosis and suppuration. 4. Bronchiectasis. 5. Tendency to the occurrence of chronic pneumonia fol- lowing failure of pneumonia to undergo resolution. All these changes are doubtless referable to the severity of the primary injury to the lower air passages. In the presence of destructive changes in the bronchi man}^ bacterial species, including B. influenza?, pneumococci of various types, streptococci (notably hemolytic strepto- cocci) and staphylococci may invade the lungs and produce acute inflammation. The anatomic characters of the pneu- monic lesions following influenza are equally varied. In order to obtain insight into the pathogenesis of these lesions, it is desirable to imitate the historical development of knowledge concerning the characters and causes of dis- ease, namely, first to define accuratelv the lesions concerned L38 PNEUMONIAS AMi INFECTIONS OF RESPIRATORS TRACT and later to determine with what microorganisms these lesions are associated. The difficulties of this undertaking are increased by the multiplicity o( the microorganisms concerned and by the well-known truth that the same mi- croorganism, e. <;V FOLLOWING I N KM ' KX/A 145 tissue containing a layer of smooth muscle and their cali- ber varies approximately from 1 to 0.5 mm. It is con- venient to designate as respiratory bronchioles 24 the ter- minal ramifications of the bronchi; they are lined by a single layer of columnar ciliated cells passing over into cuboidal nonciliated epithelium and are beset with small air sacs lined by flat cells or epithelial plates similar to those of the alveoli elsewhere. Not infrequently these alveoli oc- cur along only one side of the bronchiole, the remainder of the circumference being covered by a continuous layer of cubical epithelium. The respiratory bronchiole by branch- ing along its course or at its end is continued into several alveolar ducts which unlike the respiratory bronchioles have no cubical or columnar epithelium but are closely be- set by alveoli lined by flat epithelial plates. The alveolar duct is recognized by the absence of cubical epithelium and the presence of bundles of smooth muscle which occur in the wall. The infundibula or alveolar sacs arise as branches from the alveolar ducts and like them are beset with alveoli, but smooth muscle does not occur in their walls. The base of the infundibulum is wider than its ori- fice, which Miller states is surrounded by a sphincter-like bundle of smooth muscle. Changes in the main bronchi and their primary branches are usually less severe than those in bronchi of smaller size. The epithelium is often intact, the superficial cells being columnar and ciliated, but not infrequently des- quamation of superficial cells has occurred and the lower layers alone remain. Occasionally (Autopsy 471) there is necrosis of epithelium with which, although the architec- ture of cells is preserved, nuclei have disappeared. Accu- mulation of blood or serum may separate epithelium from the underlying basement membrane (Fig. 1). Complete loss of epithelium occurs, usually in small patches. 24 Mil1er, VV. S.: Am. Rev. Tuberc, 1919, Hi, 65. 14l! PNEUMONIAS AX1' INFECTIONS OF RESPIRATOR? TRACT Polynuclear leucocytes are numerous upon the surface of the epithelium and are sometimes fixed in process of migration through epithelium and basement membrane. The blood vessels of the mucosa are engorged. There is sometimes edema or hemorrhage, and in the superficial part of the mucosa polynuclear leucocytes are often fairly abundant. When superficial epithelium has been lost, poly- nuclears arc numerous immediately below the surface of Fig. 1. — Acute bronchitis showing engorgement of blood vessels of mucosa and elevation of epithelium by serum and blood. Autopsy 3r>2. the exposed tissue. Fibrin is often present upon the de- nuded surface and extends for a short distance into the tissue below. In the deeper part of the mucosa, about the muscularis and especially about and between the acini of the mucous glands, the tissue is infiltrated with lymphoid and plasma, cells. Changes in the mucous glands are invariably present. These changes are distention of ducts and acini with mu- PATHOLOGY AND BACTERIOLOGY FOLLOWING I NTL1 KXZA 147 cons, degenerative changes occasionally ending in necrosis of cells, disappearance of acini, dense infiltration of inter- stitial tissue with lymphoid and plasma cells and finally proliferation of this interstitial tissue. The duet of a mu- cous gland, dilated and filled with mucus, may be sur- rounded by lymphoid and plasma cells in great number. Acini, similarly dilated, contain mucus and are composed of cubical cells which have discharged their mucous content. In some instances (e. g., Autopsy 257) the cells of the acini have undergone necrosis; the cytoplasm stains homogen- eously and the nuclei have disappeared. Where necrosis has occurred, polynuclear leucocytes may penetrate into the dead cells. In association with degenerative changes in the acini there is abundant infiltration of the interstitial tissue within and about the glands with lymphoid and plasma cells. When the acini have disappeared there is proliferation of fibroblasts and new formation of fibrous tissue, and mucous glands are found in which a few atrophied acini are separated by newly formed fibrous tissue. With the bronchitis of influenza the small bronchi (with no cartilage or mucous glands) show every stage of transi- tion from early acute inflammation characterized by accu- mulation of polynuclear leucocytes within the lumen, en- gorgement of blood vessels, and infiltration of the wall with polynuclear leucocytes, through various stages of destruc- tive changes to complete disappearance of the bronchial wall and formation of an abscess cavity at the site of the bronchus. In the early stages of acute bronchitis, hemor- rhage is frequently associated with the lesion. Blood may be abundant within the lumen of the bronchus, and in the mucosa red blood corpuscles often infiltrate the tissue around greatly distended blood vessels, or accumulating below the epithelium, separate it from its basement mem- brane. Hemorrhage is not limited to the wall of the bron- chus, but frequently occurs into the alveoli in a zone en- circling the bronchus. 14S PNEUMONIAS AND [NFECTIONS OF RESPIRATOR'S TRACT With acute bronchitis there may be desquamation of epithelial cells with partial or complete loss of epithelial lining. In the smallest bronchi the single layer of colum- nar cells may be separated in places from the underlying tissue, so that intact rows of cells are round within the lumen. Tn somewhat larger bronchi, lined by epithelium in multiple layers, superficial columnar ciliated cells may be lost. In some instances superficial epithelial cells ap- pear to have lost their cohesion and are separated by nar- row spaces: in these instances, polynuclear leucocytes are often numerous between epithelial cells. Epithelium is oc- casionally separated from its basement membrane by small accumulations of serum or blood. Occasionally necrosis of epithelial cells with disappearance 1 of nuclei is seen and is doubtless caused by the action of bacteria; the affected cells may be raised from the underlying tissue by accu- mulated serum (Autopsy 253). The changes which have been described bring- about partial or complete loss of the ciliated lining of the bronchial tube. The severity of changes in the bronchial wall is in direct relation to the extent of destruction of the lining epi- thelium : when the epithelium remains intact polynuclear leucocytes may be found in considerable number imme- diately below it, but as the lesion progresses, cells in great part mononuclear, namely, lymphoid and plasma cells, ac- cumulate in large number throughout the wall of the bron- chus. There is often abundant cellular infiltration within and about the bundles of the muscular coat. The changes assume the character of chronic inflammation. When the lining epithelium of the bronchus is lost, fibrin tends to accumulate over the surface of the defect, to which it is firmly attached. It remains separated by a conspicu- ous space from adjacent intact epithelium over which it may project. This superficial network of fibrin merges with a similar network, extending to a variable depth within the tissue. "What mav well be described as coagulative PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 149 necrosis has often occurred, and structures, such as white fibrous bundles or wall of blood vessels, are marked out by hyaline material which merges with fibrin. When the walls of the blood vessels which are invariably engorged are involved, the lumen is plugged by a fibrinous thrombus. Little patches of fibrin adherent to the inner surface of the bronchus may occur in spots where epithelium has been lost ; with uniform loss of epithelium the entire circumfer- ence may be lined with fibrin forming a circular zone occasionally quite uniform in thickness. Accumulations of polynuclear leucocytes doubtless bring about conditions which cause solution of fibrin or prevent its formation (when disintegration of leucocytes sets free leucoprotease in abundance). The activity of the infecting microorganisms, usually hemolytic streptococci or staphylo- cocci, may cause complete necrosis of a part or all of the bronchial wall. The cavity which is formed may penetrate into lung tissue that has previously undergone pneumonic consolidation. Further changes caused by the bronchitis of influenza will be considered under peribronchial hemorrhage and edema, peribronchial pneumonia and bronchiogenic ab- scess. Purulent bronchitis is almost invariably associated with dilatation of the bronchi, the affected bronchi being- distended with pus. With increasing dilatation bronchiec- tasis becomes evident upon gross examination of the tissue, and is much more advanced in the small bronchi than in the larger cartilaginous passages. This subject will be further considered under bronchiectasis. In association with the acute bronchitis of influenza the epithelium of bronchi not infrequently looses its superficial columnar ciliated cells and assumes some of the characters of a squamous epithelium being covered by polygonal or flat cells (Figs. 17 and 18). The condition is often de- scribed a "squamous metaplasia," although it doubtless represents a stage of regeneration following injury rather 150 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT than a true metaplasia. The basal cells of the epithelium have a cubical or columnar form; above them the cells be- come polygonal and as the surface is approached, cells are Mat and even scale-like. The nuclei of these superficial cells are often lost. There is no close resemblance to the squamous epithelium of the skin, for intercellular bridges are not seen. This change may occur within six days after onset of influenza, though in most instances the duration of illness lias been two weeks or more. It may affect either large or small bronchi, but it is more frequently found in the latter. Whenever ciliated columnar cells are lost, super- ficial cells tend to become fiat. Epithelium on one side of a bronchus may have a squamous character, whereas that elsewhere is columnar and ciliated. The flat epithelium may undergo thickening so that it is 0.1 mm. or more in thick- ness. It is noteworthy that regenerating epithelium grow- ing over a denuded surface has the squamous character which has been described (Plate XIV, Fig. 22). Bacteriology of the Bronchitis of Influenza. — With the pneumonia of influenza, bronchitis is invariably present. Cultures have been made from the right or left main bron- chus or from the very small bronchi which contained puru- lent exudate. A routine method of making the culture has been adopted. The right main bronchus, exposed by draw- ing the right lung out of the chest and toward the midline, was widely seared with a hot knife; the bronchus was par- tially cut across through the seared surface with a heated knife and a platinum needle inserted into the lumen. The bacteria obtained named in the approximate order of their relative frequency have been: ]>. influenza 1 , pneumococci, hemolytic streptococci, staphylococci (aureus and albus), B. coli, S. viridans, M. catarrhalis, and diphthoid bacilli which have not been identified. Mixed infections occurred in most instances. The following list arranged by grouping PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 1 5 1 bacteria in the order cited above, shows how varied have been the combinations which occur: B. influenzae .'; Pneumococci 5 S. hemolyticus 3 Staphylococci '.', B. coli 3 S. viridans 1 B. influenzae, pneumococci 17 B. influenzae, S. hemolyticus 18 B. influenzae, staphylococci 4 Pneumococci, S. hemolyticus 1 Pneumococci, staphylococci 3 S. hemolyticus, staphylococci 4 S. hemolyticus, B. coli 2 Staphylococci, S. viridans 1 B. influenzae, pneumococci, S. hemolyticus 6 B. influenzae, pneumococci, staphylococci 15 B. influenzae, pneumococci, S. viridans 2 B. influenzae, S. hemolyticus, staphylococci 16 B. influenzae, S. hemolyticus, M. catarrhalis 1 B. influenzas, staphylococci, S. viridans 1 Pneumococci, S. hemolyticus, staphylococci 3 Staphylococci, B. coli, S. viridans 1 B. influenzas, pneumococci, S. hemolyticus, staphylococci 7 B. influenzae, pneumococci, staphylococci, M. catarrhalis 1 B. influenzae, S. hemolyticus, staphylococci, B. coli 1 B. influenzae, S. hemolyticus, staphylococci, S. viridans 1 B. influenzae, S. hemolyticus, staphylococci, M. catarrhalis 1 B. influenzae, staphylococci, S. viridans, M. catarrhalis 1 B. influenzae has been present in the bronchi in 79.3 per cent of instances of pneumonia referable to influenza. Com- binations which have been found most frequently are B. influenza? and pneumococci (17 instances), B. influenzae and hemolytic streptococci (18 instances), or the same combina- tions with staphylococci, namely, B. influenzae, pneumococci and staphylococci (15 instances), and B. influenzae, hemo- lytic streptococci and staphylococci (16 instances). There is little doubt that B. influenzae was not identified in some instances in which it was present ; when other microorgan- isms are very numerous its inconspicuous colonies may be overgrown even though the presence of pneumococci, strep- 152 PNEUMONIAS AND [NFECTIONS OF RESPIRATOR!? TRACT tococci or staphylococci tends to increase the size of its col- onics. Moreover, it is not improbable thai the microorgan- ism may disappear Prom the bronchi. Comparison with observations made upon influenza suggests that multiple methods of examination mighl have demonstrated a much higher incidence of B. influenza?. Throat cultures alone made during life demonstrated the presence of B. influenza" in only 65.7 per cent of patients with acute influenza, whereas when cultures were made from the nose, throat and sputum, and a mouse was inoculated with sputum from each patient, B. influenza 1 was found in every instance. After the acute stage of the disease had passed, the num- ber of microorganisms diminished, and in many instances I), influenzae disappeared from the upper air passages. In some of our autopsies B. influenzae doubtless present dur- ing life has similarly disappeared before death due to pneumonia caused by pneumococci or streptococci. In view of these considerations it is not improbable that B. iuflu- enzse demonstrated by a single culture in 80 per cent of instances has been constantly present. Table XXVIII represents the incidence of pneumococci, hemolytic streptococci, staphylococci, and B. influenza' in the bronchi, lungs and blood of those individuals with pneu- monia in whom baeteriologic examination has been made at autopsy. The number of cultures made from the bronchi, lungs or blood of the heart is given in the second column of the table and in other columns are given the incidence in number and percentage of the microorganisms which have been mentioned. Table XXVIII ■ - I'XEFMOCOCCl HEMOLYTIC STREPTOCOCCI STAPHYLO- COCCI B. INFLU- ENZAE > O o £ ft. (3 W S c ft. 6. > Z ft. Be O E- B2 "/. fcj O 6. ft. H • 7. O o y. p., H O ft. ft. Eh pi y. cu w £ O E-. sa w W o a. ft. Bronchus Lung Blood 121 l.-,:; 218 56 68 87 46.?, 44.4 39.9 58 77 85 47.9 50.3 39.0 61 37 1 50.4 24.2 0.5 96 70 1 79.3 45.7 0.5 PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 153 Cultures from the bronchus represent the bacteriology of the bronchitis of influenza. Infection of the Lung fol- lowing influenza doubtless occurs by way of the bronchi, so that the bacteria which cause pneumonia are present in the bronchi before they enter the lung tissue. The figures in Table XXVIII, similar to those previously cited, show the high incidence of B. influenzae, and the occurrence of pneumococci, hemolytic streptococci and staphylococci each present in approximately half of all autopsies. The figures in Table XXVIII are an index of the capacity of the microorganisms which enter the bronchi to invade the lungs and finally the blood. Pneumococci were pres- ent in the bronchi in 46.3 per cent of instances, in the lungs in only slightly less, and in approximately 40 per cent of autopsies they had penetrated into the blood. Hemolytic streptococci enter the bronchi with the same frequency and exhibit an equal ability to penetrate into the lungs and blood. Staphylococci enter the bronchi in half of these in- dividuals, but penetrate into the lungs in only a fourth of the instances. They have entered the blood only once (Au- topsy 263) in this instance in association with hemolytic streptococci. B. influenzae has been present in the bronchi in approximately 80 per cent of autopsies. It is notewor- thy that it has been found in the lung in little more than half this percentage of instances and has entered the blood only once (Autopsy 474), in this instance in association with hemolytic streptococci. In a limited number of autopsies there was purulent bronchitis recognized by the presence of mucopurulent ex- udate in small bronchi. It has been stated that this group of cases is not sharply separable from other instances of bronchitis, because in some cases death has occurred before a purulent exudate has accumulated or in other instances a purulent exudate has been disjriaced by edema. Table XXIX shows the bacteriology of instances of purulent bronchitis : 154 PNEUMONIAS AND [NFECTIONS OF RESPIRATORS TRACT Table X X 1 X s. K : - z o Bronchus 66 i-M iMOcoeci w > H O E* c^ a x 6 O w o :-". s. - - 33 50.0 HEMOLYTIC STREPTOCOCCI K > H O Eh • M a i. O o u; o X. ft. a. ft. 32 48.5 STAPH! I.o- . (KVI p 6 36 54.5 B. iM'i.r- enz^: o 6 V. ft. 53 80.3 The percentages of various bacteria with purulent bron- chitis do not differ essentially from those obtained from all autopsies with pneumonia. B. influenzae is found in ap- proximately 80 per cent of autopsies. In 16 instances cul- tures were made Prom the purulent fluid contained in a small bronchus and the incidence of B. influenza 1 (namely, 81.4 per cent) has not differed from that in the main bron- chus. In 7 of 8 instances in which cultures were made, both from the right main bronchus and from the purulent fluid in a small bronchus, B. influenza 1 was found in one or other in all but one autopsy (87.5 per cent) ; in this instance (Au- topsy 472) respiratory disease began thirty-seven days be- fore death and cultures from large and small bronchi at autopsy were overgrown by B. coli. Since observations upon influenza made during life have shown that B. influ- enza? is constantly demonstrable when multiple methods are employed for its detection, the figures just cited give sup- port to the suggestion that B. influenzae is constantly pres- ent in the bronchi with the bronchitis of influenza. Lobar Pneumonia The frequency with which the confluent lobular consol- idation of bronchopneumonia involving whole lobes or parts of lobes follows influenza has emphasized the desira- bility of distinguishing carefully between lobar and conflu- ent lobular pneumonia. The pulmonary lesion has been designated lobar pneumonia when it exhibited the well- known characters of this lesion, namely, firm consolidation of large parts of lobes, coarse granulation of the cut sur- PATHOLOGY AND BACTERIOLOGY FOLLOWING I X I'LT KXXA L55 face, fibrinous plugs in the bronchi and, on microscopic ex- amination, homogeneous consolidation and fibrinous plug- within the alveoli. With confluent lobular consolidation of* bronchopneumonia the consolidated area is in most cases obviously limited by lobule boundaries, and well-defined lobules of consolidation occur elsewhere in the lungs. Lobar pneumonia occurred in 98 among 241 instances of pneumonia following influenza, namely, in 40.7 per cent of autopsies. The difficulty of separating lobar and bronchopneumonia following influenza has been increased by the frequent com- bination of the two lesions in the same individual. There were 34 instances in which lobar and bronchopneumonia occurred together. The anatomic diagnosis of lobar pneu- monia was made only when lobes or parts of lobes were firmly consolidated and exhibited the characters of the le- sion enumerated above ; in several instances, in which there was some doubt concerning the nature of the lesion, micro- scopic examination was decisive. The associated broncho- pneumonic lesions represented all the types which have been associated with influenza. In the group of 34 cases of coexisting lobar and bronchopneumonia, lobular consolida- tion occurred 10 times, peribronchiolar consolidation 14 times (recognized in all but 4 instances by microscopic ex- amination), hemorrhagic peribronchiolar consolidation 9 times, peribronchial pneumonia 4 times. The intimate re- lation of these lesions to changes in the bronchi is well shown by the frequent presence of purulent bronchitis. The associated lesions of the bronchi in these cases were as follows : purulent bronchitis in 23 instances ; peribronchial hemorrhage in 6; bronchiectasis in 11. The frequency of purulent bronchitis and other bronchial lesions in associa- tion with coexisting lobar and bronchopneumonia is in sharp contrast with the occurrence of these lesions in asso- ciation with lobar pneumonia alone; with 69 instances of 151 ) PNEUMONIAS AN1> INFECTIONS OF RESPIRATOR'S TRACT Lobar pneumonia alone purulenl bronchitis occurred 17 times and bronchiectasis once. Lobar pneumonia following influenza passes through the usual stages of red and gray hepatization. Red hepatiza- tion was found l(i times, combined red and gray hepatiza- tion 28 times, and gray hepatization 20 times. The average duration of pneumonia with red hepatization was 3.7 days, with combined red and gray hepatization 5.1 days and with gray hepatization 7..") days. These figures, it will be shown later, have seme importance in relation to the stage at which hemolytic streptococcus infects lungs the site of lobar pneumonia. Bacteriology of Lobar Pneumonia. — Table XXX is com- piled with the purpose of determining the bacteriology of the bronchi, lungs and heart's blood in autopsies performed on individuals with lobar pneumonia. In some instances bacteriologic examination of one or other of these organs was omitted; the percentage incidence is an index of the presence of pneumococci, hemolytic streptococci, staphylococci or B. influenza 1 in the bronchi, lungs or heart's blood and measures the invasive power of these mi- croorganisms during the course of lobar pneumonia fol- lowing influenza. Table XXX PNEUMOCOCCI HEMOLYTIC STAPHYLO- B. INFLU- 6. s = 1 6 _ V. o STREPTOCOCCI COCCI ENZAE £ A S3 s ° £ ft. ° £ fiS 53 a o ft. ft. B jH ri 53 s ° &5 ° £ s 55 K O ft, ft. g a S3 p o 85 ti r. K O 6- ft. g ^ S3 P >5 ft. BE a a. ft. Bronchus 44 29 56.9 14 31.8 22 50.0 37 84.1 Lung 53 41 77.3 13 24.5 8 15.1 26 49.1 Blood 87 57 (i.1.5 11 12.6 Pneumococci, the recognized cause of lobar pneumonia, were found in the lungs in 73.3 per cent of autopsies; fail- ure to find the microorganism in all instances is doubtless the result of its disappearance from the lung, which, it is well known, occurs not infrequently particularly during PATHOLOGY AND BACTERIOLOGY FOLLOWING [NFLUENZA 157 the later stages of the disease. In 65.5 per cent of instances of fatal lobar pneumonia pneumococci have entered the heart's blood. Hemolytic streptococci unlike pneumococci were found more frequently in the bronchi than in the lungs; this mi- croorganism which exhibits little tendency to disappear, once it has established itself within the body, found en- trance into the bronchi in 31.S per cent of instances of lobar pneumonia and in 24.5 per cent entered the lungs. Its inva- sive power is further illustrated by its penetration into the heart's blood approximately in half this proportion of au- topsies. Staphylococci enter the bronchi in many instances (50 per cent), but relatively seldom (15.1 per cent) invade the lung and rarely if ever penetrate into the blood. The high incidence, namely, 84.1 per cent, of B. influenzae in the bronchi is particularly noteworthy; it exceeds that of pneumococci, the well-recognized cause of lobar pneu- monia, within the lung. It is found much less frequently within consolidated lung tissue and shows no tendency to invade the heart's blood. B. influenzae finds the most fa- vorable conditions for its multiplication within the bronchi. In view of the frequent occurrence of coexisting lobar and bronchopneumonia it has appeared desirable to de- termine how far the existence of obvious bronchopneumonia modifies the bacteriology of lobar pneumonia. In Table XXXI the incidence of pneumococci, hemolytic streptococci, staphylococci and B. influenzae after death with lobar pneu- monia on the one hand is compared with their incidence after combined lobar and bronchopneumonia on the other. Pneumococci are found in the lung more frequently with lobar than with combined lobar and bronchopneumonia. The incidence of hemolytic streptococci and of staphylo- cocci in the lung is on the contrary higher when broncho- pneumonia is associated with lobar pneumonia. It is not improbable that these microorganisms have a part in the L58 PNEUMONIAS AND [NFECTIONS OF RESPIRATOR"! TRACT Table x.\ xi With Lobab Pneumonia Alone HEMOLYTIC STAPHYLO- 15. INFLU- PNEU1 oc ■S. STREPTOCOCCI COCCI ENZA u Be - - td 1 « w W g w fc > g > = g E- - r- E- •- r- & O Eh H U Eh . ij _• /. M y. -; so BS M ^ <« as r. ^ «J 65 W c t p o K O O o £ O O O K O p o w o X u X ft. 6. ft. £ ft. ft. ft. X ft. ft. ft. :■ ft. ft. ft. Bronchus 30 20 66.6 9 30 15 50 26 86.7 Lung 3 1 2D 85.2 7 20.6 3 8.8 18 52.9 Blood 54 36 66.7 7 13 With Combined Lobar and Bronchopneumonia w P a: ° 1 6 p 55 u PNEUMOCOCCl hemolytic streptococci STAPHYLO- COCCI B. INFLU- ENZA EH s ° 2 ft. as x w o ft, ^ 64.3 63.2 63.1 g jH s ° X ft. 1 w O Eh fti 55 H O ft, ft. > EH p o £ ft. 1 B O Eh as 55 w o ft. ft. Eh O O X. a. 1 £ C^ Eh es 55 w o ft. ft. I'.i onchus Lung Blood 14 19 33 9 12 21 5 6 4 34.3 31.6 12.1 7 5 50 26.3 11 8 78.6 42.1 production of associated bronchopneumonia. The fre- quency with which microorganisms invade the blood is al- mosl identical in the two groups. The relative frequency with which different types of pneumococci produce lobar pneumonia under the conditions existing when Camp Pike was attacked by an epidemic of influenza is indicated by Table XXXII in which in- stances of lobar pneumonia alone and of combined lobar and bronchopneumonia arc listed separately. Pneumococcus I and II, which are found approximately in two-thirds of instances of lobar pneumonia occurring in cities, have an insignificant part in the production of these lesions. Pneumococcus IV and atypical Pneumococcus IT, which are commonly found in the month, are the predom- inant cause of these lesions, and with Pneumococcus III, also an inhabitant of the months of normal individuals, have been the cause of two-thirds of all instances of lobar pneumonia observed in this camp. PATiioi/xiY and bactuuioi/hjy following infi.ckxza 59 Table XXXII With Lobar Pneumonia PNEUMO- PNEUMO- PNEUMO- PMEUMO- PNEUMO- COCCUS COOCUS coccus coccus coccus M * a I II II (Atyp.) III IV 2 ° £ ft, H O ft, ft, | Eh i— i 2 ° !z ft, V A g ° £ H O 0- ft. > O c X ft. » g « EH « W w o ft- ft. E p o X ft. E-i y, g ° e w o ft. ft. g X ^ O o 'A ft. W O ft, ft. Bron- chus 30 1 3.3 1 3.3 4 13.3 4 13.3 10 33.3 Lung 34 1 2.9 2 5.9 9 26.5 6 17.6 1] 32.4 Blood 54 2 3.7 2 3.7 12 22.2 3 5.6 17 31.5 With Combined Lobar and Bronchopneumonia pneumo- PNEUMO- PNEUMO- PNEUMO- PNEUMO- coccus COCCUS COCCUS COCCUS COCCUS w I II , II (Atyp.) III IV H Eh EH EH Eh fc w Z W w £ w H fc g eq fc g g A g o # P p s > M > EH g h- 1 Eh > Eh ° B >— 1 Eh n 2 w 5; £ p O o w o p 6 W O p o w o 2 ° a o p o H O Q 2 a, a. ft. %■ ft. ft, ft. Jz; ft. ft. ft. £ ft. ft. ft. Bron- chus 14 2 14.3 1 7.1 3 21.4 3 21.4 Lung 19 1 5.3 5 26.3 6 31.6 Blood 33 2 6.1 3 9.1 4 12.1 12 36.4 There is no noteworthy difference in the occurrence of these types of pneumococci among instances of lobar pneu- monia, on the one hand, and of combined lobar and broncho- pneumonia, on the other. Different types exhibit no note- worthy differences in their ability to penetrate into lungs and blood. Hemolytic Streptococcus with Lobar Pneumonia. — There can be no doubt that the concurrent infection with microorganisms other than pneumococcus modifies the progress of lobar pneumonia. With lobar pneumonia alone hemolytic streptococci have entered the bronchi in 30 per cent of instances and have penetrated into the lungs in 20.6 per cent ; with associated lobar and bronchopneumonia the same microorganism has entered the bronchi in 34.3 per cent of instances and invaded the lung in 31.6 per cent. Hemolytic streptococci are the only microorganisms other than pneumococci which, in association with lobar pneu- L60 PNEUMONIAS A.ND INFECTIONS OF RESPIRATORS TRACT monia, have found their way from the hums to the Mood stream; more than one-third of all instances of lobar pneu- monia in which hemolytic streptococci find entrance into the bronchi die with streptococcus septicemia. Separation of instances of lobar pneumonia into groups on the hasis of the occurrence of red or gray hepatization shows that infection with hemolytic streptococcus is more likely to occur during the early stages of the disease. The average duration of lobar pneumonia with red hepatization lias been .'!." days, with red and gray hepatization, 5J days, and with gray hepatization, 7.5 days. Infection with hemo- lytic streptococcus has occurred in association with red or gray hepatization as shown in Table XXXIII. Table XXXIII NO. OF XO. "WITH HEMO- PER CENT WITH AUTOP- LYTIC STREPTO- HEMOLYTIC SIES COCCUS STREPTOCOCCUS Lobar pneumonia with red hepatization lfi 6 37.5 Lobar pneumonia with red ami grav hepatization 28 6 21.4 Lobar pneumonia with gray hepatization 20 1 5.0 Notwithstanding the longer duration of the disease and consequent prolongation of exposure to infection, lobar pneumonia, which has reached the stage of gray hepatiza- tion, lias shown the smallest incidence of infection with hemolytic streptococci. In the stage of gray hepatization there is diminished susceptibility to secondary infection with this microorganism. Characterstic histologic changes have been found in the lungs of those who have died with lobar pneumonia fol- lowed by invasion of lungs and blood by hemolytic strepto- cocci {e.g., Autopsies -7'.], 430), hut with no evidence of suppuration found at autopsy. Within the pneumonic lung occur patches of necrosis implicating both exuded cells and alveolar walls; in some places nuclei have disappeared; elsewhere nuclear fragments are abundant. PATHOLOGY AND BACTKUIOLOO V FOLLOWING INFLUENZA L61 In these patches of necrosis Gram-positive streptococci in short chains occur in immense number. In some instances {e.g., Autopsies 273, 346, 470) interlobular septa are very edematous and often contain a network of fibrin; lymphat- ics are dilated and contain polynuclear leucocytes in abun- dance. Streptococci are found within these lymphatics. The histologic changes which have been described repre- sent the earliest stages of abscess formation and interstitial suppuration, lesions almost invariably caused by hemolytic streptococci. Relation of Lobar Pneumonia to Influenza. — Some writ- ers have suggested that lobar pneumonia, heretofore ob- served during the course of epidemics of influenza, is an >5r-pt. S ZS 30 Oct 5 /O 15 ZO ZS 30 Chart 2. — Showing the relation of (a) date of onset of cases in which autopsy dem- onstrated lobar pneumonia, indicated by upper continuous line with single hatch, and of (i>) date of death of these cases, indicated by lower continuous line with double hatch to (c) the occurrence of influenza, indicated by the broken line, and to (d) the total num- ber of fatal cases of pneumonia, indicated by the broken dotted line. Each case of fatal pneumonia is indicated by one division of the scale as numbered on the left of the chart; cases of influenza are indicated by the numbers on the right of the chart. 162 PNEUMONIAS AND [NFECTIONS OF RESPIRATORY TRACT Lndependenl disease with no relation to influenza, both dis- eases being referable perhaps to similar meterologic or other conditions. Chart 2, which shows by weeks from September 1 to October 31 the relation of deaths I' rem lobar pneumonia (indicated by double hatch) to deaths from all forms of pneumonia, disproves this suggestion. The two curves follow parallel courses; thai representing lobar pneumonia reaches a maximum approximately one week after the outbreak of influenza had reached its height. Lo- bar pneumonia, like other ''onus of pneumonia, was second- ary to influenza. When a chart is plotted to represent the dales of onset of fatal eases of lobar pneumonia (indicated by single hatch in Chart 2), it becomes evident that the greatest number of these cases of pneumonia had their on- set at the beginning of the influenza epidemic, approxi- mately one week before it reached its height. Fatal lobar pneumonia developed less frequently in the latter pari of the epidemic; to obtain an explanation of this relation it is necessary to chart separately cases of lobar pneumonia with secondary streptococcus infection, for we have already learned that streptococcus infection was the predominant cause of death in the early period of the influenza epidemic. Exclusion of these instances of secondary streptococcus in- fection makes no noteworthy change in the character of the chart. Fatal lobar pneumonia, like all forms of fatal pneumonia (p. 140), was more frequent in the first half than in the second half of the epidemic. This differ- ence is referable either to greater virulence of the virus of influenza or to the greater susceptibility of those first se- lected by the disease or, as more probable, to conditions such as crowding together of patients with influenza, favor- ing the transmission of microorganisms which cause pneu- monia. Bronchopneumonia For the purpose of the present study it is convenient to •jroii)) together instances of bronchopneumonia which have PATHOLOGY AND BAOTttTMOT.OGY FOLLOWING INFLUENZA L63 been unaccompanied, on the one hand, by lobar pneumonia (]). 155) or, on the other hand, by suppuration, which with few exceptions is caused ])y hemolytic streptococci or by staphylococci. A group of cases in which lobar and bron- chopneumonia have occurred in the same individual have already been considered. In many instances, bronchopneu- monia is accompanied by abscess formation or by some other form of suppuration; these lesions will be discussed elsewhere. Bronchopneumonia unaccompanied by lobar pneumonia or by suppuration occurred in 80 autopsies. Pneumonic consolidation distributed with relation to the bronchi exhibits considerable variety, and an attempt to define a type of bronchopneumonia characteristic of influ- enza would be futile. Nevertheless, the bronchopneumonia of influenza has in many instances distinctive* characters. Lesions of bronchopneumonia which are frequently found in the autopsies under consideration may be con- veniently designated by descriptive terms, indicative of their location in the lung tissue. These lesions, of which two or more often occur in the same lung, are : 1. Peribronchiolar consolidation with which the inflam- matory exudate is limited to the alveoli in the immediate neighborhood of the bronchioles. 2. Hemorrhagic peribronchiolar consolidation in which gray patches of peribronchiolar pneumonia occur upon a deep red background produced by hemorrhage into alveoli. Pfeiffer believed that this lesion was characteristic of in- fluenza. 3. Lobular consolidation with which consolidation is lim- ited to lobules or groups of lobules. 4. Peribronchial pneumonia with which small bronchi are encircled by pneumonic consolidation. Each one of these lesions will be discussed separately. Following is a list of the bacteria which have been iso- lated from the consolidated lung of individuals with bron- L64 PNEUMONIAS AND INFECTIONS OF RESPIRATOR'S TRACT chopneumonia unaccompanied by Lobar pneumonia or by suppuration : B. influenzse 1 Pneumococci 5 s. hemolyl icus 5 S. viridans 1 B. influenzse, pneumococci si B. influenzse, S. hemolyticus 4 B. influenzae, staphylococci 4 Pneumococci, S. hemolyticus 1 I'liriiiiKHM.rri, staphylococci 2 S. hemolyticus, staphylococci 1 S. hemolyticus, B. coli 1 Staphylococci, S. viridans I Stapliylococci. B. coli 1 B. influenzse, pneumococci, stapliylococci 1 B. influenzse, pneumococci, S. viridans 1 B. influenzse, S. hemolyticus, staphylococci - B. influenzse, pneumococci, staphylococci, S. viridans 1 No microorganisms found 6 47 The similarity of this list to that representing the bac- teriology of bronchitis is evident; there is the same multi- plicity of microorganisms and the frequent occurrence of mixed infections. B. influenzae is much less frequently found in the lung. The relative pathogenicity of the large group of microorganisms enumerated above is better indi- cated by the following list which shows what microorgan- isms have penetrated into the blOod in autopsies performed on individuals with bronchopneumonia: Pneumococci 20 S. hemolyticus 23 S. viridans .1 Pneui ;occi, S. hemolyticus 2 No bacteria found 2.1 Total 71 Table XXXIV shows the percentage incidence of pneu- mococcus, hemolytic streptococcus, staphylococcus and PATHOLOGY AND BACTI5IUOLO0Y FOLLOWING I X KLCKX/A 1 65 B. influenzas in the bronchi, lungs and blood and is in- serted for comparison with the similar table (Table XXX) showing the incidence of these bacteria in lobar pneumonia. Table XXXIV PNEUMO- HEMOLYTIC STAPHYLO- B. INFLU- w COCCI STREPTOCOCCI COCCI ENZAE H Eh EH Eh w W J5 W H £ w w £ W g Y< r > Eh > En • 02 03 3 > Eh ° B P3 02 Eh S3 02 6 o O o W O O o W O O o H O ^ o £ Ph Ph Ph % Ph Ph Ph !Z Ph 22 Ph Ph 'A Ph Bronchus 37 19 48.6 13 35.1 59.5 28 75.7 Lung 47 20 42.6 14 29.8 13 27.7 23 48.9 Blood 70 22 31.4 24 34.3 Table XXXIV shows that pneumococci have a less impor- tant part in the production of broncho than of lobar pneu- monia; with lobar pneumonia this microorganism was found in the lungs in 77.3 per cent of instances and in the blood, in 65.5 per cent, whereas with bronchopneumonia it was found in the lungs in 42.6 per cent and in the blood in 31.4 per cent. Hemolytic streptococci (in lungs and blood) and staphylo- cocci (in lungs), on the contrary, were more common with bronchopneumonia, and doubtless have a part in the pro- duction of the lesion. Streptococcus viridans, B. coli and M. catarrhalis, which are not infrequently found in the bronchi (p. 151), occasionally enter the lungs with bron- chopneumonia but are rarely found with lobar pneumonia. B. influenzas has been found in less than 80 per cent of instances in the bronchi and in about half of the lungs, maintaining an incidence approximately the same as that with lobar pneumonia. Table XXXV shows the types of pneumococci found in association with bronchopneumonia and is inserted for comparison with the similar table (Table XXXII) show- ing types of pneumococci with lobar pneumonia. With broncho as with lobar pneumonia pneumococci com- monly found in the mouth, namely, atypical II, and Types III and IV, have a more important part in production of the l(i(! PNEUMONIAS AXn [NFECTIONS OF RESPIRATORS TRACT TAB! r .WW PNEUMO- PNEUMO- PNETJMO- PNEUMO- PNEUMO- COCCTJS COCCTJS ( oci US ( ii el s COCCUS S. H X fe - O E-. . - s ° I II fAtyp.) TT III IV - > Eh O o » Ph - - - ■- ^ r. - r ft. ft. Eh _• /- - C V. ft. w - H O - (V e Eh Z 04 - u a o ft. ft. > 5 o .4 a. « - - Eh ti /. W O ft. ft. si g H W - O Eh « w w o a. ft. Bron- chus 37 1 2.7 3 8 J 14 37.8 Lunij -17 •) 4.3 2 L3 2 4.. ,: ! 2 4.3 12 2.~>. 2 Blood 70 1 1.4 1 1.4 5 7.1 4 5.7 1 1 1 5.9 lesion than the so-called fixed types, I and II. Atypical Pneumococcus II lias been less frequently encountered with broncho than with lobar pneumonia. Peribronchiolar Consolidation. — In many instances of bronchopneumonia, usually in association with lobular or confluent consolidation, small firm nodules of consolidation are clustered about the bronchioles (Fig. -). These nodu- lar foci of consolidation are usually 1..1 to 2 mm. in diam- eter, being sometimes slightly smaller or slightly larger. They are usually gray and occasionally surrounded by a red halo; sometimes they are yellowish gray. They are clustered about the smallest bronchial tubes to form groups which are from 0.5 to 1 cm. across. A group of nodular foei of consolidation occupies the central part of a lobule of lung tissue. When pneumonia has been of short duration these foci are fairly soft and not sharply defined, and in many instances this form of bronchopneumonia is first rec- ognized by microscopic examination. When the disease has lasted from ten days to two weeks, the consolidated nodules are very firm and sharply circumscribed, closely resem- bling tubercles. When they have assumed this character, microscopic examination shows that chronic changes indi- cated by new formation of interstitial tissue have occurred. The lesion may be designated peribronchiolar consolida- tion. It has occurred usually in association with other types of pneumonic lesion in (il instances, being recognized at autopsy in 18 and by microscopic examination in 4.'!. PATHOLOGY AND BACTERIOLOGY FOLLOWING I \ I'LI ' KX/A 1 67 Fig. 2. — Acute bronchopneumonia with nodules of peribronchiolar consolidation and puru- lent bronchitis. Autopsy 429. 168 PNEUMONIAS A\'l» INFECTIONS OF RESPIRATOR'S TRACT In association with this lesion there are almost invari- ably severe lesions of the bronchi. Purulent bronchitis was noted in 47 of the 61 instances, in which this nodular bron- chopneumonia was Pound at autopsy. An index of the se- verity of the bronchia] injury is the frequency with which bronchiectasis has occurred; dilatation of small bronchi was observed in 24 instances. In 10 instances the bronchi were encircled by conspicuous zones of hemorrhage. In association with this peribronchiolar lesion the lung is often voluminous and fails to collapse on removal from the chest. Pressure upon the lung squeezes from the smallest bronchi, both in the neighborhood of the nodular consolida- tion and elsewhere, a droplet of viscid, semifluid mucopuru- lent material. The presence of this tenacious material throughout the small bronchi doubtless explains the failure of the lung tissue to collapse. Interstitial emphysema has been present in some of these lungs. A red zone of hemorrhage has occasionally been observed about the Foci of peribronchiolar pneumonia. A further stage in the same process is represented by hemorrhage into all of the alveoli separating these patches of consolida- tion. This hemorrhagic lesion, which will be described in more detail later, has been found repeatedly in the same lung with peribronchiolar pneumonia, being present in 8 among the 61 autopsies cited. Lobular bronchopneumonia accompanied the peribronchiolar lesion 27 times and lobar pneumonia accompanied it 20 times. When an abscess caused by hemolytic streptococcus is associated with peribronchiolar pneumonia, empyema is present, but otherwise pleurisy is absent or limited to a scant fibrinous exudate. Histologic examination demonstrates very clearly the re- lation of this lesion to the bronchioles (Fig. II). These passages are tilled and distended with an inflammatory ex- udate consisting almosl entirely of polynuclear leucocytes. The respiratory bronchioles are beset with alveoli often PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 169 limited to one sido of the tubule and these alveoli are filled with leucocytes. The alveolar duets, distinguishable from the bronchioles by the absence of columnar or cubical epi- thelium and by possession of smooth muscle, are similarly filled with leucocytes; the numerous alveoli which form the walls of the alveolar ducts are distended by an inflamma- tory exudate. In sections which pass through an alveolar Fig. 3. — Acute bronchopneumonia with peribronchiolar consolidation; a respiratory bronchiole partially lined by columnar epithelium passes into alveolar duct and the adja- cent alveoli are filled by polynuclear leucocytes. Autopsy 333. duct and one or more of its infundibula, the further exten- sion of the lesion may be determined (Fig. 4). The infun- dibulum in proximity with the alveolar duct contains poly- nuclear leucocytes and the same cells are seen in the alveoli which here form its wall, but the intensity of the inflamma- tory reaction diminishes toward the periphery, so that the distal part of the infundibulum, which is much distended L70 PNEUMONIAS A.ND [NFECTIONS OF RESPIRATORS TRACT and in consequence mere readily definable than usual, is free from inflammatory exudate. Occasionally there is irregularly distributed hemorrhage and perhaps some edema in the alveoli immediately adja- cent to those which form the peribronchiolar focus of in- flammation. In such instances small bronchi, thai is, air passages, lined by columnar epithelium and devoid of trib- utary alveoli, may be surrounded by a /one of hemorrhage; immediately surrounding the bronchus, the wall of which shows intense inflammation, alveoli, in a /one of which the radius represents several alveoli, are filled with blood. This hemorrhagic /one is continued Prom the bronchus over the focus of inflammation which surrounds the bronchiole, PATHOLOGY AND BACTEUIOLO( J V FOLLOWING INFLUENZA 171 Another variation in the character of the lesion is doubt- less referable to variation in the severity of primary bron- chial injury. Alveoli immediately surrounding small bron- chi are filled with dense plugs of fibrin. The alveoli which beset the walls of the bronchioles contain fibrin, bu1 the alveolar duct and its tributary alveoli are filled with poly- nuclear leucocytes. The bacteria which have been cultivated from the lung in autopsies with peribronchiolar pneumonia are as follows : Fneumococcus 5 S. hemolyticus 8 B. influenzae, pneumococcus 5 B influenzas, S. hemolyticus 7 B. influenzas, staphylococcus 1 Fneumococcus, staphylococcus 2 S. hemolyticus, staphylococcus 2 B. influenzae, pneumococcus, S. hemolyticus 2 B. influenzae, pneumococcus, staphylococcus 1 B. influenzae, S. hemolyticus, staphylococcus 2 Pneumococcus, S. hemolyticus, staphylococcus 3 No organism 3 Total 41 The following list which shows the bacteria found in the blood is an index to the pathogenicity of pneumococci and hemolytic streptococci : Pneumococcus . . 22 S. hemolyticus 20 Pneumococcus, S. hemolyticus 1 No organism 11 Total 57 The percentage incidence of pneumococcus, hemolytic streptococcus, staphylococcus and B. influenzae in bronchus, lung and blood, given in Table XXXVI, is inserted to indicate with what readiness each one of these microorgan- isms passes from the bronchus through the lung into the circulating blood. L72 PNEUMONIAS AND [NFECTIONS OF RESPIRATORY TRACT Table XXXVI HEMOLYTIC PNEUMOCOCCUS STREPTOCOCCUS STAPHS l.ii- COCCUS li. INFLUENZA Bronchus Lung Blood • 39.4' i .17.7% 4.:.'.", r.i.o% 40.3% 36.8% 60.67o 21.9% 0. % 84.8% 43.9% 0. % B. influenzae is presenl in the bronchi in a very Large pro- portion (84.8 per cent ) of those in whom this type of bron- chopneumonia has been round at autopsy; it is much less frequently recovered from the Lungs. Staphylococci, in pari S. albus and in part S. aureus, are less frequently found in the bronchi and are recovered from the Lungs in a relatively small proportion of autopsies. The percentage incidence of piieiunococci and streptococci in Lungs and blood demonstrates the pathogenicity of these microorgan- isms, for whereas pneumococci and hemolytic streptococci are found iii the consolidated lungs in 43.9 and 61.0 per cent o!' instances of the lesion respectively, they make their way into the blood in 40.3 and 36.8 per cent of instances. Coexisting- infection with pneumococci and hemolytic streptococci has been not uncommon e.g., Autopsy 275 in which both were in the blood; in 2 instances (Autopsies 333 and 378) in which pneumococci were obtained from the blood, hemolytic streptococci were found in the lungs and bronchi; in 3 instances (Autopsies 258, 27.". and 445) in which hemolytic streptococci were present in the blood, pneumococci were obtained from the lungs. In the group of autopsies under consideration, examina- tion of the sputum was made during life and after onset of pneumonia in 11 instances. The microorganisms found in the sputum and at autopsy were as follows : IN BLOOD, U'XCX OK BRONCHUS SPUTUM AT AUTOPSY Autopsy 240 Pneum. IV Pneum. IV 246 Pneum. atyp. TT, B. inf. 247 Pneum. IV, B. inf. Pneum. IV 250 Pneum. atyp. II, B. inf. Pneum. atyp. II 253 Pneum. atyp. II Pneum. II 285 Pneum. atyp. II, B. Inf. ft. hem., B. inf. 288 S. hem., B. inf. ft. hem., B. inf. PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 173 ]X BLOOD, LUNGS QB BRONCHUS SPUTUM AT AUTO) Autopsy 291 Pneum. IV, B. inf. Staph., E. inf. 300 Pneum. atvp. II, B. inf. Pneum. atyp. IT, P.. inf. 312 Pneum. IV, S. hem., B. inf. S. hem., P.. inf. :;4<; Pneum. IV, B. inf. S. hem, B. inf. Iii 2 instances (Autopsies 285 and 346) among this small group of eases, pneumoeocci but no hemolytic streptococci were found in the sputum several days before death., whereas death occurred as the result of secondary invasion with hemolytic streptococci and no pneumoeocci were found at autopsy. It is probable that this sequence of event- - not uncommon. B. influenza? finds its way into the bronchi and pneumoeocci follow it : pneumonia limited to peribron- chiolar alveoli may occur in consequence of this invasion. Later hemolytic streptococci may follow the same path and cause death with bacteremia. Hemorrhagic Peribronchiolar Consolidation. — Peribron- chiolar pneumonia accompanied by diffuse accumulation of blood within the alveoli is one of the most frequent com- plications of influenza. The lung tissue is laxly consoli- dated, and on section there is a homogeneous dull deep red background upon which are seen small gray spots (1.5 to 2 mm. in diameter) grouped in clusters about the smallest bronchi (Fig. 5). Wide areas of lung tissue are implicated and the lesion is more common in the dependent parts of the lung than elsewhere. In common with other forms of bronchopneumonia the lesion is in most instances associ- ated with changes in the bronchi : in 55 instances of hemor- rhagic bronchiolar pneumonia purulent bronchitis was found in 43 instances : it is noteworthy that purulent bron- chitis often is not evident in the presence of pulmonary edema and edema is not infrequent with this pneumonic lesion. Microscopic examination demonstrates the presence of acute bronchitis: the lumina of the small bronchi contain polynuclear leucocytes and red blood corpuscles. Accumu- lation of blood may separate the epithelium from the base- 174 PNEUMONIAS AND INFECTIONS OF RESPIRATOR! TRACT incut membrane. The mucosa immediately below the epi- thelium contains polynuclear leucocytes in Pair abundance and the blood vessels of the bronchial wall are much en- gorged. Respiratory bronchioles are distended with poly- nuclear leucocytes and red blood corpuscles. In a /one aboul each bronchiole, in areas corresponding to the small gray spots seen upon the cut surface of the hum', the alveoli are tilled with polynuclear leucocytes. In the lung tissue intervening between these spots of leucocytic pneumonia the alveoli are distended with red blood corpuscles. Fig. 5.— Bronchopneumonia with hemorrhagic peribronchiolar consolidation. In favorable sections it is occasionally possible to follow the bronchiole and alveolar duet, both tilled with leuco- cytes, into an infundibulum. The proximal part of the in- fundibulum contains polynuclear leucocytes, whereas the distal part and its tributary alveoli are filled with serum and red blood corpuscles. When the lesion has persisted for a short time there is evidence of beginning migration of polynuclear leucocytes from the blood vessels into the alveoli which are filled with Pathology and bacteriology following ixi'm-kx/a L75 Mood. The alveolar walls contain numerous polynuclear leucocytes and leucocytes which have entered the intraal- veolar blood arc numerous in contael with the wall bul occur in scant number in Hie center of the alveolar lumen. Alveolar epithelium in contact with the blood in the lu- men is usually swollen and often uniformly nucleated. The inflammatory process is evidently transmitted Prom the bronchioles and to a less degree from the small bronchi to the adjacent alveoli. Polynuclear leucocytes fill the lu- men of the bronchiole and the alveoli immediately adja- cent; at the periphery of the focus of pneumonia, the alve- oli may contain fibrin. In such instances small bronchi (lined by a continuous layer of columnar epithelial cells) may be surrounded by alveoli containing fibrin. In sections from one part of the lung, the alveoli between the peribronchiolar foci of pneumonia may be uniformly filled with red blood corpuscles, whereas in sections from another part pneumonic foci may be surrounded by a zone of intraalveolar hemorrhage or of hemorrhage and edema outside of which some air-containing tissue occurs. There are transitions between this halo of intraalveolar hemor- rhage and edema surrounding each bronchiolar focus and complete hemorrhagic infiltration of all intervening alveoli. Large mononuclear cells are occasionally fairly numer- ous within the alveoli containing blood. These cells act as phagocytes ingesting red corpuscles, so that at times they are filled with corpuscles. Disintegration of red corpuscles occurs and brown pigment remains within the cell. It is not uncommon to find numerous mononuclear pigment con- taining cells which resemble those found with chronic pas- sive congestion of the lungs. Lungs, the site of hemorrhagic peribronchiolar pneumo- nia, may undergo chronic changes which will be described elsewhere. The lesion which has been designated hemorrhagic peri- bronchiolar pneumonia is that which Pfeiffer regarded as 176 PNEUMONIAS AND [NFECTIONS OF RESPIRATOR'S TRACT the characteristic type of influenzal pneumonia. In the small bronchi containing pus and in lung tissue, Pfeiffer -laics, influenza bacilli arc predominant and present in as- tonishing riumber in smear preparations. The demonstra- tion of I). influenzae by cultures from pneumonic lung is mentioned by him bul its association with oilier microor- ganisms in such cultures is not discussed. Microorganisms which we have isolated from the Lungs of individuals with hemorrhagic peribronchiolar pneumo- nia are as follows : B. influenzae 1 Pneumoeoccus 2 s. hemolyticus 10 B. influenzae, pneumococcus 7 15. influenzae, S. hemolyticus 3 B. influenza', staphylococcus 2 S. hemolyticus, B. coli 3 B. influenza 1 , pneumococcus, staphylococcus 2 B. influenza', S. hemolyticus, staphylococcus 5 Pneumococcus, S. hemolyticus, staphylococcus 1 No organisms 2 Total 38 With this type of pneumonia B. influenzae has not been isolated in pure culture: B. influenzae alone is recorded only once (Autopsy 435), but in this instance the culture has been so obscured by contamination that the occurrence of pneumococci or streptococci cannot be excluded; S. hemo- lyticus lias doubtless been present in this lung, Tor it has been found in the heart's blood, in the bronchus, and in the peritoneal exudate of the same individual. The incidence of pneumococci and hemolytic streptococci in this list does not differ materially from that with peri- bronchiolar pneumonia unaccompanied by extensive intra- alveolar hemorrhage, though hemolytic streptococci are somewhat more frequent with the hemorrhagic lesion. The following table shows the frequency with which pneumo- cocci and hemolytic streptococci have penetrated into the blood : PATHOLOGY AND BACTERIOLOGY FOLLOWING INKLUEXZA 177 Pncumococcus 11 S. hemolyticus 24 Pneumococcus, S. hemolyticus 1 No organism J 2 Total 48 Table XXXVII showing the percentage incidence of pneumococci, hemolytic streptococci, staphylococci and I>. influenzas further emphasizes the similarity between the bacteriology of peribronchiolar pneumonia (Table XXXVI) and the closely related hemorrhagic lesion : Table XXXVII Bronchus Lung Blood of heart PXEUMOCOCCUS 44.0% 31.6% 25.0% HEMOLYTIC STREPTOCOCCUS 64.0% 57.9% 52.1% STAPHYLO- COCCUS 44.0% 26.8% 0% B. INFLUENZAE 72.0% 52.6% 0% Pneumococci have been found in the lungs (31.6 per cent) and blood (25 per cent), somewhat less frequently than with peribronchiolar pneumonia (43.9 and 40.3 per cent respectively), and hemolytic streptococci have been found in the blood more frequently (52.1 per cent) than with the latter (36.8 per cent) but otherwise the bacteriol- ogy of the two lesions corresponds closely. The low inci- dence of B. influenzas in the bronchi (72 per cent) with hem- orrhagic peribronchiolar pneumonia is perhaps incorrect as the result of the relatively small number of bacteriologic examinations (namely, 25), but the incidence of the same microorganism in the lung has been higher (52.6 per cent) than with nonhemorrhagic peribronchiolar lesion (43.9 per cent). In some instances infection with hemolytic streptococci has occurred after the onset of pneumonia. The following list compares the results of bacteriologic examination of the sputum made after the onset of pneumonia with that of blood, lungs or bronchus after death : 178 PNEUMONIAS AND [NFECTIONS OF RESPIRATORY TRACT SIM TIM IX BLOOD, LUNGS OK BRONCHUS AT AUTOPSY Aut< ipsy 237 s. hem. s. hem. 242 Pneum. atyp. II, B. inf. Pneum. atyp. 1 1 2 17 Pneum. IV, B. inf. Pneum. 1 V 266 s. hem. S. hem., n. inf. 346 Pneum. IV. B. inf. S. hem., B. inf. 376 | No. s. hem.) s. hem., staph., 1'.. inf. Instances of secondary infection with hemolytic strepto- coccus occur in the list, namely, Autopsies 346 and 376. From the foregoing studies of the bacteriology of peri- bronchiolar and hemorrhagic peribronchiolar pneumonia the following conclusions may be drawn: (a) B. influenzae is found in most instances of these lesions in the bronchi and in aboul half of all instances in the lungs, but does not occur unaccompanied by other microorganisms, (h) In a considerable number el' autopsies pneumococcus is the only microorganism that accompanies B. influenzae; from the lungs it penetrates into the blood from which it is obtained in pure culture, (c) In a considerable number of instances 8. hemolyticus accompanies B. influenzae, and in some of these instances (representing a large proportion of the rel- atively small number of eases examined during life), exam- ination of the sputum has demonstrated that infection has been secondary to a pneumonia with which no hemolytic streptococci have been found in the sputum. Lobular Consolidation. — Consolidation of scattered lob- ules or groups of lobules has occurred in nearly all in- stances, namely, 71 of 80 autopsies with bronchopneumonia unaccompanied by lobar pneumonia or by suppuration. When death follows shortly after the onset of pneumonia, patches of consolidation have a dull deep red color; blood- tinged fluid escapes from the cut surface which is almost homogeneous or finely granular. The consolidated tissue seen through the pleura, which is raised above the general level, has a bluish red color. Isolated lobules or groups of lobules which have undergone consolidation may be scat- tered throughout the lungs, but nol infrequently there is confluent consolidation of the greater part of lobes, of PATHOLOGY AND BACTERIOLOGY FOLLOWING IX FLCKX/A 170 whole lobes or of almost an entire Lung. Such Lungs are very heavy and may weigh 1,400 or 1,500 grains; bloody serous fluid exudes from the cut surface. The lesion resem- bles the red hepatization of lobar pneumonia, but confluent patches of pneumonia are usually well defined by lobule boundaries. The tissue is soft and the granulation of lobar pneumonia is absent. In many instances the lobular or con- fluent areas of consolidation are reddish gray; in some in- stances consolidated tissue is in places red and elsewhere gray, and in a smaller group of autopsies there is gray consolidation only (Fig. 6). Ked lobular consolidation is often seen in those who have died within the first four days following the onset of pneumonia, but is almost equally fre- quent after from five to ten days ; the average duration of pneumonia in these cases was 5.5 days. Combined red and gray consolidation was more frequently found when pneu- monia had lasted more than five days, the average duration of pneumonia being 7.3 days. The greater number of in- stances of gray consolidation were found after seven days of pneumonia, the average duration of the disease being 10.0 days. These figures are cited to show that lobular, like lobar, consolidation passes gradually from a stage of red to gray hepatization, but the change occurs more slowly and is often long delayed. Lobular pneumonia, which occurred 71 times among 80 cases classified as bronchopneumonia, may be regarded as an almost constant lesion of the disease. It is found not only in association with other lesions of bronchopneumo- nia, but with lobar pneumonia of influenza as well. The bacteriology of this lesion shows no deviation from that of the slightly larger group of bronchopneumonia (p. 163). All types of pneumococcus have been found in association with the lesion, Pneumococcus I in 2 instances, Pneumococcus II in 1 instance; atypical Pneumococcus II and Pneumococcus IV have been found much more fre- quently. Pneumococci have been found in more than a ISO PNEUMONIAS A.ND [NFECTIONS OF RESPIRATOR'S CRACT Fie 6— Acute bronchopneumonia with confluent gray lobular consolidation in lower part of upper lobe and hemorrhagic peribronchiolar pneumonia in lower lobe; purulent bronchitis. PATHOLOGY AND IJACTKUIOLOOY FOLLOWING I N VIA 'KXZA LSI third of these autopsies (42.9 per cenl in the lungs, 33.3 per cent in the blood) ; hemolytic streptococci in less than one- third (28.5 per cent in the lungs, 30.2 per cent in the blood). The following list shows the bacteriology of a small group of autopsies in which the sputum was examined after onset of pneumonia : SPUTUM BLOOD, LUNGS OR BRONCHI'S AT AUTOPSY Autopsy 233 Pneum. atyp. II Pneum. 237 S. hem. S. hem. 242 Pneum. atyp. II, B. inf. Pneum. atyp. II 250 Pneum. atyp. II, B. inf. Pneum. atyp. II 253 Pneum. atyp. II Pneum. atyp. II, staph., B. inf. 266 S. hem. S. hem., B. inf. 274 Pneum. IV S. hem. 291 Pneum. IV, B. inf. Staph., B. inf. 312 Pneum. IV, S hem., B. inf. S. hem., staph., B. inf. In one instance of streptococcus pneumonia (Autopsy 274) infection with streptococci occurred subsequent to the examination of the sputum made five days before death; pneumococcus was found in the washed sputum. With lobar pneumonia there was evidence that superim- posed infection occurred more frequently during the stage of red than of gray hepatization. With the lobular con- solidation of bronchopneumonia this relation has not been found. Among 27 instances of red lobular consolidation, hemolytic streptococcus has occurred 6 times, namely in 22.2 per cent ; among 26 instances of red and gray consol- idation, 8 times, namely, in 30.7 per cent; among 13 in- stances of gray consolidation, 5 times, namely, in 38.5 per cent. Infection with hemolytic streptococci is more fre- quent when the lesion has persisted to the stage of gray hepatization. This difference between lobar and broncho- pneumonia is probably dependent in part at least upon the more severe and persistent lesions of the bronchi with bronchopneumonia. The histology of consolidation which is definitely limited to secondary lobules or groups of lobules varies consider- ably. When death occurs in the early stage of the lesion, L82 PNEUMONIAS AXI» [INFECTION'S OF RESPIRATOR'S TRACT consolidated patches are deep red and somewhal edema- tous, so that bloody serous fluid escapes from the cut sur- face of the Lung and red blood corpuscles are present in the alveoli in greal abundance together with polynuclear leu- cocytes, fibrin and serum in varying quantity. It is not uncommon to find evidence thai the lesion lias had its or- igin in the bronchioles and extended Prom them to other parts of the lobule. Polynuclear leucocytes max- be rela- tively abundant within and immediately about the bronchi- oles and alveolar ducts, whereas the intervening alveoli and infundibula are filled with red blood corpuscles among which are polynuclear leucocytes and perhaps some fibrin. It may be evident that bronchiolar pneumonia with hemor- rhage into intervening alveoli is in process of transforma- tion into a more diffuse leucocytic pneumonia. Tor polynu- clear leucocytes are making their way from the alveolar wall into the blood-filled lumen and, as the result of the presence of blood, remain for a time close to the lining of the alveolus. When the consolidated lobules have assumed a gray or reddish gray color, jiolyiruclear leucocytes are more abun- dant and often almost homogeneously pack every alveolus within the boundaries of the lobule. In some instances there is fibrin partially obscured by the presence of leuco- cytes in great number. Although fibrin is less abundant with bronchopneumonia than with lobar pneumonia, nevertheless in a considerable proportion of instances it is a very conspicuous element of the inflammatory exudate within the bronchioles, alve- olar ducts and alveoli. It is unusual to find the alveolar ducts and alveoli uniformly plugged with fibrin containing leucocytes; there is a variegated distribution of exudate which has little resemblance to that of lobar pneumonia. Occasionally (Autopsies 242 and 247) polynuclear leuco- cytes (ill the bronchioles, alveolar ducts and infundibula, whereas the surrounding tributary alveoli contain fibrin PATHOLOGY A5TD BACTEIt 10 I, 00 Y FOLLOW I NO INFLUENZA L83 and polynuclear leucocytes in moderate number; red blood corpuscles may be present iir sufficient number to give a homogeneously red color to the lobular consolidation. In association with lobular pneumonia, fibrin within the lung tissue undergoes certain changes which outline very sharply the alveolar ducts and the other structures usually ill defined in preparations of the lung. A remarkable ap- pearance is produced by the deposit of hyalin fibrin upon the surface of the alveolar ducts and infundibula. This lesion has been described by LeCount. Within the alveolar tissue of the lung, spaces are seen lined by a layer of fibrin which stains homogeneously and very brightly with eosin. They are recognized as alveolar ducts b}^ the presence of scattered bundles of smooth muscle in their wall. The layer of hyaline fibrin overlying the surface of the alveolar duct usually forms a continuous lining and covers over the orifices of the alveoli which sur- round the alveolar duct, These ducts are rendered still more conspicuous by the character of their contents which exhibits a sharp contrast with that of the surrounding alveoli. The alveoli duct occasionally contains a bubble of air, but more frequently it is filled with serum in which red blood corpuscles are sometimes numerous. There is within the lumen scant fibrin and very few cells, among which poly- nuclear leucocytes are predominant. In the surrounding alveoli on the contrary leucocytes and fibrin are abundant. A similar change is found in the infundibula very clearly defined by their conical form, which is especially well out- lined below the pleura or in contact with interlobular septa. The infundibulum is outlined by hyaline fibrin which passes over the orifices of the tributary alveoli and separates the serous contents of the infundibulum from the cellular fibrin- ous contents of the alveoli about. The lesion which has been described is often associated with acute bronchitis and bronchiolitis, and the alveoli im- mediately about the respiratory bronchioles may be filled 1S4 PNEUMONIAS AXI> [NFECTIONS OF RESPIRATOR'S TRACT with polynuclear Leucocytes. It is very common to find Large bubbles of air sharply defined within the purulent contents of the bronchiole. In some Lobules the alve- olar ducts, infundibula and alveoli intervening between these foci of leucocytic pneumonia arc almost uniformly filled with fibrin and polynuclear leucocytes, but in other places the formation of complete Layers of hyaline fibrin is in process. Bubbles of air arc often seen within the al- veolar ducts, and about them is an irregular Layer of fibrin formed by the penetration of air into a channel previously filled with a loose network of fibrin containing serum in its meshes. The fibrin compressed against the walls of alve- olar duct and infundibulum remains as a compact Layer sep- arating these structures from the alveoli which project Prom their walls. The bubble of air is doubtless later ab- sorbed and replaced by serum, so that many alveolar ducts are filled with serum almost wholly free from cells, whereas alveoli outside the fibrinous membrane contain a network of fibrin with leucocytes in greater or less abundance. In association with this fibrinous pneumonia, which has been described, hyaline thrombosis of the capillaries is not uncommon. This hyalin material within the capillaries gives reactions of fibrin, and in sections stained by the Grram-Weigert method for demonstration of fibrin, these thrombosed vessels have the appearance of capillaries ir- regularly injected with a blue material. The interstitial tissue surrounding consolidated lobules is often edematous; the lymphatics are distended with serum and contain a moderate number of lymphocytes and polynuclear leucocytes. Among the lungs which have been studied histologically, pneumococcus has been almost invariably associated with the lobular lesions which have just been described, whether hemorrhagic, leucocytic or fibrinous; the histologic changes accompanying infection of the lung with streptococcus will be described Later. Pneumococcus has been cultivated from PATHOLOGY AND BACTERIOLOGY KOLLOVVINO INFLUENZA L85 h, d x Ol 4- 4- *- -3 ^5 '-O OJ H O Ol Ol t4- 4- 4-4- Tl O Gi GO Gi |4- Ol OS 4- to -} 1 CO - 1 4-10 2 Q r a t> * h w w W WWW CD 13 CD CB Ct P-. M pj p P- ^. a o Wg W Wg W CD ■ B, CD CD ^, CD Pj H pu Pj ■— ' Pj g B B WW o g EC S> O CfQ CfQ CfQ CfQ CfQ CfQ t" 1 O s ^ pi fo 53 P P 93 V) VI V! V] VI V| [M « t-< t 4 t- 1 B -1 CD B" 1 CD B" CD S f ^J J B ^ B ^ CD J MCjocdOcdB" 3 3» M> M- h-i- B O M * CT 1 C^ & o CD C ►j H 4 C^ H (^ 2 4_ o o fa cd p cd'V O H M CD O O V| O O O p CD o S ^ ^ CfQ ^ 2 ^ 3* pi B era qtq m". g P P M" w ^ 5 CO J ,2. 53 hJ. p „ CO CO co n co co co J ,2. p co E ^ O y O y CD B B ^ Pj pj pj 5 5 w 9 eum. a Pneum ^ M B T3 CD B p CD Wm P B M 2 CD p ? 3 P > S Ed ^3 ^ Cj - ES 3 - MM a M<] M ^ i— i M H M hj y O W ^g >-d Hd S " M B " CD CO CD CD W g W CD • t- 1 tr 1 d . atyp. eum. I . inf. aur. um. IV aur. P • P g H'g Ms ' 1— 1 - 1— 1 < < ' ^ M pre 3 •^ M M P= M d w w o i— i Ms g Pneum Pneum. S. aur. B B 5 w S 3 w 3 3 CD CD P B 3 3 o d - CO 02 CQ S CQ - o d 1— 1 M- 1^1"^ M M 2! E3 ^ U-J F'" F~ co M/ *• K « g w ' - w W td p" ' w w cq a rt- ' o P H . g" m- >-■• BC M,* M . g pr 1 1* ■.: Ms Ms -T 5 P 1 ~ V. L86 PNEUMONIAS AXli [NFECTIONS OF RESPIRATOR'S TRACT the consolidated Lung and is found in section of the lung. B. influenzae is Pound in cultures made from the bronchi. Table WWII I includes those instances in which the histology of the consolidated lung accords with the descrip- tion given above. Pneumococcus was found in all but 2 instances, and in one of these (Autopsy 336) the only culture was from the, heart's blood and in the other (Autopsy 498) cultures were unsatisfactory because proper media were not obtainable. Pneumococci of Types I, II, II atypical, III and IV are rep- resented in the list. B. influenzae has been found in a con- siderable number of instances in which cultures have been made from the lung and in every instance in which cultures have been made from the bronchi. Staphylococci are often found in the bronchi, but in most instances they do not penetrate into the lung. Another group of cases of lobular pneumonia are im- portant because in association with necrosis of lung tissue recognized by tlie microscope hemolytic streptococci have been found in the lungs. In such instances serum is abun- dant and polynuclear leucocytes are relatively scant though their distribution varies considerably; in some places leucocytes are fairly abundant though elsewhere al- most absent, but this distribution bears no obvious relation to the bronchioles. In some instances (Autopsies 274 and 487) red blood corpuscles are numerous but in others (Au- topsies 27o and 312) they are inconspicuous. The char- acteristic feature of the lesion is the occurrence of patches of necrosis within which the nuclei both of exudate and of alveolar walls have partially or completely disappeared. In these areas of necrosis short chains of streptococci are found in immense number whereas in living tissue they are present in moderate number. There has been a relatively inactive inflammatory reaction, great proliferation of streptococci and necrosis of invaded tissue. The bacte- riology of instances of lobular pneumonia with necrosis is shown' in Table WXFX, PATHOLOGY AND BACTIC1UOLOO V KOLLOWf MO IXI'U'KXZA L87 ^ d £ *. CO t3 ts H O ~3 1— » -1 -1 o • QO IS Ol fr- ^ o Xfi •*) 9 o £ W fcd W - S p, p. ° 2 CD 95 95 5 5 ? P^ oq cn? "~ 2 o 95 95 V) ^ O ' g 3 s „ tr 1 tr 1 Cr iT) CD ^ g ft) f3 f t^s C3 g in 3 cd M- ri- CD CD B £ So CD O > 2 (-5 CD 5 O O i-i CD CD >-. CD o a cro h". m".cto CD CD g 95 d h a H o hj m d t> t- 1 GO GO GO g GO W i^ CD na d - p) H H R CD CD p 02 (3 CD CD 5 P P i— i 2. ° § S GO GO o tr 1 GO CD CD GO K3 B ^- P t-> d ■ , , pJ t _ rJ d w CD « CD g H M w p 1 w o P P o g Ha Ha Ml pQ GO GO o ! 1 .. d a tr 1 CD CD GO B CO O H- H H- P CD r 3 ^ 2 ^ p ^ D2 ^ g pa 73 ^S v * o H tJ 1 td tr" td Ol W « d ^ P a 2 Ha Ha F o ! ss PNEUMONIAS AXh INFECTIONS OE RESPIRATOR'S TRACT Lobular pneumonia, in some of these instances al Least, has been caused primarily by pneumococci; necrosis lias been the result of secondary invasion by streptococci. In Autopsy -7o Pneumococcus IV lias been obtained from the blood, but in the presence of streptococci has presumably disappeared from the lung and bronchus. In the case rep- resented by Autopsy 274, Pneumococcus IV lias been found in the sputum live days before death at the onset of pneu- monia, but at this time no hemolytic streptococci have been Pound. In the case represented by Autopsy 312, Pneumo- coccus IV, B. influenzae and a Pew colonies of hemolytic streptococci have been obtained from the sputum two days after recognition of pneumonia and five days before death. The hemorrhagic and edematous consolidation of the early pulmonary lesions of influenzal pneumonia is their most distinctive feature. Red confluent lobular pneumonia is frequently found in those who have died within the first week following the onset of influenza. The lungs are vol- uminous and heavy and may weigh as much as 1,500 grams; the pleura which overlies the consolidated area is blue or plum colored and usually shows scant if any evidence of pleurisy. Scattered patches of consolidation are accu- rately limited to lobules, but in addition there are large areas often involving the greater part of the lobes and not infrequently situated in the lowermost part of the lower lobes. This confluent consolidation may be obviously lim- ited by lobule boundaries. The consolidated tissue is deep red and laxly consolidated; red serous fluid escapes from the cut surface. The lesion not infrequently occurs in as- sociation with hemorrhagic peribronchiolar pneumonia. The histology of this confluent lesion has been studied in Autopsies 242, 244, 303, 336, 464, 474 and 506. The his- tology varies, because, in some instances, leucocytes, in other instances, fibrin, is abundant, but the presence of red blood corpuscles in large number within the alveoli gives a red color to the consolidated tissue. In these cases pneu- PATHOLOGY AND BACTERIOLOGY FOLLOWING INI'U'KXZA L89 mococci, associated in the lungs or in the bronchi with I'». influenzae, have been the cause of pneumonia. In two au- topsies studied histologically (Autopsies 274 and 478) there was red lobular and confluent pneumonia and the blood and lungs contain hemolytic streptococci demonstrated by cul- tures; microscopic examination showed the presence of a widespread necrosis of the lung tissue. In the group of autopsies in Table XL tliere was red con- fluent lobular pneumonia. These autopsies are separated from those just cited because there was no histologic ex- amination of the tissue. Table XL NO. OP BACTERIOLOGY OP BACTERIOLOGY OF BACTERIOLOGY OP TOPSY HEART 'S BLOOD LUNGS BRONCHUS 289 Fneum. IV Pneum. IV Pneum. IV, B. inf., staph. 297 Pneum. IV, B. inf. Pneum. IV, B. inf., S. hem. (a few) 306 339 Fneum. IV 364 S. hem. 418 Pneum. atyp. II Pneum. atyp. II, B. inf., S. vir. 424 Pneum. IV. This group of autopsies confirms the view that the red confluent lobular pneumonia is caused by pneumococci in association with B. influenzae. Hemolytic streptococci may invade secondarily. In Autopsy 297 a few hemolytic strep- tococci were found in the bronchus but apparently had not entered the lungs. In the absence of histologic examina- tion it is not possible to determine if the invasion of hemo- lytic streptococcus (in Autopsy 364) has caused necrosis of the pneumonic tissue. Peribronchial Hemorrhage and Pneumonia In a considerable number of instances, namely, in 19 au- topsies, hemorrhage about the small bronchi has been rec- ognizable upon gross examination of the lung. A conspicu- ous zone of hemorrhage 2 or 3 mm. in thickness surrounds 190 PNEUMONIAS ANIi [NFECTIONS OF RESPIRATORS TRACT small (with qo cartilage) often dilated bronchi and on lon- gitudinal section may be tracted for a considerable distance along the bronchus I Fig. 7). In many additional instances peribronchial hemorrhage has been round by microscopic examination. In sonic instances the peribronchial zone of hemorrhage is firmer than the tissue elsewhere and it is occasionally difficult to determine whether the lesion is hemorrhage or pneumonia. In 7 instances Prank rod con- Fig. 7. — Bronchopneumonia with purulent bronchitis and peribronchial hemorrhage. solidation of peribronchial tissue was recognized at au- topsy; this lesion will be considered later under peribron- chial pneumonia. Hemorrhage about bronchi, like other evidences of severe injury to bronchi following influenza, is more frequently found in the lowermost parts of the lungs than elsewhere. It is invariably associated with severe bronchitis; the bronchi have contained purulent PATHOLOGY AND BACTERIOLOGY FOLLOWING I X I'M ' KXZA 11)1 fluid in 15 of L9 instances of peribronchial hemorrhage and in 10 instances the lesion has been associated with dilata- tion of the bronchi. Microscopic examination furnishes further evidence of the severity of the bronchial changes which have broughl about hemorrhage into the surrounding alveoli. The lumen of the bronchus contains blood and leucocytes; the epithe- lium is sometimes raised in places from the underlying basement membrane by blood; blood vessels of the bron- chial wall are engorged, and there is hemorrhage into the tissue of the bronchus. More frequently the bronchial epi- thelium is completely lost and the denuded surface is often covered by a layer of fibrin intimately adherent to the in- flamed mucosa. Transitions between simple hemorrhage and pneumonia are found, polynuclear leucocytes being mingled with red blood corpuscles. In several instances the alveoli in immediate contact with the bronchial wall have contained fibrin, whereas those in the surrounding- zone have contained blood. Bacteria found in the bronchi in 10 instances of peri- bronchial hemorrhage have been as follows; Staphylococci 1 B. influenzae, pneumococci 1 ' ' S. hemolyticus 2 pneumococci, staphylococci 1 S. hemolyticus, staphylococci 4 No organism found 1 The high incidence of B. influenzae and the frequent as- sociation of B. influenza? and hemolytic streptococci are noteworthy. The instance in which no organisms were found is probably due to a defect in media and should per- haps be excluded from the list. The percentage incidence of pneumococci, hemolytic streptococci, staphylococci and B. influenzae in the bronchus, lungs and blood of the heart is an index of the facility with which these microorganisms penetrate internal organs when the bronchi are the site of this hemorrhagic lesion. 192 PNEUMONIAS AND INFECTIONS OF RESPIRATOR'S TRACT Table \u X - O H _• 5 - _ y. Z PNEUMOCOCC1 HEMOLYTIC STREPTOCOCCI ST \l'll\ LO- COCCI B. IXKI.VKXZ.K W 5 Eh . s v. - X. > - E - - OS £ _ r - - w g ° ? X. - E-i W pa g > g . £ ° ? Z — ' E-< W w Pi o a Pd w - - E ° ? H W o E w ° £ p. Bronchus Lung Blood 10 L3 17 >> 4 1 120.0 30.8 23.5 6 7 9 60.0 53.8 52.9 6 3 (50.0 23.1 8 5 80.0 38.5 When these figures are compared with those for ;ill forms of bronchitis no very noteworthy differences are found ; the incidence of pneumococci here is less and that of hemo- lytic streptococci greater. In association with the severe changes present in the bronchi, hemolytic streptococci which enter the lungs almost invariably find their way into t he blood. Tn 6* instances there lias been frank pneumonic consolida- tion limited to a zone encircling small and medium-sized bronchi which have often been obviously dilated. On cross section these patches of pneumonia are circular, from 1 to 2 cm. in diameter and each contains a bronclius at its center. When the bronchus is cut longitudinally it is evident that pneumonic consolidation forms a cylindrical sheath about the tube. The consolidation varies in color from red to grayish red. In one instance (Autopsy 253) the consoli- dated tissue has formed a gray zone in contact with the bronchus and is red in a peripheral zone; microscopic ex- amination shows that the alveoli about the bronclius con- tain fibrin, whereas those at a greater distance contain red blood corpuscles. In this instance, the associated pneu- monia in another part of the lung has been somewhat anomalous and has had characters both of lobar and bron- ehopneun ia. for scattered in the left lung there have been patches of firm consolidation not more than 2 cm. across. The smaller of these patches are deep vrd, but the larger are coarsely granular and gray in the center. The patchy PATHOLOGY AND BACTERIOLOGY FOLLOWING I X FH 'K.\7 A 1!).'! character of the lesion has suggested bronchopneumonia, but the coarse granulation on section and the presence of fibrinous plugs within the small bronchi have presented a close resemblance to lobar pneumonia. This autopsy is one of the few instances in which Pneumococcus II has been found, Pneumococcus II being present in blood and lungs, B. influenzae, in lungs and bronchi. In 2 additional in stances (Autopsies 374 and 392) peribronchial pneumonia, recognizable at autopsy, has been associated with consoli- dation having the characters of lobar pneumonia. In one instance, Autopsy 374, the right lung has contained two patches of firm, mottled red and pinkish red coarsely gran- ular consolidation each about 6 cm. across, one situated in the upper lobe and the other in the lower lobe. Elsewhere in the lung, in definite relation to dilated bronchi, occur patches of firm, red, coarsely granular consolidation from 1 to 1.5 cm. in diameter when cut transversely. The bron- chus in the center has contained purulent fluid. In the op- posite lung similar consolidation has been limited to zones about dilated bronchi which contain purulent fluid. Pneu- mococcus IV has been obtained from the blood of the heart. The peribronchial pneumonia which has been described occurs in association with evidence of profound injury to the bronchial wall. In 5 of 6 instances purulent bronchitis has been found at autopsy; in half of these instances bron- chiectasis has been noted. The epithelium of the bronchus has been found separated from the underlying tissue by se- rous exudate, blood and leucocytes ; epithelial cells undergo necrosis and disappear, the denuded surface being covered by fibrin. Necrosis extends a varying depth into the wall of the bronchus ; blood vessels are engorged, and there is in some instances hemorrhage throughout the wall of the bronchus. The character of the exudate in the alveoli surrounding the bronchus differs considerably in different instances. In some instances (Autopsies 374 and 392) red blood cor- L94 PNEUMONIAS A\"D [NFECTIONS OF RESPIRATORY TRACT puscles are predominant in the alveoli in contacl with the bronchia] wall, whereas in a peripheral zone polynuclear leucocytes are more abundant. In other instances (Autop- sies 253 and 402) alveoli next the bronchial wall contain abundant fibrin and these are surrounded by a zone in which the alveoli are filled wil li blood. Peribronchial pneumonia is the result of the direct ex- tension of the inflammatory process through the wall of the bronchus; it occurs when the epithelium of the bronchus is destroyed and the underlying tissues are injured, but may be present in a wide encircling /one even when the lesion has not penetrated the bronchial wall. The dis- tribution of the pneumonia demonstrates very clearly that the inflammatory process does not reach the affected peri- bronchial alveoli by way of the bronchioles tributary to the bronchus. The bacteriology of these instances of peribronchial pneumonia is noteworthy. (Table XLTT.) Tabu: XLIT AUTOPSY BLOOD LTTNG BRONCHUS 253 Pneum. II Pneum. II, B. inf. Staph., B. inf. 374 Pneum. IV 387 Pneum. II, S. hem. Pneum. II, staph.. Pneum. II, S. horn., B. inf. staph., B. inf., 392 Pneum. II 402 Pneum. IV, S. hem. 424 ? Pneum. IV Pneumococcus has been found in every instance either in the lungs or blood. Pneumococcus IT, which has been un- common with the pneumonia following influenza at Camp Pike and has occurred only ten times in more than 200 autopsies, has been present in one-half of these cases. The constant association of the lesion with pneumococcus is particularly significant when a comparison is made between the incidence of pneumococcus with peribronchial hemor- rhage, on the one hand, and'peribronchial pneumonia on the other; pneumococcus has been present in less than a third PATHOLOGY AND BACTERIOLOGY FOLLOWING I X PL! 'KXZA 195 of the instances of hemorrhage but in all instances of pneu- monia. In addition to the instances in which gross peribronchial consolidation has been noted at autopsy, microscopic ex- amination has demonstrated the presence of fibrinous pneu- monia surrounding- bronchi in a considerable number of autopsies. In a zone encircling- small bronchi (with no cartilage) alveoli are rilled by plugs of dense fibrin ( Pig. 20) containing in variable number polynuclear leucocytes and mononuclear cells. The width of the zone is often equal or greater than the diameter of the bronchus. Alve- oli outside the zone of fibrinous inflammation may contain red blood corpuscles or serum, and desquamated epithelial cells are often abundant. Of 21 instances of peribronchial fibrinous pneumonia 20 were associated with purulent bronchitis. Further evi- dence of the relation of the lesion to profound injury to the bronchi is its association with bronchiectasis in 17 in- stances. Peribronchial fibrinous pneumonia, like other lesions en- circling the small bronchi, bears a direct relation to the severity of microscopic changes in the bronchus. The epi- thelium of the bronchus is either partially or completely lost. Occasionally epithelium is raised by hemorrhage or leucocytes from the underlying tissue but more frequently it is wholly lost and the surface is covered by a layer of fibrin. In the early stages of the lesion, polynuclear leuco- cytes may be numerous throughout the bronchial wall, in- dicating that the inflammatory irritant within the lumen is affecting the entire wall and extending its influence to the surrounding pulmonary tissue. Later lymphoid and plas- ma cells are more abundant than polynuclear leucocytes. Coagulative necrosis and disintegration of the bronchial wall, proceeding from the inner surface outward, may ex- tend more or less deeply, and fibrinous inflammation of adjacent alveoli is often more extensive about that segment l!)li PNEUMONIAS AND INFECTIONS OF RESPIRATORS TRACT of ilif bronchus which shows the greatesl change. In some instances segments of the bronchial wall or even the entire wall has disappeared, so thai alveoli containing fibrin form part of the wall of the cavity thus formed. When bron- chiectasis lias occurred, there arc often fissures from the lumen through the entire wall extending into the surround- ing lung tissue: hen* fibrinous pneumonia is particularly conspicuous, occurring in a zone about the edges of the defect. This deposition of fibrin within the alveoli adja- cent to the injury doubtless has a pari in limiting the dis- tribution of bacterial infection. Nevertheless breaks in the continuity of the bronchial wall are no1 essential to the production of the lesion and the irritant, which is respon- sible for the lesion, may penetrate through the bronchial wall to surrounding alveoli and from alveoli to other al- veoli immediately adjacent. Willi this peribronchial pneumonia the smallest bronchi are distended with pus and their walls are infiltrated with polynuclear leucocytes, lymphoid and plasma cells. In a broad zone encircling the bronchus the alveoli are tilled with plugs of fibrin. Bronchioles are similarly distended with polynuclear leucocytes; the alveoli which occur upon the wall of the bronchiole are often limited to one side of lie wall and are filled with fibrin. This fibrin occasionally projects into the lumen of the bronchiole and forms a con- tinuous layer in contact with the wall on the same side. The alveolar duet and inl'undibulum are distended with polynuclear leucocytes. The alveoli upon the wall of the alveolar duct and upon the proximal part of the infundib- uluni are filled with fibrin. The bronchus, bronchiole, alveolar duct and part of the infundibulum are thus sur- rounded by a continuous /-one of alveoli containing fibrin. The alveoli about the distal part of the infundibulum may be filled with polynuclear leucocytes. Lung tissue between adjacent zones of fibrinous pneumonia may contain serum and desquamated epithelial cells. PATHOLOGY AND BACTERIOLOGY FOLLOWING [INFLUENZA IDT Organization of peribronchial fibrin was found in LO of the 22 autopsies in which peribronchial fibrinous pneu- monia had been found. Fibroblasts have invaded the fibrin and newly formed capillaries have p.enetrated into it. In some instances the iiiteralveolar septa are thickened and infiltrated with lymphoid and plasma cells, and in 7 in- stances there was chronic pneumonia with thickening and mononuclear infiltration of the interstitial tissue about the bronchi and blood vessels, and elsewhere. The duration of the fatal illness in 12 instances with no organization was usualty from ten days to two weeks, though in 3 instances there was no organization although the respiratory disease had lasted from seventeen to nineteen days (average dura- tion with no organization, 13.5 days). The duration of illness in 10 instances with organization of fibrin was slightly less than three weeks (average 18.9 days). These figures do not accurately represent the duration of pneu- monia which usually develops after a period of several days following onset of influenza. This group of instances of peribronchial fibrinous pneu- monia has offered an opportunity to study the bacteriology of pneumonia with organization and to determine if it pre- sents any unusual characters. The bacteriology of autop- sies with peribronchial fibrinous pneumonia with no or- ganization is shown in Table XLIII: Table XLIII AUTOPSY BLOOD LUNG BRONCHI'S 289 372 376 Pneum. IV Pneum. IV Pneum.' IV, B. inf., staph. S. hem. S>. hem. S. hem., B. inf., S. aur. 409 410 S. hem., B. inf. S. aur. 412 Pneum. II Pneum. II, B. inf. 420 S. hem. S. hem., B. inf. S. aur. 423 S. hem. 8. hem., B. inf. 440 B. inf., S. aur. B. inf., S. aur. 448 482 B. inf., Pneum. IV B. inf.. Pneum. IV, S. hem. 489 Pneum. IA T , B. inf. Pneum. IV, B. inf. 198 PNEUMONIAS AXIi INFECTIONS OF RESPIRATORS TRACT The bacteriology of instances of peribronchial fibrinous pneumonia with organization of the Lntraalveolar fibrin is shown in Table XL1 V : Table XLIV AUTOPSY BLOOD LUNG BRONCHUS 283 Pneum. 1 V Staph., B. inf. R. inf., Pneum. IV, st; iph 291 1'.. inf., staph. ig •IIP Pneum. [I, B. inf. Pneum. 1 1, B. inf. IL'1 S. hem. Pneum. IV, S. hem. 422 Pneum. Tl atyp., B. inf. +25 S. hem. s. hem., B. inf., S. alb. 433 s. hem., B. inf., S. aur. 460 S. hem. S. hem., B. inf. s. hem., B. inf., staph. 463 B. inf., staph. !'.. inf., staph., Pneum. rv B. influenzae lias been presenl in the bronchi in every in- stance save one in which cultures have been made, and it is probable thai in this exceptional instance cultures have remained sterile because the media employed have been de- fective'. The incidence of B. influenza' in the lung has been unusually high both with and without organization (66.7 per cent with no organization; 77.8 per cent with organ- ization). Streptococci and staphylococci have been found in a considerable proportion of all instances of peribron- chial fibrinous pneumonia, but there has been no notable preponderance of these microorganisms when organiza- tion has occurred. Organization has been present in in- stances in which pneumonia is referable to pneumococcus associated with B. influenzae and unaccompanied by either streptococci or staphylococci (Autopsies 419 and 422). Wadsworth 1 found no organization after inoculation of the lungs of dogs with pneumococcus or with staphylococcus alone, but produced organization when he inoculated an- imals with both microorganisms. Injury to bronchi produced in part at least by B. in- fluenzae exposes the bronchi and lung tissue to repeated infection with a variety of microorganisms; absorption of 'Wadsworth, A. B.: A Study of Organizating Pneumonia. Jour. Med. Research, 1918, xxxix, 147. PATHOLOGY AND BACTERIOLOGY FOLLOWING [NFLUENZA 190 fibrin an Xs OTT RESPIRATOR'S TRACT abscess cavity was separated from the pl< ural cavity by remains i t' the pleura which was as thin as 1 issue paper and in other instances perforation had occurred (Fig. 9). En Autopsy 480 the abscess cavity which had perforated the pleura was in five communication with a bronchus of me- dium size. In most instances of suppurative pneumonia there have been associated lesions of bronchopneumonia which have been peribronchiolar, hemorrhagic or lobular and have cx- hibited no unusual characters. The abscess or abscesses are situated within an area of pneumonic consolidation which is not limited by lobule boundaries and has no1 the characters of bronchopneumonic consolidation. In some instances this consolidation is limited to a '/cue immediately about the abscess, but often it involves the greater part of a lobe. The tissue is laxly consolidated and flabby; on sec- tion it has a dull, conspicuously cloudy appearance and is grayish red, pinkish gray or gray; it is homogeneous or very finely granular. Turbid gray fluid, which sometimes resembles thin pus, oozes from the cut surface 1 . Widespread necrosis of tissue is not infrequently a con- spicuous feature of this pyogenic pneumonia (Fig. 8). Upon a cloudy gray background of consolidation are nu- merous opaque yellowish gray or yellow patches, occasion- ally 2 or 3 cm. across, giving a mottled character to the cut surface. Upon the pleura these necrotic patches ap- pear as dull opaque yellow spots. They may be sur- rounded by a zone of hemorrhage. The opaque material is a1 first firm but may undergo softening, becoming semi- solid and finally purulent. Necrotic patches may be scat- tered throughout a lobe, but fully formed abscesses are with few exceptions immediately below the pleura (Fig. 9). The duration of illness in cases of pneumonia with ab- scess varied from a week- or less (11 instances) to more than four weeks. The duration of the greater number of cases (17 instances) was between one and two weeks. In PATHOLOGY AND BACTERIOLOGY FOLLOWING [NFLTJENZA 201 Fig. 8. — Streptococcus pneumonia with massive necrosis. Autopsy 354. 202 PNEUMONIAS AXD INFECTIONS OF RESPIRATOR'S TRACT Fig. 9. — Abscess below pleura with perforation caused by hemolytic streptococci. Heal- ing suppurative interstitial pneumonia indicated by yellowish gray lines marking inter- lobular septa at base of lower lobe. Autopsy 474; right lung. (See left lung, Fig. 10.) PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 203 one instance onset occurred with symptoms of influenza, pneumonia was recognized two days later, and death oc- curred only four days after the onset of illness. When the duration of the illness was less than a week the symptoms of onset were in some instances those of pneumonia. Table XLV shows the incidence of pneumococcus, S. hem- olyticus, staphylococcus and B. influenzae in instances of suppurative pneumonia with abscess formation, 4 instances of abscess with interstitial suppurative pneumonia being excluded : Table XLV O Eh PNEUMOCOCCI HEMOLYTIC STREPTOCOCCI STAPHYLO- COCCI B. INFLUENZAE H Eh O o £ Ph Z > O H P3 W W O Ph Ph > 9 ° g Ph £ > U Eh P3 M W O Ph Ph > O o % Ph to oi 1 PER CENT bs b POSITIVE > Eh s ° £ Ph PER CENT POSITIVE Bronchus Lung Blood 24 36 37 5 9 6 20.8 25.0 16.2 22 30 31 91.6 83.3 83.8 12 14 18 8 75.0 22.2 In over 80 per cent of instances of pulmonary abscess hemolytic streptococcus has been found in blood, lungs and bronchus and, when cultures have been made, in the in- flamed pleural cavity as well. Streptococci have been found in immense number in sections from the necrotic lung tissue and the abscesses which have been formed. It is evident that hemolytic streptococci have caused suppura- tive pneumonia and death, being found in the blood of the heart just as frequently as in the lungs (83 per cent). The relative unimportance of pneumococci is indicated by their low incidence in the blood (16.2 per cent) when compared with that of lobar pneumonia (65.5 per cent) or of broncho- pneumonia (31.4 per cent). B. influenza^ has been found in three-fourths of these autopsies in the bronchus, but its incidence in the lungs has been much smaller. In 3 instances of suppurative pneumonia with abscess formation no hemolytic streptococci were found ; they are as follows: 204 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT Autopsy 380. — Bronchopneumonia with gray and red Lobular consolida- tion in right npper and lower lobes; peribronchiolar nodules of consoli* dation in left lower lobe; abscesSj 1.5 cm. across, below the pleura of the posterior border of the lefl lower lobe near its base; fibrinopurulenl pleu- risy ".i 1 " c.c.) on right side; serous pleurisy (200 c.c.) on left. Pneumo- coccus HI was found in cultures from the blood of the heart from the righl lung and with B. influenzae from the righl pleural cavity. No culture was made from the left lung which contained the abscess, [n sections of the abscess gram positive streptococci in chains of I to 8 cocci were numerous. Autopsy 406. — Acute lobar pneumonia with red hepatization of greater part of right lung; patch of consolidation in lower lube of left lung con- taining an abscess cavity 2.5 x L.5 cm.; localized seropurulent pleurisy i .".7.1 <■.<■.< on left side. Pneumococcus 1 V was obtained from the blood of the heart; a culture from the lung was contaminated. Tissue from the abscess was no1 saved for histologic examination. Autopsy 416. — Suppurative pneumonia with necrosis and abscess forma- tion in right lower lobe; fibrinous pleurisy on right side. Pneumococcus IV was obtained from the blood, right lung and right main bronchus. No streptococci were found in sections from the abscess in the right lung. The foregoing observations demonstrate that suppura- tive pneumonia with abscess formation following influenza is with few exceptions caused by S. hemolyticus. The autopsies (Table XLVI) in which pneumococci have been round in association with hemolytic streptococci in the blood or lungs indicate that pneumococci have had a pari in the production of fatal pneumonia. Table XLVI AUTOPSY CULTURE FROM BLOOD CULTURE FROM LUNGS CULTURE FROM BROXCHUS 258 s. hem. S. hem., Pneum. IV B. inf. 282 s. hem., Pneum. II S. hem., Pneum. II s. hem., B. inf. Pneum. II, staph. 345 S. hem., Pneum, IT. staph. 378 Pneum. atyp. II s. hem., Pneum. a1 vp S. hem., B. inf., II Pneum. atyp. II 381 s. hem. S. horn., Pneum. TT Pneum. IV, staph. 383 Pneum. Ill S. hem.. Pneum. TIT B. inf. 387 s. hem. Pneum. IT, staph., s. hem., pneum., B. inf. staph., B. inf. These autopsies, notably those in which pneumococci have been found in the blood, suggest that infection with PATHOLOGY AND BACTERIOLOGY FOLLOWING I X I'M I KXZA 205 pneumococci has preceded suppurative pneumonia caused by hemolytic streptococci. In a small number of instances the sputum was examined in life after onsel of pneumonia. Table XLVII AUTOPSY SPUTUM CULTURES FROM BLOOD, LUNGS AND BRONCHI'S 282 288 376 Pne am. IV. B. inf. S. hem., B'. inf. (No S. hem., Oct. 8) S. hem., Pneum. II, staph., B. inf. S. hem., B. inf. 8. hem., staph., B. inf. (Oct. 11) In 2 of these 3 cases infection with hemolytic streptococ- cus occurred subsequent to the onset of pneumonia. Several observations help to explain the occurrence of abscess in association with the pneumonia of influenza. The fissures which will be described in association with bronchiectasis represent traumatic ruptures of the bron- chial wall consequent upon weakening by necrosis and over distention. They expose the injured bronchial wall and the alveolar tissue adjacent to it to infection by the micro- organisms contained within the lumen of the inflamed bronchus. Occasionally a favorable microscopic section demonstrates the relation of pulmonary necrosis and con- sequent suppuration to injuries of the bronchial wall. Peribronchial fibrinous pneumonia occurs about the bron- chi of which the epithelial lining has been destroyed, and when a fissure penetrates the bronchial wall fibrinous pneu- monia is almost invariably found in a zone about the tear ; it doubtless tends to limit the extension of the process. Occasionally, wide areas of necrosis occur within consoli- dated tissue near the site of the fissure (Autopsy 312 with S. hemolyticus and B. influenzae, p. 254). Accumulation of polynuclear leucocytes between living and dead tissue may form a line of demarcation (Autopsy 387) ; finally, fairly large' irregularly formed, abscess cavities are found. Necrosis and beginning suppuration in contact with the lumen of the bronchus will be described in association with bronchiectasis (Autopsies 312, Fig. 24, and 423, p. 256). In 206 PNEUMONIAS AX!> [NFECTIONS OF RESPIRATOR'S TRACT the following autopsies upon individuals who have f small bronchi. They help to explain the pathogenesis of abscess in association with influenza. Autopsy 376. — 11. M., white aged twenty four, a fireman, residenl of Oklahoma, had been in military service one month. Onset of illness oc- curred October 1, ten days before his death; he was admitted to the base hospital on the fourth day of his illness with the diagnosis of broncho- pneumonia. Anatomic Diagnosis.- -Acute bronchopneumonia with patches of lobular nml confluent lobular consolidation in both Lungs and hemorrhagic peri- bronchiolar consolidation in right upper lobe; abscess in right upper lobe below pleura; librinopurulent pleurisy on right side; purulent bronchitis; bronchiectasis at base of left lobe. An irregular abscess. 2x1 cm., filled with creamy purulent fluid is separated from the interlobular surface of the right upper lobe by a thin membrane representing the pleura. The right pleural cavity contains 200 c.c. of turbid vellow fluid in which is soft fibrin. The bronchi contain purulent fluid in great abundance. The bronchi at the base of the lel'i lower lobe are widely dilated, so that many small bronchi with no car- tilage in their wall measure from 3 to 5 mm. in diameter. Cultures show the presence of hemolytic streptococci in the blood of the heart and in three plates from the lung; B. influenzae and S. aureus were found in the left bronchus. The bronchi have wholly or partially lost their epithelium and there is deep erosion of the walls. Cavities containing polynuelear leucocytes occur within the alveolar tissue; in some instances pus containing cav- ities are surrounded by alveolar tissue, but in other places it is evident that they have had their origin in bronchi. In a short segment of the circumference the wall of the preexisting bronchus is preserved and consists of squamous epithelium, vascular connective tissue and smooth muscle. The remainder of the bronchus has disappeared and a cavity is produced. The very irregular wall of the cavity is formed by partially destroyed alveoli filled with fibrin and leucocytes. Autopsy 387. — C. M., white, aged twenty one, laborer, resident of Miss- issippi, had been in military service twenty-one days. Illness began on >' | >f ember 22, nineteen days before death, ami the patient was admitted to the hospital on the same day with a diagnosis of bronchitis; a diagnosis of bronchopneumonia was made on October 2, nine days before death. The leucocytes on October 3 numbered 8000 (small mononuclear, 36 per cent; large mononuclear, 5 per cent ; polynuelear, 59 per cent). PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 207 Anatomic Diagnosis.— Acute bronchopneumonia with consolidation in right upper Lobe and hemorrhagic peribronchiolar consolidation in lefl lower lobe; abscess below pleura in left lower lobe; purulent pleurisy on both sides; edema of mediastinum; purulent bronchitis; bronchiectasis. There is advanced bronchiectasis, and bronchi with no visible cartilage are dilated to from 4 to 8 nun. in diameter; they contain purulent fluid which wells up from the cut surface. About dilated bronchi there is in places dull red or grayish red consolidation forming an encircling zone. Situated below the pleural surface within an area of consolidation at tin- posterior border of the left lower lobe there is a spot 3 em. across where the tissue is yellow and has in places undergone purulent softening. Sev- eral smaller abscesses occur nearby. Cultures from the blood of the heart and from the edematous medias- tinum contain hemolytic streptococci. From the abscess are grown S. albus, Pneumococcus II and B. influenzas. The purulent contents of a small bronchus contains S. hcmolyticus, B. influenzas, S. aurens and a few pneumo- cocci. Microscopic examination shows that the epithelium of dilated bronchi has disappeared and the denuded surface is covered by fibrin and polynuclear leucocytes; fissures extend from the lumen through the bronchial wall into the surrounding alveolar tissue. A zone of fibrinous pneumonia surrounds these bronchi and fissures in the bronchial wall penetrate into this zone. One dilated bronchus 2.-I mm. in diameter with no cartilage in its wall has vascular connective tissue covered by epithelium on one side, whereas the remainder of the circumference is formed by exposed alveoli filled with fibrin, the bronchial wall having disappeared. A section through a part of the abscess which has been mentioned shows a very irregularly formed cavity approximately 1 x 0.7 cm. Remains of bronchial wall, consisting" of very vascular tissue covered hy flat epithelium in several layers, indicate the origin of the cavity. Between these remnants of bronchi deep pockets extend into the pulmonary tissue which in the margin of the cavity is the site of fibrinous pneumonia. In one place, in contact with the cavity, a wide area of consolidated tissue has undergone necrosis and both alveolar walls and their contents have lost their nuclei. Leucocytes which are accumulating at the margin of the necrotic patch form a line of demarca- tion between living and dead tissue. Abscess may be the result of the profound changes which occur in the bronchi as the result of influenza. Necrosis caused by bacteria within the bronchi weakens and in places destroys the wall. Bacteria penetrate into the sur- rounding tissue and hemolytic streptococci (or staphylo- cocci) may produce localized abscesses. These abscess- are usually situated near the pleural surface of the lung, be- cause destructive changes causing rupture of the bronchial 208 PNEUMONIAS AM* INFECTIONS OF RESPIRATORY TRACT wall occur more frequently in the smaller peripheral bron- chi than in the larger bronchi containing cartilage. Al>- - ;esses occur more frequently at the liases of the lungs, because the mosl severe changes in the bronchi occur in the dependent part. (See "Bronchiectasis," p. 240.) Healing - of Abscess. — The following autopsy is of interest in relation to the treatment of pulmonary abscess and as- sociated empyema. Autopsy 467. — P. ('.. white, aged twenty-five, a farmer from Missouri, had been in military service three months. Illness began September 27, thirty days before death, and the patient was admitted the day following onsel with headache, backache and cough. Pneumonia with consolidation in the right lower lobe was recognized on the sixth day of illness. On the ninth day 500 c.c. of fluid were withdrawn from the righl pleural cavity; there were cyanosis and dyspnea. On the eleventh day 700 c.c. of fluid were withdrawn. On the twelfth day thoracotomy was performed and 100 c.c. of greenish fluid were removed. The patienl V condition improved for a time, but on the twenty-sixth day 1,000 c.c. of straw colored fluid were aspirated from the left pleural cavity and on the twenty-eighth day the same amount of seropurulent fluid was withdrawn. Anatomic Diagnosis. — Healing abscess of righl lower lobe communicating with the pleural cavity; acute purulent pleurisy with closed thoracotomy wound cm the right side; purulenl pleurisy cm tie' left side; acute broncho- pneumonia with lobular consolidation in the left lung; purulent bronchitis; bronchiectasis with formation of spherical bronchiectatic cavities; acute splenic tumor. A i tin' base of the right ehesl is a (dosed thoracotomy wound 2 cm. in length; the rigid pleural cavity contains 200 c.c. of thick creamy pus and the cavity is lined by a thick tough membrane. The left pleural cav- ity contains son e.C. of white purulent fluid thinner than that on the right side. The right lung is compressed into the posterior and inner part of the chest. The upper lobe is pink and air containing: the posterior and lower part of the lower lobe is red and atelectatic, and fibrous septa are more conspicuous than elsewhere. The pleura of the external surface near the basal edge, in an area - cm. across, is depressed and yellowish gray in color. In the center of this area is a small opening communicating with a pocket 0.5 cm. across within the substance of the lung. In the lower lobe beneath the interlobular surface are two spherical bronchiectatic cavities, each about 1.5 cm. across, with smooth lining in continuity with two branches of the same bronchus of medium size. Bacteriologic examination showed the presence id' S. hemolyticus in the blood of the heart. No growth was obtai 1 from the left lung; the hit pleural cavity contained hemolytic streptococci and S. aureus, the laltcr in PATHOLOGY AND BACTEBIOLOGY FOLLOWING I X I'M lOX/A 201) small number. S. hemolyticus and B. influenzas were grown from the Lefl main bronchus. A microscopic section through the abscess and its communication with the pleura shows that its cavity contains polynuelear leucocytes and the wall is formed by granulation tissue covered by fibrin. Some alveoli out- side the abscess contain compact balls of fibrin containing a few fibroblai I : this fibrin stains deeply with hematoxylin as if it contained calcium. The surface of the lung is covered by fibrin in process of organization. In the foregoing instance a pulmonary abscess on the right side lias ruptured into the pleura and, completely separated from the adjacent lung by a wall of newly formed tissue, is in process of healing. It shows that these pul- monary abscesses below the pleura may heal provided drainage is established by rupture into the pleural cavity and subsequent evacuation of pleural exudate. It is note- worthy that in this instance empyema extended from the right to the left pleural cavity, both S. hemolyticus and S. aureus were found at autopsy. The thoracotomy wound on the right side was closed at autopsy. Interstitial Suppurative Pneumonia A second type of suppurative pneumonia is characterized by acute inflammation of interstitial tissue between the sec- ondary lobules of the lung and by acute lymphangitis ; sup- puration involves the interstitial septa and the walls of the lymphatics. The lesion is designated by Kaufmann, 1 Beitzke 2 and others acute interstitial pneumonia. Pneu- monia dissecans in which solution of interstitial tissue iso- lates sections of lung tissue is said to be a consequence of the lesion. Many text books of pathology, overlooking the occurrence of this lesion, limit the consideration of in- terstitial pneumonia to chronic processes in which the in- terlobular and interalveolar fibrous tissue is increased. Acute inflammation and edema of the interlobular septa of the lung with no suppuration is often found with both lobar and bronchopneumonia and is occasionally so far ad- 1 Kaufmann: Snezielle PaHiologisclie Anatomic 1909, ed. 5. p. 260. 2 Beitzke: Respirations Organe. Aschoff's Path. Anat., 1913 ed. 3, Vol. II, p. SOS. I'll) PNEUMONIAS AND [NFECTTONS OF RESPIRATOR'S TRACT vanced that it can be recognized on gross examination of the lungs. In a small area interlobular septa are conspicu- ous as yellowish lines of edematous appearance which may be 1 to 1.5 mm. in thickness and sometimes form a network with rectangular or polygonal meshes. The gelatinous ap- pearance of the edematous fibrous tissue does no1 suggest suppuration. Microscopic examination shows that the tissue is distended by edema and contains fibrin and poly- nuclear leucocytes; the lymphatics are distended and con- tain a network of fibrin within which leucocytes are nu- merous. Inflammatory edema of the interstitial tissue has been recognized at autopsy four times in association with bronchopneumonia (Autopsy 253 with Pneumococcus II; Autopsy 335, with Pneumococcus TV and S. viridans; Au- topsy 477 with S. hemolyticus and Autopsy 498 with S. viridans); twice with lobar pneumonia (Autopsy 343 with Pneumococcus IV and Autopsy 353 with atypical Pneu- mococcus II) ; twice with combined lobar and broncopneu- monia (Autopsy 273 with S. hemolyticus and Pneumococcus IV and Autopsy 357 with Pneumococcus IV). Edema of interstitial septa was recognized at autopsy in the imme- diate neighborhood of an abscess three times (Autopsies 277 and 27S with hemolytic streptococci and Autopsy 282 with hemolytic streptococci and Pneumococcus II). In these instances of inflammation and edema the lymphatics are found distended by fibrinous thrombi, and it is probable that occlusion of lymphatics determines the occurrence of inflammatory edema within the surrounding tissue. In- flammation has not proceeded to suppuration. AVith interstitial suppurative pneumonia, interlobular connective tissue is marked by conspicuous yellow lines, 1 to 3 or even 5 mm. in thickness, forming a network with polygonal meshes which represent secondary lobules (Figs. 10 and 11). The distended septa not infrequently have bead-like enlargements at intervals and Prom the cut sur- face it is often possible to scrape away creamy yellow pus. PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 211 l^s^^ssss^essis asrs-a- s**-^ 212 PNEUMONIAS AND [NFECTIONS OF RESPIRATOR'S TRACT Fig 11.— Suppurative int.rsii.ial pneumonia; the left lower lobe is the site of almost uniform consolidation and here interstitial septa and their lymphatics arc distended with pus | is more extensive interstitial suppuration in the upper lobe where consoi- t. The cloudy appearance of the consolidated lung is well shown. Au topsy 452. PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 213 These linos of suppuration invariably extend up to the pleura and are often broadest immediately below it. Adja- cent septa which have not undergone suppuration are much thickened and have the yellowish gray appearance produced by edema. Suppurative interstitial pneumonia frequently occurs in association with bronchopneumonia consolidation which may be peribronchiolar, hemorrhagic or lobular, but there is in addition consolidation of the pulmonary tissue between the inflamed septa which may affect part of a lobe, an en- tire lobe, or parts of several lobes; it does not exhibit the characters of confluent lobular pneumonia. In approximately half of the cases consolidation, asso- ciated with interstitial suppuration, has been lobar in dis- tribution (Fig. 11). The tissue is laxly consolidated, finely granular, and has a cloudy red or gray appearance. The coarsely granular surface of lobar pneumonia is absent. The affected lung may weigh 1,500 or 1,650 grams. Oc- casionally, interstitial septa of air containing lung tissue is the site of suppurative inflammation or edema. In Autopsy 452 the lower lobe, save a small part at the base, is laxly consolidated; interstitial septa in the consolidated area are yellow, 1.5 to 2 mm. in thickness, beaded and ex- ude purulent fluid on pressure. In the adjacent part of the upper lobe there is a patch of consolidation, and a net- work of yellow thickened septa extends from it far into the surrounding air containing tissue. The weight of the right lung is 635 grams; of the left, 1,650 grams. The distribution of interstitial suppuration in 21 in- stances, including 4 in which the lesion has occurred in the same lungs with abscess formation, has been as follows : right upper lobe, 9 instances ; middle lobe, 4 ; lower lobe. 5 : left upper lobe, 7 ; left lower lobe, 6. In 6 of these autop- sies more than one lobe of the same lung has been affected by the lesion ; in 2 autopsies parts of both lungs have been affected. Localized abscess of the lung is more common in 214 PNEUMONIAS ANI> [NFECTIONS OF RESPIRATOR! TRACT the lower than in the upper lobes, bul suppuration of the interstitial tissue is more often found in the upper lobes. The duration of illness with interstitial suppurative pneumonia lias varied from six days to five weeks. In over half of the cases death has occurred during the second week of illness. The bacteriology of these cases is shown in Table XLYIM. Tabli XLVIII w m ft u O Eh v. u PNEUMOCOCCl HEMOLYTIC STREPTOCCX | | STAPHYLO- COCCI B. IXI'I.IKXZ.K ■r. o ? v. - Eh H g & - o Eh . K o ? Is - z E - a £ Eh . X o ? X - Eh K o s « 'k w ? Eh v. 3 = x - .- - v. > - - Bronchus 10 9 90.0 5 50.0 10 100.0 Lung 20 1 5.0 17 85.0 5 25.0 7 35.0 Blood 21 >) 9.5 17 81.0 S. hemolyticus lias been almost invariably present in lungs, heart's blood and bronchi. In 16 of 21 autopsies hemolytic streptococci have been obtained from the blood in pure cultures, in one instance associated with pneumo- coccus. With associated empyema, pericarditis or peri- tonitis, the same microorganism lias been found in the pleural cavities, pericardium or peritoneum. Further- more, microscopic examination lias demonstrated the pres- ence of chains of streptococci in the affected interlobular tissue and in much greater abundance in the distended lymphatics. Nevertheless in 2 instances no streptococci have been found. These cases are as follows: Autopsy 330. — Illness began with symptoms of influenza ten days before death; signs of pneumonia were recognized three days before death. There is firm, gray red consolidation of the entire left upper lobe; the interlobular septa are here indicated by yellow lines of obvious suppuration and thick pus- like fluid exudes from the cut surface of the consolidated tissue. The upper half of the lefl lower lobe has undergone gray hepatization, bul here there i- no distention of the interlobular septa. There is fibrinopurulent pleurisy on the left side with accumulation of 400 c.c. of fluid. Pneumocoecus IV is PATHOLOGY AND BACTERIOLOGY FOLLOWING I X I'M ' KXXA 215 obtained from the blood of the heart and from the Lung. In the suppurating tissue diplococci which stain by Gram's method are present in Large number; there are a few short chains. Autopsy 379. — Illness began seven days before death with influenza; signs of pneumonia were first recognized the day before death. The middle lobe of the right lung is firmly consolidated; on section there is mottling of deep red and pinkish red and the cut surface is coarsely granular. The inter- stitial septa are distended by fluid and are grayish yellow. There is fibrino- purulent pleurisy on the right side with .accumulation of 600 C.C of fluid. Pneumocoecus atypical II is obtained from the blood of the heart. A large bacillus unstained by Gram's method is obtained from the right lung and from the right main bronchus. In the bronchus are a few influenza bacilli. In the suppurating and necrotic tissue of the interstitial septa are found diplococci and chains of i to 6 cocci in great number; a few large Gram-negative bacilli are found. In both these autopsies consolidation had the characters of lobar pneumonia, and pneumococci were obtained from the blood of the heart. It is possible that streptococci failed to grow or while present elsewhere were absent at the spot- where cultures were made. It is noteworthy that B. influenzae was found in the bron- chi in every instance (10) in which cultures were made, but was obtained much less frequently from the lung. In one instance (Autopsy 474) this microorganism was found in the blood in association with hemolytic streptococci. There was suppurative interstitial pneumonia in the left lung and abscess in the right lower lobe with rupture into the cavity and empyema. Hemolytic streptococci and B. influenza? were found in the bronchus, right rjleural cavity and blood of the heart. In 4 instances (Autopsies 251, 259, 295 and 474) inter- stitial suppurative pneumonia has been associated with abscess formation. In one instance (Autopsy 251) the right middle lobe has been the site of interstitial suppura- tion and abscess formation; in another (Autopsy 295) the left lower lobe has been the site of both lesions, but in the other 2 instances suppurative interstitial pneumonia and abscess formation have occurred in opposite lungs. In all 216 PNEUMONIAS AXn INFECTIONS OF RESPIRATOR'S TRACT 4 autopsies hemolytic streptococci have been found in the blood o!' the heart and in Lungs or bronchi. Empyema lias been present in all bu1 3 of _1 instances of interstitial suppurative pneumonia. Histologic examination of hums with interstitial sup- puration shows that the interlobular septa arc distended by serum and contain a conspicuous network of fibrin. Poly- Fi,~. 1-- — Suppurative interstitial pneumonia, showing an immensely dilated lymphatic containing purulent exudate, a short distance below the pleura. Autopsy 474. nuclear leucocytes are present in varying number, and at times densely in lilt rale the distended tissue; it is not un- common to find a zone of densely crowded polynuclear leu- cocytes along- each edge of the septum, whereas the central part contains comparatively few. Occasionally, there is hemorrhage into the distended connective tissue. PATHOLOGY AND BACTERIOLOGY FOLLOWING I X I'M ' KX/A 1\ ( Within the distended septa occur greatly dilated Lym- phatics filled with polynuclear leucocytes (Figs. L2 and L3). Thrombosis of the distended lymphatics has usually oc- curred, and a conspicuous network of fibrin in which are polynuclear leucocytes plugs the lumen. Streptococci in chains of variable length are found in the inflamed inter- stitial tissue, but are present in far greater number within the distended lymphatics. KKKMijSHKaflQ y< . Fig. 13. — Suppurative interstitial pneumonia showing a dilated lymphatic. Autopsy 42S Necrosis of the cells which fill the lymphatics occurs in spots, usualry in the center of the thrombus, and occasion- ally affects the entire contents of the lymphatic ; polynu- clear leucocytes have lost their nuclei or in some the nu- cleus has undergone fragmentation. In these spots the net- work of fibrin has disappeared. Not infrequently the wall of the lymphatic in a small sector or throughout the cir- 218 PNEUMONIAS AND INFECTIONS OF RESPIRATOR! TRACT cumference has undergone necrosis, and spots of necrosis may occur in the interlobular septa distended by inflam- matory exudate. Wherever necrosis has occurred, chains of streptococci are present in immense number. Accumulation of polynuclear leucocytes, necrosis of these cells, solution of fibriD at first in the centers of the lym- phatic thrombus and later throughout, occasionally with necrosis of the wall of the vessel, result in the formation of an abscess at the site of the distended lymphatic. These lymphatics, dilated by purulenl fluid, may have a diameter Prom 2 to 3 mm. and may cause considerable compression and collapse of immediately adjacent alveoli. Lymphan- gitis, distention of lymphatics, thrombosis and finally sup- puration may occur in the lymphatic vessels encircling the blood vessels and in those situated in the adventitia of the bronchi of medium size. The alveoli adjacent to the distended septa are tilled by inflammatory products; edema is almost invariably pres- ent and the alveoli may contain serum and desquamated epithelial cells; fibrin is often present, hut more frequently polynuclear leucocytes are predominant. Not infrequently, abscess formation, recognized microscopically, has oc- curred in contact with septa most often immediately below the pleura. Polynuclear leucocytes are present in immense number and alveolar septa have disappeared; occasionally, with abscess formation there is more or less widespread necrosis of tissue, cells both of the exudate ami of the alve- olar walls having lost their nuclei. Lymphatics in many places are distended and plugged by fibrinous thrombi, whereas elsewhere softening of the thrombus has been brought about by suppuration. Sup- puration, both within the lymphatic and in adjacent alve- oli, appears to he secondary to lymphatic obstruction. In some instances the lymphatic appeal's to have undergone distention after the thrombus has formed, for between the PATHOLOGY AND BACTERIOLOGY FOLLOWING INTLUEXZA 219 thrombus and the wall of the lymphatic a channel is occa- sionally found containing uncoagulated lymph. Acute endophlebitis has been repeatedly observed in as- sociation with interstitial suppurative pneumonia (Fig. 14). The lesion usually occurs in veins situated within the septa which are the site of intensely acute inflammation associated with necrosis. The wall of the vein appears to be so injured by the surrounding changes that polynuclear :l^ r - '"'t-Vj^v . , ^: ;* ^.y> S^^fejfLT:^ •- - • itfit ' *- t*, ! f ! .-I . , ! . ^v" • ;' ' ' il>* I*- •.-•''■ * Vl" -'• • v;i"'. '..-. ;»"""* -v i "oif"- >'.-. f'. *"*'-* 'V -, » ' -^. Ww*** Fig. 14. — Endophlebitis occurring in association with suppurative pneumonia; the intima contains lymphoid cells in great number; at one spot there is a small thrombus adherent to the intima. Autopsy 325. leucocytes and small mononuclear cells accumulate below the endothelium. Throughout the circumference of the veins, often 0.5 to 1 mm. in diameter, the endothelium is separated from the underlying media by polynuclear leu- cocytes which form a conspicuous zone encircling the lu- men. Some cells of lymphoid type are usually present among the polynuclear leucocytes. Polynuclear leucocytes 220 PNEUMONIAS AM' INFECTIONS OF RESPIRATORY TRACT are often adherenl to the endothelial lining of the vessel and are do1 infrequently fixed in the process of passing through tlif endothelium. The lesion may be more severe (Autopsy 325), so thai the endothelium lias disappeared, and upon the exposed surface fibrin is deposited; within this fibrin polynuclear leucocytes are numerous and nu- clear fragmentation lias occurred. The middle coat of the vessel usually contains few cells: some polynuclear leuco- cytes within it may be stretched out as it' in process of wan- dering through the wall. Tn other instances the accumulation of cells below the endothelium is almost wholly mononuclear. Cells of the type of lymphocytes occur, but more abundant are slightly larger cells with more abundant cytoplasm. These cells may form a thick zone below the intima throughout the en- tire circumference of the lesion. It seems probable that these cells, like the polynuclear leucocytes, are derived Prom circulating blood within the lumen of the vessel, for small cells of the type of lymphocytes are not infrequently found adherent to the lumen and occasionally one is fixed in process of passing through the endothelium. This endophlebitis appears to be the result of changes outside the vessel; there is usually necrosis of the adjacent tissue and the production of the lesion is favored by lymph stasis: as the result of injury to the vessel wall, polynuclear leucocytes in response to chemotaxis, or with milder irrita- tion, mononuclear cells, wander through the endothelium and accumulate below it perhaps on account of the greater impermeability of the middle coal to the passage of cells. The lesion described does not occur exclusively with in- terstitial suppurative pneumonia caused by hemolytic streptococci, but has been found in association with abscess formation (Autopsies 354 and 383) caused by hemolytic streptococci or (Autopsy 322) caused by staphylococci. Tn 1 instance it has been found with lobar pneumonia (Au- topsy 320) caused by atypical Pneumococcus II and in 2 PATHOLOGY AND BACTETt I O I, OiiY FOLLOWING I X I'M I KN'ZA 22] instances with combined lobar and bronchopneumonia (Autopsy 357 with Pneumococcus IV; Autopsy •!!)-! with Pneumococcus II). In these 3 instances there has been in- terstitial inflammation, edema and lymphangitis without suppuration. Interstitial suppurative pneumonia of long standing may occasionally be accompanied by chronic changes which bring about thickening of the interlobular tissue. In the following autopsy acute suppurative inflammation in the left lung has been associated with conspicuous thickening of interlobular septa in the right lung. Autopsy 474. — I. H., white, aged twenty-one, was a native of Oklahoma and had been in military service one month. His illness began with influenza thirty-six days before death; he was admitted to the base hospital thirty-one days before his death with signs of pneumonic consolidation of the right lower lobe. Evidence of fluid in the right pleural cavity was obtained two weeks before death, and from 100 to 700 c.c. of thick purulent fluid were as- pirated on five occasions. Hemolytic streptococci were found in the aspirated fluid. Anatomic Diagnosis. — Interstitial suppurative pneumonia in left lung; abscess of right lower lobe with rupture into pleural cavity; thickening of interlobular septa of right lower lobe ; double purulent pleurisy with thorac- otomy on right side ; serofibrinous pericarditis. The right pleural cavity contains 85 c.c. of thick purulent fluid; the right lung (Fig. 9) is collapsed and pushed to the median line, being bound by firm adhesions to the pericar- dium. Over the external and basal surfaces is a localized cavity walled off by adhesions. An abscess cavity in the lower part of the lower lobe communicates through a per- foration in the basal surface of the lung with the pleural cavity and is in free communication with a small bronchus. About the abscess the lung is red and laxly consolidated, but elsewhere air containing ; throughout the lower half of the lower lobe, the interlobular septa are marked by con- spicuous yellowish gray lines about 1 mm. in thickness. Between these thickened septa the lung tissue contains air. The lung weighs 600 grams. The left lung (Fig. 10) is vo- luminous and heavy, weighing 1,320 grams. The surface is 222 PNEUMONIAS AND [NFECTIONS OF RESPIRATOR'S TRACT everywhere covered by thickened pleura and fibrin, the pleural cavity containing 150 c.c. of thick purulent fluid. The lung is consolidated varying in color from a fleshy red to yellowish gray. The surface is very conspicuously marked by yellow lines 2 or 3 mm. thick, corresponding to the interlobular septa which have undergone suppuration. The septa have bead-like swellings along their course, and when pus escapes from the cut surface small cavities re- main at the site of these swellings. Bacteriologic examination has shown hemolytic strepto- cocci in the blood, lefi lung, right and Lefi pleural cavities, and right bronchus. B. influenza 1 has been found in the bronchus, in the righl pleura and in the heart's blood. A few colonies of S. aureus have been found on the plate from the right pleural cavity (site of thoracotomy). Microscopic examination of the right lower lobe shows that the interstitial septa are much thickened by young fibrous tissue infiltrated with lymphoid and a few plasma cells. Large mononuclear cells with granular cytoplasm are very numerous. A lymphatic is much distended and con- tains a few polynuclear leucocytes and many lymphoid and large mononuclear cells. There is no suppuration. Sec- tions from the right lung show suppurative lymphangitis with suppurative inflammation of interstitial tissue. The right lung is the site of a healing lesion of the inter- stitial tissue which has developed simultaneously with acute interstitial suppurative pneumonia in the left lung. Both lesions are doubtless caused by S. hemolyticus. This healing lesion exhibits little similarity to the interstitial bronchopneumonia described by several observers with both measles and influenza. The following autopsy furnishes further evidence that interstitial suppurative pneumonia exhibits a tendency to heal. Proliferation of endothelial cells lining the inflamed lymphatics gives rise to phagocytic cells which aid in re- moving the accumulated leucocytes. PATHOLOGY AND BACTERIOLOGY FOLLOWING [NFLUENZA 223 Autopsy 397. — N. P., white, aged twenty-one, farmer, a native of Okla- homa, had been in military service twenty-one days. Illness began twenty-two days before death, the patient being admitted on the day following onset with influenza, pharyngitis and bronchitis. A diagnosis of lobar pneumonia was made fourteen days before death. The Lef1 pleural cavity was aspirated twelve days later and 800 c.c. of thick yellow pus were withdrawn. Hemolytic streptococci were found in the sputum five days before death. Anatomic Diagnosis. — Interstitial suppurative pneumonia in lefl upper lobe; acute bronchopneumonia with lobular consolidation in righl upper lobe; localized purulent pleurisy ou left side with compression and atelectasis of left lung; compensatory emphysema of right lung; purulent bronchitis; be- ginning serofibrinous pericarditis; chronic passive congestion of liver, spleen and kidneys. The right lung is very voluminous, free from coal pigment and bright pink save over lobular patches of consolidation -which have a bluish red color; the bronchi contain mucopurulent material. The anterior surface of the left lung is bound to the chest wall by firm adhesions, but over the external and posterior surfaces of the lung there is a localized cavity containing 1,100 c.c. of turbid fluid. The left lung is collapsed and airless with deep fleshy red color. In the upper lobe there are scattered patches of consolidation 1.5 to 2.5 cm. across where the tissue is grayish red and coarsely granular. In the adjacent tissue interstitial septa are thickened to 1 or 2 mm. and are con- spicuous as gray bands. Along their course occur bead-like swellings from which purulent fluid can be scraped. These septa at one point reach the anterior surface of the lung where the pleural cavity is in large part obliter- ated by adhesions; here there is an encapsulated pocket 4 x 1.5 em. con- taining thick creamy pus. Bacteriologic examination of the blood shows the presence of hemolytic streptococci; cultures from the lungs contain hemolytic streptococci and B. influenza?. Microscopic examination shows that interlobular septa are thickened and infiltrated with plasma cells in large number. Leucocytes in the center of much dilated lymphatics have undergone necrosis and have lost their nuclear stain. About the periphery of the lumen and evidently derived from the swollen endothelial cells which surround it, are numerous large mononuclear cells. They act as phagocytes and ingest polynuclear leucocytes. Multinu- cleated giant cells, derived from these cells, occur. In several places throm- bosed lymphatics in process of organization occur ; the lumen is filled with compact fibrin which is invaded by fibroblasts and newly formed capillaries. The process just described is analogous to that which oc- curs whenever an unopened abscess heals; mononuclear cells accumulate and act as phagocytes ingesting polynu- clear leucocytes. 224 PNEUMONIAS AND INFECTIONS OE RESPIRATORS TRACT The following instance of streptococcus empyema is note- worthy because no suppurative pneumonia has been found in association with it. Nevertheless the character of the changes present in the lung indicate that the organ has been the site of an interlobular inflammation which has healed. Autopsy 499. — J. II. M., white, aged twenty Pour, a farmer from Arkan- sas, had been in military service five months. Onsel of illness began two weeks before his admission to the hospital on November 15 with cough, fever, headache and malaise; on admission there was acute bronchitis. Thirteen days after admission the patient developed parotitis (mumps?); five days later and five days before death pleurisy \v:is recognized on the right side and pneumonia was suspected. Death occurred thirty-six days after onset. The temperature on admission was 103.2 F. and remained elevated during cue week falling by lysis; from tins time until the pleurisy was recognized it w;is normal and later it remained approximately 103° F. Anatomic Diagnosis. — Fibrinopurulent pleurisy on right side; fibrinous pleurisy on left side; fibrinopurulenl pericarditis; chronic interstitial (inter- lobular) pneumonia in process of healing; purulent bronchitis; acute splenic tumor; parenchymatous degeneration of kidneys. The right pleural cavity contains 1,650 c.c. of grayish yellow fluid con- taining an abundant sediment of softened fibrin. Part of this fluid, inure opaque than the remainder is confined in a localized pockel between the inner surface of the lung and the pericardium. The apex and anterior surface of the right upper lobe, over an area about 7 cm. across, is held by fibrinous adhesions to the chest wall; when this adhesion is broken a pocket is exposed 6.5 x 2.5 cm. containing fibrin and fluid. The pericardial cavity is distended by -"'.lO c.c. of turbid yellow seropurulent fluid. The pericardial surfaces are covered by shaggy, tough gray fibrin. The right lung is collapsed; the lower and posterior part of the upper lobe is deep red and atelectatic. Throughout the upper lobe the interlobular septa are thickened, often 1 mm. across and very conspicuous; in the lower i in 1 anterior tip of the lobe is an area where tissue is firm grayish red and heavier than water. The lower and posterior half of the righl lower lobe is firm and airless, and the tissue is reddish gray or gray and in places finely granulaT on section; interlobular septa are conspicuous. Although the lung is cut into thin sections, no abscesses are found. Bronchi throughout the lung < ontain mucopurulent fluid. The left lung over its lower half is covered by a thin layer of fibrin. The tissue is crepitant throughout and moderately edematous. Bronchi contain mucopurulent fluid. Hemolytic streptococci in pure culture are obtained from the blood of the heart, right pleural cavity and pericardium. No growth is obtained on a plate inoculated with material from the right lower lobe. The right bronchus contains hemolytic streptococci and 15. influenza;. PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 225 The pleural surface of the right lung is covered by a thick layer of fibrin which has undergone advanced organization. Fibrous sepia within the lung are much thickened by the presence of newly formed fibrous tissue; the in terstices of the tissue are distended and contain fibrin into which fibroblasts and new blood vessels have penetrated. Home lymphatics are plugged with fibrin and contain polynuclear leucocytes, lymphoid and large mononuclear cells. In several places organization of these thrombi is beginning. About the blood vessels are thrombosed lymphatics in which polynuclear leucocytes and mononuclear cells, are equally abundant. Alveoli immediately adjacent to blood vessels and to fibrous septa often contain fibrin, and alveoli elsewhere contain desquamated cells in abundance. Ill association with hemolytic streptococci in the blood, pleura and pericardium, there has been inflammation of the interlobular septa of the lungs with acute lymphangitis; there has been no suppuration and the lesion is in process of healing with new formation of fibrous tissue. It is evi- dent that this lesion, as well as pleurisy with advanced or- ganization, preceded the exacerbation of the patient's ill- ness which occurred five days before death. The advanced chronic changes found at autopsy indicate that the pul- monary and pleural lesions had their origin during the illness which was present at the time of admission to the hospital. Interstitial pneumonia caused by hemolytic streptococci was of mild character and did not produce suppuration within the lung ; nevertheless, hemolytic strep- tococci which reached the pleura caused empyema. Suppurative Pneumonia with Multiple Clustered Abscesses Caused by Staphylococci In the preliminary report of this commission published in The Journal of the American Medical Association, loc. cit., pg. Ill, we described suppurative pneumonia with mul- tiple abscesses caused by staphylococci and cited 4 instances of the lesion which followed influenza. Chickering and Park 4 published in a subsequent number of the same journal ■•Chickering, H. T. and Park, J. II. : Staphylococcus Aureus Pneumonia, Tour. Am. Med. Assn. 1919, lxxii, 617. _L(> PNEUMONIAS AND INFECTIONS OF RESPIRATOR! TRACT an account of staphylococcus pneumonia, a lesion which has heretofore attracted very little attention. In a small group <>f cases abscesses in the hums have had characters which serve to distinguish them Prom the ab- scesses previously described. Small, sharply circumscribed yellow nodules, which in t heii- centers have undergone sup- purative softening, form a cluster upon a red, airless back- ground (Figs. 15 and Ki). One or more of these groups several centimeters across, occur in the lungs. 11 is usually evident that the abscesses are clustered about a medium- sized bronchus, but occasionally with increase in the size of the small cavities the lung tissue assumes a honey-combed appearance. These clustered abscesses occur in association with bron- chopneumonia and have been in all instances associated with purulent bronchitis. The mucosa of the small bronchi may be destroyed so that the surface is eroded. These small clustered abscesses are seen as conspicuous yellow spots immediately below the pleura, but there lias been no associated empyema. In 2 instances these abscesses were accompanied by fibrinous pleurisy, but in the remaining au- topsies the pleura has been normal. The infrequency of empyema is in contrast with its almost invariable presence when a streptococcus abscess is found below the pleura. Autopsy 280. — Onset of illness with malaise, headache, cough and fever was on September 24, eight days before death. At autopsy there were hem- orrhagic peribronchiolar rind lobular bronchopneumonia, clustered foci of sup- puration in right lung, purulent bronchitis and fibrinous pleurisy, Hemo- lytic streptococci were obtained from the consolidated lung .and from a bronchus. A culture from the right lung was contaminated. In the bronchus were found B. influenza' and a few staphylococci. Microscopic examination of the abscesses shows thai they contain Gram-staining cocci grouped into staphylococcus like colonies. Autopsy 286. — Duration of illness, which began September l'.~ with symptoms of influenza, was nine days. At autopsy there were lobular ami cunfliiriit patches of bronchopneumonia, clustered abscesses in the right lung below tlic pleura, purulent bronchitis, ami serofibrinous pleurisy localized in the neighborhood of the abscesses. PneUmococcus IV was obtained from the blood of the heart, and Pneumococcus IV, staphylococci and P.. influenza' from the right main bronchus; growth failed to occur on plates from right PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 227 Fig. 15. — Abscesses in two clusters caused by S. aureus in upper part of right upper lobe; confluent lobular consolidation in lower part of lobe. Autopsy 333. 228 PNEUMONIAS AXli INFECTIONS OF RESPIRATOR'S TRACT and left lungs. Microscopic examination shows the presence of clumps of cocci with staphylococcus grouping in the centers of the small abscesses. Section through one abscess shows its continuity with the wall of a bronchus j along one side of the abscess is epithelium composed of flattened epithelial cells in multiple layers continuous with thai of the bronchus; the remainder of the abscess wall is formed by disintegrated lung tissue. Autopsy 322. — The patient was admitted with influenza eight days be- fore death; signs of pneumonia appeared two 'lays later, and on the follow- ing day Pneumococcus IV was obtained from the sputum. At autopsy 1 •"—■■- -«-_ 1 e Xg ""^BHe ■ W k j£jf ^^H fc^*)re^*8 ■ ~JL #t| ll/la \ 4 ■ \ : ^ '' (* \ ■ ■ - Fig. 16. — Abscesses in cluster caused by S. aureus at apex of right upper lobe. Autopsy 322. there were bronchopneumonia with lobar consolidation, abscesses clustered aboul a bronchus in the right upper lobe and purulent bronchitis. The blood was sterile; S. aureus was obtained from the consolidated part of the left lung; S. aureus and Pneumococcus III from the abscesses of the right lung. Microscopic examination of sections of abscesses showed the pres- ence of Gram-staining cocci in staphylococcus like colonies, surrounded by necrotic material and polynuclear leucocytes; Gram-negative bacilli re- sembling B. influenzae were seen. (See Fig. 16.) PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 'I'li) Autopsy 333. — The onset of influenza was fifteen days before death; a diagnosis of pneumonia was made seven days before death. At; autopsy there were confluent bronchopneumonia, clustered abscesses in the right lung and purulent bronchitis (no pleurisy). The Mood contained Pneumococcus II atypical. S. aureus and Pneumococcus II atypical were obtained from the abscesses; S. hemolyticus, from the consolidated left lung; 8. aureus, B. in- fluenzae and a few hemolytic streptococci, from the bronchus. (See Fig. 15.) Autopsy 370. — The patient was admitted seventeen days before death and signs of pneumonia were noted three days after admission. At autopsy there were lobular and confluent bronchopneumonia and small abscesses clus- tered about bronchi and situated within the gray consolidated lung; purulent bronchitis and patches of atelectasis, with distention of the lungs, so that they failed to collapse on removal. No growth was obtained from the heart 's blood; S. aureus in pure culture was obtained from the abscesses of the right lung; Si. aureus, Pneumococcus IV and B. influenzae were obtained from a small bronchus on the left side. Autopsy 425. — Illness began with influenza twenty-nine days before death; a diagnosis of pneumonia was made fourteen days before death. At autopsy there were chronic bronchopneumonia with tubercle-like nodules of consolidation with some large patches of consolidation, multiple small ab- scesses giving a honey-combed appearance to part of the right middle lobe, purulent bronchitis and bronchiectasis. S. hemolyticus was grown from the heart's blood; S. hemolyticus, B. influenzae and S. albus from the lung. Sec- tions of an abscess contain clumps of cocci. An abscess cavity has along one side remains of a bronchial wall covered by squamous epithelium; a dilated bronchus, cut longitudinally, terminates in this irregular abscess cavity. Table XLIX shows the incidence of pneumococci, hemolytic streptococci, staphylococci and B. influenzae in the foregoing autopsies with abscesses clustered about bronchi : Table XLIX w ° t PNEUMOCOCCI HEMOLYTIC STREPTOCOCCI STAPHYLO- COCCI B. INFLUENZAE > ° ? E-i H S > w a « o > Eh H m ° ? > ° ? PER CENT POSITIVE Eronchus Lung Blood 4 6 6 2 2 2 50.0 33.3 33.3 2 3 2 50.0 50.0 .33.3 4 4 100.0 66.7 4 2 100. 33.3 Staphylococcus shows in the lung the same tendency to produce localized abscesses which it exhibits in other tis- sues of the body ; it invades the lung by way of the bronchi. 230 PNEUMONIAS A.\l> INFECTIONS OF RESPIRATOR'S TRACT bu1 shows no ability to invade lymphatics, and in the cases we have examined rarely enters the pleura or the blood. In all of these cases r>. influenzae has been Pound in the bron- chi and perhaps precedes the staphylococcus as an invader of the Lower respiratory passages. Pneumococci atypical 1 1. Types III and I V liave been found in over half of these cases. The significance of this organism is emphasized by the 2 cases in which it has been found in the heart's blood ;it autopsy. It appears not improbable that S. aureus has invaded the lung already the site of bronchopneumonia caused by pneumococci. Notwithstanding the small number of autopsies, the fig- ares in Table X LI X. showing the incidence of pneumococci, streptococci, staphylococci and B. influenza?, arc cited so that they may be compared with the corresponding figures for the usual type of streptococcus abscess (p. 203). Tin 1 incidence of hemolytic streptococci is relatively low, whereas that of staphylococci approximates 100 per cent. S. aureus was present in great number in the lung of Au- topsies 322 and 333 and in pure culture in the abscess of Autopsy 370. Microscopic examination of sections from the abscesses which have been described, demonstrated the presence of Gram-staining cocci in characteristic staphylo- coccus-like clumps within the exudate of the abscesses; scat- tered chains of streptococci were not found. In those in- stances (Autopsies 2S0 and 286) in which cultures failed to demonstrate staphylococci, microscopic examination dem- onstrated staphylocoecus-like clumps of bacteria within the abscess cavity. Cultures were usually made from the con- solidated lung near the abscess where the pleural surface could be seared, rather than from the pus, so that in some instances the microorganism has doubtless escaped detec- tion although present. In association with the multiple abscesses which have been described, injury to the bronchi and bronchopneu- monia have been invariably present. Purulent bronchitis PATHOLOGY AND BACTUUIOLOG Y FOLLOWING I X I'M 'ION/A 231 has boon present in nil instances of this lesion; in 2 in- stances there has been dilatation of the bronchi, and in 1 instance in which the onset of influenza was twenty-nine days before death, there has been advanced bronchiectasis. Microscopic examination shows that the epithelium of the bronchi is partially or completely destroyed and that de- struction of the underlying' tissue, with acute suppurative inflammation, penetrates to a greater or less depth into the wall. When the epithelium of the bronchus is wholly destroyed and the lumen is filled and distended with poly- nuclear leucocytes, a cross section of the tube has the ap- pearance of a small abscess ; but more careful examination often shows that the engorged mucosa is still intact. Occasionally, a network of fibrin forms a layer covering the denuded mucosa. Disintegration of the superficial tissue may extend to the muscularis or through it, and may pene- trate the wall of the bronchus. The tissue in contact with the exposed surface contains man}'' polynuclear leucocytes and blood vessels plugged with fibrinous thrombi, but deeper in the tissue lymphoid and plasma cells are more numerous. In 2 instances (Autopsies 286 and 425) favor- able sections have demonstrated that the wall of an abscess on one side consists of the remains of a bronchus, covered by epithelium composed of squamous cells, whereas the remainder of the wall, here very irregular, is formed by partially destroyed alveoli plugged with fibrin. The sup- purative process has penetrated the wall of the bronchus on one side and extended into the surrounding alveolar tissue. In other instances, abscess cavities occur within the alveolar tissue of the lung and their relationship to bronchi is not evident. In the mass of polynuclear leuco- cytes which rill the abscess cavity, are clumps of staphy- lococci in great abundance, usually forming characteristic colonies which are conspicuous with the low power of the microscope. 232 PNEUMONIAS ANH [NFECTIONS OF RESPIBATOR'S TRACT Empyema, Pericarditis and Peritonitis No sharp line can be drawn between nonpurulent and purulent pleurisy. A diagnosis of empyema lias been made when the fluid in the chest has become opaque and fibrin has undergone softening or solution. The lesion has been designated seropurulenl when there has been abundanl thin, opaque, gray fluid. Pleurisy lias been designated flbrinopurulenl when the cavity lias contained opaque fluid and raided soft white or yellowish fibrin ad- herent to the chest wall; this fibrin is evidently in process of disintegration and there may be numerous shreds and Hakes of fibrin which subside to the bottom of the fluid. The amount of fluid in the cavity may occasionally exceed 1,700 c.c : that in both pleural cavities may exceed 2,500 c.c. The lesion has been designated purulent when fibrin has almost wholly disappeared and the cavity contains thick yellowish white fluid. In 4 of 5 instances in which tho- racotomy had been performed, empyema has assumed this otherwise uncommon type. Some inflammation of the pleura is almost constantly found in association with all forms of pneumonia, but in many instances is so slight that it has no noteworthy sig- nificance. Table L shows the incidence of various types of pleurisy. Table L SUPPURA- INTERSTI- LOBAR BRONCHO- TIVE PNEU- TIAL SUPPU- PNEUMONIA PNEUMONIA MONIA WITH RATIVA. ABSCESS PNEUMONIA No. % No. % No. % No. [ % Xo pleurisy noted 30 46.9 44 55 1 2.6 1 5.9 Serous pleurisy 5 7.8 9 11.2 Fibrinous pleurisy 10 l.-,.i; 6.2 1 2.6 Serofibrinous pleurisy 12 18.2 14 17.5 3 7.7 Seropurulent pleurisy 9 23.1 1 5.9 Fibrinopurulent pleurisy 7 10.9 5 6.2 17 43.6 12 70.6 Puruleni pleurisy 3 3.7 8 20.5 3 17.6 Total 64 80 39 17 PATHOLOGY AND BACTEKIOLOGY FOLLOWING I \ I'M K XX A 233 Empyema has occurred, on the one hand, in 12.4 per cent of instances of lobar pneumonia and in 9.9 per cent of in- stances of bronchopneumonia alone. It lias occurred, on the other hand, in 87.2 per cent of instances of suppura- tive pneumonia with abscess formation and in 94.1 per cenl instances of interstitial suppurative pneumonia. These suppurative lesions are caused by hemolytic streptococci, and when cultures are made from the pleural exudate this microorganism is isolated. Of 16 instances in which empyema has occurred in asso- ciation with lobar pneumonia or bronchopneumonia unac- companied by suppuration in 6 there has been infection with hemolytic streptococci. Empyema has occurred in the absence of hemolytic streptococci only 10 times. Empyema Caused by Hemolytic Streptococci. — When necrosis preceding abscess formation has occurred in the lung, streptococci are found in immense numbers in the dead tissue. The pleura overlying the abscess undergoes necrosis and occasionally streptococci are particularly nu- merous upon the pleural surface of the necrotic tissue. In Autopsy 376 a membrane thin as tissue paper, representing the pleura, separated an abscess containing thick pus from the pleural cavity which was the site of empyema. The abscess may rupture into the pleural cavity and at the same time may be in free communication with a bronchus (Au- topsy 480). In one (Autopsy 467) instance an abscess which had ruptured into the pleural cavity had completely discharged its contents and was in process of healing, newly formed fibrous tissue being abundant in its wall. With few exceptions empyema has accompanied sub- pleural abscess caused by hemolytic streptococci, being- found on the side corresponding to the abscess. Among 39 instances of pulmonary abscess, empyema has been limited to the side of the abscess in 23 ; it has been present on the opposite side as well in 10 instances. In 2 instances there have been abscesses in both lungs; in one (Autopsy 234 PNEUMONIAS AND [NFECTIONS OF RESPIRATOR'S TRACT 385 A) there lias been double empyema, and in the other (Autopsy 487) empyema only on the left side. In one in- stance abscess lias been recognized by microscopic exami- nation and iis location is not recorded. In 5 instances of abscess formation there lias been no empyema. In Autopsy .'!">.'! there lias been no pleurisy noted: in Autopsy 41(i there lias been fibrinous pleurisy and in Autopsies 1*77, 290 and .'Nc. serofibrinous pleurisy. Empyema has been almost invariably found in associa- tion with interstitial suppurative pneumonia. This lesion extends by way of the lymphatics np to the pleural surface and is often more conspicuous just below the pleura than elsewhere. Empyema has been absenl in only 3 of 21 ex- amples of the lesion and in one of these there has been serous effusion. In 12 instances interstitial suppuration has occurred only on one side and empyema has been lim- ited to this side; in 5 instances with interstitial suppura- tion on one side there has been empyema on both sides; in l! instances with interstitial suppuration in both lungs there has been double empyema. The amount of fluid in the pleural cavity lias varied from less than 100 to 1,500 c.c. The fluid has occasionally been seropurulent or yellow, thick and purulent, but in most instances the exudate is best described as fibrinopurulent. There is ycIIoav or yellowish gray purulent fluid contain- ing flakes of soft ragged fibrin. The foregoing study has shown, on the one hand, that empyema is a frequent complication of streptococcus pneu- monia and, on the other hand, that empyema following in- fluenza with relatively few exceptions is caused by hemo- lytic streptococci. Empyema caused by this microorgan- ism exhibits in some instances characters not seen with other varieties of pleural inflammation. The tissue be- tween sternum and pericardium is often edematous and the adjacent fat has a firm brawny consistence. Tn some in- stances the exudate contains blood, and hemolysis has oc- PATHOLOGY AND BACTERIOLOGY FOLLOWING [NFLUENZA 235 curred so that the fluid has a diffuse red color. The occur- rence of multiple! pocketed collections of purulent fluid within the pleural cavity is peculiar to streptococcus empy- ema. These pockets have been found 6 limes in association with abscess and 5 times with interstitial suppurative pneu- monia. In the presence of an exudate within the pleural cavity, some part of the lung, usually the anterior surface behind the sternum and costal cartilages, is glued by fibrin- ous adhesions to the parietal pleura. Here occur pockets containing thin purulent fluid and softened fibrin or thicker creamy pus walled off by fibrin about the edges of the pocket. At the site of the lesion the lung, after it is sepa- rated from the chest wall, is marked by a shallow depres- sion surrounded by the fibrin which has walled in the pocket. The little cavity thus formed, varying much in size, is usually oval, the long diameter being from 1 to 3 cm. These pleural pockets may occur over the external sur- face of the lung (Autopsies 452, 455, and 472) or between the internal surface and pericardium (Autopsy 452). Oc- casionally with partial fibrinous adhesion between the pleu- ral surfaces there are both scattered pockets containing purulent fluid and a larger encapsulated collection of fluid ; in Autopsy 455 the pleural surfaces were adherent and there was 100 c.c. of purulent fluid encapsulated in a space over the external surface of the lung, 12x8 cm. In Autopsy 452 the lower part of the pleural cavity was encapsulated and contained 650 c.c. of fluid. This tendency of empyema caused by S. hemolyticus to form encapsulated pockets is doubtless of considerable importance in the treatment of the condition. Stone, Bliss and Phillips 5 have described these encap- sulated pockets as "subcostosternal pus pockets" and have maintained that they are formed about the sternal lym- phatic nodes. "We have found them so widely scattered that this relation seems improbable. 6 Stone, W. J., Phillips. B. G., and Bliss, W. P.: A Clinical Study of Pneumonia Based on S71 Cases. Arch. Int. Med., 1918, xxii, 409. 236 PNEUMONIAS AXU INFECTIONS OF RESPIRATORS TRACT Pneumococcus Empyema. — Empyema occurred in asso- ciation with pneumonia referable to pneumococci LO times, once with Pneumococcus 1 1 : (5 times with Pneumococcus atypical 11: once with Pneumococcus 111 and twice with Pneumococcus [V. The lesion was seropurulent once: fibrinopurulenl 8 times and purulent once. Fibrin in sev- eral instances was somewhal voluminous. In the following instance voluminous masses of fibrin had an important in- fluence upon the attempted treatment. Autopsy 473. — A. D. P., white, aged twenty-one, a student from IWis- souri, had been in military service two weeks. He was admitted to the hospital with influenza twenty-eight days before his death, and four days after admission there were signs of pneumonia. Paracentesis was per- formed mi the righl side on the eleventh day after admission; 4 c.c. of cloudy fluid which contained Pneumococcus III were obtained at this time and later in the day 800 c.c. were withdrawn. On the thirteenth day at- tempted withdrawal of fluid from both pleural cavities failed. On the eighteenth day aspiration of the right pleura] cavity yielded only 30 c.c. of fluid. On the nineteenth day 400 c.c. of purulent fluid were withdrawn from the right pleural cavity. On the twenty-fifth day there was cyanosis and delirium, shortly before death aspiration of the right pleural cavity was attempted, luit only 4 c.c. of fluid were obtained. Anatomic Diagnosis. — Chronic bronchopneumonia with lobular and peri- bronchiolar consolidation in left lung; flbrinopurulent pleurisy on both sides; purulent bronchitis and bronchiectasis. On removal of the sternum, encysted purulent pleurisy is found be- tween the inner surface of the right lung and the pericardium; there is here 450 c.c. of very thick creamy, greenish yellow pus entirely separated from the remainder of pleural cavity. The external part of the cavity contains 1,450 c.c. of fluid and voluminous masses of firm fibrin which placed in a measuring cylinder occupy 450 c.c. The left pleural cavity con- tains 400 c.c. of seropurulent fluid in which there is abundant sediment of fibrinous particles. The right lung is compressed; the bronchi exude purulent fluid. The left lung is voluminous; in the upper and lower lobes there are small yel- lowish gray nodules of consolidation, grouped in (dusters, and gray patches of lobular consolidation occur. Bronchi are dilated and filled with puru- lent fluid. I'.acteriologic examination shows the presence of Pneumococcus III ob- tained in pure culture from the blood of the heart and from the right pleural cavity. S. viridans is grown from the left lung; a plate from the right bronchus contained B. influenzae, S. viridans and a few colonies of staphylococcus and M. catarrhalis. PATHOLOGY AND BACTERIOLOGY FOLLOWING I X I'M'KXZA 237 The foregoing case is particularly noteworthy because aspiration failed repeatedly to yield more than a few cuhic centimeters of fluid, doubtless because the voluminous masses of fibrin present in the cavity prevented escape of fluid. Aspiration was attempted shortly before death, but only 4 c. c. of fluid were obtained; nevertheless, at autopsy the right pleural cavity contained 2,350 c.c. of exudate. An- other factor of much importance in relation to treatment is the encapsulation of 450 c.c. of purulent fluid between the inner surface of the right lung and the pericardium. It is possible that free drainage might have emptied the main cavity and perhaps even freed the encapsulated fluid. Pericarditis. — Among 241 autopsies on individuals with pneumonia following influenza, pericarditis occurred 23 times ; these lesions were classified as follows : Serous peri- carditis, 1 ; serofibrinous pericarditis, 9 ; seropurulent peri- carditis, 1 ; fibrinopurulent pericarditis, 10 ; purulent peri- carditis, 2. It is noteworthy that in 12 of 23 instances of pericarditis the lesion was associated with S. hemolyticus infection of the lung and whenever in these instances cultures were made (Autopsies 434, 485, 499 and 504) hemolytic strepto- cocci were obtained from the pericardial exudate in pure culture. The tendency of interstitial suppurative pneumonia to produce pericarditis is especially evident. Among 21 in- stances of interstitial suppurative pneumonia pericarditis occurred 6 times (28.6 per cent) ; among 39 instances of sup- purative pneumonia with abscess formation, pericarditis occurred twice (5.1 per cent) ; whereas among all other autopsies, namely, 181, the lesion occurred 15 times (8.3 per cent). Pericarditis occurred in association with pneumonia re- ferable to Pneumococcus I, once, (Pneumococcus I isolated from the pericardium) ; to Pneumococcus II, once ; to atypi- cal Pneumococcus II, 5 times (twice isolated from the peri- 238 PNEUMONIAS AND [NFECTIONS OF RESPIRATOR? TRACT cardium) ; and to Pneumocoecus IV. twice (once isolated Prom the pericardium). Peritonitis. — Purulent peritonitis occurred only twice, in both instances in association with pneumonia caused by hemolytic streptococci. Purulenl peritonitis was part of a genera] serositis involving both pleural cavities, peri- cardium and peritoneum in 2 noteworthy instances: Autopsy 465. — J. EL, white, aged twenty-two, farmer from Oklahoma, had been in military service one month. He \\ :i s admitted to the hospital with influenza, sore throal and bronchitis twenty-four days before his death. Signs of pneumonia were recognized thirteen days later and at the same time there was otitis media on the righl side. Empyema and peri- carditis were found three days before death and two days later looo c.c. of cloudy fluid were withdrawn from the chest. Anatomic Diagnosis. — Suppurative pneumonia with consolidation and abscess in right lower lobe below pleura; purulent pleurisy on right, sero- j. undent pleurisy on left side: beginning serofibrinous pericarditis; fibrino- purulent peritonitis; purulent bronchitis. The body is emaciated. The right pleural cavity contains 350 <-.<■. of thick, creamy yellow pns in which are Hakes of fibrin; the right lung is collapsed and lies at the back and inner side of the cavity. The lefl pleural cavity contains .100 c.c. of turbid, yellow, seropurulent fluid in which is soft fibrin. The lower lobe of the right Inn- is consolidated throughout, flabby, gray red and finely granular on section. Below the pleura of the posterior border is a wedge-shaped cavity with its base 1.5 em. across, in contact with the pleural surface. About the cavity consolidated tissue has an opaque, yellow color. Bronchi in both lungs contain mucopurulent fluid. The pericardial cavity contains 20 c.c. of turbid fluid; the left auricular appendage is bound by a thin layer of fibrin to the parietal pericardium. The peritonea] cavity contains 100 c.c. of thick, creamy, yellow, purulent fluid. Between the diaphragm and liver is a layer of fibrin, in places 1.5 cm. in thickness: fibrin is present upon the peritoneum overlying the kidneys and base of mesentery. Bacteriologic examination shews the presence of hemolytic streptococci, obtained in pure culture from the blood of the heart, right pleural cavity and peritoneum. From the right bronchus are grown S. hemolyticus, B. influenza' and a few colonies of S. viridans and staphylococcus. Autopsy 504. — Gr. El. < '., white, aged twenty-eight, farmer from Alabama, had 1 n in military service three months. Onset of illness occurred six- day- before death, ami two days later he entered the hospital with fever - In.",. | F. ), pains in the abd< sn and vomiting. Con si did at ion at the bases of the lung was recognized on the day following admission and on the day before death 000 r.r, of greenish brown fluid were aspirated from the left pleural ca\ Lty. PATHOLOGY AND BACTERIOLOGY FOLLOWING I X KM ' KN'XA 239 Anatomic Diagnosis. — Interstitial suppurative pneumonia with eon oli elation in left lower lobe; purulent pleurisy on both Hides; purulent peri- carditis; purulent peritonitis; parenchymatous degeneration of kidneys; acute splenic tumor. The body is that of a large well- nourished man. The lefl pleural cavity contains 975 c.c. of creamy, yellow fluid; right pleural cavity contains 425 c.c. of purulent fluid thinner than that on the lefl side. The lefl lung is collapsed; the posterior and lower half of the lower lobe is consolidated, flabby, deep rod and fleshy in appearance. The interstitial septa are yel- low, thickened with bead-like enlargements and contains creamy purulent fluid which flows away and leaves small cavities. This interstitial sup- puration is more advanced below the outer surface of the lobe than else- where. The pericardial cavity contains 25 c.c. of creamy, yellow, purulent, fluid; the epicardium is dull, covered in a few places by a small amount of fibrin and below it are ecchymoses. The peritoneal cavity contains 100 c.c. of thick, yellow pus; the peri- toneal surfaces are injected and between the liver and diaphragm is fibrin. Bacteriologic examination shows the presence of S. hemolyticus in pure culture from the blood of the heart, the lower lobe of the left lung, peri- cardium and peritoneum. The right main bronchus contains the same microorganism, B. influenzae and a few staphylococci. General serositis lias been caused by hemolytic strep- tococci which in one instance have entered the pleura from a snbpleural abscess, and in the other from the suppurating interstitial tissue of the lung. In one of these cases the patient entered the hospital with symptoms suggestive of acute peritonitis. Bronchiectasis Acute dilatation of the bronchi is a common result of the bronchitis of influenza, and its frequent occurrence is an index of the severity of the changes in the bronchial wall. In some instances the smaller bronchi in well-local- ized areas are uniformly dilated; in other instances, large cavities, several centimeters in diameter, are formed and all transitions between the two extremes occur. The occurrence of bronchiectasis following influenza is mentioned by Leichtenstern 6 . He states that evidence of «I,oc. cit., p. 110. 240 rxi:r.M<>xiA> and infections of respirator's tract bronchiectasis can persisl for weeks or months and never- theless end with complete restitution of the lungs to normal. Lord 7 lias (described instances of bronchiectasis occurring in association with infection by B. influenzae and Boggs 8 has recorded similar observations. We have had abundant opportunity to observe early stages in the production of bronchiectasis and to study the much discussed pathogenesis of the condition. The following figures show the predilection of bronchiec- tasis Tor the left lung and for the lower lobes: Bronchiec- tasis occurred 30 times in the left lung alone, 9 times in the right lung alone and 13 times in both lungs, the total being 52. Among 30 instance's in which the lesion occurred only in the left lung, in 24 it was limited to the lower lobe, and in 15 of these 24 instances to the base of the lower lobe. Among 9 instances in which dilatation oC bronchi occurred only in the right lung, it was limited to the lower lobe in 4 instances and to the base of the lower lobe in 2 of these 4 instances. When the lesion is limited to the base of the lower lobes small bronchi with no recognizable cartilage in their wall are dilated to a diameter of from 3 to 6 cm. and are dis- tended with thick mucopurulent fluid. The tenacious char- acter of the bronchial contents and the action of gravity doubtless have a part in the production of the dilatation. In several instances dilatation of the bronchi was limited to the basal parts of both upper and lower lobes. When bronchiectasis occurs throughout a whole lung, usually the left, or in both lungs, the lesion is more ad- vanced and conspicuous (Fig. 26). There is diffuse dila- tation of small and medium-sized bronchi. Dilated bronchi with deeply injected mucosa and filled with yellow muco- purulent fluid, are seen throughout the sectioned lung. A bronchus cut longitudinally may have a nearly uniform 7 Lord, F. T.: Infections of the ■Respiratory Tract with Influenza Bacilli, Boston Med. and SurR. Jour., 1905, clii. 537. 574. s Boggs, T. R. : Influenza Bacillus in Bronchiectasis, Am. Jour. Med. Sc, 1905, exxx, 902. PATHOLOGY AND BACTERIOLOGY FOLLOWING I X I U 'K.\ZA 241 diameter of from 5 to 9 mm. for a distance of 5 or 6 cm., maintaining this diameter to within 1 cm. of the pleural surface, where normally only small bronchi occur. More advanced bronchiectasis is represented by the oc- currence of spherical bronchiectatic cavities, having a diameter from 1 to 2.5 cm. In some instances there have been two or three of these cavities but occasionally there may be many. Cylindrical dilatation of the bronchi usu- ally occurs widely distributed in the lungs. In Autopsy 440 a small bronchus, cut longitudinally, was dilated to a diameter of 5 mm. for a distance of 5 cm. and terminated in a spherical cavity 2 cm. in diameter; there was another smaller spherical cavity nearby and dilated bronchi oc- curred elsewhere. In Autopsy 467, in the upper part of the lower lobe, two spherical cavities 1 and 1.5 cm. in diame- ter communicated with a bronchus of medium size. Autopsies with bronchiectasis are listed in the order of the duration of illness to show the parallel increase in the severity of the lesion (Table LI). In 2 instances (Autopsies 244 and 314) bronchiectatic cavities surrounded by firm fibrous tissue have evidently existed before the onset of the fatal illness, which has lasted in one instance approximately four and in the other six days; these autopsies have been omitted from the table. The table shows that bronchiectasis observed within twelve da} 7 s after onset of illness with symptoms of influ- enza is moderately advanced and almost invariably limited to the left lower lobe and usually to the base of the lobe. Advanced dilatation, indicated by the formation of spheri- cal or cylindrical cavities, occurs with increasing frequency as the duration of the respiratory disease increases. Bronchiectasis has been almost invariably associated with purulent bronchitis. The dilated bronchi contain mu- copurulent material and throughout the lungs the same con- dition is usually widespread. Among 137 instances of pur- ulent bronchitis bronchiectasis consequent upon influenza has been present in 50. 242 PNEUMONIAS AND INFECTIONS OF RESPIRATORS TRACT Table LI 1 DURATION 0< ITION CHAB UTKK OP T\ PE OF OT BRON- OF BRON- BACTERIA IN NO. OF Il,l.~. PNEUMON] \ CHIECTASIS CHIECTASIS BRONCHUS AUTOPSY IN DAYS 394 5 ? Broncho Rt. base Dilatation 359 7 + Lobar and broncho l.i. lower lob( Dilatation 322 8 Abscess ph.) Lt. 1 ase Dilatation 325 8 [nterst. sup pural ion I.t. base Dilatation S. hem., B. inf., staph. 352 8 Lobar and broncho Lt. lower lobe Advanced dilatation 429 8 .' Broncho Rt. base 1 >ilatation 288 LO Abscess Lt. base Dilatation s. hem., B. inf. 374 10 Lobar and Rt. and It. Advanced broncho lungs dilatation 376 in Abscess Lt. base Dilatation S. hem. 437 n Lobar Rt. lower lobi Ad\ anced dilatation 182 n Broncho Lt. base Dilatation B. inf., Taenia. IV. S. hem. 489 11 Lobar and broncho Lt. lung I > il at ati on B. inf., Pneum. IV. 287 12 Lobar and Lt. lower lobe Advanced Pneum. IV.. ] ironcho dilatation B. inf., staph. 289 12 Broncho Lt. lower Ink Advanced Pneum. IV., B. inf. staph. 295 12 [nterst. sup. Rt. lung Advanced S. hem.. and abscess dilatation B. inf. 336 12 Broncho Lt. bass Dilatation 375 12 Broncho Rt. and lt. liases Dilatation 422 12 .' Lobar and broncho Lt. base 1 Mlatation 381 13 Abscess Lt. base Spherical 391 13 Lobar and broncho Lt. lung I dilatation 40] 14 ? Lobar and broncho Rt. and lt. 1 1 1 1 1 g s .Spherical 402 14 Chronic broncho Rt. lower lobe 1 dilatation 410 1 1 .' Abscess Rt. upper lobe 1 dilatation 333 15 Al>sc. ss (staph.) Lt. upper lobi 1 (ilatation S. aur., B. inf. 8. hem. 389 1.1 [nterst. sup pural inn Lt. lung Advanced dihitat ion 412 l.l Lobar and broncho Lt. lower lobi Cylindrical 398 16 Broncho Rt. and It. lungs Advanced dilatat ion 423 16 Broncho Lt. base Dilatation PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 243 Table LI — Cont'd DURATION LOCATION . CHARACTER NO. OF OF TYPE OF OF BRON- OF BRON- BACTERIA IN AUTOPSY ILLNESS PNEUMONIA BRO ( in a IN DAYS CHIECTASIS CHIECTASIS 488 16 Abscess Lt. lower lob< 1 >il;ita1 ion 8. Item., Pneum. atyp. II., 312 17 Broncho Rt. and It. lungs Dilatation S. hern., B. inf. staph. 372 17 "Broncho Rt. lung Dilatation 385 C 17 Interst. sup- puration Lt. base Dilatation 448 17 Broncho Lt. lung Dilatation 460 17 Abscess Lt. lower lobe Spherical S. hem., B. inf., staph. 291 18 Broncho Lt. base Ad van cod dilatation B. inf., staph. 296 18 Abscess Lt. base Dilatation S. hem., B. inf., 387 19 Abscess Rt. and lt. Advanced S. hem., B. lungs dilatation inf., S. a"r. Pneum. II. 421 19 Chronic . broncho Rt. lung Advanced dilatation 440 19 Chronic Rt. and lt. Spherical B. inf., S. broncho lungs aur. 419 20 Broncho Rt. lung Dilatation' Pneum. II, B. inf. 463 20 Chronic Rt. and lt. Spherical B. inf., broncho lungs staph., Pneum. IV 431 23 Chronic broncho Lt. base Dilatation 468 23 ? Lobar and broncho Lt. lung Dilatation S. aur., B. inf., S. vir. 465 25 ? Broncho Lt. base Dilatation S. hem., B. inf., staph., S. vir. 445 27 Broncho Lt. lower lobe Spherical S. aur. 449 27 Abscess Rt, and lt. lungs Spherical S. hpm., B. coli. 378 28 Abscess Lt. base Cylindrical S. hem., B. inf., P'neum. atvp. II. 473 28 Chronic Lt. lung Advanced B. inf., S. broncho dilatation vir., staph., M. catarr. 425 29 Abscess (staph.) Rt. and lt. lungs Cylindrical 467 30 Abscess Rt. lower lobe Spherical S. hem., B. inf. 472 37 Chronic Rt. and It. Advanced B. coli broncho lungs dilatation 487 55 Abscess Rt. and It. lungs Cylindrical B. inf. S. hem. 244 PNEUMONIAS AND [NFECTIONS OF RESPIRATOR? TRACT The bacteriology of autopsies with bronchiectasis is shown in Table LII. Table LII Q x a . - O X x w PNEU- Mm 01 CI - S. HEMOLY- TICUS STAPHY- LOCOCCUS B. 1XKUT.NZ.K E 2 I X > - a - c > ■- _• BG - O X pi, £ 5 3 E EH _• /. O o X Ph b i 11 w j> O o X P, S 2 Bronchus Lung Blood 29 37 50 9 16 12 31.0 43.2 24.0 15 18 .i.i 51.7 t8.6 44.0 16 10 55.2 27.0 23 lit 7!».:: 51.4 Comparison of the percentage incidence of the organisms which have to be found associated with bronchiectasis and with purulent bronchitis unaccompanied by bronchiectasis shows that there is no noteworthy difference in the occur- rence of pneumococci, hemolytic streptococci or B. influ- enzae within the bronchi. When allowance is made for the difficulty of demonstrating B. influenzae in the presence of a large number of other microorganisms, it is not improb- able thai this organism lias been constantly present in the purulent contents of the bronchi with purulent bronchitis, with and without bronchiectasis. Pneumococci, strepto- cocci and staphylococci are each present in the bronchi in about one-half of the instances of bronchiectasis and mixed infections are very common, S. viridans, B. coli and M. catarrhalis being occasionally Pound in the bronchi. The table shows that pneumococci, streptococci and staphyl- ococci show no greater tendency to enter the lungs and blood when bronchiectasis and purulent bronchitis coexist than with purulent bronchitis alone. .Moderate dilatation of the small bronchi at the base of the left lung was round in several instances eight days after onset of symptoms referable to the respiratory pass- ages. Advanced, diffuse dilatation of the bronchi was seldom seen before the lapse of two weeks, and bronchiec- tasis with formation of spherical or cylindrical cavities PATHOLOGY AND BACTERIOLOGY FOLLOWING I X I'M 'KX/A 245 was found with few exceptions three weeks after onsel of the fatal illness. Long continued, purulent bronchitis does not necessarily produce dilatation of the bronchi. It is noteworthy that the average duration of the fatal illness in 137 instances of pneumonia and purulent bronchitis with no bronchiectasis was 12.5 days, Avhereas the average dura- tion of 49 instances of pneumonia with purulent bronchitis and bronchiectasis was only 16.5 days. Bronchiectasis is almost invariably associated with pur- ulent bronchitis in which tenacious mucopurulent fluid ac- cumulates in the bronchi. It begins at the bases of the lower lobes and is usually more advanced here than else- where. Mechanical distention of the small bronchi by viscid fluid, expelled with difficulty, brings about their dila- tation and gravity appears to have a part in accentuat- ing the process. Histologic examination of the changes accompanying bronchitis show that lesions which penetrate into the muscular layer and presumably weaken the bron- chial wall are not uncommon and partial or complete de- struction of the wall may result. To what extent infiltra- tion of the muscular wall by polynuclear leucocytes or by lymphoid and plasma cells is accompanied by changes which weaken the wall may be questioned. When the epithelial lining of the bronchus is destroyed coagulative necrosis of the underlying tissue occurs and may extend a variable distance into the bronchial wall, not infrequently pene- trating into or entirely through the muscular layer. These changes furnish an explanation of the occurrence of bron- chiectasis following influenza. Acute bronchiectasis may be found following influenza after the illness has lasted eight or ten days. There is no increase of fibrous tissue. Small bronchi with no cartilage, which in normal lungs have a diameter approximating 1 mm., are dilated to 3 mm. or more. The surface epithelium is wholly or partially lost. Necrosis occurs in places and extends deep into the tissue, destroying muscle and often 246 PNEUMONIAS AND INFECTIONS OF RESPIRATOR'S TRACT penetrating the entire thickness of the wall which in these small bronchi consists in large part of fibrous tissue con- taining greatly engorged blood vessels. In this necrotic material nuclei are absenl and the tissue containing fibrin stains deeply with eosin. In it occur fissures or tears which extend from the lumen a variable distance, very frequently penetrating the entire thickness of the wall and entering adjacent alveoli (Figs. 17 and 10). Alveoli thus exposed Fig. 17. — Acute bronchiectasis showing fissures penetrating into bronchial wall ami at one place entering surrounding alveolar tissue; the surrounding alveoli are filled with fibrin. Autopsy 425. almost invariably contain plugs of dense fibrin. Where these rents have occurred, adjacent edges of the bronchial wall, held together by underlying lung tissue, have sepa- rated from one another, so that the circumference of the bronchus has been increased (Fig. 18). These breaks in the continuity of the wall may occur in several places, so that a fourth or a third of the circumference maybe formed PATHOLOGY AND BACTERIOLOGY FOLLOWING I X I'M ' KXXA 247 by exposed alveolar tissue which has become the site of fibrinous pneumonia (Fig. 20). During life, though the in- flamed bronchus is filled by mucopurulenl exudate, disten- tion of loose alveolar tissue, uniting the interrupted bron- chial Avail, is doubtless greater than it appears in the Lung fixed by hardening fluids. Kecently dilated bronchi have an irregularly stellate lu- men as the result of clefts penetrating at intervals into or •^ -ft* i/t - > it 'j&* SS&Ssfe; i^Sp* Fig. 18. — Acute bronchiectasis showing fissures in the bronchial wall extending into neighboring alveoli which in zone about are filled with fibrin; one fissure has separated widely; peribronchial fibrinous pneumonia (fibrin is black). Autopsy 425. through the bronchial wall (Fig. 26) . Longitudinal fissures mark the lining of these dilated bronchial tubes. When the fatal illness has lasted more than two weeks, abundant new formation of fibrous tissue occurs in a zone surrounding the dilated bronchus. Adjacent alveolar walls are thickened by young fibrous tissue. Alveoli, much di- minished in size, are filled by hyaline fibrin into which fibro- 248 PNEUMONIAS AND [NFECTIONS OF RESPIRATORY TRACT blasts and aewly formed blood vessels have penetrated. These changes are limited to a wide /.one in immediate con- tact with the dilated bronchus, whereas at a greater dis- tance alveolar walls have undergone no thickening and alveoli contain no fibrin. Fig. 19.— Acute bronchiectasis; the bronchial wall indicated by engorged mucosa shows a varying degree of destruction, fissures extending into and through the bronchial wall. Autopsy 352. PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 2V.) This stage is well represented by Autopsy 421 after an illness of nineteen days. Bsonchieetatic cavities, from .'j to 6 mm. in diameter, are numerous in sections of the lung; their lumina are irregular in outline and often irregularly stellate. Microscopic examination shows the presence of Fig. 20. — Acute bronchiectasis; with destruction of bronchial wall exposing alveoli filled with fibrin; peribronchial fibrinous pneumonia is seen about several bronchi present in the section; Gram-Weigert fibrin stain. Autopsy 425. 250 PNEUMONIAS ANh INFECTIONS OF RESPIRATOR'S TRACT clefts which interrupt the bronchial wall a1 intervals throughout its entire circumference. The original wall is well indicated by the very richly vascularized connective tissue containing scattered muscle bundles and is infil- trated with Lymphoid and plasma cells in greal number. Where fissures have occurred the adjacent edges of the in- terrupted wall have separated Prom one another, leaving a wide interval where underlying alveolar (issue is exposed. Two changes lend eventually to render the fissures incon- spicuous, namely, regeneration of epithelium and new for- mation of fibrous tissue. Exposed alveoli filled with fibrin are in process of organization and epithelium which lias as- sumed a squamous type has grown down over the exposed -in faces of the interrupted bronchial wall. It has begun to cover or in some instances lias completely covered the sur- face of rents entering alveoli plugged with fibrin (Fig. 21). In the periphery of the bronchus alveolar walls are thick- ened and infiltrated with lymphoid and plasma colls. The same changes affect bronchi containing cartilage which is undergoing atrophy. The reinforcement of the fissured bronchial wall by new formation of fibrous tissue, by thickening of the interalve- olar walls and by organization of fibrin within the alveoli is well shown after four weeks (Autopsy 425; Fig. 28). There are spherical bronchiectatic cavities more than a cen- timeter in diameter surrounded by a dense fibrous Avail in which are atrophied alveoli lined by epithelium of cubical form. Occasionally, the fibrous wall is interrupted and al- veoli, plugged with organizing fibrin, are in immediate con- tact with the lumen. When these plugs of fibrin which are slowly absorbed disappear, evidence of preexisting rents in the bronchial wall are lost, and there are in this lung bron- chiectatic cavities of which the wall is a continuous circle of dense fibrous tissue. Epithelium lining the dilated bronchi is at times com- pletely destroyed (Fig. 28), but more frequently it persists PATHOLOGY AND BACTERIOLOGY FOLLOWING I X I'M ' KXXA 25] in part. That which remains has almost constantly the character of squamous epithelium (Figs. '2'2 and 23). The lowermost cells arc cubical; those above them are poly- gonal, tending to become flatter as the surface is ap- proached; upon the surface are cells often much flattened and occasionally they have lost their nuclei and slain deeply Fig. 21. — Bronchiectasis with fissures extending through the bronchial wall into alve- olar tissue which is the site of fibrinous pneumonia; epithelium has grown down into these fissures and has covered the exposed surfaces. Autopsy 463. 252 PNEUMONIAS A Nli INFECTIONS OE RESPIRATOR'S TRACT with eosiu as the result of superficial necrosis. The change should not be regarded as metaplasia, for the epithelium assumes this squamous type when the superficial columnar cells have been lost. Actual necrosis of superficial ciliated columnar cells is occasionally seen (Autopsy 352); injured cells have separated from one another and desquamated Fig. 22. — Regeneration of epithelium over fissures which have been formed in the wall of a bronchus; the epithelium in the neighborhood of and within the fissure is squamous. PATTTOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 253 into the lumen of the bronchus. The epithelium which re- mains after the superficial cells are lost consists of cells which become flatter from base to surface, but the intercel- lular bridges characteristic of the epithelium of the skin are not found. When epithelium is in process of regenera- tion, a layer gradually diminishing in thickness extends . « ■~g * .,-• * u. * -' <■.* t _^~ «•'«*« »vj; 'i.i & Fig. 23. — Squamous epithelium growing over the defect in the bronchial wall shown in Fig. 22 more highly magnified; squamous epithelium is present above and columnar epithelium below. 254 PNEUMONIAS AXI> I X l-T.CTloxs OF RESPIRATORY TRACT over the denuded surface, the advancing edge being formed by very lint cells in a single layer. The epithelium grow- ing into fissures which have penetrated the bronchial wall may completely cover the exposed alveolar tissue. The newly formed epithelium may follow a fissure into an alve- olus which lias been opened and conic into contact with the fibrin which fills the alveolus. Bronchiectasis usually affects the small bronchi with no cartilage. It is not uncommon to find greatly dilated bron- chi with no cartilage in close proximity to cartilage con- taining bronchi of smaller caliber. In one instance (Au- topsy 421) a bronchus of medium size with cartilage meas- ured 3 mm. in diameter, whereas two bronchi with no car- tilage were dilated to 4 and mm., respectively. Neverthe- less, larger bronchi are occasionally the site of superficial loss of epithelium, necrosis extending into the bronchial wall, formation of fissures and si retching of the wall at the spot which is weakened. In association with these changes atrophy of the cartilage may occur (Autopsies 421, 425, 440, 4(53). Plates of cartilage in process of atrophy are readily recognized by their irregularly indented outline and often by their small size. The fibrous tissue surround- ing the cartilage is the site of chronic inflammation and is densely infiltrated with lymphoid and plasma cells among which polynuclear leucocytes are scant. Nevertheless, polynuclear leucocytes are abundant in immediate contact with the cartilage and appear to have an important part in the solution of its matrix, for about them occur indenta- tions of the edge. Leucocytes penetrate into the cartilage. The necrosis and tears which occur in the wall of the bronchus are not always limited to the bronchus, but may extend deeply into the surrounding tissue. In Autopsies 312 (Fig. 21) and 423 wide areas of necrosis have pene- trated deeply into the tissue about the bronchi. Autopsy 312. — Illness began with influenza on September 26, seventeen days befoi-f * 1 < • ; 1 1 1 1 : ;i diagnosis <>f lobar pneumonia with consolidation of PATHOLOGY AND BACTERIOLOGY FOLLOWING IXI U'K.YXA 255 the right lower lobe was made ten days after onset and Pneumococcua IV, B. influenzae and S. hemolytieus wore found in the sputum. Af autop . there was bronchopneumonia with rod and gray lobular and confluenl lobular patches of consolidation and right and Lef1 serofibrinous pleurisy; there was purulent bronchitis; no abscesses were scon. Small bronchi throughout both lungs were dilated and often surrounded by a zone of hem- orrhage. Hemolytic streptococci were found in the heart's blood, in the pleural exudate, consolidated lung and bronchus; B. influenzee was found in the lung and in a small bronchus, and staphylococci in the contents of a small bronchus. '■■•■$£$:& ? r \ : 3 ,.;■;.:■, <}S\A^' -,-.-:>-i . ■ ;:->. K*fi L. "%&&■ Fig. 24. — Acute bronchiectasis with fissures extending through bronchial wall which is marked by great engorgement of blood vessels; at one point a fissure has penetrated deep into the alveolar tissue and formed a small cavity containing purulent exudate and surrounded by fibrinous pneumonia. Autopsy 312. Bronchi which are the site of acute inflammation have lost their epi- thelium wholly or in part, and deep fissures penetrate the entire thickness of the bronchial wall, extending into the surrounding lung tissue which is the site of fibrinous pneumonia. In some instances plugs of fibrin within the alveoli are bisected by these tears. There is some superficial necrosis along the edge of each fissure, in several places extending outward from defects in the walls of small bronchi dilated to approximately 1.5 mm. There are wide patches of necrosis affecting both alveolar walls and con- 256 PNEUMONIAS A.ND [NFECTIONS OF RESPIRATORY TRACT tints of alveoli and extending 2 nun. into the lung tissue. When a fissure has penetrated from the lumen of the bronchus into necrotic tissue (Fig. 21), polynuclear leucocytes have accumulated within tin' necrotic t issue, disintegration of tissue occurs, and a small cavity communicating with tin' bronchus is formed. Autopsy 423. — ('. 11., white, aged twenty-live, resident of Oklahoma, had been in military service one month. Death occurred sixteen days after onset of influenza. Anatomical Diagnosis. — chronic bronchopneumonia with peribronchiolar consolidation throughoul righl lung and in left lower lose; right purulent pleurisy; purulent bronchitis; bronchiectasis at base of left lung. The right lung weighs 1,260 grams; in the upper lobe are yellowish gray nodules having the appearance of tubercles clustered about small bronchi; in places similar nodules occur upon a background of pinkish gray consolidation occupying the greater part of the lower lobe. Bron- chi contain purulent fluid. The left lung weighs 760 grams; it is edema- tens and small, yellowish gray nodules of consolidation in the lower lobe are clustered about terminal bronchi. Bronchi at the base of the lower lobe are dilated. Bacteriologic examination shows the presence of hemolytic streptococci in the blood of the heart; hemolytic streptococci and B. influenza? in the lung. .Microscopic examination shows that the walls of the bronchi are in- filtrated with lymphoid and plasma cells; these cells are very numerous in peribronchiolar patches of consolidation. A small bronchus 1 mm. in diameter lias squamous epithelium alone.- one side; on the opposite side, the wall is completely absent and there is superficial necrosis of exposed al- veoli tilled with fibrin. A deep fissure passes from the bronchus into the consolidated tissue; its edges are necrotic and it is filled with polynuclear leucocytes. A small cavity in contact with the bronchus has been formed. In another part of the lung a distended bronchus has lost its epithelium on one side, and here alveoli filled with fibrin form the wall of the bronchus which is tilled with leucocytes. Extending outward from the eroded wall is a focus of necrosis where both alveolar walls and contained exudate have lost their nuclei. The necrosis which lias had its origin in the bronchi is soon followed by accumulation of polynuclear leucocytes, softening and disintegration of tissue. Discharge of the disintegrated tissue through the bronchi results in the for- mation of a small cavity continuous with the bronchus. These changes are well illustrated by the bronchogenic abscesses which have been described elsewhere (Autopsies 376, p. 206, and 387, p. 206). When disintegrated tissue PATHOLOGY AND BACTEKIOLOG'Y FOLLOWING I X FL1 ' KXZA 257 is discharged by way of the bronchi no accumulation of pus occurs, but cavities will be formed, in part by dilation of bronchi, in part by erosion of the adjacent lung tissue. His- tologic examination shows that these changes have pro- duced the advanced bronchiectasis found in Autopsy 445 (Fig. 25). Autopsy 445. — W. F., white, aged twenty-three, from Mississippi, had been in military service one month. His illness began September 22, twenty- seven days before death, with severe coryza, weakness, nausea and vomit- ing; great pain in bones, cough and sore throat. He was admitted to the base hospital one week later with diagnosis of influenza and bronchitis. On October 3, sixteen days before death, signs of consolidation were found on the left side over the back and a diagnosis of lobar pneumonia was made. On October IS there was severe headache, pupils were dilated, and there was rigidity of neck; lumbar puncture was made and pneumococci were found in the fluid obtained. Death occurred on the following day. Anatomic Diagnosis. — Bronchiectasis with unresolved pneumonia limited to the left lower lobe; acute bronchopneumonia with peribronchiolar con- solidation in right lung; purulent bronchitis, peribronchial hemorrhage and organizing bronchiolitis in right lung; adherent pleura on left side; purulent meningitis. The left upper lobe is crepitant throughout. The outer and posterior two-thirds of the left lower lobe is riddled with cavities often rounded and varying in diameter from 0.5 to 3 cm. but not infrequently irregular in shape and in communication with adjacent cavities (Fig. 25). In places cavities pass in a tortuous course from pleura to the midpart of lung. The lining of these cavities is usually smooth, but in places is covered by gray necrotic material. Communication between the cavities and me- dium-sized bronchi is occasionally found. The lung tissue between the cavities is in part grayish red and consolidated, in part pink and air con- taining. The right lung is edematous throughout ; the bronchi in the lower part of the right lung contain purulent fluid and are in places surrounded by zones of hemorrhage. The spleen is very large (14 x 11 x 5 cm.) and firm. The spinal fluid is cloudy and blood vessels over the lumbar enlargement and lower thoracic region are congested; in the upper thoracic region the cord is covered by purulent exudate. Bacteriologic examination demonstrates the presence of hemolytic strep- tococci in the blood of the heart; plates from the left lung contain a few colonies of S. aureus and Pneumococcus IV; plates from the right main bronchus contain S. aureus and a large bacillus which does not stain by Gram's method. Three plates from the spinal meninges contain Pneu- mococcus IV. Microscopic examination shows that the cavities which have been de- scribed are lined by very vascular connective tissue containing many cells; 258 PNEUMONIAS A.ND INFECTIONS OF RESPIRATOR? TRACT Fig. 25.— Advanced bronchiectasis throughout lower left lobe. Autopsy AAb PATHOLOGY AND BACTERIOLOGY FOLLOWING [NFLUENZA 259 there is no epithelial lining and the surface is in places covered by fibrin. On the surface poly-nuclear leucocytes are numerous, bu1 immediately be low, large mononuclear cells occur and frequently contain one or several ingested polynuclear leucocytes. None of the structures peculiar to the bronchi can be identified in the wall of these cavities, and in many places it is evident that lung tissue lias undergone destruction, for in places the lining of vascular connective tissue is interrupted and an extension of the cavity penetrating into the lung substance is surrounded by alveoli filled with fibrin; in contact with the cavity there is some necrosis. The cavities communicate with the bronchi and are lined in part by vascular connective tissue which may in part represent preexisting bronchial walls, but no epithe- lium is present and the relation to the bronchi cannot be es- tablished with certainty. These cavities have extended by necrosis which has broken the vascular connective tissue of their wall and penetrated into adjacent lung tissue. Death has been the result of purulent meningitis caused by pneu- mococcus, and the histologic changes in the walls of the cavities suggest that the activity of the inflammatory reac- tion here is subsiding, for large mononuclear cells are nu- merous and are ingesting polynuclear leucocytes. The changes described would, if continued, result in the forma- tion of cavities lined by fibrous tissue and resembling many of those formed as the result of dilatation of the bronchi. A study of the progress of the changes which result in the formation of bronchiectatic cavities has shown how the inflammatory irritant within the bronchus destroys the epi- thelium of the bronchus, penetrates into the deeper tissues and produces fissures which extend through the entire thickness of the bronchial wall at one or usually several places. These longitudinal fissures, which at first often give a stellate outline in cross section to the cavity of the affected bronchus, permit the separation of the edges of the fissure, so that an increase in the circumference occurs. The base of the fissure is formed by surrounding alveolar tissue and its edges are the site of necrosis. Tears may extend into the surrounding alveolar tissue, thus permit- ting further stretching of the bronchial wall. The conse- 260 PNEUMONIAS AND [NFECTIONS OF RESPntATOIfX TRACT quences of rupture of the small bronchi into the adjacent alveoli are to some extent overcome by the inflammatory reaction which plugs the adjacent alveoli with fibrin. Compression of the lungs by forced expiration, even though the glottis were closed as in coughing, would not dilate the bronchi, because pressure outside and within the bronchi would be equally elevated (Thornton and Pratt ). The pressure within the bronchi does not differ greatly from atmospheric pressure, whereas the negative pressure within the pleural cavity may vary from approximately 6 mm. of mercury during quiet inspiration to 30 mm. with forced inspiration. Excess of pressure upon the inner sur- face of the bronchial walls will vary with coughing and other respiratory efforts, between these limits depending upon the readiness with which pressure is equalized within and without the bronchi by penetration of air into the alve- oli. The presence of viscid mucopurulent fluid within bron- chioles will obstruct these tubules and retard the entrance of air into alveoli. Weakening of the bronchial wall by the changes which have been described will cause lasting dilatation of the bronchi. Whatever increases pressure within the bronchi will increase the tendency to dilatation; the bronchi being filled with mucopurulent exudate dilatation usually ap- pears first at the bases of the lung, since gravity increases intrabronchial pressure here. New 7 formation of fibrous tissue within the wall of the bronchus, thickening of adja- cent alveolar walls, and organization of fibrin reinforce the weakened bronchial wall and limit the dilatation which fol- lows injury to the wall. "Regeneration of epithelium cov- ering the dilated tube will further obscure the early changes which have made dilatation possible. The changes which weaken the bronchial wall permit dilatation at a time when there is no new formation of fibrous tissue. When the bronchial lesion has persisted several weeks, •Thornton and Pratt: Hull. Johns Hopkins Hosp., 1908, xix, 230. PATHOLOGY AND BACTERIOLOGY KOLLOWIXC IXI'U'KXZA 'K\\ chronic pneumonia is associated with it. It has been sug- gested that the contraction of newly formed fibrous 1 issue within the substance of the lung might cause bronchi to be enlarged by traction upon their walls. Newly formed con- nective tissue is most abundant in the wall of the bronchi- ectatic cavity, and here contraction would tend to diminish the size of the cavity. Unresolved Bronchopneumonia Chronic bronchopneumonia is characterized by changes similar to those associated with chronic inflammation in other parts of the body, namely, by thickening of the inter- stitial tissue of the lung, by accumulation of mononuclear cells, by proliferation of fibrous tissue and by organization of exuded fibrin. In a few instances these changes have be- gun at the end of two weeks after onset of influenza, but they have been little advanced until three weeks has elapsed ; advanced chronic inflammation has occurred after from four to eight weeks. Chronic inflammation primarily affects those structures which are most severely injured by the acute lesion and is most conspicuous in immediate prox- imity to the small bronchi and bronchioles; the perivascu- lar and interlobular connective tissue are secondarily involved. Corresponding to each of the lesions of the alve- olar tissue which, have been found with bronchopneumonia, namely, peribronchiolar, hemorrhagic peribronchiolar, lob- ular and peribronchial consolidation, there is a chronic le- sion which develops when pneumonia has failed to resolve. The term interstitial bronchopneumonia has been used by MacCallum to designate a lesion which he has found in association with measles at Fort Sam Houston. This name he states does not describe accurately the early stage of the lesion, for its interstitial character is not evident at first. In his monograph on ''Epidemic Pneumonia in the Army Camp," published in 1919, MacCallum describes and pic- _!>_ PNEUMONIAS AND INFECTIONS OF RESPIRATOR'S TRACT twees instances of the lesion which we have designated in- terstitial suppurative pneumonia and classifies them as in- terstitial bronchopneumonia. We have shown thai this Le- sion, which is the result of infection of the Lymphatics with S. hemolyticus, hoars no necessary relation to the lesion which is characterized in its early stage by peribronchiolar pneumonia and in its later stages by chronic inflammation with mononuclear infiltration and proliferation of the peri- bronchial, perivascular and interalveolar tissue. At Fort Sam Houston, nearly every patient with measles was in- fected with hemolytic streptococci; we observed, following influenza, similar prevalence of hemolytic streptococci in certain wards in the base hospital at Cam]) Pike. Among the cases at Fort Sam Houston there were doubtless instances both of interstitial suppurative pneumonia caused by hemo- lytic streptococcus and of chronic bronchopneumonia not referable to this microorganism. Studying pneumonia following influenza at Camp Lee, A'a., and later at Camp Dix, X. J., during the fall of 1918, MacCallum reached the conclusion that "interstitial bron- chopneumonia" following influenza was caused by B. influ- enzae of Pfeiffer. This lesion attributed to B. influenzae differed from that previously referred to hemolytic strep- tococcus in the following characters: the lymphatic chan- nels in the bronchial walls and widened interlobular septa are inconspicuous and none are found distended with exu- date ; there is no intense infection of the pleura, and poly- nuclear leucocytes are inconspicuous in the alveolar exu- date and in the w T alls of the bronchi. It seems probable these differences are explained by the absence of hemolytic streptococci which tend to invade lymphatics and produce severe inflammatory changes in the pleura. Chronic Bronchitis. The earliest changes in the bron- chial wall with bronchitis of influenza are hyperemia, leu- cocytic infiltration and hemorrhage, and they may occur even though the lining epithelium remains intact. Epithe- PATHOLOGY AND BACTEBIOLOGY FOLLOWING IXFU'KXZA 263 lium frequently undergoes partial or complole dcsl i-iu-tion, and with this severe injury the influence of the Lnflanraia tory irritant may extend directly through the wall of the bronchus, for in some instances there is hemorrhage into all the alveoli in a zone encircling the bronchus. Since these alveoli have only indirect communication with the affected bronchus through alveolar tissue not involved in the in- flammatory process, it is evident that the surrounding hemorrhage is secondary to the lesion of the bronchus. Fibrinous inflammation in other instances, similarly local- ized in a zone of alveoli encircling a bronchus, is doubtless the result of direct extension of the inflammatory process through the bronchial wall. After the disease has existed during two or three weeks inflammation is still active im- mediately below the inner surface of the bronchus; here polynuclear leucocytes are numerous whereas in the deeper parts of the mucosa and about the muscularis leucocytes are scant but lymphoid and plasma cells are very numerous. The severity of the inflammatory reaction may be judged by the abundance and extent of this cellular reaction and is in close relation to the intensity of the changes affecting the mucous membrane of the bronchus. Infiltration of the entire bronchial wall with lymphoid and plasma cells is almost invariable when the primary injury to the bronchus has destroyed the epithelial lining, and this infiltration is not limited to the bronchial wall but extends outward into the contiguous alveolar septa which are thickened by it. The sheath of the pulmonary artery which accompanies the bronchus exhibits a similar change, and the alveolar septa, as a fringe about it, are thickened and infiltrated with mon- onuclear cells. Interlobular septa continuous with the bron- chus often show some infiltration. A later phase in this series of changes is represented bv new formation of fibrous tissue. The bronchial walls and interalveolar septa are thickened by proliferating fibrous tissue, young fibroblasts and newly formed collagen fibrils 264 PNEUMONIAS AND [NFECTIONS OF RESPIRATOR'S TRACT being abundant (Fig. i N : also Fig. ."lit). This increase of fibrous tissue is especially noteworthy immediately sur- rounding the walls of the small bronchi, which are often considerably dilated, and aboul the smaller of those bron- chi which have cartilage; with thickening of alveolar walls immediately adjacent to the bronchus every stage in the obliteration of the alveoli may he found. Their walls are thickened and their lamina are diminished in size and often flattened in a direction concentric with the bronchus. Such atrophied alveoli lined by cubical epithelial cells occurring within the thickened peribronchial fibrous tissue give evi- dence that this tissue has replaced alveoli. Alveoli sur- rounding and within the new fibrous tissue are fre- quently tilled with fibrin, and organization indicated by penetration of fibroblasts and capillaries into the fibrin may he far advanced. There is some increase of perivascu- lar and interlobular tissue. The bronchiectasis which is almost invariably found with unresolved bronchopneumo- nia has been described. Squamous transformation of epi- thelium (page 251) is frequently found in association with the chronic bronchitis of unresolved pneumonia. Organizing Bronchitis and Bronchiolitis. — When the bronchial epithelium is destroyed, fibrin is deposited upon the denuded surface and may partly or completely fill the lumen of the bronchial tube. The plug of fibrin is adherent to the underlying tissue wherever epithelium is lost hut is separated from the bronchial wall by a well-defined space where epithelial lining is still intact. Fibroblasts promptly migrate Prom the wall of the bronchiole into this fibrin, and fibroblasts, fixed during ameboid movement, are irregularly elongated in a direction toward the fibrin. Organization of fibrin occurs within the smallest bronchi (diameter 0.3 to 0.5 mm.) or within respiratory bronchioles. It lias been found in 8 autopsies. In one instance it has been present eleven days after the onset of influenza, hut usually it is seen three or four weeks after onset of symp- PATHOLOGY AND BACTERIOLOGY FOLLOWING I X FL1 ' KXZA 265 toms of respiratory disease. In the early stages of the lesion a plug of fibrin within the lumen of the bronchus or bronchiole is. invaded by fibroblasts, plasma cells and newly formed capillaries. These capillaries have their origin in the wall of the tube and enter the fibrin at points where in consequence of loss of epithelium fibrin is continuous with the connective tissue. When the bronchiole is cut longitudinally, partially or completely organized fibrin may be found adherent at several places with intact epithelium, sometimes beautifully ciliated, between the sites of attach- ment. The fibrin is finally replaced completely and the lumen of the bronchiole contains a mass of organized fibrous tissue in which young fibroblasts and plasma cells are numerous. The lesion has been associated with chronic bronchopneu- monia in 6 of 8 instances. In Autopsy 445, p. 257, organ- izing bronchitis and bronchiolitis occurred in the right lung unassociated with other chronic lesion, although there was advanced bronchiectasis with fibrous induration in the left lung. In Autopsy 499 (p. 224) organizing bronchiolitis occurred in association with chronic changes which appear to have followed interstitial suppurative pneumonia caused by S. hemolyticus. Other severe lesions of the bronchi have accompanied organizing bronchitis and bronchiolitis. Purulent bronchitis has been present in 7 of 8 instances; bronchiectasis in 5 of 8 instances. The bacteriology of autopsies with organizing bronchitis and bronchiolitis is shown in Table LIII. The bacteriology of these cases presents no constant feature. Invasion of the blood by S. hemolyticus has been present in a large proportion of cultures, namely, in 5 of 7 (71.4 per cent). In one of the 2 instances in which hemo- lytic streptococci have been found, neither in the blood nor lungs, Pneumococcus III has been found in the blood and S. viridans in the lungs and bronchus ; in the other, S. aureus has been found in the lung and bronchus. Staphylococci 266 PNEUMONIAS \\l> INFECTIONS OF RESPIRATOR'S TRACT TAB] E I.I I I AlTdl'SV Dl RAMON OF ILLNESS BLOOD I CJNGS BRONCHI S 4L'0 11 days S. hem. s. hem., B. inf.. 8 102 14 " Pneum. I V, S. aur. 370 457 ll'l 17 " 17+ " 19 " hem. s. hem. s. aur. Pneum. IV, s. S. aur., Pneum. IV. B. inf. Pneum. IV, 11. inf. 445 27 " S. hem. hem. Pneum. IV, S. aur. S. aur. 473 499 28+ " 36 " Pneum. 1 1 r S. horn. S. vir. B. inf., S. vir., staph., M. catarr. S. hem. B. inf. have been round frequently in the bronchi (60 per cent) and in the hmgs (50 per cent). B. influenzae lias been pres- ent in the bronchi in the usual proportion of instances (80 per cent). The lesion lias occurred in the presence of 15. influenzas combined with streptococci or staphylococci. Thrombosis of lymphatics in the Avail of bronchi adjacent to blood vessels and in interlobular septa occurs, and occa- sionally organization of the fibrinous plug within the lym- phatic is in progress (Autopsies 2S3, 425 and 463). Fibro- blasts and capillaries penetrate from the wall of the lym- phatic into a mass of hyaline fibrin which fills the lumen. Unresolved Bronchopneumonia. — The most common type of pneumonic lesion following influenza is characterized by acute inflammation of the alveoli immediately adjacent to the bronchioles and the lesion is associated in many in- stances with hemorrhage or edema. If this lesion persists unresolved during several weeks, evidences of chronic in- flammation are found. Peribronchial, perivascular and in- terlobular connective tissue is thickened and richly infil- trated with lymphoid and plasma cells, large mononuclear cells and many young fibroblasts. Interalveolar septa ad- jacent to the walls of bronchi and between alveoli surround- ing inflamed bronchioles are implicated in the process. PATHOLOGY AND BACTERIOLOGY FOLLOWING I NTL1 ' B X ZA 267 Interstitial changes characterize the lesion only in its late stage. It appears undesirable to give the name "interstitial pneumonia" to the early stage of a lesion which begins and in most instances terminates as an acute relatively super- ficial inflammation of the bronchi, bronchioles and peri- bronchiolar alveoli. Chronic bronchopneumonia is often overlooked at au- topsy because newly formed connective tissue is not present in sufficient quantity to attract attention (Fig. 26). When the lesion is advanced conspicuous gray white patches of fibrous tissue may be seen about the bronchi (Autopsy 487; Fig. 27) and interlobular septa may be obviously thickened (Autopsy 472). The most distinctive feature of the lungs is the presence of small, firm, gray or yellowish gray nod- ules of consolidation which resemble miliary tubercles. They represent the peribronchiolar patches of broncho- pneumonia present during the acute stage and have assumed the well-defined outline and firm consistence of tubercles because polynuclear leucocytes and red blood cor- puscles have in large part disappeared, interstitial tissue is increased, and exudate is in process of organization. These nodules are grouped in clusters about the small bronchi. With unresolved bronchopneumonia the lungs are very voluminous and fail to collapse after they are removed from the chest and in some instances even after incision. The air containing tissue is usually dry. In our autopsies the lungs have been pink in color and often free from coal pig- ment, because those suffering with pneumonia have been in considerable part men from rural districts. Thick muco- purulent material exudes from the small bronchi which have been cut across ; purulent bronchitis has been present in 20 of 21 instances of chronic bronchopneumonia. Bron- chiectasis has been present in 13 instances; dilatation is often advanced, so that throughout the lungs are found bronchi with no cartilage distended to a diameter of 0.5 cm. 268 PNEUMONIAS A.ND [NFECTIONS OF RESPIRATORY TRACT I'ig. 26, -Unresolved bronchopneumonia with tubercle-like nodules of peribronchiolar consolidation best seen in lower lobe; bronchiectasis. Autopsy 425. PATHOLOGY A X I ) I iA ( !TE RIOLOGY FOLLOWING [NFLUE N ZA 269 In addition to the firm peribronchiolar tubercle-like nod- ules of consolidation there are scattered patches of gray lobular or confluent lobular consolidation. Yellowish nod- ules, grouped about bronchi and resembling those found elsewhere in air containing tissue, are occasionally seen scattered upon the cut surface of a patch of gray, confluenl lobular consolidation (Autopsies 421, 423, 431). Microscopic examination demonstrates the presence of those changes which have been described in association with chronic bronchitis and bronchiectasis. There is abun- dant new formation of fibrous tissue about the bronchi of small and medium size, thickening of adjacent interalveolar walls and incorporation of alveoli into the thickened bron- chial wall (Figs. 27, 28, 30, and 31). In half of the in- stances of chronic bronchopneumonia there has been peri- bronchial fibrinous pneumonia, and organization of fibrin within the alveoli is usually well advanced. In one instance (Autopsy 487; Figs. 27 and 28) after an illness of fifty-five days this process has resulted in the formation of conspic- uous patches of firm, grayish white fibrous tissue surround- ing dilated bronchi. Organization of fibrinous exudate within the lung has not been limited to the alveoli but has occurred in the bronchioles as well. Organizing bronchio- litis has been present in 5 instances (Autopsies 370, 402, 457 and 473). Increase of fibrous tissue occurs about the blood vessels and in the septa between the lobules, which are infiltrated with mononuclear wandering cells and fibroblasts. Dila- tation and thrombosis of the lymphatic vessels have oc- curred in both situations, and in 3 instances (Autopsies 283, 425 and 463) organization of these fibrinous thrombi has occurred. Thickening, cellular infiltration and fibrosis of the bron- chial walls with interstitial inflammation and fibrosis of im- mediately adjacent alveolar septa are found about the ramifications of the bronchial tree and may be followed 270 PNEUMONIAS AND INFECTIONS OF RESPIRATORS TRACT I r ig. 27. — Unresolved pneumonia with peribronchial formation of fibrous tissue; bron- chiectasis. Autopsy 487. PATHOLOGY AND BACTERIOLOGY FOLLOWING I X FIJ'KXXA 271 to the smallest bronchi. When the respiratory bronchioles are readied it will be found that the alveoli which stud 1 heir walls are implicated in the change. The fibrin which they contain is infiltrated with lymphoid and plasma cells, and with progress of the lesion is invaded by fibroblasts and capillaries. Infiltration and fibroid thickening extends from the bronchiolar wall to the alveolar septa continuous with it (Fig. 31 with measles). Similar changes occur aboul s%** ■> *$if* Fig. 28. — Unresolved pneumonia with bronchiectasis showing new formation of fibrous tissue about a greatly dilated bronchus of which the epithelial lining has been lost. Autopsy 487. the alveolar ducts, and about the orifices of the tributary infundibula (Fig. 32), peribronchiolar foci of acute inflam- mation having assumed the characters of a chronic inflam- matory process. Fibrin within the alveoli contains round cells and fibroblasts. With thickening of alveolar walls the alveolar lumina may be much diminished in size and often persist as spaces lined by cubical cells. Polynuelear leu- cocytes are usually numerous within the alveolar duct and Li_ PNEUMONIAS AND [NFECTIONS OF RESPIRATOR? TRACT in a few alveoli immediately adjacent to it, but elsewhere throughoul the focus of inflammation round cells arc pre- dominant. The changes which have been described corre- spond with the transformation of ill-defined, gray or red- dish gray spots of consolidation grouped about the termi- nal bronchi into firm sharply denned grayish while nodules having the consistence and appearance of miliary tubercles. One of the most constant characters of pneumonia fol- lowing influenza is its hemorrhagic character. In the earlier stages of pneumonia phagocytosis of red blood cor- puscles by large mononuclear cells is frequently seem. In association with the chronic changes which have been de- scribed, large mononuclear cells filled with brown pigment, doubtless formed from red corpuscles, are often found within the alveoli. These pigment containing cells are sim- ilar to those commonly associated with chronic passive con- gestion of the lungs. In one instance (Autopsy 457) hemorrhagic peribron- chiolar pneumonia has been found in process of organiza- tion. The bronchioles and alveoli adjacent to them contain polynuclear leucocytes, but intervening alveoli almost uni- formly contain blood and are the site of new formation of connective tissue. Interalveolar septa are thickened and alveoli which arc lined by cubical epithelium are often di- minished in size. In many places fibroblasts have pene- trated in considerable number into the blood within the al- veoli and occasionally newly formed capillaries are found within them. Lobular patches of pneumonia are often found in process of organization (Autopsies 370, 421, 42:5, 433, 463, 472 and 473). Microscopic examination shows that whole lobules well defined by thickened septa are the site of chronic in- teralveolar inflammation and intraalveolar organization of exudate, whereas adjacent lobules are air containing and relatively normal. In the earlier stages of the process fibrin present within the alveoli is invaded by fibroblasts, PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 273 mononuclear wandering cells and Mood vessels bill in tlie later stages fibrin lias disappeared; the lumina of the alve- oli are occupied by cellular fibrous tissue and in places the thickened alveolar Avails and intraalveolar fibrous tissue have been fused to form wide patches of new tissue. With chronic bronchopneumonia confluent lobular con- solidation occasionally has a gray ground upon which are scattered small yellow spots clustered about the small bronchi (Autopsies 421, 423 and 431). Microscopic exam- ination has shown that the yellowish spots correspond to dilated bronchioles filled with purulent exudate and sur- rounded with alveoli containing many polynuclear leuco- cytes. In the interstitial tissue about the bronchiole and between adjacent alveoli plasma cells are often present in great number. Between these spots of subacute bronchio- lar inflammation lung tissue is the site of interalveolar pro- liferation of fibrous tissue and intraalveolar organization of exudate. In all instances of chronic bronchopneumonia there has been peribronchial pneumonia in a zone encircling small bronchi with no cartilage and the smallest of the bronchi which have cartilage in their wall; thickening of interal- veolar septa, organization of peribronchial fibrinous pneu- monia and partial disappearance of alveoli have been de- scribed. In the following autopsy peribronchial fibroid pneumonia has been so advanced that conspicuous patches of gray white tissue surrounding bronchi have replaced in some parts of the lung a considerable part of the lung sub- stance. Autopsy 487. — W. C, white, aged twenty-seven years, a farmer from Mississippi had been in military service twenty-one days. Illness began on September 17, fifty-five days before death, with chill, fever, cough, back- ache, pain in the chest and coryza. The patient was admitted two weeks after onset with the diagnosis of influenza. Eight days later his sputum was blood tinged and there were signs of bronchopneumonia. One month after admission the patient developed a rash and a diagnosis of scarlet fever was made. l!<4 PNEUMONIAS AND INFECTIONS OF RESPIRATOR'S TRACT Anatomic Diagnosis.— Chronic bronchopneumonia with peribronchial fibroid induration; bronchiectasis; purulenl bronchitis; abscesses at the bases Qf both lungs; seropurulenl pleurisy on the left side. The body, is much emaciated. The left pleural cavity contains 650 <•.<•. of opaque, 'lull yellow, thin, purulent fluid. The surface of the left lung is covered in spots by white partially organized fibrin. On section of the right lung | Pig. 27) the tissue is found in great part air containing but there are numerous linn, gray patches, irregular in shape and from 1 to _ cm. across. In these spots the tissue is tougb and resembles fibrous tissue: within them are much dilated bronchi. In the central part of the upper lobe is a group of cavities with smooth wall, the largest of these cavities being 12 mm. in diameter; immediately adjacent are di- lated bronchi. Between and surrounding these cavities is gray tissue, like that described above. Below the outer surface of the upper lobe is an extensive area 7 cm. from above downward, thickly studded with bron- chiertatir cavities, in the walls of which there is tough fibrous tissue. In the middle lobe are several dilated bronchi, the largest of which is 7 mm. in diameter, and elsewhere occur dilated bronchi with thickened walls. At the base of the lung below the pleura are two abscesses, which are yellow in the center and surrounded by hemorrhagic tissue. At the posterior part <<\' the lower lobe there are numerous firm, nodular, yellowish spots grouped in (dusters upon a background of red, air containing tissue. The bronchi throughout the lung contain mucopurulent fluid. In the left lung patches of fibrous tissue are more numerous than on the right side and are irregular in shape, from 1 to 2 cm. across and most abun- dant in the center of the upper lobe. This fibrous tissue is in great part gray but in places it has a yellowish tinge. The bronchi everywhere are moderately dilated. At the base of the lung below the pleura is an abscess. The other organs show no noteworthy change. Bacteriologic Examination. — The fluid in the left pleura and right main bronchus contain S. hemolyticus. B. influenzae is found in the right lung and right main bronchus. Microscopic examination shows that the patches of dense fibrous tissue seen at autopsy almost invariably surround dilated bronchi with no cartilage in their walls (Fig. 28) and with a diameter of from 1 to 2 or more milli- meters. These bronchi have lost their epithelial lining; they' contain poly- nuclear leucocytes, and their wall in contact with the lumen is infiltrated to a varying distance with the same cells. Their inner surface is very irregular, and superficial necrosis occurs. The limits of the preexisting bronchial wall is no longer recognizable in the dense surrounding fibrous tissue richly infil- trated with lymphoid and plasma cells. In contact with the bronchus, often in a wide zone, all traces of alveoli have been destroyed, but further outward alveoli are represented by spaces lined by cubical epithelium. At the peri- phery of the zone of fibroid induration alveolar walls are much thickened and richly infiltrated with mononuclear wandering cells; the lumina of the alveoli contain plugs of organized fibrous tissue often covered by flat or cubical epithelium. In the surrounding tissue a few small bronchi are lined by col- PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 275 umnar epithelium; there is scant new formation of fibrous tissue but the alveolar walls are thickened and infiltrated with cells. Epithelium of the larger bronchi with cartilage in their walls is usually intact and there is aboul them little peribronchial inflammation. Advanced induration about the bronchioles represents a late stage of chronic peribronchiolar pneumonia. A bron- chiole cut transversely is found in the center of a focus of induration situated within relatively normal air containing lung tissue. Next the bronchiole which in some instances has wholly or partly lost its epithelium there is very cellu- lar fibrous tissue ; further from the bronchiole alveoli are much diminished in size, lined by flat or cubical epithelium and separated by thick cellular walls. Plugs of cellular fibrous tissue sometimes fill the alveolar duct. In favorable sections, cut in a plane which shows the alveolar duct open- ing out into infundibula, it is found that newly formed fi- brous tissue surrounds the alveolar duct and extends into the walls of its tributary alveoli ; alveoli may be obliterated by this fibrous tissue. Induration of alveolar walls is evi- dent along the proximal part of the infundibula which are readily demonstrable because they are much dilated. (See Fig. 32.) The distal parts of the infundibula are sur- rounded by alveoli with delicate walls. One bronchus retains along one side part of its epithe- lium which has assumed a squamous form. In other places the wall has undergone necrosis which at one spot extends deeply into the surrounding tissue. Necrotic tissue in an- other part of the circumference is infiltrated with polynu- clear leucocytes and separated from the surrounding tissue by a space filled with leucocytes. An abscess communicat- ing with the bronchus is thus formed. The foregoing instance is an example of the chronic fi- broid pneumonias with bronchiectasis which occur as se- quela? of the epidemic of influenza. It is not improbable that a considerable number of those who suffer with chronic bronchitis and bronchiectasis following influenza have less extensive lesions similar to those which have been described. 276 PNEUMONIAS AND [NFECTIONS OF RESPIRATOR'S TRACT Bacteriology of Unresolved Bronchopneumonia. — Bacte- ria Pound in the bronchi in 10 instances of chronic broncho- pneumonia have been as follows: Bacteria i\ Bronchi with Chronic Bronchopneumonia B. eoli 1 B. influenzae and pneumococcus 1 B. influenzae and S. hemolyticus 2 B. influenzae and staphylococcus 1 s. hemolyticus and B. coli 1 B. influenzae, pneumococcus and staphylococcus 3 B. influenzae, S. viridans and M. catarrhalis 1 Bacteria found in the lungs in 17 instances of chronic bronchopneumonia wore as follows: Bacteria in Lungs with Chronic Bronchopneumonia B. influenzae 1 Staphylococcus 1 s. \ iridans 1 B. influenzae and pneumococcus 1 B. influenzae and S. hemolyticus 3 B. influenza' and staphylococcus 3 Pneumococcus and S. hemolyticus 1 s. hemolyticus and B. coli 2 I'., influenza', S. hemolyticus and staphylococcus .1 Xo organism found 1 A noteworthy feature of these lists is the multiplicity of microorganism found, namely, B. influenzae, S. hemolyticus, pneumococcus, staphylococcus, S. v iridans, B. coli, and M. catarrhalis. More than one microorganism is usually found in both bronchus and lung. In the one instance (Autopsy 472) in which B. coli alone has been found in the bronchus, B. eoli and S. hemolyticus have been found in the lung and hemolytic streptococcus in the blood; it is evident that B. coli alone has not been responsible for the lesion. In one instance (Autopsy 487) B. influenza? alone has been found in the lung but hemolytic streptococci have been found in the bronchus, pleura and blood of heart; with S. aureus alone in the Lung (Autopsy 370), S. aureus, Pneu- mococcus IV and B. influenza' have been found in the bron- chus. With S. viridans alone in the lung (Autopsy 473), PATHOLOGY AND BAGTUUIOLOG Y FOLLOWING INFLUENZA ( ( Pneumococcus III has been found in the pleura and in the Mood of the heart and tins doubtless had an importanl part in the production of pneumonia; S. viridans, M. catarrhalis and B. influenzas have been found in the bronchus in this in- stance. No single microorganism is associated with the lesions but combinations of B. influenzae with hemolytic strepto- cocci or staphylococci arc common (over 50 per cent). In Autopsy 422 B. influenza 1 and Pneumococcus atypical II have been present in the lungs. Among 10 instances in which cultures have been obtained from the bronchus B. influenza?, is found 8 times, and in the 2 instances in which it has not been identified B. coli has been present. B. in- fluenza? has seldom been found (Table XXVII) in the pres- ence of B. coli, and it is not improbable that B. coli out- grows and obscures the presence of B. influenza?. Table LIV shows the per cent incidence of pneumo- cocci, hemolytic streptococci, staphylococci and B. in- fluenza? in the bronchus, lung and heart's blood with chronic bronchopneumonia and serves as an index of the readiness with which each of these microorganisms passes from bron- chus to lung and from lung to the blood in this disease. Table LIV PNEUMOCOCCUS PER CENT POSITIVE HEMOLYTIC STREPTOCOCCUS PER CENT POSITIVE STAPHYLO- COCCUS PER CENT POSITIVE B. INFLUENZAE PER CENT POSITIVE Bronchus Lung Blood 40.0 12.5 16.6 30.0 56.2 55.6 50.0 37.5 80.0 68.7 Comparison of Table LIV with the analogous figures for acute bronchopneumonia shows little noteworthy dif- ference. Pneumococci are less frequently found, in the lung (12.5 per cent) and in the blood (16.6 per cent) with chronic bronchopneumonia than with acute bronchopneu- monia (lung 43.9 per cent ; blood, 40.3 per cent) . Hemolytic streptococci and staphylococci are not more frequently 278 PNEUMONIAS A.ND [NFECTIONS OF RESPIRATOR? TRACT found with unresolved than with acute bronchopneumonia and failure to resolve cannol be referred to either or to both microorganisms, for bronchopneumonia nol infrequently re- mains unresolved in their absence. B. influenzae is present in the bronchi in at least 80 per cent of instances and per- haps in all: it is usually combined both in the lungs and in the bronchi with one of the pyogenic cocci. The severity of the injury to the walls of bronchi result- ing in continued infection with a variety of bacteria, appears to be the factor determining failure of resolution and the persistence of bronchopneumonia. The Relation of Unresolved Bronchopneumonia to Inter- stitial Suppurative Pneumonia Caused by Hemolytic Strep- tococci. — Hemolytic streptococci have been present in a considerable proportion of those who have had unresolved bronchopneumonia and its occurrence in the bronchi, lung and blood of the heart indicates that it has had an impor- tant part in causing death. Unresolved bronchopneumo- nia, following measles, designated by MacCallum "inter- stitial bronchopneumonia" in a series of autopsies at Fort Sam Houston in the spring of 1918, was constantly asso- ciated with hemolytic streptococci. Among the lesions de- scribed as interstitial bronchopneumonia was at least one which was evidently what we have designated interstitial suppurative pneumonia. Lymphangitis was not infre- quently found with "interstitial bronchopneumonia" fol- lowing measles. At Camp Lee and Camp Dix, following the epidemic of influenza, MacCallum found "interstitial bronchopneumonia" with no hemolytic streptococci and noted that lymphatics in the interstitial septa were incon- spicuous and that none was found distended with exudate; empyema was not present. We have shown that interstitial suppurative pneumonia is an acute lesion caused by hemolytic streptococci. Unre- solved bronchopneumonia is accompanied by chronic pneu- monia and has no necessary relation to this microorganism. PATHOLOGY AND BACTEIUOLOO Y FOLLOWING INFLUENZA 279 In a foregoing section we have described instances of in- terstitial suppurative pneumonia unaccompanied by chronic changes, and in the present section we have described in- stances of unresolved bronchopneumonia with no infection by hemolytic streptococci. We have pointed out that the incidence of streptococcus infection with unresolved bron- chopneumonia does not materially differ from that willi acute bronchopneumonia even though the greater duration of the disease gives more opportunity for infection. In some of the autopsies made by MacCallum at Fort Sam Houston, lesions of streptococcus infection doubtless coex- isted with unresolved bronchopneumonia. In the 3 autopsies described below, interstitial suppura- tive pneumonia with empyema caused by hemolytic strepto- coccus occurs in association with unresolved broncho- pneumonia. Autopsy 420. — J. E. S., white, aged thirty-two years, born in England and resident of Los Angeles, Cal., had been in military service one month. Onset of illness began on October 3, eleven days before his death. He was admitted to the hospital on the following day with the diagnosis of influenza and acute bronchitis. Pneumonia believed to be lobar was recognized eight days after admission. Anatomic Diagnosis. — Unresolved bronchopneumonia with hemorrhagic peribronchiolar consolidation in right lung; interstitial suppurative pneumonia with consolidation in left upper lobe; fibrinopurulent pleurisy; purulent bron- chitis. The left pleural cavity contains 200 e.e. of turbid yellow fluid in which are flakes of fibrin. In the inner and upper part of the left upper lobe there is an area of consolidation where the tissue has a cloudy, pinkish gray color and is finely granular on section. Here the interstitial septa are distended by edema, so that they are in places 0.5 c.e. across; in some spots they have a bright yellow color. In the posterior parts of the middle and lower lobes there is flabby consolidation where the tissue has a cloudy, red color with scattered ill-defined yellow spots. Bacteriologic examination shows the presence of hemolytic streptococci in the blood of the heart; hemolytic streptococci with B. influenza? and S. aureus in the left lung and S. hemolyticus with S. aureus in the right lung. Microscopic examination shows that bronchi, bronchioles, alveolar ducts and the greater part of the infundibula are filled with polynuelear leucocytes, whereas the alveoli surrounding these structures contain fibrin. The walls of the small bronchi are thickened and contain mononuclear cells; the adjacent 280 PNEUMONIAS AND INFECTIONS OF RESPIRATORS TRACT alveolar walls are similarly infiltrated and thickened and the fibrin within them is undergoing organization, being invaded by plasma cells, fibroblasts and ne.wly formed blood vessels. In some sections interstitial septa are dis- tended l'\ edema and contain fibrin in abundance; in places the tissue contains polynuclear leucocytes closely packed together. There are lymphatics greatly distended by polynuclear leucocytes with some fibrin, lymphocytes and red bl 1 corpuscles. Autopsy 428. — I). 11. . while, aged twenty-five, a farmer from Oklahoma, had been in military service three weeks. Onset of illness was on September 21, twenty-five 'lavs before death, with fever, cough and mucopurulent ex- pectoration. The patient w.is admitted with the diagnosis of acute bilateral bronchitis. Pour days Inter bronchopneumonia was recognized, and subse- quently there was otitis media and empyema; 600 c.c. of thin, purulent fluid were aspirated from the right chest three days before death. Anatomic Diagnosis. — Unresolved bronchopneumonia; suppuration of in- terstitial tissue of upper right ami lower left lobes; purulent bronchitis; fibrin opurulent pleurisy; thoracotomy wound at the base of the righl chest; collapse of both lungs; serofibrinous pericarditis. The left pleural cavity contains ;">() c.c. of turbid seropurulenl fluid in which are numerous Hakes of soft fibrin. The right pleural cavity contains 150 c.c. of similar fluid. The mediastinum is edematous. The pericardial cavity contains 50 c.c. of yellow fluid. The right lung is moderately collapsed. In the upper and lower lobes are small patches of red, lobular consolidation. The upper third of the upper lobe is laxly consolidated and near its inner surface the interstitial septa are thickened to from 1 to 1.5 mm. in width, and at intervals occur bead-like swellings from which creamy purulent fluid exudes upon the cut surface. In the left lung small patches of gray consolidation occur throughout the lower lobe and here the interstitial septa are thickened, beaded and contain puru- lent fluid. Bacteriologic examination shows that the Mood contains S. henmlyt icus : from the right lung and from the right main bronchus hemolytic streptococci and B. influenza? are grown. Microscopic examination shows that the epithelium of the bronchi lias undergone hypertrophy; the wall is infiltrated with lymphoid ami plasma cells and thickened by new formation of fibrous tissue; there is similar thicken- ing of adjacent alveolar septa and alveoli, often lined by cubical cells, are diminished in size. Connective tissue about the blood vessels and the inter- stitial septa are thickened and infiltrated with mononuclear cells. In parts id' the lung the interstitial septa are edematous and contain polynuclear leu- cocytes, in some places in great number. Lymphatics are greatly dilated and filled with polynuclear leucocytes which in the center of some lymphatics have undergone necrosis. In one place a small abscess is in contact with a de- fended lymphatic Lymphatics contain ( i ra m-sta i ning cocci in pairs and short ehains, present in immense number where uecrosis has occurred. Autopsy -433. — B. .L, white, aged twenty-seven, from Arkansas, has been in military service one mouth. Onset of illness was on September 28, nine- PATHOLOGY ANM) BACTERIOLOGY FOLLOWING I N FL1 'KX/A 281 teen days before death, with cough and expectoration. Pneumonic consolida tion was recognized two days later and 20 c.c. of cloudy fluid were aspirated from the left chest on the same day. Hemolytic streptococci were found in a culture from the throat nine days before death. Anatomic Diagnosis. — Unresolved bronchopneumonia with peribronchiolar and confluent lobular consolidation ; interstitial suppuration of the righl lower lobe; purulent bronchitis; fibrinopurulcnt pleurisy. The right pleural cavity contains 7(io c.c. of .yellowish gray purulent fluid containing flakes of fibrin. The left pleural cavity contains seropurulenl fluid localized over the external part of the lung. The right lung is voluminous and free from consolidation save at the lower and posterior part of the lower lobe where the tissue is deep red and studded with firmer spots of yellow color clustered about the bronchi. In places the interstitial septa are thickened and yellow. Surrounding some of the bronchi near the apex of the left lung are red patches of consolidation. Culture from heart's blood remained sterile. S. hemolyticus was grown from right pleural cavity, and S. hemolyticus and B. influenzae were grown from the right lung. Culture from the left lung contained S. aureus and contaminating microorganisms. Microscopic examination shows the presence of peribronchiolar patches of pneumonia in which there are few polynuclear leucocytes and many lymphoid and plasma cells; the alveolar walls are thickened and infiltrated with mono- nuclear cells. In some sections the tissue is wholly consolidated and the site of advanced organizing pneumonia. Interlobular septa and connective tissue about blood vessels are thickened and cellular. Small bronchi have lost their epithelial lining, their walls are thickened and there is peribronchial organ- izing pneumonia. In some sections the lymphatics are immensely dilated and distended with polynuclear leucocytes. There is necrosis of the walls of the lymphatics and of the polynuclear leucocytes within the lumen. In the discussion of acute bronchopneumonia it has been shown that S. hemolyticus is not infrequently a secondary invader of a pneumonic lesion perhaps caused by pneumo- cocci. With progress of the disease hemolytic strepto- cocci persist. In the autopsies with unresolved pneumo- nia just described, hemolytic streptococci have found their way into the lymphatics and produced suppurative lym- phangitis with inflammation of the interstitial septa of the lung. CHAPTEE V SECONDARY [NFECTION IX THE WARD TREATMENT OF MEASLES James C. Small, M.D. A study of !)"!' cases of measles Mas made in the base hospitals of Camps Funstoii and Pike from July to Decem- ber, 1918, with the purpose of establishing any existing re- lation between the prevalence of the hemolytic streptococci and the incidence of the graver complications of measles, especially the pneumonia following measles. The greater number of these cases occurred at Camp Pike coineidently with the influenza epidemic, so that the picture is modified during this period by a summation of the after effects of the two diseases. The work undertaken includes: (a) Pontine throat cultures on admission of all patients with measles. (b) Separation and treatment in separate wards of the patients harboring hemolytic streptococci and those free from such streptococci. (c) Investigation of the bacteriology of all cases under treatment, by weekly throat cultures during the period in the hospital. (d) Bacteriologie study of the complications of measles during life and at autopsy. (e) Study of the throat bacteriology of men on duty in the camp, to establish the prevalence of hemolytic strep- tococci and of B. influenzae in normal individuals. The work is further divided into that done at Camp FWstoi] during the latter pail of July and throughout August, and that done at Camp Pike during September. October, November and December, 1918. SECONDARY INFECTION IN WARD TREATMENT OF MEASLES 283 Studies at Camp Funston. — The work done at Camp Funston is limited strictly to the identification of hemo- lytic streptococci in the throats of all patients with measlos coming into the base hospital at Ft. Riley and to the same study of a group of normal men on duty. During the period of study hemolytic streptococci were identified by throat culture in about 1 in 5 of all the normal men ex- amined. Two instances of otitis media represent the only complications developing in the 112 cases of measles. Cul- tures from both patients showed staphylococci. The entire absence of streptococcus complications appears the more surprising in view of the fact that the prevalence of hemo- lytic streptococci among patients under treatment in the ward was for a time as great as that among the normal men. No special hospital management w T as instituted on the basis of the findings in throat culture. S. hemolyticus carriers remained in the wards and were treated alongside the "clean" cases. The sheet cubicle system was used for bed patients. Face masks were not worn. Convalescent patients were not segregated, and they assisted in the care of the bed patients and in the ward kitchen. After the initial throat culture on admission, the throats were gargled with argyrol and afterwards sprayed with the same solution three times a day. This solution was also em- ployed to relieve the discomfort caused by the conjunctivitis during the acute stage of the disease. Throat Culture and Identification of Hemolytic Strep- tococci. — In general the methods for the isolation and identification of hemolytic streptococci as adopted by the Medical Department of the Army were used. All organ- isms were isolated in pure culture, grown in broth, exam- ined microscopically and subjected to tests for hemolysis, (a 5 per cent suspension of sheep corpuscles being em- ployed) , and for bile solubility. Beef infusion broth and beef infusion agar constituted the two basic media used. They were prepared so that the 284 PNEUMONIAS ami INFECTIONS OF RESPIRATOR! TRACT finished producl titrated aboul 0.3 per cent acid to phe- oolphl kalein. Brotli tubes were carried to the bedside, hi swabbing, the attempt was made to produce gagging. This causes the tonsils to protrude Prom behind the anterior pharyn- geal pillars and places a slighl tension en the capsule which lends to squeeze material from the crypts. The surfaces of (he tonsils thus protruding toward the midline were brushed quickly with a small cotton swab which was Lastly touched to the posterior pharyngeal wall and withdrawn so as to avoid touching any other parts. The swab was im- mediately ini reduced into a tube of broth, twirled freely under the surface of the liquid and discarded. The ma- terial thus washed into the broth was carried to the labo- ratory and kept in the ice bos until plating, which was ac- complished with as little delay as possible. Tubes of melted agar containing 12 c.c. cooled below 45° C, after receiving 0.6* c.c. of sterile deflbrinated horse Mood, were inoculated with a loopful of this broth. Thor- ough mixing and pouring into Petri dishes (10 cm. diam- eter) followed. After cooling, a second loopful was st leaked over the surface of one half of the plate. Deep and superficial planting were thus effected on the same plate. This method was found to he very useful. It can he used with advantage provided one is not called upon to make a great number of cultures when its time consuming factor is a greal inconvenience. Another disadvantage is the dif- ficulty of picking single colonies for subculture. Tn spite of the most careful selection and fishing of a dee]) colony, subcultures are less likely to he pure than when surface colonies are chosen. By careful regulation of the amount of agar in the tubes, the addition of a measured amount of blood to each enabled one to pour standard blood agar plates. Uniform thorough mixing of the blood is essential so that the plate may present the desired "silky" rather SECONDARY INFECTION IN WARD TREATMENT OE MEASLES 285 than a " curdled" appearance when viewed by transmitted light. The plates wore incubated eighteen to twenty-four hours when subcultures in broth were made from the hemolytic colonies. After growing those for a similar period the additional tests were carried out as indicated above. Hemolytic Streptococci with Measles. — The incidence of hemolytic streptococci in the throats of patients with measles admitted to the base hospital at Ft. Riley was found to be remarkably small. Table LV Hemolytic Streptococci with Measles in all Patients Adm Wards at Camp Funston ITTED TO THE days in hospital approx- imate DAY OF DISEASE NO. OF PATIENTS CULTURED NO. WITH HEMOLYTIC STREPTO- COCCI PER CENT WITH HEMO- LYTIC STREPTO- COCCI First Culture Second Culture Third Culture to 1 3 to 10 8 to 23 1 to 8 4 to 16 12 to 26 112 86 58 3 11 14 2.67 12.79 24.14 The first culture represents the findings on admission, in a series of 112 cases; 86 patients being cultured twice; 58 patients three times. Of the 112 cases examined on admission only 3, or 2.67 per cent were found to carry hemolytic streptococci. Those patients who were recultured after from three to ten days in the hospital showed an incidence of 12.8 per cent. A third culture including patients from eight to twenty-three days in the hospital, showed an incidence of 24.1 per cent. Hemolytic Streptococci in the Throats of Normal Men. — A total of 274 throat cultures from normal men on duty at Camp Funston (Table LVI) shows that 21.9 per cent car- ried hemolytic streptococci at a time when there were few upper respiratory infections in the camp. A small group of men resident in the hospital shows a slightly higher prevalence of hemolytic streptococci (29.3 per cent). The figures in Table LVI are in sharp contrast with those for measles patients on admission to the hospital. 286 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRAIT Table LYI Incidence op Hemolytic Streptococci, Camp Funston. f£ 5 7. ~. P < w HEMOLYTIC STREPTOCOCCI PRESENT PER CENT WITH HEMOLYTIC STREPTOCOCCI (id White Men: 70th Int'antrv 24 4 16.7 210th Engineers, Co. C 26 6 23.1 164th Depol Brigade, Co. 15 50 Pi 20.0 L64th Depol Brigade, Co. 18 51 13 25.5 164th Depot Brigade, Co. 28 50 13 26.0 Total 201 46 22.9 {b) Colored Men, Detent ion < 'amp No. 2 : T * " 4 1 i i Depot Brigade, Prov. Co. 22 25 6 24.0 3d Development Battalion, Co. A 24 3 12.5 .'M Development Battalion, Co. D 24 5 20.8 Total 73 14 19.2 (c) Men resident in the hospital: Laboratory workers 10 Q 30.0 Patients in surgical ward 14 4 28.6 24 7 29.3 T\yo organizations from which normal men were chosen for examination Furnished a considerable number of cases of measles and offer data (Table LVII, A and B) for fur- ther comparison. Table LVII A. Hemolytic Streptococci with Measles in 164th Depot Brigade, Company 28. days in hospital NO. OF NUMBER WITH PER CENT WITH patients HEMOLYTIC HEMOLYTIC CULTURED STREPTOCOCCI STREPTOCOCCI First Culture to 1 23 Second Culture 3 to 9 23 4* 17.4 Third Culture 10 to 21 21 4 19.05 Normal men of Co. 28 50 13 26.00 B. Hemolytic Streptococci with Measles in Seventieth Infantry First Culture to 1 38 Second Culture .1 to 9 25 1 4.0 Third Culture 8 to 17 12 2 16.7 Normal men on duty with 70th Infantry 24 4 16.7 'Two cases positive for hemolytic streptococci on this examination were negative on next examination. SECONDARY INFECTION IN WARD TREATMENT OF MEASLES 287 No one of the 61 cases of measles from the two organ- izations was found to be positive on admission to the hos- pital. Yet among normal men in one of these organiza- tions the incidence of hemolytic streptococci was 26 per cenl and in the other, 16.7 per cent. In both organizations the incidence among normal individuals compares closely with that of the patients after a period in the measles wards of the hospital. Discussion. — Three features of the data collected at Camp Funston are noteworthy. First, the small percent- age of S. hemolyticus carriers among the men admitted to the hospital with measles as compared with the percentage found in normal men in the camp. Second, the increase in the number of S. hemolyticus carriers among patients during their stay in the hospital, the increase continuing until it approaches that of the normal men on the outside. Third, the prevalence of hemolytic streptococci in normal throats. In comparing men arriving at the hospital acutely ill with measles with normal men in the organization from which they came, only one variable can be found on which to base the differences observed in the two groups. This is the advent of the acute disease. The figures seem to sug- gest a temporary disappearance of hemolytic streptococci from the. throats of patients acutely ill with measles, at least, to such an extent that the same cultural methods fail to identify the organisms. The increase in the S. hemolyticus carriers among pa- tients with measles after a period in the hospital might depend upon two factors: First, the exposure to contact infections in the hospital ward, depending on the length of time in the ward as well as on the character of the ward management; second, the passing of the acute stage of measles with a return of the bacterial flora of the throat to the condition existing before the onset of the acute disease. The first appears the more probable. The second has only 1> S PNEUMONIAS AND [NFECTIONS OF RESPIRATOR1 TRA< 'T Hie supporl of the observation thai the streptococci were absenl from tlie throat during the acute stage of measles or were much less frequently Pound in patients with measles than in normal men and later their incidence approached that in norma] individuals. The rather high incidence of hemolytic streptococci in normal men at ('amp Funston may have been due to the very recent assembling of the 10th Division which now occupied the cam]). It is probable that the housing of large numbers of men in barracks is at- tended by the same contact dissemination of mouth organ- isms that occurs in hospital wards. Measles at Camp Pike. — All cases of measles coming into the base hospital at Camp Pike between September 15 and December 15, 1918, a total of 867 cases, are included in the report. Upon the arrival of the commission at Camp Pike early in September, a plan for the separation of cases car- rying hemolytic streptococci and those free from these or- ganisms was put into operation. The preliminary arrange- ments included the allotment of suitable wards for treat- ment of the different classes of cases; a throat culture sur- vey of all patients with measles under treatment at the time; their separation in accordance with the results of bacteriologic examination, and the transfer of each group of patients to its designated ward. By September 15 these preliminary arrangements had been completed. Cases of measles admitted on this date and afterwards were held in an observation ward pending the report upon a throat cul- ture before they were transferred to the treatment wards. Beginning September 15 the following system of hand- ling measles cases was maintained in the wards of the base hospital. All patients were received in an observation ward where they remained until the results of a throat culture for hemo- lytic streptococci could be reported back' to the wai'd. ( lases reported positive or negative were immediately trans- ferred to their respective treatment wards. .Ml patients in SECONDARY INFECTION IN WAED TKEATMENT OF MEASLES 289 the treatment wards were cultured al intervals of one week and cases found positive were 1 ransferred from 1 lie "clean" treatment wards to a treatment ward for cases carrying hemolytic streptococci. The ward personnel attending pa- tients in the "clean" treatment wards was examined by throat cultures from time to time with the purpose of elim- inating- S. hemolyticus carriers. Patients segregated in the streptococcus wards remained there, if uncomplicated, throughout their hospital treatment even though subse- quent repeated throat cultures showed that the carrier con- dition had disappeared. Two wards were provided to care for the pneumonia following measles. One received only patients whose throat cultures were negative for hemolytic streptococci; the other, those positive. It is essential that the throat culture on which this differentiation is made he taken as soon as the complication is reported and that transfer be made promptly on receipt of the report of the culture. To facilitate this transfer, cases of pneumonia complicating measles were reported to the laboratory as soon as diagnosed and cultures were taken at once. The case remained in the measles Avard during twenty-four hours, isolated as well as possible, awaiting report of cul- ture before transfer. Within the positive ward for measles pneumonias, distinction was made between streptococcus pneumonias and nonstreptoeoceus pneumonias harboring hemolytic streptococci in their throats. The two classes of cases were treated in separate sections of the ward. Ear complications were seen and treated by medical of- ficers from the otological service. These patients remained in the measles wards while in the acute stage of measles, but later w r ere transferred to the service of otology when- ever further surgical treatment became necessary. Within the individual wards for treatment of measles and measles pneumefnias, precautions for minimizing the dangers of contact infections were carried out as well as possible. Throughout the study we had the hearty cooper- 290 PNEUMONIAS ami [NFECTIONS OF RESPIRATOR'S TRACT ation of the base hospital authorities and earnest, well- directed effOrl to perfecl ward management on the part of the ward surgeons and their staffs. Difficulties encoun- tered during the emergency created by the sudden explosion of ilif influenza epidemic, in spile of the besl efforts of all, did much to disrupt the plan which had been instituted for the control and study of the complications of measles. Scarcely had wards been designated and all measles pa- tients on hand differentially allotted to them, when the in- fluenza epidemic appeared and quickly Tilled the hospital beyond its capacity. Measles wards were taken over For the care of influenza patients. Measles patients, of which there were not a great number at the time, were necessarily crowded together, so that compartments of wards instead of separate wards had to be used in maintaining our sep- aration of the two groups of patients. While the base hos- pital was yet filled with patients with influenza and in- fluenza pneumonia, admission of patients with measles in- creased, so that one ward after another was reclaimed for the care of this disease. During this period the measles wards were at times overcrowded and the strictest ward technic could not he practiced. Again new wards were, on occasions, partly filled by admission and transfer before they were properly equipped to receive patients. This dis- organization was directly due to the necessity of treating a rapidly increasing number of measles patients before the hospital was cleared of patients with influenza and pneumo- nia. After this emergency, the system of ward management was rapidly readjusted, and admissions were limited to the normal capacities of the wards. The cubicle system was used in all wards. Bed patients were not required to wear masks, but the mask was strictly enforced upon all patients leaving the cubicle. All attend- ants were required to wear gowns, caps and masks while in the wards. An attempt was made to prevent the congre- gating of convalescents. Guards were posted at the latrine SECONDARY INFECTION IN WARD TREATMENT 03? MEASLES 201 doors to limit admission to the capacity of the latrine. Bor- rowing and lending of any materials between patients were strictly forbidden. Paper sputum cups were provided, kept clean and covered. In the measles pneumonia wards hand disinfectant solutions were provided for use by at- tendants when they passed from one patient to another. The ward floors were scrubbed at intervals with lysol in water. Dry sweeping of the wards in the morning is re- grettable. Bacteriologic Methods Used in the Study. — The methods used for the identification of hemolytic streptococci here were essentially the same as those used at Camp Funston and described above, the one exception being the use of surface cultures on blood agar instead of the combined sur- face and deep culture. Blood agar plates containing 5 per cent defibrinated horse blood were poured and used while fresh. The throat swabs were carried to the laboratory in sterile test tubes. The plates were inoculated by touching the swab lightly to the surface of the agar plate at two places, one near either extremity of a given diameter of the plate. On touching the swab to the agar, the swab stick was rolled between the fingers so as to turn it through one revolution and thereby bring all points of the circum- ference of the cotton swab in contact with the agar surface. The material thus inoculated on the plates was spread by means of a platinum wire slightly turned over at the end in "hockey stick" fashion. The wire was passed back and forth several times over the point of inoculation and then multiple streaks and cross streaks were made over the agar surface. The initial contact of the wire with the point of in- oculation was not repeated. The cross streaking serves to spread and distribute this material evenly over the surface. Well seeded plates by this multiple streak method are the rule and the uniform distribution of well separated colonies, over the surface makes it very easy to pick pure cultures, and renders plate reading easy. 292 PNEUMONIAS AND INFECTIONS OF RESPIRATORS TBACT Very early in the course of our study of throal cultures a1 Camp Pike, the greal frequency of abundanl growths of \\. influenzae was observed. Consequently, the throat cul- tures of all measles patients examined Prom September 15 in October 20 were studied for the identification of 1>. influenzae. In all cases identification was based on the cul tural, staining and morphologic characteristics. Tests for growth on hemoglobin free media were no1 made as a rout inc. Relation of Measles and Pneumonia Following Measles to the Influenza Epidemic. — The influenza epidemic at Camp Pike was recognized on September 23 because of an alarming increase of hospital admissions. It ran its brief course, and ten days later, October 3, the decline began. The first four days of October rank highest in admissions of patients with pneumonia following influenza. The onset of 20 scattered cases of measles occurred before Septem- ber 25, and later the number slowly increased reaching its height about the middle of October; after this time a grad- ual decline began, and continued during about three weeks before the preepidemic level was reached. During this period of six weeks following September 25, 709 cases of measles occurred. Table LYTII Onset of Measles and of Pneumonia Following Measles by Weeks prow September 11 to December 11, 1918 | PNEUMONIA Dates MEASLES FOLLOWING U EASLES s .pt. 11 to 17 18 Sept. IS to 24 20 n Sept. 25 to Oct. 1 74 ii OH. o to 8 143 i:; Oct. !) to 15 178 9 Oet. 16 to 22 158 16 Oct. L 1 :: to 29 Km n Oct. 30 to Nov. 5 56 3 Nov. 6 to 12 .'',8 1 Nov. 13 to 19 2.1 1 Nov. 20 to 2fi 29 1 Nov. 27 to Dec. 3 22 1 Dec. 1 to 10 8 1 Dec. 11 1 SECONDARY INFECTION IN WARD TREATMENT OF MEASLES 293 Pneumonia following measles began to appear on Octo ber 5, and within the week following L6 cases occurred. An equal number of cases appeared each week- during aboul three weeks and fewer scattered eases occurred throughout November and December. Table LVi 1 1 shows dale of onset of measles and measles pneumonia cases. Chart 3 presents the occurrence of measles and of the pneumonia following measles by weeks of onset compared with that of epidemic influenza. I " • "I T T~ T 1 T J t J 400 - jh J 1 1 1 I TC n | i50 - I ;>UU - J I ?s>n 1 lDU - 1 I 7i\r\ , LwV / h 1 1*50 - i I.^fr L i_ wu r [ £ \ \ L [ RC\ t v JO V i W 4 II 18 25 T i i 6 Z3 30 NOV i 3 I 27 DEC 4 II IB 3 Chart 3. — Shows the relation of the epidemic of measles to that of influenza at Camp Pike, and the relations of the pneumonia following measles to both measles and influenza. The large incomplete curve represents influenza; the intermediate curve, measles; the small curve, pneumonia following measles. 294 PNEUMONIAS ANli INFECTIONS OF RESPIRATORS TRACT It will be noted from the overlapping of the two curves in Charl .'! that a considerable portion of the measles cases appeared before the influenza had subsided in Camp Pike. This occurrence of the two epidemics at the same time makes ii impossible to separate the parts played by cadi disease in producing the pneumonias and other complica- tions following measles. Analysis of the charl, however, shows that the pneumonia with measles occurred in large part during the first hall' of the measles epidemic. This is of particular significance since it was during this period that the effects of the influenza wave were fell most se- verely. In Table LIX the cases of measles are grouped into fifteen day periods according to their dates of onset and the pneumonias arising from each group are tabulated. This tabulation shows very clearly that the pneumonia complications developed in large pari in patients with measles entering the hospital during the influenza period, that is. late in September and during the first half of October. Table LIX Patients with Measles and with Subsequent Pneumonia HATES TOTAL CASES OF MEASLES DURING INTERVALS OF 15 DAYS TOTAL CASES OF PNEUMONIA FROM SAME PER CENT INCIDENCE OK PNEUMONIAS Sept. 11 to 30 861 433 347 ) 14] 16.28 1 9.7% 8.07 1 U2 Oct. 1 to 15 28 J 0<-t. 16 to 31 270' 8' 2.96 Nov. 1 to 15 91 434 2 •14 2.2 3.295 Nov. in to 30 56 1 7.15 J T)oc. 1 to 15 17 o. The high incidence of pneumonia among measles patients coming into the hospital prior to, with, or immediately fol- lowing the height of the influenza epidemic is very striking. It so happens that half of the total number of measles cases SECONDARY INFECTION JN WARD TREATMENT OE MEASLES 295 considered, date their onsets prior to October 15. Prom the 433 cases included in this first half, 42 cases of pneumonia arose, while from the 434 cases arising during the two months following October 15, only 14 or one-third as many cases of pneumonia developed. These figures very strongly suggest that influenza played a large part in the production of the pneumonia with measles in this group of cases. Again the 9.7 per cent incidence of pneumonia in the first half of cases considered, approaches the 12 per cent inci- dence of pneumonia following influenza observed in the epi- demic at Camp Pike, while the incidence of 3.2 per cent in the second half of the cases conforms more nearly to figures for pneumonia following measles in the army prior to the pandemic of influenza. It has been shown that the prevalence of B. influenzae at Camp Pike increased with the passing of the wave of in- fluenza (p. 40) and that this increase applied to the measles admissions. For a time the separation of measles patients carrying B. influenza? as identified by throat cul- ture on admission, from those free from it, was practiced. All cases were then followed up by weekly throat cultures, and cases in negative wards on being identified as positives were transferred. This practice was discontinued as impractical when it became apparent that about 80 per cent of patients with measles would be found positive for B. influenza? when re- peated throat cultures were made during their hospital treatment. The dissemination of B. influenza? through the wards from which we were attempting to exclude it took place much faster than we could follow its spread by cul- tural methods. When this became evident, the practice of separating the two groups of patients with reference to B. influenza? was discontinued and the great inconvenience of repeated transfer of patients was largely eliminated. Table LX gives the findings in 426 cases of measles cultured for B. influenza? during the period when the prac- 296 PNEUMONIAS AND INFECTIONS OF RESPIRATOR'S TRACT KOISSIROV NO 'jsi :i HOH 3AIXVD3N S3SV3 !>\ciiv\ IXYd OX SSAIXISOd JO X.S3J Had d.lOHl) ' CO o3 aiva oj. MM -:l UOd SAUISOd d.lOHO JO X.M3J H3d (^ t~ s NOISSIKin NO "J SI -11 HOJ 3AIJ.Vtr.lN- S3SV0 M 31\a OX ONIJCnHAHd SSAIXISOd 30 d.lOH'J 3 - 'JIViI 01' '3X1 - II 5103 3ATJJS0d "ON dnOSIO CI CJ fc» C) OQ W D °o u ssvij HOva si 'os 3HAX1.10 HXr 3H.ix-i.io ails: 3H.in.io a.N'o 3M.1X'I.1D XS[ 1 + I* 00 Ol o t> a ci o I + + I 1 1 4- + 1 + J + + + 1 1 1 I + + + 1 + 1 1 1 | 1 + + + + -r K r; C) CK) C] H fl H H H rl 1 1 1 I+ + +++I l + l 1 1 1 1 1 1 1 1 ++ +■+ + .voissmav ko 3.uxvd:jn; 'o\- .i.ioHri 1 3 a d.noHD ni aamixino H3aK.lM '1VX0X ■* O CJ PL, o £ o ■2 II 1st and L'n-1 culture, after ono week in hospital III 1st, 2ud and 3rd cul- tures after two weeks in hospital IV 1st, 2nd, 3rd and 4th cultures after three lseeks in hospital SECONDARY INFECTION IN WARD TREATMENT OF MEASLES 297 tice of separating measles patients carrying l'>. influenzae from those not carrying the organisms was followed. On admission 35.6 per cent of the patients were found positive for B. influenzae. Repealed throat cultures were not confined to those appearing negative on this initial cul- ture, but were made on all patients without regard to their being previously positive or negative. By a summation of the results of the weekly cultures of all patients, the per- centage of patients carrying B. influenzae rises from 35.6 per cent on admission, to 62.7 per cent after one week; to 77.7 per cent after two weeks; to 84 per cent after three weeks in the hospital. To gain some idea of the rate of spread of B. influenzae in wards receiving only patients whose throat cultures were negative for B. influenzae on admission, a similar summa- tion of the results of repeated throat cultures on patients in negative wards shows weekly increases from 47.5 per cent after one week, to 68.1 per cent after two weeks; to 79 per cent at the end of three weeks. These results demonstrate quite clearly that the measles wards were saturated with B. influenza? during the period of the influenza epidemic. Conditions within the measles w T ards with regard to B. influenzae were not at all dif- ferent from those in the camp community during this pe- riod. "While no clinical methods could be relied upon to diagnose influenza in the presence of an acute attack of measles, there is every reason to believe that the occurrence of clinical influenza with measles was no less frequent than was its incidence in the camp at large, that is, about 20 to 25 per cent. That influenza played a large part in deter- mining predisposition to the complications of measles in this series seems evident. Hemolytic Streptococci with Measles at Camp Pike Between September 15 and December 15, 1918, 867 cases of measles, admitted to the wards of the base hospital, were L' l| S PNEUMONIAS A.ND INFECTIONS OF RESPIRATORS TRACT studied and handled according to the system outlined above. AJbOul one half of these cases appeared during tin' firsl month of the study. During this month hemolytic streptococci played a very Lnsignificanl role. This micro- organism did aol appear with alarming prevalence until after the wards had been thoroughly overcrowded. After the emergency, when better ward conditions were provided, S. hemolyticus carriers continued to develop in the wards and were removed when identified. The first S. hemolyti- cus carriers to develop in the wards were identified on Oc- tober 8. The first case of streptococcus pneumonia de- veloped on October 17, while streptococcus otitis as a com- plication of measles did not begin until a little later. Driv- ing the latter two mouths of the study, S. hemolyticus be- came rampant in the wards. The streptococcus compli- cations date their onset at some time during these two months. Table LXT shows the number of admissions to the measles wards by weeks and the patients among them found to he carrying hemolytic streptococci. It also shows the num- ber of S. hemolyticus carriers developing each week among patients under treatment in the "clean" wards, as identi- fied by throat cultures repeated at weekly intervals. For purposes of orientation, the number of cases developing streptococcus pneumonia and otitis media with its subse- quent mastoiditis are given for each week during the period of observation. An admission to the measles ward can generally be re- garded as an acute case of measles. There are a few ex- ceptions to this statement and these are cases of measles treated in barracks and afterwards transferred to the base hospital. A relatively small number of such cases fur- nished 1<> of the cases positive for hemolytic streptococci on admission to the measles ward. An admission to the measles ward does not indicate ad- mission to the hospital, because a considerable number of SECONDARY INFECTION IN WARD TREATMENT 03? MEASLES 299 to t3 w H £ H H < PM a ' to rt o o S o «3 o o ft r^ ft 1* o J h-l ~ w ft flW m o CO 07 m H - to H - o O EH w -. W O M B to ft • W O W ra ft w ft ft K ft ft to n 02 9 -,• h fc gag to <- eh °P o Eh to ft cc 3 ft o ft as ft ft Ph M EH Ph to u o 07 « ft ft o ft © £ to ft P Ph o £ - Ph o CO rH i-H CQ £ £ fc £ g o 300 PNEUMONIAS AND [NFECTIONS OF RESPIRATOR'S TRACT cases of measles developed from time to time among pa- tients under treatmenl in the hospital for other conditions. Since these patients remained in other wards not subjecl to the same ward management and with no distinction be- tween those positive and those negative for hemolytic streptococci, they cannot be included in figures to show the incidence of hemolytic streptococci in patients with measles at the time of admission to hospital from the cam]). Two classifications of the 37 cases, positive when first observed, are necessary. 1. Division of cases according to days in the hospital before first culture was taken : Days in Hospital No. of cases 0-1 (admission) 15 (2 not acute) 2-7 10 More than 7 12 2. Classification according to stage of the disease: During acute stage 21 cases After acute stage 16 cases The first classification shows only 13 cases positive when cultured on admission to the hospital and also during the acute stage of the disease: the incidence of S. hemolyti- cus in patients on admission is very low (1.7G per cent). The second classification shows a slightly higher in- cidence for cases during the acute stage of the disease, re- gardless of whether they were admitted to the measles ser- vice from camp or from another service of the hospital (2.4 per cent). These findings conform with those at Fort Riley in a smaller series el' cases and support the opinion that the hemolytic streptococci temporarily disappear from the throat during the acute onset of measles. Unfortu- nately controls among normal men in Camp Pike were not taken at intervals throughout the period of three months represented by this study of measles, but all controls taken show a higher incidence than that found among measles SECONDARY INFECTION IN WARD TREATMENT OF MEASLES 30] patients on admissions over ;i period of time comparable to that of the control series. The gradual increase in the percentage of patients de- veloping hemolytic streptococci in their throats in wards receiving only streptococcus free cases demonstrates that the admission culture and the subsequent weekly cultures, with the separation of all patients ind'entified as carriers, did not suffice to control the spread of streptococcus in this group of cases. It is interesting to note that the greatesl incidence of streptococcus carriers among these patients occurred three weeks after the height of the measles epi- demic, when it became about four times that observed at the height of the measles epidemic. . When we consider the time relations of the strepto- coccus complications, it is noteworthy that they begin to appear somewhat after the appearance of streptococcus carriers and then increase parallel with the increase in the numbers of carriers. The relative number of complications developing among the first carriers which were identified is less than that among the carriers appearing later. This suggests an increase in virulence of hemolytic streptococci attending their wider dissemination. Tables LXII and LXITI are introduced for the purpose of showing to what extent duration of stay in the hospital increases the individual's chances of acquiring hemolytic streptococci. Table LXTI includes all cases admitted to and treated in the measles wards. On repeated cultures, prev- ious positives and negatives were cultured alike and the total positives reported for each week. Table LXIII includes only those cases treated in the "clean" wards and known to be negative on previous cul- ture. A comparison of Tables LXII and LXIII gives some indi- cation of what might have been expected if the carriers had not been removed from the treatment wards at weekly in- tervals. "With the carriers removed from the "clean" 302 PNEUMONIAS a\'I> [NFECTIONS OF RESPIRATORS TRACT TAB] E I. XI I [NCIDF.nce of Hemolytic Stki ptococci IX Thkoats OF MEASLES CASES WITH Reference to Period in Hospital ( All cases treated in the wards ) P] mod IN MEASLES WARD (Admission i 1 week 2 weeks .". weeks i weeks 5 weeks ii weeks 7 weeks 8 weeks 9 weeks 10 Weeks ] 1 weeks NO. CASES (i LTURED 867 768 479 240 133 82 53 25 13 it 6 Mi. POSITIVE FOR HEMOLYTIC STREPTO( i" I i 37 si 109 63 44 26 14 8 1 1 PKK CEXT POSITIVE FOB EEMOLYTIC STREPTOCOCCI 4.2 10.9 22.8 26.2 33.1 31.7 •_'<;. i 32.0 7.7 11.1 Table LXIII Weekly Development of Hemolytic Streptococci in Throats of Patients Treated in "Clean" Wards period in m easles "ward xo. cases CULTURED NO. POSITIVE FOR HEMOLYTIC STREPTOCOCCI PER CEXT POSITIVE FOR HEMOLYTIC STREPTOCOCCI 1 week 738 67 9.1 2 weeks 424 74 17.4 3 weeks 195 34 17.4 4 weeks 92 16 17.4 5 weeks 4fi 7 15.2 6 weeks 26 4 15.4 7 weeks 14 3 21.4 8 weeks 8 9 weeks 5 10 weeks 4 11 weeks 3 cases and segregated in a separate ward so as to be re- moved effectively as sources of spread of the S. hemolyti- cns in feci ion to elcaii cases, the percentage incidence with all cases considered rose to a point nearly twice as high as that ever readied in the wards where clean cases alone were allowed to remain. Had these carriers not been sep- arated, and remained in contact with cases free from hemo- lytic streptococci, they would have served as jnst so many more sources of infection, and an incidence of at least twice SECONDARY INFECTION IN WARD TREATMENT OP MEASLES 303 that recorded for all cases combined, or Four- limes that of the treatment wards, might have been expected. These results indicate that the weekly separation of carriers from clean cases did, to a considerable extent, lower the indi vidual's danger of acquiring S. hemolyticus infection while in the hospital. Complications of Measles In Table LXIV the complications developing in the mea- sles patients under observation at Camp Pike are tabulated. In the division of the complications developing in "carri- ers" and "noncarriers" of the hemolytic streptococci, ref- erence is made only to the records of the throat cultures. The division is therefore not dependent upon the bacteriol- ogy of the complications. For example, only 9 of the 12 cases of pneumonia developing in ' ' carriers ' ' were streptococcus pneumonias. On the other hand, the cases of mastoiditis following otitis media were almost invariably due to hemo- lytic streptococci. Of the 10 otitis cases occurring in "non- carriers," 4 developed mastoiditis and 3 of these showed hemolytic streptococci on culture from the mastoid cells at operation. Missed cases of identification of S. hemo- lyticus by throat culture in cases which develop S. hemo- lyticus complications may arise from a number of causes. It is desired here only to direct attention to these dis- crepancies. Pneumonia Following Measles. — Fifty-six cases of pneu- monia following measles occurred during the period of ob- servation in this group of 867 cases of measles. Of these, 9 were streptococcus pneumonias. This gives an incidence for streptococcus pneumonias of 1.04 per cent, while that for all the pneumonia is 6.4 per cent. There were S cases of lobar and 48 cases of bronchopneumonia. Seventeen fatal cases occurred giving a mortality rate of 30.4 per cent for the group. Five of these fatal cases occurred among 304 PX MONIAS A\l> IX FEC i\: iPIRATORl' TRACT Table LXIV Complications Developing in 867 Cases of Measles \t Camp Pike. Distribution op Complications Between 242 "Carriers" and 625 " noncarriers ' ' op bemolytic streptococci prow septem ber 15 to i ' cbeb 15, 1918 NUMBER OCCURRING IN PER CENT IX NAME OF -' - - ' ' NONCARRIERS ill' EEM. STREP. IX COM RD OP LTURES - - — - Eh O Eh « « • OMPLICATION — ~ r. r. M — _* — & % H CASKS WITH PLETE RECO PHROAT CU w - < « 3 . - a s H - ■- !C as u a S w o W ? fc » o Pneumonia 12 44 56 (5.4 5.0 7.0 otitis media :;i 11 6 48 5.5 L2.8 1.8 Mastoidil is i follow- ing otitis media i 15 4 4 23 2.6 6.2 0.6 Local meningil is (ex tension from mas toid) •> Frontal sinusil is 1 H 1 Ethmoidal sinusitis (i 1 n 1 Suppurative ••nth litis 1 i) o 1 ( 'ervical adenitis 1 1 Acute bronchitis 4 •> 6 Acute tonsillitis 4 1 II .l Acute laryngitis and aphonia 1 i) 1) 1 Acute pleurisy 2 1 (1 3 Erysipelas of face ii 1 (1 1 Epidemic meningitis 1 1 Note. — The percentages of incidence of pneumonia and otitis media in the "earner" and "noncarrier" groups are at direct variance. It would appear from these findings thai streptococci very readily invade the middle ear from the throat and set up grave disorders. The invasion of the lung from the throat occurs with less frequency. Hemolytic streptococci perhaps never initiate the pneumonic processes and can be regarded as more or less accidental secondary invaders. the 9 streptococcus pneumonias. The mortality rate for the streptococcus pneumonia thus was 55.5 per cent; thai for the nonstreptoeoccus group was 25.5 per cent. All 1) cases of streptococcus pneumonia developed empyema. In 7 eases it was diagnosed clinically; in 2 at autopsy only. No eases of empyema developed in the group of nonstrepto- eoccus pneumonias. SECONDARY INFECTION IN WAED TREATMENT OF MEASLES 305 The relation of these pneumonias following measles, to the influenza epidemic lias been discussed. The time rela- tions between the onsets of measles and that of the sub- sequent pneumonia vary widely. There appeaj-s to be nothing constant in the length of time between the onset of measles and that of the pneumonia. In 30 of the cases this period is less than ten days; in the remaining 26 cases, it ranges from ten to thirty -two days (Chart 4). In the ward treatment of these cases of pneumonia, they were divided into three groups according to their clinical characters and according to the results of throat and sputum cultures. (a) Streptococcus pneumonias 9 cases (b) Pneumonia with hemolytic streptococci in the throat without symptoms referable to the streptococcus 13 cases (c) Pneumococcus pneumonias not carrying hemolytic streptococci 34 cases The streptococcus-free cases were treated in a separate ward. Cases were admitted to this ward directly from the "clean" measles wards, but only after a throat culture taken prior to their transfer had been negative for the hemolytic streptococcus. The other two groups were treated together in another ward, but in strictly separate compartments of it. This precaution was carried out on the assumption that patients with an acute streptococcus pneumonia were real sources of danger in the ward because of a heightened virulence of the organism causing the grave symptoms. The pneumo- nias subsequently developing hemolytic streptococci in their throats, without their presence modifying the course of the pneumonia, came to be regarded as being in the same class with uncomplicated cases of measles carrying hemo- lytic streptococci, in so far as their being potential sources of danger in a ward is concerned. , , i— — — ■ — > — ■ ■ — . _■ __ —J . 4 • — 1 ________ _____ — — ' — — 10 15 10 25 30 Chart 4. — Shows the time interval between the onset of measles and the onset of the subsequent pneumonia in the 56 cases of pneumonia following measles at Camp Pike. Each case is represented by one of the small blocks measured along the ordinate. The onset of measles in all eases is represented by the line at the extreme left of the chart. The onset of pneumonia in each ease is indicated by the limit of the block marked off in days to the right of this line. SECONDARY [INFECTION IN WAKD TREATMENT OE MEASLES 307 (a) Streptococcus Pneumonias. — Nine cases of strepto coccus pneumonia developed. Of the 867 cases of measles studied, 242 showed throat cultures positive Tor the hemo- lytic streptococci at some period of their stay in the hos- pital. It appears then that 3.7 per cent of the patients carrying hemolytic streptococci in their throats developed streptococcus pneumonia. Thirty-seven cases had positive throat cultures when first observed on admission to the measles wards. It is significant to note that not a single case of pneumonia of any kind developed among these cases. MEASLES PNEUMONIA; STREPTOCOCCUS GROUP Case 98, O. McN. Onset of measles, Sep. 19 ; admitted to hospital Sep. 21 ; onset of bronchopneumonia, Oct. 21 ; of empyema, Oct. 23- Recovered from pneumonia ; convalescent in empyema ward. Bacteriology. — 1. Throat culture for: (a) S. hem.: Sep. 21, -; 28, -; Oct. 9, -; 20, -; 23, +; Nov. 2, -;9, -; 15, -; (b) B. influenza;: Sep. 21, +; 28, -; Oct. 9, +. 2. Pleural fluid (culture) S. hem- Oct. 23, +. Case 141, J. G. G. Autopsy No. 438. Onset of measles, Sep. 28; admitted to hospital, Oct. 1; onset of bronchopneumonia, Oct. 6; of otitis media (bilat- eral), Oct. 12; died, Oct. 18. Bacteriology. — 1. Throat culture for: (a) S. hem., Oct. 2, -; 6, -; 8, -; (b) B. influenzas, Oct. 2, -; 6, +; 8, +. 2. Autopsy cultures: Heart blood, neg- ative; left lung, Pneumococcus II atypical, B. influenzae and S. viridans; right lung, S. hem. and B. influenzas ; right bronchus, S. hem. and B. influenzae. Case 147, S>. W. Autopsy No. 442. Onset of measles, Oct. 1; admitted to hospital, Oct. 2; onset of bronchopneumonia, Oct. 17, with chill and rapid development; died, Oct. 18. Bacteriology. — 1. Throat culture for: (a) S. hem., Oct 2, -; 9, -; 15, -; 18, +; (b) B. influenzas, Oct. 2, -; 9, -; 15, -; 18,-. 2. Autopsy cultures: Heart blood, S. hem. ; right main bronchus, S. hem. and B. influenzae. Case 281, T. M. Onset of measles, Oct. 6 ; admitted to hospital Oct. 9 ; on- set of bronchopneumonia, Oct. 21 ; of empyema, Oct. 23 ; recovered from pneu- monia ; convalescent in empyema ward. Bacteriology— -1. Throat culture for: (a) S, hem., Oct. 10, -; 20, -; 24, +; Nov. 2, +; 9, +; 15, + ; (b) B. influenza-, Oct. 10, -; 20, +. 2. Culture from pleural fluid, Oct. 23, S. hem. Case 285, J. H. Onset of measles, Oct. 4; admitted to hospital, Oct 9; onset of lobar pneumonia, Oct. 29 ; of empyema, Nov. 9 ; convalescent in em- pyema ward. Bacteriology. — 1. Throat cultures for: (a) S. hem., Oct. 11, -; 20, -; 24, + ; 29, -; Nov. 2, -; 9, -; (b) B. influenza?, Oct. 11, -. 2. Cultures from pleu- ral fluid, Nov. 9 and 13, S. hem. 308 PNEUMONIAS AXP [NFECTIONS or RESPIRATORY TRACT Case 714, W. II. Onsel of measles, Oct. 26; admitted to hospital, Oct. 28; otitis media, Noy: s : onset of bronchopneumonia, Nov. 9; of empyema, Nov. 17: convalescent in pneumonia ward. Bacteriology— 1. Throat culture's for: S. hem., Oct. 28, -; Nov. 4, -; 12, +; 23, : 30, : ; Dec. 7, ; 12, . 2. Sputum: Nov. L0, Pneumococcus 11 atypical, S. hem. and r>. influenza}. Case 730, W. S. Autopsy No. 491. Onset of measles, Oct. 26; admitted to hospital, Oct. 29; onset of bronchopneumonia, Nov. 10; of empyema, Nov. 11; of cervical adenitis, Nov. 5; (lied, Nov. 15. Bacteriology.— 1. Throat culture for: S. hem., Oct. 30, -; Nov. 4, +. 2. Sputum: Nov. 10, S. hem. •".. Pleural fluid: Nov. 11. S. hem. Autopsy bac- teriology: Heart Mood, S. hem.; right main bronchus, V>. influenza?, B. eoli ; right lung, S. hem. and B. influenza;; right pleura, S. hem.; peritoneum, S. hem. Case 751, P. B. Autopsy No. 492. Entered hospital, Oct. 19; onset of measles, Oct. .'!(l; of bronchopneumonia, Nov. 5; of right empyema, Nov. 12; died, Nov. 16. Bacteriology. — 1. Throal cultures for: S. hem., Nov. 1, -; 4, + ; 15, +. 2. Sputum: Nov. 13, B. influenza? and S. hem. 3. Autopsy cultures: Heart blood, S. hem.; right lung, S. hem., Pneumococeus IV, B. influenza?, B. coli; pericardium, negative; right pleura, S. hem.; peritoneum, S. hem. Case S80, B. McN. Autopsy No. 507. Onset of measles, Nov. 30; entered hospital, Dec. 3; onset of bronchopneumonia, Dee. 11; of empyema, Dec. 14; died, Dec. 14. Bacteriology. — 1. Throat cultures for: S. hem., Dec. 3, -; 5, -; 12, +. 2. Cultures from pleural fluid, Dec. 14, S. hem. ?>. Autopsy cultures: Heart blood, S. hem.; right main bronchus, S. hem., B. influenza?, staphylococcus (a few) ; left lung, S. hem. ; left pleura, S. hem. The average period in the hospital before the develop- ment of the streptococcus pneumonia is about two weeks. Cases 98 and 285 were in the hospital thirty and twenty days respectively before the onset of pneumonia. There is a record of from one to four negative throat cultures on each ease before streptococcus was found in the throat. This enables us to fix the onset of the pneumonia with reference to the appearance of the streptococcus in the throat. Case 141 stands alone as representing a class in which S. liemolyl ieus was implanted upon a pneumoeoecus pneu- monia during its course. In this instance two throat cul- tures on alternate days after the onset of the pneumonia wen- negative for hemolytic streptococci. Unfortunately SECONDARY INFECTION IN WARD TREATMENT OF MEASLES 309 the last record of a throat culture is for one taken ten days before the fatal termination of the case, and it can only he stated that the S. hemolytieus infection was implanted within the last ten days of the course of the; pneumonia, perhaps on or about October 12 when bilateral otitis media developed. In Cases 285 and 730 hemolytic streptococci were found in the throats five and six days respectively before the onset of pneumonia. They represent the 2 cases of pneumonia which developed in patients isolated in the streptococcus "carrier" ward. Case 285 is of particular interest for several reasons. It is the only case of lobar pneumonia in the group and happens also to be the only case from which B. influenzas was not obtained. S. hemolytieus was found only once on throat culture, i. e., five days before the onset of the pneumonia. Three throat cultures after the onset of the pneumonia were negative. The case ran the course of a lobar pneumonia. Eleven days after the onset (November 9) a small amount of pleural fluid was diag- nosed. Aspirated fluid on this date and again four days later showed many streptococci in smears and pure cultures of S. hemolytieus. The remaining 6 cases belong to a group in which hemo- lytic streptococci were first identified in the throats after the cases had been reported to the laboratory as pneumonia sus- pects to be examined by culture before transfer from the measles ward. In all these cases the culture taken at this time was positive while all cultures taken before were nega- tive. In some cases, e. g., Cases 98, 147, and 281, throat cultures taken only one or two days before the onset of the pneumonia were negative. In these cases the onset of the pneumonia, and the appearance of the streptococcus in the throats appear to be simultaneous. It should be noted that the period between the appearance of the hemolytic streptococci in the throat and the develop- ment of the pneumonia is very short in all cases. In this .'!1D PNEUMONIAS A\H INFECTIONS OF RESPIRATOR'S TRACT small group of cases S. hemolyticus infection which lias complicated pneumonia lias been acquired at <>r near the lime of onset of the pneumonia. ( b ) Pneumonia with Hemolytic Streptococci in the Throat without Symptoms Referable to the Streptococcus. —Thirteen cases of pneumonia associated with measles de- veloped into S. hemolyticus "carriers." without having the course of the disease affected by the presence of the organ- ism in the throat. Cases 705, STL', and 1SS are of interest in that hemolytic streptococci were identified in the throats from one to six days prior to the onset of the pneumonia. Tn spite of their presence, the symptoms, course and out- come of the pneumonia were apparently unaffected. One of these cases (Case 872) died. Autopsy showed lobar pneumonia with no signs of invasion of the lung by hemo- lytic streptococci. Cultures at autopsy showed thai pneu- monia was duo to a pneumococcus, Type II atypical. A few hemolytic streptococci were found in culture from the right main bronchus. Of the remaining 10 cases 1 developed S. hemolyticus in a throat culture at the end of the first week of the pneu- monia; 3 during - the second week; 1 during the third week, and 5 farther along in the convalescent period. Tn 8 cases hemolytic streptococci appeared in the throat, at a time when invasion of the lower respiratory tract by the strep- tococcus might he expected, and yet none of them developed evidence of streptococcus pneumonia. The f) cases with hemolytic streptococci appearing late in convalescence are not of particular interest, since the dangers of lower res- piratory invasion are much reduced after the acute stag*' of the pneumonia has passed. Three of these cases (Cases 078, ~'1~) and 31)8) did however develop ear complications directly referable to the streptococcus invasion of the throat. Two of them terminated in mastoiditis with op- eration. These cases emphasize the greater tendency of S. hemolyticus to invade the middle ear rather than the lung. SECONDARY INFECTION IN WAIU) TUEATMEXT OF .MEASLES .'} 1 1 In 3 fatal cases of pneumococcus pneumonia in which dur ing life no hemolytic streptococci were found by throal cul- ture, a few hemolytic streptococci were round at autopsy in culture from the main bronchi, along with predominating growths of pneumococci and B. influenzae. In 2 instances there was frank lobar pneumonia and in the third broncho- pneumonia; there was no evidence to show that hemolytic streptococci had airy relation to the pneumonia which was found. MEASLES PNEUMONIAS; GROUP CARRYING HEMOLYTIC STREPTOCOCCI Case 705. Onset of measles, Oct. 25; admitted to hospital, Oct. 27; onset of bronchopneumonia, Nov. 10; acute pleurisy, Nov. 16; convalescent in pneu- monia ward. Bacteriology. — 1. Throat cultures for: S. hem., Oct. 27, -; Nov. 4, -; 11, + ; 15, + ; 23, -; 30, -; Dec. 7, -; 12, -. 2. Sputum: Nov. 10, Pneumococcus II atypical, S. hem. and B. influenzae. Case 872. Autopsy No. 508. Onset of measles, Nov. 29; admitted to hos- pital, Nov. 30 ; onset of lobar pneumonia, Dec. 10 ; died, Dec. 14. Bacteriology. — 1. Throat cultures for: S. hem., Nov. 30, -; Dec. 5, +; 10, +; 12, +; 14, +. 2. Autopsy culture: Heart blood, Pneumococcus II atyp- ical; right main bronchus, Pneumococcus II atypical, B. influenzae, S. hem. (a few); left lung, Pneumococcus II atypical; left pleura, Pneumococcus II atypical. Case 1SS. Onset of measles, Oct. 3 ; admitted to hospital, Oct. 4 ; onset of bronchopneumonia, Oct. 14; recovered and discharged from hospital, Nov. 24. Bacteriology. — 1. Throat cultures for: (a) S. hem., Oct. 5, -; 8, +; 12, +; 19, +; 20, +; 27, -; Nov. 2, -; 9, 4; 15, -; (b) B. influenzas, Oct, 5, -; 8, -; 12, +; 19, +. Case 678. Onset of measles, Oct. 23; admitted to hospital, Oct. 25; onset of bronchopneumonia, Nov. 2 ; of otitis media, Nov. 9 ; of mastoiditis, Nov. 13 ; mastoid operation, Nov. 20 ; still under treatment. Bacteriology. — 1. Throat cultures for: S. hem., Oct. 25, -; Nov. 4, -; 5, -; 12, +. 2. Sputum: Nov. 3, Pneumococcus Type IV, and B. influenza?. 3. Cul- ture from mastoid bone at operation, Nov. 20, S. hem. Case 389. Admitted to hospital, Oct. 2, with diagnosis of influenza; onset of bronchopneumonia, Oct. 7; onset of measles, Oct. 13; phlebitis (right leg), Oct. 22 ; otitis media, Oct. 31 ; recovered. Bacteriology. — 1. Throat cultures for: (a) S. hem., Oct. 16 -; 20, -: 27, 4; Nov. 2, +; 9, +; 15, -; 23, -; 30, -; Dec. 7, -; 12, -; (b) B. influenzae, Oct. 16, -. Case 725. Onset of measles, Oct. IS; one week in measles barracks; ad- mitted to hospital, Oct. 27; onset of lobar pneumonia, Oct. 23; otitis media, Nov. 7; mastoid operation, Nov. 20; still under treatment. 312 PNEUMONIAS AND [NFECTIONS OF RESPIRATOR'S TRACT Bacteriology. — 1. Throat cultures for: (a) S. hem., Oct. 29, -; Nov. 1, -; 5, -: 12. +: (6.) B. influenzae, Oct. 29, +. 2. Sputum: Nov. 2, Pneumococcus II atypical. B. influenzae. •"■. Culture from mastoid at operation, Nov. 20, S. hem. (c) Pneumococcus Pneumonias not Carrying Hemolytic Streptococci. Thirty-four cases of pneumonia following measles wcnl through their entire course iii the hospital with no throat culture positive for hemolytic streptococci. In some of these cases there are records of twelve negative throat cultures. Eleven fatal cases occurred in this group. Autopsy findings and bacteriology showed in each instance that S. hemolyticus was not the cause of the pneumonia. Measles During the Course of Pneumonia. Eleven cases of pneumonia which developed measles during the course of the pneumonia came under observation. Hemolytic streptococci appeared in the throats of 3 of these patients during convalescence, but there was no evidence that it in- vaded the lung. In one fatal ease autopsy showed that there was no streptococcus pneumonia; pneumonia followed influenza and the onset of measles occurred three days after the onset of bronchopneumonia. Bacteriology of Pneumonia Following Measles. — When observations made during life are combined with the results of postmortem cultures, the bacteriology of 35 of the 56 cases is available and is as follows: Pneumococcus Type II atypical in 36 per cent, Type IV in 22.9 per cent, Type I in 2.8 per cent, Type III in 2.8 per cent, hemolytic streptococci in 22.4 per cent, and B. influenzae in 88.6 per cent of these cases. Otitis Media and Mastoiditis Complicating Measles. — The occurrence of otitis media and mastoiditis complicating measles in patients harboring hemolytic streptococci in their throats has already been presented (Table LXTV). The bacteriology of these complications was not studied by this commission. The records of the base hospital lab- oratory at Camp Tike contain reports of twenty-nine cul- tures made at operation from pus in the middle ear and SECONDARY INFECTION" IN WARD TREATMENT OF MEASLES 313 the mastoid bone. Hemolytic streptococci were found in 22 of these cases. Throat culture's were, in accord with these positive findings in all except a few instances. The throat culture serves as a fairly reliable index of the bac- terial nature of these complications. By combining our records of throat cultures with the results of the cultures from the lesions, hemolytic streptococci were obtained from 37 of the 48 cases of otitis media. In 23 cases of mastoditis following the otitis media, hemolytic streptococci were dem- onstrated in all except 2. It is evident that the great ma- jority of these complications were due to hemolytic strep- tococci. The relation between the appearance of hemolytic strep- tococci in the throat and the onset of the otitis is recorded in all except 4 of the 31 instances of otitis media occurring in patients with throat cultures positive for hemolytic streptococci. These four patients had positive throat cul- tures when first observed and represent the only patients who carried hemolytic streptococci when admitted to measles wards and developed complications. The first of these patients had been under treatment in an otologic ward during a month before measles developed. Measles caused a recurrence of disease of the ear with double mastoiditis requiring bilateral ox^eration. Two other patients had been in the hospital ten and eleven days respectively before they were admitted to the measles ward; on admission to the ward otitis media was present in one patient and in the other it developed six days later. The fourth patient was admitted to the measles wards di- rectly from the camp, and culture from the throat on the day of admission showed the presence of S. hemolyticus. Two weeks later at the time of onset of otitis media, culture from the throat contained no hemolytic streptococci. Re- peated cultures during the next three weeks were negative. No complications of otitis media developed and no direct cultures from the ear are recorded. 314 PNEUMONIAS AND INFECTIONS OF RESPIRATOR"? TRACT £ < ta = • O V 3 o O f> £•*= "£.* i «H u 2 w «> - -._ o-3 o i» >,~ o = C w 2 r3 — 53 c °°.!S 5 hxoa ve ted nsio ; T3 S'So'ag « - c u-o > a cci epre jrov with - o t- <^ •£•"■." t t^OE — >, x ~ ij o CO p ° 5;^ t« c. +- — ■•; u .s.2 ii > c '- — - 2 O CS te° J2 r/l i/o ,„ "«-■£ s *J So ° ° rt n U S.S'O.ag — O J- g p rt « .-— Eunj SECONDARY INFECTION IN WAED TREATMENT OF MEASLES 315 Iii this series of cases (Chart 5) the appearance of S. hemolyticus in the throat and the onset of otitis media are very closely associated in those patients in whom further extensions of the streptococcus infection occurred. In in- stances in which appearance of streptococci and of otitis media are separated by an interval of more than seven days, no further extension occurred. In 8 cases in which this in- terval is seven days or less there has been no further ex- tension of the infection. The Dissemination of Hemolytic Streptococci in Wards Beginning October 24 cultures for the identification of carriers of hemolytic streptococci were made from all pa- tients in a ward and repeated at intervals of one week. Prior to this time individual patients had been examined at intervals of one week, so that an entire ward was never studied on any particular day. This system did not iden- tify and remove all "carriers" in a ward at a given time and was abandoned because it failed to show the conditions present. Investigation of wards as units proved much more satisfactory. The studies made in four of the double wards used for the care of patients with measles are presented in Table LXV. During the time of this study hemolytic streptococci were more prevalent than at an earlier period. Cultures from the throats of all patients entering these wards were negative for S. hemolyticus on admission. The table showing the incidence of " carriers" of hemolytic streptococci each week in these wards demonstrates : 1. The separation of "carriers" and "rionearriers" by throat culture made on admission does not prevent the in- crease of streptococcus "carriers" in wards. 2. Removal of all "carriers" found by cultures on ad- mission and at weekly intervals is inadequate. 316 PNEUMONIAS A X I > [NFECTIONS OF RESPIRATORS TRACT Table LXV Ward Conditions with Reference to Hemolytic stkki'toi'ixvi-s Infection •' ^ - - - w COMPLICATIONS -- g'fcj H H 15 H Eh ASSOCIATED WITH 2 - -: E* - :- • • v. S g > CD " /. P: HEM. STREP. WITH DATES OF OXSET REMARKS c -- ■ = C | w r - ZiU ZhH i. i. - Ward 57 11-3 11-10 11-17 Ward 58 11-3 11-10 11-17 Ward 49 10-25 11-] 11-8 11-15 11-22 Ward f)0 in 25 11-1 11-8 11-15 1 1 -22 Ward 41 10-28 11 -4 11-11 Ward 11-21 11-28 12-5 12-12 Ward 12 10-28 11-4 Ward 10-21 11-28 12-5 12-12 35 1 13 2 16 6 7 38 11 4 6 o 37 7 31 3 35 9 32 18 in 7 29 o 43 o 32 3 20 11 11 -1.1 4 34 9 12 8 closed —No 13 8 4 12 4 4 3 90 43 7 •losed —No 16 4 12 1 20 10 14 7 2.8 15.5 37.5 is. I 36.4 33.0 18.9 9.7 25.7 56.3 43.8 3.4 4.6 9.4 55.0 0.0 8.9 26.5 66.6 pal Lents. 0.0 50.0 33.3 75.0 16.3 pal tents. 25.0 12.5 50.0 .-.ii.ii None Otitis media : 11-8 1 ease .11-7 1 ease Otitis media 10-2.1 2 10-26 10-28 11-15 11-18 11-27 rases case ease case ease case Otitis media : 11-8 1 case 11-13 1 ease 11-22 1 case si reptococeus in i hi ia : (11-9 1 11-10 1 Otitis media: L0-29 11-4 11-5 11-11 11-27 1 2 3 pneu- case) case ease case ease case case ease Streptococcus I uinonia : 11-10 1 12-11 1 Otitis media : 10-29 1 1 2-3 1 12-6 1 ease case case case case Wards .".7 and 58 served by same ward staff. Members of staff cul- tured on 11-5, 11-12 and 11-19. No positives Wards 49 and 50 served by same ward staff. Ward staff cultured : 11-5 1 posit i\ e 11-12 1 positive 11-26 2 positives Case of pneumonia developing on 11-9 was transferred to the "clean" pneu- monia ward without a throat culture to warrant its trans- fer; last cull ii re 1 1-4 negative ; cul- ture 11-12 in pneu- monia ward posi- tive Wards 4 1 and 12 served by same ward staff. Ward staff cult lired 1 1 5 2 posil ive 11-12 2 positive 11-20 2 posil ive 12-2 1 positive SECONDARY INFECTiON IN WARD TREATMENT OF MKASI.KS .'117 Table LXV — (Concluded) Ward 59 SI reptococeus pneumonia : The '■'< cases of si rep tococcus pneumonia acquired S. hemoly- 10-24 37 6 16.2 10-17 1 ease 1 Lcus infection while 10-31 27 5 18.5 10-21 1 case patients in the 16 11-7 9 3 33.3 10-29 1 case bed south section 11-12 7 1 14.3 ( Mitis media : 11-1 1 case of this ward Case developing 10- 29 was removed from section a few days before onset of pneumonia Ward 60 Wards 59 and 60 Streptococcus served by same pneumonia : ward staff. 10-24 22 1 4.5 10-21 1 case Ward staff cultured: 10-31 17 2 11.7 Otitis media : 11-5 positive 11-7 8 1 12.5 10-31 1 case 11-12 1 positive 11-12 6 1 16.6 11-19 positive When the streptococcus complications are traced hack to the wards in which the streptococcus infection of the throat was acquired, it is found that with the exception of Case 141 (already cited) all the streptococcus pneumonias arose from two double wards. Wards 41 and 42 furnished 4 cases at times when streptococcus was rampant in them and 3 of these cases arose within a period of a few days. Wards 59 and 60 furnished 4 cases, very closely associated. In 3 cases the streptococcus infection was acquired in a section of Ward 59 containing 16 beds. These patients were in beds, of which the positions are represented by num- bers 2, 5, and 7, along one side of the ward. The fourth instance of pneumonia appeared at the same time in Ward 60, which was attended by the same ward personnel, but no other connection can be established between this case and the other three. The otitis media appeared in patients scattered through- out those wards for measles in which the weekly incidence of "carriers" was rising rapidly. This relation is illus- trated by Wards 58, 50, and 41. The same observation ap- plies to streptococcus pneumonia arising in Wards 41 and 42. In Ward 41 the weekly percentage of carriers are October 28, 8.9, November 4, 26.5 and November 11, 66.6. 318 PNEUMONIAS AND [NFECTIONS OF RESPIRATOR? TRACT On November 9 and 10 tin' first 2 cases <>f streptococcus pneumonia arising Prom this ward developed. At the same time, November ML a third case appeared in another part el' this same ward unit (Ward 42) where the spread of hemolytic streptococci had been very active. These ob- servations suggesl thai hemolytic streptococci may build up its virulence as the result of rapid dissemination to such a degree that it is capable of causing grave compli- cations. The relation of complications to "carriers" iu Wards 59 and 60 is different from that in the wards just cited. Wards 59 and 60 were opened on October 9 and before Oc- tober 17; when the first case of fulminating streptococcus pneumonia occurred, only three "carriers" bad been found in them. From October 17 to 24 when tbe record in Table LXV begins eight "carriers" were removed. Tbe appear- ance of a ease of severe 1 streptococcus pneumonia in an unusually clean ward was followed by tin 1 rapid develop- ment of "carriers," and tin 1 appearance within twelve days of 3 other cases of streptococcus pneumonia, 2 of which were in beds close to the first case. This sequence suggests focal dissemination of a streptococcus from a case in which it bad suddenly assumed high virulence. An outbreak of infection with S. hemolyticus was recog- nized on November 12 in a measles-pneumonia ward which bad been opened for several weeks and bad continued free from streptococcus. In three patients hemolytic strepto- cocci were found by throat cultures. Inquiry revealed that a nurse in tbis ward, recognized as a streptococcus "car- rier" tbe week before, bad been retained on duty. Two patients well advanced in tbe course of their pneumonias, bad acquired S. hemolyticus demonstrated by throat ex- amination. Both patients developed otitis media with mas- toid extension requiring operations. Cultures from both at operation showed hemolytic streptococci. SECONDARY INDUCTION IN WARD TREATMENT OF MEASLES 319 The third patient, with acute pneumonia, had been sent into the ward on November 11 from Ward 42, which a1 the time was a highly infected ward; no culture of the throal was made before transfer. This patient developed strepto- coccus pneumonia with empyema requiring subsequent op- eration. Discussion. — At Camp Funston, where the prevalence of S. hemolyticus in the measles wards did not rise above that among normal men in the camp at large, 112 consecutive eases of measles were treated without a single complication due to hemolytic streptococci. At Camp Pike, the investigation began at the onset of a small epidemic of measles at a time when hemolytic strep- tococci were an almost neglible factor. The epidemic of measles was followed throughout its course; and, with the passing of the epidemic, there was an increase in the prev- alence of hemolytic streptococci which assumed alarming importance in the production of complications. The epidemic of measles was in part superimposed upon the epidemic of influenza, so that deductions concerning complications strictly due to measles became impossible. It is evident that influenza pla3^ed a considerable part in producing the complications of measles at Camp Pike. The dissemination of hemolytic streptococci through measles wards was controlled only in part by the methods used. This partial control may have served to limit the incidence of streptococcus pneumonia, nine instances oc- curring among 867 cases of measles. In the ward treatment of measles effort should be di- rected to prevent the exposure of patients free from hemo- lytic streptococci to S. hemolyticus "carriers." By this means the rate of development of S. hemolyticus "car- riers ' ' may be reduced. Measures which should be adopted are as follows : 1. Adequate wards should be prepared in advance for the treatment of measles. The rather gradual onset of epidemics of measles makes this provision possible. 320 PNEUMONIAS A\l> IXI'I'.i ITIONS OF RESPIRATOR'S TRACT 2. The separation of S. liemolyticus "carriers" Prom other patients should be enforced. Observation wards, where stricl technic to prevent transfer of infection is practiced and where throal cultures arc made on admission, are essential. Those wards should be promptly evacuated to wards for the care of S. hemolytic "carriers" on the one hand and for "noncarriers" on the other. As far as pos- sible patients should be admitted to a ward until it is filled and then another ward should receive consecutive cases in the same manner. It is desirable to have all cases in each treatment ward in the same stage of the disease. With this system of ward rotation convalescent wards are neces- sary, so that cases requiring a period of hospitalization longer than the average may bo segregated, thus rendering treatment wards available for another levy of acute cases. 3. Strict ward technic elaborated to prevent transfer of bacterial infection from one patient to another must be employed. 4. Throat culture for identification of "carriers" is la- borious but essential. An accurate method for identifying and reporting "carriers" as speedily as possible must be eni] doyed. A competent bacteriologist is essential. A twenty-four hour interval between culture and its report is desirable. The following scheme is recommended: (a) A culture from the throat made on admission to the observation ward (first day in hospital). (h) A culture made on the first day in the treatment ward (third day in hospital). (c) A culture made one week later (tenth day in hos- pital). If the ward incidence of hemolytic streptocoooi reaches 10 per cent, especially in a filled ward, the cultures should be repeated on the thirteenth day in the hospital. If the incidence of "carriers" of hemolytic streptococci increase rapidly, cultures on alternate days should be made so that "carriers" may be removed from the ward. AVherever SECONDARY TNFUCTIOX IX WARD TREATMENT OF MEASLES 321 possible, culturing of the treatment wards as units should he practiced. 5. Patients developing acute symptoms in any way sug- gestive of infection with S. hemolyticus should be imme- diately isolated ; culture from the throat should be made at once and final disposal of the patient should depend apoii its result. Carriers of Hemolytic Streptococci During the winter of 1917-18, with the establishment of the army camps, it very soon became evident that in many of the serious and fatal complications of measles and other respiratory diseases, hemolytic streptococci were playing a very important role. The epidemic prevalence of hemo- lytic streptococci among hospital cases, and later among men on duty in the camps, was established by bacteriologic studies. Prior to this time in civil life, hemolytic strep- tococci under epidemic conditions had been studied in milk- borne epidemics of sejjtic sore throat, such as are reported from Chicago in 1911-13 1 ; from Boston in 1911 2 ; and from Baltimore in 1911-12 3 . Contact air-borne infection has not been emphasized in considering the dissemination of hemo- lytic streptococci. Smillie 4 reports a few cases of hemo- lytic streptococcus throat infections which he attributes to contact infection. Conditions within the arm}' camps were such as to suggest the dissemination of hemolytic streptococci by contact air-borne infection. Some knowl- edge of the percentage of individuals showing positive throat cultures became desirable at the very beginning of studies of contact dissemination of hemolytic streptococci. Smillie found that only one of 100 normal throats har- bored the Beta hemolytic streptococci of Smith and Brown. Levy and Alexander 5 report the presence of hemolytic iCapps, J. A., and Davis, D. J.: Arch. Int. Med., 1914, xiv, 650; Illinois Med. Jour., November, 1912. 2 Windsor, C.-E. A.: Jour. Infect. Dis., 1912, x. 73. 3 Hamburger, D. P.: Tour. Am. Med. Assn., April 13, 1912, lviii, 1109. "Smillie, W. S.: Jour. Infect. Dis., 1917, xx, 45. B Devy and Alexander: Jour. Am. Med. Assn., 191S, lxx, 1827. 322 PNEUMONIAS AND [NFECTIONS OF RESPIRATOR'S TRACT streptococci in 83.2 per cenl of healthy men al Camp Tay- lor, and hemolytic organisms (not definitely identified as streptococci) in 14. S per cenl of recruits arriving at Camp Taylor. Irons and Marine 6 Pound hemolytic streptococci among 70 per cenl of healthy men at Camp Custer. Among measles patients on admission to the hospital at Port Sam Houston, Colo and MacCallum 7 report 11.4 per cent and CummingS, Spruit and Lynch," 35 per cent of throat cultures positive for hemolytic streptococci. At Camp Taylor, Levy and Alexander report 77.1 per cent positive among 388 cases of measles on admission to the hospital. The spread of hemolytic streptococci in measles wards was shown by Cole and MacCallum when on admission 11.4 per cent of eases had positive throat cultures, 38.6 per cent after Prom three to five days, and 56.8 per cent after from eight to sixteen clays in the ward. Tn our study of hemo- lytic streptococci with measles at Camp Funston, 2.6 per cent of the cases had positive throat cultures on admission, 12.8 per cent after three to ten days, and 24.1 per cent after eight to twenty-three days in the hospital. Tn a similar study at Camp Pike we found 1.7 per cent positive on ad- mission; 10.!) per cent after one week; 22.8 per cent after two weeks; 26.2 per cent after three weeks; and, 33.1 per cent after four weeks in the hospital. Hemolytic Streptococci in the Throats of Normal Men.— The percentage of normal individuals harboring hemolytic streptococci in their throats was investigated in three dis- tinct classes of men, classified according to the degree of exposure to contact infection. The first group includes men largely from country dis- tricts, cultured within an hour after being assembled by their local draft board. The laboratory car "Taster" was sent to Hot Springs, Ark. to meet the November draft of '•Irons and Marine: Jour. Am. Med. Assn., 1918, lxx, 687. T Cole and MacCallum: Jour. Am. Med. Assn., 1918, lxx. 1146. 8 Cummings, Spruit and Lynch: Jour. Am. Med. Assn., 1918, lxx, 1066. SECONDARY INFECTION" IN WAItl) TREATMENT OK MEASLES 323 men to l>c sent to Camp Pike. These men were returned to their homes when the armistice was signed, so that there was no opportunity to study them after they had lived un- der camp conditions. The second gronp includes men on duly in Camps Funs- ton and Pike. These men, while largely from country dis- tricts, had been living crowded together in the camp for a period varying from a few weeks to several months. The third group includes normal men resident in the base hospitals at Ft. Riley and Camp Pike. This group includes at Camp Pike the medical personnel of the measles and measles pneumonia wards and represents individuals most exposed to contact infection with hemolytic strep- tococci. On the other hand, the group includes doctors, nurses and seasoned medical detachment men who are per- haps less susceptible to respiratory infections than are raw recruits. The results of studies of these groups are presented in Tables LXVI and LXVII. Table LXVI Hemolytic Streptococci in Throats of Normal Men Not Resident in the Base Hospital PLACE OF STUDY Ph r-l M > m £-< ■ Eh fe § DATE o S >Z H Eh H t m REMARKS ^ Ph W ° & « - in « to fi o << 2 o Hog £ o £ fe P- Ph X Camp Funston, 274 60 21.9 Men on duty in camp in- Kan., cluding 201 white and 73 Aug., 1918. colored; in great part newly drafted men Camp Pike, Ark., 337 25 7.4 Largely white men on duty Nov. 5 to Dec. 10, in camp 1918 Hot Springs, *64 0.0 Men from country districts, Ark., assembled by the local Nov. 12, 1918 draft board * Sputum or saliva cultures on 50 of these men yielded 1 positive for S. hemolyticus. Sputum or saliva injected intraperitoneally into white mice and cultures made from the peritoneal exudate of such mice, yielded 2 additional positives in the same group of 50 men. These 3 positive cases showed very few colonies of hemolytic streptococci. 324 PNEUMONIAS AND [NFECTIONS OF RESPIRATOR'S TRACT Table l.X\ II Strei ococci in Throats op Normal Men Resident w the Base Hospital PLACE OF STUD"! DATE o w 6, g X E y o a - - • * O o X El. I'l R CENT POSITIVE FOR EEM. STREP. REMARKS Ft. Riley, Kan., Aug., L918 24 7 29.2 14 convalescent patients in a Burgical ward ; 10 lab- oratory workers Camp Pike, Ark.. Sept. 10 to Nov. 30, 1918. 1.33 22 *7.5 Personnel of measles wards Per cenl positive, mi one culture only, erage two per pei son as follows : Cultured No. Cases Once L53 Twice 90 3 times 39 4 times 15 Repeated throat cultures, av- Positives 11 The group of men studied at Hot Springs represents individuals among whom there was little chance for contact dissemination of hemolytic streptococci. It is a control series of men from outlying districts examined before their throat bacteriology has been complicated by the inter- change of mouth organisms which occurs when a group of men are crowded into close quarters. The entire absence of hemolytic streptococci by the throat culture method is noteworthy. By multiplying the chances of identifying hemolytic streptococci by making parallel cultures from the saliva, and from the peritoneal exudates of mice in- oculated with saliva, hemolytic streptococci were found, in small numbers, in '•] instances. The findings in this group were only three throats lightly infected with hemo- lytic streptococci. They are in direct contrast with the findings among individuals living in camps under crowded conditions and arc in accord with the findings among re- cruits arriving in cam]) as recorded by Levy and Alexander. In the second group, men living for a time in camp, the findings at Camp Funston and at Camp Pike show rather SECONDARY INFECTION IN WARD TREATMENT OF MEASLES 325 striking differences. The lower percentage incidence at Camp Pike is the more remarkable since the studies were made soon after the influenza epidemic had swept the camp and made necessary the hospitalization of about 20 to 25 per cent of the camp population. In the third group, namely, individuals resident in the hospital, percentage rates at Camp Funston are slightly higher than for men resident in camp. This difference disappears for the entire group at Camp Pike if we con- sider a single throat culture, as we must for the sake of comparison. The majority of these individuals at Camp Pike served in measles wards from which patients carry- ing hemolytic streptococci were removed at weekly inter- vals. Seven and one-half per cent of the ward personnel were positives when first cultured. An additional 7.5 per cent acquired the streptococcus while under observation. Duration of the "Carrier" State. — Unfortunately there are very few observations with regard to the duration of the "carrier" state which can be determined only by re- peated cultures at short intervals. \Ve have made no ob- servations of the duration of the "carrier" state in healthy men. Two hundred and forty-two individuals carrying hemolytic streptococci were identified in the ward treat- ment of measles. All except 37 of these cases were "non- carriers" when first observed. The remaining 205 include 166 contact "carriers" and 39 patients with acute symp- toms of infection by hemolytic streptococci. The complete record of throat cultures on these cases is presented in Table LXVIII. Group I includes 37 cases positive for hemolytic strep- tococci on admission. (a) Twenty-two of these remained positive throughout the period of observation. Four patients became negative after one or two weeks and later showed positive findings, leaving the hospital as positives. These are classified as "irregular." The results of culture were as follows: Cul- 326 PNEUMONIAS AXii [NFECTIONS OF RESP] RATOR"5 TRACT Table LXVIII Results of Throat Cultures ix 242 Hospital Patients Identified as "Carriers"" o)- Eemolytic Streptococci; Cultures Taken at Weekly [nterv \i.s p - a - - u -J '- - 3 — 3 '_ •o c - - 3 o ■3 - CO ; 3 3 ■- 1 3 3 - - IO 3 - - •- - - t- - — - - - = 3 - — . - 3 3 - 9 - 3 3 •_ X, 02 - ° n u 5 -9 o - o o £2 E g D = O ft "■ -= Is 1 1 i| .". , Cases 1 1 + 1 1 1 1 1 7 + 1 + 1 1 1 1 7 +1+1+1 6 +1+1+1+ 2 + 1-1 1 8 +1-1-1 1 +1-1-1- - 1 +1+1-1 1 +1-1+1 12 + 1-1-1- - + + + 1 +1+1-1- + + + 1 ii| J7|Cases -l + l 1 26 3 -l+l+l 12 5 -1+1+1+ 2 2 -l+l-l 9 1 -|+j-j- 1 | -l+l+l- 2 1 -1+1+1+ + - - + - 1 -1+1-1+ 2 in 74|Cases| I -1-1+1 38 5 ^r ^r -l + l + 5 3 -1+1+ + 4 1 -1-1+1+ + + 2 -i-i+i- - - 1 | -i-i+i-i 4 I -1-1+1 + - - - - 1 ! -1-1+1+ - 2 -1-1+1+ - - - 1 -1-1+1+ + + - 1 -i-i+i- + 1 -i-i+i- + + 2 -i-i+i- + + + 1 -i-i+i- - + + 1 -1-1+1+ + - - + 1 i 1 SECONDARY INFECTION IN WARD TREATMENT OE MEASLES 327 Table LXVIII— Cont'j> CM b o 3 3 u +J w rH u 3 3 o c 3 3 o CO 9 3 3 o .3 ■~ 3 3 o A 3 o A CO 3 6 A t- 9 6 A 00 3 3 o A 3 u o 4) 3 M 3 u A -t-> — u 3 3 o A +-> CM w fll o r O S o : o o - /. - 3 ffi.2 cu a! 3S ° a — -G COO NO. OF AUTOPSY nno^ ^^ n^^^ ^ss^?;^^ 0 sO Cm ^i On 4- 1m. Cn DURATION OF ILLNESS Cm p— MMl-K » Cn CM Ov N3 h- Cn CO -J Cm O Cn Cm 4- 1 ^- •— I oO\ DURATION OE PNEUMONIA wcawr rw rrararawrawrtaw car CLINICAL DIAGNOSIS l T) h Tl ^d *"0 '"d ^o * '■o *"0 *"0 ^o "tj ""U PURULENT BRONCHITIS + : +: : +:::+::::: : LOBAR PNEUMONIA g; + g +++gg-f-g+g + S PERIBRONCHIOLAR CONSOLIDATION : ++ : + _ : ++ : : HEMORRHAGIC PERI- BRONCHIOLAR CONSOL. + + +++. + +++ ++ LOBULAR CONSOLIDATION g g § g; : g: g PERIBRONCHIAL CONSOLIDATION 2 + Z + ABSCESS + + + INTERSTITIAL SUPPURA- TIVE PNEUMONIA MULTIPLE ABSCESSES IN CLUSTERS M KM w M EMPYEMA + - r +++ : + ++ : BRONCHIECTASIS + - f ++ : + : : + UNRESOLVED BRONCHO PNEUMONIA + : : + ; ORGANIZING BRONCHITIS — re 3 re 3 2« 3 " — -. 3 S CO re 3 J) re 3 3d co 3 22 3 3 -"a 3 1 5 3 > 3 f) re 3 race Z: o . CO; re . 2! 3 CO 3* re 3 'A' 3 . d ; 3 CO 3" ti 3 ~ / o CO 3" ti 3 BACTERIA IN SPUTUM re 3 P M 5' V re 3 CO - re 3 = ' CO P = 5 = 2 P CO — n 5 ra w - - -■ = Wot n P ; a — — a - CO -- -■? 3 2 3 5 £: = p CO re y re 3 - 5' 30^ -■ n 3 C 3 Co[_ - ~ 3 P ~ ■ re 3_ spa /ico CTP -. - 3 p n 1 11 E to BACTERIA IN BRONCHUS - •/ 3 • re cr 3 rt 3 3 CI co P p '-d co 3 re o C o 3 of 5 w coco gv 3 2 Ti- ll . E re 3 o_ <: td 6S - co-a j-. re n I-., re —■ coLco p P B- -. x = P " - 2 CO < BACTERIA IN LUNG - e 3 F CO — re 3 ►a = re c 3 » o 05 — -. 3 3° =: s - 2 2 i p cc- X c: o - re P BACTERIA IN BLOOD OF HEART 336 PNEUMONIAS AND INFECTIONS 03? RESPIRATOR'S TRACT monia, was doubtless due in pari at least to its association with purulent bronchitis and peribronchiolar pneumonia (Table LXXI). Changes in Bronchi.- The changes in the bronchi do not differ in character Prom those associated with pneumonia following influenza. Purulenl bronchitis recognized at au- topsy by the presence of mucopurulent material in the small bronchi was found in a much Larger proportion of Instances in this group of autopsies occurring in 13 of 18 instance- (72.2 per cent), whereas it was present in only 55.6 per cent of autopsies on individuals with pneumonia following influenza. There was peribronchial hemorrhage recognizable on gross examination in 3 autopsies and mi- croscopically in 3 additional instances. Bronchiectasis was present in a considerable proportion of these autopsies, dilatation of bronchi being noted in 7, but it was usually moderately advanced and at times limited to the bases of the lungs. The short duration of respira- tory disease perhaps explains the infrequency of advanced bronchiectasis. The incidence of the lesion is greater with measles (43.7 per cent) than with influenza (22.4 per cent). Microscopic changes in the bronchi do not differ from those found after influenza. Evidence of acute inflamma- tion, often hemorrhagic in character, is found within the lumen of the bronchus and in the tissues immediately in contact with the lumen. Not infrequently the epithelium is lost ; there is superficial necrosis and deposition of fibrin upon the surface and within the tissue. In the deeper tis- sues of the bronchial wall there is infiltration with lymphoid and plasma cells, which in the larger bronchi is particularly advanced about the mucous glands of which the acini ex- hibit degenerative changes. With the onset of chronic changes new formation of fibrous tissue occurs in the wall of the bronchus and in the contiguous interalveolar walls. The lining epithelium often loses its columnar cells and assumes a squamous type. PATHOLOGY AND BACTERIOLOGY FOLLOWING MEASLES 361 Changes in the bronchi with bronchiectasis have been similar to those following influenza. Weakening of the wall permitting dilatation is brought about by necrosis ex- tending outward Prom the lumen a varying distance into the bronchial wall and permitting the formation tears which diminish resistance to intrabronchial pressure. Lobar Pneumonia. — Lobar pneumonia following measles occurred in 4 instances. Onset in these cases was on ap- proximately the 9th, 10th, 11th or 14th day of measles; the onset of bronchopneumonia bore a similar time relation to the onset of measles, the average interval being nine days. Hepatization with lobar pneumonia was in 1 instance red, in 3 instances gray, and in all save 1 instance the consolidation was firm and coarsely granular on section. In the excep- tional instance the greater part of the right upper lobe was laxly consolidated and rather finely granular but the mi- croscopic appearance was in all instances that of lobar pneumonia. Lobar pneumonia in 2 of these cases was as- sociated with purulent bronchitis present in parts of the lung that had not undergone consolidation, whereas in the other 2 instances there were acute bronchitis and peri- bronchiolar pneumonia recognized by microscopic exam- ination. In one instance hepatization of the lung presented some noteworthy features. Autopsy 450. — G. D., white, aged twenty-one, a farmer, resident of Arkan- sas, had been in military service twenty-nine days. Onset of illness began on October 2, nineteen days before death, and on admission on the same day the diagnosis of measles was made. Signs of pneumonia, regarded as bron- chopneumonia, were recognized five days before death. Three days later there was otitis media and paracentesis was performed. On October 3 and 10 neither S. hemolyticus nor B. influenzae was found in the sputum; on Octo- ber 17 and 20 S. hemolyticus was not found but B. influenzae was present. Anatomic Diagnosis. — Acute lobar pneumonia with gray and red hepati- zation in right upper and lower lobes; edema and peribronchial hemor- rhage in left lung. The entire lower lobe of the right lung (Fig 29) with the exception of a narrow air-containing zone in contact with basal surface is firmly con- solidated. The greater part of the consolidated tissue is yellowish gray. 338 PNEUMONIAS AND [NFECTIONS OF RESPIRATORY TRACT Fig 29 -Lobar pneumonia following measles, showing extension of gray hepatiza- tion from lower to upper lobe through a tlcfecl in the septum separating the two lobes. Autops PATHOLOGY AND BACTERIOLOGY FOLLOWING MEASLES 339 firm and coarsely granular. The uppermost pari of the consolidated tissue is softer than elsewhere as if it has undergone autolysis. The lowermost part of the consolidated tissue in a zone from 2.5 to .'5.5 em. in breadth is firmly consolidated but deep red. The bronchi contain stiff plugs of fibrin. In the upper lobe continuous with the consolidated part of the lower is a semicircular patch of yellowish gray consolidation. It overlies the line of the interlobular cleft at the site of a break in its continuity. Consolidation appears to have spread from the lower lobe into the upper at the site where the alveolar tissue of the two lobes is continuous but is absent from that part of the upper lobe separated from the lower by the interlobular cleft. This semicircular patch of yellowish gray consolidation is separated from air containing tissue of the upper lobe by a zone of red hepatization about 1 cm. in thickness. Bacteriologic examination showed the presence of Pneumococcus IV in the blood of the heart; B. influenzas alone was obtained from the right lower lobe and B. influenzas and staphylococcus from the left main bron- chus. The distribution of lobar pneumonia in the foregoing autopsy indicates that it has spread like a wave from the upper part of the lower lobe (Fig. 32) penetrating into the upper where the alveolar tissue of the two lobes is in con- tact; gray hepatization is everywhere separated from air containing tissue by an advancing zone of red hepatiza- tion. It may be assumed that lobar pneumonia was caused by Pneumococcus II atypical in 3 instances although it was recovered from the lungs only twice, for in the third in- stance (Autopsy 486) it was found in the bronchus and in the inflamed pleural cavity; pneumococci were doubtless previously present in the lung, but had disappeared at least from that part from which the culture was made. Pneu- mococcus IV was evidently the cause of pneumonia in 1 instance (Autopsy 450), for it was found in the blood of the heart although it was absent in the culture from the lung. Little significance can be attributed to the observation that B. influenza? was present in pure culture in the lungs from Autopsies 450 and 486, for the presence of Pneumo- cocci IV in the blood of the heart in Autopsy 450 and of .'HO PNE1 MONIAS A\H [NFECTIONS OF RESPIRATOR'S TRACT Pneumococcus 1 1 atypical in the pleura in Autopsy 486 fur- nishes evidence in view of the occurrence of lobar pneu- monia thai pneumococci had disappeared Prom the Lungs. B. influenzae was found both in the lungs and bronchus or iu the bronchus alone in 3 of these 4 cases. The relation of hemolytic streptococci to the lesion is of interest. In 3 of 4 instances of lobar pneumonia this mi- croorganism had entered the bronchi but was not round in tlic bums or in the heart's blood; and gross and histologic examination showed none of the lesions which are usually caused by it. In 1 instance (Autopsy 508) hemolytic strep- tococci, absent from the throat when the patient was ad- mitted to the hospital with measles sixteen days before death, appeared in a culture made five days later and was subsequently found three times; it had penetrated into the bronchus but failed to roach the lung. Observations made upon lobar pneumonia following influenza have shown the relative insusceptibility of lobar pneumonia with gray hepatization to secondary infection with hemolytic strepto- cocci (p. Kid). Autopsy 508 demonstrates thai occurrence of hemolytic streptococci in the sputum of a patient with pneu- monia does not furnish conclusive proof of the existence of si reptococcus pneumonia. Bronchopneumonia. — Bronchopneumonia has been found in every instance of pneumonia following measles save 3, namely in Autopsy 486, Autopsy 505 with lobar pneumonia and Autopsy 507 with interstitial suppurative pneumonia. It is not improbable that further histologic study might have demonstrated small patches of peribronchiolar pneu- monia, for purulent bronchitis was present in the two autop- sies with lobar pneumonia. This small group of cases has re- produced all of the important features of bronchopneumo- nia following influenza. Hemorrhagic peribronchiolar con- solidation characterized by the presence of small gray spots clustered about terminal bronchi upon a homogeneously red background has been found in 5 of 18 instances of pneu- PATHOLOGY AND BACTERIOLOGY FOLLOWING MEASLES 341 monia with measles. Pfeifrer regarded this lesion as char- acteristic of the pneumonia of influenza. Peribronchiolar patches of consolidation with no surrounding hemorrhage were found in 14 instances, being recognized first by mi- croscopic examination in half of this number. Lobular consolidation occurred in 11 autopsies and peribronchial fibrinous pneumonia was present in a third of the autopsies on patients with pneumonia of measles. Bronchial, peribronchial and intraalveolar hemorrhage is much more commonly associated with the pneumonias of influenza than with the more familiar types of acute bron- chopneumonia. Exuded blood may undergo absorption; and with bronchopneumonia which, persisting unresolved. has assumed the characters of a chronic lesion, it is com- mon to find mononuclear cells often in great abundance filled with brown pigment derived from the hemoglobin of red blood corpuscles. Autopsy 439 is an example of acute hemorrhagic broncho- pneumonia; there are red lobular and confluent lobular patches of consolidation which upon the pleural surface have a blue or purplish color. In the dependent part of the left lung occupying a large part of the lower lobe there is lax, red consolidation marked by gray or yellowish gray spots of peribronchiolar pneumonia and in this lobe bronchi are encircled by zones of hemorrhage. Pneumococcus II atypical was obtained from the lung. In Autopsy 444 the lesion has the same hemorrhagic character although lob- ular patches are in a stage of grayish red hepatization. Pneumococcus II atypical has been found in the heart's blood, and with B. influenza? in lungs and bronchus. Au- topsy 441 is an example of the occurrence of conspicuous nodules of peribronchiolar consolidation in some parts of the lungs with the same lesion in other parts on a back- ground of hemorrhage. B. influenza? and S. aureus have been found in both lungs and bronchi. 342 PNEUMONIAS AXli INFECTIONS OF RESPIRATORY TRACT Steinhaus 1 states that the pneumonia of measles is never lobular inflammation bu1 occurs in small patches several of which may be Pound in a single lobule. Chronic fibroid pneumonia following measles character- ized by cellular infiltration and proliferation of the intersti- tial tissue of the lung has been described by Bartels, 2 Stein- haus, Hart,' MacCallum 8 and others. Vig. 30. — Unresolved bronchopneumonia with measles showing new formation of fibrous tissue about a bronchus and in immediately adjacent alveolar walls; partially obliterated alveoli occur in the peribronchial fibrous tissue. Autopsy 481. The incidence of unresolved bronchopneumonia among instances of bronchopneumonia following measles is higher than that among bronchopneumonias following influenza. There have been 6 instances of chronic or unresolved bron- chopneumonia among 18 pneumonias following measles, 'Steinhaus: Ziegler's I'.eitr. 1901, xxix, 524. -I'.jtrtels: Virchows Arch. f. path. Anat.; xxi. 3 Loc. cit., p. 116. ■•Hart: Deutsch. Arch. f. Klin. Med., 1904, Ixxix, 108. PATHOLOGY AND BACTEEIOLOGY FOLLOWING MEASLES 343 namely 33.3 per cent. The incidence of unresolved broncho- pneumonia among 241 autopsies on pneumonia following in fluenza has been 21, namely 8.7 per cent. The essential fea- tures of this chronic lesion have been as follows: (a) chronic peribronchiolar pneumonia indicated by the presence of firm nodules of peribronchiolar consolidation which have considerable resemblance to miliary tubercles. Induration of sap mm ■ 7* j*»v *f X Fig. 31. — Unresolved bronchopneumonia with measles showing a nodule of chronic fibrous pneumonia surrounding a respiratory bronchiole. Autopsy 481. the nodule occurs because the walls of alveoli surrounding and adjacent to a respiratory bronchiole (Fig. 31) become thickened and infiltrated with cells and there is organiza- tion of exudate within the alveoli. New formation of fibrous tissue (Fig. 32) occurs where the acute inflamma- tory reaction of peribronchiolar consolidation is most ad- vanced (p. 169 and compare with Figs. 3 and 4), namely, about the respiratory bronchiole, alveolar duct and the ;U4 PNEUMONIAS AXU [NFECTIONS OF RESPIRATOR'S TRACT proximal parts of the infundibula, disappearing as the dis- tal half of the Lnfimdibulum is approached. Distention of the alveoli explaining the distent ion of the lung and its fail- ure to collapse on section is a noteworthy feature of the lesion. {!>) Chronic peribronchial inflammation (Fig. 30) with new formation of fibrous tissue about the smaller and medium-sized bronchi extending into immediately adjacent F" TBr s^F-, L££ x r \ r Jb, WKkJb^ Fig. 32. — Unresolved bronchopneumonia with measles showing chronic pneumonia about a respiratory bronchiole and alveolar duct; alveoli about the proximal parts of three distended infundibula are filled with polynuclear leucocytes, whereas inflammatory changes disappear as the y central suppuration. There is empyema on the righl side, fibrinopurulenl pericarditis, and purulent peritonitis. Hemolytic streptococci had been found in the sputum three times, the lirst examination being thirteen days before death. This microorganism is found in pure culture in the blood of the heart and with Pneumococci IV, B. coli and B. influenzae in the lung. Hemolytic strepto- cocci were found in the righl pleural exudate and perito- neum. The pneumonias following measles give opportunity to consider the relationship of suppurative interstitial pneu- monia to unresolved or chronic bronchopneumonia, which is characterized by infiltration and proliferation of the lil irons tissue of the lung's. A number of those who have studied the pneumonia of measles have recognized that this chronic interstitial lesion is a common sequela of measles. MacCallum has designated the lesion "interstitial broncho- pneumonia," and has included under this name its acute stage in which the interstitial character of the lesion is not more evident than with other forms of acute bronchopneu- monia. He has regarded S. hemolyticus as the cause of "interstitial bronchopneumonia" following measles. A review of the autopsies which he has described shows that he has included under the same designation typical in- stances of interstitial suppurative pneumonia associated with suppurative lymphangitis. Instances of unresolved, chronic or "interstitial" bronchopneumonia and of inter- stitial suppurative pneumonia which we have observed after measles, demonstrate that the two lesions are distinguish- able both by their anatomic characters and by their etiology. Three instances of suppurative interstitial pneumonia occurred among the pneumonias following measles (Au- topsies 44l\ 4!)1 and 507). The lesion is characterized by suppuration of 1 he interlobular septa and particularly note- worthy is the occurrence of suppurative lymphangitis, PATHOLOGY AND BACTERIOLOGY FOLLOWING MEASLES 849 lymphatics being immensely dilated and distended with purulent fluid so that their irregularly dilated, bended ap- pearance is recognizable upon the section of the Lung. In the group of pneumonias following measles this lesion has not been associated with unresolved or chronic broncho- pneumonia; no nodular tubercle-like foci of bronchopneu- monia have been found at autopsy, and there has been no thickening of the interstitial tissue. The lesion has accom- panied confluent lobular pneumonia in 2 instances (Autop- sies 442 and 491). In the third instance (Autopsy 507) there was in the neighborhood of the suppurative lesions diffuse consolidation which had the cloudy, gray red color of streptococcus pneumonia, but this consolidation was not lobular in distribution. The etiology of interstitial suppurative pneumonia es- tablished by study of instances following influenza is con- firmed by Table LXXII (p. 345) showing the bacteriology of instances of acute bronchopneumonia following measles. Pneumococci are almost invariably found in uncomplicated instances of bronchopneumonia and hemolytic streptococci have been absent, whereas in 3 instances of suppurative interstitial pneumonia hemolytic streptococci have been found in the sputum during life, in pure culture in the blood of the heart and in the lungs and bronchus (missed in the bronchus in one instance, Autopsy 507). In the 3 instances of the disease B. influenzae has been found in the bronchi. Table LXXIII shows that suppuration has accompanied unresolved bronchopneumonia ("interstitial bronchopneu- monia") in 2 instances (Autopsies 438 and 492), but in .these instances the interlobular tissue of the lung has not been the site of suppuration and there has been no suppura- tive lymphangitis. Localized abscesses have been formed ; hemolytic streptococci, as with abscesses following influ- enza, have been found. Empyema has occurred only 5 times in association with pneumonia following measles and in these 5 instances has 350 PNEUMONIAS AND [NFECTIONS OF RESPIRATOE1 TRACT been associated with suppurative pneumonia caused by hemolytic streptococci. In Autopsy 492 there was frbrino- purulenl pleurisy on both sides. Aspiration had been per- formed 3 times and at autopsy the righl pleural cavity con- tained L50 c.c. of purulent fluid. In small pockets, corre- sponding to shallow oval depressions upon the anterior surface of the lung, fluid was walled off from the general cavity. The pericardial cavity contained 25 c.c. of turbid yellow fluid containing yellow Hakes of fibrin and the peri- toneal cavity contained thick purulent fluid. Hemolytic streptococci present in the heart's blood and lung were re- covered from the righl pleural cavity and Prom the peri- toneum. Among 3 instances of empyema accompanying interstitial suppurative pneumonia, in 1 (Autopsy 491) there were walled off pockets of fluid similar to those just described. Aspiration of the right pleural cavity had been performed 3 times; at autopsy 100 c.c. of fibrinopurulent fluid was found on the right side and 450 c.c. on the left. There was general purulent peritonitis and the peritoneal cavity contained 350 c.c. of thick yellow pus. Hemolytic streptococci were obtained from the heart's blood, right lung, right pleural cavity and peritoneum. Among 4 instances of lobar pneumonia following measles there was serofibrinous pleurisy 3 times; in 1 instance there is no record of pleural change. In 1 instance of lobar pneumonia (Autopsy 505) the right pleural cavity con- tained 800 c.c. of serofibrinous exudate and the pericardial cavity contained 510 c.c. of opaque, yellow seropurulent fluid; Pneumococcus II atypical in pure culture was ob- tained from the blood, lung and pleural and pericardial exudates. Among 9 instances of bronchopneumonia follow- ing measles there was fibrinous pleurisy .'! times, serofibrin- ous 3 times, and no recorded lesion of the pleura 3 times. Empyema, like suppurative pneumonia following measles, is in most instances, but not constantly, caused by invasion of hemolytic sf reptococci. PATHOLOGY AND BACTERIOLOGY FOLLOWING MEASLES 351 The foregoing study has shown thai pneumonia which lias followed measles lias reproduced all of the lesions usually found after influenza. There is no pulmonary lesion peculiar to measles. Lobar pneumonia follows the disease in some instances, but bronchopneumonia with purulent bronchitis is more common. The same tendency to hemorrhagic inflammation found with the pneumonia of influenza is seen after measles. Unresolved pneumonia with chronic inflammatory changes in the interstitial tissue of the lung has all of the characters of the similar lesion following influenza hut has been found in a larger propor- tion of the pneumonias of measles. B. influenza? has been found in the bronchi in 14 of 16 examinations, namely in 87.5 per cent of fatal instances of pneumonia. In 1 instance in which B. influenza? has not been found at autopsy, it has been isolated from the sputum during life. It is not improbable that B. influenza? has been constantly present in the inflamed bronchi both after influenza and measles. It is noteworthy that the outbreak of pneumonia following measles has been in part coincident with, in part slightly subsequent to, an epidemic of influ- enza which has exposed every individual in the camp to in- fection with this disease. B. influenza? has been found in the lung with the pneumo- nia of measles in 7 of 17 examinations, namely, in 41.2 per cent of instances. The microorganism with measles, as with influenza, is found in the inflamed lung only half as frequently as in the bronchi. It appears to be peculiarly adapted for multiplication within the bronchial tubes, and its isolation from the inflamed lung in less than half of the cases of pneumonia is perhaps referable to its presence in the small bronchi and bronchioles. The presence of B. in- fluenza? in the lungs in pure culture in 3 instances at first sight suggests that the microorganism produces pneumo- nia, but a more intimate survey of these cases gives little support to this view. In Autopsy 450 B. influenza? has been .>•>_ PNEUMONIAS AND [NFECTIONS OF RESPIRATORY TRACT found in pure culture in the hum-, bul Pneumococcus IV lias been isolated Prom the blood of the hearl and has been with Little doubl the cause of t\ pical lobar pneumonia present in this instance. In Autopsy 486 the condition is almost iden tical, for in the presence of lobar pneumonia B. influenzae has been round in the lung in pure culture, bul Pneumococ- cus II atypical lias been isolated from the pleural cavity and from the bronchus; in both autopsies the pneumococci which have caused lobar pneumonia have disappeared from thai part of the consolidated lung from which a culture has been made: and here doubtless its invasion has been effec- tively resisted although it is still present in other organs. In Autopsy 4S1 in which B. influenza? has been isolated from the lung in pure culture, the part of pneumococci in the production of the fatal disease is less evident; in this in- stance. Pneumococcus II atypical, S. hemolyticus and I>. in- fluenzae have been isolated from the bronchus. The presence of microorganisms which have a well-es- tablished etiologic relation to pneumonia explains the occur- rence of pneumonia and makes unnecessary the assumption that B. influenzae, which is present in the lungs in less than half of the instances examined, is essential to the production of the pneumonic consolidation. In view of the well-recog- nized etiology of lobar pneumonia we may conclude that this lesion is referable to the pneumococci ( Iuioumococcus II atypical in 3 instances and Pneumococcus TV in 1 in- stance) isolated from the autopsies in which this lesion oc- curred. Pneumococcus (Pneumococcus IT atypical in 3 in- stances and Pneumococcus T in 1 instance) has been isolated from the lungs or heart's blood in 4 of 5 instances of acute bronchopneumonia unaccompanied by suppuration. With unresolved bronchopneumonia with no suppuration, pneu mococci have been in no instance found in the lungs or blood, though their presence in the washed sputum during life or in the bronchus at autopsy su.i^'ests the possibility that they may have disappeared from the lungs. PATHOLOGY AND BACTERIOLOGY FOLLOWING MEASLES 353 In all instances in which suppuration lias occurred hemolytic streptococci have been found in the lungs or blood, or in both. The occurrence of pneumococci in the lungs in 2 of 5 instances of suppurative pneumonia indi- cates that infection with S. heinolyticus is in some instances at least superimposed upon acute bronchopneumonia caused by pneumococci. Bronchopneumonia in 3 instances has the character of that caused by pneumococci. It is probable that the sequence of infection frequently observed after in- fluenza, namely, bronchial infection by B. influenzae, fol- lowed by pneumonia caused by pneumococci, followed in turn by infection by hemolytic streptococci with necrosis or suppuration, is not uncommon after measles. Pneumonia Associated with Acute Infectious Diseases Other than Influenza and Measles. — A small group of au- topsies have been excluded from the list of those which accompanied the epidemic of influenza, because pneumonia has been associated with an acute infectious disease to which it is perhaps secondary. These few instances of pneumonia, like those following measles reproduce char- acters of the pneumonia following influenza and may be in part referable to influenza which has attacked an individual suffering with typhoid fever, mumps or scarlet fever. In 2 instances pneumonia followed typhoid fever and ap- peared on September 23 and 26 shortly after the epidemic of influenza had become evident. In the following autopsy there was acute lobar pneumonia which appeared ten days after onset of typhoid fever. Autopsy 245. — O. H., white, aged twenty-one, a farmer, resident of Okla- homa, had been in military service twenty-one days. Onset of illness was on September 13 with chill, headache, cough and nausea. The patient was admitted two days later with the diagnosis of acute bronchitis. On Sep- tember 20 the abdomen was tense, the spleen was enlarged and rose spots were present. Signs of lobar pneumonia were found September 23. Death occurred September 25, twelve days after onset of typhoid fever and two days after recognition of pneumonia. Anatomic Diagnosis. — Typhoid fever with necrotic ulcers in lower ileum and in colon; hyperplasia of ileocecal lymphatic nodes; acute splenic tumor; 354 PNEUMONIAS A\'l> [NFECTIONS OF I'.KSI'I KAToi; V TII.U IT parenchymatous degeneration of liver and kidneys; acute lobar pneumonia with gray hepatization in left lower lobe and rod hepatization and edema in left upper lobe and In righl lung; serofibrinous pleurisy on left side. The lefl pleura] cavity contains 75 c.c. of yellowish gray turbid Quid. Over the lefl lower lobe there is a layer of fibrin. The upper half of the lobe is firmly consolidated, pinkish gray and coarsely granular; the bronchi contain plugs of fibrin. The lower and posterior pari of the lower lobe is consolidated deep red and edematous. The left upper lobe is edematous and a layer in the lowermosl part in contact with the lower lobe is deep red ami consolidated. The lefl lung weighs 1,490 grms. The lower half of the righl upper lobe and the posterior border of the lower is consolidated deep rod and edematous: the lung weighs 970 grms. Bacteriologic examination shows that the Mood of the ln-art contains Pneumococcus 1 1 atypical. The foregoing autopsy is of interest because typical lobar pneumonia appears to have spread from the left lower lobe, where consolidation is firm and gray, to the adjacent part of the upper lobe where consolidation is red and edematous. The second instance of pneumonia following typhoid fever is an instance of suppurative pneumonia caused by S. aureus. Autopsy 329. — J. B., white, aged twenty-two, laborer, resident of Okla- homa, had been in military service two days before onset of symptoms of typhoid fever. He was admitted to the hospital on August L'7 and 1'.. typhosus was found in cultures from the Mood on September 2 and 3. Acme bronchitis appeared on September :2f> when the epidemic of influ- enza had almost readied its height. A diagnosis of bronchopneumonia was made on the day preceding death, which occurred forty-one days after onset of typhoid fever and eleven days after onset of bronchitis. Anatomic Diagnosis. — Typhoid ulcers of ileum; acute splenic tumor; acute bronchopneumonia with red hemorrhagic peribronchiolar and lobular consolidation in right lung; multiple abscesses forming a circumscribed group in left upper lobe; purulent bronchitis. The pleural cavities contain no excess of fluid. The lungs are voluminous and there is interstitial emphysema. Below the pleura art' bluish red spots of lobular consolidation; in the right upper lobe is a large patch of red consolidation marked by yellowish gray spots in (dusters. In the external and upper part of the left upper lobe is a patch of gray consolidation within which, beneath the pleura, there are small abscesses grouped to form a cluster 1.5 cm, across. Bacteriologic examination demonstrates no microorganisms in the blood of the heart; of two cultures from the left lung one contains S. aureus in pure culture, the other S. aureus and a few colonies of Pneumococcus IV. PATHOLOGY AND BACTERIOLOGY FOLLOWING MEASLES 355 Cultures from the left main bronchus and from the mucopurulenl exudate in a small bronchus both contain P>. influenzas, 8. aureus and Pneumococcus IV. Iii the foregoing case bronchitis has appeared thirty days after onset of typhoid Cover on September 26, imme- diately preceding the. height of the epidemic of influenza. In association with hemorrhagic bronchopneumonia there is suppurative pneumonia with small abscesses forming a circumscribed group below the pleura; there is no em- pyema. The lesion has the characters of the staphylococ- cus abscesses following influenza, and S. aureus is found in association with the lesion; B. influenzae is identified in two cultures from the bronchi. In 2 instances pneumonia was associated with parotitis which was diagnosed mumps. Autopsy 403. — C. T., colored, aged twenty-five, a laborer, resident of Ar- kansas, had been in military service one month. Illness began September 27 with swelling of face behind jaw and difficult mastication; the patient was admitted to the hospital on the same day with the diagnosis of mumps. Pneumonic consolidation was recognized on October 8. Death occurred Octo- ber 13, sixteen days after onset of illness and six days after recognition of pneumonia. Anatomic Diagnosis. — Acute lobar pneumonia with red and beginning gray hepatization of lower and parts of upper and middle right lobes; acute bronchopneumonia with lobular consolidation in left lung; purulent bron- chitis; bronchiectasis in left lung. The lower lobe of the right lung with the exception of the anterior and basal edge is firmly consolidated; the posterior part of the middle lobe and a small corner at the posterior and lower part of the upper lobe is similarly consolidated. The consolidated tissue is gray and coarsely granular on section. The remainder of the lung is dry and voluminous, and the bronchi contain purulent fluid. The left lung contains red and gray patches of consolidation, from 0.2 to 3 cm. across. Bronchi contain purulent fluid and in the lowermost parts of both upper and lower lobes are moderately dilated. Bacteriologic examination shows that the blood of the heart contains Pneumococcus III. It is noteworthy that there was in this case, as in many instances of influenza, both lobar and bronchopneumonia. Purulent bronchitis was present and there was bronchiec- tasis throughout one lunsr. 356 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT In the following case the diagnosis of mumps may be questioned since the lesion of the parotid has characters of terminal suppurative parotitis. Autopsy 417. — H.W.D., white, aged twenty-four, a farmer, resident of Oklahoma, had been in military Bervice one month. He said thai he had had pneumonia four times. He was admitted to the hospital delirious and the diagnosis of lobar pneumonia was made. Parotitis regarded as mumps appeared five days before death and suppuration occurred on the righl si.le of the face. Death of the patient occurred thirteen days after admis- sion to the hospital. Anatomic Diagnosis. — Acute bronchopneumonia with lobular consolida- tion in both lungs; suppurative pneumonia with necrosis and beginning ab- scess formation in left lung; purulent pleurisy in left side; purulent bron- chitis; bronchiectasis; acute parotitis. The left pleural cavity contains 100 c.c. of purulent fluid of creamy con- sistence. The left lung is voluminous and bound to the chest wall in places. There are numerous patches of lobular consolidation. At the apex of the lung there is a large area of consolidation, 7 cm. across, where the tissue is cloudy gray and soft in consistence. In the upper lobe is a well-defined patch of grayish yellow color, (> by 2 cm., with opaque yellow edges; puru- lent fluid escapes from the cut surface. Bronchi throughout the lung are widely dilated and contain purulent fluid. The right lung is voluminous and contains lobular patches of consolidation; bronchi of this lung are widely dilated. Bacteriologic examination shows the presence of hemolytic streptococci in the blood of the heart; hemolytic streptococci and B. influenzae in the lung, and hemolytic streptococci, B. influenza? and S. aureus in a main bronchus. In association with bronchopneumonia there have been necrosis and beginning abscess formation with empyema, the suppurative lesions being caused by hemolytic strep- tococci which had finally entered the blood stream. There was purulent bronchitis, and the lungs bad the voluminous character often associated with this lesion; there was be- ginning bronchiectasis. B. influenzae was obtained both from the lung and from the bronchus. In 2 instances (Autopsies 323 and 335) the diagnosis of scarlet fever was made in patients suffering with pneu- monia following influenza. These lesions have been in- cluded in the list of influenzal pneumonias. In the follow- ing instance the patient was admitted with scarlet fever, PATHOLOGY AND BACTERIOLOGY FOLLOWING MEASLES 00/ later developed acute follicular tonsillitis, and finally sup- purative pneumonia caused by hemolytic streptococcus. Autopsy 311. — E. J., white, aged twenty-two, a tinsmith ami automobile repairer, resident of Arkansas, had been in military service three months. Onset of illness was on September 18 with headache and sore throat. The patient was admitted September 24 with the diagnosis of scarlet fever; two days later there was acute follicular tonsillitis. Pneumonic consolidation on the right side was recognized October 2, three days before death. Anatomic Diagnosis. — Acute suppurative pneumonia with three small ab- scesses below pleura of right lower lobe; acute fibrinopurulent pleurisy on both sides; serous pericarditis. The right pleural cavity contains 1500 c.c. of turbid, dirty yellow fluid containing masses of fibrin; the left cavity has 500 c.c. of similar contents. The pericardium contains 30 c.c. of turbid fluid containing a small quantity of fibrin; there are ecchymoses below the epieardium. The right lung is col- lapsed and in the lower lobe contains three small subpleural abscesses, the largest of which is 1.5 cm. across. Bacteriologic examination shows the presence of hemolytic streptococci in pure culture in the blood of the heart and in the right lung. From the right main bronchus are obtained hemolytic streptococci, B. influenza?, Pneumococcus IV and a few staphylococci. In this instance there has been infection with strepto- coccus which is a common sequela of scarlet fever. In the absence of evidence of bronchopneumonia there has been abscess formation below the pleura with empyema and pericarditis. B. influenzae has been found in the bronchus. The pneumonias found in association with measles re- produce the characters of the pneumonias described in as- sociation with influenza. Particularly noteworthy is the occurrence of lobar pneumonia, hemorrhagic peribronchio- lar pneumonia, interstitial suppurative pneumonia, severe bronchitis with bronchiectasis and unresolved bronchopneu- monia. In the presence of an epidemic of influenza at- tacking more than one fourth of the population of a camp, those suffering with diseases, such as measles, typhoid fever, mumps, etc., are unlikely to escape entirely, and it is probable that the tendency to the occurrence of pneu- monia present in association with these diseases will be increased. The close resemblance between the pneumonias 358 PNEUMONIAS AND INFECTIONS OF RESPIRATOR'S TRACT which we have found with the diseases mentioned, on the cm' hand, and the pneumonias of influenza on the other, l>oth being characterized by the occurrence of hemorrhagic, suppurative and chronic pulmonary lesions, indicates thai influenza has had a part in the production of the pneumonia found with measles and some other infectious diseases dur- ing the progress of the epidemic of influenza. CHAPTER VII SUMMARY OF THE INVESTIGATION AND CON- CLUSIONS REACHED Eugene L. Opie, M.D. There is no reason for believing that the influenza which prevailed in this country differed in any essential feature from that of previous epidemics and particularly of the pandemic of 1889-90. Our studies have shown that an or- ganism with the morphologic and cultural characters of B. influenza? of Pfeiffer has been constantly found in associa- tion with the disease, and so frequently demonstrated in association with its pulmonary complications that there is little doubt of its constant presence. The bronchial and pulmonary complications of influenza present characters which, while varied, are not usually observed in the absence of epidemic influenza, and in this pandemic agree with those of the former pandemic so far as it is possible to determine from the descriptions available. Especially noteworthy is the severity of the changes within the bronchial passages. Clinical studies have shown that purulent bronchitis has occurred in 36 per cent of in- stances of influenza. The sputum with this condition has contained B. influenza? in all instances, but although there were no signs of pneumonia it has been constantly associ- ated with other microorganisms, namely, pneumococci (in 11 of 13 instances), S. hemolyticus, S. viridans, M. catar- rhalis, etc. Identification of the bacteria which have been present in the bronchi of those dead with pneumonia following in- fluenza have determined what microorganisms have pene- trated into the lower respiratory passages. B. influenzae 359 360 PNEUMONIAS AND [NFECTIONS OF RESPIRATOR! TRACT lias been found so frequently (80 per cent) thai there is good reason to believe thai it lias been constantly presenl ami has not been isolated in every instance because it 1ms been overgrown by other microorganisms on the plates or after long continued illness has disappeared from the bron- chi. .Mixed infections of B. influenzae and other microor- ganisms are constantly found in the inflamed bronchi; com- binations of I>. influenza 1 and pneumococci, B. influenzae and hemolytic streptococci or these combinations with staphylo- cocci or the four organisms together are common. Other microorganisms such as B. coli, S. viridans, M. catarrhalis and diphtheroid bacilli are not infrequently associated with those winch have been mentioned. Purulent bronchitis has been found in 137 of 241 autop- sies; its bacteriology differs in no respect from that which has just been described and indeed no line can be drawn between this condition and the bronchitis invariably pres- ent with the pneumonias of influenza. Other evidence of profound injury to the bronchi is the frequent occurrence of hemorrhage in a zone ensheathing the smaller bronchi, and the common occurrence of bronchiectasis when the fatal disease lias lasted more than two or three weeks. Microscojoic study demonstrates that the changes in the bronchial walls are such as destroy the defences against invasion by microorganisms. The bronchial epithelium undergoes destruction which is not infrequently limited to the superficial ciliated cells, but often complete loss of epi- thelium occurs. The mucous glands of the larger bronchi exhibit a special susceptibility to injury, and in the early stages of the lesion profound degenerative changes are found in the secreting cells, whereas at a later stage chronic inflammatory changes are almost invariably present. Pneumonia following influenza is in most instances bron- chopneumonia, bid typical lobar pneumonia has been found in autopsies representing 40.7 per cent of pneumonias of in- fluenza. Lobar pneumonia is frequently accompanied by SUMMARY OF I INVESTIGATION AM) CONCLUSIONS 361 purulent bronchitis, and in a considerable number of au- topsies (34 of 98 with lobar pneumonia) lobar and broncho- pneumonia have occurred in the same individual. Statistics based upon the clinical diagnosis of lobar and bronchopneumonia following influenza are so inaccurate that they have little if any value. Notwithstanding care- ful study of the symptomatology of the disease, lobar and bronchopneumonia following influenza are not ac- curately distinguishable by the means usually employed, and an erroneous diagnosis has been recorded on the pa- tient's history in 36.6 per cent of 227 fatal cases with au- topsy. A diagnosis of suppurative pneumonia is rarely if ever made. The difficulties of diagnosis are in part ex- plained by the frequent association of lobar pneumonia with purulent bronchitis, with bronchopneumonia or with both, and by the occurrence of bronchopneumonia with con- fluent lobular consolidation involving a large part of a lobe or whole lobes. There are many defects in the present knowledge of the symptomatology of the pneumonias under considera- tion. The symptoms of suppurative pneumonia are not clearly defined. Many of these deficiencies might be sup- plied by further application of the time-honored method of comparing the clinical course of the disease with the changes found at autopsies, supplemented by bacteriologic studies made during life and confirmed after death. With peribronchial pneumonia bronchi of medium size, on the cut surface of the lung, are surrounded by sharply defined zones of pneumonic consolidation perhaps 0.5 em. in radius, and this lesion furnishes conclusive proof that the inflammatory process can extend directly through the bronchial wall reaching all alveoli within a limited dis- tance for these alveoli bear no relation to the distribution of the terminal bronchi of the affected bronchus. This peribronchial pneumonia is usually characterized by fibrin- ous exudate, and jmeumococcus has been found either iii 362 PNEUMONIAS AND [NFECTIONS OF RESPIRATOR'S TRACT the blood of the heart or in the lung in all of (i instances in which peribronchial consolidation has been recognized a1 autopsy; in half of these autopsies Pneumococcus Type 11 has been isolated and this relationship is especially note- worthy because Type II has been uncommonly associated w it h t he pneumonias of influenza. Lobar Pneumonia. — The distribution of lobar pneumonia lias repeatedly furnished evidence that the process spreads like the peribronchial lesion directly through the tissue of the lung and is not necessarily disseminated by way of the bronchia] tree. PneumoCOCC] doubtless enter the lung by way of the bronchi; the occurrence of lobar pneumonia in frequent association with influenza which exhibits a pecu- liar capacity to destroy the defences of the lower respira- tory passages is in harmony with this view. The presence of pneumococci in the blood furnishes no evidence that infection is hematogenous, for bacterial infections, par- ticularly at their onset, are frequently accompanied by bac- teremia. The wave-like spread of lobar pneumonia may be indicated by a narrow zone of red hepatization separating a large patch of firm, gray consolidation from engorged but air containing lung tissue. A semicircular patch of con- solidation not infrequently extends from the left lower lobe into the upper lobe at the site where the interlobular cleft is absent. This patch may be firm and gray in continuity with similar consolidation in the lower lobe but surrounded over its convex surface by a zone of red hepatization. There is no reason to doubt that the lobar pneumonia which Ave have found with influenza has been constantly caused by pneumococci. We have encountered no instance of lobar pneumonia caused by the capsulated bacillus of Friedlander. The incidence of different types of pneumo- cocci in the lung with lobar pneumonia has been as follows: Type IV, 32.4 per cent; Type II, atypical, 26.5 per cent; Type III, L7.6 per cent; Type II, 5.9 per cent; Type I, 2.9 per cent; no pneumococci found 14.7 per cent. It is note- SUMMARY OF INVESTIGATION AND CONCLUSIONS 363 worthy that this distribution of types is in sharp contrast with the lobar pneumonia of civil life with which Types I and II constitute the cause of two-thirds of all instances, and is in agreement with the etiology of the pneumonias found in an army camp (Punston) in the absence of in- fluenza in epidemic proportion. Bronchopneumonia. — Bronchopneumonia is associated with intense bronchitis penetrating to the finest bronchioles and is characterized by consolidation distributed in such definite relation to the bronchial tree that dissemination of the inflammatory irritant by way of the bronchi is evi- dent. Consolidation occurs (a) in foci affecting alveoli in immediate proximity to the respiratory bronchioles and in consequence clustered about the terminal bronchi, the intervening alveolar tissue containing air; (b) in foci of the same character surrounded by intraalveolar hemor- rhage whch occupies all alveolar tissue between adjacent foci; (c) throughout whole lobules or groups of lobules, intervening lobules being unaffected ; (d) surrounding bron- chi of medium size like a sheath. The lobar pneumonia of influenza is characterized by frequent association with purulent bronchitis and broncho- pneumonia. The bronchopneumonia of influenza exhibits characters which serve to distinguish it from other forms of bronchopneumonia; (a) The associated lesions of the bronchi are unusually severe ; purulent exudate accumulates within the lumen and the lining membrane is destroyed. (b) Pneumonia is frequently hemorrhagic with accumula- tion of blood within the alveoli and within and surrounding the bronchi, (c) There is unusual susceptibility of the in- jured bronchi and of the pulmonary tissue to secondary in- vasion by streptococci and staphylococci with consequent necrosis and suppuration, (d) Bronchiectasis frequently accompanies bronchitis, (c) Bronchopneumonia frequently fails to resolve and the lesion assumes the character of a chronic pneumonia. 364 PNEUMONIAS ANH INFECTIONS OF RESPIRATOE'S TRACT AYith bronchopneumonia pneumococci are found with B. influenzae in the bronchi and lungs in nearly half and in the blood in approximately one-third of instances of the disease, 1 m t hemolytic streptococci, staphylococci, S. viri- dans, P>. coli, M. catarrhalis and other microorganisms are very frequently found in various combinations: they un- doubtedly have a pari in the production of the lesion. Mixed in feet ion of the lung and even of the blood with pneu- mococci and hemolytic streptococci is often found, and study of the sputum during life has repeatedly shown that pneumococci alone are present shortly after the onset of the disease, whereas hemolytic streptococci appear later or are first discovered at autopsy. In such instances pneu- mococci have not infrequently disappeared from the lung and at autopsy hemolytic streptococci alone are demon- strable. The part which B. influenza' has in the production of bronchopneumonia is of great interest. This microorgan- ism is demonstrable by cultures in at least three-fourths of all instances of bronchopneumonia but is obtained from the inflamed lung tissue in less than half. In no instance of pneumonia have we found B. influenzae unassociated with other microorganisms, whereas repeatedly pneumococci have been the only microorganism demonstrable in the lung and very frequently the only organism present in the blood. In view of the difficulty of demonstrating the mi- croorganism in plates overgrown by other bacteria, it is probable that its incidence in the bronchi is much higher, if it is not constantly present, whereas its isolation from the lung is in part referable to its presence in the small bronchi where it can he readily demonstrated by cultures or by microscopic preparations. We have been almost uni- formly unsuccessful in demonstrating the microorganism in the alveoli of the lung. Goodpasture and Burnett, 1 who 'Goodpasture, E, AW. and Burnett, P. T,.: The Pathology of Pneumonia Accompany- ing Influenza, U. S. Nav. Med. Bull., 1919, xiii, No. 2, P. 21. SUMMARY OF INVESTIGATION ANT) CONCLUSIONS 365 have devised a special method For the demonstration of B. influenzae in tissues, have found few of these microorgan- isms in the alveoli of the lungs. Pneumonia characterized by the occurrence of small (peribronchiolar) spots of leukocytic pneumonia upon an almost homogeneous background of intraalveolar hemor- rhage, was regarded by Pfeiffer as the characteristic lesion produced by his microorganism. B. influenza 1 in our autop- sies has borne the same relation to this lesion which it has exhibited to other forms of bronchopneumonia; pneumo- cocci have been present with approximately the same fre- quency and hemolytic streptococci have often been found. Streptococcus Pneumonia. — The occurrence of strepto- coccus pneumonia with suppuration occurring in the trail of influenza was frequently observed during the pandemic of 1889-90. It is now well recognized that the streptococcus concerned is one capable of causing hemolysis. Suppura- tive pneumonia referable to hemolytic streptococci is of two types which are readily separable by their anatomic characters: (a) One or several abscesses are situated below the pleura and accompanied by empyema. Their relation to severe lesions of the bronchi is not infrequently demon- strable, for a destructive lesion of the bronchial wall has penetrated into the surrounding alveolar tissue so that ne- crosis of tissue and subsequent abscess formation occur r continuity with the bronchial lumen. The localization of the abscess below the pleura is referable to the greater severity of the lesions of the small bronchi which are most numerous at the periphery, to the greater severity of these bronchial lesions at the bases of the lung, and to the rela- tion of lymphatics within the interior of the lung to those of the pleura. It is not improbable that stasis of lymph caused by thrombosis of the lymphatics has a part in the production of abscess. Preceding or accompanying ab- scess formation, the lung tissue undergoes consolidation and in a wide area about the abscess has a homogeneous gray 366 PNEUMONIAS A.ND [NFECTIONS OF RESPIRATOR? TRACT cloudy appearance occasionally mottled by opaque patches of necrosis. (M [nterstitial suppurative pneumonia is a lesion nol infrequently found in association with influenza (ill times among 241 autopsies) and rarely, if ever, seen in its absence. There are few references to this lesion in the pathologic literature of the English language and those of German origin in great part refer to the period of the pan- demic of L889-90. The lesion is essentially suppurative lymphangitis, and both thrombosis and suppuration of the lymphatics are widespread throughoul the affected lung. In proximity to the inflamed lymphatics and the surrounding interstitial septa, lung tissue throughout parts of the lobes or even throughout a whole (lower) lobe lias undergone consolidation and lias the gray, cloudy appearance of strep- tococcus pneumonia. Staphylococcus Pneumonia. — Abscesses produced by staphylococci differ in anatomic characters and sequelae from those caused by hemolytic streptococci. Small ab- scesses occur in one or several localized clusters; these ab- scesses are grouped about a bronchus and have their origin in its terminal branches. This relation may be readily dem- onstrated in microscopic sections. The lesion tends to re- main localized and pneumonic consolidation is limited to the immediate neighborhood of the group of abscesses. There is no lymphangitis and the lesion is not accompanied by empyema. Empyema. — Empyema is almost invariably associated with suppurative pneumonia caused by hemolytic strep- tococci. Among our autopsies purulent fluid has been found in the pleural cavity 55 times; it occurred 1.1 times among 17s instances of lobar or bronchopneumonia and 50 times among 60 instances of suppurative pneumonia re- ferable to S. hemolyticus. In our experience hemolytic streptococci and pneumococci are the only microorganisms which exhibit a noteworthy capacity to penetrate from the lung to Ihc pleural cavity. We have not found nonhemo- SUMMARY OF [INVESTIGATION AM) CONCLUSIONS 367 lytic streptococci (e.g., S. viridans) in association with em- pyema. Staphylococcus has failed to invade the pleural cavity even when a pulmonary abscess has been present below the pleura, and in the only instances in which staphylococci have been isolated from the pleural cavity thoracotomy had been performed for empyema caused by hemolytic strep- tococci (2 instances) or an abscess communicating with both bronchus and pleura. B. influenzae has been found in the pleural cavity with empyema only once and in this instance cannot be regarded as the cause of the lesion, for it has accompanied hemolytic streptococci. Bronchiectasis. — Bronchiectasis has been frequently found as a sequela of the severe bronchitis of influenza and there has been abundant opportunity to study the lesion in process of development. These observations have fur- nished a satisfactory explanation of its etiology and patho- genesis. Infection of the bronchi by B. influenzae, accom- panied by a variety of other microorganisms, notably hem- olytic streptococci and staphylococci, has caused profound changes in the bronchial wall beginning with destruction of the epithelial surface, and followed by necrosis pene- trating partially or completely through the w T all and oc- casionally extending into the surrounding alveolar tissue. The difference between the atmospheric pressure within the bronchi and the lower inspiratory pressure within the surrounding alveoli, accentuated by forced inspiration at intervals and by occlusion of the bronchioles with mucopur- ulent exudate, ruptures the necrotic tissue and produces longitudinal fissures which are recognizable both macro- scopically and microscopically. In consequence of the sep- aration of the edges of these fissures by intrabronchial pres- sure the circumference is increased. These rents in the wall are limited and partially healed by fibrinous pneu- monia about them, by new formation of fibrous tissue from the bronchial wall, and adjacent interalveolar septa, by 368 PNEUMONIAS AX1> [NFECTIONS OF RESPIRATOR'S TRACT organization of fibrin within adjacent alveoli and finally by growth of epithelium over the denuded surfaces. Bronchitis caused by B. influenzae and pyogenic micro- cocci with necrosis of the bronchi wall is the essential fac- tor in the production of bronchiectasis, but advanced bron- chiectasis is found only in those individuals who have sur- vived the onset of illness during several weeks, for dila- tation under the influence of positive intrabronchial and negative extrabronchial pressure occurs slowly. Unresolved Bronchopneumonia. — Unresolved lobar pneu- monia lias not been recognized among instances of pneu- monia following influenza, but unresolved bronchopneu- monia is of frequent occurrence and lias well definable gross and microscopic characters. There are purulent bronchitis, bronchiectasis and distention of the lung tissue, so that it fails to collapse; particularly characteristic are the indur- ated foci of peribronchiolar pneumonia, which being firm and sharply defined, have the appearance of miliary tu- bercles. When the process is sufficiently long continued there are recognizable patches of fibroid pneumonia. ]\li- croscopic examination shows that the lesion is characterize* I by organization of fibrinous exudate not only within the alveoli but within bronchioles as well, and by thickening of the alveolar walls, thickening of fibrous tissue about the bronchi and blood vessels, and thickening of interstitial septa. These changes may occur as peribronchiolar patches of consolidation, producing tubercle-like nodules, or may in- volve areas of hemorrhagic peribronchiolar or of lobular consolidation, or may be limited to the immediate neigh- borhood of bronchi (peribronchial). Xo peculiarity of the bacterial flora of the bronchi or of the lung offers a satisfactory explanation of the failure of pneumonic exudate to resolve. Mixed infections have been common and S. hemolyticus, staphylococci, pneumococci, S. viridans, B. coli, etc., have been found in association with B. influenza' but the incidence of these microorganisms has SUMMARY OF [INVESTIGATION AND CONCLUSIONS 369 not been greater than with bronchitis. The lesion lias oc- curred in association with I>. influenzae and pneumococci unassociated with oilier microorganisms. It seems prob- able that the severity of injury to the bronchial and al- veolar walls accompanied by recurring bacterial invasion or by continued infection with B. influenzae and one or sev- eral cocci, is the factor concerned in the inhibition of reso- lution and the production of chronic pneumonia. II' the disease does not result in early death, chronic pneumonia has an opportunity to manifest itself. In this investigation of the bacteriology and pathology of influenza and its complications, certain microorganisms have been found so frequently that it is desirable to discuss the pathogenicity of each and to define the character of the lesions which it causes. Bacillus Influenzae. — The microorganism has been con- stantly found in association with influenza when cultures and animal inoculations have been made from various parts of the respiratory tract within from one to five days after the onset of the disease at a time when there have been acute symptoms of the disease. It is often identified with difficulty in the presence of other microorganisms and may be overlooked when a single culture is made. Repeated cultures from the throat alone made from the fourth to the eighth day after admission to the hospital, at a time when temperature had fallen to nor- mal, have demonstrated the presence of B. influenza? in 30.5 per cent, whereas the incidence of the microorganism in similar cultures on admission had been 63.4 per cent. The incidence of B. influenzae in the present epidemic of influenza is not less than that found by Pf eiffer in the epi- demic which he studied in 1892. Nevertheless we have found that B. influenza? is fre- quently an inhabitant of the mouth and throat of normal in- dividuals. By inoculation of mice with the saliva or sputum of 76 patients with influenza, the microorganism 370 PNEUMONIAS AN'li [NFECTIONS OF RESPIRATORS TRACT has been found in 80.3 per cent; by inoculation of mice with tlic saliva of IS.") normal men at army cantonments, it was found in 41.6 per cent; by inoculation of mice with saliva from 50 recruits immediately after they were as- sembled from isolated farming communities where only a few cases of influenza had occurred, it was found in 22 per cent. Figures for the same groups examined by a single throat culture were as follows: 65.7 per cent, 25.9 pel- cent and per cent. Experiments which we have performed on monkeys show that inoculation of the nasopharynx with B. influenzae ob- tained from patients with influenza is followed by ill- defined symptoms associated with the presence of B. in- fluenzae within tlie throat. After from two to eleven days the symptoms and the microorganism disappear. Injection of B. influenzae into the trachea causes bronchitis and the microorganism may be recovered from the inflamed bronchi two or three days after inoculation. The constant association of B. influenzae with influenza suggests that it is the cause of the disease. Its widespread occurrence in the throats of normal individuals does not contradict this view, since pnoumoeocci long indistinguish- able from those which usually cause lobar pneumonia are commonly found in the throats of healthy men. It is pos- sible that B. influenzae is a secondary invader, entering the respiratory tract when susceptibility is increased by an un- known virus causing influenza; but there is no convincing evidence in favor of this view. It is desirable to determine if microorganisms having the characters of B. influenzae found with influenza differ in type from those found in the throats of healthy men and if t lie invasion of the respiratory tract by B. influenzae is followed by the appearance of im- munity reactions in the serum of the patient. Experiments on monkeys demonstrate the pathogenicity of the micro- organism. SUMMATIY OF INVESTIGATION AND CONCLUSIONS '■'>( 1 The relation of B. influenzae to 11k- bronchitis of influenza indicates that it lias a part in the production of the pul- monary sequela of influenza. The microorganism has been found by a single culture from the bronchial passages in 80 per cent of instances of bronchitis with fatal pneu- monia following influenza and is probably constantly pres- ent, usually in immense number, in the bronchial mucus. It is obtained from the pneumonic lung in only about 40 per cent of instances, and microscopic examination of pre- pared tissue shows that a bacillus with the morphology of B. influenza? is often demonstrable in the bronchial pas- sages but seldom in the alveoli of the lung. The microor- ganism is well adapted to multiply under conditions present in the bronchi but doubtless readily disappears from the alveoli which are the site of an inflammatory reaction. The microorganism has an important part in the production of the associated mucopurulent and hemorrhagic inflammation of the bronchi, but it is rarely if ever found in pure cul- ture, being associated with a considerable variety of pyo- genic cocci and occasionally bacilli. Infection of the bron- chi with B. influenzae in immense numbers offers an ex- planation of the severity of the inflammatory process within the bronchi, and of the subsequent dilatation and other chronic changes which occur in them. The presence of the microorganism and the accompanying injury to the cil- iated epithelium and mucous glands are important factors in lowering the resistance of the bronchial passages to secondary bacterial infection. We have obtained no evidence that B. influenzae alone is capable of causing pneumonia. Its occurrence in less than half of all pneumonic lungs is explainable, in part at least, by its presence in the terminal bronchi which are cut across whenever the lung is punctured for culture. B. in- fluenza? alone has been found only once among 153 pneu- monic lungs from which cultures were made, and in this instance (Autopsy 487) S. hemolyticus present in the blood 372 PNEUMONIAS AND [NFECTIONS OF RESPIRATOR'S TRACT of the heart, pleural cavity and bronchus doubtless had a part in the production of the associated pneumonia. Pfeif- fer maintained thai the lesion we have designated hemor- rhagic peribronchiolar consolidation was characteristic of infection with his microorganisms. With this lesion B. influenzae lias been round in the lungs in slightly more than half of our autopsies luit never alone, pneumococci being found in a third, hemolytic streptococci in more than a half and staphylococci in a fourth of the lungs examined. B. influenza? has relatively little capacity to penetrate from the bronchi into the hint;- tissue and rarely penetrates into the pleural cavity (once with Pneumococeus III, once with S. hemolyticus and once in pure culture), and only once has it been found in the blood of the heart, in this instance in company with S. hemolyticus. Capacity of the microorganism to penetrate from the bronchi into other tissues, both in man and as our experiments have shown in the monkey, is increased by association with pyogenic cocci. Pneumococeus. — Lobar pneumonia following influenza, like lobar pneumonia in civil life unassociated with in- fluenza, has been caused by pneumococci, but there is the notable difference that the pneumococci usually found are those types which are commonly present in the mouths of healthy men, namely, Types IV, III and atypical II and not the so-called fixed types, namely, Types I and II, which represent the usual cause of lobar pneumonia unassociated with influenza. It appears that influenza increases suscep- tibility to lobar pneumonia, so that it is frequently caused by microorganisms which under other conditions are less capable of producing- this lesion. The association of the pneumococci usually found in the mouth with the lobar pneumonia of influenza does not exclude the possibility that pneumococci transmitted from one individual to another, when newly recruited troops are brought together, have an Important pari in the production of pneumonia. SUMMARY OF INVESTIGATION AND CONCLUSIONS 373 Bronchopneumonia is frequently caused by pneumococci and the types which are recovered from the lung and Mood do not differ from those found with lobar pneumonia, those usually present in the mouth being predominant, but the incidence of pneumococci with bronchopneumonia has been much less than with lobar pneumonia. Both lobar and bronchopneumonia caused by pneumococci have undergone secondary infection with hemolytic streptococci in a large proportion of instances and both pneumococci and strep- tococci are often recovered at autopsy. Nevertheless, the bacterial flora of the bronchi and lungs is much more varied with broncho than with lobar pneumonia, and it is evident that microorganisms other than pneumococci are capable of causing bronchopneumonia. In instances of bronchopneumonia associated with pneu- mococci, fibrin has been abundant in the alveolar exudate. The pneumococcus exhibits a notable tendency to pro- duce an inflammatory process which extends through the bronchial walls and from one alveolus through the alveolar walls to those adjacent, for in 6 instances in which the bronchi were surrounded by pneumonic consolidation rec- ognizable at autopsy, pneumococci were uniformly the causative agent, Pneumococcus Type II, otherwise rarely found, being present in half of these cases. Pneumonia caused by one type of pneumococcus does not necessarily confer immunity from other types of pneu- mococci, and with somewhat limited opportunity we have observed a number of instances in which, following recov- ery from pneumonia caused by one type of pneumococcus, a second attack of pneumonia, usually fatal, has been as- sociated with pneumococci of a different type. This re- curring pneumonia in a considerable proportion of the rela- tively small number of instances observed has been pro- duced by Pneumococcus Type II which otherwise has been seldom found among the cases which we have studied. The 374 PNEUMONIAS AND [NFECTIONS OF RESPIRATORS TRACT virulence of this microorganism doubtless explains its abil- ity to cause recurrent pneumonia. Streptococcus Hemolyticus.- -Secondary infection withS. hemolyticus is a common evenl during the course of Lobar pneumonia following influenza. It is noteworthy thai this streptococcus infection of the Lung Lias almost invariably occurred in the stage of red hepatization, whereas with gray hepatization, when the alveoli are Tilled with polynuclear Leucocytes, S. hemolyticus rarely invades the hum'. It is possible that infection with S. hemolyticus tends to prolong the stage of red hepatization. The most significant change produced in the pneumonic hum- by streptococci is necrosis. When after death with lobar pneumonia hemolytic streptococci, usually associated with pneumococci, are found both in the lungs and blood of the heart, the Lung contains patches of necrosis recog- nized microscopically, in which the alveolar walls and ex- uded cells have uniformly lost their nuclei. Microscopic examination demonstrates the presence of chains of strep- tococci in immense number in these necrotic foci; elsewhere chains of streptococci occur but are much less abundant. In some instances streptococci exhibit a tendency to enter Lymphatics and to cause acute lymphangitis with lymphatic thrombosis and edema of the adjacent interstitial tissue. Eemolytic streptococci have been more frequently found in association with broncho- than with lobar pneumonia. In 24.5 per cent of instances of lobar pneumonia, doubtless in all instances caused by pneumococci, hemolytic strep- tococci have invaded the lungs and in 12.6 per cenl of in- stances have found their way into the blood With bron- chopneumonia hemolytic streptococci have been obtained from the lungs in 29.8 per cent of instances and from the blood of the heart in 34.3 per cent. With Lobar pneumonia there is Little doubt that pneu- mococcus has been the primary cause of pneumonia, but with bronchopneumonia pneumococci have been less fre- SUMMARY OF INVESTIGATION AND CONCLUSIONS d70 quently found. Tt is difficult to determine how often hem- olytic streptococci have invaded a bronchopneumonia lesion, caused by pneumococci because pneumococci tend to disap- pear. In numerous instances in which the sputum had been studied during life, it was evident that pneumonia was pri- marily referable to pneumococci, and hemolytic streptococci made their appearance in the sputum late in the disease or were first recognized at autopsy. When hemolytic streptococci occur in association with bronchopneumonia, foci of pulmonary necrosis similar to those found under the same conditions with lobar pneu- monia have been repeatedly found by microscopic exam- ination. In the patches of necrosis, cocci in chains are much more abundant than in the tissue elsewhere. In some instances of pneumonia, caused by hemolytic streptococci, opaque gray or yellowish gray patches of necrosis occur upon a background of flaccid homogeneous consolidation which has a peculiar cloudy, gray color. This mottled consolidation may implicate an entire lower lobe and has the characteristic features neither of lobar nor of bronchopneumonia. More frequently the lesion is less widespread and necrosis occurs in one or several spots which undergo softening so that finally a small abscess cavity may be formed ; it is surrounded by pneumonic con- solidation which is soft and has the cloudy appearance de- scribed above. These pulmonary abscesses are almost in- variably situated below the pleural surface; the adjacent pleural cavity is infected by streptococci and there is puru- lent inflammation of the pleura. Streptococcus infection, which has been described, doubt- less has its origin in the bronchi, for in favorable sections it is not infrequently possible to demonstrate that necrosis extends through the bronchial walls into the surrounding alveolar tissue and is followed by suppuration with abscess formation. Localization of abscesses below the pleura is 376 PNEUMONIAS AND [NFECTIONS OF RESPIRATORS TRACT in pari at least referable to transmission of streptococci by way of the lymphatics. Streptococci in the lung, as in other tissues, often invade lymphatics and produce an acute inflammatory reaction within and aboul these vessels. The peculiar lesion which may be designated suppurative interstitial pneumonia is a suppurative lymphangitis associated with inflammation and edema of the interstitial tissue Lymphatics invaded by streptococci are the site of acute lymphangitis : occlusion by fibrinous thrombi occurs and finally the immensely dis- tended lymphatics, filled with purulent fluid, take a char- acteristic nodular or beaded form and pus (lows from them when they are cut. Streptococci are present in vast num- bers. Suppurative inflammation may extend to the sur- rounding interstitial tissue which is distended by inflam- matory edema. This interstitial suppurative pneumonia extends up to the pleural surface and empyema is almost invariably associated with it. The lesion is seldom seen in the absence of influenza. One of the most significant characters of S. hemolyticus is its ability not only to enter the bronchi and penetrate into the tissue of the Inns;, but to find its way into more distant structures, namely, the pleural cavity, pericardial sac and peritoneal cavity and to penetrate into the blood. Among 121 examinations, hemolytic streptococci were found in the bronchi in 47.!) per cent; among 153 examina- tions of the lung- it was present in approximately the same proportion, namely, 50.3 per cent; among 218 examina- tions of the blood it was found in 39 per cent. In 4 of 5 fatal pneumonias in which the organism has penetrated into the bronchi it has ultimately found its way into the blood. Nonhemolytic Streptococci. In contrast with S. hemo- lyticus nonhemolytic types have rarely been encountered in association with the pneumonias of influenza. S. viri- dans has been found only 5 times among 153 autopsies in which cultures have been made from the lung and has been SUMMARY OF INVESTIGATION AND CONCLUSIONS Oil invariably associated with oilier microorganisms. In no instances have nonhemolytic streptococci been found with empyema. In one autopsy with lobular bronchopneumonia S. viridans has been isolated from the blood of the heart and in this instance it has been found in the bronchus and lung as well. This type of streptococcus is evidently little adapted to invade the bronchi and produce lesions of the lung- and adjacent tissues. Staphylococci. — Staphylococci have been very frequently isolated from the bronchi in association with the pneu- monias of influenza, being found in approximately half of our autopsies. Their isolation in cultures from the lung in a fourth of the autopsies examined is in part perhaps referable to their presence in the small bronchi cut across when the lung is punctured for cultures. S. aureus shows little ability to invade the pleura, being found in associa- tion with empyema only 3 times; in these autopsies there has been opportunity for entrance from the exterior through thoracotomy wounds in 2 instances and from a bronchus in free communication with an abscess which had ruptured into the pleural cavity in 1 instance. Abscesses of the lung caused by staphylococci have been found in a small number of autopsies and have exhibited characters which differ from those ordinarily seen in as- sociation with S. hemolyticus. Small, sharply denned ab- scesses are grouped about terminal bronchi, so that they occur in one or several isolated clusters. Microscopic ex- amination demonstrates that these abscesses have arisen by destruction of the bronchial walls and extension of sup- puration into the surrounding alveolar tissue; clumps of staphylococci are found in sections through the abscess, and cultures made from the pus within the abscess cavity demonstrate the presence of S. aureus or albus, but the microorganism may be missed if the culture is made from the adjacent lung tissue. It is noteworthy that there is little tendency for the staphylococcus to infect the pleura 378 PNEUMONIAS AND [NFECTIONS OF RESPIRATOR'S TRACT for even though these clusters of abscesses have been situ- ated jusl below the pleura, there lias been ao associated em- pyema. Staphylococci have scant tendency to cuter the blood and have been obtained Prom the blood of the heart only once, in this instance with hemolytic streptococci. Pneumonia of Measles. -Pneumonia following measles lias been responsible for a considerable pari of the deaths occurring in the United States Army during the period of the war. The importance of measles as a factor in the production of pneumonia is illustrated by the history of pneumonia at Camp Funston from the establishment of the cam]) in September, li)17, until September, 1918. Pneu- monia following measles occurred throughout the year; but in association with the high incidence of measles dur- ing the second half of November and the first half of De- cember, 1917, there was an outbreak of related pneumonia characterized by frequent empyema and a mortality of 45.3 per cent. During the period of our investigation at Camp Funston there were 11_! cases of measles, but no pneumonia occurred among- them. At Camp Pike, during the period of observa- tion, there was an outbreak of measles almost coincident with the epidemic of influenza, and among 867 cases pneu- monia occurred in 56, otitis media in 48, and mastoiditis in 23. Pneumonia following measles was almost coincident with that of influenza, and it is not improbable that the epi- demic of influenza had an important part in the production of pneumonia in individuals suffering with measles. In !> of 56 instances of pneumonia following measles at Camp Pike, S. hemolyticus had invaded the lung and caused pneumonia: among 48 instances of otitis media following measles a very large proportion were caused by hemolytic streptococci, and l'l of 23 instances of mastoiditis were caused by the same microorganism. No complication SUMMARY OF INVESTIGATION AND CONCLUSIONS 379 caused by S. hemolyticus occurred among '.'>7 patients who carried this microorganism when admitted to the hospital. A special study has been made to determine if those pa tients with measles who carry S. hemolyticus in their throats are especially susceptible to complications during the course of measles. The low incidence of streptococcus "carriers" among those admitted to the hospitals with measles was noteworthy both at Camp Punston (2. 07 per cent) and at Camp Pike (4.2 per cent). Indeed, it was found at both places that the incidence of hemolytic strep- tococci in the throats of normal men in the camp was higher (Camp Funston 21.9 per cent; Camp Pike 7.4 per cent) than that in the throats of those admitted with measles. While in the hospital there was a gradual increase of the incidence of S. hemolyticus, so that in three weeks it had risen to 19 per cent at Camp Funston and to 26.2 per cent at Camp Pike. It seems not improbable that hemolytic streptococci disappear from the throat in the early stages of measles, so that they are not demonstrable by cultural methods. During the course of the disease in the hospital ward the number of those with S. hemolyticus has increased in some wards with great rapidity, infection being appar- ently transmitted from one individual to those adjacent. At Camp Funston the incidence of S. hemolyticus in the throats of those convalescent with measles was almost identical with that among normal men in organizations from which the patients had come, but at Camp Funston the percentage of hemolytic "carriers" among convalescents was much higher than that obtained among normal men in the camp. The demonstration of S. hemolyticus in the throat of a patient suffering with pneumonia is not conclusive }Droof that the lungs have been invaded by this microorganism. Pneumonia in indivduals carrying S. hemolyticus in the throat may pursue a favorable course and exhibit no evi- dence that the microorganism has found its way into the 380 PNEUMONIAS AND [NFECTIONS OF KKSIMKATOUY TRACT lung. In some instances hemolytic streptococci have been round in the bronchi at autopsy yet none have entered the lung or blood and the lung exhibits none of the lesions which are referable to hemolytic streptococci. Nevertheless, the occurrence of S. hemolyticus in cultures from the throat of a patient with pneumonia suggests the probability thai he is suffering with streptococcus pneumonia. Pneumonia following measles studied in 18 autopsies upon patients who died during or shortly after the epi- demic of influenza, exhibited all the characters exhibited by the pneumonias of influenza. In 4 instances there was typ- ical lobar pneumonia; bronchopneumonia was found in all but 3 instances, being- associated with lobar pneumonia twice. All the noteworthy features of the bronchopneu- monia of influenza have been reproduced among- these in- stances of pneumonia with measles; there is severe injury to the bronchi, and purulent bronchitis has been present in 13 instances ; pneumonia has frequently had a hemorrhagic character, hemorrhagic peribronchiolar pneumonia occur- ring in 5 instances ; secondary infection of the pneumonic lungs with hemolytic streptococci has been common; bron- chiectasis has been associated with bronchitis (in 8 in- stances) when purulent bronchitis has persisted several weeks; and unresolved bronchopneumonia has been more frequent (6 instances or one-third of the autopsies) than with influenza. The bacteriology of pneumonia following measles has been the same as that of influenzal pneumonia. B. influ- enza? is found with few exceptions in the bronchi and much less frequently in the pneumonic lungs. Pneumococci have been obtained from the blood or lungs in 5 of 13 instances of lobar or bronchopneumonia unac- companied by suppuration; when suppuration has been ab- sent no hemolytic streptococci have been found. Pneumo- cocci concerned in the production of pneumonia of measles, as with influenzal pneumonia, have been types usually SUMMARY OF INVESTIGATION AND CONCLUSIONS 38] found in the mouth; Pneumococcus II atypical 1ms been found 6 times, Type IV once, Type I once. Hemolytic streptococci have invaded the pneumonic lung in 5 instances. They have produced subpleural abscesses accompanied by empyema in 2 instances. Interstitial sup- purative pneumonia, a lesion repeatedly found in conse- quence of secondary infection with S. hemolyticus follow- ing influenza and rarely found in this country, at least in the absence of an epidemic of influenza, has occurred 3 times among 18 instances of pneumonia following measles. The foregoing observations show that the pneumonia fol- lowing measles, which has occurred almost coincidentally with pneumonia accompanying epidemic influenza has re- produced the lesions found with influenzal pneumonia. The}'' indicate that influenza attacking patients with measles has had a part in the production of this pneumonia. The Transmission of Streptococcus Pneumonia. — The im- portance of streptococcus as a cause of pneumonia follow- ing influenza was recognized during the pandemic of 1889- 90. Patients suffering with pneumonia following influenza or measles are susceptible to infection by S. hemolyticus and this streptococcus pneumonia may be transmitted from one patient to another throughout a ward in which patients with pneumonia are assembled. There is no evidence that primary pneumonia caused by S. hemolyticus has prevailed as an epidemic in the army or elsewhere in the absence of preceding infection with influenza or measles. Our autopsies demonstrate that at least half of all deaths which have occurred at Camp Pike have been caused by hemolytic streptococci which have invaded the lung and entered the blood. It is significant that this mortality had its origin in the first half of the epidemic of influenza at a time when the military and medical organization of the camp was confronted with an unforseen emergency which overwhelmed all agencies for the care of disease. Curves prepared by referring cases of pneumonia in which an- 382 PNEUMONIAS AND [NFECTIONS OF RESPIRATOR'S TRACT topsy demonstrated the nature of the fatal infection back to the date of the ousel of influenza, demonstrate thai fatal streptococcus pneumonia was frequently acquired during the early period of the epidemic, the maximum number of cases occurring September 23 and 24 and became grad- ually less common as a sequela of the influenza which be- gan at a Later period. Fatal pneumococcus pneumonia had its origin with increasing frequency at a later period, the maximum incidence following influenza which had its onset September 29 and 30. Overcrowding of influenza patients in infirmaries, ambulances and hospital had an important pari in the dissemination of streptococcus pneumonia among influenza patients whose disease might otherwise have pursued a benign course. The most important factor in the high incidence of strep- tococcus pneumonia has been the spread of the disease in the hospital wards. On September 24 the base hospital contained 2,789 patients, although it had been planned to care for only 2,009. With the progress of the epidemic the number of admissions increased very rapidly, so that on September 30 the hospital contained 8,587 patients and on October 5, 4,233. After September 24 the milder cases of influenza were treated in barracks. The pressing need of diminishing the overcrowding of the hospital was fully rec- ognized and adjacent barracks were transformed into hos- pital wards; between October 3 and 6, 1,362 patients were transferred from the hospital to these quarters. In the main hospital, during the period of overcrowding 20 wards for patients with pneumonia were added to the two which already existed. These hastily organized and over- crowded wards have been attacked by outbreaks of strep- tococcus pneumonia, which during certain periods have been fatal to more than two-thirds of those who have been admitted with pneumonia, whereas in the two loni»- estab- lished wards for pneumonia isolated cases of streptococcus infection, which have appeared, have failed to spread to SUMMARY OF INVESTIGATION AM) COXCU 'SIOXS 383 other patients and pneumococcus pneumonia with few ex- ceptions has been found in those who have died, in one newly established ward 07.5 per cent of those admitted within a period of three days have died, and in all of the 23 autopsies which have been performed, streptococcus pneumonia has been found. In another ward 50 per cenl of all who have been admitted during a period of one week have died, and among the autopsies performed on these individuals pneumococcus pneumonia has been found in 6 and streptococcus pneumonia in 14. The sputum of 9 patients in this ward has been examined on admission, and pneumococci, but no streptococci, have been found. All these patients have died, and infection with S. hemolyticus has been found at autopsy in 7. Transmission of Pneumococcus Pneumonia. — Our study of secondary ward infection has not only shown that pa- tients with pneumococcus pneumonia following influenza are susceptible to infection by S. hemolyticus, but that patients suffering with pneumonia caused by one type of pneumococcus may be infected with another type during the course of the disease or after convalescence has begun, the second infection being acquired from patients in ad- jacent beds. Pneumonia caused by Type IV has ended in crisis and has been followed by a period of normal tem- perature; recurrent pneumonia has been fatal and Pneu- mococcus Type II has been found in the organs at autopsy. Pneumonia caused by Type I has been followed by recur- rent pneumonia caused by Pneumococcus II atypical ac- quired from a patient in the next bed. These secondary pneumococcus infections acquired within the hospital are apparently not uncommon. Prevention of the Transmission of Pneumonia. — The es- sential factor in the management of influenza and rmeu- monia is such isolation of each patient that microorganisms cannot be transmitted from one to another or from attend- ants or others to patients. This condition may be fulfilled ..S4 PNEUMONIAS AND [NFECTIONS OF RESPIRATORS TRACT by the separation of patients in rooms or isolated compart- ments especially constructed for the treatment of pneu- monia and by the employmenl of all possible means to pre- vent the transmission of infection from one patient to an- other by physicians, nurses and orderlies. It is desirable to examine attendants to determine it' they carry hemolytic streptococci in their months and to exclude those who are found to be "carriers." Inllnenza is a self-limited disease which, in the absence of complications implicating the lower respiratory tract, is of relatively mild character. When death occurs as the result of influenza it is with very rare, if any, exceptions referable to pneumonia; we have invariably found pneu- monia in those who have died in consequence of influenza. The individual attacked by influenza may carry within his upper respiratory passages pneumococci or hemolytic streptococci capable of invading the bronchi and causing pneumonia, but in most instances the microorganism which produces serious pulmonary complications is derived from others with whom the influenza patient has come into con- tact. The greatest source of danger to one with influenza is contact with patients who have acquired pneumonia, and this danger is immensely increased when infection with S. hemolyticus makes its appearance among pneumonic pa- tients. Hospital epidemics of streptococcus pneumonia will be prevented when the disease is dreaded as much as puerperal fever or the hospital gangrene of former years, and widespread knowledge of the suppurative pneumonias of influenza will bring a clear recognition of the fatal char- acter of streptococcus infection in patients suffering with pneumococcus pneumonia. Overcrowding of barracks has been an important fac- tor in the propagation of acute respiratory disease and in the transformation of otherwise trivial inllnenza into fatal pneumonia. Crowded troop trains have doubtless had a part in disseminating infection among newly as- SUMMARY OF INVESTIGATION AND CONCLUSIONS 385 sembled recruits. Should these dangers he recognized they may be avoided by appropriate measures which will pro- mote rather than retard those military aims which must be placed foremost in time of Avar. It may be possible by ade- quate expenditure to avoid the death of thousands of re- cruits within one month of their entrance into military service. A second factor in the increase of death rate from pneu- monia is the overcrowding and confusion of hospital facil- ities in Uie presence of an epidemic disease. When troops are maintained in camps precautions should be taken to pro- vide effective safeguards against the overcrowding of the base hospital. Isolation of each patient with pneumonia is the most ef- fective way of protecting him from infection and of pre- venting him from becoming a possible source of danger to others. The effectiveness of this isolation will depend upon the separation of patients by some means more effective than the cubicles composed of sheets heretofore employed, upon an aseptic technic sufficiently rigid to prevent the transfer of pyogenic infection to pneumonia patients, and upon the exclusion from the ward of those who harbor S. hemolyticus. Even should each patient be completely isolated from his neighbors, no effort should be neglected to determine, as far as possible, the nature of the infection with which he suffers. In the presence of an overwhelming epidemic such as that which attacked our army camps, the bacter- iologic work which is required may be far beyond the facil- ities which are available and in many instances it may be wholly impossible. Nevertheless effective control of strep- tococcus pneumonia will depend upon its recognition as soon as it appears, and bacteriologic examination of the sputum offers the readiest means for its identification. The routine performance of autopsies will furnish an index of the success of the measures in force, and the discovery 386 PNEUMONIAS A N I ' INFECTIONS OF RESPIRATOR! TRACT of suppurative pneumonia will suggest the presence of im- minenl danger. However perfecl the organization of pneumonia wards and however accurate the aseptic technic in force, it is desirable to separate as far as possible those infected with streptococcus from those who arc free from this infection, so that the accuracy of the technic in force may not be put to too severe a test. When streptococcus pneumonia has appeared in a ward it should he closed to further admissions. These who arc concerned in the planning and construc- tion of military and other similar hospitals iniejit well ,<>ive special attention to the possibility of epidemics such as those which we have experienced, and special provision might he made to avoid overcrowding in the presence of a demand far in excess of the routine need for hospital facil- ities. In the construction of these hospitals appropriate provision should be made for the care of patients with pneumonia. Medical officers should receive detailed in- struction in the organization and conduct of wards designed for the treatment of pneumonia. APPENDIX EXPERIMENTAL INOCULATION OF MONK EYS WITH BACILLUS INFLUENZAE AND MICRO- ORGANISMS ISOLATED FROM THE PNEUMONIAS OF INFLUENZA Eugene L. Opie, M.D. ; Allen W. Freeman, M.D. ; Francis Gr. Blake, M.D. ; James C. Small, M.D. ; and Thomas M. Rivers, M.D. Experiments were undertaken at Camp Pike in Decem- ber, 1918, to determine whether bacteria freshly isolated from patients suffering with influenza and pneumonia dur- ing the outbreak of influenza and its associated pneumo- nias were capable of producing similar diseases when in- troduced into the respiratory passages of monkeys. The number of animals available for the study was limited. The attempt was made (a) to determine if B. influenzae produces in monkeys a disease comparable to influenza of human beings, and (b) to determine so far as possible, with the limited opportunity, the character of the lesions produced by combinations of pneumococcus or S. hemo- lyticus with B. influenzae and to compare these lesions with lesions produced by pneumococcus or by hemolytic strep- tococcus alone. Pfeiffer 1 found monkeys alone susceptible to invasion by B. influenzae and obtained no evidence of multiplication of the microorganism within the body of any other animal. A suspension containing mucus from the sputum of a pa- tient with influenza was injected into a monkey. There was elevation of temperature and the animal died after seven days. Lobular patches of atelectasis occurred along the sharp edges of the lungs and the adjacent bronchial iPfeiffer: Ztschr. f. Hyg., 1S93, xiii, 357. 387 388 PNEUMONIAS AND [NFECTIONS OF RESPIRATOR! TRACT branches contained mucus. Cultures on agar from tlu v bronchi remained sterile. Microscopic examination showed the presence of bacilli resembling !>. Influenzae. Death was caused, the author states, by an abscess at the site of in- oculation and aol by the process in the hums. Three mon- keys received each 0.5 c.c. of bouillon containing a blood agar culture injected into the hum' through the chest wall. There Avas elevation of temperature lasting Prom three to five days with return to normal every morning. There was cough but little evidence of illness. B. influenzae was introduced by a platinum loop into the nose of a monkey. Febrile reaction is recorded Lasting four or live days. Pfeiffer found that guinea pigs and mice were resistant to the microorganism. Large doses injected intravenously caused in rabbits intoxication with dyspnea and evidence of profound muscular weakness. Kamen 2 used a culture of B. influenzae which was nonpath- ogenic tor mice, but when it was inoculated into the peri- toneal cavity with streptococcus both influenza bacilli and streptococci appeared in the blood. Jacobson 3 found that B. influenza? appeared in the blood and viscera of mice killed by intraperitoneal inoculation of B. influenzae mixed with cultures of streptococcus either living or killed by heat. B. influenza? which had successively passed through mice, simultaneously inoculated with killed streptococci, acquired such virulence that it was capable of producing septicemia when inoculated alone. Richie 4 introduced by lumbar puncture a suspension of two blood agar cultures of B. influenzae obtained from the meninges of a patient with influenzal meningitis into the subdural space of a rhesus monkey. Death occurred in eighteen hours and there was beginning meningitis. B. in- fluenzae was present in the exudate in abundance. -Kamen, L : Centralbl. f. Bakteriol., 1901, xxix, Erste A1>t. 339. 'Jacobson, G.: Arch, de med. exper. et d'anat. path., 1901, xiii, 425. 4 Ricbie, J.: Journal Path, and Bacterid., 1910, xiv, 615. APPENDIX oSfJ In two species of monkeys Wollstein 5 produced fatal meningitis by injecting suspensions of l>. influenza' into the subdural space by lumbar puncture. During the course of our investigation of pneumonia and influenza, sputum of approximately 400 normal individuals or patients with influenza was injected into the peritoneal cavity of mice. B. influenzae was found in approximately 150 instances. In only 4 instances was B. influenzae found in pure culture in the blood ; in all other mice in which B. influenzas appeared in the blood it accompanied pneunio- coccus or S. hemolyticus. Before experiments were performed cultures were made from the throats of all monkeys in order to exclude the presence of B. influenza?. Blood agar plates inoculated with a swab applied to the nasopharynx failed to show in any instance B. influenza?, pneumococci, or hemolytic strep- tococci. Streptococci causing green discoloration of blood agar were usually found. Inoculation of the Nose and Pharynx with B. Influenzae. — B. influenzas was introduced into the nose and pharynx of two healthy monkeys. An actively growing culture of the microorganism made on alkaline blood agar and sixteen hours old was used. The culture was the first subculture from a growth obtained from the nose and throat of a patient with influenza. A cotton swab moistened with broth was applied to the surface of the culture. It was introduced into the nostrils and smeared over the pharynx of the animals. A swab moistened with sterile broth was applied to the nose and pharynx of a third monkey as a control; cultures from this animal kept in a cage removed from those inoculated failed to show B. influenza?. Experiment 1 November 21, 1918. — Small female monkey; throat culture: negative. No- vember 23. — 10:20 A.M. — White blood corpuscles, 16,700; polynuclear leuco- cytes, 68 per cent; small lymphocytes, 17.5 per cent; large lymphocytes, 8 per 5Wollstein. M.: Am. Jour. Dis. Child., 1911, i, 42. 390 PNEUMONIAS AND INFECTIONS 01 RESPIRATOR'S TRACT (••■nt: large mononuclears, I pex centj eosinopbiles, 2.5 per cent; basinophiles, 0.5 per cent. 10:30 A.M.— Mucous membranes of nose and throat were inoc- ulated with B. influenzae as described above. November 25.- The animal ap- pears si.k and is huddled Ln back of its cage; the nose is running. White blood corpuscles, L3,500; polynuclear leucocytes, II per cent : small lymphocytes, 30 per cenl ; large lymphocytes, 22 per cent : large mononuclears, 3 per eenl ; eosin- opliiles, 1 per cent. 3:40 P.M. — Free epistaxis occurred after culturing of nose; the swab was discolored with old brownish blood indicating previous epistaxis. Nose culture: B. influenzae present in abundance; Gram-positive cocci present. Throat culture: negative for B. influenzae. November 28.— Monkey is more active and appears to be fairly well. Nose and throal cultures: negative for B. influenzae. December 4.— Monkey is apparently well. Experiment 2 November 21, 1918. — Small male monkey. Throat culture: negative. No- vember 23. — 10:10 A.M. — White blood corpuscles, 10,900; polynuclear leuco- cytes, .31' per cent: small lymphocytes, is per cent; largo lymphocytes, 25 per cent; large mononuclears, I! per cent; eosinophiles, 2 per cent. 10:15 A.M. — Mucous membranes of nose and throat wen' inoculated by means of moist swab with 4 strains of B. influenzal recently isolated from acute cases of in- fluenza. November 24. — Monkey is quiet and takes no interest in surroundings. November 25. — Animal appears sick and remains huddled at back of its cage. Nose culture: B. influenzae present. Throat culture: B. influenzal present. Swab applied to nose is stained brown with old blood indicating previous epistaxis. November 2G. — Animal is still sick; nose is running. White blood corpuscles, 14,400; polynuclear leucocytes, 61 per cent; small lymphocytes, 23 per cent; large lymphocytes, 15 per cent; large mononuclears, 1 per cent. No- vember 27. — White blood corpuscles, 11,300. November 28. — Nose culture: negative for B. influenza?. Throat culture: B. influenzal present. November 29. — Animal is active, but still appears sick. White blood corpuscles, 19,300. December 4. — Monkey appears well. Throat culture: B. influenza 1 present. These animals were sick two and six days following in- oculation. There was discharge from the nose. In both in- stances there was epistaxis. The temperature of the ani- mals was subject to such wide variation in relation to ex- ternal temperature that it could not be used as an index of the progress of the disease. There was no leucocytosis, but in one animal there was some increase in the numbers of leucocytes during recovery. In one animal B. influenzae present in the nose after two days was absent after four days. In the other animal the organism was repeatedly found in the nose and throat and was still present in the throat eleven days after inoculation. The two animals suf- APPENDIX .j Jl fered with a self-limited disease resembling many cases of influenza. Introduction of Bacillus Influenzae into the Trachea. — In the attempt to reproduce the bronchitis which occurs in a considerable proportion of all cases of influenza and is al- most invariably associated with B. influenzae, this organism was introduced into the trachea of monkeys. In Experi- ment 3 a suspension containing young cultures of freshly isolated B. influenzas was introduced into the trachea by a silver catheter passed through the glottis and larynx into the trachea. Young cultures of B. influenzas, subcultured only once after isolation from early cases of influenza, were used. The microorganism was recovered in abundance by throat swab two days later and again from the bronchus at autopsy three days after inoculation. Tuberculosis of mesenteric lymph nodes, of intestine and of liver and several small tuberculous nodules in the lung were found at autopsy. A secondary invasion of the lung by staphylococci had oc- curred. There was bronchitis with an inflammatory infil- tration of the subepithelial tissue of the bronchi by lym- phoid and plasma cells. Bronchopneumonia was present, and the bronchi and many of the alveoli contained blood. These changes do not differ essentially from the changes found in many instances of pneumonia following influenza. In three instances cultures of B. influenzas were injected into the trachea by means of a hypodermic syringe. In one of these experiments (Experiment 4) intratra- cheal injection of 2 c.c. salt solution suspension of B. in- fluenzas (isolated at autopsy from bronchus of the monkey used in Experiment 3), representing growth on iy 2 blood agar plates, was made with a needle inserted into trachea just above the suprasternal notch. On the following day a throat culture contained B. influenzas in abundance. Three days after inoculation the monkey appeared to be very sick and there was profuse nasal discharge. The animal 392 PNEUMONIAS AND [NFECTIONS OF RESPIRATOR'S TRACT coughed and sibilant rales were beard over the chest. There was no Leucocytosis. A throat culture contained B. influenzas. Four days after inoculation the monkey was still sick and weak, luit appeared much improved and was killed. The trachea and Large bronchi contained thick vis- cid mucus. In the middle Lobe of the righl Lung was a patch of grayish red, airless tissue, firmer than the lung substance elsewhere. Cultures from the trachea, bronchus and lung contained a variety of microorganisms, but B. influenzae was not recovered. In two additional experiments (Experiments (> and 7) cultures of B. influenzae forty-eight hours old were injected into the trachea of monkeys. The microorganism was re- covered in cultures made Prom the pharynx two days later. These animals were only slightly sick. Introduction of B. Influenzae and S. Hemolyticus into the Trachea. — In view of the frequent association of B. influen- zae and S. hemolyticus in the sputum of patients with strep- tococcus pneumonia following influenza and in the bronchi and lungs of those who have died with this disease, the two microorganisms were injected simultaneously into the tra- chea of monkeys. B. influenzae and 8. hemolyticus in Experiment 7 pro- duced bronchitis and bronchopneumonia. There was acute inflammation of the interstitial tissue of the lung, and acute lymphangitis with numerous polynuclear leucocytes within the lumen of the lymphatics was present. B. influenzae and S. hemolyticus were present in the trachea at autopsy four days after inoculation. It is probable that part of the in- jected culture entered the tissue outside the trachea, for an abscess was formed in this situation. It is noteworthy that acute pericarditis occurred and both S. hemolyticus and B. influenzae were found in the pericardial exudate. B. influ- enzae not infrequently exhibits this tendency to penetrate in association with other bacteria localities which it does not invade independently. APPENDIX 393 In a second experiment (Experiment 8) in which B. influ- enzae and S. hemolyticus wore injected into the trachea, both microorganisms were recovered from the throat on the day following inoculation; on the fifth day S. hemo- lyticus alone was recovered and on the sixth day a throat culture was negative both for S. hemolyticus and B. influ- enzae Introduction of B. influenzae and of Pneumococcus or of Pneumococcus Alone into the Trachea. — In two experi- ments B. influenzae and Pneumococcus Type III were simul- taneously injected into the trachea. In Experiment 9 a large male monkey was used and intra- tracheal injection made with syringe and needle of 5 c.c. salt solution suspension of Pneumococcus Type III and B. influenzae (growth. on 5 blood agar plates of mixed cultures of Pneumococcus III and B. influenzae). On the following clay the animal was very sick, lying on the floor of its cage, and was dead two days after inoculation. The dosage of bacteria in this exrjeriment was large. The lesions in gross appearance and microscopically resembled those seen in many instances of pneumonia following influ- enza. In the trachea there was loss of ciliated epithelium, congestion of the subepithelial tissue, hemorrhage and infil- tration with plasma cells. The lungs were consolidated and red and there were hemorrhage and edema. B. influenzae, as in human cases, was abundant in the bronchi, less abun- dant in the consolidated lung, being present though scant in the left lung, and absent in cultures from the right. B. influenzae as in Experiment 8 with streietoeoeeus had en- tered the left pericardial cavity in company in this experi- ment with Pneumococcus III. In Experiment 10 a very large monkey received by intra- tracheal injection, made with syringe and needle, 5 c.c. salt solution suspension of Pneumococcus III and 3 strains of B. influenzae, (2 recently isolated from cases of influenza 394 PNEUMONIAS AXD INFECTIONS 01 RESPIRATORS TRACT and 1 from autopsy in a case of postinfluenzal pneumonia). The animal 3ied twenty-four hours later. This simultaneous introduction of l>. influenzae and Pneu- mococcus III in large quantity lias produced rapidly fatal pneumonia with lobar distribution. Eepatization was homogeneous and rod, and outside the consolidated parts of the lung there was hemorrhage and edema. The lesion resembled thai round when death lias occurred within a few days after the onset of pneumonia following Influenza, but had no distinctive characters establishing its relation to pneumonia following influenzae. In Experiment 11 Pneumococcus III alone in small amount was introduced into the trachea of a small monkey. The animal was very sick, but its condition improved and recovery seemed probable. The animal was killed seven days after inoculation, and typical lobar pneumonia with gray hepatization was found at autopsy. Experiment 11 November 20, 1918. — Small monkey; throat culture: negative for B. influ- enzae, pneumococcus and S. hemolytieus. November 28 and December f>. — Nose and throat cultures again negative for B. influenzae. December 0. — 4 ::!ii P.M. — Intratracheal injection with syringe and needle of 0.33 c.c. of an eighteen hour broth culture of Pneumococcus Type III. December 10. — The animal is sick, huddled up in his cage with head down; there is rapid respi- ration with expiratory grunt ami the mucous membranes are moderately cya- notic. There is frequent cough. Throat culture: Pneumococcus 111 presenl in abundance. December 15. — The animal appears to be better. Respirations are still rapid but less labored. December 16. — The animal is improving but very weak and emaciated. Autopsy. — The pleural cavities contain no Quid. On the right side arc sev- eral strands (if fibrin. The right lower lobe with the exception of a small patch at the summit and the lower part of the middle lube are voluminous, have a dull gray surface covered by a scant layer of fibrin and are firmly con- solidated. On section the consolidated tissue has a gray color and is con- spicuously granular, the granulation resembling, on a slightly smaller scale, that seen in human lobar pneumonia. The bronchi contain a small amount of viscid fluid. Bacteriology. — Direct smears from the trachea and the lower lobe of the left lung contain Gram-positive diplocoeci. Cultures from the trachea and from the blood of the heart contain Pneumococcus lib Cultures from the left lower lobe, from the liver and from the spleen remain sterile. APPENDIX 395 Microscopical Examination. — There is abundant infiltration of the subepi thclial tissue of the trachea with plasma cells. Superficial ciliated epithelium is in places lost. At one point is a small focus of hemorrhage. Alveoli in the consolidated part of the lungs contain polynuelear leucocytes and fibrin and exhibit the appearance seen in Lobar pneumonia in man. In Experiment 12 B. influenzae was injected into the tra- chea and two days later identified in a culture made i'rom Fig. 33. — Experimental lobar pneumonia in the stage of gray hepatization produced by injection of Pneumococcus III into the trachea of a monkey (Experiment 11). The alveoli are uniform!}' filled with plugs of fibrinous exudate. the pharynx ; four days after inoculation Pneumococcus IV was injected into the trachea. The animal was killed seven days after the first inoculation, and three days after inocu- lation with pneumococcus. The lower half of the upper lobe of the right lung and the greater part of the lower and 396 PNEUMONIAS A\l> [NFECTIONS OF RESPIRATI »i;v TRACT middle lobes were consolidated. The pleural surface of the consolidated areas was dull m] and covered by a small amount of fibrin. The lower lobe, with the exception of a small part at the summit, was very firmly consolidated, on section pinkish gray in the anterior part and deep rod in a small /.one at the posterior border. The cu1 section was conspicuously granular. The trachea and bronchi con- tained mucus. Cultures Prom the trachea, the right lung and the right pleural cavity contained Pneumococcus IV in pure culture. Alveoli in the consolidated pari of the lung were filled with polynuclear leucocytes and fibrin. Lobar pneumonia has been produced by the introduction of Pneumococcus IV into the trachea. It is doubtful if pre- ceding inoculation of B. influenza? has influenced the course of the disease. The foregoing experiments have shown that B. influenzae introduced into the nasopharynx or into the trachea of monkeys is capable of causing lesions of the mucosa of these structures; the microorganism persists within the nasopharynx or trachea and is recoverable during a vari- able period of from two to eleven days after inoculation. Spontaneous infection of monkeys with B. influenzae has not been observed. The animals infected with the microor- ganism are ill during several days, but the experimental disease like most instances of human influenza is self lim- ited. Following inoculation of the nose and throat of mon- keys with B. influenzae there is discharge from the nose, tendency to epistaxis and absence of leucocytosis. Bronchitis was produced by the introduction of B. influ- enza' into the trachea of monkeys, and the microorganism was recovered from the nasopharynx two and three days following inoculation. There was no leucocytosis. In two experiments death occurred following inoculation, and in both instances it was found that the animal suffered with tuberculosis which had produced only trivial lesions of the APPENDIX 397 lungs. In both animals staphylococci were obtained from the internal organs. There was bronchitis with changes in the bronchi which, although not characteristic, resembled those found in association with B. influenzae in man. It is noteworthy that B. influenzae is usually found mixed with other bacteria in the bronchi of those who have died with bronchitis and pneumonia following influenza. In the ex- perimental animals there was in places superficial loss of ciliated epithelium, exudation of polynuclear leucocytes, in- filtration of the subepithelial tissue with plasma cells and hemorrhage into this tissue. In one instance simultaneous injection of B. influenzae and S. hemolyticus, freshly obtained from autopsy upon a man dying with pneumonia following influenza, caused bronchi- tis and bronchopneumonia; there were acute lymphangitis and infiltration of the interstitial tissue of the lung with polynuclear leucocytes such as occurs in human cases, but the lesion had not proceeded to suppuration. In man B. influenzae is usually found in greatest abun- dance upon the mucosa of the respiratory passages, less frequently it invades the alveoli of the lungs and is almost invariably found in association with other microorganisms. In company with other microorganisms B. influenzae pene- trates into tissues outside the lungs. In Experiment 7 it has entered the pericardium, with streptococcus, and in Experiment 9 with pneumococcus. When B. influenzae and streptococcus are injected into the peritoneal cavity of a mouse both organisms appear in the blood, whereas in the absence of streptococcus, B. influenzae seldom leaves the peritoneal cavity. Typical lobar pneumonia has been produced for the first time in monkeys by injecting pneumococci (in quantity as small as 0.33 c.c. of suspension) into the trachea. "With the animals available it has not been possible to adjust the dos- age of the two microorganisms so that the influence of one 398 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT upon the other might be determined. Pnenmoeoccus III, in small quantity, introduced into the trachea has produced typical acute lobar pneumonia in the stage of gray hepati- zation. A similar lesion has been produced with Pneumo- coccus IV obtained from the lung- of a man dead with pneu- monia. INDEX A Abscess of lung, bacteriology of, 203 empyema with, 233 healing of, 208 measles with, 347 parotitis with, 356 pathogenesis of, 205, 375 scarlet fever with, 357 staphylococcus causing, 199, 225, 366, 377 S. hemolyticus causing, 199, 365 Autopsies, table of, 118, 120, 335 Autopsy protocols, No. 280, 226; No. 286, 226; No. 312, 254; No. 322, 228; No. 330, 214; No. 333, 229; No. 370, 229; No. 376, 206; No. 379, 215; No. 380, 204; No. 387, 206; No. 397, 223; No. 406, 204; No. 416, 204; No. 420, 279; No. 425, 229; No. 428, 280; No. 433, 280; No. 445, 257; No. 465, 238; No. 467, 208; No. 473, 236; No. 474, 221; No. 487, 273; No. 499, 224; No. 504, 238 Bacillus influenzae. 369 bronchi and, ' 178, 215, 346 bronchitis and, 153, 371 experimental inoculation Avith, 389 history of, 25 influenza and, 30, 42, 43, 46, 49, 76, 370 isolation of, 30, 32, 38, 44. measles with, 26, 40, 43, 295, 351 meningitis and, 26 normal men carrying, 34, 42, 45, 369 pathogenicity of, 26, 48, 370, 387, 396 pneumococcus pneumonia with, 62, 178 Bacillus influenza — Cont'd pneumonia with, 72, 75, 76, 173, 364, 371 Bronchi, inflammation of mucous glands of, 146 Bronchiectasis, 239, 269, 355, 367 abscess with, 254 bacteriology of, 244 bronchitis Avith, 245 measles with, 336 pathogenesis of, 245, 259 Bronchiolitis, organizing, 264 Bronchitis, 40, 142, 195, 359 bacteriology of, 56, 150, 164, 359, 371 bronchiectasis with, 245 chronic, 262 clinical course of, 58 measles with, 336 organizing, 264 purulent, 47, 56, 60, 63, 74, 143, 149, 153, 360 Bronchopneumonia, 60, 63, 66, 162, 360, 363 bacteriology of, 68, 163, 171, 176, 181, 184, 189, 194, 197, 345, 364 fibrin with, 182 lobar pneumonia with, 155, 157 measles with, 340 secondary infection by S. hemolyti- cus with, 172, 177, 181, 374 C Carriers of B. Influenza?, 46, 101, 369 of S. hemolyticus. 99, 285, 287, 298, 303, 309, 310, 315, 319, 321, 332, 379 Cartilage, atrophy with bronchiectasis of, 254 Contact infection in influenza, pre- vention of, 98 in measles, 289 in pneumonia, prevention of, 98 Cubicles to prevent contact infection, 98, 290 Cyanosis, 144 399 401) INI' E \ E Empyema, 64, 67, 224, 226, 233, 304, 366 abscess of lung and, 233 encapsulated, 235 interstitial suppurative pneumonia with, 216, 234 measles with, ."• is' pneumococcus, 236, 350 streptococcus, 233, 350 Endophlebitis, 219 H Hemorrhagic and edematous consolida- tion with bronchopneu- monia, 188 peribronchiolar consolidation with b r o n c hopncumonia, 163, 17::, 272, 340 Hepatization with bronchopneumonia, 17!', 181 with lobar pneumonia, 160 Influenza, B. influenzae with, 30, 73 bronchitis with, 55, 56 clinical course of, 28, 53, 73, 80 coryza with, 5 I cyanosis with, 54 epidemic in fall of 1918, 52, 108, 359 epidemic in spring of 1918, 47 fever with, 53 gastrointestinal symptoms with, 55 laryngitis with, 54 lobar pneumonia and, 161 measles and, 292, 319, 331, 351, 357, 380 pandemic of 1889-90, 109, 115 pandemic of 1918-1 it, 27, 359 pharyngitis with, 54 pneumococcus with, 33 pneumonia with, 55, 59, 74, 81, 139 pulmonary lesions of, 137 pulse with, 54 secondary infection with, 28, 15, 57, 95 sputum with, 55 S. hemolyticus with, 103 Interstitial bronchopneumonia, 261, 278, 348 suppurative pneumonia, 199, 209, 366, 376 bacteriology of, 214 [nterstitial suppurative pneumonia — Cont'd chronic inflammation with, 221 empyema with, 216, 234 healing of, 222, 224 measles with, 348 pericarditis with, 2::7 Lobar pneumonia, 60, 63, 154, 360, 362 bacteriology of, 64, L56; L64, 339, 362 bronchopneumonia with, 155, 157 experimental production in mon- keys of, 394, 397 influenza and, 161 measles with, 337 purulent bronchitis with, 60, 63, 66 secondary infection by hemolytic streptococci with, 64, 159, 340, 374 spread in lung of, 339, 354 typhoid fever with, 353 Lobular consolidation, confluent, 188, 341 with bronchopneumonia, 163, 178, 272, 341 Lymphatics, suppurative inflammation of, 217, 218, 376 thrombosis of, 217, 218 Lymphangitis, experimental produc- tion with S. hemolyticus of, 392 M Masks to prevent contact infection, 98, 290 Mastoiditis, 303, 312, 332 Measles, 119, 288 B. influenza? with, 26, in, 4::, 295 bronchiectasis with, 336 bronchitis with, 336 bronchopneumonia with, 340 complications of, 303, 378 empyema with, 349 influenza and, 292, 319, 331, 351, 357, 380 interstitial suppurative pneumonia with, 348 lobar pneumonia with, 337 pneumococcus pneumonia with, 312 pneumonia and, 292, 303, 312, 332, 334, 378 secondary infection w ith, 282 INIMiX 401. Measles — font 'd S. hemolyticus with, 285, 287, 297, 319, 330, 331, 353, 378 suppurative pneumonia with, 345, 347 unresolved bronchopneumonia with, 342 Methods, 29, 51, 283, 291 Mortality of pneumococcus pneu- monia, 140 of pneumonia following influenza, 139 of streptococcus pneumonia, 140 Mumps, 119, 355 N Necrosis with bronchopneumonia caused by S. liemolyticus, 186, 375 with lobar pneumonia caused by S. liemolyticus, 160, 374 with S. liemolyticus, 199, 200 O Oedema, interstitial, 209 Organization of pneumonic exudate, 197 Otitis media, 289, 303, 312, 317, 329, 332 Peribronchiolar consolidation -with b rone hopneumonia, 163, 166, 267, 340 Pericarditis, 64, 237 Peribronchial consolidation with b r o n c hopneumonia, 163, 192, 361 hemorrhage, 189 Peritonitis, 238 Phagocytosis of red blood corpuscles, 272 Pneumococcus, 372 bronchitis and, 153 bronchopneumonia with, 165, 184, 373 empyema, 236 experimental lobar pneumonia with, 393 influenza with, 33 lobar pneumonia with, 158, 372 pneumonia, 60, 75, 104 clinical course of, 62 measles and, 312, 332 I'neumococcus, pneumonia — Cont'd mortality of, 140 secondary pneumococcus infection with, 61 secondary streptococcus infection with, 62 transmission of, 91, 383 secondary infection in pneumonia with, 91 Pneumonia, B. influenzae causing, 72, 76, 371 bacteriology of influenza and, 60, 74, 107 bacteriology of measles and, 351 chronic fibroid, 273 clinical course of influenza with, 62 diagnosis of, 136, 334, 361 dissecans, 209 immunity following, 373 influenza with, 59, 76, 81, 109, 360 measles and, 119, 292, 303, 312, 332, 334, 378 mumps and, 119 pneumococcus, see Pneumococcus pneumonia prevention of, 98, 319, 383 scarlet fever and, 119 secondary infection with, 83, 106 spread through lungs of, 194, 373 staphylococcus, see Staphylococcus pneumonia streptococcus, see Streptococcus pneumonia S. hemolyticus in throat with, 310, 329, 379 Pseudoinfluenza bacilli, 26 S Scarlet fever, 119, 356 Squamous transformation of bron- chial epithelium, 149, 251, 275, 336 Staphylococcus, 153, 377 pneumonia, 112, 225, 354, 366 pneumonia, pathogenesis of, 230 Streptococcus empyema, 233 hemolyticus, 374 bronchitis with, 153 dissemination in wards of. 315 experimental production of acute lymphangitis with, 392 identification of, 283 influenza with, 103 lobar pneumonia with, 64, 159 measles with, 285, 287, 297, 330, 331, 345, 353, 378 40L 1 INIM'A Streptococcus li 'molyticua — Cont M normal men with, 285, 322 secondary infection in pneumonia with, 84, L06, L78, 204, 374 nonhemolytic, 376 peritonitis, 238 pneumonia, 60, 70, 75, 11."), 307, 365 bacteriology of, 71 clinical features of, 71 measles with, 303, 305, 307, 318 mortality of, 140 transmission of, 84, 381 viridans, 377 Suppurative pneumonia, li'!'. ■"•17 w ith measles, 3 15, 347 Thrombosis of capillaries with bron- chopneumonia, 184 Typhoid Eever, lobar pneumonia with, 353 staphylococcus pneumonia with, ' 354 U Unresolved bronchopneumonia, 261, I'tHi. .".42, 3I5S bacteriology of, 27(5 interstitial suppurative pneu- monia with, 278 COLUMBIA UNIVERSITY LIBRARIES This book is due on the date indicated below, or at the expiration of a definite period after the date of borrowing, as provided by the library rules or by special arrangement with the Librarian in charge. DATE BORROWED DATE DUE DATE BORROWED DATE DUE N0V ] fY*F C28( 3- 52) lOOM 0p3 1921 Opie^ E.L. Epidemic respiratoiy disease. C OLUMBIA UNIVERSITY LIBRARIES 0041076354