COLUMBIA LIBRARIES OFFSITE HEALTH SCIENCES STANDARD HX64134814 RC731 .A15 The bacterial diseas RECAP t Columbia Wini\itx&itp intijeCitpofi^efaoPorfe College of ^Ijpgicians anb burgeons! i^eference Hihvavp THE BACTERIAL DISEASES OF RESPIRATION, AND VACCINES IN THEIR TREATMENT R. W. ALLEN, M.D., B.S.(Lond.) LATE EDITOR, 'JOURNAL OF VACCINE THERAPY*; LATE CLINICAL PATHOLOGIST TO THE MOUNT VERNON HOSPITAL FOR DISEASES OF THE CHEST; LATE PATHOLOGIST TO THE ROYAL EYE HOSPITAL ; LATE GULL STUDENT OF PATHOLOGY, GUV's HOSPITAL Printed in En,s;land ] PHILADELPHIA P. BLAKISTON'S SON & CO. IOI2 WALNUT STREET 1913 PREFACE A /r OST of the matter herein contained has already appeared as a series of articles in the numbers of the Journal of Vaccine Therapy from February, igi2 to January, 1913 inclusive. These have been revised and fresh matter included, the most important additions being in the sections devoted to pulmonary tuberculosis. Chapter XI is entirely new. My endeavour has been to treat my subjects in as practical a manner as possible ; to lay before my readers the various considerations which should influence them in seeking help from specific treatment ; and to point out those methods of application which a considerable practical experience has convinced me yield the best results. To Dr. Ralph Vincent I am greatly indebted for taking the numerous excellent photographs and photo-micrographs which illus- trate this book. 128. Harley Street ; Jainiary, 1913. Digitized by the Internet Archive in 2010 with funding from Open Knowledge Commons http://www.archive.org/details/bacterialdiseaseOOalle CONTENTS PAGE Introduction ......... i CHAPTER I. The Bacteriology of the Respiratory Tract in Health . . 4 CHAPTER II. The Respiratory Tract in Disease— Methods of Investigation- Technique OF various Staining Methods .... 8 CHAPTER III. Cultural Methods for Investigating the Bacteriology of the Respiratory Tract — Description (with Plates) of the various Pathogenic Bacteria which may be present . . .23 CHAPTER IV. Results of Observations into the Bacteriology of the various Diseased Conditions of the Respiratory Tract— Nasal and Post-nasal Catarrh — Diseases of the Accessory Sinuses — Eustachian Catarrh and Otitis Media — Tracheitis and Laryn- gitis — Pulmonary Catarrh, Bronchitis and Asthma — Whooping- Cough — Pulmonary Phthisis ...... 42 CHAPTER V. The Vaccine Therapy of Respiratory Disorders — General Con- siderations — Control of Dosage and Intervals — Special Con- siderations — Preparation and Administration of the Vaccine 58 CHAPTER VI. Vaccines in the Treatment of Nasal and Post-nasal Catarrh, Tracheitis and Laryngitis, and Infections of the Accessory Spaces ........ -79 X CONTENTS. PAGE CHAPTER VII. Vaccines in the Treatment of Bronchitis and Asthma . . 90 CHAPTER VIII. Vaccines in Pneumonia— Bacteriology — Prophylaxis — The Patho- logy AND ITS Bearing on Vaccine Treatment : Technique and Results — Unresolved Pneumonia— Empyema and Lung Abscess —Broncho-Pneumonia ....... 103 CHAPTER IX. Vaccines in Whooping-Cough, Diphtheria, Pyorrhoea alveolaris, Hay-Fever, Ozjena, Rhinoscleroma . . . . .121 CHAPTER X. The Mixed Infections of Pulmonary Tuberculosis and Vaccines in their Treatment — Import of Mixed Infection — Technique OF Specific Therapy — Results— Prophylaxis . . . 140 CHAPTER XI. Infections by the Tubercle Bacillus and the Use of Specific Products in their Treatment— The Tubercle Bacillus and its Toxins— The Defensive Mechanism of the Body— The Tuber- culins AND their Use in the Diagnosis of Pulmonary Tuber- culosis : The Various "Tests" — Classification of Cases of Pulmonary Tuberculosis— Choice of Tuberculin— Control of Dosage and Intervals — Treatment by the Induction and Control of Auto-inoculations— Conclusion . . . .192 INDEX. THE BACTERIAL DISEASES OF RESPIRATION, AND VACCINES IN THEIR TREATMENT. INTRODUCTION. When first I began the study of this question just ten years ago, the one thing that struck me beyond all others was the utter inadequacy of the information obtainable from works in the English language, and, indeed, in any tongue, -either bacteriological or dealing with general medicine, upon this very important subject. Despite the great impetus given to exact bacteriological research by the developments of vaccine therapeutics, especially within the past five years, the omission has not yet been repaired in any single book or collection of books to which I have had access. The true importance of any disease is to be estimated neither by its rarity nor by its mortality-rate, but rather by its frequency and its disabling power. Granting the truth of this statement, it follows that diseases of the respiratory tract are of supreme importance to the human race ; in frequency they excel all others, in the production of impaired health of varying periods and to varying extents they are fruitful to an extreme degree. It has occurred to me that a brief but systematic description of the bacterial diseases of the respiratory tract would have a certain value and prove of interest to many. This I shall endeavour to carry out according to the following scheme."^ A. The Respiratory Tract in Health. (i) Post-mortem results. (ii) Results obtained during life ; methods ; carriers. B. The Respiratory Tract in Disease. (i) Methods of investigation. * For the photographs and photo-micrographs I am entirely indebted to the kindness of Dr. Ralph Vincent. I THE BACTERIAL DISEASES OF RESPIRATION. (a) Swabs from nose ; precautions necessary in taking from turbinal bones, antra and sinuses. (6) Secretion from nose; precautions necessary in collecting. (c) Swabs from throat and Eustachian tubes ; necessity of excluding or allowing for presence of pyorrhcea alveolaris, or tonsillitis (follicular or otherwise). (d) Sputum ; precautions necessary in collecting. {e) Lung puncture. (/) Examination of the specimen. (i) Chemical determination of source ; salol test ; albumen test. (2) Staining methods for cells and bacteria. (3) Cultural methods. (ii) Description of the bacteria which may be present : Tubercle bacillus, *lepra bacillus, ^Streptothrix actinomy- cosis, *Spiroch(2ta pallida, *Staphylococctis albus, aureus, citreus, candicans, Streptococcus group, pneumococcus, B. influenzcB, B. Bordet-Gengou of whooping-cough, *bacillus of Koch-Weeks, B. diphtherice, "^S. Hoffinanii, *B. xerosis, B. septiis, M. catarrhalis group, M. para- tetragenus, M. tetragenus, bacillus of Friedlander group, B.proteus group, B. pyocyaneus, B. coli, B. typhosus, ■^various organisms associated with pyorrhoea alveolaris and tonsilhtis, such as vibrios, streptothrices, micro- cocci and fusiform bacilli, t B. ozcsnce, t B. of rhino- scleroma. * To these bacteria short reference only will be made. t For description of these bacteria see Chapter IX. (iii) Results of observations. (i) In nasal and post- nasal catarrh. (2) In diseases of the accessory sinuses. (3) In Eustachian catarrh and otitis media. (4) In tracheitis and laryngitis. (5) In pulmonary catarrh, bronchitis and asthma. (6) In whooping-cough. (7) In pulmonary phthisis. (iv) Vaccine therapy of respiratory disorders. (a) General considerations. (b) Special considerations. (i) Nasal and post-nasal catarrh, tracheitis and laryn- gitis, and infections of the accessory spaces. (2) Bronchitis and asthma. THE BACTERIAL DISEASES OF RESPIRATION. 3 (3) Pneumonia. (4) Whooping-cough. (5) Diphtheria. (6) Pyorrhcea alveolaris. (7) Hay fever. (8) Ozsena or atrophic rhinitis. (g) Rhinoscleroma. (10) Pulmonary tuberculosis. (a) Mixed infections : their import and treatment. (b) Infection by the tubercle bacillus and the use of specific products in treatment. CHAPTER I. A. THE BACTERIOLOGY OF THE RESPIRATORY TRACT IN HEALTH. It is only those who have devoted years to research in one of the "exact sciences," such as physics or physical chemistry, who can adequately realise the supreme importance to any investigation of the performance of sufficient " control " observations. It is owing to the peculiar difficulty in securing subjects which can in any way be regarded as absolutely normal or healthy individuals, and as suitable, therefore, to act as "controls," that medicine has failed in the past, and, perforce, will fail in the future, to take a place among the exact sciences. The multiplication of careful control observations upon individuals as healthy as can be obtained in regard to the parts under study serves to a considerable degree to eliminate erroneous conclusions. The artificial conditions of modern life have rendered it peculiarly difficult to secure for investigation an adequate number of individuals any part of whose respiratory tracts could be regarded as strictly healthy, especially from the bacteriological standpoint. It may be recalled that some people appear constantly to harbour the Micrococcus catarrhalis in their nasal passages, yet only very occasionally suffer from acute nasal catarrh, and then for strictly limited periods only, whilst from the throats of others the pneumococcus or Bacillus diphthericB can be constantly recovered, yet never have they suffered from pneumonia on the one hand or diphtheria on the other. The study of these so-called " carriers " would tend to the conclusion that these, therefore, could not be pathogenic bacteria, yet the contrary we know to be the case. It is perhaps fortunate that the results of vaccine treatm.ent in diseases of the respiratory tract enable us to confirm deductions made from observations inherently fallacious and difficult to control. In any bacteriological research it is above all essential that two conditions be fulfilled : (i) that the material be obtained from the THE BACTERIAL DISEASES OF RESPIRATION. 5 desired situation without chance of contamination in the process ; (2) that it be speedily prepared in film form for direct examination ; this done, that it be immediately transferred to suitable media for cultural observation. By suitable media is meant such as each and ever\' one of the bacteria present may find adapted to their growth. Through failure to comply in one or other direction with these prime essentials practically all investigators upon the respiratorv tract, with the exception of some who have worked within the last five or six 3-ears, have rendered their observations so untrustworthy as to be almost valueless. As the procedures adapted to the studv of patholo- gical conditions are a fortiori suitable in normal or healthv states, their consideration is deferred to the next section upon the bacteriology of the respirator}- tract in disease. Inasmuch as many of the domestic animals, such as cattle, horses, cats, dosrs, and rabbits are susceptible to respiratory disorders like those of man, the comparative study of the respiratory systems of these animals in health and disease would prove illuminating ; unfor- tunately this has not been done, and such information as we have is therefore incomplete. Observations upon the dead human subject are also liable to prove very misleading owing to ''"'agonal spasms'" and other causes, except in the instance of those who have died a violent death ; investigation upon these latter is wholl}' lacking. The recent observations upon animals by Cobbett (Proc. Roy. Sac. Med., Jul}', 1911,- p- 205) have, howe\-er. brought out clearly one important fact. He there states that he has never failed to find bacteria in the lungs of the various animals that he examined — these were killed instantaneously and examined at once so that agonal and post-mortem infection can be absolutely excluded. Among the germs he commonly found in the lungs of rabbits and guinea-pigs were moulds, streptothrices, spore-bearing bacilli and cocci — in fact, just the ordinary micro-organisms of the air. Spraying experiments by Hurtl and Hermann and by Bastel and Neumann have been confirmed by Cobbett. and show that air-borne bacteria freely enter the air-passages and get carried to the lung ; the bronchial mucous membrane, like the intestinal, must, therefore, for practical purposes be regarded as part of the surface of the body. Nor is this the only route whereb\- bacteria reach the lungs of the normal and so a fortiori of the unhealthy individual. While it is pro- bably true that the various lymph-glands, and especially the bronchial, cervical and abdominal ones, are ver}- efficient guardians of the general circulatory system against bacterial infection, it yet certainly happens that occasionally bacteria penetrate the defence and find ingress into the blood-stream. The two organs in particular which from their 6 THE BACTERIAL DISEASES OF RESPIRATION. structure are peculiarly adapted for the filtration of these chance invaders are the lungs and spleen ; it thus happens that a certain number of bacteria reach the lung via the circulation. That the air, especially of cities, is laden with bacteria is common knowledge ; the proportion of pathogenic to non-pathogenic organisms is, however, small. Experiments upon purely nose-breathers has shown that the filtration of the air in the nasal passages is efficient to an extraordinary degree ; the mouth-breather loses this protective action, and is consequently much the more prone to respiratory disorders. It is of obvious interest to know in what part of the nasal passages this daily host of bacteria is stopped and what is their fate. One fact upon which all investigators are agreed is that the vestibule of the nose is swarming with bacteria ; another is that in health the accessory air- spaces and the upper meatus of the nose are approximately sterile. The precise degree of bacterial infection commonly existent below the level of the middle turbinal has not been accurately determined owing to faulty methods of observation. The most satisfactory published investigations are those of Lewis and Logan Turner (Edin. Med. Journ., 1905, vol. ii, p. 393). It is to be regretted that their cultural methods were not beyond criticism^ the failure to make an invariable rule of employing blood-agar as a medium being a very important omission. By means of smears and cultures they examined 26 specimens from 16 persons ; only 3 of these proved to be sterile. 13 specimens from 7 persons showed only one variety of bacterium. 9 55 >j 7 J5 ,, two varieties ,, I " 5, I „ ,, three ,, „ Staphylococcus albus was present in 13 specimens. Streptococcus ,, 6 Pneumococcus Hoffmann's bacillus Staphylococcus aureus Bacillus niesentericus Spirillum Bacillus of Friedlander Proteus vulgaris The pathogenicity of the organisms was determined upon rabbits and guinea-pigs in eleven instances — an investigation, in my opinion, entirely lacking value and only likely to prove misleading. Nine of them appeared to be non-pathogenic, two were pathogenic, viz, a streptococcus and a Staphylococcus aureus. Their conclusion was that the organisms of the healthy nose belong to the same varieties as those found in abnormal conditions, but differ in that they— (i) Are present in much fewer numbers. ,, u 4 „ 2 ,, 2 jj 2 jj 2 „ I specimen „ I J5 THE BACTERIAL DISEASES OF RESPIRATION. 7 (2) Afford purer cultures. (3) Possess less vigorous power of growth. (4) Are of low pathogenicity. These observations are in practical accord with my own, and it would appear that by far the greater proportion of the bacteria which enter the healthy nose are deposited in the vestibule and the inferior meatus. Of their precise fate we know little. Many are removed by the use of the handkerchief; some certainly are phagocytosed by the epithelial cells, which possess this power to a very high degree ; whether any undergo lysis by the aid of the mucus is unknown. That nasal mucus is absolutely devoid of bactericidal power I showed some years ago ; that it may possess a lytic action is possible, but appears not to be the case from a number of experiments which I have made to elucidate this point. Any attempt at discussion as to what is the bacteriology of the healthy mouth would be of purely academic interest, in as much as the perfectly healthy mouth is for all practical purposes non-existent. Somewhere or other in every mouth or pharynx careful search will reveal a focus of disease : it may be a carious tooth, inflamed dental papillae, a condition of pyorrhoea alveolaris, confined perhaps to the gum round a wisdom tooth or behind the upper incisors, follicular tonsillitis, an infection of the supra-tonsillar fossa difficult of detection, a granular pharyngitis or some other condition giving rise to little or no discomfort, but none the less surely there. A perusal of the volumi- nous writings upon the bacteriology of these conditions would lead to but one conclusion : that if one or the other of these conditions be normally present in the mouth or pharynx, then so varied is the bacterial content already of the oral cavity that it must surely be a hopeless task to endeavour to elucidate the bacteriology of any other focus of disease in or near the mouth or pharynx. In actual practice the diffi- culty is by no means as great as it would appear, provided that due recognition be paid to the possible fallacies thereby introduced, and measures be taken for their exclusion ; how this can be done will appear presently. Of the organisms which have been found in more or less normal oral cavities the following is a very imperfect list : Staphylococcus albus and aureus, streptococcus, Micrococcus catarrhalis, various small micrococci, both staining and failing to stain by Gram's method, vibrios, spirilla, spirochaetas, fusiform bacillus, B. necrodentalis, B. huccalis maximus, Cladothrix buccalis, B. proteus, B. inesentericus, B. subtilis, B. fluovescens, sarcinae, yeasts, and moulds. CHAPTER II. B. THE RESPIRATORY TRACT IN DISEASE. (i) Methods of Investigation. These are to be pursued upon material obtained either by oneself or by one more highly trained in the technique of catheterising the various accessory air-spaces, or else upon material supplied by the patient. By each and every one of these special precautions must be observed in order that the bacteriological findings may not be unduly obscured. Some of the more important points may here be mentioned. {a) In the securing of "swabs" from the turbinal bones, septum, antrum, and accessory air-cells and Eustachian tubes the nasal route must perforce be adopted. To the fact that the vibrissas, vestibule and inferior meatus are swarming with the bacteria caught up from the air- stream attention has been already drawn. It is therefore obvious (i) that these bacteria should be removed as far as possible ; (2) that contact with these parts by the swab or loop must be carefully avoided. The former object is attained, for all practical purposes, by washing the hands well with hot water and ethereal soap, then by means of the finger-tips, moistened with soap and hot sterile water, the orifice of the nose is thoroughly cleansed ; a pledget of sterile wool moistened Mfith absolute alcohol is employed to swab out the orifice. A sterilised nasal speculum is next inserted, and through it the swab or platinum loop is carefully passed and secretion taken up from the desired spot. Adequate illumination and considerable technical skill are requisite if the materies is to be collected from the Eustachian tube, antrum or accessory sinuses. Particular care must be directed to the withdrawal of the swab or loop as contamination is then particularly liable to occur. The methods of examination of the specimen by direct observation of suitably stained films and by cultural examination will be detailed later. Attention may, however, be drawn to this fact that inasmuch as specimens of nasal mucus frequently contain but few organisms, so few as to be difficult of detection in film preparations, a sufficiency of material must be collected not only for the insemination of plates, but also for the preparation of quite thick smears. THE BACTERIAL DISEASES OF RESPIRATION. 9 (b) If the specimen of mucus is to be furnished by the patient, instruction must be given in this method of cleansing the nasal orifice, and two steriHsed, wide-necked bottles be supplied : two bottles are requisite for this reason, that especially in cases of antral or sinus infection the bacteriology of the two sides may by no means be the same ; the necessity of securing specimens from both sides is therefore obvious. The patient receives the following instructions : Immediately on waking the nose is cleansed as indicated above, the stopper removed from one bottle, which is then held against one orifice, the other being closed by means of a finger-tip ; a forcible nasal effort then expels some of the secretion directly into the bottle, which is at once stoppered. This operation is repeated with the other side, and the specimens forwarded for examination without delay. (c) and [d) Considerable as is the care necessary for the collection of nasal specimens, it is relatively quite inconsiderable to that requisite for the collection of secretion from the naso-pharynx, pharynx, and lower respiratory tract. Of all the cavities of the body the mouth and pharynx bacteriologically are incomparably the foulest ; go per cent., at least, of all residents in the United Kingdom carry in their mouths foci of bacterial infection — undetected pyorrhoea alveolaris ravages their gums, poisons them locally and generally, impairs the digestion, the appetite and general health, produces chronic invalids, gives rise to obscure pains and pyrexias, complicates respiratory phthisis, and, let it well be borne in mind, of itself produces a premature end in by no means an inconsiderable number of cases. Follicular tonsillitis also frequently escapes the e5/e, not only of the patient, but likewise of the medical man : cursory examination will by no means suffice for its detection, especially when the follicles infected by those immediately posterior to the anterior pillar of the fauces or those of the supra- tonsillar fossa ; careful pressure upon and around the anterior pillar will frequently reveal an unsuspected focus of infection. Into the bacteriology of these conditions, which is so characteristic as to reveal their presence when naked-eye observation has defaulted, I shall enter fully later, but let it here be mentioned that several of the commoner bacterial agents of these conditions are precisely those responsible for catarrhs of the respiratory tract, colds, asthma, bronchitis, pneumonia, and the mixed infections of phthisis ; others which are not responsible for these conditions also are productive of extra-cellular toxins so potent that one minim of a sterilised broth culture injected sub- cutaneously may sufiice to produce vomiting and rigors. When, therefore, a patient presents himself for treatment of a respiratory disorder, and pharyngeal, laryngeal, or bronchial specimens lO THE BACTERIAL DISEASES OF RESPIRATION. are contemplated, it behoves us first and foremost carefully to scrutinise the mouth and pharynx ; to examine the gums, especially behind the upper incisors and around the back molars and wisdom teeth, for the presence of pyorrhcea alveolaris, the tonsils for inflamed and infected crypts and follicles— and here let me urge upon your notice, crowned teeth or bridges practically invariably indicate an accompanying pyorrhoea, for the recession of the gum has given ample room for the fixation of the denture. Such supreme importance do I now attach to these conditions in respiratory^disorders, that should I detect their presence and the patient refuse to have them properly treated, then I firmly and finally refuse to undertake the treatment of the respiratory condition. To allow oneself to be so handicapped at the outset is foolish beyond measure. The bacterial content of the mouth incidental to food residues also needs elimination. All fallacies introduced by the above causes may be satisfactorily ehminated by the following procedure, which merely needs the more careful performance should pyorrhaea or ton- silitis have been detected. A jug of well-boiled water is provided, and a new, moderately hard tooth-brush taken and dipped for a few seconds twice or thrice into the boiling water, which is then cooled to a com- fortable temperature. The teeth are now thoroughly brushed with the new brush and sterile water, no powder or antiseptics being employed. The mouth is well rinsed out and the throat gargled with the water, of which two or three mouthfuls then are swallowed. Swabs are now taken from the naso-pharynx, pharynx, tonsils or larynx, and employed for direct and cultural examinations in the manner presently to be related. Should the area of infection be too low in the respiratory tract for us to reach, the patient is instructed to carry out the above procedures immediately on waking, then give one, or at the most two, coughs, and expectorate directly into the wide-necked sterile bottle with which he has been furnished. If accurate bacteriological in- vestigation be desired, too much stress can hardly be laid upon the due observance of these preliminary precautions. {e) Lung puncture. — Occasionally in cases of suspected lung infection no sputum can be voided for examination — a dilemma in which I myself have been placed on at least three occasions. Recourse must then be had to puncture of the lung, a procedure altogether void of danger if due precautions be observed, but not devoid of pain. Briefly, the method is as follows : Careful percussion and auscultation having revealed a suspected area the skin is sterilised, best with strong tincture of iodine, and may then be anaesthetised with ethyl chloride spray. A 5-10 c.c. all-glass syringe with a strong wide needle is sterilised by boiling and i or 2 c.c. of sterile peptone broth taken into it. The THE BACTERIAL DISEASES OF RESPIRATION. I I patient is then instructed to expire and cease respiratory movement ; in this way tearing of lung tissue and resultant pain is minimised. The needle is plunged boldly into the selected area, o'5-i"o c.c. of the broth expelled, and gentle aspiration applied ; if necessary the needle may be withdrawn a little or inserted further and the procedure repeated. The specimen so obtained is to be examined by direct and cultural observa- tion ; the results are very satisfactory as risk of contamination is minimal ; in this way I have secured cultures of B. influenzce, pneumococcus, and B. typhosus directly from the lung. (f) Examination of the materies morbi : (i) Chemical determination of source. — The mere bacteriological examination, direct and cultural, will not suffice for all cases. To enter into a full discussion of the con- stituents of the sputum and nasal secretion would be beyond the scope of this paper; attention may, however, be briefly directed to the following few points. Among the more important constituents of the sputum are : water, salts, cells, mucin, serum albumen (coagulated and uncoagulated), serum globulin, ferments, excreted medicaments, and bacteria. These vary within very wide limits under different conditions. To the chemical constituents of the sputum little attention has been paid in practical medicine; the following recent observations, however, are of considerable interest, and may prove of great service in the diagnosis of obscure lung conditions. Falk and Tedesco {Wien. med. Woch., igog, xxii, g54) have noted the fact that salicylic acid present in the blood appears in inflammatory exudates in the lung, but is not excreted by the bronchial mucosa ; the application of the following test will therefore assist in differentiating disease processes hmited to the bronchial mucosa from those which have extended to the lung. Thirty grains of sodium salicylate are given by the mouth and the sputum collected during the ensuing twelve to eighteen hours. It is slightly acidified with acetic acid and shaken thoroughly with five times its volume of absolute alcohol. The mucus and albumen are precipitated in coarse flocculi and removed by filtration. The clear filtrate, which contains all the sahcylate acid, if any be present, is rendered slightly alkaline, and evaporated to dryness over a water bath ; the residue is dissolved in water, slightly acidified, and sugar of lead added till no more precipitate forms : this latter is removed by filtration and washed with water, the washings being added to the acid filtrate, which is then extracted with ether. The ethereal extract is evaporated to dryness, the residue dissolved in lo c.c. of water, and I c.c. of 10 per cent, aqueous solution of ferric chloride is added. The formation of a violet colour indicates the presence of salicylic acid. Patients suffering from catarrhal bronchitis, bronchitis, emphy- 12 THE BACTERIAL DISEASES OF RESPIRATION. sema, bronchial asthma, purulent bronchitis, and bronchiectasis all gave negative results, whereas cases of lobar pneumonia reacted strongly. The reaction gradually lessens until the crisis is reached, when it rapidly disappears, and varies in intensity roughly with the extent of lung affected. In phthisis the results varied ; a positive result was always obtained, but the intensity was not proportional to the clinical severity or the extent of the process. Generally, however, acute cases gave a stronger reaction than chronic. Falk and Tedesco hold that a repeatedly negative result is strong evidence that the process is limited to the bronchial mucosa, and is therefore exclusive of pneumonia or pulmonary phthisis. ■ Lesieur and Prirez {Paris Medical, 191 1, vol. iv, p. 29) have investi- gated the sputum voided in various conditions for albumen content : 5 c.c. of sputum are taken; to this 20 c.c. of normal salt solution and five or six drops of acetic acid are added. The mixture is well shaken and filtered ; the filtrate is then tested for albumen by boiling or with nitric acid. If the reaction by boiling be doubtful the addition of a further 20 c.c. of salt solution and fresh boiling will sometimes give a positive result. Lesieur and Prirez found that of cases without physical signs which subsequently proved to be tuberculous 75 per cent, gave a positive reaction ; that all cases with tubercle bacilli in the sputum were positive ; that in miliary tuberculosis and pleurisy the result was not constant ; that cases of acute lobar pneumonia reacted, and that when the reaction persisted into convalescence a new focus or a complication was indicated. Acute broncho-pneumonia and acute pulmonary oedema were also positive. On the other hand, in acute bronchitis it was usually negative, in chronic bronchitis and in emphysema always so. In cardio-renal cases a positive reaction was often seen. In 840 observations by various authors the reaction was given in 100 per cent, of cases where tubercle bacilli were present, in 82 per cent, of cases which were probably tuberculous and in 37 per cent, of non-tuberculous cases. As with the salicylic acid test, it would thus seem that a positive reaction indicates a pulmonary origin of the exu- date and excludes a bronchial source, and that the more marked and more constant the result the greater the likelihood of phthisis or pneumonia. (2) Staining methods for cells and their derivatives. — The most complete account of the constituents of the sputum other than bacterial and how these vary in health and disease is to be found in Etude Histochimique et Cytologique des Crachats, by Israels de Jong, from which I have taken many of the following particulars. The staining method which de Jong found most generally useful is as follows : A thin film of the secretion is prepared and allowed to dry without the application of THE BACTERIAL DISEASES OF RESPIRATION. 13 heat ; it is then fixed for two or three seconds in i per cent, aqueous solution of chromic acid, washed well under the tap, stained for three minutes in undiluted polychrome methylene-blue of Unna, differentiated with go per cent, alcohol, washed well with v^^ater, dried by the appli- cation of gentle heat and examined by the aid of artificial light. Owing to the metachromatic properties of this stain, red corpuscles, mucin, epithelial cells, leucocytes and their granules are coloured differently. The red cells appear green, mucin reddish, the nuclei of the epithelial cells characteristically a deep violet, almost black, their cytoplasm a light violet to lilac, the nuclei of the leucocytes a deep violet to black, their cytoplasm a light violet, the granules of mast- cells reddish ; those of the eosinophiles are unstained, yet clearly visible on account of their refractility and double contour. Unna's polychrome methylene-blue is a by no means easy stain to manage, and requires considerable practice in order to obtain satis- factory results. As an alternative, still better as a supplementary method, one of the various modifications of Romanowsky's stain, preferably Leishman's, may be employed. Here let me just mention that if one makes up the liquid stain for himself the following points must be observed : (i) Use only Grubler's stain and the purest methyl alcohol ; (2) dissolve o"4 grm. of the former in 200 c.c. of the latter, place in a well-corked flask, shake daily for a fortnight, and filter thoroughly when transferring to the stain bottle ; at least a fortnight's maturation of the solution is requisite. The technique for Leishman's stain is as follows : Films should be made upon well-cleaned slides, spread thinly and allowed to dry in the air without the application of heat. The slide is covered with the stain, which is allowed to remain for three minutes in hot weather, for five in cold; the preparation is then flooded with distilled water, which is well mixed with the stain by means of a pipette. The mixture is allowed to remain for fifteen minutes, then poured away and the slide plunged into plenty of distilled water ; in this the preparation is agitated until no more stain comes away ; it is then washed with fresh distilled water, lightly blotted between filter- paper and dried by warming gently. Examination is best made without the use of a cover-slip. Bacteria are stained blue, cell nuclei dark blue, cytoplasm lilac or pink according to the cell, basophile granules violet, acidophile granules red, red blood-corpuscles red, mucin a dirty blue. The cells of the pharyngeal mucosa (Plate I, fig. I) are very large cells, irregularly polygonal in shape, with a large oval nucleus placed either centrally or near the periphery. With Unna's stain the nucleus of the undegenerated cell takes on a deep violet colour, the cytoplasm a feeble blue-violet. With Leishman's stain the nucleus 14 THE BACTERIAL DISEASES OF RESPIRATION. is deep blue, the protoplasm reddish-violet. These cells are fre- quently seen crowded with bacteria, especially when beginning to degenerate (as in Fig. I). The degenerative process proceeds rapidly, the cell then having a greater affinity for acid than for basic stains, so that the cytoplasm may appear a bright red with Leishman's stain. The cells of the bronchial mucosa (Plate I, figs. \la and 116). — The bronchial mucosa consists of several layers of stratified cylin- drical epithelium with a superficial ciliated layer. Normal bronchial cells are rare in sputum except in cases of severe early trancheitis or in acute asthma ; in these instances violent fits of coughing may lead to the tearing off of small portions of the mucosa ; even here a certain amount of degeneration has as a rule set in. The ciliated superficial layer consists of a cylindrical cell with large oval nucleus. The outer end of the cell is flat and covered with cilias ; the other end is drawn out, sometimes bifid, and insinuates itself beneath the neighbouring cell or cells (Fig. 11a). The deeper cells are polyhedral or shaped like a truncated cone with large nuclei. By Unna's stain the nucleus of the normal cells stains violet and uniformly, the cytoplasm bluish. The normal cell, as said before, is very rarely seen ; usually degeneration has already set in. The nucleus then appears reticulated, swollen, and occupying perhaps two thirds of the cell ; later it may be drawn out into a long network protruding from the cell (Fig. 116) ; still later the cytoplasm may entirely disappear and the nuclear reticulum be drawn out into long strands, which have often been mistaken for fibrin, and may include polynuclear cells in their network — an appearance often seen in acute and chronic bronchitis. The cytoplasm of the degenerating cell with Unna's stain appears of a lilac colour, the nucleus, unlike that of most other cells, stains reddish with a slight violet tinge like mucin. Leishman's stain is but ill adapted for showing the bronchial cells in their various stages of degeneration ; with it the nuclear reti- culum appears lilac to blue, according to the amount of washing to which the preparation is subjected. The cells of the pulmonary alveoli (Plate I, figs. Ill and IV). — These, unlike the bronchial cells, are frequently to be seen in the sputum in their more or less normal condition, as well as in their degenerative forms. The normal alveolar epithelium consists of a thick layer of large plaques without nuclei bound together by a kind of cement ; between these lamellar cells are small dark protoplasmic areas with well-defined nuclei. The layer of unnucleated cells covers the capillary network, whilst the nucleated protoplasm occupies the mesh of the blood-vessels. PLAT£ 1. j^^2S^ Diagrammatic representations of constituents of sputum (after Israels de Jong). Fig. I. Pharyn- geal cell with bacteria. Fig. II a. Cell of superficial layer of bronchial mucosa. Fig. II b. Bronchial cell undergoing degeneration with extrusion of nucleus. Fig. III. Small pul- monary cells. Fig. IVa. Macrophagic pulmonary cell. Fig. W b. Ditto with pigment- granules. Fig. V. Sputum of pneumonia at about eighth day : (a) Polynuclears ; (6) Sero- albuminous exudate; (c) Hyaline mucus: {d) Pulmonary alveolar cells; {e) Mucinous reticulum derived from cell nuclei, and containing in its mesh polynuclear cells and bacteria. THE BACTERIAL DISEASES OF RESPIRATION. I 5 The precise origin of the unnucleated plaques is unknown, but they are probably derived from the small nucleated cells. In the sputum these cells may appear in the following forms : {a) As the above small nucleated cell (Figs. Ill and V^); {b) as a large macrophagic cell often laden with pigment (Figs. IVa and IV h) ; (c) as a degenerated reticulum. The small nucleated alveolar cell somewhat resembles the mononuclear cells of the blood, but differs from them in certain particulars. The nucleus is round or oval, occupying the centre of the cell and filling about two- thirds of it. The cell itself is small, round, or slightly oval, the cytoplasm apparently granular. With Unna's blue the nucleus stains a dark violet, the cytoplasm a much lighter violet, and showing innumerable tiny basic granules ; this cell is very common in the sputum of pneumonia, broncho-pneumonia, pulmonary congestion, softening phthisis, and capillary bronchitis ; it is rare in acute bronchitis and in emphysema with bronchitis. If they make their appearance during the course of a bronchitis they indicate capillary extension, pulmonary congestion, or an area of pneumonia ; these cells are distinguished from the mononuclears of the blood, which probably appear but very rarely in pulmonary exudates, by their nucleus being more oval, more compact, and staining too deeply, by the protoplasm being more abundant, and with greater affinity for stains. The endothelial macrophages (Figs. IVa and YVh) are large cells with an excentric nucleus ; sometimes they are bi- or even tri-nucleated ; sometimes the cytoplasm is abundant, vacuolated, and stains feebly except at the periphery ; sometimes it is quite scanty and stains deeply. Between this cell and the small alveolar cell there are all gradations, and the former is probably only a specialised form or derivative of the latter. The macrophages are often laden with particles of pigment, derived either from the air, when they are deep brown or black, or from the blood-pigment, when they are golden (Fig. IV 6). They are found in such conditions as resolving pneumonia and broncho-pneumonia, in bronchitis with pulmonary congestion, and in pulmonary congestion due to granular kidney. As with the bronchial cell, so with the pulmonary in an advanced stage of degeneration, all that may remain of the cell is a reticulum derived from the nucleus, and having the staining reactions of mucin. With Unna's blue they stain red and more deeply than the bronchial reticula, from which they also differ in being more compact, less drawn out and less fine, and in frequently containing bacteria and leucocytes in their mesh (Fig. V^). With stains such as Leishman's this reticulum preserves its basis affinity much more strongly than does that derived from the bronchial cell ; sometimes the reticulum appears to 1 6 THE BACTERIAL DISEASES OF RESPIRATION. preserve the outline of the cell ; sometimes those derived from several cells appear to unite to form a larger network. Blood-cells in the sputum. — For the study of these elements no stain is so well adapted as that of Leishman ; their appearances are too well known to need description. It will suffice to mention (i) that red cells are found in any form of acute pulmonary congestion, and that their appearance in the sputum of bronchitis is indicative of alveolar extension; (2) that degenerative changes occur, the nuclei of polymorphonuclears undergoing extrusion, lying as a long thread attached to the cell or by the side of it, and staining the reddish colour characteristic of mucin, whilst the granules, especially of the coarsely granular eosinophiles, are frequently shed from the cells as if by a violent explosion. This is especially well seen in sputum from a case of acute asthma, in which disease only, tuberculosis excepted, do coarsely granular eosinophiles appear in considerable numbers in the sputum. The mucin of the sputum (Plate I, fig. Vc). — So much attention has been drawn to the degeneration of the nuclei of the bronchial and pulmonary cells as a source of mucin that the question may well be asked. Is this the source of all the mucin of the sputum ? The answer is, Certainly not ; the great bulk of sputum is composed of mucus secreted by the special mucous glands, the product apparently of their nuclear activity, but differing from that previously described by its hyaline non-reticular structure (Fig. Vc). These glands are most numerous in the trachea, less so in the bronchi ; as the bronchi approach the lung the mucous glands become fewer and fewer until they cease to exist in the smaller bronchioles. It may appear somewhat superfluous further to labour the point that much of what has been described in the past and is regarded at the present as fibrin in sputum is not fibrin, but mucin, but the point is a very important one, for fibrin is the coagulated form of the sero- albuminous exudate from lung-tissue proper, the significance of which has already been referred to under the salol and albumen tests. The sero-albuminous constituents of sputum (Plate I, fig. Yb). — As has been already stated, mucin stains reddish to reddish-violet with Unna's blue, violet to blue with Leishman's stain, and very feebly blue with Weigert's stain ; fibrin, on the other hand, stains blue-grey to blue-green with Unna's blue, red with Leishman's stain, and deep blue by Weigert's method. The fibrinous reticulum is composed of straight fibrils crossing each other in every direction, vs^hile the mucous reticulum is wavy, and composed of fibrils which anastomose in various curves. If the sputum of such conditions as acute pulmonary cedema. THE BACTERIAL DISEASES OF RESPIRATION. 1 7 phthisis, or early pneumonia be stained, by the above methods numerous rounded masses which often seem to coalesce are seen stained violet- blue or blue-grey. These droplets vary in size and shape (Fig. Vb) : the smallest have about thrice the diameter of a red blood-cell and are round ; the largerare oval ; larger still they are irregular and lobulated as if by the coalescence of several droplets — in acute pulmonary oedema practically the whole of the exudate consist of this body ; in pneumonia they appear during the stage of hepatisation and disappear with the redux crepitation ; they may constitute the whole groundwork of the prepara- tion as if the droplets had all run together. Inasmuch as precisely similar effects are obtained by suitably stained serum, pleural exudate, ascitic fluid or albuminous urine, there is little doubt that this substance is derived from the blood, and like the albuminoid constituents of the blood, possesses a somewhat complex constitution. We now pass on to consideration of the staining methods suitable for demonstrating the bacterial flora of the respiratory passages in smear preparations and in culture films. The payment of attention to the following points will be found distinctly advantageous : (i) Smears and films alike should be made, not upon cover-slips, but upon new, well-cleaned slides ; the gain in ease of manipulation is considerable. (2) Due heed should be paid to the selection of the specimen ; it is little use selecting a piece of laryngeal or tracheal mucus when the desire is to ascertain the pulmonary conditions as regards bacterial contents. Sometimes it is necessary to prepare multiple smears, for even to the naked eye the specimen supplied may not present a homo- geneous appearance. Thin films have a distinct advantage over thick ones except when we are dealing with nasal mucus, and it is not desirable to cover more than, say, the middle third of the slide with material. (3) Stains which are liable to sedimentation should be carefully filtered immediately prior to use. (4) A good lens is a prime necessity and a movable stage a decided advantage ; it should be made an invariable rule to use either natural or artificial illumination, not sometimes one, sometimes the other. (5) The gravity of an infection is not necessarily proportional to the number of bacteria present in a smear, nor in mixed infections is the relative import of the several invaders proportional to the respective numbers ; due care should therefore be taken in searching the slide lest amidst the many the few be missed. In the study of the bacteria of the respiratory tract skill in the technique of the following staining methods is essential : Gram's ; 1 8 THE BACTERIAL DISEASES OF RESPIRATION. Ziehl - Neelsen's with Spengler's modifications, Leishman's or Giemsa's ; Muir's (for capsules) ; Van Ermengen's or Muir-Pitfield's (forflagella). Satisfactory results with each of these should be secured by adopting the following procedures : Gram's method. — Materials required: Saturated alcoholic solution of gentian violet (5 grms. in 100 c.c. of 90 per cent, alcohol), Lugol's solution of iodine (iodine i grm., potassium iodide 3 grm., distilled water 300 c.c.) ; saturated aqueous solution of aniline oil, absolute alcohol, I per cent, aqueous solution of neutral red. Procedure. — A thin uniform smear on a clean slide is allowed to dry in the air, fixed by passage three or four times through the Bunsen flame, while warm flooded with the aqueous solution of aniline oil which is filtered at the time ; the alcoholic gentian violet is then allowed to drop upon the slide, one drop at each quarter fnch ; this ensures proper mixture of stain and mordaunt, which is allowed to remain for between two and three minutes ; it is then poured off and the slide washed under the tap. The preparation is now covered with Lugol's iodine solution for fifteen seconds, washed under the tap, and flooded with absolute alcohol, which is replaced by fresh alcohol after two or three minutes. After a like interval the smear is again washed with water, held slightly aslant, and absolute alcohol dropped upon it ; when no more stain appears in the washings decoloration is complete. Wash again with water, pour on the slide the aqueous solution of neutral red, leaving it on for sixty seconds in cold weather, for forty-five seconds in hot, wash with water, dry gently between folds of filtered paper, and then over the Bunsen flame. Those bacteria which retain a violet colour are said to be Gram-positive, those which lose it and assume a light red from the neutral red are said to be Gram-negative. Most varieties of bacteria are definitely either Gram + or Gram — , but a few, such as Micrococcus paratetragemis and some strains of B. coli occurring in urine are not definitely either one or the other and may be called Gram ±. In a few other instances certain strains of a bacterium retain Gram's stain more or less definitely, while those which do not yet fail to assume the neutral red ; some strains of the tubercle bacillus are in point. Ziehl-Neelsen's method. — Materials required : Carbol-fuchsin {basic fuchsin I grm., carbolic acid crystals 5 grm. ; dissolve in 100 c.c. distilled water and add 10 c.c. absolute alcohol), 15 per cent, aqueous solution of nitric acid, absolute alcohol, i per cent, aqueous solution of toluedene blue. Procedure. — Fix film by passage or three four times through Bunsen flame, place vertically in staining dish (to prevent deposition of stain), filter the carbol-fuchsin which has been heated to about 40° C. into the THE BACTERIAL DISEASES OF RESITRATIOX. 19 dish till slide is quite immersed ; place the whole in incubator for five to ten minutes, take out the slide and wash well in water, immerse in 15 per cent, nitric acid for fifteen to twenty seconds, wash in water, again place in acid, wash with water, then with absolute alcohol till no more stain is discharged, again with water ; finally counter-stain for one to two minutes with i per cent, aqueous toluedene blue, wash well under the tap, blot lightly and dry. The bacteria, such as the tubercle, smegma, lepra, and Timothy-grass bacilli which retain the carbol-fuchsin stain after this procedure are said to be acid-fast. In as much as the presence of scanty numbers of tubercle bacilli in a specimen of sputum may be detected only with considerable difficulty when this procedure is strictly followed, various modifications of Ziehl-Neelsen's method have been devised. Some of these are con- cerned with the actual staining processes, others merely with the preliminary treatment of the sputum ; under the former head fall Spengler's methods I and II, under the latter the antiformin and pepsin methods. Spenghrs method jVo. I. — The smear is allowed to dry in the air. then covered for thirtv to sixty seconds with i per cent, aqueous solu- tion of caustic soda : this dissolves the mucus, but certainly does not seem to displace the bacilli; the caustic soda is poured off"; of what remains adherent to the slide as much as possible is removed b}- touch- ing with the edge of filter-paper, the smear is then dried best in the incubator or very cautiously over the Bunsen flame, covered with Loffler's methylene blue for two to three minutes, washed well with water, stained as before in warm carbol fuchsin, washed well with water, decolorised and counterstained by flooding the slide for thirty to fortv-five seconds with Loffler's methylene blue to which five to ten drops of 15 per cent, aqueous solution of nitric acid have been added. The slide is then washed well with water, blotted lightly and dried carefully. Spengler's method Xo. II. — Allow a thin smear to dry in the air, stain as before at a temperature of 35"-40" C. in carbol fuchsin, without washing flood the slide with a mixture of equal parts of absolute alcohol and of either Esbach's solution or of a saturated aqueous solution of picric acid, pour oft" after about flve seconds, wash for a few seconds with 15 per cent, nitric acid, flood with picric acid-alcohol; when the smear is of a hght yellow colour, wash with distilled water, dry carefully, wash with 60 per cent, alcohol, then for a few seconds with 15 per cent, nitric acid, and again with 60 per cent, alcohol. Finally contrast stain with the picric acid-alcohol until the smear is well coloured, wash with distilled water, and dry carefully. This method is somewhat tedious, but verv reliable, and by it forms which Spengler 20 THE BACTERIAL DISEASES OF RESPIRATION. has named " splitter" are well demonstrated; these frequently appear as minute red granules, and are probably infant bacilli. By it I have frequently been enabled to detect tubercle bacilli in sputum which other methods have entirely failed to reveal. The antifovmin method has been devised not only for the concen- tration of the tubercle bacilli in a specimen of sputum, so that very scanty numbers may be detected with ease, but also for the obtaining of pure cultures of the tubercle bacilli direct from the sputum; it per- forms both ends with conspicuous success. Antiformin is a mixture of equal parts of a 15 per cent, aqueous solution of caustic soda and the liquor sodse chlorinatas of the B.P. The procedure is as follows : 5 c.c. of the sputum are placed in a sterilised test-tube supplied with a well- fitting rubber cork; to this 5 per cent, of a 30 per cent, aqueous solution of antiformin are added, the tube is stoppered, well shaken till all the sputum is dissolved and a homogeneous mixture secured. It is then placed in the incubator at 37° C. for one hour. The liquid is distri- buted into two sterile centrifuge tubes and centrifuged at a high speed for five minutes, the supernatant liquid is pipetted off, to the sediment in each tube 5 c.c. sterilised distilled water are added, and thorough centrifugalisation performed ; this procedure is twice repeated. The final sediment is employed for the insemination of tubes of Dorset's egg medium, and for the preparation of smears which are stained according to one or other of the preceding methods — best by Spengler No. II. Personally, I add 5 c.c. of the mixture after incubation to one centrifuge tube, and 2 or 3 c.c. only to the other, making the volume up to 5 c.c. with absolute alcohol. The latter tube has a distinctive mark, and subsequent washings of the sediment are carried out with 40 per cent, alcohol. The addition of the alcohol lowers the specific gravity of the liquid, and facilitates the deposit of the tubercle bacilli; this tube cannot be used for culture purposes, but only for the pre- paration of smears. The pepsin and trypsin methods depend upon the digestion of the sputum with acid pepsin or alkaline trypsin prior to centrifugalisation. In opposition to the view of their advocates I do not think they have any advantage whatever over the antiformin method, which, in my hands as well as those of others, has proved most reliable and valuable. Leishuuin's method has been already described on p. 13, and serves well to display the spirochastes, vibrios and spirilla of the mouth; ]f more intense staining be desired, a 10 per cent, aqueous solution of carbol-fuchsin may be applied for forty-five seconds, followed by thorough washing in running water. Even in this dilution carbol-fuchsin is both an intense and diffuse stain ; it must therefore be remembered that the bacteria as seen under the microscope will appear unduly large. The ERRATUM. Page 20, line 13, instead of "to this 5 per cent, of a 30 per cent, aqueous solution " read " to this 5 c.c. of a 30 per cent, aqueous solution " THE BACTERIAL DISEASES OF RESPIRATION. 2 1 Stains which give the truest pictures are Loffler's methylene and carbol- methylene blue, but unfortunately they are not of general utility; their use is too well known to require description. Muir's method for capsules in my hands has proved as good as any. An advantage is its simphcity ; a disadvantage the fact that the capsules thereby are stained a weak blue or sometimes not at all, in which case, however, they stand out as a clear zone around the bacillus. The following is the composition of the fixative and mordant : Saturated aqueous solution of corrosive sublimate 2 c.c, 20 per cent, aqueous solution of tannic acid 2 c.c, saturated aqueous solution of potash alum 5 c.c; mix. The film is dried in the air, then fixed in the above for two minutes, washed in water, then in methylated spirit, and again in water. Stain in warm carbol-fuchsin for three to five minutes, wash in water, place in mordant for three minutes, wash in water. Stain for three minutes in a saturated aqueous solution of methylene blue, differentiate with methylated spirit— a process requiring considerable care — wash with water and dry carefully. Bacteria which form capsules as a rule do so only in the body, occasionally when cultured in milk or fluid media containing body fluids, rarely when allowed to incubate in the secretions in which they are voided ; it thus follows that in warm weather when, say, pneumococci may multiply in the sputum during transit, only some of the forms will be seen to be capsulated in smears prepared from such a specimen. (Fig. i shows bacillus of Friedlander capsules stained by this method.) Van Ermengens method for flagella. — Inasmuch as this is a precipita- tion process and not a true staining one, it necessarily results in an undue enlargement of the stained elements ; on the other hand, it is much the most reliable method. To secure good results it is absolutely essential that due regard be paid to the following points : (i) New slides which have been thoroughly cleansed must alone be used for the preparation of the specimen. (2) Young cultures grown on solid and not in liquid media should alone be employed. (3) A small portion of the growth should be emulsified very gently in distilled water contained in a clean watch-glass, a drop of the emul- sion taken up with the platinum loop and carefully led over the centre of the slide rather than rubbed upon it ; the film should be allowed to dry in the air and not heated ; if too thick it should be discarded. (4) Plenty of sensitising fluid should be available, and no portion of it should be used a second time even for the same preparation. Three solutions are required : (a) Fixing solution composed of 2 per cent, solution of osmic acid in distilled water i part, 20 per cent, solu- tion of tannin in distilled water 2 parts; {b) sensitising solution, o"5 2 2 THE BACTERIAL DISEASES OF RESPIRATION. per cent, silver nitrate solution in distilled water ; (c) reducing solution composed of gallic acid 5 grm., tannin 3 grm., fused potassium acetate 10 grm., dissolved in 350 cc. distilled water and carefully filtered. The procedure is as follows : The air-dried film is placed in a bath of the fixing solution at a temperature of about 50° C. for ten minutes, washed thoroughly with distilled water, then with absolute alcohol for four to five minutes, and again with distilled water. It is placed in the sensitising solution for thirty to forty seconds, and without washing transferred to the reducing solution until it turns yellow- brown : this usually takes between one and two minutes. The specimen is then transferred to a bath of fresh sensitising solution until it turns brown-black ; this usually takes only a few seconds. It is washed with plenty of distilled water, very carefully "dried with filter-paper, then over the Bunsen flame. This method is particularly useful for the demonstration of spirochaetes, spirilla and vibrios, but, as said before, it must be remembered that the micro-organisms will appear unduly large. (Fig. 2 shows B. siibtilis with flagella.) PLATE II. Fig. I. — Bacillus of Friedlander (capsules) and B. inflnenzce in sputum. (Muir's method.) x looo. Fig. -B. xiibtilis, with flr X 2O0O. sUa. .-^ Fig. 4 — Streptothrix from case of bron- chial catarrh. Film from agar culture stained by Gram's method. x lOOO. Fig. 3. — B. tuberculosis. Antiformin method. Six weeks' growth. Fig. 5. — Streptothrix. Agar cul t u re. (Slightly reduced.) CHAPTER III. CULTURAL METHODS FOR INVESTIGATING THE BACTE- RIOLOGY OF THE RESPIRATORY TRACT: DESCRIP- TION OF THE BACTERIA WHICH MAY BE PRESENT. To enter into a full description of all the cultural methods applicable to this study would be quite beyond the scope of this small book ; there are, however, certain methods which are indispensable, and one or two others which I have devised myself for special pur- poses, and these may be here considered. Two preliminary points require emphasis : (i) that plate cultures have a great advantage over tube-slopes for isolation purposes. The surface is much greater and more accessible, while naked-eye appearances are more easily studied. (2) One medium is above all others indispensable ; if cultures upon this be not made, then the investigation is vitiated and worthless from the outset. I refer to blood-agar, and for its preparation human blood and not that of animals should be employed. For two years my assistant and self have furnished all the blood we have required and never have we had a contaminated plate. The procedure we have adopted is as follows : 12-15 c.c. of sterilised 5 per cent, sodium citrate are placed in a sterile tube ; a capillary pipette is made from a piece of glass tubing -f^ in. in diameter, sterilised and fitted with a strong rubber teat. The tips of the middle fingers of the left hand are sterilised with 20 per cent, lysol, which is washed off with absolute alcohol. The finger tip is flexed, and with a surgical needle one or two punctures are made in the middle of the terminal joint. The blood should flow freely, and is taken up by means of the pipette, into which a little of the citrate solution has been already taken. About 2 c.c. of blood should be furnished by the one finger and are sufficient for one tube of citrate solution. To 10 c.c. of 2 per cent, melted agar {+ 10 Eyre's scale) at 60° C. about 1*5 c.c. of the blood citrate solution are added, and well mixed with the agar by the rotation of the inclined tube between the palms. The mixture is then poured quickly into a sterilised Petri dish of 3f in. diameter. No lump of unmelted agar should disturb the surface of the plate. About eight 24 THE BACTERIAL DISEASES OF RESPIRATION. plates can thus be prepared from one finger tip. Any effort to conserve the agar is to be strongly deprecated, for frequently plates require three days' incubation, at the end of which time the unduly thin plate will have so dried in the incubator as to be ill-adapted for bacterial growth ; the above quantity, lo c.c, is the least which should be used for a plate of 3I in. in diameter. Other media which are necessary for the more or less complete study of this question are : Agar (+ 10 Eyre's scale). Serum-agar (blood serum one part, 2 per cent, agar three parts). Acid-blood agar (blood agar made as above except that to the agar [+10 Eyre's scale] i per cent, hydrochloric acid has been added). Dorset's egg medium (take fresh hen's egg, sterilise shell, break, mix yolk and white thoroughly, add distilled water to 25 per cent., pour into sterile test-tubes one inch in diameter, avoiding all bubbles, slant, heat in inspissator at 85° C. for half an hour on each of three successive days). Peptone broth — Peptone water (0*5 per cent, peptone solution). Sugar media (o"5 per cent, peptone water to which 2 per cent, of the various sugars has been added ; of these it is well to have dextrose, levulose, saccharose, lactose, maltose, galactose, mannite, dextrin, sor- bite, dulcite, inulin). Acid-blood-peptone broth, /.^. 10 c.c. peptone broth, i c.c. blood citrate mixture, to which have been added o"5 per cent, of lactic acid and o"5 per cent, potassium tartrate (for mouth organisms). Special media such as MacConkey's are at times useful, and a contrivance for anaerobic incubation may be necessary. The preliminary examination of stained srhears will enable the decision to be made as to what media are to be employed, the use of a blood agar plate being obligatory : it will also indicate how much material is to be employed for insemination purposes. As a rule the amount of secretion taken up by a platinum loop one tenth of an inch in diameter will suffice ; with this the blood agar plate is lightly streaked, the last stroke being made parallel to, but at the margin of the plate opposite to the first. In this way discrete colonies are certain to be secured; if they develop too thickly on the first few streaks they will be sufficiently separate on some of the subsequent ones. The plate is incubated at ^y° C. for twenty-four hours and examined by direct observation and by means of stained films. It is then returned to the incubator for another twenty-four hours, for some bacteria such as B. influenza, B. Bordet-Gengou, may have developed but slightly by the end of the first day, but will be easily seen by the end of the second. THE BACTERIAL DISEASES OF RESPIRATION. 2$ Subcultures may be made upon plates or slopes. Upon blood-agar the following varieties of bacteria will freely grow : Staphylococci, streptococci, pneumococci, B. infliienzcB, B. Bordet-Gengou, B. Koch- Weeks, B. diphthericE, B. Hoffmanii, B. xerosis, B. septus, M. catarrhalis, M. paratetragenus, M. tetragenus, B. of Friedlander, B. ^rofcHs, B.pyo- cyaneus, B. coli, and B. typhosus; in fact all the pathogenic bacteria of the respiratory tract with the exception of the tubercle bacillus, lepra bacillus, streptothrix actinomycosis, Spirochceta pallida, and the vibrios, streptothrices, spirochgetes, and fusiform bacilli associated with pyor- rhoea alveolaris — the artificial cultivation of all these is not yet possible; to those which can be cultured the following methods are applicable : The tubercle bacillus. — The sputum having been treated by the antiformin method as already outlined, several loopfuls of the final sediment are streaked upon the surface of one or two tubes of the above-mentioned Dorset's egg-medium : after twenty-four to forty- eight hours' incubation at 37° C. the cotton plug is flamed, pushed down the tube, and the orifice fitted with a rubber cap in order to prevent undue evaporation of moisture. After two to three weeks' incubation, pin-head colonies of the tubercle bacillus will be visible in the great majority of cases in which this organism is present (Fig. 3). The streptothrix actinomycosis. — By far the best medium for the growth of this organism is the hydrochloric acid blood-agar. After forty-eight to seventy-two hours' incubation there will be a strongly acid odour like acetic acid, the colour of the medium will be turned brownish instead of blood-pink (from the formation, I beheve, of methhasmoglo- bin), and small colonies, white in colour, horny in consistency, and crinkled on the surface will be found strongly adherent to the surface ; after another day or two's incubation they seem to have actually eaten their way into the agar. The vibrios, streptothrices and spirochsetes of the mouth and sputum are peculiarly difficult to grow; the most useful medium is the blood peptone broth with lactic acid and potassium tartrate above referred to. With this I have at times secured abundant growth, sometimes after anaerobic, sometimes after aerobic incubation, sometimes after only six hours' incubation, sometimes after forty-eight hours. The products of growth are intensely toxic. Very occasionally pure growths can be obtained upon agar or blood agar from this blood broth (see Figs. 4 and 5) . When pure cultures of each of the bacteria seen in the smears, or of as many of them as can be induced to grow, have been obtained, the study of their behaviour on the special differentiating media which appear to be indicated may be pursued. The characteristics, morpho- logical and cultural, which I have found of the greatest value for differentiation purposes will be referred to briefly in the following section. 26 THE BACTERIAL DISEASES OF RESPIRATION. The Tubercle bacillus may very rarely require to be differentiated from the lepra bacillus, the smegma bacillus, and the B. Phlei (Timothy- grass bacillus), and the Mycobacterium lacticola; of these the first only is of importance in diseases of the respiratory tract inasmuch as 40 per cent, of lepers are said to die from tuberculosis. The presence of vast numbers of acid-fast bacilli within the typical leprous cell is suggestive of leprosy, but fails to disprove the possible simultaneous presence of the tubercle bacillus. Lepra bacilli do not grow, except in subcultures, commonly or with any freedom upon Dorset's egg-medium, hence the appearance of copious growth in three to four weeks thereon is almost proof positive of the presence of tubercle bacilli. If no growth be obtained, the inoculation of a rabbit and a guinea-pig with some of the materies morbi may be necessary to confirm the presence of the tubercle bacillus. For recent work upon the cultivation of the lepra bacillus the reader must be referred to the writings of Clegg {Philippine Journal of Science, December, igog, p. 403) ; Williams (sup- plement, Indian Med. Gazette, May, igii ; Brit. Med. Journ., December i6th, igii, p. 158), Rost, Twort, and Bayon {Brit. Med. Journ., November nth, igii, p. i26g). Once the lepra bacillus has been obtained in 'pure culture it is said by Clegg to grow readily upon any of the ordinary laboratory media, growth upon glycerine-agar or Dorset's egg-medium being so profuse in three days that the whole surface may be covered with a heaped-up moist, creamy growth, which can be readily detached and emulsifies easily in salt solution. The main problem which confronts us in regard to the B. tuberculosis is the determination of the type to which the given specimen belongs ; is it of human or of bovine origin ? The utility of Spengler's staining methods for this end I am unable to confirm. Growth upon Dorset's egg-medium affords no indication. Agglutination tests have no value. Inoculation tests have a distinct value, but are difficult to carry out, and facilities for their performance not easy to obtain. The growth in broth and determination of the acid or alkali formed at weekly intervals (Theobald Smith's method) is the best available test, but is, again, by no means easy to perform. In the case of the human strain the medium will remain acid throughout, whereas in the case of the bovine strain, after a preliminary rise in the acidity an alkaline reaction will finally appear. In short, to any but the specialised laboratory worker upon the tubercle bacillus differentiation is a practical impossibility. The reflection that in a certain small percentage of cases mixed infection by both types exists will not excite unduly the enthusiasm of the already busy man. How the difficulty can be obviated I will indicate later when I come to section IV (8). THE BACTERIAL DISEASES OF RESPIRATION. 2 7 The Streptothrix actinomycosis. — This term is a generic one com- prising many members. That transmission of infection by the Actino- myces bovis to man from horses or oxen does occur is certain, whilst infection without such an intermediary direct from barley is also possible. Streptothrices of various kinds are exceedingly common in the infected foci of pyorrhoea alveolaris, and to their astiological signiii- ■cance but scant attention has been directed. Upon three occasions lately I have isolated a streptothrix from the sputum in cases of acute bronchial catarrh (Figs. 4 and 5), while an organism somew'hat similar to mine but grouped as a leptothrix has been described by McDonald (Jonrn. Path, and Bad., igo8, p. 447) as the probable cause of a number of cases of cerebro-spinal meningitis. The relationship of these various organisms to the common .Streptothrix actinomycosis bovis is undetermined. Streptothricial ■disease of the lung in man is probably much commoner than is supposed to be the case, the greater proportion of instances being missed for these reasons : (i) The organism is difficult to cultivate ; •(2) the typical yellow granule if detected in the sputum may be mis- taken for a food-particle or for a fragment of a plug discharged from a follicular tonsillitis and examination be neglected. These plugs are by no means uncommon in sputum from such cases, and on exami- nation may be found to contain numerous streptothricial filaments — the clubs and spherical bodies (gonidia) and arrangement of the colonies typical of the true ray fungus will however be lacking, while cultural tests will assist in the discrimination. The discharge of yellow granules in the sputum from a case presenting obscure pulmonary symptoms should always awake suspicion of an actinomy- •cotic or streptothricial infection. The Spirochceta pallida is hardly likely to make its appearance in the sputum or nasal discharge ; on the other hand, its presence may be anticipated in smears prepared from scrapings taken from ulcerated surfaces of the respiratory tract, and it will be necessary to dis- criminate it from the common Spinchata refringens of the mouth. Space forbids me entering into this question, and the reader must be referred to any one of the numerous monographs which have appeared ■of late upon this subject. The staphylococcus {albus, aureus, citreus, candicans) is too well known an organism to require any detailed description. It is the commonest inhabitant of the upper respiratory tract under ordinary ■conditions ; in the pathological state it tends, if anything, to be dis- placed by the new invaders ; to estimate its significance in disease is, therefore, no easy matter. Its role in pulmonary phthisis will be referred to fully in Section IV (8) {a). In diphtheria of the throat it is fre- 2 8 THE BACTERIAL DISEASES OF RESPIRATION. quently present, but the fact that spraying with Hving cultures of the Staphylococcus atcreus has been strongly advocated by several observers as a most useful means of destroying such diphtheria bacilli as persist during convalescence may be taken to indicate that it exercises any- thing but a prejudicial action in this condition. As secondary infection in lupus, syphilis, leprosy and tuberculosis of the upper passages it is well recognised as playing an important part. In some cases of rhinitis caseosa which I have examined it would appear to have possessed an setiological significance, but in the various catarrhal infections of the respiratory tract it apparently is not con- cerned excepting in cases of empyemata of the accessory spaces, and here but rarely. The pigment formation is a variable property, and it is by no means certain that the aureus is incapable of transformation into the albus. The term " citreus" is for all practical purposes a perfectly useless one and is best abandoned. The Staphylococcus, or better-termed Micrococcus candicans, is probably a distinct and always non-pathogenic variety, possibly identical with the Micrococcus urece ; colonies on gelatin or agar are round, moistly shining, porcelain-white and slightly elevated. Microscopically they are about V2 \x in diameter, i.e. about half as large again as the ordinary staphylococcus. Usually they present a dividing line in the centre, and are Gram-positive. The streptococcus is an exceedingly important group in catarrhal diseases of the respiratory tract ; its importance is far beyond that which would be gathered from any publication upon the subject. The numerous attempts which have been made to divide and classify the various members of the group have failed utterly, na}^ more, they are intrinsically misleading. To call a certain strain a Streptococcus sali- varius or Streptococctis nnicosus was synonymous, until very recently, with attributing it with total lack of pathogenicity ; nothing could be further from the truth, and I would suggest, except in purely academic dis- cussion, the abandonment of all such terms as " salivarius,'' " mucosus," " fcBcalis," and " viridans." At the same time I must admit that the study of many scores of different strains has left me unable to suggest a better classification. The discrimination between the pneumo- coccus and some strains of mouth streptococci is by no means easy. It is stated that incubation with pure ox-bile for thirty minutes will result in the lysis of all varieties of the streptococcus but the pneumo- coccus and the so-called Streptococcus salivarius. It is also stated that the Streptococcus salivarius may possess capsules like the pneumococcus. The sugar reactions are so variable as to be almost devoid of value, and in the pathogenicity tests I am a total disbeliever, being unable to forget an experience when on the staff PLATE III. Uu;;*>6->'^ Fig. 7. — Streptococcus maximi (asthma). x looo. Fig. 10. — Streptococcus longus (asthma). x 1000. Fig. 6. — Streptococcus maximus (blood agar). Natural size. P'lG. 8. — Streptococcus large from mouth (agar). Natural size. Fig. 9. THE BACTERIAL DISEASES OF RESPIRATION. 29 of the Royal E3''e Hospital. We had an epidemic of conjunctivitis of extreme severity and of extremely rapid course — in eighteen to twenty- four hours a complete hypopyon with ulceration of the cornea usually ensued. The lanceolate, Gram-positive, capsulated diplococci were tested on rabbits and guinea-pigs, stated to be non-pathogenic and therefore not pneumococci — could anything be more absurd ? I do not for one moment wish to decry the value of close scientific observation, but so far its results as regards the streptococcus group have been most unsatisfactory. There is one variety of this organism appear- ing to possess constant characteristics, which is of the utmost importance in certain pathological conditions of the respiratory tract, and which, probably owing to the fact that it is highly hasmophilic and refuses to grow on agar alone, appears to have escaped recognition ; for reasons which will appear I have called it Strepto- coccus Jiiaxiuius. Frequently in the sputum from cases of bronchitis and asthma there may be seen long chains of a very large strepto- coccus, the individual members of which are about double the size of the ordinary Streptococcus pyogenes longus from an abscess. By Gram's method they stain diffusely, decolorising with a certain amount of ease, so that some members of the chain may be quite Gram + , others Gram±, and yet others Gram — . Fig. 7 is an excellent reproduction by Dr. Ralph Vincent of this organism ; it will be noticed that here and there is an element which has failed to retain the Gram stain. The chains may be composed of many individuals, 20, 40, 100, or even 200, the average being 40 to 60. Occasionally there may be obtained from the mouth a strain which microscopically closely resembles this one, but culturally is entirely distinct ; in broth it forms a compact sediment, which on being shaken up speedily settles again to the bottom, grows readily on agar (Fig. 8), on blood agar forms discrete white colonies no larger than a small pin's head (Fig. 9), but readily visible by reflected or transmitted light. In the case of Streptococcus maximus peptone broth remains clear, a slim}' deposit forming, which on being shaken up shows its viscid nature. On agar it very rarely shows any growth at all, on blood agar it grows with the utmost ease; on plates sown not too thickly colonies may attain a diameter of well over | in. ; they are round, almost colour- less, dew-droppy in appearance, slimy, and tend to coalesce. On blood agar slopes the colonies are difficult to see except with oblique illumination. Dr. Vincent has had great difficulty in securing a photograph of the growth, but finally, by deft manipulation of the illumination, secured the picture seen in Fig. 6. An excellent idea of the nature of the growth may be formed if it be remembered that the colonies are perfectly colourless when viewed by natural reflected light ; 30 THE BACTERIAL DISEASES OE RESPIRATION. the size of the colonies and their tendency to coalesce are well shown. The above characteristics suffice amply to identify this Streptococcus maximiis, and to differentiate it from the large streptococcus of the mouth. In other cases, especially of asthma with scanty viscid mucus, there is frequently. to be seen a totally different streptococcus; both in smears and cultures it forms chains of exceeding length which may traverse half a dozen fields of the microscope (see Fig, lo). In size the individual members of the chain show no variation from the ordinary Streptococcus pyogenes longus, and I have discovered no method of differentiating between the two. For the rest I can merely say that we may have streptococci pos- sessing only two, six, eight, a dozen or twenty members in a chain, streptococci possessing lOO or 200 in a chain ; we may have streptococci which on blood agar turn the blood green or turn it brown, hsemolyse or do not hsemolyse, which form colonies which are dry or moist, white or almost colourless, which in broth form flocculi, a uniform haze, or dense deposit ; all these characteristics mean little or nothing in the present state of our knowledge. The fact remains that each and every one may under suitable conditions become pathogenic to the human subject in a greater or less degree, and there is no laboratory test which will settle the question whether in the particular case under review they are concerned in the process of disease or are not concerned in it. It is experience and a general review of the whole bacterio- logical flora which will guide aright, and the results of vaccine treat- ment which will confirm or refute the accuracy of the deductions. For the purposes of this paper the streptococci, then, will be divided merely into these groups — maximns, longus, and brevis. The pneumococcus, as seen in stained preparations of the secretions, is typically a Gram-positive, capsulated, lanceolate coccus, usually occurring in pairs, occasionally in short chains of four to six members (Fig. 11). The best medium for its cultivation is human blood-agar, upon which it appears in twenty-four hours as minute, round, transparent, dew-drop- like colonies, thicker at the periphery than in the centre so that they present a ring-like appearance ; usually they hsemolyse the medium so that there is a clear area around each colony; sometimes they also appear to turn it green, a sign, some observers maintain, of their high virulence ; sometimes again they appear to turn the medium brown (Fig. 12). Stained films of such a growth show Gram-positive lanceolated cocci, usually arranged in pairs, sometimes in short chains'of four, six, or eight members (Fig. 13). In broth a slight uniform turbidity is produced, the addition of a little blood to the broth increasing the amount of growth ; a slight dust-like deposit may settle to the bottom of the tube. If a hanging PLATE IV. Fig. II. — Pnemnococci in sputum. (Gram's stain.) X looo. S^ >:Si^, Fig. 13. — Pneumocorcus. (Gram's stain) x lOOO Fig. 12. — Piieumococcus. (Blood agar) Natural size. Fig. 14. — B. influenzce (Carbol fuchsin.) X looo. Fig. 15. — Koch-Weeks' B. (Carbol- fuchsin.) X looo. THE BACTERIAL DISEASES OF RESPIRATION. 3 I drop or stained film be examined numerous chains of four, six, or eight individuals will be observed. The fact that growth does not occur on gelatine or agar at room temperatures assists to differentiate the pneumococcus from some strains of the short mouth streptococcus ; the distinction, however, is not an absolute one, for some of these latter also fail to grow under like conditions. I have already referred to the failure of inoculation tests to prove or negative the fact that a given organism is a pneumococcus. With those who hold that some strains of the mouth streptococcus are capsulated and behave like the pneumococcus when incubated with ox-bile I am unable to agree, and consider that they were dealing with true pneumococci of low virulence, and that it is best to regard all capsulated. Gram-positive, lanceolate diplococci which give the charac- teristic colonies on blood-agar as true pneumococci, no matter what their fermenting powers or pathogenic properties in animals. The Bacilhts influenza, B. of Koch- Weeks, and B. of Bordet-Gengou are very closely allied organisms, nay, further, the former two are probably identical, although the fact that with the acute conjunctivitis due to the Koch-Weeks' bacillus it is very rare to find a concurrent respiratory catarrh is rather against this view ; microscopically they are indistinguishable (Figs. 14 and 15). The Bacillus inflnenzce and B. Koch-Weeks only grow in or on media containing blood or haemoglobin, viz. blood broth or blood-agar. If a thin layer of blood-broth be inseminated and incubated at ^y° C. for twenty-four hours, delicate white flocculi are to be seen ; on blood-agar after twenty-four hours' incubation at 37° C. pin-point colonies^ round, perfectly colourless and moist, are formed ; after forty-eight hours these may attain a diameter of y^ in. and by reflected light are per- fectly colourless, by transmitted light grey to whitish. Microscopically they consist of very narrow short rods, 0*4 ju broad, i'2-i'5 ju long, which fail to retain the stain by Gram's method, but take up the neutral red. Weak carbol fuchsin shows them up most clearly, but from its intense and diffuse action causes them to appear unduly large (Figs. 14 and 15). Sometimes they appear in pairs, sometimes short filaments are formed, this characteristic being peculiar to certain strains of unusual luxuriance of growth which are, perhaps, pseudo rather than true influenza bacilli. In the secretion they often appear inside the cells, and yet more frequently are aggregated around the pulmonary or polynuclear cells. The Bacillus Bordet-Gengou (of whooping-cough) differs from the B. influenzce in being slightly larger, ovoid, more regular in size and in exhibiting polar staining. In cultural properties it also differs, growing best upon glycerine-potato- 32 THE BACTERIAL DISEASES OF RESPIRATION. blood-agar, and on serum agar, upon which latter medium the influenza bacillus grows with difficulty. Upon the former medium after twenty- four hours' incubation at ^y° pin-point colonies may appear ; these will be B. influenzcB. After forty-eight to seventy-two hours much larger and more vigorous colonies which do not haemolyse the blood medium may be seen. These are colonies of the bacillus of Bordet-Gengou. In sub- cultures they form a dense, grey, glistening, and very vigorous growth of discrete colonies. The tendency of the B. influenzc^, on the other hand, is to die out rapidly when sub-cultured. The addition of various bacterial toxins, as of the B. coli, pneumococcus or staphylococcus to the blood agar will frequently result in an extraordinary profuse growth of the B. inflnenzcB {vide Vaccine Therapy, 3rd edition, pp. 174, 175). It may be noted that in the majority of cases of whooping- cough the B. infliienzcB appears to be present along with the Bordet's bacillus. The significance of this fact in the treatment of whooping- cough by means of vaccine is obvious. The Bacillus diphtheric^ (Klebs-Loefiler), B. of. Hoffmann, B. xerosis and B. septus constitute the group of so-called diphtheroid bacilli. While it is true that the first of these is usually associated with the formation of a membrane, be it in the throat, larynx, nose or eye, it yet happens that it may be resident in the throat in the absence of any membrane, either persisting for months after the subsidence of all acute symptoms of a diphtheritic attack, or maintaining a constant sapro- phytic existence there, at no time causing any symptoms, but being a continual potential source of danger either to its host or to others to whom it may be conveyed : such individuals are known as " carriers." The bacillus of Hoffmann is a frequent cause of epidemic sore thro.at, not so frequent, however, I believe, as it is held to be by many observers, who may possibly have confused it with the Bacillus septus. So far as I know Hoffmann's bacillus does not invade the nose, and would not appear ever to cause an acute rhinitis. The Bacillus xerosis is believed to be non-pathogenic ; whether it is entirely devoid of pathogenicity is in my opinion debatable, but whether it be or not, its pathogenicity is certainly very low. It is commonly found associated with other bacteria in chronic inflammatory conditions of the ocular and urethral mucous membranes. It might therefore be anticipated that it would frequently be found resident on the nasal mucosa, especially in those suffering from conjunctival inflammation ; such, however, I have not found to be the case ; the only diphtheroid commonly found in the nose is the Bacillus septus. The Bacillus septus is associated with catarrhal affections of the nose, naso-pharynx, and throat. Only once have I found it in the sputum PLATE V. ►^ f Fro 1 6. — B. septus and M. catarrhalis. x lOOO. %5> V Fig. 23. — Diphtheria bacillus, Fig. 2i. — 5. Hoffmann, twenty- twentv-four hours. (Gram.) four hours. (Gram.) x looo. Fig. 17. — B. diphthericB, twenty-four hours. Natural size. Fig. 18. — B. xerosis, twenty - four hours. Natural size. Fig. 19. — B. septus twenty-four hours. Natural size. THE BACTERIAL DISEASES OF RESPIRATION. 3 3 from a case of bronchial catarrh (see Fig. i6, a smear of the sputum of this case ; the deeply-stained cocci are M. catarrhalis, the faintly stained rods B. septus). This was a long-standing infection, the expectoration was profuse and very purulent-looking, although almost free from cells and consisting almost exclusively of mucus and bac- teria and was most offensive ; if incubated for twenty-four hours the odour was overpowering, with a suggestion of impure petrol about it. This case will be more fully referred to in a subsequent number. Upon two other occasions I have isolated from the sputum a diphtheroid bacillus which was not a member of any of these four groups. On agar and blood agar it formed round, discrete, moist, oily colonies, the colour of which closely resembled that of honey ; it emulsified with ease, but almost immediately agglutinated and refused to be again emulsified. To enter into a detailed description of the characteristics, morpho- logical and cultural, of the members of this family is forbidden by the scope of this paper^ but it will perhaps prove of service if I tabulate the more important points of differential diagnosis (see Table I). A knowledge of the clinical features of the case and of the source of the material will assist one whose experience of the morphology and cultural characteristics of these organisms is limited in arriving at the correct differential diagnosis. The Micrococcus catarrhalis group. — Of all the micro-organisms in- fecting the respiratory tract, this is at once the largest, commonest, and most widely distributed group. In the present state of knowledge it is a term applied to all the cocci found in these parts which fail to retain the stain by Gram's method, with the single exception of the meningococcus or micrococcus of epidemic cerebro-spinal meningitis (Weichselbaum). I have isolated at least fifty members of this group differing the one from the other in some detail, morphological or cul- tural; and the following description must be taken as only applying strictly to the form most commonly found in catarrhal infection of the respiratory tract. It is a Gram-negative coccus, closely resembling the gonococcus in shape, and, like it, frequently growing in pairs ; it differs from the gonococcus in being less definitely kidney-shaped, and on the whole larger, and in showing greater variation in size ; every film will show some forms larger than the majority and decolorising with less ease ; and in the fact that arrangement into tetrads is quite common, chain-formation does not occur in what is to be regarded as the typical Micrococcus catarrhalis, aggregation into clumps is the rule. The following table will help in the differential diagnosis (Table II). Whether the smaller ^s^M^o-catorrAa/is is ever pathogenic is doubt- ful, and it may be given as a general rule that the larger the individual 3 34 6 <: 5s ■ 1 05 + + Throat and nose. As a rule growth profuse, on plates may attain diameter of Jin. ; more opaque and deeper white than any of the others ; centre raised and ringed. Profuse growth of dense white colonies which may coalesce (see Fig. 19). Short ovoid rods which stain more deeply at ends; may even fail to stain in centre, so that appearance may be that of a diplococcus ; no club forms (Fig. 23).* Gram +. Involution forms very few or none at all; rods longer; both ends ■ roimded, but one end larger than other ; unstained median band more marked. No polar granules. '0 re _>% B. xerosis. o. Eye, nose rarely. Even after 48 hours at 37° scanty growth of minute colonies, round, discrete and almost colourless. In 24 hours punctate colonies closely resembling those of gono- coccus but drier, more granular and more opaque (see Fig. 18). Short rods, some of which show banded appearance, some club forms (Fig. 22). Gram +. Involution forms very numerous; club forms -1- ; banded appear- ance marked (Fig. 25). S re re "o Cu C re < c ■| X c re CC + Throat. Same as B. diphtheria but rather more luxuriant. As on agar but more profuse. Short rods usually in pairs, each being .shaped like aspear point, the bases being approximated, the points directed away from each other (Fig. 21)* (better seen in methy- lene-blue preparation). Gram -1- . As at 24 hours ; no invohilion forms. .2 a. 0) !«! OJ 1) _C - tn -Ji it u ■OD u. X Cu 6 < -1- + -1- Throat, larynx, nose, eye. Minute colonies, rather larger than those of Streptococcus longus; dis- crete, dull white, centre darker than periphery by transmitted light, may be almost brown. As on agar but rather more profuse ■ (see Fig. 17). Very variable, wedge shaped rods, long cylindrical rods (3-4/1 long) rods with clubbed swellings (Fig. 20). Gram + . Involution forms, numerous club forms -1- (Fig. 24). aj 0) Ji re re CU C C CU aj- cu re j= u Oj Q- T3 '0 re 2 2 OQ ."2 '0 re T3 "D O >^ 'o 'c re CU man. Sites where found Growth on agar. Growth on blood- agar. Microscopic ap- pearance, with Gram's stain, lit 24 hours. At 48-72 hours. 're 'aj 2 Sugar reactions in 3 days in — Glucose broth. Lactose broth Saccharose broth I Maltose broth. PLATE VI. ^ / Fig. 22. — B. xerosis, twenty-four hours. (Gram.) x looo. Fig. 22.— B. septus, twenty-four hours. (Gram.^ x lOOO. Fig. 24 — Diphtheria bacillus, three days. (Gram ) x 1000. ''it\ >le "^ Fig. 25.-5. xerosis, three days. (Gram.) X 1000. Fig. 26. — B. septus and M. catarrhalis. (Gram counterstained neutral red.) X 1000. /p%T?>-' * V-i '''^' '^'. <'&^^i^^' ^'^ ^Jr •^ PiQ_ 27. — M. catarrhalis. (Gram counterstained neutral red.) X 1000. THE BACTERIAL DISEASES OF RESPIRATION. 35 ending to cultures, y Gram- ; of indi- iie gono- -celluiar ; wn ; alis, and 1. ften not cro- t of >%o To " S -> - £ ->^-;i :£: u — IS tfi X re . t. re Q. = i_ = ^. P^ X "" £ = " £ C -*:.•- X members of tlie grc tn "" .-tl '7, C -" c c ^ i; ^•i^ re — = > 4; -p X £ 1 ~ '5 1 . - — 00 ^ bo UJ C X re m -^ ■5-5^ o S^l jz X re — ■- li re.E:£ "i ^ = ^ p ^'-5 ^ C > c "? Itl. — Alypica 2 £ P-i >." £-^ = ct '■ £; > re - X re X ^ •£^ii^ "3 c .^ . ;i = X = ^- '■'' re J c ^ 2 Ji -2 £ £ 1^1 § - Ci 0. t. cc .. fe . < - t r u u: u. ic o- o r= a), c X >^ .2 -a i 5.-5 •= & -8.5 c S- - X --^-S. r § ^"H A^ X ^ — X <^ i: c t; S c ^„i 3 "5 D bo 2 Ui-= .^ -^.S «-5 P.~ m C -C •- — ^-:£ ""OH . "C. — •- re c mm I- -" •^ g- 5^ 5 -^ b. 3 c c tt} a j=. c "re c _o 'x re u b/j > -o bo •x ^ -C P i J- w _ re ^ r^ S ^£ £ - >-^ « 2 uT - . = c re 0) *^ - - "= ~ oS ^--^ ^'^ C" — CI __ c " c '— E r ;!^ -^ _re ~ E- ~ ;5 'x £ 2 re drt?. 1 2 >. = C c c re > — . c "x "! U-: - JL)- C ^ O S • ■5 5 > £ „ 52 £ . ^ X - c 2^1-1 -^ re -* C X c c bo- c g ^-2 5 -Hi-. £ ^ c c ^ ^ V, -1- X = r E = - ^ w^ .2 ■" ? c = -= _£ X 5- r "re - . u, -c £ '^ -H. . 5? S ^ § 8 5 c X -^ J5 -;; '^ ^ ?; = V- i' ' re ^ J-- • > re •^ re c ^ X '- £ To 5 ■. bo.2 p . re X £ . ^ s ^ re re — P re X J:: - - oj - - £ w = J c £ J? — c^ ' - X ■" ■ ££ ^- - ■-5 s 1 > 5 11 ■90 bo a '^'cB .0 < 36 THE BACTERIAL DISEASES OF RESPIRATION. members of the M. catarvhalis the greater is the likelihood of, its being pathogenic ; to this statement there is, however, an exception ; there is a form which morphologically is a true M. catarvhalis, except that it is in size rather less than two thirds that of a gonococcus (see Fig. 30). Culturally, however, it is favoured by anaerobic conditions, the colonies on blood agar then being much smaller than those of the typical M. catarvhalis, discrete and almost invisible instead of heaped-up, aggre- gated, crinkled and brownish. It appears to be strongly pathogenic, and whether it really belongs to the M. catarvhalis group must be left an open question. It will be remembered doubtless against me that when discussing the streptococcus group apparent exception was taken to value being attached to exact laboratory research in this domain, and I shall certainly be exposed to a charge of inconsistency in advocating the necessity for accurate laboratory research being conducted, upon the Micrococcus catarrhalis group ; it is therefore incumbent upon me to anticipate this charge and make a defence. What I really objected to in regard to the streptococcus group was not the performance of minute investigation, but the attachment of greater value to pathogenic experiments upon animals and the reactions in various sugar media than to clinical observation, a tendency which certainly has had an existence, but now happily is passing away. The case with the Micrococcus catarrhalis group is not quite parallel. These micro-organisms so far as the respiratory tract is concerned are ubiquitous ; they exist, as apparently does the streptococcus, in every mouth and throat, but they exist in far greater variety, and under far more widely divergent conditions. If in the nasal mucus of a case of acute rhinitis a Micrococcus catarrhalis be found in profusion, little doubt exists as to the causal relationship of the bacterium to the disease, and it is rare indeed to find divergent strains in such a case; in regard to the sputum, however, it is quite another matter. From practically every mouth, pharynx, and naso-pharynx in health or in disease numerous Gram-negative cocci can be recovered, and considerable variations will be discoverable, both morphological and cultural. As I have said, I have recorded about fifty strains, differing in some slight detail the one from the other. Now it will be urged that there are at least two hundred strains of streptococci; true, but I believe that each and every one of these is either pathogenic to, or capable of being roused into pathogenicity to, its host. Not so with the Micrococcus catarrhalis group. Some, nay, most of its members are probably absolutely devoid of pathogenic properties, and supposing that even half a dozen different strains are isolated from the materies inovbi, we are at present without any means whatsoever of determining which strains are responsible for PLATE VII. E,j>^, i^ Fig. ."!3. — M . paratetragenus. Slightly reduced. Fig. 28. (agar). -M. catar.rhalis Natural size. F'iG. 29. — M. catarrhalis (blood-agar). Slightly reduced. Fig. 34. — Sarcina lutea. Slightly reduced. Fig. 35. — M. tetragenus. Natural size. Fig. 37. — Bacillus of Fried- lander. Natural size. THE BACTERIAL DISEASES OF RESPIRATION. 37 the condition and which are not, of deciding which strains to incorporate in a vaccine and which to leave out. We have no alternative but to include them all. Just as I object to over-much regard being paid to the laborator}' classification of a streptococcus and consequent neglect of it as a possible factor in the given pathological condition, so I regret the absence of a rehable method of differentiating the Micrococcus catarrhalis group, and our consequent inability to separate strains which are pathogenic from those which are not. Opsonic index estimations may help, but are much likely to prove of no avail ; agglutination tests are inadmissible owing to active spontaneous agglutination in the emulsion. The Micrococcus paratetrageims. — The first to ascribe pathogenic properties to this organism was Bezancon. Benham has found it in a case of pulmonary abscess, and constantly in an epidemic of colds. I also found it a causal factor in almost every case of catarrh investigated during two epidemics. The last two years it has not been in evidence ; this year it is, however, again occurring in a certain percentage of cases. As its names imphes, it is a micrococcus usually occurring in tetrads, but also in pairs. These are usually grouped together in a zooglceal mass. They are not capsulated, but both in sputum and in culture films the mucoid material faintly stains, giving a capsular appearance. Fig. 31 is a photo-micrograph of a smear of sputum showing dark masses of Micrococcus paratetragenus and more faintly stained bacillus of Fried- lander. Fig. 32 shows admirably the appearance of a stained film of a pure culture. The more darkly stained kidney-shaped tetrads are seen imbedded in the faintly stained zooglceal mass. The Micrococcus paratetragenus is the best of all instances of organisms which may be styled Gram ±. Unless decolorisation with absolute alcohol be very complete the gentian violet will be retained, feebly but definitely, so that even two minutes' staining with neutral red will fail to displace it. Strictly I think it should be regarded as a Gram-positive organism. In smears it is apt to be confused with the Micrococcus tetragenus and with the Sarcina liitea ; from the former it is differentiated by its larger size and peculiar staining properties (compare Figs. 32 and 36), from the last by its smaller size, from both by its cultural properties {cf. Figs. 33, 34 and 35). It grows well on agar (Fig. 33 ; cf. Fig. 34 of Sarcina lutea and Fig. 35 oi Micrococcus tetragenus), better on blood-agar. When sown thinly the colonies are white, rounded, dry, umbonate ; they adhere to the medium like the Micrococcus catarrhalis, and emulsify with some difficulty ; once emulsified, however, there is little or no tendency to spontaneous agglutination. Heating to 6o°-yo° C. aids emulsification, whereas with Micrococcus catarrhalis it often tends to stronger agglutination; when 38 THK BACTERIAL DISEASES OE RESTIRATKJN. sown thickly it forms heaped-up masses. In both it produces some turbidity and a slimy deposit on the bottom. I have found it form a small amount of acid from the following sugar media : dextrose, levulose, saccharose, galactose, lactose, and from mannitol. The Micrococcus tetragenus has, I think, often been confused with the Micrococcus paratetragenus, which in several ways it closely resembles. It also is a kidney-shaped coccus, arranged in pairs or fours, and surrounded by a gelatinous pseudo-capsule, which stains faintly (well seen in Fig. 36). It is, however, distinctly smaller, about two thirds the size, and is definitely Gram-positive. It is, unlike the M. paratetra- genus, a pyogenic organism, producing in laboratory animals an abscess locally and a rapidly progressing septicaemia generally. On agar it forms, relatively to the paratetragenus, small colonies (Fig. 35), which are white, slightly elevated, shiny, and moist; the borders are at first even, later sinuous in outline. When growing on plates it gives forth an odour like glue. In broth it leaves the medium clear and forms a moderate precipitate, which on shaking rises as flocculi and then disperses. It forms acid in glucose and lactose. The bacillus of Friedlander group includes a considerable number of organisms presenting slight variation. In the secretions they occur usually in pairs, each individual surrounded by a wide capsule (see Fig. i, March number). The rods vary considerably in length (o"5-3"5 ju) and have rounded ends. They are non-motile, stain readily with any dye, but lose the stain by Gram's method and take on the neutral red (Fig. 38). They grow with extreme luxuriance upon or in almost every medium. On gelatine and agar plates when sown thinly the colonies may attain a diameter of even a quarter of an inch. They are round, grey to white, iridescent, elevated, and slimy, so that on slopes they readily coalesce and may run down to the bottom of the tube (Fig. 37) ; the water of condensation becomes turbid. Deep colonies in plates are oval or whetstone shaped. Gelatine is not liquefied. In a gelatine or agar stab well-developed growth occurs, giving the appearance of a string of pearls, while on the surface an elevated growth like a nail-head is formed. On potato a thick, moist, shiny growth yellow or greyish- brown in colour rapidly develops. Growth in broth is also luxuriant, the medium becoming quite cloudy and a slimy deposit forming. Almost all the sugar media are rapidly fermented with formation of both acid and gas. In working upon the bacteriology of the respiratory tract frequently one meets with organisms possessing characteristics varying more or PLATE VIII. Fig. 30. — M. catarrhalis, small t_\'pe. (Gram counterstained neutral red.) X 1000. Fig. 31. — Bacillus of Friedlander and If. paratt'trai(enu^ in sputum. (Gram counterstained neutral red.) x looo. l'"lG. 32. — yi . pnratetrngeiuis. (Gram counterstained neutral red.) x 1 000. «? '■^A^iK^i^:.:- Fig. 36. — y/ . tetrageniLS. (Gram.) x 1000. Fig. 38 — Bacillus of Friedlander. (Gram counterstaiaed neutral red.) X 1000. THE BACTERIAL DISEASES OF RESPIRATION. 39 less from the above. They may be capsulated or not capsulated, they may be motile or non-motile, definitely Gram — , or tending to retain the stain, they may or may not liquefy gelatine, on agar form a dry or slimy white or almost colourless growth, in a stab culture form the typical moist, heaped up, nail-head growth, or a dry, porcelain-like diffuse growth, ferment all, some or none, of the sugars. In any one or more of these particulars variations may be seen ; thus there are all gradations between the typical bacillus of Friedlander as described above and the Bacillus proteus. The Bacillus proteus vulgaris, as its name implies, is a very pleomorphic organism ; it may occur as slender rods varying in length from i to 4 /x in length, as long straight or spiral threads. It is actively motile, and does not form capsules. Its staining by Gram's method is variable. Lehmann and Neu- mann have no doubt that it is Gram-positive ; other observers are equally certain that it is Gram-negative; personally I regard it as Gram- negative. Like the bacillus of Friedlander almost any medium is suited to its growth. On gelatine it forms a delicate, grey, transparent growth, but rapidly liquefies the medium. On agar it forms grey, slimy, transparent, rounded colonies. In broth it forms considerable turbidity and abun- dant precipitate. Milk is coagulated and then liquefied. On potato it forms a scanty yellowish growth with a dull lustre. In the various sugar media it forms abundant gas and acid. Alone it would appear only infrequently to give rise to pathological conditions of the respiratory tract and its adnexa ; more often it is asso- ciated with other pathogenic organisms. I have isolated it in pure culture from several chronic cases of bronchial and Eustachian catarrh and middle-ear disease ; as these cases have recovered rapidly upon exhibition of the autogenous vaccine its causal relationship to the conditions was more or less confirmed. The Bacillus pyocyanewi (the bacillus of green or blue pus) is an actively motile Gram-positive bacillus, usually in the form of slender rods (1*5-6 ju) long, but sometimes very short and plump, sometimes almost threadlike. It is characterised by the yellow-green or blue-green fluorescence which it produces in the media upon or in which it grows, and by the early liquefaction, at first cup-shaped, later cylindrical, which it produces in a gelatine stab. That alone it is capable of pro- ducing pathological conditions is certain ; at the same time when present in such affections of the respiratory tract and its adnexa as ulcers of the mouth and pharynx, otitis media and pulmonary abscesses^ it usually occurs associated with other pathogenic organisms, and the difficulty of determining its precise role is not lessened by the following 40 THE BACTERIAL DISEASES OF RESPIRATION. considerations : (i) that in a given condition which is remaining more or less stationary the B. pyocyaneiis may be present for a few days, dis- appear for a time, then reappear — perhaps again to disappear of its own accord ; (2) that two other bacteria which appear to be entirely non- pathogenic very closely resemble the B. pyocyaneus, viz. the B. fliLorescens liquefaciens and B. fluorescens non-liqiiefaciens. The former is indistin- guishable from the B. pyocyaneus in its morphology and cultural reactions, except that it does not coagulate milk, and is said to be non-patho- genic to animals. The latter is differentiated by its failure to liquefy gelatine. Unless, therefore, the B. pyocyaneus appears to be the sole invader or is present in overwhelming numbers in a characteristic pus, I feel disposed as a rule to give it a chance of spontaneously disappearing; when, however, it fails to do this, or the patient does not make adequate progress under treatment with the vaccines of its co-invaders, I feel the time has come to use its vaccine. At the same time it must be granted that if money is no object to the patient the immediate exhibition of the /'_yoc)'a7?^«s vaccine in suitable doses, either alone or in combina- tion with other vaccines which may be indicated, is hardly likely to have any ill-effects and may be productive of good. The B. coli commnnis is so well known and so adequately described in all text-books of bacteriology that little need be said about it beyond pointing out : (i) That it is said fairly frequently to complicate pul- monary tuberculosis; personally I have found it rarely. (2) That it is often present in lung abscesses and in empyemata, especially if these be of long standing ; as a rule it is, however, not the primary infection, and unless the discharge itself be carefully examined and plating-out be conducted with unusual care the pneumococcus, streptococcus or B. influenzcs, which constituted the primary infection, may easily be missed, and the consequent treatment with a coli vaccine lead to not entirely satisfactory results. (3) That occasionally, after abdominal operations, it may produce a diaphragmatic pleuris}' or basal pneu- monia, progressing later to an empyema. I have seen such ensue after fixation of a kidney, the whole abdominal cavity remaining free from active infection. (4) That in the secretions the B. coli often retains the Gram stain so strongly that unless the treatment with absolute alcohol be thoroughly performed the bacilli may appear to be Gram- positive ; the cultural tests will, however, resolve all doubt. The B. typhosus I merely mention for this reason : It is, I believe, a far more frequent factor in the production of typhoid pneumonia than is commonly realised. In the sputum of such cases careful search should be made, not only for the typhoid bacillus, but also for the pneumococcus and streptococcus, for in cultures the first will overgrow THE BACTERIAL DISEASES OF RESPIRATION. 4I the latter two. \'accine treatment, in my opinion, offers much the best hope of recover\- in these cases, but success is largely determined by accuracy in the diagnosis of the responsible bacteria. The organisms associated with follicular tonsillitis and pyorrhcea alveolaris are legion in number. Some recent experiments of my own have shown what intensely toxic products are formed by some of these, while Mncent's fusiform bacillus has recently been shown to be pos- sessed of definitely pyogenic properties. Cases ha\-e been recorded of acute dermatitis and abscess formation as resulting from bites, and from these the fusiform bacillus has been recovered in pure culture ; it would also appear to be the cause of a peculiar form of sore very prevalent in some of the South Sea Islands. Strictly anaerobic con- ditions greatly favour its artificial culture. Most of these mouth organisms stain but faintly with most of the dves, and for the stud\- of their morphology weak carbol fuchsin is to be recommended. CHAPTER IV. B(iii). RESULTS OF OBSERVATIONS INTO THE BACTE- RIOLOGY OF THE VARIOUS DISEASED CONDITIONS OF THE RESPIRATORY TRACT. Any attempt at determining the precise role played by a given bacterium in the causation of pathological conditions of the respiratory tract is beset by numerous difficulties. The enumeration of a few only of these will help to show how real these difficulties are. (i) As one who has been working continuously on the subject for nearly ten 3^ears I am obliged to confess that one's views as to what may be and are not causal factors have been steadily changing; an organism which one now knows beyond doubt to be concerned in a given process was not even considered seven years ago, and carefully as all records have been kept, an uneasy suspicion is aroused that observa- tions even five years old are not as trustworthy as one would like them to be. (2) The results of examinations of smears of secretion are not always confirmed by the results of plating experiments; for instance a smear may show vast numbers of what appear to be B. influenzce, while a plate prepared from the same secretion may after even three days' in- cubation fail to show a single colony of that bacterium ; confirmation therefore is lacking of the identity of the bacillus seen in the smear. (3) Again, the predominant organism seen in smears may not be the predominant organism found in cultures, and even if it be granted that the former observation is more likely to give a true picture of the bacteriology of the condition than is the latter, we are faced by doubts as to whether the predominant organism necessarily is responsible for the condition rather than one of those which is present in relatively few numbers. As the result of experience I would say that in settling this question much depends upon the stage of the disease. To take one ot the simplest examples, at the very beginning of an attack of acute nasal catarrh the Staphylococcus albtis may alone be detected in the excreted THE BACTERIAL ])ISEASES OF RESPIRATION. 43 mucus and in cultures of swabs from the middle turbinals; three or four days later the Bacillus septus may reign supreme to the total exclusion of all other organisms ; after yet another interval of three or four days Staphylococcus albus, B. septus and M. catarrhalis may all be present, and the first or last of these three may predominate. Even more complex may be the results of observations upon the secretions in a case of acute or subacute sinusitis or bronchial catarrh. (4) Observations, if they are to have a definite value, must be extended over a considerable space of time. As I shall show presentl}', the results of observations made, say, last year are very dissimilar to those of observations made five years previously; this would appear to be due to the fact that either the pathogenicity of the various organisms to man rises and wanes, or the resisting powers of the human race tovv'ards a given bacterium are exalted and depressed in turn. Due allowance must therefore be made for this in the compilation of statistics as to the relative frequencies with which the various bacteria indicated are concerned in the several pathological conditions. For instance, during the four years 1905-1908 I found the B. influences in only 2*4 per cent, of the cases of respiratory catarrh which I examined, whereas during the three years igog-igii it was present in over 40 per cent, of the cases investigated. It thus follows that to the percentage figures obtained from my own long-continued observations, either alone or combined with the results of other investigators over shorter periods, undue importance must not be attached; they have a certain value and a certain interest, but that is all. (5) That whereas the truly acute attack is capable of differentia- tion from the truly chronic it is by no means easy to know under which category to place the subacute, and still less easy to know how to deal with the findings in an acute attack upon a chronic one. Of all the catarrhal organisms there is only one which, with very rare excep- tions, gives rise to acute attacks alone and not to chronic, viz. the B. septus. (6) That it is very rare for the most strictl}' localised infection to remain localised for long ; the simplest nasal catarrh in the greater majority of cases is soon complicated by an infection of one or other of the sinuses ; inasmuch as this sinusitis usually clears up rapidly of its own accord its presence easily escapes recognition. Again, in the latter stages of nasal and post-nasal catarrh, when the secretion has become thick and difficult to expel, forcible efforts at its expulsion result in a temporary dilatation of the Eustachian tube or tubes and consequently their frequent infection. This, again, as a rule, speedily subsides. Occasionally, however, infection persists in both instances, the sinuses or tubes becoming infected by the bacteria resident in the 44 THE BACTERIAL DISEASES OF RESPIRATION. parts at the time of infection, whereas the bacteriology of the nasal or post-nasal catarrh is liable subsequently to undergo a change, secondary invaders in whole or part taking the place of the primary ones. It is therefore not necessarily to be expected that the bacteriology of the nasal mucous membrane, of the antrum and the frontal sinus will be the same in a case of extension of the infection of a chronic nasal catarrh. Or again, an acute rhinitis due to the pneumococcus may extend steadily down the respiratory tract until finally a pneumococcal bronchitis is set up, or, as perhaps is more usual with this organism^ a pneumococcal laryngitis may extend simultaneously upwards and downwards, so that at the end of about five days a condition of acute rhinitis and bronchitis has superseded the primary laryngitis. The difficulty, therefore, of classifying the conditions accurately is by no means a small one. With these reservations I proceed to give a few statistics of the bacteriological findings by various observers in catarrhal conditions of the respiratory tract. (i) In Nasal and Post-nasal Catarrh. Table III. Bacteriology of Nasal and Post-nasal Catarrh (R. W. Allen's figures, 1905 to 1911 inclusive). 1905-08. 1909. • 1910. 1911. 1909-11. Number of cases 42 34 35 34 Per Per Per Per Average cent. cent. cent. cent. per cent B. influenza . 1=2-4 16 = 47 II = 31 17 = 50 43 Pneumococcus . 0=0 23 = 68 25 = 71 18 = 53 66 Streptococcus . 0= o(?) 4 = 12 II = 31 23 = 68 41 M. catanhalis • 19 = 45 17 = 50 29 = 83 22 = 65 66 M. paratetragenus . . = (?) 5 = 14 9 = 27 4 = 12 18 B. septus ■ 18 = 43 9 = 24 11=31 7 = 20 26 Bacillus of Friedlander . • 13 = 31 2=5 I = 3 2 = 6 5 Allowing for the fact that the absence of streptococci during the period of 1905-08 was probably more apparent than real, inasmuch as I did not then recognise it as a factor in the production of post-nasal catarrh, the most striking features are the great contrast in the frequency with which the B. infltienzce and pneumococcus was found in the two periods 1905-08 and 1909-11. In the Lancet of February 13th, 1909, p. 500, I recorded the incidence of this pneumococcal epidemic which has persisted till the present time ; the influenzal epidemic began about two months later, and whereas the pneumo- coccus is now showing a tendency to die out, the B. inflnenzcB has a& yet shown no such tendency. The type of concurrent complications- has, moreover, changed, neuritis and herpes zoster having been. THE BACTERIAL DISEASES OF RESPIRATION. 45 prevalent of late to the more or less exclusion of pneumonia and gastric disturbances. The B. septus on the other hand appears to have lost much of its virulence ; during the past twelve months its incidence has declined by nearly one half, and such cases as are due to it have been very mild and short. Table IV. Dy. C. H. Benhajii's Figures for Cases of Common Cold. Number of cases B. infliienzce Pneumococcus Streptococcus . M. catarrhalis . M. paraietragenus B. septus . Bacillus of Friedlander (possibly more) Dr. Benham and myself have compared our results from time to time, and such discrepancies as exist in our percentage figures for 1905-og were largely due to the fact that the pneumococcus-influenzal epidemic at the very end of 1908 and beginning of igog appeared to reach London before Brighton, whereas the reverse was the case in the instance of the M. paratetragenus, which also failed to gain the same foothold in London that it did in Brighton; these peculiarities we noted at the time. Nov. 1905-Jan. 1906. 1907-08. 1908-09. 1905-09. Total. 27 14. 49 . go Per Per Per Average cent. cent. cent. per cent. ■ 3 = II • 4 = 28 6 = 15 . 16 . (?) = (?) . 2 = 14 2= 5 • 5 . 6 = 22 . 4 = 28 II = 27 . 26 . 13 = 48 . 13 = 93 21 = 52 . 58 . 3 = II • 14 = 100 25 = 62 • 52 . 24 = 88 . II =: 78 . 25 = 62 • 74 der . 1=4 (?) 3 = 21 5 = 12 . II Table V. Dr. Will Walter's Figures for igo8-og in 100 Cases of Rhinitis {Journ. Amer. Med. Assoc., September 24th, igio, p. iogi-iog6). B. influenza Pneumococcus Streptococcus M. catarrhalis M. paratetragenus B. septus B. Friedlander 2 = 2 per cent. • 7 = 7 •5=5 . 20 = 20 (?) 12 = 12 • • 35 = 35 ■7 = 7 Swabs were taken from the nasal mucosa alone and cultures made on Loeffler's blood-serum, a medium which Walter subsequently recog- 46 THE BACTERIAL DISEASES OF RESPIRATION. nised as not altogether suitable for the purpose ; . the results, therefore, are not strictly comparable with those of Benham and myself. Table VI. C. E. Wesfs Figures for 50 Cases of Chronic Post-nasal Catarrh (Proc. Roy. Soc. Med., February, 1911, Otological Section, p. 43). B. infliienzcr . . . 0=0 per cent. Pneumococcus . • 35 = 70 ,1 ) Streptococcus . . . 12 = 24 )) M. catarrhalis (?) 10 — 20 ,, M. paratetragenns (?) B, septus 1=2 5 ) B. Ffiedlander 6 = 12 j> Staphylococcus aureus . . 13 = 26 >) The period of time over which these investigations were made is not mentioned. Swabs were taken from the pharyngeal vault by means of a guarded swab ; direct observations from smears of the swabs do not appear to have been made, and cases of acute nasal catarrh were care- fully excluded, so that these findings are not to be compared with those of the previous observers. The chief points to be noticed are : (i) The high percentage figure for the pneumococcus, \\z. 70 per cent., which very closely corresponds to my own, viz. 66 per cent, for all cases of nasal and post-nasal catarrh, acute and chronic, during the three years igog-i I. (2) The very low figure for the Bacillus septus, which also coincides with my own observation of recent months. I am therefore inclined to view West's figures merely as representing the bacteriological con- ditions in post-nasal catarrh during a limited period of time and as corresponding to the incidence of pneumococcal infection of the res- piratory tract generally. (3) The complete absence of the -B. influenzcs I can only attribute to the omission of observations upon direct smears and to a possible insufficient incubation period for the culture plates. During the past twelve months the B. influenzce has been very slow of development. (4) The high percentage incidence of the Staphylococcus auretts. West considers it a frequent factor in the production of chronic post-nasal catarrh and I am inclined to agree that it sorrtetimes is. To summarise, it would appear that any of the seven organisms, B. injluenzce, pneumococcus, streptococcus, M. catarrhalis, M. paratetra- genns, B. septus, and bacillus of Friedlander, alone or in varying corn- binations, may be responsible for a catarrhal condition of the upper respiratory passages. In perhaps 40 per cent, of cases one organism so THE BACTERIAL DISEASES OE RESPIRATION. 47 predominates as to justify the conclusion that it is the cause of the attack ; more often two or more organisms are associated toget^ier, the B. influenzcB with the pneumococcus or M. paratetragemis, the B. septus with the M. catarrhalis or M. paratetragenus, so that it becomes verv difficult to decide which organism or organisms stand in a directly causal relationship to the attack. My own belief is that mixed infections from the beginning are fairly common. In uncomplicated purulent nasal catarrh the streptococcus is the most frequent cause, next to it the Staphylococctis aureus. When sinus complications co-exist the B. influenzce and pneumococcus are by far the most frequent bacteria concerned. (2) In Diseases of the Accessory Sinuses. The observations of Torne {Central f. Bakt. «. Parasii., Jena, 1903, vol. iii, pp. 250-255) upon 36 cadavera in which the sinuses were found to be healthy would seem to indicate that in health these parts are remarkably free from bacteria ; thus in 22 instances which were examined within two and a half hours of death the sterility was complete ; of the remaining 14, which were examined between three and tvvent3'-four hours after death, 7 were sterile, 7 contained a few bacteria. He also examined 26 cavities in 26 cadavera ; 3 of these which were acutely inflamed were examined within one and a quarter hours of death, and in all the pneumococcus was present, in i case along with the Staphylococcus aureus. In 12 cases which showed a chronic purulent condition the bacteriology was most varied, strepto- coccus. Staphylococcus aureus, pseudo-catarrhalis, spirilla, proteus, B. coli, and Friedlander's bacillus being among those found. Of the 11 cavities which showed slight catarrhal changes upon examination within three hours of death, 9 were sterile, i contained Staphylococcus aureus, i Bacterium sputigeninn . Herzfeld and Hermann {Arch, fur Laryngol. u. Rhinol., Berlin,. 1895) described the bacteriology of 10 cases of antral suppuration examined during life ; streptococci were present in 8, staphylococci in 7, in both cases always along with other organisms, B. protects in 2, B. coli in 3 ; one only was monorganismal, and that was due to the bacillus of Friedlander. Whether these observers made direct examinations from smear as well as from culture films I do not know, and it is also to be noted that at this time the B. influenzce was not as yet a well-known organism and may have been missed. The results of Lewis and Logan Turner {loc. cit.) are very interesting.. They examined 57 cases of antral disease, no other sinuses being involved, i of ethmoidal sinusitis, 4 of frontal sinusitis, and 12 antral cases complicated by involvement of the ethmoidal and frontal cells. 48 THE BACTERIAL DISEASES OF RESPIRATION. The results in the 57 uncomplicated antral cases were as follows : Table VII. Streptococcus Pneumococcus Staphylococcus albus . Ps.-Diphtheria B. B. proteus B. inesenterictis B. Hojfmanni . Staphylococcus aureus B. suhtilis B. septus . 43 cases = 75"4 per cent. 42 40 8 6 6 5 5 3 = 74-1 = 70T = 14 = 10-5 = 10-5 = 87 = 87 = 5*2 = 3*5 They also took swabs from 27 cavities during operation from the nose after posturing in 42 instances. The comparative results are as follows : and swabs Pneumococcus Staphylococcus Streptococcus Ps.-Diphtheria B. Hoffmann's B. B. pyocyaneus, B. Table VIII. Direct from cavity, cases. 21 = 777 per cent. 21 = 777 21 = 777 Nasal swab. 29 = 70 per cent. 28 = 66-6 27 = 64-3 8 = 19 5 = II xerosis, B. perfriugens, leptothrix, spirillum, and B . plexiformis were each found in one instance in swabs taken direct from the antrum, while B. influenzcB, B. Friedlander, B. coli, and B. huccalis maximus were each found only in swabs from the nose; these usually showed a more profuse flora than did those taken direct at operation. In cases of less than one year's duration staphylococcus and pneumo- coccus were present in 84-6 per cent., and streptococcus in 6r6 per cent., whereas in more chronic cases streptococcus was present in So per cent., pneumococcus in 70 per cent., and staphylococcus in 66 per cent. The almost total absence of the B. influenzcz (one case only) is to be accounted for by the probable absence of any influenza epidemic during the time of their observations or within a year or two prior to them. The one ethmoidal case was a chronic one and showed Streptococcus pyogenes and Staphylococcus aureus. In the 3 cases of frontal sinusitis the findings were pneumococcus and Staphylococcus cereusflavus in one, staphylococcus, streptococcus and THE BACTERIAL DLSEASES OF RESPIRATION. 49 B. coli in the second, pneumococcus, Staphylococcus albns and auyeus Sind Sirepiococcus brevis in the third. From an experience of 30 cases of sinusitis examined during the years 1909-10-11 I am unable to agree with Lewis and Logan Turner's figures, my results having been as follows : Table IX. 1909. 1910. [91 . Total 10 9 II 30 Mean Per Per Per Per cent. cent. cent. cent. • 7 = 70 . 6= 67 9 = 82 = 73 • 5 = 50 . 6= 67 3 = 27 = 47 2 = 20 3 = 33 5 = 45 = 33 • 4 = 40 . 7 = 78 4 = 36 = 50 — I = II I = 9 = 7 — ' — I = 9 = 3 — — I = 9 = 7 • 3 = 30 . I = II = 18 = 20 — — I =r 9 = 3 Number of cases Bacillus influenzcB . Pneumococcus Streptococcus M. catarrhalis . M. paratetragenus . B. septus Bacillus of Friedlander Staphylococcus B. coli . In most instances examinations were conducted upon secretion obtained from the nose after posturing ; in a few instances, however, in which the material was also obtained either at operation or through an old operation aperture, the results differed little in the two cases ; the nasal secretion tending, as Lewis and Logan Turner pointed out, to present a slightly more complex liora. All the cases were chronic ones. One of the cases was a very interesting one of ethmoidal sinusitis and greatly distended ethmoidal bulla ; it was seen in conjunction with Mr. Herbert Tilley. The predominant organism was the B. influenzcB; streptococci were also present, and a very few -V. catarrhalis. If comparison of these results be made with the findings set out in Table III for nasal and post-nasal catarrh during the same period a general correspondence will be seen ; this would probably be more marked if cases of post-nasal infection were excluded from Table III. It is, however, to be noted that nasal infections by the B. influenza: seem especially prone to extend their energies in the direction of the acces- sory sinuses. The high incidence of the Micrococcus catarrhalis is almost certainly to be attributed to nasal swabs having been employed in the majority of my cases ; their numbers relative to the B. influenza:, pneu- mococcus or streptococcus in any given case were, as a rule, quite low. What I have already emphasised in connection with the statistics for nasal catarrh I again emphasise here : Percentage figures have little 4 50 THE BACTERIAL DISEASES OF RESPIRATION. value unless correlated over a long term of years ; they are entirely dependent upon what organism or organisms exhibit special virulence during the period of observation. Again, there is no a priori reason why the infecting agent should not change from time to time. The B. inflitenzcB, for instance, may lose its virulence and even the power of maintaining a saprophytic existence, and be replaced by a pneumo- coccus which is then exhibiting particularly pathogenic properties, this latter, in its turn, being supplanted by a more hardy streptococcus ; such a series of changes, in one or two instances, I have had an oppor- tunity of observing. Finally, in multiple sinusitis it must be remembered that the bacteriology of one infected cavity may differ totally from that of another even adjacent one. Since then the secretion obtained on one occasion may come from, say, a frontal cell, and that obtained on another occasion from an antrum or ethmoidal cell, this must not be taken as neces- sarily meaning a change of infecting agent in the event of dissimilar findings ; this is a pitfall which one must carefully avoid. (3) In Eustachian Catarrh and Otitis Media. The recognition of Eustachian catarrh as a frequent cause of preventable deafness is becoming increasingly clear ; its genesis is usually in a precedent nasal or post-nasal catarrh. Forcible efforts at expulsion of the nasal mucus during the stage of thickened secretion result in dilatation of the Eustachian tubes, and occa- sionally in the driving of some infected material into their orifices. This danger is greatly increased by the use of nasal douches — a practice highly commendable in itself, but one necessitating con- siderable care. Every patient when ordered to use a nasal douche should be warned of this, and told to allow the douche fluid to run away, and not to use any forcible efforts at expulsion of it with its contained bacteria and dissolved mucus until the cavities have been thoroughly washed out. Another hint I have found to have decided value : by firmly pressing the tragus of the ear with a finger- tip into the external meatus, counter-pressure is extended through the tympanum into the middle ear and Eustachian tube, and the risk of dilatation considerably reduced. I have noted that with most people one tube as a rule dilates much more readily than the other, and that if counter-pressure be applied to the side more liable to dilatation the douche fluid and mucus may then be forcibly expelled without danger to the Eustachian tube. This, then, being the wa}' in which Eustachian catarrh is perhaps commonly set up, it follows that the bacteriology of Eustachian catarrh THE BACTERIAL DISEASES OF RESPIRATION. 5 I should correspond to that of nasal and, more especiall}^, post-nasal catarrh. Unfortunately, reliable observations are lacking owing to the almost insuperable difficulties of obtaining swabs free from contamina- tion with nasal or pharyngeal mucus. The few observations upon which any reliance could be placed that I have been enabled to make, by the kindness of Dr. Greville Macdonald, Mr. G. S. Hett, and others, have tended to show that the M. catarrhalis, B. influenzcE, pneumo- coccus, and streptococcus are the bacteria which most commonly set up catarrh of the Eustachian tube ; upon one occasion B. septus was obtained in pure culture from a swab taken from the orifice. Clinical observation would tend to confirm these results, as the colds due to these four organisms are more particularl}- the ones in which signs of involvement of the Eustachian tubes are most evidenced. That many, if not most, cases of otitis media are sequent to Eustachian catarrh is probable. In scarlet fever and measles the streptococci almost certainly find their way to the middle ear via the Eustachian tube. This, however, is not the only route; typhoidal otitis media, for instance, probably arises -from the blood infection, and the same may be true of some pneumococcal and influenzal cases. The B. coli group, B. proteus group, and staphylococci also give rise to this condition, while otitis media due to the B. pyocyaneus, spirochaetes and streptothrix has been reported ; as these organisms are fairly common inhabitants of the mouth, infection via the tube is probable in these cases. (4) In Tracheitis and Laryngitis. Here, again, reliable bacteriological observations are lacking, but the probable truth can be deduced from clinical observations in the follow- ing way. There are certain definite clinical types of catarrhs which at one time or another in their course involve the larynx and trachea. The bacteriological findings remaining more or less constant throughout the attack, the inference appears to be justified that the bacteria which are responsible for the nasal, post-nasal, bronchial and pulmonary catarrh are likewise responsible for the tracheitis and laryngitis. For instance, we have the three following types of catarrh : (i) Definitely located in the larynx there is a dry, rough feeling as if sand-paper had been employed to line the space, the rough surface towards the mucous membrane. This gives rise to a dry, hard cough, which in a day or two may become paroxysmal ; after a severe fit of coughing a tiny pellet of mucus, clear and very viscid, may be expelled. The infection extends upwards and downwards simultaneously, so that at the end of three to five days the bronchi are definitely involved, mucous rales and rhonchi are to be heard in the chest, while nasal and post-nasal discharge is 52 THE BACTERIAL DISEASES OF RESPIRATION. abundant. The mucus is no longer clear and viscid, but yellow, muco- purulent, tending to be nummular, and easily spread upon a slide. This is a description of a type of cold during the course of which prac- tically nothing but pneumococcus is to be seen in the secretions, whether this be the tiny pellet expelled from the larynx during the first day or two or in the later muco-purulent discharge. The pneumo- coccus may therefore be assumed to have been responsible for the initial laryngitis. (2) A second type begins in a very similar manner and may likewise extend down into the chest and up into the nose ; the secretion, however, remains clear and viscid throughout, and in it the M. paratetragenus, sometimes in pure culture, sometimes along with the M. catarrhalis or pneumococcus, is to be found. The M. paratetragenus would therefore appear to cause a laryngitis. (3) Again, a dry, harsh feeling of the soft palate and post-nasal space may be followed in twenty-four to thirty-six hours by an acute rhinitis ; the infection then spreads steadily down the larynx and trachea into the large bronchi. Cough is marked, but rarely paroxysmal, and copious, thin, clear mucus, only in the later stages streaked here and there with muco-purulent strands, is easily voided. This type of cold appears to be due to the M. catarrhalis, but as other bacteria are commonly present in the secretions from the beginning it is with less certainty that one can attribute the laryngitis and tracheitis to the M. catarrhalis alone ; however, such I believe to be the case. Similarly, the B. influenzcB, and with less certainty the streptococcus, appear to be capable of setting up this condition. On the other hand, I have never found these parts involved in catarrhal conditions due to the B. septus or bacillus of Friedlander. As regards the latter, how- ever, inasmuch as at times it does attack the chest, it is highly pro- bable that it is capable of acclimatising itself in the trachea and larynx. I can only say that with an experience of eighteen catarrhal attacks due to the Bacillus of Friedlander I have never seen these parts involved. Roughly, in order of importance, I should arrange the causes of acute catarrhal laryngitis and tracheitis as follows : Pneumococcus, B. influenzce, M. catarrhalis, M. paratetragenus. It is hardly necessary for me to emphasise the fact that I am here dealing only with purely catarrhal conditions ; the diphtheria bacillus is, of course, the most important invader by far of the larynx and trachea, next to it the tubercle bacillus. (5) In Pulmonary Catarrh, Bronchitis, and Asthma. The deeper down the respiratory tract the source from which the secretion is voided, the greater obviously the danger of contaminating THE BACTERIAL DISEASES OE RESPIRATION. 53 bacteria being picked up on the wa}- ; the uncleanHness, from the bacteriological standpoint, of the fauces and mouth I have already alluded to, and it would, at first sight, appear to be almost impossible to conduct reliable observations upon material coming from the bronchi, bronchioles, or pulmonary cells. Such, however, is not the case. The precautions outlined on pp. 9 and 10 will reduce the adventitious microbes to a minimum, and a knowledge of the cytology of the sputum, as out- lined on pp. 13-15, will enable us to decide whether the actual sample under examination has been voided from the desired locality. In Table X are set out the results of my examinations in pulmonary catarrh and bronchitis during the three years 1909-11. Table X. 1909. 1910. 1911. Total. Number of cases 51 33 20 . 104 Per Per Per Mean cent. cent. cent. percentage B. inflnenzcB 21 = 42 . 9 = 27 . 12 = 60 . 40 Pneumococcus . 22 = 44 . 18 = 54 • 14 = 70 • 52 Streptococcus . 21 = 42 . 20 = 60 . 14 = 70 • 53 M. catarrhalis . 36 = 72 . 23 = 69 . 16 = 80 . 72 M. paratetragenus 12 = 24 . 9 = 27 . 3 = 15 • 23 Bacillus of Friedlander group . 5 = 10 . 1=3- I = 5 7 B. septus . 1=2. — I = 5 2 Streptothrix — 3 = 15 3 If comparison of these results be made with those for the same years for nasal catarrh set out in Table III, the only point of material difference will be seen to be in what I have already referred to — the great dis- inclination of the B. septus to make its habitat in the lower respiratory passages. These figures must also be taken as representative only of the infecting agents during the years 1909-11 ; should any given organism lose its virulence, naturally it will cease more or less to appear as an infective agent in the lower respiratory tract, just as it will do in regard to the upper passages. One other point is deserving of attention, namely this, that infections of the lower tract are commonly mixed ones, more commonly so, perhaps, than are those of the upper ; the reason of this I take to be the fact that infections of the lower passages frequently follow on those of the upper, and that these latter, as the attack progresses, tend to. become more and more mixed infections. The Micrococcus catarrhalis alone, for instance, certainly is able to initiate and maintain an acute bronchial infection, but more commonly it appears as a secondary infection to the 54 THE BACTERIAL DISEASES OF RESPIRATION. pneumococcus or B. influenza. Pure influenzal infections, again, are relatively uncommon ; more often they are complicated by the pneumo- coccus or streptococcus. The importance of the pneumococcus as the causative agent for certain cases of acute suffocative catarrh has been well brought out by Samuel West {Proc. Roy. Soc. Med., April, igii, Med. Sect., p. loi), and I am inclined to regard this organism as at the same time the most fre- quent cause of bronchial catarrh and the most dangerous to the patient. It is also worthy of notice that the B. influenzcB may be resident in the bronchi or pulmonary cells, giving rise to marked constitutional, but few localised, symptoms ; indeed the sputum voided may be almost nil. The findings in asthma. — As will be quite apparent when I come to consider the vaccine therapy of asthmatic conditions I am very far from considering bacteria as the universal cause of asthma, but regard them merely as one of the excitants of the asthmatic attack, as one of the agents capable of stimulating the nerve-endings and unstable centre. Where bronchitic symptoms are prominent the importance of bacteria is correspondingly greater. During the years igog-ii I investigated the flora of the sputum collected with suitable pre- cautions a few hours after the commencement of the attack in fifty-one cases. The results are set out in Table XI. Table XI. 1909. 1910. 1911. Total. Number of cases . 29 Per cent. II . Per cent. II . Per cent. 51 Mean percentage B. influenzcB . ■ 3 = 10 . 2= 18 . I = g . == 12 Pneumococcus 7 = 23 •4-36 . 2 = 18 = 26 Streptococcus 26 = go . II = 100 . II = 100 . = g6 M. catarrhalis 18 = 62 • 8= 73 . 10 = gi . = 72 M . paratetragenus . 4 = 13 • 3= 27 • 3= 27 . = 20 Comparison of these results with those set out in Tables III and X brings out several points of interest. The low percentage incidence of the B. influenzcB and pneumococcus is very marked, but when they do occur their significance I believe to be correspondingly greater. The almost universal occurrence of the streptococcus group is most striking, and corresponds, I believe, to its aetiological importance. The two chief varieties of streptococcus found have been already described on pp. 28-30. The incidence of the M. catarrhalis and M. paratetra- genus is approximately the same in all three tables, and their impor- tance in asthma is very difficult to determine. The organism described THE BACTERIAL DISEASES OF RESPIRATION. 5 5 by Carmalt-Jones as a possible cause of asthma he now tells me he is inclined to regard as belonging to the M. catarrhalis group. One thing which will certainly strike the investigator into the bacteriology of respiratory affections is the much less complexity of the findings in the asthmatic sputum as compared with that derived from other catarrhal affections. The total number of bacteria present is not only, as a rule, much less, but monorganismal and binorganismal specimens are much more frequently encountered. (6) In Whooping-Cough. Lack of material has prevented me making any extended investiga- tions of my own upon this question. The very careful and laborious investigations of Freeman at St. Mary's Hospital and of Martha Wol- lenstein in America have fortunately rendered any further work almost quite unnecessary. These observers corroborate the work of others, and regard the establishment of the bacillus of Bordet-Gengou as the specific cause of whooping-cough as quite complete. They have, how- ever, in addition brought out this important point : infection is very rarely a pure one; simultaneous or secondary infection by the B.influenzcB exists in a very large percentage of cases (nearly go per cent.), while the same holds true of the pneumococcus to a considerably smaller yet important degree. This accounts for the modified success which has attended the treatment of whooping-cough by means of a vaccine of Bordet's bacillus alone, and will be more fully referred to subse- quently. (7) In Pulmonary Phthisis. In this, the most important of all infections of the respiratory tract, accuracy in the diagnosis of the organisms, which accompany the tubercle bacillus, becomes more than ever necessary. Fortunately the secretion from a lung affected by phthisis by its very nature is much less likely to pick up contamination as it is voided than is the sputum of other infections. Provided the precautions detailed for the collection of speci- mens on pages 9 and 10 are carefully followed, the nummular masses of sputum only require washing twice or thrice in sterile salt solution to free them from adventitious microbes; or instead of washing, a suitable sample may be placed in a well-heated platinum dish for a few seconds ; it is then turned over and the other side likewise cooked ; by means of a sterile knife the mass may then be incised and specimens taken for direct and cultural examinations from the cold interior. Of course, when the sputum is not nummular the preliminary precautions must be carried out with especial care. Personally, I direct my 56 THE BACTERIAL DISEASES OF RESPIRATION. patients to make but one expectoration into a bottle, and prefer the early morning specimen ; at the same time it is well to take two or three other specimens at intervals during- the day, each in a separate bottle, for it by no means follows that the secondary infection at one focus of tuberculous disease will correspond to that at a second or third. How the importance of such organisms as are isolated in the diseased processes can be determined by laboratory and by clinical tests I shall detail later. Observations upon the bacteria concerned in conditions other than that of pulmonary phthisis consumed so much of the eight years' period which I have devoted to the study of the bacterial diseases of the respiratory tract that it is only during the last three years that I have been able to study the mixed infections of phthisis with adequate care. The results of my observations are set out in Table XII. Table XII. The Mixed Infections of Pulmonary Phthisis. 1909. 1910. 1911. Total. Number of cases . . 14 . 12 . 16 42 Per Per Per Mean cent. cent. cent. percentage B. infiuenzcB I = 7 — 6 = 38 = 15 Pneumococcus . 3 = 21 5 =42 7 = 43 • = 33 Streptococcus II =78 9 =75 14 = 87 . = 81 M. catarrhalis 12 = 86 10 = 83 10 = 62 = 76 M. paratetragenus 5 = 30 4 = 33 I = 6 = 22 B. septus I = 7 — — = 2 Bacillus of Friedlander I = 7 — I = 6 . = 4 S. albtis 1= 7 4 = 33 . 2 = 12 = 16 S. aureus — .2 = 16 3 = 19 = 12 Proteus I = 7 — I =z 6 ■ = 4 B. coli — — — — The yearly variations from the mean are b}' no means inconsider- able in the instance of some of the bacteria, the B. influenzce, pneumo- coccus, and M . paratetragenus, for example ; this, as before, may be due to a periodic rise and fall in the pathogenicity of these micro-organisms. One point which I feel is worthy of attention is this : there is a great tendency to speak of these as secondary infections ; the term mixed infection is far preferable, for such evidence as we have supports the view that in many instances the pneumococcus, B. influenzce or strepto- coccus is the primary infection, that by the tubercle bacillus the secon- dary one. THE BACTERIAL DISEASES OF RESPIRATION. 57 The small percentage of cases in which I have found the staphy- lococcus to be concerned is somewhat striking, the percentages of cases also in which I have found the B. influenza and pneumococcus present are also considerably lower than in the cases of pulmonary catarrh and bronchitis for the same years (vide Table X), but correspond much more closely with the figures for asthma {vide Table XI), as does also the percentage figure for the streptococcus. CHAPTER V. THE VACCINE THERAPY OF RESPIRATORY DIS- ORDERS. IV (a) General considerations. — As vaccine treatment is essentially nothing more nor less than an attempt at the artificial stimulation of such means of defence against bacterial invasion as the tissues of the body already possess when these threaten to make default, it is obviously necessary first to consider what are the defensive mecha- nisms of the body against the bacterial invasion of the parts now under conside^ration. As we have already seen, nature has endowed man with a bacterial filtration apparatus at the very vestibule of the true respiratory tract. The nasal vibrissse and ciliated epithelial cells with their coating of sticky mucus act as a filter of quite extraordinary efficiency. Some years ago I endeavoured to estimate the actual number of bacteria which escaped involvement in the nasal passages in the case of purely nasal respiration of London air. Accurate observations proved very difficult to perform, and I obtained too few thoroughly satisfac- tory ones to make them worthy of publication. The conclusion, however, appeared to be justified that at least 95 per cent, of the organisms entering the nose were entrapped therein, and accordingly failed to appear in the respiratory air as it entered the larynx ; of the remaining 5 per cent, or less by far the greater percentage must be caught up by the ciliated epithelium of the larynx and trachea ; still, as we have seen, a certain number do undoubtedly enter the bronchi and reach the lung. What, then, is the fate of these entangled bacteria ? The state- ment has been made that the respiratory mucus possesses bactericidal properties. This I have proved beyond question to be wrong ; that it may be inhibitory of bacterial growth to a slight extent is possible, but this my own experiments fail entirely to confirm. It would thus appear that the function of the mucus is a purely THE BACTERIAL DISEASES OF RESPIRATKjX. 59 mechanical one ; in health when it is secreted in small amount it serves merely to entangle the bacteria and prevent their access to the pulmonary tissues ; in pathological conditions it is increased in amount, and serves in addition to wash the multiplying bacteria and their toxic products away from the inflamed areas. Such bacteria as succeed in penetrating this defence have now to meet the opposition of the epithelial cells. No cells of the body would appear to be possessed of more strongly phagocytic powers than these epithelial cells of the upper respiratory tract ; both in the healthy and pathological state they are always to be seen crowded with bacteria. How far their phagocytic power is independent of the co-operation of opsonins and other immune bodies has not been determined, but that their inherent phagocytic power is very considerable is beyond question. As a rule these defensive agencies suffice to protect the upper respiratory passages against bacterial attacks ; at times, however, the virulence or number of the micro-organisms may be such that the outworks are penetrated and the inner lines of defence attacked. The lymphoid cells and polynuclear leucocytes now have their parts to play, and herein probably receive considerable assistance from the immune bodies of the tissues. Should these prove incapable of localising the conflict systemic infection may result, as is sometimes seen in the case of the B. influenzce, B. tuberculosis and pneumococcus, and the lymph-nodes, liver, spleen, and pulmonary tissues are involved in the struggle, filtering off and destroying the invaders with the assistance of the opsonins, lysins, agglutinins, and other immune bodies. Granting the truth of these views it becomes at once apparent that inasmuch as "immune bodies"' play but a subordinate role in protecting the respiratory passages against bacterial invasion, if we rest content merely with the endeavour to stimulate the over-produc- tion of ''immune bodies"' by the artificial introduction into healthy tissues of the corresponding bacterial vaccines, we shall be failing in our full duty to the patient. Let us then consider what are the essential preliminaries to any scheme of vaccine treatment. First and foremost, it is little use that nature has endowed man with an efficient bacterial filter if from various causes he fail to avail himself of it. Nasal respiration is a habit which should be taught in the cradle, and far too seldom is. No nurse or mother should allow an infant to sleep with the mouth open ; gentry closing it when the child is asleep will usually suffice ; should this not be the case, then an elastic band may be fixed gently over the point of the chin in order to secure the desired result ; this will have the additional good effect of preventing the child sucking its thumb, and so distorting the palatal arch. The due observance of these precautions will do much to obviate 6o thp: bacterial diseases of respiration. the subsequent appearance of enlarged tonsils and uvula, and of adenoid growths. When these occur in children who do not perform nasal respiration careful training in the habit will frequently suffice to cause their dis- appearance ; should this, however, not result, or should nasal respiration prove impossible from their presence, surgical measures must perforce be taken, and careful training be then begun. In the event of the patient having already reached adolescence or mature life attention to this point becomes even yet more urgent. Deflections of the septum, enlarged turbinate bones, polypi, adenoids or enlarged tonsils may each render nasal respiration difficult, or even impossible, to carry out. In this case surgical measures should be insisted on, and their performance encouraged by assuring the patient that they alone will frequently suffice to rid him of all his troubles without recourse being had to a long and costly course of therapeutic immunisation. When abnormalities have been adequately dealt with it still remains to teach the habit of nasal respiration. This procedure can be made not altogether unattractive to the patient in the following way. Note is made of the maximum power of expanding the chest, and he is given these instructions : A watch is to be placed by the bedside in such a position that it can readily be seen when the patient is lying in bed flat upon the back. A very low pillow, or none at all, is placed under the head, and the dorsal position assumed, legs straight and arms by the side, the only covering a single sheet. The lungs are now emptied as completel}' as possible, the residual air being got rid of by means of two or three forcible little expirations, and by bringing each arm firmly over the points of the opposite shoulder. The arms are now replaced by the side, and air taken in through the nose as slowly as possible ; when the lungs are apparently full it will be found that a little more air can still be taken in by slightly arching the back and drawing back the shoulders. The time is now noted, and the breath held ; after a certain interval the patient will feel that he can hold it no longer ; as he becomes more and more practised he will find that in reality he can retain the air until long after the head begins to swim, but this may well be left until some proficiency has been attained. A glance is then given at the time, and forcible expiration performed as speedily as possible through the open mouth. The whole procedure is then begun ab initio and repeated only twice. This is done regularly night and morning. It is no uncommon experience of mine to find that a patient who at the beginning of a course could retain the breath for no more than forty-five seconds, will at the end of four to six weeks' practice retain it with even greater ease thp: bacterial diseas?:s of respiration. 6i for quite two minutes, and that the chest expansion has meanwhile gone up from f- 1 in. to 2-2y in. Some patients regard this training as an attractive competition with themselves. It then remains to urge that whenever they are in the country walking on the hills or heath, that they should remember several times to fill and empty their lungs completely. In certain cases slight modifications have to be made ; for instance, asthmatic cases should be advised that thorough expiration is even more important than thorough inspiration ; emphysematous cases must be warned to conduct the exercises with due discretion, that, inasmuch as damage has already resulted to the pulmonary tissues, which are unduly thin and fragile, too forcible inspiratory and expiratory move- ments are to be avoided lest further damage be the result. Not only will this training in correct respiratory methods render nasal respiration easier of performance until finally it becomes a habit, but improved nutrition of the tissues generally, and thereby increased power of elaborating immune bodies therein and so of resisting bacterial attacks, will be brought about. On p. 9 I have referred to the supreme importance of scruti- nising the mouth thoroughly for the presence of pyorrhoea alveolaris and follicular tonsillitis. It is little use endeavouring to free a nasal cavity of streptococcus or Micrococcus catarrhalis by the injection of the corresponding vaccine w'hen there are pockets round the teeth or in the tonsils filled with these bacteria, more or less inaccessible both to the action of immune bodies and phagocytic cells. Crowns and bridges in a mouth I look upon as an utter abomination, and have never yet seen the mouth containing them in anything but a highly septic state. The practice, too, of leaving in the mouth one or two teeth around whose margins pyorrhoea exists merely for the better fixation of a denture is again a proceeding which cannot be too strongly condemned. Even if the micro-organisms responsible for the pyorrhoea are in no way concerned in the respiratory condition, yet the toxins they elaborate are so potent that a general lowering of the resisting powers of all the body tissues is the inevitable result. As I have already said, such supreme importance do I now attach to the presence of pyorrhoea alveolaris in sufferers from respiratory disorders, that should a patient refuse first to have this condition adequately treated by a thoroughly competent dentist, then I firmly and finally refuse to undertake the treatment of the respiratory affection. These preliminaries having been arranged, it now behoves us to con- sider in what other ways the defensive mechanisms of the body can be aided. The mechanical removal of the bacteria by means of the mucus 62 THE BACTERIAL DISEASES OE RESPIRATION. can be assisted by the careful use, night and morning, of the nasal douche ; to the precautions necessary in its use I have already alluded on p. 50. The most suitable liquid by far of which I have made trial is glycothymoline i part, warm water 3-5 parts ; not only is this quite unirritating and pleasant to use, but its solvent action on mucus is particularly good. Hygienic individuals are careful to bathe, to wash their hands and face, and clean their teeth, but the nasal cavities with the accumulated dust and dirt and bacteria of the day they are wont entirely to neglect. The careful use of the nasal douche night and morning is therefore much to be recommended. When the nasal mucosa is chronically inflamed and over-dry, as in atrophic rhinitis, the use of a mildly antiseptic but soothing oily spray in an efficient nebuliser is also advisable. The following prescription may prove of use : R Menthol . . . . . . . gr. xx Camphor . . . . . . . gr. xx Cinnamon oil ...... n\v Parolein ad 5J When follicular tonsillitis does not prove to be entirely amenable to surgical measures, careful painting of the parts twice or thrice daily with a solution of i part of chinosol in 200 to 300 parts of glycerine by means of a fine camel's hair brush may prove of service — for this hint I am indebted to my friend Mr. F. J. Steward — while sucking formamint lozenges also aids in reducing the bacterial content. Where accumulations of pus are present, as in infections of the accessory sinuses, it is obviously necessary that these be removed either by lavage, as in acute sinusitis, or by a surgical operation to establish free drainage, as in chronic sinus infections which refuse to yield to lavage. It is beyond the scope of this paper to go further into the treatment of the various local conditions which may complicate a more general respiratory disorder ; it only remains to say that the careful attention to all abnormalities may determine the final success of any more general form of treatment as by means of vaccines. Assuming, then, that due regard has been paid to all preliminaries, we may proceed to the consideration of vaccine treatment, its rationale and method of employment. Vaccine therapy depends upon this principle : " That the animal organism is capable of elaborating anti- bodies to any foreign albuminous substance introduced into it, which is soluble in the tissue fluids, and does so to an amount which is in excess of that required to neutralise the quantity of foreign matter introduced." Now bacteria are foreign albuminous substances, and the question at once occurs — Why, if this principle be true, does the body not conform THE BACTERIAL DISEASES OF RESPIRATION. 63 to it by manufacturing more than sufficient antibodies to the bacteria to neutraHse them and so put an end to the infection ? The answer to this is that in the great majority of instances it does so do; that when it fails several factors may conspire to hinder its good work, such as the following : (i) The bacteria may be introduced in such numbers that the immunising machinery may be paralysed locally or generally. (2) That when this paralysis is local other regions of the body which may be more than capable of making good the local defect in production of antibodies are incapacitated from so doing by lack of the necessar)' stimulus, viz. the bacteria are not present there to give the stimulus. (3) A more than adequate supply of antibodies may be formed in the body generally, but may not reach the areas where they are required owing to coagulation of sero-albuminous exudate or formation of thickened walls around the infected foci. (4) Certain strains of bacteria seem to be incapable of exciting the formation of immune bodies ; this would seem to be the case especialh- when their virulence is low. (5) The tissues infected may be ones incapable of forming immune bodies altogether or only in very small quantities ; this may, perhaps, be the case with the superficial layers of the epidermis. It is hard to see how bacteria infecting the most superficial layer or layers of the skin, the sweat, sebaceous and mucous glands can excite the pro- duction of antibodies ; toxins maj^ perhaps be absorbed, and anti- toxins elaborated, but unless the bacteria themselves penetrate the deeper layers, anti-bacterial bodies, such as opsonins, lysins, agglu- tinins, can hardly be formed. It will be urged that in such instances the bacteria are maintaining a merely saprophytic existence ; this is more or less true, but none the less I would maintain that they may be provocative of conditions unpleasant to the host, such as the formation of excessive secretion in the nasal or urethral passages. (6) There may be defective power, either congenital or acquired, on the part of the tissues generally in responding to bacterial invasion b}- the elaboration of antibodies. This I believe to be a more common phenomenon than is usually considered to be the case, and to afford explanation of some of the failures experienced in vaccine treatment. Let us consider how these various obstacles to the establishment of immunity may be overcome. (i) When the paralysis of the immunising machinery is general, the only hope would appear to lie in the administration, best locally into the infected areas, of sera, which should, if possible, possess both antitoxic and bactericidal properties. Unfortunately, ideal sera have 64 THE BACTERIAL DISEASES OF RESPIRATION. not yet been found capable of production. Anti-diphtheritic serum is antitoxic but not bactericidal ; anti-streptococcal serum appears to be bactericidal rather than antitoxic ; anti-cholera serum is only lytic ; the anti-meningococcic serum of Flexner appears to be both bacterio- lytic and antitoxic, but is not yet an ideal serum. (2) When the paralysis of the immunising machinery is purely local, the production of antibodies may be incited by the introduction into healthy tissues of the suitable corresponding vaccine. (3) The supply of antibodies in the body generally being sufficient, local deficiency is to be obviated in the various ways which Sir Almroth Wright has so carefully indicated, viz. abscesses may be opened, the thickened walls scraped, and the abscess cavity packed with citrated salt solution, the citrate decalcifying and so preventing the coagulation of the lymph, the salt increasing osmosis through the infected tissues ; the coagulability of the blood generally may be reduced by large doses of citric acid, hypersemia of infected areas may be brought about by local applications of heat or by passive congestion (Bier's method). (4) Diminished power of exciting antibody formation on the part of the infecting bacteria may sometimes be obviated by the introduction into the tissues of a heterologous vaccine of proved efficiency. Instances of this are chronic endocardial infections by the gonococcus and B. influenzcB, some long-standing local infections by the gonococcus and possibly by the streptococcus. (5) This class of infection is one to which local antiseptic treatment would appear to be applicable rather than vaccine therapy, and so, in fact, it usually is. At the same time I have seen instances in which careful and persistent local antiseptic treatment has failed yield well when vaccine treatment was combined with the former. (6) remains one of the problems for future studies in immunity to solve ; it is, I believe, only an exaggerated form of the failures on the part of the tissues to establish local immunity. My own feeling is that ■our present knowledge of immunity is fragmentary in the extreme, and that nothing that we know at present suffices to explain why one individual should throughout life be susceptible above his fellows to the attacks of the staphylococcus and another individual be apparently immune against the staphylococcus, but fall a ready victim to the bacillus of tuberculosis. The chemical composition of the tissues as determined probably by metabolic processes is much more intimately concerned in immunity than is at present realised. Just as one field will grow good wheat but not good potatoes, and another field good potatoes but bad wheat, so with the tissues of the human race ; lysins, opsonins, agglutinins, and all the other known immune bodies are but THE BACTERIAL DISEASES OE RESPIRATION. 65 barriers raised against bacteria, whicli are already present and in pro- cess of multiplication. True immunity, I feel sure, does not depend on these, but on some as yet quite unknown conditions which render the tissues unsuited to the very existence of, or rather unattackable by, an invader. To make my meaning clearer, our tissues are an island pro- tected by a fleet ; it is upon our fleet that we depend for our existence, not upon the land soldiers, which merely form a second line of defence to the fleet. Opsonins, lysins, and agglutinins are but land soldiers ; of our fleet we as yet know nothing, and our imperfect efforts are per- force directed to the strengthening of our land forces. The Control of Dosage and Intervals. As our main consideration is the strengthening of the defences by the aid of therapeutic inoculations, it is obviously necessary to 'discuss the means whereby determination may be made of the appropriate times and degrees of the augmentation, or in other words of ascertaining appropriate intervals and dosages. That opsonic index ■determinations have taught most of what we know in regard to the conduct of therapeutic immunisation will be readily granted, and it is therefore with some hesitation that advocacy is made of other methods of control. The bacterial diseases of the respiratory tract may be divided into two categories : (1) Those in which at some part of their course, usually at the beginning of the attack, the bacteria circulate in the blood- stream, viz. pulmonary tuberculosis, pneumonia, and sometimes, at all events, true influenza. (2) Those in w^hich the bacteria throughout the course of the attack are localised more or less entirely in the •epithelial and endothelial cells, and in the tissues in immediate juxtaposition to these ; instances of this are infections of the nasal and pharyngeal mucosa by the B. septus, of the laryngeal and bronchial mucosa by the .V. catarrhalis or Streptococcus maxiums. Constitutional symptoms, when present, must here be due to absorption of toxins, either excreted by the bacilli or the result of tissue degeneration. Such immunity curves as research has been able to evolve pursue more or less constant courses in both classes ■of infection, and are determined b\' (i) the responsive powers of the individual to an immunising stimulus, and (2} the force of the im- munising stimulus. The observations by G. G. MacDonald (vide Studies in Pathology, edited by W. Bullock) ; by Eyre [Vaccines and Sera), and by Giglioli and Stradotti {Interno alle Modificazione dell' indice opsonico nel corso di alcune vialattie acuta da infezione), who especially studied and correlated the tem.perature and opsonic index •curves in various cases of pneumonia and other acute infections 5 66 THE BACTERIAL DISEASES OF RESPIRATION. show that in practically all instances at the beginning of infection the opsonic index is low (o"4-o'8) and temperature considerably above normal. Should the disease run a favourable course it is found that at the onset of resolution there is a sudden and abrupt rise in the opsonic index and in the number of leucocytes and a corresponding fall in temperature (see Chart I), whereas in those cases which run a fatal course the opsonic index is persistently low, and the temperature continues pyrexial in type until near the end. In the former class of case the tissues have succeeded in elaboratmg an adequate supply of antibodies, antagonistic to the pneumococci and Chart I. r ■ 1 ! ! 1 iObv t ^ ~D /^eosle r- "H 1 r J ^ M N I h 1 ' , , >> , 5 .! 1 ^. / tKJ ■- H k n £ n £ \n E t M E M M E r-i p M a. n £ 'rh S ^ i '• ', i-r \ A 10,^1 t> \ \ / \ ^ h / \ / *i> 1 / -, \ / / 1 V V ^ > 1 / \ s 101 ?? V 1 S '>M ' ', I > f 10 vr> \ r' J ^^ -' ^ S r*^ ■^ >, r \ ^- -. / n(< •'? X s 'i i ^ N, r- ■^ ' V. V \ , ^^ p ilM lloS .JO IX /.6 /ji as iseases of respiration. produced with regard to the chronic infection. Here, again, careful examination of smears and cultures will prevent misconception, and indicate the necessity of preparing a fresh vaccine. A good example of a case like this is related by Dr. Roger Smith (Journal of Vaccine Therapy, vol. i, No. 3, p. 95). Briefly, then, increase of dosage is indicated by failure — (i) To obtain a slight immediate reaction ; (2) To secure improvement in the clinical condition after any dose, provided that the possibility of (a) increased activity on the part of one of the infecting micro-organisms, (6) fresh infection by another bacterium, has been eliminated. Re-inoculation is indicated by slight retrogression or failure to continue to improve on the part of the patient ; experience has shown that the interval between inoculations should be between seven and ten days. (d) General treatment. — The preliminaries to any course of vaccine treatment which should be taken have been already fully described; in addition general treatment on more or less stereotyped lines should also not be neglected. For instance, in cases of acute catarrh the patient should be confined to bed in a warm, well-ventilated room, the diet restricted in regard to meat, fish being an appropriate substi- tute ; careful attention should be paid to the bowels, and fluids limited if the mucoid discharge be unduly copious. It is most instructive to observe the effect, say, of a cup of tea upon the nasal discharge when fluids have been restricted for twenty-four hours ; within a very few minutes of the drink the secretion of mmcus may be increased many-fold, so that the discharge even drips away from the passages. Handkerchiefs should be sprinkled with two or three drops of pure formalin, and a silk one used to dry the nose ; by smearing the orifices inside and out with a little resinol or boracic oint- ment pamful excoriations may be obviated. A hot foot-bath of mustard and water and a hot-water bottle to the feet or side will increase the patient's comfort ; a hot drink of lemonade or whiske}- and lemon, followed half an hour later by a dose of the following prescription by Dr. Burney Yeo, will prom.ote diaphoresis and the action of the kidneys, and often mitigate or shorten the attack : . Tct. opii. ...... . vix. Vin. ipecac. ..... ITIX. Sp. cether. nit. ..... 5J- Liq. ammon. acet. . . . 5iij- Aq. camph. ad. ^iss M.et.f.h. THE BACTERIAL DISEASES OE RESITRATION. 83 An additional blanket should be put upon the bed, and in the event of copious sweating being produced the patient should be urged not to withdraw the hands from beneath the covering, nor to arise in the morning before cooling off by degrees ; the above prescription may be repeated with advantage immediately on waking in the morning. When laryngitis or tracheitis is present nothing does so much good as the application of a cold water compress. Sprays and antiseptic lozenges, such as formamint, conduce to comfort when pharyngitis or tonsillitis is present, but in the value of ammoniated tincture of quinine I am a profound disbeliever. Inhalations of steam saturated with the vapours of pure eucalyptus or cinnamon oil or of Friar's balsam sometimes prove of service, but rather in affections of the lower respiratory tract than of the upper. {e) Advantages accruing from Specific Treatment. (i) Acute attacks may be aborted altogether or greatl}' shortened in duration. In the great majority of instances the patient, if seen at the inception of an attack, should be perfectly able to resume his duties on the third morning after the first inoculation ; when confine- ment to the room for two days is hardly possible it is perhaps advisable to begin with a double dosage ; the reaction will be greater, but so will the immunising response, and this should be well established after an interval of eighteen hours. (2) The risk of complications is greatly minimised. As I have already said, pneumococcal infections usually begin somewhere about the larynx, influenzal ones probably higher up the tract. Vaccine treatment will almost certainly prevent extension downwards, and I think I am under- stating the truth when I declare my belief that at least 90 per cent, of the cases which are commonly stated to have died of pneumonia following upon influenza could have been saved by the exhibition of a vaccine at the commencement of the attack ; even in the later stages, when extension to the chest has already occurred, more than 50 per cent, of the deaths should be likewise obviated. As I wrote some years ago, it will be a very long time before adequate recognition is accorded to this fact ; meanwhile thousands of valuable lives will be needlessly sacrificed at every epidemic. (3) Chronic sufferers who have tried almost every other form of treatment will be either cured completely or afforded a considerable measure of relief. (4) Subsequent immunity, more or less complete, may be secured 84 THE BACTERIAL DISEASES OF RESPIRATION. against future acute attacks ; the completeness of the immunity will depend — (a) Upon the completeness of the vaccine : a vaccine containing, say, pneumococcus, B. septus and M. catarrhalis can hardly be expected to afford protection against the B. influenzcB. (b) The adequacy of the treatment. (c) The choice of suitable times for subjecting the patient to a short course of treatment. For the production of immunity against acute catarrhs an appro- priate vaccine is the combined vaccine for colds of the Wimpole Institute, w^hich is compounded of practically all the catarrhal organ- isms. It should be employed as follows : Inasmuch as the average duration of complete immunity when this is once established is about six months, two courses of treatment should be given in each year. In England the end of September or the beginning of October, and the end of January to the beginning of March usually usher in an epidemic of acute catarrhs. The patient should, therefore, present himself for treatment in the middle of September and the middle of January. A first dose of 50 millions of the combined vaccine for colds should be followed at ten-day intervals by a loo-million and a 250-million dose. Thus, by the end of the first week in October and the first week of February full immunity should have been established, and it may be anticipated with a certain degree of confidence that any prevaihng epidemic may be escaped. Against the Bacillus influenza it is a difficult matter to secure immunity ; probably a smaller dosage than 1000 or even 2000 million organisms will not prove efficient ; personally I always warn my patient that immunity against this organism cannot be assured. Post-nasal catarrh is, as a rule, a chronic infection of the naso-pharyngeal space, and is connected clinically and astiologically rather with pyorrhoea alveolaris and follicular tonsillitis than with catarrhal infections of the other portions of the respiratory tract ; it is a very important cause of preventable deafness. I have in the past been perhaps somewhat lax in differentiating sufficiently cases of chronic post-nasal from chronic nasal catarrh. Accordingly I think that the figures given in Table VI on p. 46, taken from C. E. West's paper read before the Otological Section of the Royal Society of Medicine in February, 191 2, are probably more reliable than my own given in Table III, p. 44, which have been taken from cases of both nasal and post-nasal catarrh. In virtue of the intimate relationship which exists between this complaint and pyorrhoea alveolaris and follicular tonsillitis the absolute necessity of careful search for these latter conditions and insistence THE BACTERIAL DISEASES OF RESPIRATION. 85 upon adequate treatment if they prove to be present prior to engaging upon vaccine treatment of the post-nasal catarrh is sufficiently obvious. Only rarely is this condition due to infection by a single organism, when it is, the bacillus of Friedlander is probably the one concerned, mixed infection being the rule ; streptococcus, pneumococcus, M. catarrhalis and Staphylococcus aureus may be present in any combination. Autogenous vaccines, therefore, are much more likely to prove efficacious than any stock one, the dosages to be employed are similar to those indicated for the treatment of chronic nasal catarrh ; the intervals are also similar, and the progress of the case is also to be estimated by clinical symptoms and bacteriological examinations. My own results have been particularly good ; in the cases which I have treated for otological specialists, such as Dr. Greville Macdonald, Mr. Herbert Tilley and Mr. Seccombe Hett, the report by these observers has always been that the disappearance of the catarrh has been very striking. Unfortunately the influence upon the deafness has not been correspondingly good, the cause being probably the extreme chronicity of the cases. My own private cases have been equally satisfactory as regards the catarrh symptoms. West's conclusions in regard to the efficacy of the treatment are wisely guarded, as his experiments have not yet reached finality. He, however, states that " Friedlander infections seem to do well and catarrhalis quickly disappears under vaccine treatment. Staphylococcus aureus seems to be a favourable case for vaccination, and the strepto- cocci certainly diminish or disappear in some cases. On the other hand the pneumococcus has so far defied my efforts, and has appeared to be just as numerous and just as effective in maintaining catarrhal processes after lengthy courses of vaccine as before them. It may be that fuller investigation will show a more successful method with pneumococcal infections, either by the use of still larger doses or by employing a vaccine from a specially virulent strain." In default of definite infor- mation as to dosage it is difficult to judge how far this surmise maj^ be true ; probably it is justified, my own experience being that ultimate dosages of 500 or even 1000 million pneumococci are sometimes requisite. As regards the second point I think the fault may possibly lie in the method of preparation of the vaccine. As I have already said, sometimes a pneumococcal vaccine sterilised by heat is devoid of immunising power while one sterilised by antiseptic alone secures an immediate response. At the same time I must admit that I also have at times found it impossible to prepare by any means an efficient vaccine from certain strains of pneumococcus. The effect of vaccine treatment upon chronic Etcstachian catarrh has been very striking so far as the catarrh itself is concerned, but 86 THE BACTERIAL DISEASES OF RESPIRATION. disappointing as regards any marked improvement of the actual hearing ; inasmuch, however, as all my cases have been ones of very old standing, as a rule of about twenty years or more, complicated perhaps by some degree of oto-sclerosis, and had been already subjected to all such other methods of treatment as the skill of well- known specialists could devise, the production of even a slight degree of improved audition should, I suppose^ be considered satisfactory ; in perhaps 50 per cent, of my cases this has been obtained. The best effects have, however, been the prevention of acute outbursts of the Eustachian catarrh and the resultant mamtenance of the hearing at a more steady level. In acute otitis media vaccines appear sometimes to prove of very great service in clearing up the infection ; there is, however, no little difficulty in estimating their precise effect ; for inasmuch as puncture or incision of the membrane is requisite for obtaining cultures, and this procedure, combined, of course, with such other measures as experience indicates, frequently of itself brings about a speedy cure, the good results seen after exhibition of a vaccine cannot with any degree of certainty be allocated in any particular case to this or that form of treatment. When, however, perforation of the drum has spontaneously" occurred and the infection does not appear to yield to the more stereotyped methods of treatment, the effect of vaccine treat- ment can be better gauged. One case in which double otitis media, consequent upon an attack of scarlet fever, responded with striking rapidity and completeness to inoculations of the autogenous staphylo- coccal and streptococcal vaccines I have already recorded (see Lancet, September nth, 1909, p. 780). The membranes healed with hardly any trace of scarring and the hearing when examined six months later by a well-known aurist was found practically normal. In more chronic cases it is, of course, easier to arrive at a just appreciation of the value of vaccine treatment. Good results have been obtained in infections due to the B. proteus, B. pyocyaneus, B. coli, streptococcus, pneumococcus, staphylococcus ; inasmuch as there is always a tendency for the infection to change in character, occasional bacteriological examinations of the secretion are very essential. The case for vaccine therapy in otitis media, acute or chronic, may be fairly summarised as follows : It can do no harm, while it will almost certainly prove a valuable adjunct to other forms of treatment in hastening the healing process, limiting the extent of damage and con- sequent scarring of the membrane and iixation of the ossicles and in diminishing the risk of intra-cranial complications. In acute infections the following initial dosages may be employed : THE BACTERIAL DISEASES OE RESPIRATION. 87 Streptococcus, 10 to 25 millions ; pneumococcus, 10 to 25 millions ; staphylococcus, 50 millions; B. pvoteus, 50 millions; B. pyocyaneiis, 50 millions ; B. infliienzce, 50 to 100 millions ; M. catarrhalis, 25 mil- lions. Higher initial dosages than these are not advisable unless very free drainage be maintained, for increased discharge and augmented pain usually ensue for twelve to eighteen hours. Undue haste in increasing subsequent dosages is also to be deprecated, for these cases appear to make good progress upon small doses. The usual interval is about five days or rather longer. In chronic cases trial may be made with like amounts, but in default of progress augmentations may be made rapidly with little hesitation. I have m3^self used 500-million doses of B. pyocyaneus and looo-million doses of B. pvoteus with very good result and no ill- effects. In infections of the antrum and accessory spaces, we are confronted by no little difficulty in arriving at a just appreciation of the scope and value of vaccine treatment. As to the frequency with which involvement of one or more of the accessory sinuses occurs during attacks of acute rhinitis statistics are wholly lacking. Personally I think that it does occur in at least 80 per cent, of all cases, and that it is especially frequent in acute catarrhs due to the B. influenza;, M. catarrhalis and pneumococcus. If this be so spon- taneous cure must be very frequent. The rapidity with which an antrum full of pus can clear up is very striking. I have observed a complete shadow as seen by transillumination entirely disappear within thirty-six hours and not recur. The ease with which this can happen must obviously largely depend upon the position of the opening with regard to the floor of the cavity. If this be near the floor evacuation is easy; the higher up it is the greater the obstruction to natural drainage. The poorness of the blood supply and the scanty amount of tissue covering the bony walls make it difficult to understand how the copious exudate is formed and the mechanism whereby absorption occurs of the residue which fails to drain away. The fact remains that several drachms of pus may be secreted daily and that spontaneous evacuation and absorption may occur with extreme rapidity. It is therefore with considerable hesitation that an expensive course of vaccine treatment should be suggested to any case of acute infection of the antrum until opportunity for spontaneous cure has been afforded and aided by attention to intra-nasal abnormalities, the institution of facilities for proper drainage and the application of lavage and other usual remedial measures. Here I would like to say that if artificial drainage has to be established, and the possibility of future vaccine treatment has to 88 THE BACTERIAL DISEASES OF RESPIRATION. be considered, then an intra-nasal operation will be a better procedure than puncture through a tooth-socket, for this latter affords unlimited opportunity for the continual ingress of contaminating organisms from the mouth, organisms which may prove especially refractory to vaccine treatment. As soon, however, as an acute infection shows a tendency to assume a chronic state resort should be m.ade to vaccine therapy for the following reasons : (i) Extension to neighbouring cavities may be obviated ; (2) truly chronic infections prove decidedly refractory to specific treatment. In by far the greater proportion of the thirty cases which I have seen during the past three years operative measures had been taken, and lavage persisted in for several j'ears. In none of these have I succeeded, even after two years' treatment, in producing such complete cure that vaccine treatment could be altogether discontinued. What I have achieved has been as follows : (i) Great diminution of the secretion, perhaps to such a degree that the performance of lavage once every two or three days by the patient himself has sufficed to maintain a practically complete absence of pus formation ; (2) total disappearance of exacerbations and of recurrent attacks of acute nasal catarrh ; (3) considerable improvement in the general health. The best results I have obtained have been in two very chronic cases, one of infection by the bacillus of Friedlander, the other by the B. coli. In each of these operative interference was refused, and could not be insisted on, yet the final result was almost complete cure ; a short course of vaccine treatment, has, however, had to be continued at four- to six-monthly intervals. If any measure of success is to be achieved in these very chronic cases it must be remembered (i) that very high ultimate dosages indeed may be requisite, such as 2000, or even 5000 million B. influenzce, 1000- 2000 miillion pneumococcus, 1000 million streptococcus or M. catarrhalis, 1000-2000 B. of Friedlander, B. coli or B. proteus, 2000-4000 million staphylococcus. The blood supply, especially to the antrum, frontal and sphenoidal sinuses is small, hence the amount of immune bodies carried there is small in any given blood volume; as there is difficulty in increasing the latter it is necessary greatly to augment the former. (2) That treatment may have to be prolonged, and should be re- continued after intervals, say, of every six months. (3) That in cases of multiple sinusitis the bacterial flora of the several cavities may differ, and that great care is requisite in making a correct bacteriological diagnosis, and in checking the progress of the immunisation. (4) That re-infection or fresh infection by other bacteria may at any time occur; inasmuch as the most likely new invaders are the other THE BACTERIAL DISEASES OF RESPIRATION. 89 catarrhal organisms a wise procedure is to anticipate the possibility, as far as possible, by the administration, at six-monthl}- intervals, of three progressive doses of the combined vaccine for colds of the Wimpole Institute. (5) That when large dosages are being employed the intervals must not be unduly short ; ten days or slightly longer usually proves a satisfactory one. (6) That if progress is interrupted fresh infection is a most likely cause, and is to be determined by careful reinvestigation of the bacterial flora. CHAPTER VII. VACCINES IN BRONCHITIS AND ASTHMA. (a) Bronchitis. — This condition is one pre-eminently suited for vaccine treatment. The diagnosis of the offending organisms presents few difficulties ; a suitable vaccine and therefore the production of the necessary immune bodies can be obtained with reasonable certainty ; the copious blood-supply ensures the carriage of these latter to the focus of disease, and, as I shall show, there are definite methods of estimating the progress made and so of controlling intervals and dosage. Reference to Table X, p. 53, will show that five organisms, viz. the B. iilflnenza, pneumococcus, streptococcus, M. catarrhalis and M. paratetragenus are chiefly concerned in the production of this condition; they may occur singly — a rare event — or in any of the varying combinations ; usually two or three varieties occur together. While in many cases involvement of the bronchi and bronchioles is sequent to acute catarrh of the upper respiratory tract, yet in certain cases, especially in the old and infirm, and in those specially prone to bronchial infections, the involvement of the lower passages would appear to be the primary one ; in these instances the infection is the more likely to be a simple one. Streptococci are of considerably more importance in catarrhs of the lower respiratory tract than of the upper, and may belong either to the so-called " salivariiis" type, or to the varieties depicted in figs. 7 and 10, Plate III; these latter when present would appear to be of special importance. It is fairly obvious that autogenous vaccines are more likely to be efficacious in the treatment of this complaint than are stock ones, and it is especially important to bear in mind that variation in the flora is very liable to occur during the progress of immunisation, and that a blend of vaccine admirably adapted for treatment at the beginning may be totally unsuited to the later stages; if this be carefully remembered, much disappointment, both to immuniser and patient, will be avoided. In early stages of the acute bronchitic attack bacteria may be few, the sputum being composed chiefly of hyalin mucus containing bronchial THE BACTERIAL DISEASES OE RESPIRATION. 9 1 cells in a state of rapid degeneration ; at the height of the attack mononuclear pulmonary cells make their appearance, indicative of -extension of the process to the terminal bronchioles and even the alveoli ; during subsidence the hyaline mucus becomes replaced by large mucous networks, containing within the meshes many bacteria and polymorpho- nuclear leucocytes. The examination of smears suitably stained with Unna's polychrome blue or in default of this with Leishman's stain thus affords a fairly reliable guide as to the stage and progress of the infection. The daily measurement of the sputum and its naked-eye appearance, the pulse and temperature also prove of service in esti- mating the patient's progress. The most accurate method of controlling intervals and dosage, one, moreover, applicable to all infections of the lower respiratory tract, is that based upon careful stethoscopic observa- tion. The procedure depends upon the following facts: (i) that any dose of vaccine which does not produce a definite reaction at the focus of disease is either inadequate or not compounded of the appropriate immunising agents. (2) That such a dose as causes definite improvement in the clinical signs within twelve hours is affording but a minimal stimulus, and may probably be increased with some advantage. (3) That such a dose as causes definite extension of the signs within twelve to eighteen hours, the appearance of signs where none previously existed, or an increase in their volume or moistness is indicative of correct dosage provided that rapid improvement in each of these particulars ensues within the next few hours. The patient having been placed under the most favourable con- ditions, attention having been paid to such general forms of treatment as experience indicates, and the vaccine having been prepared, systematic stethoscopic examination of the chest is then performed, and the clinical signs carefully noted upon a suitable chart ; the chest charts usually employed are not well adapted for the purpose, the outlines of the ribs occupying and obscuring too much of the space ; a much better form has been prepared for me by H. K. Lewis, and may be seen in Charts V-XI ; ample room is afforded for the insertion of such signs as we may employ, those indicated on the margin being ■convenient, and affording at a glance such information as ma}' be desired. The selected dose of vaccine is then administered and fresh •observations taken at the end of twelve and twenty-four hours and daily thereafter. Assuming that a definite reaction has been first produced, steady improvement in the condition is indication of with- holding any fresh inoculation, at all events for seven or eight days, unless retrogression occurs, especially if this be accentuated upon 92 THE BACTERIAL DISEASES OF RESPIRATION. observation twenty-four hours later, when the necessity of reinoculation is thereby indicated. Increase of dosage is necessary when improve- ment is maintained for only three or four days, or in default of adequate response. Front of Chest Back of Cheat R ^ L .^ L R :^ POST-TUSSIC o o o / . o ' o o o * X. 7 7~ , o o •A 1 — 1 HALE O o • n X ° y • o X • o <■ iz- xO o J ^ /«*• . / o y. X iZT o ^ PR/€ TUSSIC DRY-RALe . o o m ''o < . o • • < o /T o X o o OO ooo =; o • o IV • O t PR/i -TUSSIC 6 o • V • MO 1ST- RALE o s V ^ X O vr XX _ RHONCliUS YE i 1 1 Chart V. — Before first inoculation. Sputum = 6 oz. per day, Front of Chest Back of Chest R • • i!. .^ POST^uSSic KALB X o e X oX o 7 X o Ox X ° o X o o x» O o TT X o t. X X o o o PR/i TUSSIC OR r -RALE O O o V o o m o-x x° O O ox o o OO OOO - PR^ -TUSSIC MO 1ST- R All o o O o (9 IV O o o X o X o o *o* o o Y o o • • XX _ X - KHONCMUS o - ' . '. L • « <" * ^^ ^. -z X o o X X° 7 < o X • X c •XO 77 • o e> o o X o m X o K o C3 o X o X IV X ' o o ' o. o o X o X V o • o o o 'x! . o c • w • o © . • a •'. o • YE ' Chart VI. — Twelve hours after first inoculation. Sputum = lo oz. per day. Gharts V-XI will serve to elucidate my meaning, and show admirably the progress made by a certain severe case of acute recurrent bronchitis in an aged and not very hopeful case. The patient had been affected for at least ten years by chronic bron- chitis following upon an attack of apparently true influenza — three or four times during each of the last three j'ears there had been acute THE BACTERIAL DISEASES OF RESPIRATION. 93 exacerbations ; the attack for which I was consulted had lasted about a fortnight, respiration was very much embarrassed, little relief was afforded by the various stock remedies, and sleep was very difficult to procure. When I saw him the patient looked very ill indeed, but two Front of Chest Back of Chest P. 3 ° o z. ^ L o o . o . o . o*~«.^ POST-TUSSIC O X o o " X o / c X o ^ '°o 7 . O O % " ^ o X o c iZ" o o ■" X • , D c >- o n o X o c •':'y. - ^ X . ^o 2Z7 >- pp/r. -Tussic O o pc • c o c m o Ti- . o o O /F o a - CO coo = O '- * IV • o , ""H -TUSSIC * , F o • o miSf- iALl V • . • VI c 6 O D YH o Chart VII. — Twentv-fours hours after first inoculation. Sputum = 6 oz. per day. front R. ^^^ of t Che 5i L POST-TUSSIC HALE y. , ' I o tc > o X X >. n X X _ ^ PRK TUSSIC DRY -RALE J • o o m • • 1 ooo = o PRK -TUSSIC • a • IV Y XX . X - HHONCWS Back of Chest L ^ -^ R ,^ "^^ 7 1 %o o 77 >: •% - > o HI i- * * " IV ■^ V i VI 1 MI 1 i Chart VIII. — Seventy-two hours after first inoculation. Sputum = 2 oz. per day. good features were — (i) the pulse was regular and of good volume ; (2) the tissues were firm and apparently healthy despite the ill look of his face. A bacteriological examination showed that the sputum was swarming with B. influenzcs, and contained also many pneumococci and M. catarrhalis. An autogenous vaccine was prepared of each of these, and treatment begun with a dose of 50 million B. influenzcB and 25 94 THE BACTERIAL DISEASES OF RESPIRATION. million each pneumococcus and M. catarrhalis. As will be seen from the charts a marked local reaction was produced within twelve hours, the physical signs being increased considerably, as was also the amount of sputum ; of constitutional symptoms there were none beyond slight Front of Chest POST^TUSStC Pp/i TUSSIC DRY -RALE oo ooo = o PP-'i -TUSSIC MO 1ST- RALE XX . X - RHONCMUS Back of Chest R. "^ L ^ L :-- /9 i o o / X 7 X • IT o ^ o O o IT X. X X • m ^ o X o • o o m * X, ' IV . o X • o o ' a o IV V . o o , o V n . ^o ' • jn Chart IX. — Six days after first inoculation. Second inoculation. Sputum = 3 oz. per day. Front R. ^,,^ 0/ Chest £ Sa ck ( ?/ ^ ':hei 5?* POSTJUSSIC 5^ ■^ • 7 y c I c 11^ .5 D X ^ n n V. ■^ ' • '!y. - >■ m ' • PR/l TUSSIC DRY-RAie ■^ m e •^ < IV ° X t ' 00 000 i ".^ w PPjt -TUSSIC V ° Y w '3 ^ c X X X - RHONCHUS YR Chart X. — Twelve hours after second inoculation. Sputum = 4 oz. per day. increase of pulse-rate. At the end of twenty-four hours improvement began to set in, and the patient passed the best night for a fortnight ; the improvement continued markedly during the next three days, then there was a slight relapse. Accordingly on the completion of the sixth day the initial dose was repeated, again with such highly beneiicial results that at the end of the eighth day after beginning the vaccine treatment THE BACTERIAL DISEASES OF RESPIRATION. '5 the patient was sleeping well, only being awakened by one or two slight fits of coughing, was able to recline in comfort, was eating well, and expectorated only i oz. of sputum in the twenty-four hours. Con- valescence was uninterrupted, and the patient, instead of leaving for Madeira, as had been intended, was able to winter on the south coast of England. Inoculations were continued at intervals of six to eight days, and about two months after the beginning of treatment exami- nation of the sputum shov,^ed a reduction in the organisms by many hundredfold ; the same varieties, however, were still present, and expectoration persisted to the extent of 2-3 drachms per day. At this time a dosage of 250 million B. influenzce and 100 million M. catarrhalis and pneumococcus was being employed. I therefore advised the use Front of Chest Back of Chest POST^TUSSK RALE PRU -TUSSIC DKY-KALe 00 000 = o PP/t -TUSSIC MOISr-RME RHOHChUS R. ^ L .^ X •X. I A IT , • • • m IV V L -^ ^ •^ -^ i~ I y- y u V- , -i. m • -f- ' IV 9 V VI vu Chart XI. — Forty-eight hours after second inoculation. Sputum = ^ oz. per day. of double this dosage at intervals of eight days. At the end of another two months further slight reduction in the amount of sputum had been attained, and examination showed that the B. infliienzcB had almost if not entirely disappeared (none at all could be cultured); the pneu- mococci had also gone, but the M. catarrJialis had somewhat increased in actual numbers. A fresh vaccine was therefore prepared, and treatment continued with dosages of 250 millions at eight-day intervals. The patient is now practically well, merely expectorating one or two nummular masses of sputum on waking ; these contain nothing but a few M. catarrhalis. With this condition the patient is well satisfied, and it merely remains to forestall fresh infections by the use of two or three immunising doses about every four months, suitable administrations being the following sequence at eight- to ten-day intervals: (i) B. inflnenzce 100 millions, pneumococcus 50 millions, M. 96 THE BACTERIAL DISEASES OF RESPIRATION. catarrhalis loo millions ; (2) B. influenzce 250 millions, pneumococcus 100 millions, M. catarrhalis 250 millions ; (3) B. influenzce 500 millions, pneumococcus 250 millions, M. catarrhalis 500 millions. Should, despite this, a fresh attack occur, the first essential will be a re-exami- nation of the sputum in case infection has been set up by some other organism. If, however, one of the old ones shall have again come to the front, the determination of suitable dosage will depend upon the interval that has elapsed since the last immunising dose ; if this has been recent, say within a month, then treatment will be begun with the second of the above three dosages; if on the contrary it is near the end of the four months' interval, then with the first of these; but rapid advance in dosage will probably prove advisable (this, however, will be determined as before by stethoscopic and other observations). I could relate the histories of many cases similar to the above, but this would prove of httle advantage; for inasmuch as the careful clini- cian will find no difficulty whatever in understanding the rationale of the above procedure, and so of conducting such a case for himself, it only remains for him to remember that the other essentials to a suc- cessful issue are — (i) Accuracy in diagnosis of the infecting organism or organisms. (2) Careful preparation of the appropriate vaccine. (3) Repeated checking of the progress of immunisation by means of bacteriological examinations, which will at once indicate whether change of vaccine is necessary. (4) No undue haste in discontinuing treatment ; for so long as the pneumococcus or B. inflnenzcB lurks in the lung, in no matter how scanty numbers, it is always a source of continual and considerable potential danger. (5) The application of all other such adjuvants as clinical experience has proved of value. Old age and a desperate condition of the patient are no contra- indications to the application of vaccine treatment, but quite the contrary ; they merely indicate extra care in the choice of suitable dosages, which should err rather on the side of under-dosage than on that of over-dosage ; the clinical examination of the chest will afford unerring indication as to whether immunising responses are being made or not ; in the latter event dosages must be pushed and intervals between them shortened, to three, or even two days if necessary, until an immunising response is obtained ; when this has been achieved subsequent increases should be made with care and discretion, and intervals lengthened if so indicated by the clinical observations. In conclusion, I would merely add that I have never seen the case which did not benefit immediately and markedly from the administration THE BACTERIAL DISEASES OF RESPIRATION. 97 of the suitable vaccine in suitable dosages at suitable intervals, and that I do not believe such a case exists ; in no other bacterial infection of any part of the body are such gratifjnng and striking results to be secured ; even capillary bronchitis I do not regard as beyond the reach of this form of treatment. (b) Asthma. — When we consider the case of asthma we find that we are dealing with an affection of quite a different kind. Bronchitis is a bacterial disease and nothing else ; whereas, were the results of vaccine treatment in asthmatic conditions not available, it would be impossible to assert with an}- confidence that asthma is ever due to a bacterial infection. The fact, moreover, that vaccine treatment does in a certain percentage of cases prevent the onset of dyspnoeic attacks — and this it most cer- tainly does — fails to establish it as a fact that the bacteria are the true cause of the asthma ; it may only mean — and this I believe to be the case — that a bacterial irritant may suffice to set a delicately poised already existent mechanism in action — the clock may be wound up, it only requires a touch of the pendulum to set the works in motion ; this, in certain instances, bacteria or their toxins suffice to do. It thus follows in some cases, where due attention has been paid (a) to the true setiological factor of the asthmatic spasm. (6) to other accessory factors, such as diet, condition of the bowels, place of residence, etc., and where these procedures have not sufficed to cure the patient, that benefit will accrue from therapeutic immunisation. That this would be the more likely to occur in cases where bronchitic symptoms are marked, expectoration copious, and the bacterial flora profuse, might be anticipated, but within my experience this is not necessarily^ so; the best results are oft obtained in cases characterised by the scanty, viscid, stringy mucus of true asthma, containing, relativel}^ to a bronchitic sputum^ but few bacteria in but few varieties. Although I fear to become tedious by undue repetitions, here more than in any other disease with which bacteria are associated is it essential to ensure that proper treatment be first directed to all abnormalities, errors of respiration and of diet. When this has been done and the usual methods for securing cure or alleviation have failed, resort may then be made to vaccine treatment, and some hope of amelioration, if nothing more, may be offered to the patient. Reference to Table XI, p. 54, will show that the organisms most commonly found in the sputum of asthma are the streptococcus, M. catarrhalis and pneumococcus. The streptococcus, which may be brevis, longiis, or maximus in type, is present in no less than 96 per cent, of all cases, and within my experi- ence in 100 per cent, of those in which bronchitis symptoms are in abey- 7 98 THE BACTERIAL DISEASES OF RESPIRATION. ance ; the M. catarrhalis, on the other hand, is the more common in those cases in which bronchitis is a marked feature ; this also holds true for the B. influenzce, M. paratetragenus and pneumococcus. As I have already said, considerable complexity in the bacteriological findings is uncommon ; binorganismal infection, and especially by a streptococcus and the M. catarrhalis, is that most frequently found. The nature of the infection is not without bearing upon the pro- gnosis of the vaccine treatment; if the Streptococcus longus or maxiimts be present, amelioration of the asthmatic condition under judicious treatment is a practical certainty ; if the M. catarrhalis predominates bronchitic catarrh is sure to be marked, and it is no uncommon result to find that as the amount of the bronchial secretion is reduced, the difficulty in expulsion of the more tenacious and more truly asthmatic sputum becomes increasingly greater and the tendency to spasms more pronounced; this sometimes indicates that streptococci have come more to the front, and that a change of vaccine is probably advisable, but even if this be done it by no means follows that a favourable result will be achieved, and personally I regard the steering of a case of asthma to the desired haven as difficult a manoeuvre as it is easy in a case of bronchitis. There are other factors, too, which prove most difficult to control. A case of streptococcal asthma may be making all the progress one could desire, when unhappily a fresh bronchial infection by the pneumo- coccus or more especially the B. influenzce suddenly occurs. Not only may this prove difficult to eradicate, but the unfortunate result is also brought about of a resultant unstabilising of the already none too stable centre of control for the blood-supply to the lung. Dr. Alexander Francis tells me that he has frequently noticed this effect produced by infection by the B. influenzce in cases wherein he has stabilised the vaso-motor centre by means of cauterisation of the nasal mucosa, and that he, too, has found it an influence peculiarly difficult to overcome. Lest, however, it be thought that the vaccine therapy of asthma is so fraught with difficulty and disappointment as to be nothing worth, let me here remark that in a certain percentage of cases the results have been so good that the patients utterly refuse to discontinue the occasional use of their vaccines, but every six months or so go through a short course of immunisation. The initial dose of the various vaccines which I usually employ are as follows : B. influenzce loo millions, M. catarrhalis, M. paratetragenus, and pneumococcus 50 millions, streptococcus 25 millions, and whether the vaccine is likely to prove of service or not will be almost certainly determined by the response to this dose or to one of double magnitude. THE BACTERIAL DISEASES OF RESPIRATION. 99 During the night of the inoculation the patient will be awakened by an asthmatic attack, whether he be usually subject to one or not ; in the former case the attack may be a bad one and necessitate control either by the subcutaneous injection of 2-3 minims of adrenalin solution I in 1000, or by whatever means is usually found to prove efficacious ; in the latter case the attack will be a mild one and pass off within an hour or two. If the patient be likely to benefit by the treatment and such a reaction be obtained, during the ensuing five or six days there should be increased immunity from attacks both in number and severity ; tendency to relapse is the sign for re-inoculation; failure to respond by the production of a slight attack the sign for increased dosage. Occasionally, it is true, the patient does not react to the dosage emplo3^ed by the production of an attack within twelve hours, but by a decided lessening in the number and severity of attacks; this indica- tion of resulting immunity is one to which the patient will take no exception. My observations upon the vaccine treatment of asthma have by no means yet reached finality, and it is therefore impossible to be very dogmatic upon any point, whether of bacteriology, course of treatment or results ; a short history of two cases will serve, perhaps, to illustrate some few points which I have endeavoured, perhaps, with ill-success to make clear. Case i. — Mrs. A — , aged 23 years, had suffered from severe asthma since operation for adenoids and enlarged turbinate bones two years ago ; paroxysms very severe, lasting several hours, and for the past few months of daily occurrence. As she was perfectly clear in her own mind that the asthma was due to the nasal operation, she evinced a very strong objection to the performance of cautery of the mucosa, and wished first to try vaccine treatment. A bacteriological examination showed streptococcus, both longus and hrevis, and M. catavrhalis. An autogenous vaccine was prepared. On October 12th inoculation of 10 million each streptococcus and 25 million M. catavrhalis. On October 2oth she presented herself, looking much better and less jaded, and reported that she had had an attack on the second and sub- sequent nights, with the exception of the last two, when she had been perfectly free. The dosage was increased by one half. October 27th : She reported that on the night of the inoculation and that following she had had attacks of moderate severity, but since then had been quite free from any but very mild daily attacks. Repeated last dosage. November 7th : Reports a bad attack on night of October 27th ; since then only very mild daily attacks. Repeated dosage. lOO THE BACTERIAL DISEASES OF RESPIRATION. November 15th : Continued improvement in general health ; no pro- nounced reaction after last ; very slight daily attack. Repeated dosage. November 27th : Reports a bad attack on night of 23rd due probably to indigestion, otherwise only mild daily attack. Repeated dosage. December 6th : Had a bad attack on night of November 28th ; no others by day or night till morning of December 6th. Repeated dosage. December 15th : A very slight attack on night of December gth ; none whatever since ; double initial dosage given. With the result so far the patient was delighted and I more than pleased ; in the last week of December she caught the prevailing influenza epidemic, swarms of the bacilli being found in her sputum along with some pneumococci. She was quite prostrated, and as the asthmatic attacks soon recurred with all their old violence, recourse had to be had to adrenalin subcutaneously ; this controlled the severity of. the attacks admirably, but seemed to have no influence upon their frequency. A fresh vaccine of B. influenzce and pneumococcus was prepared to combine with the streptococcsd-catarrhalis one. Doses of the combined vaccines were given on January 8th, 17th, 27th, February 6th and 19th, but the infection by the B. infliienzce proved very hard to eradicate ; even when this was apparently done the frequency and severity of the asthmatic attacks, which now refused to be controlled by the original vaccines, were such that I no longer found difficulty in persuading the patient to place herself in Dr. Alexander Francis's hands; she now informs me that the result of the cauterisation has been entirely satisfactory. The unhappy effect of infection by the B. influenzce is only too well shown in this case. Case 2. — Mr. B — , aged 50 years, outdoor telegraph superintendent in the north of Scotland. Weight formerly 10 st. 6 lb., now 8 st. 6 lb. ; complains of chronic bronchitis with spasmodic asthma. History was as follows : January, 1909 : Acute attack of bronchitis, lasting for six weeks, then recovery. January, 1910 : Another acute attack lasting eight weeks, and leaving behind it considerable dyspnoea, which, by June, 1910, had assumed a spasmodic form, and become so severe that he was incapable of any exertion. On September 17th he suddenly recovered, and remained quite well till January 3rd, 1911, when a fresh acute attack of bronchitis supervened ; this persisted till the end of March, by which time partial recovery was established ; regular attacks of spasmodic dyspnoea, however, continued, and in September, 1911, he had a bacteriological examination made of his sputum, and a vaccine containing 20 million M. catarrhalis and 10 million pneumococcus was THE BACTERIAL DISEASES OF RESPIRATION. lOI prepared, but not by me, and administered at intervals of two to four days. Slight immediate improvement in the direction of lengthening of the periods of freedom from dyspnoea was produced. September, igii, to January, 1912 : Patient states that the dys- pnceic attacks continued with great regularity at an average interval of nine hours. Minimum interval, four hours ; maximum, twenty hours. The only remedy which gave any certain relief was adrenalin chloride subcutaneously. At the end of January, 1912, he consulted me by post as he had long been unable to leave the house. I examined the sputum, and found Streptococcus niaxiniiis in considerable numbers, and a few M. catavrhalis and pneumococcus. Informed him that he had hardly given the previous vaccine a fair trial, but that I thought I could compound one rather better suited to his needs if he would place its administra- tion in the hands of a medical man, who would allow me to direct treatment. Dr. K. Gillies kindly undertook the task, and began treatment with an initial dosage of Streptococcus maximns 25 millions, pneumococcus 25 millions, and M. catavrhalis 50 millions. On March 29th, 191 2, I received a report from the patient and make the following abstracts: "Prior to commencing with your vaccine I had very short periods of freedom from dyspnoea, and that with entire rest and confinement to my bed-room. Now you will observe I have much longer periods of ease and that with more movement about. These have, as is shown on the chart, been temporarily affected by an}^ labour, stress, etc. That I have been able to get out at all this cold v/eather shows a very marked improvement. My appetite is good considering the little exercise, my flesh is clear and more ruddy, and my weight has increased 6 lbs. during the last eight weeks. My sputum is becoming very scanty; you asked me to send a fresh specimen if I found my progiress not satisfactory. I do not think the time has arrived for this as I consider I am so very much improved." On May 7th I received a fresh report: from May ist to to May 5th inclusive he had only experienced one moderate dyspnceic attack, which had at once yielded to a small dose of adrenalin chloride. By this time Dr. Gillies had increased the dosage of vaccine to ten times the initial one, and doses of even this magnitude failed to excite a dyspnoeic attack. A rough idea of the progress of the case may be gathered from Chart XII. In order to arrive at a just appreciation of the result it must be remembered, as the patient saj'S, that after a long period of complete confinement to his room, he was at the time of the report indulging in considerable out-door exercise at a most trying period of year to all asthmatics. I02 THE BACTERIAL DISEASES OF RESPIRATION. In conclusion I would merely say that although many of my cases have pursued more favourable courses than these two, it is yet impos- sible for me to dogmatise at all; it must suffice to state that within my experience much good may accrue to asthmatic cases by a course of vaccine treatment, but that with this disease more than with any other each case must be considered apart and treated on its own merits, not according to any given procedure or rule of thumb. CHAPTER VIII. VACCINES IX PNEUMONIA. Definition. — Pneumonia typically is an acute febrile disease, begin- ning as a rule suddenly but sometimes insidiously, associated with massive consolidation of the lung, running a fairly definite course, and terminating within ten days by crisis or lysis. Inasmuch, however, as the course is sometimes less definite, the term is taken to include all cases of acute febrile disease accompanied by massive consolidation of the lung. Etiology. — While it is undoubtedly true that pneumonia is a disease characterised especially by sudden onset, I think that in a considerable proportion of cases of true lobar pneumonia it would be more accurately regarded as an acute exacerbation in a chronic infection by the pneumococcus of the bronchial or pulmonary tissues, an infection which originally took its rise in an acute pneumococcal infection of the upper respiratory passages, and subsequently invaded those of the chest, giving rise, perhaps, to nothing more than a bronchial catarrh, which apparently cleared up more or less completeh-. As I have already mentioned previously I have had the opportunity of watching several such cases, some for several years, and of making periodic examinations of the sputum, which may be extremely scanty, and of noting with what extreme tenacity the pneumococci retain their hold upon the tissues. In some instances the most patient treatment by means of vaccines and otherwise fails to dislodge them completely. On page 193 of No. 7, vol. i, of the Journal of Vaccine Therapy, Dr. Graham Morris tells his own stor}-, which illustrates well this tendency of the pneumococcus to persist in the pulmonary tissues. I do not for a moment mean that all attacks of acute pneumonia are due to a lighting up into virulence of pneumococci long dormant in the pulmonary tissues ; in some instances an acute nasal or tracheal catarrh rapidly tracks down into the chest, especially when the B. influenzcs is associated with the pneumococcus, and sets up an attack 104 THE BACTERIAL DISEASES OF RESPIRATION. of acute pneumonia in those who apparently have not suffered for many years from any catarrhal affection of the chest ; while yet again, and in perhaps the majority of cases, the pneumonic attack is not preceded by any obvious catarrh of the upper respiratory passages. This is entirely a question of local immunity. I have just seen a patient from Guatemala, who tells me that every year there is a pneumonia epidemic of exceptional virulence ; he himself and others of his acquaintance have never fallen victim, but are affected by very severe recurrent catarrhs of the upper passages ; in his case these are entirely confined to the nose and post-nasal space. From these parts I have taken cultures and found thousands of pneumococci in each loopful of mucus ; with him the resistance of the pulmonary tissues is obviously very high, whereas with many hundreds of the natives it is correspond- ingly low. Of this, however, I am absolutely convinced, that in the United Kingdom the percentage of cases in which the pneumococcus persists in the lung after merely causing an acute bronchial catarrh is very much greater than is commonly imagined, and that their presence there is fraught with danger to the host. The consideration of this question will be resumed later. Bacteriology.' — Until recently the pneumococcus of Frankel was regarded as the specific and only cause of acute pneumonia ; it is now known that other bacteria are capable of setting up this condition, either alone or in combination with each other or associated with the pneumococcus ; in the last instance doubt is cast upon their getiological significance. It is otherwise when they occur alone, and it must be granted that the following may be responsible : Friedlander's pneumo- bacillus, B. influenzcB, Streptococcus mitcosus, staphylococcus, B. typJwsus, B. coli. Some of these I propose to mention a little in detail. " Friedlander " pnetimonia was first described by Philippi {Munch, vied. Woch., 1902), later by Lenhart2 (N othnageV s Spezielle Path, und Therapie, Bd. iii), by Apelt {Munch, med. Woch., 1908, p. 833), and by others, while Stiihlern {Zentral. filr Bakt., Bd. xxxvi, 1904) carefully studied forty-five cases, and Kokawa {Deut. Archiv fur klin. Med., 1904) eighteen cases, and Cordier Badolle and Brissaud (Lyon Med., April 14th, 1912) have recently reviewed the whole subject of Fried- lander pneumonia. These authorities all agree that there is a distinct form of pneumonia due to this bacillus, characterised by the great formation of mucus in the infiltrated areas, by the surface of the lung being sometimes covered with slimy exudate, by the imperfect develop- ment of " redhepatisation," this having a grey to black appearance, by the absence of marked fibrinous exudate and of hemorrhage. On the other hand there is a great tendency to massive blood infection and to THE BACTERIAL DISEASES OF RESPIRATION. IO5 the disease running a malignant course : while suppuration and abscess formation are especially liable to occur. The distribution may be either lobar or lobular. Streptococcus pneumonia appears to be almost indistinguishable from the pneumococcal variety, beginning, like it, with a rigor or pleuritic pain, and being associated with herpes labialis. The pyrexia, however, tends to be intermittent, and may persist for a considerable time, while the physical signs may be those of broncho-pneumonia. Filarelow has described four such cases, and Schottmuller {Munch, nied. Woch., 1903, p. 1427) six in which it was lobar in type. TypJwid pneumonia is regSLided by some authorities as nothing else than a pneumococcal pneumonia occurring during the course of typhoid fever, in which the presence of the pneumococcus is over- shadowed by the B. typhosus, the latter being nothing more than a secondary invader. With the statement that the pneumococcus is always present in such cases I am not prepared — perhaps on insufficient grounds — to agree. In a case of typhoid pneumonia which I have recorded {Vaccine Therapy, Edit. 3, p. 158) the bacteriological findings were B. typhosus and a few Streptococcus longus. The immediate good result produced on the lung condition by an inoculation of an auto- genous typhoid vaccine would appear to show that this organism was the important aetiological factor. Influenza pneumonia is worthy of much more study than has been accorded to it. The pneumonia supervening on an attack of so-called " influenza," this latter being much more frequently a pure pneumo- coccal or a combined pneumococcal and influenzal infection, is com- monly regarded as a fresh superimposed infection by the pneumococcus ; this is an utterly erroneous view in the great majority of cases. On the other hand, a true B. influenzce infection of the respiratory tract does sometimes culminate in a pneumonia ; this pneumonia may be due to a fresh infection by the pneumococcus, but occasionally the infection remains a pure B. influenzcs one. I have only seen two such cases; the type was broncho-pneumonic, and was characterised by prolonged high pyrexia, great constitutional depression and a malignant course, each case ending as one of lung abscess. I have entered into this aspect of pneumonia somewhat fully for the following reason, When some years ago I suggested that for immunis- ing purposes a vaccine of the various paratyphoid organisms should be combined with the ordinary typhoid vaccine I was derided by several critics ; the careful work that has since been done shows that the pro- portion of cases diagnosed as typhoid fever which are really ones of paratyphoid fever is in some localities and in some epidemics anything but negligable ; in one instance 10 per cent, and in another 25 per Io6 THE BACTERIAL DISEASES OF RESPIRATION. cent, of the cases were found to be in reality paratyphoid fever. In the same way I feel sure that accurate bacteriological examinations would show that the percentage of cases of pneumonia due to bacteria other than the pneumococcus is considerably greater than is supposed. From the purely clinical aspect this may not be of great import ; to those who contemplate the routine treatment of pneumonia with vaccines it is a matter of considerable importance. This leads me to a brief consideration of the methods whereby a correct bacteriological diagnosis may be made. There are three chief ones, viz. (i) sputum examinations, (2) blood examinations, (3) lung puncture observations. To the essential precautions which must be observed in the collection of sputum for the purposes of a bacteriological examination I have already referred on several occasions. The due observance of these will tend greatly to diminish the difficulties experienced by many observers. While it is true that sputum may be very scanty or even absent in the first day or two of the pneumonic attack, this is not often the case ; a very small quantity indeed will suffice, and careful insemination thereof on blood-agar plates will almost invariably lead to the ready isolation of the pneumococci or other organisms, no matter how few these may be. At the same time if no sputum be obtainable or a hasty examination of a stained film leads to anticipation of failure blood culture should be at once resorted to ; 10 to 15 c.c. of blood should be withdrawn from a vein of the arm with due precautions ; i c.c. should be spread over the surface of an agar plate, the balance introduced into 100 c.c. of dextrose peptone broth. The failure of some observers to secure more than 25 per cent, of positive blood-cultures I believe to be due (i) to the em- ployment of too little blood — at least 10 c.c. should be taken ; (2) to the insufficient dilution of the blood with culture fluid — the blood should be diluted eight to ten times ; (3) to the use of ordinary broth instead of broth containing 2 per cent, dextrose. Occasionally incubation has to be continued for forty-eight hours, but this is very rarely so. Some observers have obtained positive blood cultures in 80 per cent, of cases, and it would appear that there is in the first few days a true bacteriasmia ; in the case of " Friedlander " and " typhoid " pneumonia vast numbers of the bacteria may be present in the blood. The procedure for lung puncture I have already described on p. 10. By a judicious combination of these methods I believe that a reliable diagnosis of the true infective agent may be made in every case without exception. THE BACTERIAL DISEASES OF RESPIRATION. lO/ Tlie Prophylaxis of Pneumonia. If the view I have already enunciated as to the manner in which many cases of acute pneumonia originate be correct, it at once follows that no case of respiratory catarrh due to the pneumococcus, B. influenzcB, streptococcus or B. of Friedlander is to be lightly regarded or to be considered as cured so long as there is any sputum in which the organism can be discovered, or so long as any physical signs persist in the chest. Treatment by means of vaccines must be continued until complete disappearance of the infection is secured ; and if this cannot be effected, as will sometimes prove to be the case, then the patient's immunity must be maintained at as high a level as possible by the administration of two or three fall doses of vaccine at seven-day intervals, say, every four months. I have in this way kept entirely free from all catarrhal attacks during the past three years a well-known personage who first consulted me at the age of eighty-four. His pneumococci have never, so far as I know, entirely gone, and I have considered it my duty to warn him that sooner or later they will make their presence felt if he allows his immunity to fall unduly. Another important point in such cases is that the factor which, above all, probably decides the lighting into virulence of the dormant pneumococci is the incidence of a fresh infection by some other catarrhal micro-organism ; chief among these is undoubtedly the B. infliienzce, probabl}- also the streptococcus and M. catarrhalis, and it is owing to this fact that an epidemic of influenza is nearly always attended by a greatly raised m.ortality, due to acute pneumonia. At the same time it must be admitted that a pure invasion of any part of the respiratory tract by the B. infliLenzcE is comparatively rare ; there is nearly always some other associated microbe and this is usually the pneumococcus, so that a certain percentage of the cases of pneumonia encountered during a so- called influenza epidemic are really due to a fresh infection by the pneumococcus associated with the B. influenzcs. In such cases the employment of the suitable vaccine in the first stages of the infection before the bacteria have actually located themselves in the pulmonary tissues would, I venture to affirm, almost entirely prevent the onset of pneumonic attacks, and many valuable lives would thus be saved at every such epidemic. The Pathology of Acute Pnetnnonia and its Bearing on Vaccine Treatment. Before it is possible to use vaccines in this condition with any prospect of achieving thoroughly satisfactory results, it is essential to io8 THE BACTERIAL DISEASES OF RESPIRATION. have a perfectly clear idea of the pathology of the disease and how recovery is brought about. In the first stage, that of congestion, the capillaries are dilated and tortuous from distension with blood; the air-cells are net as yet completely airless, but are more or less filled with frothy reddish serum albumen ; the supply of opsonin and other anti-bodies in the circulating fluids is below the normal, the leucocytes as a rule considerably above the normal. During the second stage, known as red hepatisation from the Chart XIII. ^ 1 - n n F ^4 ( R' Vn 17^ fil*J,S F" " -1 Ml 1 J 1 ^ d , , I , , /-, / ^'h " ^ M £ M , M B „ c J „ „ E „ E „ f M t n E n f irh s q \ \ A 10^ 'f' \ >, \ / ^ A / ■', \ 1 ., \ / / s J ^ \ 1 ii r "H 101 f-^ V ' s H» > f >« ^'' / ' ^- -' 1 "•v ' ^ A », ,f ^ j \ . — — -. J / 1 \ of* fl'n •5 O^ Si V ,\, ^ K r Vv -/ \ , V L' r\'r P tlM 10! .1, i» :U iji nl lit M ISi lie »s .« (ii 1^ ,„, tt ii ,fc It Si qj S« ,» 1J ^i Re T atl rf*^t "L »<. .o « 3» fcj si si ££j St (s tc ij 5o - .i" 34 it »» M [^ ii it _; Relation between Leucocytes, Opsonic Index, and Temperature in a Case OF Pneumonia (Eyre). Dotted line = number of leucocytes per cubic millimetre ; thick line = opsonic index ; thin line = temperature. resemblance which the lung then bears to the liver, the organ is of a dull red colour, finely granular in section, completely airless, solid, and sinks in water. The contents of the alveoli consist of coagulated fibrin which holds in its meshes red blood-cells, leucocytes, exfoliated epithelium and bacteria. Although the capillaries are much com- pressed, they for the most part remain pervious. The supply of anti- bodies remains low, and the leucocytes in the circulating blood have fallen considerably, although they may still be above the normal ; this fall may be due to the vast numbers stored up in the pulmonary tissues. The stage of red hepatisation passes into that of grey hepatisation, the change of colour being brought about by the extravasated red corpuscles losing their haemoglobin, by the stasis of the circulation THE BACTERIAL DISEASES OF RESPIRATION. lOQ through the capillary vessels of the alveoli, and by the increased number of leucocytes which crowd the air-cells and alveolar walls; the leucocytes in the blood-stream have now fallen to their minimum. In cases which pursue a normal course, this stage of " grey hepatisation " so rapidly passes into that of " resolution " that it may be regarded as the stage of commencing resolution; the leucocytes and exfoliated epithelium undergo granular and fatty degeneration, the fibrin softens and is absorbed, the capillary circulation becomes actively re-established, the alveoli again contain air, and the alveolar epithelium Chart XIV. Days of disease I 2 S 4 5 6 7 3 9 so n E2 SS t4- fa •7 •6 •5 •4 •S •2 Types of Reaction of the Opsonic Index in Pneumococcic Infection (after Eyre). (rt) Immediate rise as seen in mild infections ; (6) delayed rise ; (c) progressive decline as seen in severe and fatal infections. is regenerated. The commencement of this process of resolution would appear to coincide in point of time with the sudden fall of temperature, occurring in nearly 50 per cent, of cases, known as the "crisis," and with the sudden rise of leucocytes and immune bodies in the general blood-stream. The annexed chart, No. 13, of Dr. Eyre"s shows well the relationship between temperature, leucocytes and opsonic index at the various stages of the attack ; while chart No. 14 shows the course of the opsonic index in cases {a) in which the fall of temperature is by crisis, {h) where it is by lysis, (c) where the case proceeds to a fatal issue. The chief factors concerned in the processes of cure are (i) leuco- cj'tes, (2) endothelial cells of the alveoli, (3) opsonins, (4) antitoxins, no THE BACTERIAL DISEASES OF RESPIRATION. agglutinins and other immune bodies. As we have seen above, the opsonic index yields a very fair indication of the progress of immunity, and the extinction of the infective agents would appear to depend largely upon the action of opsonin which is chiefly of the thermolabile variety. The phagocytosis, however, is not, as might be supposed, carried out in the main by the polymorphonuclear leucocytes, which, as we have seen, have so largely increased in numbers at or just before the crisis, but, as De Jong has pointed out, by the endothelial cells of the alveoli, many of which become transformed into macrophages. The chief role of the leucocytes would appear to be the formation and excretion of ferment for the solution of the fibrin filling the alveolar cells; this would appear to be the explanation of the great storing up of leucocytes in this locality. It is now well recognised that the rapid respiration and high tem- perature so characteristic of pneumonia are due to a poisoning of the nerve-centres by the endotoxins liberated by the death of the pneu- mococci, this same agent being also responsible for changes in the musculature and nerve control of the heart, which may lead to circulatory failure even when convalescence appears to have been well begun. The satisfactory elaboration of the corresponding anti- bodies is therefore a very essential factor for recovery, and the pro- duction of the "crisis" is dependent upon the elaboration of such antibodies, which appear to be inoperative until they reach a certain concentration ; in such cases it seems that the reaction between toxin and anti-toxin must be " all or nothing," and so bears no resemblance to the neutralisation "in vitro''' of diphtheria toxin by antitoxin. In cases where recovery is by lysis the neutralisation must be more gradual. Let us now consider what bearing these various facts have upon the application of vaccine treatment to this disease. Our objective must be a two-fold one — to kill the bacteria and to neutralise their toxin. The question is, Are these possible of attainment ? The answer is, This depends largely on the stage of the disease, the virulence of the infection and the responsive powers of the individual. In the stage of pulmonary congestion the bacteria are circulating in the blood-stream, and are present in but scanty numbers in the pulmonary tissues ; the resisting power of the body has been obviously broken down, and bacteria circulating in the blood-stream do not appear to be capable of leading to the elaboration of antibodies ; there is thus both a local and general defect of these, but at the same time the amount of toxin formed is not considerable. If, therefore, the bacteria could be exterminated the disease process would be ended. It is now well recognised that the introduction into healthy subcutaneous or muscle tissues of a therapeutic dose of vaccine will lead to the THE BACTERIAL DISEASES OF RESPIRATION. I I I speed}^ elaboration of the corresponding antibodies. A vaccine of pneumococci is but slightly toxic, and its administration leads to the elaboration of considerable amounts of opsonin, which is chiefly of the thermostable variety, and of a small amount of antitoxin. The fact that this is precisely what is then required is the strongest possible argument for the employment of a vaccine at the very inception of the attack. It is true that the virulence of the infection then is high, but so is the responsive power of the individual. Unfortunately there are two obstacles to this procedure: (i) the fact that the opportunity does not always present itself, many cases not being seen till the disease pro- cesses are further advanced ; (2) the refusal of medical men to re- cognise every case of pneumonia as potentially a fatal one. When consolidation has occurred bacteria are still often to be found in the blood-stream, but their multiplication in the pulmonary tissues has much advanced : here they are enclosed in a meshwork of fibrin, in a warm nidus admirably suited to their growth ; the blood and lymph supply being more or less in a state of stasis, even if the amount of immune bodies in the body generally is niore than adequate these are not available, or only to a limited extent. No immediate material good might therefore be anticipated from increasing" them by means of a therapeutical inoculation ; that good does sometimes result therefrom is due to the fact that all portions of the infected lung are not in the same stage ; one area may be in a state of congestion, another in that of red hepatisation, and yet a third in that of commencing resolution. The main objective, therefore, is to relieve the strain on the heart's musculature as much as possible by lowering the viscosity of the blood with full doses of citric acid, by dilating the blood-vessels locally by the application of heat, etc., and by relieving the general blood-pressure by promoting free diaphoresis and action of the bowels, and if necessary by bleeding. At the same time we may increase the amount of anti- bodies, both antitoxic and antibacterial, and the number of leucocytes against the time when commencing resolution may enable them to be carried to the battle front. Resolution wall inevitably entail the free liberatian into the re-established circulation of quantities of toxin which have been stored up in the consolidated tissues ; hence it is very im- portant now to ensure that the leucocytes and various antibodies can reach the infected areas with the least possible difficulty, and to preserve the heart musculature as much as possible from the action of the bacterial toxins. Were a really reliable antitoxic serum available for the neutralisation of the toxins, the combination of serum and vaccine could hardly fail to prove of the utmost value during this period of resolution. Unfortunately the best available sera, Romer's and Pane's, appear to leave much to be desired ; their defects may, however, be I 1 2 THE BACTERIAL DISEASES OF RESPIRATION. more apparent than real, failures with them being perhaps as much due to their improper use — viz. insufficient dosage and non-systemic administration — as to any intrinsic imperfections. The administration of a vaccine when resolution is impending will prove of immediate service provided that — (i) The supply of anti-bacterial bodies is otherwise insufficient. (2) The tissues are capable of responding to stimulation, and this they almost invariably are. (3) The heart mechanism is sufficiently strong to withstand the attack of the toxins so copiously liberated during this stage. As we have seen, the production of the " crisis " is due to the massive neutralisation of toxin by antitoxin. Hence it is that a small dose of vaccine may at one time suffice to produce an immediate reaction as evidenced by crisis occurring and at another time may appear to fail. The power of a vaccine to stimulate the formation of antitoxin is but slight ; hence if the defect in antitoxin is small the addition of a small quantity will suffice, but if the defect be great a much increased dose of vaccine may fail to produce the additional amount requisite to make good the considerable defect ; the total amount of antibody then present being the sum of the amounts produced so far by natural means plus the amount produced b\^ the inoculation of the vaccine requires further supplementing, either by the natural response of the body to the infection or to the stimulation of another dose of vaccine, or by both these means. As has been already mentioned, when the fall of temperature is by lysis this massive neutralisation of toxin would not appear to occur, and it is worth}^ of note that the proportion of cases in which " lysis " occurs rather than " crisis " appears to be greater in vaccinated than in unvaccinated cases. These conclusions may be briefl}^ summarised as follows : (i) The administration of a vaccine in the earliest stages of a pneumonic attack can hardly fail to be productive of good in a very considerable percentage of cases, for thereby is ensured the formation of adequate bactericidal bodies, and these are precisely those which are of service at this period of the disease. (2) The administration of a vaccine during the period of consolida- tion theoretically can hardly be productive of immediate good, but the resultant immune bodies may prove of considerable service once " resolution " has begun. Owing, however, to the fact that the stage of the disease may vary considerably at different foci, the good resulting from vaccine treatment may be much greater than might be anticipated. I cannot help feeling that these are the cases where the fall of tempera- ture is by " lysis." THE BACTERIAL DISEASES OF RESPIRATION. I 1 3 (3) The administration of a vaccine during the period of resolution will prove of service especially if resolution be delayed, and if the supply of bactericidal bodies be otherwise insufficient. It must, however, be clearly borne in mind that no vaccine treat- ment will prove of service unless — (i) The vaccine be the proper one and be properly prepared. It is no use employing a pneumococcal vaccine in a streptococcal or Friedlander infection, nor is it any use employing a vaccine devoid of immunising properties. I have already mentioned that some strains of pneumococci yield a good vaccine only when heat is used to ensure sterility, others only when sterilised with antiseptic. Experience has also shown that an autogenous vaccine is preferable to a stock one, but there is much to be said in favour of beginning treatment immediately with a stock polyvalent vaccine of proved immunising powers. While some avirulent strains of the B. diphthericB yield the most potent antitoxin, and some strains of the B. typhosus of very low virulence the most powerful vaccine, with the pneumococcus the more highly virulent the strain as a rule the more potent is the vaccine. The pneumococci isolated from a given case of pneumonia may vary much in virulence amongst themselves ; it is, therefore, obvious that in the preparation of an autogenous vaccine, cultures should be taken, not from one, but from numerous colonies. (2) That adequate dosage be employed. Two things that have especially struck me in reading the clinical histories of cases reported by those who have failed to secure satisfactory results have been — {a) the inadequate dosages : for instance, in the record of nineteen cases by one observer I find that nine cases did not receive a dose of even 5 millions, and only one case a dose of 25 millions ; this is little more than playing with vaccine treatment. (b) The tendency to reduce subsequent dosages when the patient fails to make any response to a first dose, which, in fact, was itself quite an inadequate one judged b}^ the experience of all those who have achieved good results. Failure to respond in any way to a given dosage is an indication, not for reduced, but for increased subsequent doses. I might also add that increased toxemia has been at times regarded either as a bad effect or as indication for diminished dosage — in reality it may be neither. It is an indication for promoting neutralisation and excretion of the toxins by every available means, and it may also be indicative of hastening resolution and consequent increased absorption of the toxins into the general circulation, but it certainly is not indica- tive of postponing further inoculation or of diminishing the dosage : is may be so in the case of some infections, but above all, is this not the I 1 4 THE BACTERIAL DISEASES OF RESPIRATION. case with pneumococcal infections ? The toxic contents of a pneumo- coccal vaccine are so small that the amount so introduced into hea thy tissues is without effect on the circulating mass, and only leads to the elaboration of the corresponding antitoxin, while the stimulus to the formation of opsonin, and so to the phagocytosis of the bacilh and neutralisation within the macrophages and polynuclear cells of their endotoxins, is very great. Personally, I have never seen a pneumo- coccal vaccine do any injury to a patient ; per contra I have seen several cases of persistent hyperpyrexia with low muttering delirium, one or two apparently comatose, make almost immediate response to an inoculation of 25 or 50 millions — it is true that these were cases with marked bacteriasmia, but this I think they often are. In conclusion, I will briefly summarise the procedure which has been found by most experienced observers to be the best, and give a short resume of the results they have obtained. Procedure. (i) Take sputum smears and cultures : if in early stage blood- cultures, if in advanced stage perform a lung puncture, and proceed to preparation of an autogenous vaccine. (2) Immediately administer a dose of not less than 25 millions of a polyvalent stock vaccine, prepared from virulent strains and of proved immunising power. (3) If no definite response within thirty-six to forty-eight hours, repeat above dose of stock vaccine, or preferably of the autogenous vaccine if this be ready. (4) If still no response, administer double the above dose in thirty- six to forty-eight hours ; if response, as evidenced by improved clinical signs and symptoms and increased well-being of the patient, defer- re-inoculation for three days, or until the first signs of retrogression in the general condition or clinical signs and symptoms. (5) Maintain dosage or even increase it, and continue inoculations at intervals of three to four days, until the patient is perfectly well. (6) If the patient at any time takes a sudden turn for the worse, make diligent search above all for such complications as may require surgical interference. It may be advisable in such conditions to suspend specific treatment, but immediate reinoculation, perhaps with an increased dosage, may be more likely to be productive of good. (7) Use every known means throughout of securing toxic elimination, of sparing the heart from needless strain, and of tiding it over the period of greatest stress. Resume of results obtained by various observers and their conclusions. — THE BACTERIAL DISEASES OF RESPIRATION. I I 5 Although I have always been one who thinks that far too much regard can be made in medicine to statistics which may be inherently falla- cious, yet none the less it is certain that every form of treatment will, be judged by the case mortality and incidence of complications experienced during its employment. The pathogenity of the Pneumo- coccus and so the death-rate varies greatly in different epidemics, and such factors as age and previous habits of the individual are well known to be important prognostic points, so that if statistics are to have any value an adequate number of truly comparable cases treated upon orthodox lines are essential to serve as controls — this unfor- tunately is not always possible, and where it cannot be done the assumption must be made that the death-rate would have otherwise approximated to the normal, which may be taken as between 16 and 20 per cent. Wolf {Journal of Infectious Diseases, igo6^ p. 739) treated 14 cases with vaccines during an epidemic in which the total mortality was 40 per cent. II of the 14 cases, or 78*5 per cent., recovered. 3 .> M ,, 21-5 „ died. In 10 of the II cases which recovered the crisis occurred within thirty-six hours of the first inoculation. Leary {Boston Med. and Surg. Journ., 1909, p. 714) records his results in 83 cases. Of these, 34 were alcoholics in whom the normal death-rate was 50 per cent. Of these 34 cases only 5 died — a mortality of 177 per cent. Of the other 49 cases only 2 died— a mortality of only 4 per centc The death-rate among the whole 83 = 9*7 per cent. Rapid relief of toxasmic conditions was noted, and in cases of otherwise uncontrollable delirium the abatement thereof was prompt. Craig {Medical Record, November i8th, 1911) records his results in 20 cases among old sailors, all over 60, most much older (80-90 years old). Most were alcoholics, nearly all had chronic nephritis, arterio- sclerosis and dilated hearts. The average death-rate in the institution for the preceding five years from pneumonia had been 65 per cent. Yet of these 20 only 4 died, a death-rate of 20 per cent., and of these 4 only I died directly from the pneumonia, this being a very severe case of bilateral disease ; of the other 3 cases one was already complicated by purulent pericarditis, and another by acute uraemia and acute dilatation of the heart. Charteris {Glasgow Med. Journ., January, 1912, p. 19) obtained much less favourable results in 19 cases. Ten simultaneous cases which seemed on the point of crisis were used as controls. His conclusions were that the administration of a stock pneumococcal vaccine had no marked effect upon the subsequent course of the disease, the mortality I 1 6 THE BACTERIAL DISEASES OE RESPIRATION. being practically identical — 20 per cent, in the two series — that the early administration of vaccine did not abort the disease nor prevent complications, and that complications were relatively frequent in the vaccine series, viz. i case of meningitis, 2 of empyema, and i of hyperpyrexia. It is very easy to be critical and perhaps do injustice to other people, but a study of the paper leads to the following criticisms : (i) That the use of cases obviously about to crisis as controls is quite inadmissible. (2) That of the four cases which died two were alcoholics who were delirious or aemi-conscious when treated. (3) That in only eight of the nineteen cases was a dosage of 10 millions of a stock val;cine exceeded ; in eight of the cases it was under 5 millions. (4) That in two of those that died an initial dosage of 20 and 18 millions respectively was reduced subsequently to 10 and 2 millions respectively, although all the indications that can be gathered from the clinical histories were for maintaining or even increasing the dosage. For these reasons I regard his conclusions as fallacious, his controls are inadmissible, and all that the paper shows is that the administra- tion of a stock vaccine in doses already well known to be inadequate failed to reduce the mortality below 20 per cent. Parry Morgan [Proc. Roy. Soc. of Med., vol. iii. No. 9, Supplement, p. 165) treated 43 cases with 2 deaths — a mortality of 5 per cent.; one of these two died from nephritis after the pneumonia had subsided. Treatment was begun at periods of the disease from the second day onward, some cases being treated with stock vaccine, some with autogenous ; one of these latter cases proved to be a streptococcal infection. In many cases he repeated doses of 50 millions of auto- genous vaccine and never saw any harm result, but he inclines to the view that a dosage of 15 to 30 millions gives the best result in the average adult. When an artificial crisis was not produced the temperature often fell by lysis, with marked improvement in the symptoms. For seven of the most interesting cases as being complicated ones and the most convincing the original account should be consulted. From the experience gained in the treatment of these cases, Morgan says that the temperature may be a guide but often is not, one of the most noticeable features being the improvement in the general condi- tion without much change in the temperature ; the anxiety which one often feels for a patient is relieved, sleep comes readily, the appetite improves, and even if the pulse-rate does not fall its strength is well maintained. At other times there is a fall in the temperature soon after the dose, sometimes even in a couple of hours ; if this is the case another dose is indicated when the temperature rises again. THE BACTERIAL DISEASES OF RESPIRATION. I I J If there is no change in twenty-four hours the dose should be repeated, sometimes being increased, but more often decreased ; between subsequent doses a longer interval may be left. For various reasons he finds the opsonic index is frequently quite unreliable as a guide to the progress of immunity in pneumonia, and feels that some other mjeasure of it is much to be desired. Butler Harris {Brit. Med. Journ., June, igog, p. 1530, and Proc. Roy. Soc. of Med., vol. iii. No g, Supplement, p. 103) considers that— (i) Successful inoculation for pneumonia is possible. (2) Inoculation does no harm. (3) A vaccine from one or a number of virulent strains should be used. (4) It should be introduced as early as possible. (5) The estimation of the opsonic index is not necessar}-. (6) The observation of the temperature and physical signs is a sufficient guide to the repetition of the dose. (7") Infections of the lung by the pneumococcus which fail to resolve after an acute pneumonia, as well as pneumococcal infections of other areas, ought certainly to be treated with a vaccine. He found that a dose of 20 to 50 millions might be given without harm, that usually a fall of temperature was produced in a few hours. that frequently it rose again, but not to the same level, and that it was often necessar}- to repeat the inoculation once or twice. He is con- vinced that usually a distinct reaction in favour of the patient is produced, and that it is wise to begin inoculations before the nervous mechanism suffers much inhibition. In the sequelfe of pneumonia he considers the use of a pneumococcal vaccine as sure of a good result as that of a staphvlococcal one in case of boils. xA.fter comparison of the clinical histories of his cases with those of Craig and of Parry Morgan he finds that the effects seen b}- each of them as produced by bacterial inoculations in cases of pneumonia are practicallv identical, and considers that every case of pneumonia should be from the outset regarded, as possibly a fatal one, and suggests that a stock vaccine of proved immunising power should always be employed as earh' as possible in a dose not exceeding 20 millions, and that the preparation of the autogenous vaccine should be at once proceeded with. This collective evidence is surely sufficient to warrant the unpreju- diced in giving a fair trial to vaccine treatment of cases of pneumonia. What he is entitled to expect and what he is not entitled to expect therefrom has been fairly laid before him. It only remains for him to pay due heed to the various considerations, to utilise common-sense and clinical experience, and to be prepared to judge results with due impartialitv. I I 8 THE BACTERIAL DISEASES OF RESPIRATION. Unresolved Pneumonia. As we have seen, the leucocytes are held to be the chief agent in the production of resolution by means of ferment which they liberate ; hence the rational procedure in a case of unresolved pneumonia would seem to consist in the promotion of a leucocytosis, and the determination of a leucocyte flow to the infected area by fomentations, blisters and other means. Whether it has been actually observed that cases of acute pneumonia showing a relatively defective leucocytosis are especially apt to resolve badly, and that there is a leucopsenia, relative or absolute, present after failure to resolve, I know not ; observations upon these points might perchance repay the clinician for his trouble. Furthermore, as we have already seen, it is hardly reasonable to expect that the administration of a vaccine will have much immediate effect during the stage of consolidation in an acute attack. For these two reasons it would seem hardly reasonable to expect that a vaccine should have much immediate effect upon an unresolved condition. The- blood and lymph stasis is, however, not then so complete as at the height of consolidation, some attempt has been made at the re-establishment of the circulation. It therefore follows that some good may be expected to accrue from a course of vaccine treatment. It must, however, be remembered — (i) That even if the infection were an unmixed one at the inception of the attack it is hardly likely to have remained so. The streptococcus or M. catarrhalis will almost certainly complicate the picture, and to these attention may have to be directed. In the few cases which I have myself investigated a mixed infection has been always present, and I have thought it the better practice to employ a mixed vaccine. (2) That progress necessarily must be somewhat slow. (3) That the production of local reactions in the infected tissues is essential to cure, and that such dosages must be used as will produce this effect. A 50-million dose of any of the above three organisms will do to begin with, but should stethoscopic observations and clinical symptoms show failure of local reaction this dosage should be increased. Personally I have found ultimate doses of 500 milhons essential to complete cure. Periodic examinations of the sputum should be made to check pro- gress and eliminate the possibility of a new infection having been incurred, and to ensure the continuance of treatment until the pneu- mococcus has entirely disappeared from the sputum. In one very interesting case of mine it took four months' treat- ment to bring about a satisfactory clinical condition, and an additional eight months to secure the desired bacteriological result. THE BACTERIAL DISEASES OF RESPIRATION. II Q Empyema, Lung Abscess, etc. There is nothing specially to mention as regards the vaccine treatment of these conditions. Treatment will be guided by the considerations which govern the procedure in all cases of abscess formation and of sinuses in the body generally. Prevention, as always, i% better than cure, and that a considerable reduction is effected in the incidence of these .and other complications by the early application of vaccine treatment to all cases of pneumonia is agreed on by all who have had mature experience of this procedure. In the case of lung abscesses especially is the bacteriology apt to become a very complicated one as times goes on. Streptococcus. M. catarrhnlis, B. coli, B. proteiis, B. pyocyaneus, B. infiitenzcB, M. tetragenus, and B. of Friedlander are a few of the acces5or\- microbes which may make their appearance, and in the preparation and use of the autogenous vaccines considerable discrimination and care may be required. Free drainage is a sine qua non to cure in cases with external openings, and there might seem to be reasonable grounds for the fear that vaccine treatment might bring about closure of the vent or sinus, and induce local accumulations of pus. In practice it would appear that this danger ma}' be easily exaggerated. I remember one patient whom I was treating with a mixed pneumo- coccus, streptococcus, B. influenzcB vaccine for chronic antral trouble, who was also suffering from an old lung abscess, which sometimes dis- charged by bronchus as well as through a persistent external sinus, expressing great anxiety when he found that what he regarded as his safety vent was closing up. I reassured him and treatment was continued, with the result that he has not lost a day's work for two years, and that antrum and lung abscess have caused no further trouble. None the less is it wise whenever possible to make sure that any sinus is healing from the bottom by occasional probing and the instillation of citrated salt solution. Small dosages are best at the beginning of treatment, but as time goes on they should be increased with boldness ; a slight constitutional reaction and alteration in the character and amount of discharge are the best indications of adequate dosage. Broncho-pneumonia in Children. This condition will, I venture to predict, prove one of the most proiitable of all fields for the worker in vaccine therapeutics. Ignorance of what constitutes the defensive mechanism in young children against bacterial invasion has led to a somewhat natural reluctance to apply I20 THE BACTERIAL DISEASES OF RESPIRATION. methods applicable to the adult. The results achieved in the treat- ment of whooping-cough, gonorrhceal vuivo-vaginitis and conjunctivitis show clearl}^, however, that children, and even infants, do respond readily to therapeutic inoculation. In broncho-pneumonia we have a disease of such high mortality that ample justification exists for endeavours to find some specific form of treatment. The consolidated areas are not,»as a rule, so large that any considerable stasis of the circulation results, as in the case of lobar pneumonia, and upon this fact additional hope of success maybe based. Peculiar difficulties, however, present themselves. The bacteriology is a much more variable one than in the case of lobar pneumonia. Pneumococcus, streptococcus, B.influenzce, B. of Friedlander and per- haps the staphylococcus and other organisms may be responsible for the condition, either singly or in any combination. If vaccine treat- ment is to be resorted to, it is obvious that the precise nature of the infection should be determined. Unfortunately children are very apt to swallow sputum, and it may be impossible to get specimens for examination ; if they can be got, then all, so far, is well ; if they can- not, lung puncture is also liable to prove a failure owing to the small size of the consolidated areas ; blood-cultures might prove of service, but so far as I know no observations have been made in this direction. If specimens of sputum can be obtained, the best procedure would appear to be to make examination at once of stained smears, and administer stock vaccine of proved immunising power corresponding to the infection found while the autogenous vaccine is in course of pre- paration. If no specimens are obtainable and lung puncture and blood- culture fail, then I think it will be more than justifiable to employ a stock vaccine of the following composition : In each c.c, pneumococcus, 10 millions; streptococcus, lo millions; B. influenzce, 20 millions; B. of Friedlander, 20 millions ; the dosage to be, under three years, 2 minims ; three to five years, 4 minims ; five to seven years, 6 minims ; over seven years, 8 minims, the indications for repeating or increasing the initial dosage being general condition in the first place and temperature in the second. As a general rule young children bear relatively high dosages of vaccine extremely well. Of published results achieved in broncho-pneumonia there are none as yet available, but one or two private communications which I have received are very favourable to this therapy. CHAPTER IX. VACCINES IN WHOOPING-COUGH, DIPHTHERIA, PYOR- RHCEA ALVEOLARIS, HAY-FEVER, OZ^NA, AND RHINOSCLEROMA. (a) Whooping-cough. That the bacillus of Bordet-Gengou, described on pp. 31 and 32, is the true specific cause of whooping-cough is now generally accepted, the various serum reactions affording strong confirmatory evidence. Early in the attack the Bordet bacillus appears in great numbers in the secretions, but the careful investigations of Freeman and of Martha Woolstein into the bacteriology of this disease have shown that even then it has very frequently associated with it the B. influenzcs, and often the pneumococcus ; the great liability to such complications as bronchitis and broncho-pneumonia is thus explained in precisely the same way as the liability of so-called influenza attacks in the adult to develop into acute pneumonia. As early even as the end of the second week the Bordet bacillus has almost disappeared from the secretions, whereas the B. influenziS and pneumococcus, and perhaps the streptococcus and M. catarrhalis. have increased considerably in numbers. A pure infection is so rare an occurrence that the symptoms referable to the Bordet bacillus alone may be almost said to be unknown. The bearing of this upon the vaccine treatment of whooping-cough will be dealt with present!}-. The first attempt at the establishment of immunity to the disease was made by Bordet about ten years ago. He inoculated twelve healthy children with large doses of a vaccine; very soon afterwards they came in accidental contact with a case of whooping-cough, with the result that they all immediately fell victims to very severe attacks of the disease. The explanation of this occurrence is now taken to be that contact took place during the period of lowered resistance (or " negative phase ") consequent upon the use of very large doses of the vaccine. This view presented itself to Freeman, and on p. 97 of the Proceedings of the Royal Society of Medicine, vol. iii, No. g, supple- 122 THE BACTERIAL DISEASES OF RESPIRATION. ment, he gives a detailed account of the many careful observations which he made in order to determine the correct therapeutic dose. Doses varying from 2 to 120 millions were employed, the final con- clusion being that a dosage of about 100 millions gives the best results, and that a weekly repetition is quite safe. By these means he found that the average duration of the disease in his vacci- nated cases was reduced to 4*3 weeks as compared with 7*4 weeks in those who received inoculations of saline solution and served as controls. It must be remembered that many of these cases were treated with dosages which Freeman now recognises to be inadequate, and that no specific treatment was directed against the complicating organisms, such as the pneumococcus and B. influenzce. This he now advises shall be done as a matter of routine, and my own limited personal experience is entirely confirmatory of the correctness of this procedure. The following scheme of dosage may be safely followed : Age. B. Bordet. Under i year ... 25 1-2 years . . . . 50 2-3 „ . . . ; 100 3-7 „ . . . . 100 Over 7 ,, . . . 100 Reinoculation may be performed at intervals of five to seven days, and at the third inoculation a double dosage may be employed if thought advisable. As a prophylactic the initial dosage corresponding to the age may be doubled in seven days ; and this again doubled if thought advisable after another seven days. The employment of the above combined vaccine for this purpose may also be expected to diminish the liability to broncho-pneumonia, and is devoid of all risk. As to the duration of the immunity thereby conferred we as yet know nothing ; probably it is about six months, so that two series of inoculations yearly may suffice to confer the desired protection. Saunders and collaborators have described {Pediatrics, March, 1912) their results in forty cases of w^hooping-cough and in fourteen children who had been exposed to contagion. They also began with small doses, viz. 5 millions, but soon concluded that the dose was too small and increased it to 10-20 millions, repeated as required. Despite the fact that this increased dosage is still an inadequate one, they obtained results which led them to the following conclusions : (i) That as a prophylactic the vaccine has a decided value ; that whilst it is true that vaccination or some other infection will postpone B. influenzce. P neumococcus 10 2 25 5 50 5 50 10 100 10 THE BACTERIAL DISEASES OF RESPIRATIOX. 1 23 or interrupt the course of pertussis, vaccine alone will absolutelv prevent it. The immunity is of uncertain duration, but the injections may be repeated and it is of the utmost importance to postpone the disease until the child has passed the age of two. The failures reported bv some observers must be attributed to an impotent vaccine or to insufficient dosage. (2) That as a remedial agent success depends upon the promptness of administration and the freedom from complications at the time. (3) In no case should other treatment be withheld if indicated, especially in infants, who may be spared convulsions or broncho-pneu- monia by the use of emetics, sedatives, or some aromatic compound. (,4) It is quite possible that much better results may be obtained in late cases by the use of larger doses {and the combination of vaccme directed against the allied organisms). (5) That in view of the high mortality from pertussis in 3'oung children there should be a systematic effort made to determine the duration of artificial immunity and to keep them protected. (b) Diphtheria. Diphtheria from the point of view of the vaccine therapist is a disease exhibiting several points of especial interest, and it is therefore singularly strange that so little attention has been devoted to its study in this direction. In the lirst place we are in some doubt as to wherein lies the defen- sive mechanism of the body against the B. diphtherics. AVright has stated that there is no opsonin in the body fluids for this bactermm. Ruth Tunnicliffe, however, finds that the process of recover}- runs parallel to, and is due to a rise in, the opsonic index, and that the main factor in the cure of the disease is the removal of the bacilli by phago- cytosis and consequent cessation of the absorption of toxin. Antitoxin formation seems to play a ver\' subsidiary- part, for recovery is often well advanced before antitoxin can be detected in the blood — in fact it is sometimes apparently absent throughout. Emery {Immunity and Specific Therapy, p, 409) says : '• The observations referred to previously show clearly that the process of cure of the local lesions is assisted by the production of an opsonin. And there is every reason to believe that it is b}' phagocytosis that the bacilli are combated, bacteriolysis being very doubtful and of comparatively small importance. The cure of the disease is dependent, therefore, partly on antitoxin formation and partly on phagocytosis." Against this, however, is the fact that phagocytosis of the diphtheria bacillus is very rarely seen in smear preparations made from the local lesion. 124 THE BACTERIAL DISEASES OF RESPIRATION. In the second place this is a disease in which conspicuous success has attended the use of antitoxin serum both in the direction of dimin- ished mortahty and of diminished comphcations. This serum, however, appears to be solely antitoxic and quite devoid of anti-bacterial properties. In the third place recent investigations are showing more and more clearly how important are so-called "carriers," i. e. those in whom the bacilli persist locally after the subsidence of all clinical symptoms in the initiation of diphtheria epidemics. The statement has been made that other bacteria, such as the strep- tococcus and staphylococcus play an important part in causing the dis- appearance of the B. diphthericE from the throat, etc., after an acute attack, and the proposal has emanated, I believe from Germany, that the process may be hastened by spraying the infected parts with living broth cultures of the Staphylococcus aureiLS. Good results have been reported by one or two observers, but I cannot but feel that the method is fraught with danger and is quite unwarrantable. Walton Smith {Australian Med.. Gaz., October 20th, igio, p. 543) gives details of the vaccine treatment in the case of a girl in whose throat the B. diphthericB persisted for fifteen weeks after antitoxin was given, recovery being otherwise complete. The first inoculation with 6 millions B. diphtheria and 10 million staphylococcus (as this organism was also present) resulted within twenty-four hours in the production of a well-marked reaction at the site of injection, in some general dis- turbance and a temperature of 100*2° F. A week later the bacilli were still present, so an inoculation of 8 million B. diphtherice was given. The reaction was ver}' slight on this occasion. Subsequent examinations of the throat secretion failed to show the presence of any Klebs-Loeffler bacilli. The suggestion that vaccine treatment might be combined with antitoxin seems reasonable, especially in cases where the bacilli tend to persist, and there is some ground for hoping that late complications may thereby be minimised. It must be left to future observation to decide whether further combination of a vaccine of the predominant allied organism, streptococcus, staphylococcus or M. catarrhalis, is also advisable. The initial dose of the diphtheria vaccine should not exceed 5 to 10 millions for the present ; future observations may, however, show that higher dosages are advisable and devoid of danger. (c) Pyorrhoea Alveolaris. A very great amount of bacteriological research has been devoted to this disease, and numerous reports have now been published of the results of vaccine treatment. These are almost without exception THE BACTERIAL DISEASES OF RESPIRATION. 1 25 highly favourable, but I must confess to considerable scepticism. In the very earliest stages, before pus pockets are definitely formed, strict attention to oral hvgiene, careful local treatment by a thoroughly competent dentist who has time to devote to tedious scaling and polishing, perhaps combined with vaccine treatment, may suffice for cure ; by " cure " I mean cure beyond recurrence, provided that the patient does his duty for the rest of his natural life and pays a visit ever}^ six months to a competent dentist. But when the condition is definitely established, when careful pressure around the gum margins results in the appearance of pus — sure sign that there are pockets, perhaps an eighth of an inch deep or more — it is another matter. That bacteria are resident in the tissues of the gum is true, and that vaccine treatment may suffice to eradicate these is also true, but not all the vaccine treatment on earth can ever influence those lying in the space between the tooth and separated tissue of the gum. Scaling of tartar, polishing the teeth so far as this is possible, careful brushing night and morning of the teeth with a moderately hard brush and an acid antiseptic wash, such as " albodent,"' and of the gums with a softer brush, followed by massage with the finger-tip and eau-de-cologne, will all help, but these likewise will not suffice to re-establish a normal condition of the parts ; and when I read that vaccine treatment combined with much less local care than this suffices to tighten loose teeth and bring about elimination of the pus pockets, I am a grave doubter of the writers' powers of clinical observation. But, it will be said, is there no cure of this most important disease, a disease fraught with such serious immediate and remote dangers to the patient's health ? To this my answ^er is, " Certainly, in a considerable percentage of cases," but it requires a skill and expendi- ture of time which few dentists are prepared to devote to it. The fault is not altogether theirs ; the public are as much or more to blame, and the medical profession cannot be considered to be exempt from responsi- bility. The public are ignorant of the consequences of the disease, and, being ignorant, are ill-disposed to pay adequately for its cure. They go to the dentist when their teeth hurt them, and are prepared to have cavities filled. The dentist sees or fails to see a serious condition of pyorrhoea ; if he sees it he often fails to tell the patient of its presence and to urge its treatment, for he fears to lose his patient. The medical man hardly ever knows pyorrhoea when he sees it ; it is a disease rarely described in the text-books, and his teachers in student days failed entirely to demonstrate it and to impress its far-reaching consequences upon him ; if they did they would only stultify themselves in the students' eyes, for after all their talk they would perforce have to leave the condition practically in statu quo, for no facilities exist at general hospitals for its adequate treatment. The position is a very serious 126 THE BACTERIAL DISEASES OF RESPIRATION. one, but it is not easy to find the remed}- ; perhaps the movement for the systematic examination and treatment of school-children's teeth is the best that is available ; the misfortune is that the condition is often established even at this early age. As such measures as I have alread}' mentioned will most likely fail to secure complete cure resort obviously must be made to other means. Among these are the following : (i) Strictly local treatment of the tissues in the pockets. (2) Attention to such other oral conditions as follicular tonsillitis and post-nasal catarrh. (3) Perhaps combined with these the use of appropriate vaccines. Let . us consider these in turn : by (i) I mean the systematic removal of the contents of the pockets and the topical application of such medicaments as will lead to the removal of tissues diseased beyond repair, to the stimulation to repair of such tissues as are capable of repair, to the obliteration of the pockets and the complete re- approximation of tooth and gum. There are limitations to success by these means, the chief causes of failure being (i) too advanced disease, in which case extraction is the only remedy ; (2) the choice of unsuitable applications, the cause of failure with some highly skilled and con- scientious dentists ; (3') insufficient perseverance on the part of the operator or the patient, or of both. I have now carefully watched for several years patients who have been methodically treated on these lines, and have done their duty b}' themselves and have observed a completely satisfactory result in at least 60 per cent, of the cases ; when recurrence has occurred it has been slight and has soon yielded to a further short course of treatment, which is perhaps advisable in every case six months after the completion of the first. Let us now consider the second of the above points. Despite all the study that has been devoted to the bacteriology of this disease, our knowledge still remains in an unsatisfactory state ; the reasons for this are several, among which may be mentioned : (a) The obsession to find a " specific " microbe for every disease. (6) The fact that far too little attention has been paid to the question of mixed infection, and that far too much attention has been paid to the results of cultural observations as opposed to the direct examination of stained smears. Many organisms associated with pathogenic conditions of the mouth are exceedingly difficult to grow, and cultural observations may prove entirely misleading. (c) The lack of regard which has been paid to many organisms as possible causes of this pathological condition. As I have mentioned in another place, cultures of mouth spirochaites and spirilla are toxic in THE BACTERIAL DISEASES OF RESPIRATION. 12/ the extreme, yet little regard is paid to them as factors in producing either the local condition or the general constitutional symptoms. Vincent's organism is now well known to be capable of setting up an acute inflammatory condition, not only of the fauces but also of the tissues of the limbs, yet little importance is attached to this organism, even when present in enormous numbers in the pus of a pyorrhceic pocket. The truth about the bacteriology of this condition I believe to be as follows : It corresponds exacth' to that of other conditions about the mouth generallv, and closely resembles, even if it is not actually identical with, that of follicular tonsillitis : it is also related to that of post-nasal catarrh, but less intimately. At the inception any one of these conditions may be initiated by a single variety of micro-organism, the pneumococcus, Streptococcus longus or hrevis, staphylococcus {aureus certainly, albus possibl}-), and perhaps the M. catarrhalis. Secondary invasion by other organisms soon occurs, combinations of any of the preceding ma\- be established, whilst before very long the spirochsetes, spirilla, vibrios and other mouth bacteria also gain a footing, and may even in course of time completely oust the original invaders. As these conditions are similar bacteriologically the absurdity of endeavouring to treat one of them locally and of neglecting the other is at once obvious ; and in re-infection from another focus is found the explanation for many of the relapses which occur in cases of pyorrhoea that have been apparently cured. We are now in a better position to consider the question of vaccine treatment. Let us clearly realise that it is illogical and unwise in the extreme to consent to any shitting of responsibility. The dentist has his part, in my opinion the more important part, to pla}- ; the vaccine therapist cannot fill his role as understud}' ; if the dentist in attend- ance on the patient is not able or willing to deal with the infection locally in a thoroughly satisfactory way, then the ph3-sician should allow no scruples to stand in the way of advising that the help of a more able or more willing operator should be sought. Eight out of ever}^ ten of m\- pyorrhceic patients I have found to require no more than local treatment. What scope is there, then, in this condition for vaccine treatment ? Local treatment may fail to effect a complete cure which the additional help afforded by vaccine treatment may secure ; in other instances cure may be expedited and speed)' relief be afforded from some con- stitutional s\-mptoms. and arrest be brought about in the case of others. The fairest way to state its claims to consideration is that it will rarelv fail to yield some definite assistance to careful methodical local treat- ment, and will sometimes succeed in brin^ins;' about verv material 128 THE BACTERIAL DISEASES OF RESPIRATION. improvement, if not actual cure, in cases which obstinately refuse to yield to local treatment. /\s I have said, the determination of the true bacteriology is no simple matter in any case. It will not by any means suffice to express pus from various pockets and culture it on agar or blood-agar and in broth. Special media may assist the growth of certain varieties of organism which will otherwise refuse to grow, but a conclusion as to the relative importance of the various bacteria seen in films and grown in cultures is best made only after a week or more of careful local treatment. In this way saprophytes and organisms merely resident on the surface of the diseased tissues are to a considerable extent elimi- nated ; by means of a line glass capillary pipette a little secretion is then removed from the bottom of several pockets, examined directly in smears and cultured on the selected media ; a little scraping from the gum lining the pockets should be similarly treated. If growth be obtained of the organisms which direct examination of the secretion and infected tissues indicates as being likely to be concerned in the process, vaccines may be prepared therefrom. If thought desirable opsonic index determinations may be made towards the bacteria which have been isolated ; personally I don't regard it as worth the time and money expended thereon. Suitable initial doses of the various orga- nisms, perhaps, are streptococcus 5-10 millions, pneumococcus 10 millions, staphylococcus 100 millions, M. catarrhalis 25 millions, streptothrix 10 millions, the interval between inoculations being live to seven days. Treatment may have to be continued for six or even twelve months, and repeated for short periods at intervals to guard against relapse. Results of Vaccine Treatment. A few abstracts from various sources will serve to show the divergent views taken as regards the aetiology of this disease and the benefits claimed for vaccines in its treatment. Williams {Anier. Journ. of Med. Sciences, May, 1911, p. 666) has reported his results in two small series of cases. The organisms which he held to be accountable were streptococcus, pneumococcus, M. catarrhalis, and staphylococcus, singly or grouped. Inasmuch as the only nutrient medium apparently employed was agar, the thoroughness of the bacteriological examination cannot be regarded as all that was to be desired. He claims that eight cases which received autogenous vaccines were intractable cases of long standing which had received careful dental treatment, while twelve other cases were dispensary ones which were treated with a stock vaccine made from a mixture of four of the above THE BACTERIAL DISEASES OF RESPIRATION. 1 29 autogenous ones. Reaction to an inoculation was shown within one to two days by increase of sensitiveness and discomfort of the teeth, and once by sweUing of a lymph-node on the floor of the mouth. I append short details of the cases treated with the autogenous vaccines. Case i. — Infection streptococcal. Four years' careful intermittent dental treatment had afforded some relief of symptoms, but this became of shorter and shorter duration. Eleven inoculations were given in thirteen weeks ; the initial dosage was 10 millions, the final 90 millions. After the third administration the patient was as free from symptoms as after any completed course of dental treatment. The ultimate result was* apparent cure, which was durable twenty months later. Case 2. — Duration of disease about five years : Streptococcal infec- tion. Two years' active local treatment had produced great improve- ment but not cure. Two years after discontinuing local treatment there was a bad relapse. Three doses of 20, 30 and 40 millions of stock vaccine brought some improvement ; local treatment was then recommenced, and seven doses of an autogenous vaccine of from 25-80 millions were given at intervals of a week. Eighteen months later there was no apparent relapse. Case 3. — Streptococcal infection. Thirty teeth were badly involved and the general condition was very unsatisfactory. Fourteen inocula- tions of an autogenous vaccine were given in fifteen weeks, at the end of which time only one pocket was discharging, the others being apparently cured. Case 4. — Mixed streptococcal and staphylococcal infection. Nine inoculations were given in seven and a half weeks, the dosage of the streptococcal vaccine being increased from 6-60 millions, that of the staphylococcal being twice these amounts. After three months there was no relapse from an apparent cure. Case 5. — -A very severe case of streptococcal infection. In thirty weeks eighteen inoculations were given in dosages of from 10-50 millions. All subjective symptoms disappeared and there was very great improvement of the pyorrhoea. Case 6. — Also a severe case of streptococcal infection. Thirteen inoculations of from 7-50 millions were given. Eight months after the last inoculation slight pus was found in one pocket. Case 7. — Again a severe streptococcal infection. Some teeth were so loose that they had to be extracted. Eighteen inoculations of 6-90 millions resulted in apparent cure. Case 8 was one of at least fifteen years' duration. Two inoculations of 12 and 16 millions of a stock streptococcal vaccine and two of autogenous vaccine were given. This resulted in considerable improve- 130 THE BACTERIAL DISEASES OF RESPIRATION. ment. Treatment was then discontinued. At the end of three months the improvement was maintained. Of the thirteen cases treated with stock vaccine, only four received more than six inoculations. Three of these seemed greatly improved, and a favourable opinion was formed of the results to be obtained in this class of case from the use of a stock vaccine. MacWatters {Proc. Roy. Soc. Med., October, 1910, supplement, p. 172) relates his experience of forty-eight cases, of which thirty had completed treatment ; this consisted in removal of tartar, the use of tooth-brush and carbolic powder before each meal, and a mouth-wash of 4 per cent, sodium chloride and 0*5 per cent, sodium citrate to promote osmosis. No local applications were used. Streptococcal vaccines, autogenous when possible, were alone used, the initial dosage being 5 millions, repeated at intervals of eight days, and increased to 10 millions as the lower dosages ceased to produce a reaction. He states that the effect upon such constitutional disturbances as dyspepsia morning vomiting, rheumatic pains and depression of spirits was very marked. The thirty completed cases received an average of ten inoculations : of these twenty-one showed no return of pus two months after the cessation of treatment, while the other nine were greatly improved. The obvious comment upon these results is that a lapse of two months after the cessation of treatment is utterly inadequate for judgment upon the question of cure : complete absence of symptoms after six months will point to the probability of cure, and after twelve months may, perhaps, justify the application of this term, inasmuch as it must remain an unsettled point whether recurrence after this period of time is not entirely a matter of re-infection instead of a recrudescence of the old infection. Eyre and Payne {Proc. Roy. Soc. Med., December, igog, Odonto- logical Section, p. 2g), carefully studied the bacteriology in thirty-three advanced cases ; inasmuch, however, as they began these investigations, which were to guide them in treatment, with the preconceived idea, based on the animal experiments of Washbourn and Goadby with this organism, that the Streptococcus brevis is a harmless saprophyte, which it most certainly is not, a fallacy was introduced into their observations from the very beginning. In the thirty-three cases they assigned the setiological role to the following organisms ; Staphylococcus aiireus ...... 2 cases. M. catarrhalis ,. . . . . . . g ,, Streptococcus pyogenes longus . . . . 7 ,, M. catarrhalis a.nd Streptococcus pyogenes longus . 11 ,, Pneumococcus ....... 4 ,, THE BACTERIAL DISEASES OF RESPIRATION. I 3 I The Streptococcus brevis was present in all the cases, but its signifi- cance was disregarded; as, however, the term Streptococcus pyogenes longus was applied to all the streptococci which were pathogenic for animals some of their group may include forms which other observers would have classified as "brevis.''' In twenty-six cases which were selected because either they were of great severity or refused to yield to local treatment autogenous vaccines were employed : In 2 cases the etiological factor was held to be Staphylococcus aureus. „ 6 „ „ „ „ „ M. catarrhalis. „ 6 „ „ „ „ „ Strept. pyogenes longus. ,, 8 „ „ „ „ „ -V. catarrhalis and Strept. longus. „ 3 .. '' " " " Pneumococcus. Before beginning vaccine treatment the teeth were scaled and the pockets packed on two occasions with some antiseptic, such as copper sulphate, tincture of iodine, a 10 per cent, solution of formialde- hyde, and a mildly antiseptic mouth-wash, such as o"2 percent, solution of formaldehyde or hydrogen peroxide 5-10 volumes. The doses of the various vaccines were — staphylococcal 50-250 millions, M. catarrhalis 2"5-500 millions, streptococcus 5-250 millions, pneu- mococcus 5-100 millions, their later experiences leading them to employ the smaller dosages. Their intervals were seven to fourteen days, the number of administrations was from four to twenty-five, the average being six to twelve, and treatment was con- tinued over periods ranging from one to nine months. " Cure *' they regarded as being established when the teeth were firm, the mouth comfortable, mastication painless, no pus could be expressed, and the muscular and arthritic pains and digestive disturbances had dis- appeared. They state that rapid improvement was noted in most cases, some being more resistant, and that the etiological factor is of some impor- tance in this connection. Infections b}' the staphylococcus respond most quickly, next those b}^ the pneumococcus, next those b}' the streptococcus, then those by the M. catarrhalis, the most refractory being the double infections by the streptococcus and 3/. catarrhalis. They claim to have examined the cases after considerable intervals and that in — 7 " cure " still persisted after 12-15 months. 12 ,, „ g-i2 2 ,, „ under g Four were improved, i had died from malignant disease. Three of the cases described as " cured " were shown at the 132 THE BACTERIAL DISEASES OF RESPIRATION. meeting before which the paper was read, and the consensus of opinion among the dentists present was that the cases were not " cured," the condition being very similar to what might have been anticipated after local treatment only. Goadby has been working at the bacteriology of this condition for many years and experience has compelled him frequently to modify his views, so that whereas he regarded the Streptococcus brevis as a harmless saprophyte in i8g6, he later came to regard it as the setiological factor in a considerable percentage of cases. To a variety of the streptococcus which he prefers to call a strepto-bacillus, but which appears to be almost identical with the Streptococcus conglomeratus, so commonly present in the mouth and especially around and in the tonsils, he now assigns the chief role. For the results which he has obtained with various vaccines the original articles must be con- sulted {Proc. Roy. Soc. Med., February, igio, Odontological Section, p. 55 ; Lancet, 1909, vol. i, p. 663 ; ibid., 1909, vol. ii, 1875, etc.). In the earliest stages he considers the prognosis to be 60 per cent, of cures, these cases apart from vaccine treatment being regarded as destined not only to advance of the p37orrhoea but to the diseases which have been shown to be associated with that condition. The fallacy in this conclusion is that adequate local treatment of the disease at this stage, with proper supervision of the mouth at six- monthly intervals and the inculcation upon the patient of the proper hygiene of the mouth, should result in 100 per cent, of cures. A result of 60 per cent, of cures in this stage is synonymous with grave deficiences on the part of both dentist and patient. Carmalt Jones, from the ubiquity of the Streptococcus brevis in the lesions, concludes that in the majority of cases this organism is the original cause of the condition, infection by other organisms being frequently superadded. He states {Therapeutic Inoculation, p. 112) that twenty cases of simple pyorrhoea without complications have been treated at St. Mary's Hospital by vaccines of the Streptococcus brevis in doses varying from 10-50 millions, the usual initial dose being 20 millions. The results of treatment lasting from one to two months have been as follows : cured, six cases ; much better, seven cases ; better,, four cases ; unchanged, three cases. Secondary infections by the M. catarrhalis in four cases, diphtheroid bacillus in one case and a coliform bacillus in one case were also dealt with. Distinct benefit to the com- plications was often noticed. In summarising the results obtained by the various observers we find that good results are claimed alike by those who attach supreme setiological significance to the ubiquitous Streptococcus brevis and by those who entirely disregard its claims ; assuming for the sake of argu- THE BACTERIAL DISEASES OF RESPIRATION. I 33 ment that the clinical observations of all are equally reliable, the only reasonable conclusion that can be arrived at is that on the one hand we have those who, in the majority of their cases, are treating the primary infection and tend to neglect any secondary" ones, and on the other hand we have those who pay exclusive attention to secondary or mixed infections and disregard the primar}' one. Some good is to be antici- pated from either procedure and appears to be actually obtained. Of the sum total of good achieved, in my opinion the major portion is to be ascribed to the limited amount of local treatment which is also given, and to the fact that the patient's attention is more clearh* focussed on the existence of the disease and on the ordinary hygienic measures which promote a healthier condition of the mouth. A clearer conception of the true bacteriology of the complaint and of the prevalence of mixed infection would broaden the view that should be taken of the applicability of vaccine treatment and of the lines along which it should be conducted. Conclusions. (i) The responsibility for the treatment of pyorrhoea alveolaris primarily rests with the dentist. Despite tlie great amount of attention which has been paid to this disease in recent years treatment is still frequently inefficient. Lack of thoroughness and of persistence and the use of improper local applications are perhaps the commonest cause of failure on the part of the dentist. (2) Vaccine treatment cannot possibly alone suffice for cure ; it should always be subordinated to careful adequate dental treatment. (3) That it should be resorted to when the latter has already failed or appears to be likely to fail to effect a cure, or when such constitutional symptoms as chronic articular rheumatism, muscle pains, gastro-intes- tinal disturbances, or anaemia, simple or pernicious, require urgent attention. (4) When the pyorrhceic condition is so advanced that extraction is the only course, and the extraction of one or two teeth is followed by violent constitutional disturbances, a few inoculations with the appro- priate vaccine may greatly assist in raising the patient's resisting powers to the absorbed bacteria and their toxins, and enable the dentist to complete the extractions with less danger and discomfort to the patient. (5) If vaccine treatment is to prove of any service adequate dosages must be emploj'ed and a prolonged course may be necessary-. The signs of adequate dosage are the production of a definite but mild reaction, such as any of the following : slight malaise within eighteen hours ; increase in local or general symptoms, as tenderness of the gums or teeth, joint or muscle pains ; in default of these a definite improvement in the local 134 THE BACTERIAL DISEASES OF RESPIRATION. condition showing no signs of relapse after five to six daN's. When the appropriate dosage has been found it should not be increased so long as steady progress is being made ; when this ceases, or reactions fail any longer to be produced, then increase to double dosage may be safely made. (6) When apparent cure has been brought about careful re-examina- tion should be made at intervals of six months. In the event of relapse two or three visits to the dentist should be insisted on, and a short course of vaccine treatment recommenced. (7) In those patients in whom constitutional symptoms are marked two or three inoculations every six months will probably assist in the maintenance of good health. (8) Owing to the complexity of the bacteriology of this condition and the consequent difficulty in preparing the appropriate vaccine, fail- ures in its vaccine treatment are especially apt to be experienced ; in such instances the vaccine itself should come under suspicion and a reinvesti- gation of the bacteriology be made. The flora of the several pockets may vary greatly the one from the other, so that it is not sufficient to examine the pus from one or two foci and assume that a similar con- dition will be found in that from others. A member of the streptococcus group is the commonest causal organism, but it is not the only one, and mixed infections are not uncommon. (9) Autogenous vaccines are much to be preferred to stock ones. The latter should only be used when insuperable difficulties stand in the way of the preparation of the autogenous. (d) Hay -fever. In this distressing complaint we have a condition of instability of the vaso-motor centre, and a great susceptibility of the mucous membranes of the eyes and nose especially to certain influences, the result being that the stimuli applied to the nerve-endings in the nasal mucosa upset the unstable balance of the vaso-motor centre ; profuse lacri- mation, reddening of the conjunctivse, sneezing, swelling of the nasal mucosa, excessive formation of nasal, tracheal and bronchial mucus, and perhaps spasm of the unstriped muscle of the bronchial tubes with resultant asthma are thereby set up. The stimuli may be of various kinds, such as certain perfumes, either of flowers, or of the products of incomplete combustion of petrol or other oils ; more frequently it consists of a toxin, occasionally of bacterial origin but much more commonly, as Dunbar has shown, one derived from the pollen of various flowers and grasses. Various lines of treatment may be therefore followed, such as : (i) Stabilising the vaso-motor centre by cauterisation, electrical or THE BACTERIAL DISEASES OF RESPIRATION. 1 35 chemical, of the nerve-endings in the nose. This method has yielded good results in certain hands. (2) Removal of the patient from the reach of the stimuli — a course taken with many who leave England and Germany v/hen the pollen is ripening, and depart to places such as Heligoland where there is no pollen. (3) Determination of the toxin to which the patient is susceptible and immunisation against it either by means of serum or vaccine. Dunbar, b}^ inoculating horses with pollen, produced an anti-serum, which, while yielding good results in some cases during an attack, has, however, not proved very satisfactory in preventing the annual recur- rence. Recourse has, therefore, been made to active immunisation by means of vaccine. As has been already mentioned, bacteria or their toxins are occasionally able to produce the condition. In two or three instances I have isolated the B. septus in pure culture from the nasal mucosa and secured complete immunity by inoculations with 250 and 500 million doses of the autogenous vaccine. I have also heard of one or two instances where the use of my combined vaccine for colds has produced a similar result. Carmalt Jones {Therapeutic Inoculation, p. 126) also secured considerable improvement in one patient b}-" the use of an autogenous vaccine of the B. aerogenes. Cases such as these wherein a bacterial infection is the active agent must form a very small percentage of the total. The recent researches of Noon afford a certain method of determining whether susceptibility exists to pollen toxin ; it is based upon the well-known ophthalmo- reaction first applied to the diagnosis of tuberculosis, and the procedure is as follows : One gramme of the pollen of Phleuni pratense is extracted with 50 c.c. of water, and for the sake of convenience the extract is arbi- trarily assumed to contain 20,000 units of toxin in each c.c. The follo\\'- ing dilutions are prepared from the extract : 5000, 1500, 500, 150, 50, 15 and 5 units in each c.c, this wide range being necessary owang to the extreme variation exhibited by various individuals in their susceptibility to the toxin. Two or three drops of each dilution are put up in glass capillary tubes similar to those employed for the tuberculo-ophthalmic reaction. The test is applied in a precisely similar way ; the patient sits with head thrown back, and the contents of a capillary tube of the 5-unit strength are instilled into the conjunctival sac of one eye, the other serving as control. After two or three minutes the eye is examined for a reaction ; the first sign is usually a tickling at the inner canthus, which is very soon followed by a slight but distinct reddening of the caruncle ; this constitutes a " slight " reaction. If the congestion extends to the adjacent conjunctiva it is called " marked," and if to the 136 THE BACTERIAL DISEASES OF RESPIRATION. whole conjunctiva it is regarded as " very marked." If no reaction be obtained by the end of five minutes, the next stronger dilution, viz. the 15-unit strength, is instilled into the other eye and developments awaited. If no reaction is again obtained the next stronger dilution is employed, reverting to the eye first tested and so on until, if necessary, the strongest toxin has been used. If there is still no reaction immunity to the toxin of the pollen of this and closely allied grasses may be considered proved. If, however, a reaction is obtained with any of the dilutions, then susceptibility has been demonstrated. If a "slight" reaction be obtained with any strength then a "marked" reaction will be obtained with a triple strength, and a " very marked " reaction with a ten-fold strength. Not only does this ophthalmo-test serve to demonstrate suscepti- bility, but it also indicates the suitable dosage for subcutaneous inoculation with a view to the production of immunity, as it has been observed clinically that the suitable dose for the latter purpose is one third of a cubic centimetre of the strength which yields the " slight " ophthalmo-reaction. Thus, if the latter be obtained with the 150-unit strength, the suitable dose for inoculation is ^ c.c. of this strength of toxin or I c.c. of the 50-unit strength. For purely protective pur- poses this dose should be repeated in eight to ten days. After a similar interval the next higher dosage may be employed, and so on, success- ful immunisation being shown to have been secured by failure to respond to the ophthalmo-test with the 5,000-unit strength. During the hay-fever season it is well to begin treatment with half the dosage as above determined, the same rule holding in the event of the patient seeking relief from an actual attack ; in this event not only should the dosage be halved, but the intervals between administrations should be likewise reduced; five days is then a suitable interval. Just as the application to the eye of two or three drops of the 5000-unit strength will indicate final immunity, so the failure to respond to the applica- tion five days after each inoculation of two or three drops of the strength triple that used for the last inoculation will serve to indicate that increased dosage is then advisable. The elaboration of this highly scientific method of treatment is of such recent date that it is hardly as yet possible to dogmatise about results. So far as one can judge from the experience of the past season, a considerable measure of success is to be anticipated. Many patients have escaped completely, and the greater majority have suffered from nothing but very mild attacks. With the adoption of a more highly polyvalent vaccine even better results may be secured. Ellern {Dent. nied. Woch., No. 34, 1912) records an interesting series of observations made during the past season in Germany. He tested THE BACTERIAL DISEASES OF RESPIRATION. 1 37 both the ophthalmo-reaction and the therapeutic effect of pollen toxin prepared at St. Mary's Hospital in a series of thirteen cases. He found that the concentrations required for obtaining the ophthalmo-reaction in his patients reached higher levels than in Freeman's observations ; being that of 50 units only in the most susceptible cases ; the greater number showed subjective symptoms only with one of 500 units and distinct objective signs only with the 1500 units concentration. Healthy individuals were not affected by the 5000 unit strength. As to the relation of the ophthalmo-reaction to the therapeutic dose, he found that, at least during the period of prevalence of hav-fever, this was by no means constant, and that in some patients who felt sub- jective improvement in their symptoms the concentration required to produce the ocular reaction fell. For therapeutic purposes he began with a dose corresponding to one fifth of the concentration required to produce the ophthalmo-reac- tion and repeated it at intervals of five days : higher initial dosage he does not consider desirable. No serious symptoms ever appeared as the result of inoculation and there was no rise of temperature ; attacks of typical hay-fever of short duration occasionally occurred and once an asthmatic attack supervened. Doughy swelling with tension and pain at the site of inoculation frequently occurred, but these symptoms sub- sided in from one to two days. The number of injections varied from 4 to g — only few received less than 6 ; the dosage from 25 to 125 units as an initial and 100 to 250 units (the latter in nine cases) as the final dosage. The results were : unchanged 2, improved 5, markedly improved 6, as compared with attacks in previous years. The two unimproved cases gave up treatment prematurely. Most of the patients declared their willingness to again undergo treat- ment next year, but all suffered from hay-fever for shorter or longer intervals. Ellern draws attention to the fact that in Germany hay-fever has been less severe this year than last ; for instance, he made inquiry of twenty cases not treated specifically ; their experience had been, 4 as last year, 14 less severely attacked, and 2 very much less severe attacks. He therefore considers that the difference between the two series is too small to enable any definite conclusion to be formed, but admits that he may also have started the treatment too late in the season. {e) Ozcena or Atrophic Rhinitis. Bacteriology. — Abel made a bacteriological examination of the atrophic nasal mucosa in 100 cases of ozsena. and found in each one of them a bacillus resembling, but not identical with, the bacillus of Fried- lander. It is a non-motile capsulated Gram-negative bacillus which 138 THE BACTERIAL DISEASES OF RESPIRATION. forms a colourless sticky growth on agar, which is so moist that it slides down to the bottom of the slope. In stab cultures it spreads out over the surface of the agar and does not form the nail-head growth characteristic of the bacillus of Friedlander. Its growth on gelatine is similar to that on agar and does not liquefy the medium. It does not produce indol in peptone water. Its fermentative properties are much less active than those of the bacillus of Friedlander. In two or three days it forms slight acid in litmus-milk, but no coagulum. It forms acid and gas in mannite, dextrose, maltose and raffinose within two days, in adonite and dextrin within three days, in saccharose, sorbite and lactose within four or five days, but not in dulcite or inulin at all. When this organism is injected subcutaneously into mice it proves fatal, when subcutaneously into guinea-pigs no abscess is formed, but if the peritoneal route be adopted death is brought about in about half the animals. Abel found this organism in every case of atrophic rhinitis, but never in any other diseased condition of the nose. He employed it to inoculate a healthy human nasal mucosa and initiated an atrophic condition. Vaccine treatment. — Page {Jonrn. Medical Research, July, 1912, p. 489) found this organism in two cases of ozaena and employed vaccines of it in them for therapeutical parposes. In the first case inoculations were given every three days (no dosage is indicated). The patient noted continued subjective improvement, there was diminished crust-forma- tion and increased secretion of mucus. After three months' treatment the improvement under this form of treatment alone was marked, but inasmuch as the right frontal sinus was involved cure had not then been produced, nor was this to be anticipated. The second case was one of twenty-five years' standing. In addition to the B. ozcencB, the B pyocyaneus, streptococcus and Staphylococcits candidus were also present A mixed vaccine of the first two organisms was employed ; after four inoculations at weekly intervals the fcetor was diminished, the nose and throat not so dry, and the discharge was moister but less profuse. The treatment was being still continued. Cobb and Nagle {Annals of Otology, Rhinology and Laryngology, St. Louis, 1912, vol. xxi) have also found vaccine treatment of distinct value in cases of atrophic rhinitis. I have myself found this ozgena bacillus in four cases of early atrophic rhinitis and employed autogenous vaccines, combined with another of strepto- coccus, pneumococcus. Staphylococcus aureus and M. catarrhalis in the respective cases. Initial doses of fifty millions were repeated or in- creased at intervals of seven days. The case wherein the Staphylococcus aureus was also present made very slow progress, and after six months' treatment was still not quite cured. The other three cases were cured THE BACTERIAL DISEASES OF KESI'IRATION. I 39 after about this interval ; final dosages of 500 and 1000 million organisms were necessary in these instances. (/) Rhinoscleroma. Bacteriology. — Although the aetiology of this distressing complaint is still in doubt, there seems some justification for regarding it as a bacil- lary infection due probably to the bacillus of Frisch {vide " Zur iEtio- logie des Rhinoscleroms," Wien. med. Wochenschr., 1882, Nr. 32, and also Kolle and Wassermann's Handbuch der pathogenen Mikro-organis- men, 1903, Bd. iii, pp. 414-424). This organism is a member of the bacillus of Friedlander group, but differs from others in appearing to be actively motile, and in retaining Gram's stain with some tenacity in sections of tissues hardened with Muller's fluid. Though the majority of experimental inoculations on animals with this organism have given a negative result, in a few instances typical scleromas have been produced. Vaccine treatment. — Guntzer {Medical Record, July 24th, 1909, p. 129) has reported on two cases treated with vaccines after X-ray and other treatment had failed. In the first case, where the nose, glottis and larynx were all affected, he gave three doses of 250 millions of the autogenous vaccine at intervals of four and eight days ; the last two of these injections pro- duced marked local and general reactions, bloody discharge from the nose, malaise, headache, and rise of temperature. Subsequently doses of 375, 500 and 1000 millions were given at varying intervals, until the patient had received forty-three inoculations. At the end of this time, although cure had not been attained, the infiltrations had retrogressed, there was no longer dyspnoea even on exertion, and the patient had been able to resume work. A year later, although treatment had been discontinued for some time, the improvement had not only been well maintained, but had been even continued. The second case was a very advanced one, the general condition was bad, there was nodular deformity of the nose, the anterior nares were almost closed, and there was infiltration of the upper lip ; the tonsils and pillars of the fauces were grown together into a compact mass and nearly touched on opposite sides ; the naso-pharynx was almost obliterated, and the hard palate, but not the larynx, was involved. The vaccine was given in doses of 250 to 1000 millions, at intervals of three to seven days, until thirty-two injections had been given. Local reaction was marked after each inoculation. At the time of the report the disease had not in any way decreased, but it had like- wise not advanced, and the patient's general condition was very much improved. Treatment was to be continued. CHAPTER X. THE MIXED INFECTIONS OF PULMONARY TUBERCU- LOSIS AND VACCINES IN THEIR TREATMENT. Out of the chaos into which the specific treatment of pulmonary tuberculosis had fallen a certain amount of order has now been evolved, but there is still much confusion and much misapprehension, and this it will be my endeavour to remove in this and the succeeding chapter. Difficulties have been created by the too ardent disciples of the various forms of treatment, who have tried to reduce man to a mathematical formula, and haye based their treatment according to their solution of an algebraical problem. They have failed adequately to realise that they have insufficiently differentiated the signs and symptoms due to infection by the tuberculosis bacillus from those due to infection by allied invaders ; more often than not they have ascribed to one invader what should have been attributed to another, with the inevitable result that the prescribed form of treatment has been misdirected and fore- doomed to failure. They have also failed sufficiently to realise that the human being is a very highly specialised mdividual, and that what applies to one individual may fail entirely to hold with regard to another. No scheme or system of treatment can therefore be evolved which will suit each and every phthisical person ; the treatment must be moulded to the individual, not the individual to the treatment. It will be my aim in this chapter to consider the first of these points in some detail, and to endeavour to demonstrate the paramount importance assumed by the allied or secondary invaders in many cases of pulmonary tuberculosis, and to indicate the means whereby this may be minimised or altogether removed and the case brought back to the much simpler form of an uncomplicated tuberculosis. In the succeeding chapter I shall endeavour to consider how specific therapy can best be utilised in this simplified condition as well as in that of pulmonary tuberculosis as yet uncomplicated by the advent of secondar}^ or allied invaders. THE BACTERIAL DISEASES OF RESPIRATIOX. 141 The Import of Mixed Infection. The term •'•'mixed"' infection is much to be preferred to that of "secondary" infection for the reason that certain bacterial diseases of the lung predispose to subsequent invasion of the pulmonary tissues by the B. ttiherculosis, the latter infection being then the secondary one, the former the true primary one. In other instances the reverse holds true, to a primary invasion of the tissues by the B. tuberculosis secondary invaders become superadded. The ultimate result may be the same, but in the earlier stages the conditions are very different, and the methods of treatment may require to be verv different. In the earl\- stage in the first instance the problem is the prevention of the advent of the tubercle bacillus to pulmonarv tissues which are in a condition called by French physicians '"' pras-tuberculous/' and to remedv this prse-tuberculous state ; in the latter instance the problem is to prevent the advent of other pathogenic bacteria to pulmonary tissues already invaded by the B . tuberculosis and to remedy this tuberculous condition. In the later stages m both instances we have to deal with a co-existent infection by the B. tuberculosis and other pathos-enic bacteria. At the present time the most widely divergent views are held as to the influence which other bacterial infections of the lungs exercise both upon the initiation of the tuberculous process and upon its subsequent course. Some authorities, basing their view upon the verv faUacious observations that many of the organisms isolated from tuberculous sputum are of low vitality and of very little virulence towards animals. maintain that the part they play is a very subsidiarv one — in the language of the stage, it is little more than a ■'■' walking-on '" one. Thev point out that as fever, wasting, caseation and softening mav all, under certain conditions, be produced directly b_v the tubercle bacillus, the symptoms of the disease should in all cases be attributed to this bacillus, and to it alone. Other authorities would attribute a preponderating influence to the other bacteria in the production of the advanced processes of this disease : others, again^ have opinions of every intermediate grade between the two extremes, and I may perhaps be permitted to make the following quotations : Powell and Hartley {Diseases of the Lungs, fifth edition, p. 402) write as follows : " For ourselves we cannot but believe that when such micro-organisms are present their action must be harmful, and that they at least prepare the way for the invasion of the tissues by the tubercle bacillus, and assist in that suppurative process which leads to the elimination of caseous products and manifests itself clinicallv bv 142 THE BACTERIAL DISEASES OF RESPIRATION the well-known phenomena of hectic. The matter requires further investigation, but for the present we cannot ignore the part played by secondary micro-organisms and must do all in our power to prevent their gaining access to the patient." Sir A. E. Wright writes : " While the suggestion that mixed infec- tions must be expected in the common suppurative processes which occur in connection with surfaces which harbour microbes ma}^ well be universally acceptable as not breaking in on any accepted ideas^, the sug- gestion that mixed infection must therefore be considered in every case of phthisis, lupus, tubercular caries, tubercular cystitis and tubercular ulceration, in the very nature of things will be unacceptable to many clinicians. Such a suggestion will be felt to throw doubt not only on the clearness of vision of those who have sought for anti-tuberculous remedies in these diseases, but also on the critical acumen of those, who, without taking into account the fallacies which are incidental to clinical methods, have confidently undertaken to pass final judgment on anti-tuberculous remedies by the observation of their clinical effects in cases in which, in addition to the tubercle bacillus, other pathogenetic microbes may have been at work. " Be it acceptable or unacceptable, there is no escape from the fact that practically every case of suppurating lupus is complicated by a staphylococcus infection and every aggravated case of lupus with a streptococcus infection. What holds true of lupus, mutatis mutandis is true of every tuberculous affection to which microbes can find access." Foulerton [Transactions of the British Congress on Tfibercnlosis, London, igo2, vol. iii, p. 612) points out that "an ox may have the most extensive tuberculous infection of the pleural or peritoneal sacs and yet will frequently be in absolutely prime condition ; there is no suggestion of disease until the tuberculin test is applied or the animal is slaughtered. But, given a breaking-down of tubercles in the lung substance with secondary infection of the cavities or an ulceration of tuberculous lesions in the intestine, and one finds the same high temperature, the general wasting, and the same active destruction of the infected tissue which characterise the average case of chronic pulmonary phthisis in man." Webb {Tiiherculosis, Klebs, igog, p. 5gg) writes as follows : " It is perhaps a fact that many of these secondary organisms are of low vitality and non-virulent, but it is just as impossible for such patients to rid themselves of these as of local infections, such as acne and furunculosis, both such frequent afflictions of the tuberculous. Sur- geons, familiar with bone tuberculosis, know how well patients with pure tuberculous disease improve, and yet how intractable are those THE BACTERIAL DISEASES OF RESPIRATION. 1 43 cases with mixed infection. Prudden's well-known experiments on rabbits show conclusively that the concurrent action of two distinct pathogenic germs may result in a considerable modification of the lesions which either could produce alone." The question of mixed infection I propose to discuss according to the following scheme : (i) Theoretical consideration of the question as to how far con- comitant infection may be truly primary or truly secondary. (2) The nature of the bacteria associated with the B. tuberculosis in cases of pulmonary phthisis. (3) Method of determining the effect of the toxins of other bacteria upon the growth of the tubercle bacillus in vitro, results and theoretical deductions. (4) Method of determining whether deductions from observations in vitro hold with equal force in the living subject, and the application of the facts so learnt to the prevention and cure of mixed infections. Theoretical Consideration of the Question as to how far Concomitant Infection may be truly Primary or truly Secondary. The determination of the precise period of life at which invasion of the pulmonary tissues by the tubercle bacillus has occurred in any given person is a \-ery difficult question. That infection of the glandular system occurs in a very high percentage of children in the first few years of life is an unquestioned fact. Some authorities maintain that in cities it is of almost universal occurrence. Mac- Conkey and MacFadyen actually found virulent tubercle bacilli present, usually in the mesenteric glands, of about 25 per cent, of children who died from non-tuberculous causes. The assumption that the pulmonary phthisis, which makes its appearance in considerably later years of life, is due to this infection contracted during childhood leads to many difficulties, such as that of explaining why the germs should lie latent, often over a period of many years, and then suddenly take on active growth. Also careful observations have tended to show that for about 50 per cent, of the cases of glandular tuberculosis in children, the bovine type of the tubercle bacillus is responsible ; whereas in pulmonary phthisis the bacillus is found to be almost invariabl}^ of the human type. It thus follows that in 50 per cent, of the cases a metamorphosis of the bacillus in the direction of change of type must have occurred ; and for the possibility of this occurrence there is little or no experimental evidence. Reinfection by the human type bacillus must then have happened, 144 THE BACTERIAL DISEASES OF RESPIRATION. and what is true for 50 per cent, of the cases is equally likely to be true for, at all events, a considerable proportion of the other 50 per cent. Naegeli has found that in g6 per cent, of autopsies conducted upon bodies of between the age of eighteen and thirty years evidence of tuberculous infection was present, while in those above thirty none were found free. Infection by the tubercle bacillus is thus a practically universal occurrence, but in only a relatively small proportion of the cases do active pulmonary symptoms supervene. As to the interval of time that must elapse between the infection of the pulmonary tissues by the tubercle bacillus and the production of such symptoms as enable the detection of the process to be possible, no definite limits can be fixed. It varies much, probably with each individual, and may be a few weeks or a few years. The determination^ therefore, of the ques- tion whether it was some other bacterial infection that predisposed the patient to infection by the tubercle bacillus and accelerated the process when infection had occurred, and if so, precisely what was its nature, is fraught with difficulty. As, however, I shall produce clear evidence of the effect of concomitant infection upon the growth of the tubercle bacillus, it is only reasonable to suppose that prior manuring, as it were, of the soil will conduce to subsequent invasion by the B. tuher- culosis. Clinical observations have shown that certain bacterial infections are frequently antecedent to the outbreak of symptoms of pulmonary tuberculosis. Thus whooping-cough and measles are antecedent to a large proportion of cases of tuberculosis in children ; it is frequently to be observed that glandular enlargements in the neck are preceded b}' decayed teeth, a condition of pyorrhoea alveolaris, eruptions on the scalp, enlarged tonsils and adenoids, or b}' the sores set up by chicken- pox, and that unless prompt treatment be directed against these disorders definite tuberculosis of the glands may ensue, and it is only logical to suppose that stimulation of the tubercle bacilli at other foci, such as the mediastinal and bronchial glands or in the pulmonary tissues, may simultaneously occur. Pneumonia and neglected colds, again, enter into the history of a large proportion of cases of phthisis, and such importance do some French physicians attach to bronchitic and asthmatic conditions as predisposing causes of pulmonary phthisis that they are wont to call them prse-tuberculous conditions. Whether in any given case some antecedent bacterial infection has been definitely responsible for invasion by the tubercle bacillus must, however, rest entirely upon pure inference. THE BACTERIAL DISEASES OF RESPIRATION. 145 The Nature of the Bacteria associated with the B. Tuberculosis in cases of Pulmonary Phthisis. I have, during the past four years, carefully and minutely examined the sputum of fifty-two cases of pulmonar}^ tuberculosis with a view to the determination of the nature of any concomitant infection, with the following results : Table XIII. Total Numher of Cases, 52. Streptococcus . M. catarrhalis . Pneumococcus . B. influenza M. paratetragenns Staphylococcus albus Staphylococcus aiireus Diphtheroid B. B. of Friedlander B. proteus . B. coli Only exceptionally was the mixed infection found to be mon- organismal, this being more frequently the case with such organisms as the staphylococcus, B. of Friedlander, or B. proteus, than with those which come above them in the above list ; more often it was found to be binorganismal, in such combinations as B. influenza and pneumo- coccus, streptococcus and M. catarrhalis, pneumococcus and M. catar- rhalis ; and still more frequently the combination was a threefold one, such as B. influenzce, pneumococcus and M. catarrhalis; pneumococcus, streptococcus and M. catarrhalis. At times the precise character of the mixed infection would spon- taneously vary from time to time, this being determined to a certain extent by the incidence of a general catarrhal epidemic among the populace ; for instance,. one case which I had carefully watched and repeatedly examined during two years without ever finding any con- comitant infection other than that by the Staphylococcus albus, suddenly contracted a superadded infection by the B. influenzcE and pneumo- coccus, with the unfortunate result that not only was the whole of the marked progress made during two years lost, but the process was transformed from a fibroid one into an acutely pneumonic one, and in less than a month I heard of the patient's death. 10 present 42 times = 81 per cent 41 = 80 19 = Z7 „ 12 = 23 ,, 10 ,, = 20 8 = 15 6 = 12 3 = 6 „ 2 = 4 „ 2 = 4 M I )> = 2 146 THE BACTERIAL DISEASES OF RESPIRATION. During the past eight years I have had exceptional opportunities of making myself acquainted with the precise nature of the bacteria responsible for prevailing catarrhal epidemics, and v^hile I do not think that phthisical cases are more disposed to catarrhal infection than other people, what I have certainly found to be the case is that there is a greater tendency for the bacteria to invade the structures in the chest instead of confining their activities to the upper respiratory tract, and that they cling there with greater pertinacity when once they have gained a hold. It thus follows that one or two examinations of the sputum of a phthisical case by no means suffice to determine what is the nature of the true accessory infection — by that I mean the infecting organism which is always present irrespective of the fact whether a general catarrhal epidemic may be in progress or not ; even the minute observations which I have bestowed on several cases have not sufficed to enable me to determine what was the true primary accessory infec- tion. The methods which I have elaborated, however, enable us to sort out the bacteria present at a given time, and say which are exerting a malignant influence and which apparently are not. It is due to causes such as the above that lists by various observers, attempting to show the relative frequency with which the various bacteria occur as complicating agents in cases of pulmonary phthisis, show such considerable variations. It does not become me to belittle the work of other investigators, but I have already pointed out the extreme care with which observa- tions upon the bacteriology of chest infections must be conducted ; in the case of some it is easy to determine that sufficient care has not been so bestowed ; with others sufficient details to estimate the probable accuracy of their observations are not available. It thus becomes a difficult, nay, an impossible, matter to collate the various records and draw up anything like an accurate table to display the relative frequency with which the various bacteria play the part of secondary invaders to the B. tuberculosis. At the same time there is a considerable degree of concordance in the findings as regards the frequency with which the streptococcus, M. catarrhalis, pneumococcus and staphylococcus are found ; for instance, this is the exact order of frequency with which they were found by Dr. T. W. Hastings (quoted in Kleb's Tuherculosis, p. 591) as well as by myself. Other observers have found the Staphy- lococcus {albus or aureus) of practically universal occurrence, but this I feel is due either to lack of care in excluding contamination from the mouth and pharynx, or to the observations having been conducted upon cases in very advanced stages of the disease, for although I cannot offer figures in support of my view, I yet feel strongly that the earlier the stage of the disease, the less the likelihood of invasion of the THE BACTERIAL DISEASES OF RESPIRATION. 1 47 tuberculous foci by the more purely pyogenic bacteria, and the greater the probability of the more purely catarrhal organisms complicating the infection. The results of post-mortem examinations such as are recorded by numerous observers I think should be altogether excluded from con- sideration, for it is impossible to exclude agonal and post-mortem infection, and even granting that such had not occurred, observations derived from so far advanced cases are not of practical application to cases in the early stages, and these are those with which we are the more concerned. The frequency with which some observers have found the B. coli communis I am altogether unable to explain ; personally I have only once encountered it in cases of pulmonary phthisis and only in one case out of several of lung abscess, that particular case having a very doubtful history of an early tuberculous lesion several years before the onset of the abscess at a quite different place. In cases of basal phthisis complication of the infection by the B. coli would be more likely to occur than when the tuberculous process is confined to the upper lobes. The value of the precise determination of the frequency with which the various bacteria play the role of accessory invaders in phthisis would, as I have already hinted, be much increased if more regard were also paid to the record of the stages of the disease in which they are found ; to this, personally, I intend in future to pay more heed, for the bearing upon the question of prophylaxis is obviously a most important one. If, as I believe, the catarrhal organisms, M. catarrhalis, pneumococcus, B. influenzce, M. paratetragenus and some varieties (non- pyogenic as a rule) of the streptococcus, show a far greater predilection for earl}^ cases than do the more purely pyogenic organisms which appear to follow in their tract, measures for preserving, not only early phthisical cases, but also those who merety seem to be predisposed to pulmonary phthisis, from catarrhal attacks assume a 3'et greater importance. Method of Determining the Ejfect of the Toxins of other Bacteria upon the Growth of the Tubercle Bacillus ''in vitro'' ; Results and Theo- retical Deductions. During my investigations into the bacteriology of the catarrhal diseases of the respiratory tract, I have been frequently struck by the observation that in certain cases of almost pure infection by the B. infiuenzce this organism refused to grow on the culture plates unless, perchance, development also occurred of a few colonies of such organisms 148 THE BACTERIAL DISEASES OF RESPIRATION. as the staphylococcus, pneiimococcus, or M. catarrhalis. Luxuriant growth of the B. infitienscB would then occur in immediate proximity to these colonies, but not elsewhere. It occurred to me to study this symbiosis further, and I found that it sufficed to add to the melted blood agar 2 or 3 c.c. of a killed broth culture of these various bacteria prior to pouring the plates and inseminating them with the B. infltienzce. By this device I have obtained growths of this organism so profuse that they looked more like cultures of the B. coli than of the influenza bacillus. Previously I had recorded in the Lancet the extraordinary inhibitory effect that the bacillus of Friedlander exerted upon the growth of other micro- organisms in, or on, the same medium. The thought then suggested itself — I wonder what is the effect upon the growth of the tubercle bacillus that is produced by the simultaneous growth of the other such bacteria as occur in secondary infections of pulmonary phthisis, or by their toxins. The inability to isolate the tubercle bacilli from my cases was at first an obstacle to the solution of this question, but this fortunately was removed by the discovery of the antiformin method of securing pure cultures of the tubercle bacillus. By the methods already outlined I proceeded to prepare pure cultures of the tubercle bacillus and of all the accessory microbes from several of my cases. Subcultures of the accessory microbes were then prepared in suitable fluid media — broth for staphylococci, blood- broth for the B. influenzce and pneumococcus, serum-broth for the M. catarrhalis — and these allowed to incubate at 37° C. until such time as full development of any toxin they might form had taken place — usually three to six weeks — by which time free growth of the tubercle bacillus upon the Dorset's egg medium had also occurred. Tubes of the same media without prior insemination with any bacterium were also placed in the incubator to incubate along with the other tubes, and served as controls in the way which will be indicated. The fluid cultures were then sterilised by heating for one hour at a temperature of 6^°-yo° C. The control tubes were similarly treated. A sufficiency of large tubes of Dorset's egg medium was then prepared from the same egg-mass and inspissated and sterilised together, so that there should be no doubt at all events of the initial precise similarity of the soil upon which future growths were to be obtained. Care was taken that exactly equal amounts of medium were added to every tube, and that the angle of slope in the inspissator was the same for all ; the tubes being the same size, the area of the surface of the medium should be the same ; if measurement showed that some failed in this direction they were not utilised for the purposes of these experiments. PLATE IX. Fig. 39". — No toxin. Five weeks' growth. Fig. 39. — Pneumococcal toxin. Five weeks' growth. Fig. 40". — No toxin. P'ive Fig. 40*. — Auto-pneumo- Fig. 40''. — Auto-streptococcus weeks' growth. toxin. Five weeks' growth. toxin. Five weeks' growth. PhotograpJis by D>-, Ralph Vincent. THE BACTERIAL DISEASES OF RESPIRATION. 1 49 That number of tubes of the finished medium which corresponded to the number of cultures of the accessory microbes plus the same number to act as controls were taken and all water of condensation pipetted off from them. They were then treated as follows ; To tube T' 2 c.c. of the sterile toxin, say of the pneumococcus, was added ; To tube V 2 c.c. of the fluid from the control tube correspond- ing to the pneumococcal one ; To tube IT' 2 c.c. of the sterile toxin, say of the B. infltienzcs ; To tube ir^ 2 c.c. of the fluid from the control tube correspond- ing to the B. influenzcB one ; and so on, the (") tubes alwa3's serving as controls. These various tubes were then lightly plugged and sloped so that the added fluid bathed the whole surface of the egg medium ; they were set aside in the incubator at 37° C, until such. time as the surface of the medium was moist, but nothing more. This occupied two or three days. From the growth of the tubercle bacillus, which had been isolated from that same case, an emulsion in i per cent, salt solution was then prepared and centrifugalised at very high speed for several minutes ; the upper portion was pipetted off and examined for the presence of any clumps ; if these were present further centrifugali- sation was performed until a thin, perfectly uniform emulsion had been ensured. By means of a very fine sterile glass capillary pipette exactly equal volumes of the emulsion of tubercle bacilli were added to each of the above egg-medium tubes and very carefully distributed over the surface of each. The tubes were then sloped and placed in the incu- bator for forty-eight hours, when they were re-plugged with dry sterile woollen plugs, covered with a rubber cap, returned to the incubator in an upright position and allowed to incubate. At the end of three to five weeks the appearances of the various tubes were found in certain instances to differ in the most striking way. Some of the results are shown in figs. 39 — 42, Plates IX and X, For instance, figs. 39" and 39'', Case (i), show the different growths obtained after five weeks' incubation upon two tubes of Dorset's egg medium, the former having been manured with 2 c.c. of blood broth, • the latter with 2 c.c. of blood broth in which a pneumococcus, isolated from the same case as that from which the tubercle bacillus had been derived, had been allowed to elaborate its toxin. The acceleration in rate of growth of the tubercle bacillus produced by the pneumococcal toxin must roughly be million-fold. The specimen of sputum was sent to me by Dr. Roemisch, of the Wald Sanatorium, Arosa ; it came, I believe, from a rather early and subacute case which was not doing well. 150 THE BACTERIAL DISEASES OF RESPIRATION. Figs. 40% 40^ and 40'^^ (Case 2) illustrate the results obtained from a case in which the left upper lobe was little more than a mere shell surrounding a huge cavity, the left lower lobe being in a condition of almost complete consolidation ; there was a very doubtful focus of infection at the right apex ; a chain of enlarged glands ran down the right side of the neck. Dr. Rufenacht Walters kindly confirmed my clinical observations. Two organisms, a pneumococcus and a Strepto- coccus long'us, were isolated from the sputum. The effect their respec- tive toxins produced upon the growth of the concomitant B. tuberculosis is well seen in the preparations ; it will be noticed that the acceleration produced by the toxin of the Streptococcus longus was greater than that produced by the toxin of the pneumococcus. Figs. 41** and 41^^ (Case 3) illustrate what occurred in the instance of a case of chronic phthisis. The only accessory microbe seen in smears and isolated in cultures was a peculiar diphtheroid, not Bacillus septus. It will be noticed that the growth in the manured tube was in no respect better than that in the unmanured one ; and it may there- fore be deduced that if this diphtheroid organism did elaborate a toxin, this latter was without influence on the rate of growth of the allied B. tuberculosis. Case 4, illustrated by means of figs. 42'', 42'' 42^ and 42^^, was one of very chronic and slowly progressive tuberculosis of both apices, and of advanced but very slowly progressive laryngeal phthisis. Repeated examinations extended over a period of two years failed to reveal the presence of any accessory microbe other than the Staphylococcus albus. Figs 42'' and 42'' show the respective growths obtained after eight weeks' incubation upon an unmanured soil in the first tube and upon one manured with the Staphylococcus albus toxin in the second ; they will be seen to be practically identical. These observations were repeated several times, always with the same result ; if anything, there was a shade better growth upon the unmanured medium than upon the manured one. The significance of this will be considered later. Other experiments equally clearly showed that the toxins of certain bacteria had a very marked influence upon the rate of growth in artificial cultures of the tubercle bacillus associated with them in any given case of phthisis. It therefore remained to ascertain whether in those cases in which no such accelerating effect was evidenced the failure was due — (i) To an inabihty on the part of that particular strain of tubercle bacillus to respond to the stimulus of the toxin, i. e, whether the fault lay with the B. tuberculosis. (2) To an inability on the part of that particular toxin to stimulate PLATE X. Fig. 41 . — Auto-bacillary Fig. 41".— No toxin. Five toxin. Five weeks' growth. Fig. 42".— No toxin. Six weeks' growth. weeks' growth. Fig. 42'. — Anto-.staphylo- '^^^^' Fig. 42''. — Hetero-strepto- coccustoxia. Six weeks' Fig. 42'. — Hecero-pneumo- toxin. Six weeks' growth. growth. toxin. Six weeks' growth. Photographs hy Dt. Ralph I'lnceni. THE BACTERIAL DISEASES OF RESPIRATION. I 5 I the growth of the tubercle bacillus, i. e. whether the fault lay with the toxin. If the former of these hypotheses were the correct one, then it should not be possible to stimulate the growth of that particular B. tuberculosis by manuring the soil with any other toxins of proved powers of stimulation derived from allied organisms in other cases of tuberculosis. Accordingly some of the pneumococcal toxin from Case I (above) and some streptococcal toxin from Case II (above) were employed to manure the soil of two culture-tubes. These experi- ments were conducted side by side with those already detailed as 42^ and 42'', the same control, 42% sufficing ; here also no acceleration in the rate of growth of this strain (IV) of the B. tuberculosis was produced, cf. figs. 42% 42% 42'^ and inasmuch as repetition on several occasions with other toxins produced the same result, the deduction appeared to be justified that this particular strain of the B. tuberculosis was incapable of stimulation in this manner, at all events by one strepto- coccal, one influenzal, two pneumococcal and one staphylococcal toxin. If the latter hypothesis were correct then the staphylococcal toxin should prove incapable of stimulating the rate of growth of strains of the B. tuberculosis derived from other sources. Experiment showed clearl}^, however, that it did possess this power towards an alien strain of the B. tuberculosis, and justified the conclusion that in this particular strain of the B. tuberculosis, there was an inherent lack of power to respond by increased rate of growth to the stimulus afforded by the perfectly efficient toxin liberated by the concomitant invader, and also to that afforded by such other active toxins as were investigated. From these experiments it follows : (i) That there are certain strains of tubercle bacilli, whose rate of growth, in vitro, can be accelerated by the aid of the toxins of a con- comitant invader. (2) That there are certain strains which cannot be so acted on by toxins derived either from a concomitant invader or from a heterologous source. (3) That there are toxins elaborated by certain strains of bacteria which have the power of accelerating the rate of growth of the tubercle bacillus obtained from a concomitant infection. (4) That there are toxins which fail to exercise this power upon the tubercle bacilli derived from the same source, and yet are perfectly efficient towards other strains of the B. tttberculosis. It remained to investigate the following questions : {a) Are the strains of tubercle bacillus falling under (i) above like- wise capable of stimulation by the toxins of heterologous bacteria, and if so, of what bacteria ? 152 THE BACTERIAL DISEASES OF RESPIRATION. {b) Do the toxins which possess the power described under (3) also influence ahen strains of the tubercle bacillus in a similar way ? (c) Are there toxins (if such be formed b}' the bacilli) which fail to stimulate both the allied B. tuberculosis a.nd alien strains as well. (d) Will the filtered products of bacterial growth act in the same way as the killed suspensions of the bacteria in their culture media. To question {a) numerous experiments enable , me to reply that a strain of tubercle bacillus capable of stimulation by the toxins of associated bacteria is also capable of stimulation by the toxins of bacteria isolated from other cases of pulmonary phthisis, the degree of stimulation given varying, however, with different organisms and with different strains of the same organism : with some the acceleration of growth is very great, with others it is very slight. Roughly, the bacteria may be arranged as follows in regard to their accelerating powers, those with the greatest power being placed first : Streptococcus. \ M. paratetrageims. Pneumococcus. I Staphylococcias aureus. B. influenzcB. B. diphtheria. M. catarvhalis. Staphylococcus albiis. 'B. coli. The experiments which enable me to give an affirmative answer to question {a) likewise afford an answer in the positive to question (6). To question (c) I am not yet in a position to give an answer in either direction. Question {d) I have fully investigated for all bacteria associated with pulmonary phthisis which are considered not to form extra-cellular toxins, and have found that cultures of bacteria, even of many weeks growth, fail to produce any acceleration upon the rate of growth of the tubercle bacillus if these cultures are sterilised by filtration through Chamberland candles instead of by the aid of heat. The presence of the bacterial elements seems essential for the production of the effect. Assuming that these bacterial toxins are able to exercise the same influence in the human body as the}^ do under artificial conditions — and in support of this hypothesis I will adduce certain evidence — it then follows that the mixed infections in cases of pulmonary phthisis may play a two-fold part, viz. : (i) that of exerting an accelerating influence upon the rate of multiplication of the B. tuberculosis, and (2) that of producing the results which we have learnt to associate with their presence in other parts of the body, each variety of bacterium causing changes peculiar to itself. For instance, the staphylococcus is known to elaborate three substances : (i) a leucocidal substance, giving rise to cell necrosis and liquefaction of the tissues ; (2) an endotoxin, whose liberation on the death of the cocci produces a general as well as a THE BACTERIAL DISEASES OF RESPIRATION. I 5 3 local toxic effect ; (3) a hsemolysin, to which the body almost always contains an ample antibody, so that anemia is not a striking charac- teristic of staphylococcal infection. The deduction may fairlv then be made that a complicating staphylococcal infection must play some part in cavity formation and in the production of toxic symptoms ; as, how- ever, the staphylotoxin is an endotoxin and only liberated by the death and lysis of the bacteria, the toxic effect should be a limited one. This, in practice, we find to be the case; high pyrexia is only exceptionally found in cases in which pulmonary tuberculosis is complicated by a pure staphylococcal infection. Again, the pneumococcus appears to form not only a leucocidin and a powerful endotoxin, but also possibly some little exotoxin ; inasmuch as the leucocidin is certainly not so powerful as that of the staphylococcus, while the toxins are considerably more potent, it might be anticipated that with a concomitant pneumococcal infection cavitation effects would be rather less marked and toxic effects more marked than with the staphylococcus ; this appears to be the case. Again, as the Micrococcus catarvhalis appears to give rise to no leucocidal substance and probably to no exotoxin, the part it can play in the causation of cavitation and pyrexial symptoms must, therefore, be a small one ; its energies are devoted to the production of catarrhal symptoms ; its power of stimulating the rate of growth of the tubercle bacillus, as judged from certain test-tube experiments, would appear to be considerable. Finally the 5. influenzcB^Novi\6. appear to form little or no leucocidin, but considerable quantities of a very potent endotoxin ; whether it forms exotoxin is not known. Its influence in the production of cavities should, therefore, be small, but in the production of pyrexial symptoms great. Some confirmation of this is afforded by clinical observations. •Inasmuch as we have learnt from the preceding experiments that the presence of a concomitant infection does not necessarily mean the exercise of an accelerating influence upon the growth of the B. tuber- culosis, either owing to the fact that the micro-organism in question is incapable of elaborating such a stimulin altogether, or because the stimulin it does form is ineffective towards the particular strain of the B. tuberculosis with which it is associated, or finally because the latter is incapable of stimulation by the toxin of any other micro-organism, and inasmuch, moreover, as the action peculiar to the associated micro- organism may by no means necessarily be for evil — for instance, the lytic action of the staphylococcus may not necessarily be prejudicial to the patient, but, on the contrary, may lead to softening of the foci, the voiding of vast numbers of the tubercle bacillus, and ultimate 154 THE BACTERIAL DISEASES OF RESPIRATION. healing of the cavity so formed — it necessarily follows that when a con- comitant infection is present the precise role played by each of the allied invaders should be accurately determined. Every case of pulmonary tuberculosis is a complete law unto itself, and generalised deductions are, therefore, fraught with danger. Careful observation has convinced me that in the most rapid cases of pulmonary phthisis, such as the miliary and broncho-pneumonic, mixed infections may be altogether absent, or the numbers of the associated micro-organisms relatively to those of the B. tuberculosis may be extremely small. It does not, however, necessarily follow that the extremely rapid multiplication of the tubercle bacilli is not due to a prior manuring of the soil, say with the toxins of the pneumococcus or B. influenzcB in the first case, or that the supply of manure furnished by the few concomitant invaders in the second place is altogether insufficient or is ineffectual in producing an ill-effect. I have the opportunity of determining the accelerating effect in vitro of the secondary invaders upon the B. tubei'culosis from one case only of acute broncho-pneumonic phthisis. The experiments were not altogether conclusive, but they appeared to show that the toxins of the associated micro-organisms produced no acceleration on the growth of the associated tubercle bacillus. The numbers of the secondary invaders relativel}^ to those of the tubercle bacillus in specimens of sputum voided from this case were extremely small from the inception of the infection to the very end. On the other hand, in the case illustrated by figs, sg*" and 39'', the numbers of the pneumococci in the sputum relatively to those of the B. tuberculosis were also very small, yet we see how great was the influence of the toxin of the former upon the rate of multiplication of the latter. We therefore learn if these cultural experiments have any definite value — and this I hope to show is certainly the case — that actual numbers of secondary invaders appearing in the sputum have little bearing upon the future progress of the case. Their true importance may be estimated by cultural experiments and observations upon the patient in the manner which I shall now describe. Method of Determining whether tJie Deductions made from Cidtural Observations have any Value when applied to the Human Subject, and the Application of the facts so Learnt to the Prevention and Cure of con- comitant Infection. If the observations made in vitro hold with equal force in regard to the human body, it should obviously follow that if a concomitant infec- THE BACTERIAL DISEASES OF RESPIRATION. I 5 5 tion can be stamped out not only should such symptoms as are directly referable to the secondary organism or organisms be caused to disappear, but also a definite effect should, in most instances, be produced in course of time upon the growth of the tubercle bacillus itself. The question at once arises in any given case of phthisis, is it possible to determine the precise role that is being played by allied invaders and the tubercle bacillus respectively ? While I am not prepared to state that this can always be accomplished, in many cases it most certainly can be done. The method depends largely upon the most careful stethoscopic examination of the chest and the detailed observation of the change in physical signs produced by the inoculation of therapeutic doses of autogenous vaccines and of tuberculin respectively. Inasmuch as the determination of the precise nature of the concomitant infection is not a very difficult matter, the task before one would be greatly simplified if the exact nature of the physical signs which may be produced in the chest by each micro-organism were known ; this, unfortunately, is not the case. That all the physical signs producible by the B. tuberculosis + a concomitant infection, with the single exception perhaps of those of cavitation, may be produced by a perfectly pure infection by the B. tuberculosis, I believe to be the case, but none the less is it true in the great majority of instances that by far the greater proportion of the physical signs which most clinicians would assign to the action of the B. tiibercidosis are in reality due to the other micro-organisms present. The precise part played by the B. tuberculosis and by the allied organisms respectively is determined in the following way. The patient is confined to bed under the most favourable conditions that can be secured ; the temperature and pulse are recorded four- hourl}^ and the daily amount of sputum measured. Specimens of the sputum are examined in the ways already indicated, cultures made of the B. tuberculosis and of all the secondary invaders, vaccines and toxin preparations of each of the latter prepared, and in due course of time the accelerating effect of the toxin of each associated micro-organism observed. Daily stethoscopic examinations of the chest are also made and the observations recorded upon a suitable chart ; the best form for this purpose is the diagrammatic one employed here, as this affords ample room for the insertion of such signs as we may employ. When the patient has settled down into a more or less constant condition as regards pulse, temperature, physical signs and expectoration, by which time vaccines should have been prepared, we are ready to proceed. Obviously 156 THE BACTERIAL DISEASES OF RESPIRATION. there are two possible ways of beginning*: (i) by employing tuberculin inoculations and observing their effects ; (2) by employing the vaccines either singly or in combination and observing their effects. The tuberculin and vaccines should never be employed together as the effect of one will completely mask that of the other. Personally I think the best procedure is to estimate the effect of the vaccine before that of the tuberculin and to employ the vaccine of one organism at a time, in order that the precise influence of each maybe determined. To this, however, there is one prachcal objection to which reference will be made later. Accordingly the physical signs in the chest having been again recorded a therapeutic inoculation of the vaccine is performed, such dosages as the following being employed : (i) B. infliienzcz, 100 millions ; (2) Staphylococcus, 100 millions ; (3) B. septus or other diphtheroid, 100 millions; (4) M. catarrhalis, 50 millions; (5) M. paratetragenus, 50 millions ; (6) B. of Friedlander, 50 millions ; (7) B. protetis, 50 millions ; (8) Streptococcus, 25 millions ; (g) pneumococcus, 25 millions; (10) B. coli, 25 millions. As a second examination of the chest should be made in about twelve hours it is most convenient to select an hour between 8 and 10 p.m. for the inoculation. The records of temperature and pulse are of course continued, and the sputum measured at first at twelve-hourly intervals, later at daily ones. Subsequent observations then of the chest are made after the lapse of twelve, twenty-four and forty-eight hours and daily thereafter. If the organism of which the vaccine was employed be concerned in the production of signs and symptoms and the dosage employed be adequate, a definite effect should be produced in any one or more of the following directions within twelve hours : (i) There may be rise in the pulse-rate of 10-20 beats; (2) there may be rise in the temperature of o'5-i*5° F. ; (3) there may be an increase in the quantity of sputum ; (4) there may be an increase or alteration in the physical signs ; and of these the last is the most important. Comparison of Charts 15" and 15* will serve to illustrate the actual changes so produced in a certain case. Fresh examination at the end of twenty-four hours should show a swing back in the condition of the patient : (i) The pulse-rate should be the normal of the patient ; (2) the temperature should have fallen to its old level or to a lower one ; (3) the sputum may be diminishing ; (4) the physical signs should be improving, and may correspond to THE BACTERIAL DISEASES OF RESPIRATION. D/ what thev were before the inoculation or a certain amelioration may have been produced (Chart 15'') ■ At forty-eight hours the changes noted after twenty-four hours should have advanced further in the same direction (Chart 15-^). In some instances there is a somewhat delayed reaction : the changes which are described above as being typical of the twelfth hour have not been evidenced till the twenty-fourth hour, those of the twenty-fourth hour not being evidenced till the forty-eighth hour. By the end of seventy-two hours there may be a further improvement in the clmicai signs of the patient and this may continue for several days. A time will, however, come, largely dependent on the dose of vaccine given, when instead of improvement a retrogression will be initiated, this is the signal for a repetition of the vaccine. Front of Chest Back of Che^t POSTJUSSIC HALE PRK TUSSJC CSY-RAie 00 00c r PR/€ -WSSIC MOIST-RALE XX X - RHONChUS R > "^ L ^ ° I t a 5^ a ' G a X n * ° ' '/ ^ y . m ^0 • e • , c IV e D V J L ^ R 9 X. I c X • (J a IT ^0 a 1 V -i. p" ' X m ^ • < <5 IV X 1 i • 1 V • e X VI i 1 . VR Chart 15". — Before first inoculation. Sputum = 6 oz. per day. Occasionally it will happen that no reaction whatsoever is obtained; this indicates one of two things, either [a) that the dose was too small, or (6) that the vaccine itself has no power of stimulating the formation of immune bodies. If the former alternative be thought likely a double dose is given at the expiration of seventy-two hours and observations continued as before ; this, I think, should alwavs be done before assuming the latter alternative, (h) that the vaccine itself is useless, which indicates that the corresponding organisms are producing no effects at the infected foci, and that trial of a vaccine of another of the organisms should now be made. If this procedure be carefully carried out it will be found that in those cases in which the secondary infection is a multiple one, there is a marked difference in the response which is made to inoculations of the several vaccines : that some produce much more effect upon the Front of Chest Back o-f Chest R • • • .^ L • • • «**" R .^ POST-TUSSIC X o 6 oX o 1 X o Ox o X o o *Z X o O X X° I < o V. o .0 , o X o X ■%o n o>. oX O o n X O ,5 X ' o • • 0,0 CO ooo = o o • * O o o w O o o >t o K o o f'Pf -TOSSIC o * o ■ o V ° X ' o • * o MOIST-RMl o * a Y ^ o • o • • o o °< . o VT o . • o e> •*. XX _ X - KHOHCMUS o • ' . ' o • YR • Chart 15*. — Twelve hours after first inoculation. Sputum = 10 oz. per day. Fi'ont of Chest Beck of Chest POST-TUSSIC HALE "R/f TUSSIC DRY-RAie 00 000 - f»/C -TUSSIC i^OiST- {All XX X ■ R. ° Z. >-. X c X / % x: ^ iZ D :>'■ • m • 7^ . - * . IV . • " V • • . £. . 0.0. >-, 6? X -< '0 I , , X c n X -^ X .; " m , IV . X « • , V ' * VI YE "^ .„,.:,:.«>< Chart is"-'. — Twenty-four hours after first inoculation. Sputum = 6 oz. per day. front of Chest Back of Chest R > ^ L ^ L "^ .9 ^^ POST-TUSSIC RALE -A , X • ' I X. ■ / X X X >. n X X ^ ^ x' ■X.0 n • •X ''", - « " HI ' - i- ' PFK TUSS/C DRY-RALf • m • « • • • • rV •/■ 00 000 = • ' IV PR/i -TUSSIC V V VI XX X - RHONCMUS vn Chart 15''. — Forty-eight hours after first inoculation. Sputum = 2 oz. per day. Front of Che5\ Back of Chest R > ^ ^ L ^^ L "^ P. t'vsT-rossic o o / X 7 o 7'- o o " o IT X. ■*. X X • n o ^0 K • V.'I = ' • m X o <= o X Pfijt TUSSIC o • 6 o o >< m • X. * IV . o X • oo ooo = o O o o w fff^ -TUSSIC V . o o * o • o Y n ' ' t> ' X X X - RHONCtlUS MI Chart 15". — Six days after first inoculation. Sputum = 3 oz. per day. Second inoculation. front of Chest Back of Cheat /; > ■^ iL .^ POSTjTUSSIC • / KALE ^ X *. > " u s. >. X '/.-t - :> 'J PRK TUSSIC DRY-KAie m - X 7<, ZZ7 C • • /F <= B ' y VI p ^ YR ° Chart 15A — Twelve hours after second inoculation. Sputum = 4 oz. per day. front of Chest Back of Cheat POST^TUSS'C RALE PR/l TUSSIC DRY-RALE PP/e -TUSSIC MOIST- RAIE XX . X - RHONCHUS R. ~^ L ^ L ^ ■^ R ► X V. / V- ' r A n . • V- V. n •*• . . ■i m ' -f- « . *• m IV m w V Y VI m Chart 15^. — Forty-eight hours after second inoculation. Sputum = i oz. per day. l6o THE BACTERIAL DISEASES OF RESPIRATION. patient generally and upon the physical signs in particular than do others. The interesting fact now comes out in the great majority of cases that the vaccine which will produce the greatest effect is of that organism which likewise causes in vitro the greatest acceleration upon the growth of the B. tuberculosis, and that this organism is not necessarily the one which predominates either in smears or in cultures of the sputum. It is thus apparent that theoretically the way in which the fullest use is to be made of laboratory observations, and according to which the greatest benefit is likely to accrue to the patient, provided that the clinical condition warrants such delay, is to prepare immediately vaccines of all the allied organisms, to estimate the accelerating influence of the toxin of each, and then to begin treatment with the vaccine of that organism which produces the greatest accelerating effect. So much time has been occupied in the preliminary stages of these investigations that opportunity for the application of the lessons learnt has as yet been scanty. In the instance, however, of Case 2, illustrated by figs. 40% 40'*, 40^, Plate IX, this procedure was adopted, with the striking results that are depicted in Charts 16*^ to 16''. The clinical history was as follows : A male, aged 40 years, had had practically no illness till two years prior to my seeing him ; enlarged glands then appeared on the right side of the neck ; suppuration followed, then healing. Nine months later a severe cough came on, followed by pneumonia and pleurisy for which he refused to take to bed : three months afterwards tubercle bacilli were found in the sputum. Although his general condition had remained good his appetite had become very bad, and there had been a loss of weight of 8 to 10 lbs. There had been no night sweats and the bowels were regular. There was a nightly rise of temperature to between ioo°-ioi° F. On examining the patient the clinical condition briefly was as follows : In the mouth eleven stumps were seen and very advanced pyorrhoea alveolaris. To this cause the enlarged glands were attributed. These ran down the right side of the neck, each constituent being about the size of a hazel-nut. The left side of the chest moved badly and was somewhat retracted, and there was marked sinking in over the left clavicle. There was amphoric resonance from the first to the fourth left ribs in front, and below the level of the nipple there was marked dulness. Behind there was absence of resonance above the clavicle, and ver}' marked dulness from just below the spine of the scapula to the level of the eighth rib. THE BACTERIAL DISEASES OF RESPIRATION. i6i The right side appeared normal back and front, both to inspection and percussion- On auscultation there were crackling rales to be heard all over the left chest, back and front, and some rhonchi ; over the space in front extending from below the first rib to the level of the fourth rib cavernous rales were audible. Here also there was bronchophony and marked pectoriloqu}^ The only abnormality detected on the right side was a slightly prolonged expiratory murmur at the apex in front. The diagnosis was made of advanced phthisis of the left upper lobe with great cavitation, consolidation of the whole left lower lobe with commencing softening, and some bronchitis. Infection of the right apex doubtful. Front of Chest Back o-f Chest POST^TUSSIC RALE PRK. -TUSSIC DRY-RALe oo ooo - o PR/E. -TUSSIC MO/ST- RALE XX _ X - RHONCtlUS C.'Cc^^rz -6*/-- HI TV V 2^j TT- r / /Ji /^ o o V L o o o R • K o o I o O ° 6 n 6 o X m o O K IV o ^0 o ^ V \ o o o o a o VI o o o vn Chart i6". — Case 2, before inoculation with Vaccine I. Specimens had previously been forwarded to me, and the tubercle bacillus, pneumococcus, Streptococcus longus isolated. The patient was sent to bed, and on the second day the eleven stumps and few remaining sound teeth extracted ; the sockets were sprayed repeatedly with hydrogen peroxide, and a chinosol mouth- wash prescribed. Three days later the patient already declared that he felt better and that his appetite had improved. As by the sixth day the evening temperature had remained steady for three consecutive days at 99*8° F. and the morning one at 98*6^- 98*8° F. it was resolved to begin treatment with the streptococcal vaccine. Chart 16^ shows the then existing condition of the chest. A 50-million dose was given at 7 p.m., and subsequent observations made next morning at 9 a.m., at 7 p.m. at night, and at 7 p.m. on subsequent evenings. Charts 16^, IP, etc., illustrate the findings. 1 1 Front of Chest Back of Cheat R. ■^ o O a c3 ^^ fOST^TUSSIC I ><> n i 4^' PR/f -TUSSIC DRY-RA.LE m ^ ^ coo = PRK -TUSSIC IV V X X Ox XX _ X - KHONCMUS X , <* > ^ r'"'^ /K e> X O 6 V o ^ > w o o5» w: Chart i6''. — Case 2, fourteen hours after inoculation. Front of Chest Back oi Chest POSr^Tvssic HALS fRK TUSSIC DKY-KALB oo ooo = o ff>/€ -TUSSIC MOIST-KAU XX . X - KHONCMUS R > ^ o L ^ I ^ 7"' > , n / ^ y ^. "A r> o o IV o o O X A 0° Y <} o o a L ^ R '^^^ ■X o ^ o I o X 0" R o X a " o III o < IV X o o 'o' V o o o VI YH Chart i6^'. — Case 2, twenty-four hours after inoculation. Front of Chest Back of Chest POST^TUSSIC RALE PR/l TUSSIC DRY -RALE OO ooo = o PR/C -TUSSIC '■iOlsr-RA.lE XX . X - -RHONChUS A > ^ ^ L ^ I ?^ '^K' p n 7y > m > o IV o X K V o L o ^ R o ^ ^ iT n 1^ ^ ':'y. = ^0 m PRK TUSSIC DRY -RALE m V « o X o o „". / IV oo ooo = w o X x •^/P-f -TUSSIC o o X V Y o X o o C7 *o vr fi:HONCHUS w: Chart 16". — Case 2, six days after first inoculation ; second inoculation Vaccine I. Front of Chest Back of Chest R. ^ ^^ /L -^ L :-- ^ ^ R \^ POST-TUSSIC I ^ ^V \ I X " n n Yr •;:; = Cf m PR/l TUSSIC m c» / CJ a IV 00 000 = w Pff/t -TUSSIC V MOIST-RALE , Y yi XX . X - ^HONCHUS MR Chart i6^ — Case 2, eleven days after first inoculation ; third inoculation Vaccine II. Front of Chest Back of Chest POST-TUSSIC RAL£ .PRM. -TUSSIC DRY-RALE 00 000 - PRK -TUSSIC MOIST-RALE XX . X - /iHONCnUS R > ^ "^ L -^ L '^ R > 1 V (2^ I n ^ b ■ X n ^0 m m r/ IV — — IV ° - V Y VI w: Chart 16". — Case 2, twelve hours after third inoculation. 1 64 THE BACTERIAL DISEASES OF RESPIRATION. It will be observed that at the end of fourteen hours there was some exacerbation of the signs, and the temperature was raised o'5° F.; by the end of twenty-four hours improvement had begun to set in, although the temperature was still raised o'5° F. Thereafter steady improvement continued till the evening of the sixth day, when there was a slight exacerbation. The 50-million dose of streptococcal vaccine was accordingly repeated, with the result that a similar sequence of effects was produced. On the twelfth day of treatment, although there were no signs of relapse, I decided to give a 50-million dose of the pneumococcal vaccine, Front of Chest Back o-f Chest POST-TUSSIC RALE PR/l -TUSSIC DRY-RALE 000 = PR/E -TUSSIC MOIST-RALE XX . X - KHONChUS R > ^ L ^ L ^ R, I y I n '/ X n X m m "0 e - IV IV ^ V V n m Chart 16''. — Case 2, fifteen days after first inoculation, left for home three days after third inoculation. as the patient had to return four days later, and as he would pass out of my care thereafter I thought it well to ascertain the value of this vaccine, with a view to combining it, if found advisable, v/ith the streptococcal one for employment by the doctor in the country. A shght increase in the signs was noticed twelve hours later (Chart 169), but this rapidly passed off, and when I examined the patient on the morning of his departure {i. e. the sixteenth day) I was more than gratified to find that the condition was that depicted in Chart 16^. The dulness over the lower lobe, back and front, had completely gone, the amphoric breathing, bronchophony and pectoriloquy were reduced, and only a very occasional small rale was to be heard any- where. Even post-tussic rales could not be elicited elsewhere. When seen four months later the patient was looking and feeling very well indeed ; he had recovered all his lost weight, and an occa- sional fine rale at the end of inspiration was all that could be heard. THE BACTERIAL DISEASES OF RESPIRATION. 1 65 The subsequent history of the patient was one of continued pro- gress for a period of over two years, interrupted only by an attack of influenza, which soon yielded to treatment, and by a slight pyrexial attack set up by active exercise to escape the attentions of a very much excited bull. He then contracted a severe pneumococcal influenzal infection, neglected himself, and soon died. The experience I had in this case of the effect producible by a suitable vaccine has been confirmed in other cases. Inasmuch, however, as the estimation of the accelerating effect of the toxins occupies about ten weeks of time, and this delay may prove anything but advantageous to the patient, two alternative procedures have sug- gested themselves : (i) The prior estimation of the action of tuberculin upon the physical signs, which is carried out in precisely the same way, merely substituting for the vaccine such doses of tuberculin as are thought advisable ; (2) The more or less empirical employment of vaccines of some or all of the organisms isolated from the sputum, choice being made of combinations which experience indicates as being likely to benefit the patient : this empirical choice is subsequently confirmed or modified by the laboratory experiments and by the progress of the patient. The latter of these alternatives I consider the better, inasmuch as experience tells me that in the class of case which is likely to benefit from vaccine treatment, the effects produced by the vaccines are much more rapid and much more marked than would be those produced by any limited course of tuberculin therapy. In illustration of the validity of this position, I will give a short description (with charts) of a case in which this procedure was adopted. Mrs. A , aged 48 years. History briefly as follows : x\bout five years before consulting me several haemorrhages from the lung. Went to Midhurst for five months, where man}- tubercle bacilli were found, and the diagnosis made of tuberculous disease of both lobes of the right lung. Improved considerably, and told she was almost dry. Went home, and almost immediately contracted a severe bronchitis, which threw her back. Remained at home under open-air treatment for about a year, then went to Rosa for six months. The high altitude did not seem to suit her, so returned to England in the summer, which she spent at Margate. Here she had a haemorrhage from the bowel and some pvrexia, which persisted. Since then she had stayed in England, spending the last two winters at Falmouth. Despite the fact that she has had much mental worry, she was more than holding her own. Unfortunately last winter she was placed in a damp bed, con- i66 THE BACTERIAL DISEASES OF RESPIRATION. tracted influenza, had several haemorrhages, and lost ground consider- ably. This influenzal attack she has been unable to throw off. Her usual rectal temperatures have been g8° in the morning, 99° in the evening; sometimes 100° in the evening, and occasional!}' 101° — this vi'hen she contracts a cold, and to these she is very subject. Her periods are regular, the evening temperature rising about 06° for the preceding six or eight days and while they last, then falling to her normal. She has not lost weight, in fact the tendency to increase is such that she limits the amount of milk and cream in her dietary to counteract it. When I saw her she had been in bed for about two months and looked rather pale, but otherwise in robust health. Tubercle bacilli were very numerous in her sputum, allied invaders being the B. influcnzco. 'front of Chest Back of Che^t R. L ^^ POSTjTUSSie I ^A '/y r ^"0 „ n A / PR/l -TUSSIC DRY-RALE 0'" . ^ . m y ^/* ' 00 000 = f/f/E -TUSSIC ^ • e IV /. y/ V XX . X - KHONCHUS Chart 17". — Mrs. A — , before inoculation with vaccine- — B. Influenza lOO millions, M. catar- rhalis, 50 millions, pneumococcus and streptococcus each 25 millions. M. catarrhalis, Streptococcus brevis and Pneumococcus. Her tem- perature rose in the evening to about ioo° F. The main points revealed by clinical examination of the chest were as follows : it was well covered, there was no sinking in above the clavicles or elsewhere ; the respiratory movements were poor, especially on the right side. On percussion there was impaired resonance in front above the right clavicle and in the first space, and over the whole of the right chest behind. Elsewhere it was not quite satisfactory without being actually defective. On auscultation the condition shown in Chart ly" was found. In front on the left side was bad air-entry from the clavicle to the fifth rib; in the second and third space an occasional clicking rale was heard at the end of expiration; in the fifth and sixth spaces external to the Front of Chest R. ^.^ r — L Back oi Chest POST^TUSSiC HALE XX . X - RHONCHUS L ^ R ' / I / n y / / m / / / IV m / / TP^ o / W -'o ' o o w: * # - a o Chart 17*. — Mrs. A — , eighteen hours after inoculation. Front of Chest R. ^^ r-^ L Back of Chest PR/C -TUSSIC MOIST-RALE XX . X - KHONCnUS -^» Chart 17'-.— Mrs. A—, five days after first inoculation ; similar condition on twenty-sixth day. Front of Chesi Back of Chest R. ^ ^ L .^ POST^TUSSIC X - / • I X n ^ c«* *« ^ PR/l -TUSSIC y. m 00 000 = Pff/E -TUSSIC / .d / , IT MOIST-RALE /. K y V /^ X^ XX . X - RHONCHUS / / / L ^ ^ 0/^ ' 0,' .-. 'y^ y ' I ' '/^ 7^ ^ M 0-0 '0 .y y y- m >:: - . '0 ' IV /* V • VI ' - YH • • t Chart ly. — Mrs. A — , eighteen hours after fourth inoculation, which equalled one and a half times initial dose. Looking pale and " feeling rather out of sorts." Front R. ^^^ Qf Chest z. Back of Chest POsr^Tussic X I / I K n ■> ^^ *^ ■^^•^^ u / V m / PPJf. -TUSSJC DRY-RALE A m / IV (^'0 '• 000 = w PRK -TUSSIC V \//> / V t ^«< ^ vr X. y #/^ fy "/ KHONCtlUS / T2r -7- T^'— Chart 17". — Mrs. A — , forty-eight hours after fourth inoculation. Front of Chest Back of Chest posr^wssic fiAL£ PR/l -TUSSIC DRY -RALE 00 000 = o PRK -TUSSIC ■ MOIST-RALE XX . X - fiHONCtlUS R > ■> ^ L X V / / / n / ;ncc j£c>^ '^ m A ey4- 7 IV / / V ' y L -^ ^ R :^ I X ^ >f ^ ^ n - /^-. ^ m K c /' V IV ^ V \£j w wr Chart 17A — Mrs. A — , before sixth inoculation 1 of double initial dosage). Front of Chest Back of Chest R. L ^ POST-JUSSIC RALE / ^ ^ n RRA TUSSIC DRY-RALE m 00 000 ~ PP/t -TUSSIC IV V XX . X - JiHONCnuS L ^ > ^ ■ gin tuberculin treatment in cases which are suitable for this procedure. The usual answer given is — " As soon as possible. '^ Person- ally I think this needs some qualification. Cases with mixed infection are not necessarily to be excluded from treatment, and, indeed, most observers frequently treat such cases with tuberculin, failing to recog- nise that mixed infection is really present ; in these it is not wise to combine vaccine and tuberculin treatment, for the effect of each is likely to mask the effect of the other. I think I have amply demon- strated in Chapter X that the wiser course is to deal first with the mixed infection and then with the tuberculous process, so that I think the proper answer to the question is " as soon as possible after any mixed infection present has been adequately dealt with." Tlic Choice of Tuberculin. As a necessary preliminary to the consideration of this question it is well to recapitulate a few important points. Firstly, that tuberculin is an actively immunising substance ; it contains albumins constituting the toxic elements formed by the bacterial growth, as well as those constituting the essential proto- plasmic substance of the bacilli. Some of the tuberculins contain only one or other of these bodies, some contain both. The human tissues are capable of elaborating antibodies to these albumins, so that immunity can be excited both against the toxins and the bacilli themselves. Of these antibodies little is known, but among them lysin, agglutinin, opsonin, antituberculin and possibly antitoxin may be mentioned. In cases of pulmonary tuberculosis the general symptoms are due to the action of a toxic component of lysinised tuberculin upon the central nervous system, the focal changes are due chiefly to secreted 2 20 THE BACTERIAL DISEASES OF RESPIRATION. endotoxins^ the range of their activities being more or less confined to the infected areas. The true ultimate objective of treatment is to bring about extinction of the infection, but the production of bactericidal effects is complicated by the existence of a peculiar sensitiveness of the tissues to lysinised tuberculin, and the consequent necessity of establish- ing a high degree of tolerance to the toxin. When general symptoms are little marked these difficulties are minimal, but when constitutional disturbances are severe or easily excited it is necessary that attention should be directed to the establishment of a high degree of tolerance. The statem.ent is often made that all the varieties of tuberculin are capable of producing the same results, the only difference being that some are more powerful agents than others. But with this I do not absolutely agree : there is, and must be^ a difference in the immune bodies which they are capable of inciting corresponding to the differ- ence of their constitution. Thus T.R., and to a less degree B.E., will lead more especially to the production of antibodies to the proto- plasmic albumin ; T.O-xA.., and old tuberculin, on the other hand, will incite the production of antibodies more especially to the soluble toxins, and so will the more powerfully stimulate the development of toler- ance. While old tuberculin is absorbed with considerable rapidity, B.E. is absorbed very slowly ; the production of antibodies is correspondingly affected, and it therefore follows that in febrile and highh' sensitive cases B.E. is less likely to lead to violent reactions than is old tuber- culin, and this preparation is therefore preferred for use at the begin- ning of the treatment of such cases. Sahli and others state that of all tuberculins Beraneck's contains the least amount of non-specific toxins, and at the same time a high content of specific toxin and essential protoplasmic albumin ; they therefore consider it to be the best preparation for general use. The preparations derived from the bovine strain of bacilli probably differ from those derived from the human strain mainly in the direction of being much milder in their actions, and therefore less liable to produce severe disturbances. Although it is not possible to give definite values for the immunising powers of the various tuberculins, it is possible to arrange them roughly as follows in descending order, the attached numerals being an approximate value of their respective strengths : Denys' B.F. (500), T. (200), P.T. (40), B.E. and T.R. (5), and P.T.O. (i). Until one has had a fair amount of experience of tuberculin therapy, it is well to restrict oneself to the use of a few preparations only ; for most purposes old tuberculin, or T., will serve well, and it is perhaps advisable to employ this preparation alone till considerable practice has THE BACTERIAL DISEASES OF RESPIRATION. 22 1 brought familiarity with dosage, and the various \va3-3 in which the human tissues react thereto. In dispensary work and the treatment of ambulant cases the use of P.T.O., P.T., and T. in sequence has much to recommend it, the slight toxicity of the first preparation minimising the risk of exciting undesirable reactions. Personally, I think that in every instance treatment should be con- cluded by a course of bacillar}' emulsion, a two-fold reason for this existing in the facts — (i) that this preparation is a whole bacillar\- product. and is therefore best suited for the production of anti-bacterial immunity, and (2) its rate of absorption being slow the immunity which has been established is thereby maintained at a high level for a con- siderable period. As transition is made from one tuberculin to another, it is necessary to keep in mind the approximate relative strengths of the respecti^"e preparations ; for instance, if the dosage of P.T.O. has been raised to o'l c.c, and it is thought advisable to make substitution of P.T., it will not be good practice to begin with a minimal dose such as "ooooi c.c, for thereby time will be lost and opportunity also given for tolerance to drop from that high level to which it has been raised with so much care. The dose of P.T. corresponding to O'l c.c. of P.T.O. being about '^ c.c. or '0025 c.c, there will be little danger in beginning with a dose of "0005 c.c. of P.T. A similar calculation will give the appropriate initial dose of other preparations as they are substituted in turn. Personally, in making transition, I prefer to begin with onh' one-fifth of the calculated dosages. Conduct of the Course of Treatment : Dosage and Intervals. The procedures which have been devised for the administration of tuberculin are almost as many in number as are the specialists in the use of the drug. It is quite impossible to enter into a discussion of the merits and demerits of each, and I propose to give onlv such general instructions as experience has shown to be applicable to the great majority of cases, and to point out how these may require modification to suit individual cases, for let me once more emphasise the fact that in tuberculosis, more than in any other disease, it is necessar_v to pay the most strict attention to the peculiarities of each individual case, and that it is only by doing this that the incidental dangers can be avoided and the best results secured. While it must be admitted that the establishment of a high degree of tolerance of the tissues to tuberculo-toxin is a very important essen- tial, inasmuch as it is only by the achievement of this end that the grave constitutional disturbances due to intolerance of the toxin can be removed and kept in abeyance, I would join serious issue with all those who make this the sole objective of their treatment, and assume 2 22 THE BACTERIAL DISEASES OF RESPIRATION. that high tolerance and extinction of infection go hand in hand, and are necessarily the same thing. The true aim of all treatment should be the extinction of the infection, and the best indication of progress in this direction is the condition of the local lesions. Now, observa- tions of pulse and temperature and the general condition of the patient are easy, and are carried out as a mere routine in the treatment of all severe forms of bacterial infection, but however valuable they may be in themselves they do not necessarily afford a good indication of the condition of the local lesions, and this contention holds with especial force in regard to pulmonary tuberculosis. No sound observer would be content to treat a case of tuberculous laryngitis without making close scrutiny of the progress of the lesion, nor be satisfied that all was going well with a case of pneumonia without carefully examining the chest, yet many, if not most, authorities advise the control of tuberculin therapy by means of pulse, temperature, and general condition, to the neglect of careful observation of the chest. For this two things must be held responsible : firstly, disinclination or inability to devote the time to careful systematic stethoscopic observa- tions ; secondly, the entirely fallacious view already mentioned as held by many, that a general reaction can be elicited in the absence of a focal one, T have already mentioned the production of the former is dependent upon the production of the latter, for the amount of toxin that can be formed by the tuberculo-lysin from any but the largest therapeutic doses of tuberculin falls far below that necessary for the poisoning of the central nervous system upon which constitutional symptoms depend ; the local reaction maybe so produced, but the focal and general reactions are dependent upon the increased elaboration of antibodies set up by the inoculation, and the action of these upon the innumerable bacilli at the foci of infection. It is a matter of common observation that marked focal changes can be detected in cases of lupus, tuberculous laryngitis and iritis after such a dose of tuberculin as fails to produce the least constitutional disturbances, and it is only the lack of careful stethoscopic observations at suitable intervals that has given rise to this prevalent fallacy. Occasionally, of course, lesions may be deep-seated in the lung, or be productive of few signs discover- able by the stethoscope, but a considerable experience enables me to affirm that such cases are clinically rare ; I have never yet seen a case in which alterations, at all events in breath-sounds, were not produced by a therapeutic dose of tuberculin which sufficed to produce even the mildest constitutional disturbance. Such cases may, however, exist, and there are others where intolerance is very marked relatively to the focal reactions, and it is only in these, and in, cases where opportunities cannot be afforded for close clinical observations, that the guidance THE J3ACTERIAL DISEASES OF RESPIRATION. 223 of the general reaction should be substituted for that of the focal reaction. The best procedure of all obviously is that wherein due regard is paid to all the varying aspects of the case, and wherein the local, focal, and general reactions are all carefully correlated and weighed together. The procedure to be followed in the stethoscopy of the chest after the administration of a therapeutic dose of tuberculin is precisely similar to that which has already been so fully described and illustrated in Chapter X-, pp. 155-170, for the control of dosage and intervals in the treatment, by means of vaccines, of the mixed infection, and needs little further consideration. As with all other methods, treatment is begun with such a minimal dose of the selected tuberculin as the clinical condition of the patient and other considerations indicate ; this, for most cases, may be 'ooooi c.c. of either P.T.O., T.R. or B.E, -000005 P-T., "000002 T., 'oooooi T. Beraneck ; if the case be a pyrexial or very early one half the above dosages may be employed. If the patient be a strong healthy subject or the disease be of long standing and few symptoms, the above dosages may be safely increased two- or even live-fold, but inasmuch as the increase of dosage is, as a rule, rapid, there is little occasion for this. If neither focal nor general reaction results, the initial dosage is doubled in three days, and this procedure continued until one or other reaction is produced, a focal one being, as 1 have said, almost always discoverable before a general one. As soon as a dosage is attained which does produce a reaction a slight reconsideration of the clinical features of the case is necessary, the principles of tuberculin -.therapy differing slightly from those of other forms of vaccine therapy in that tolerance has to be taken into account as well as antibacterial imm.u- nity. Accordingly, if tolerance is low, as evidenced by slight degrees of exercise causing auto-inoculatory phenomena, it is desirable to produce a rapid increase of tolerance ; clinical experience has shown that this can only be done by giving increased dosages at short intervals, viz. of about three to five days. Under these circumstances increased dosage will be given at each inoculation provided that careful observa- tion of the focal reactions show that these are not being unduly excited, and that sufficient time is allowed to lapse between inoculations to permit the local condition deriving full benefit from the focal reaction ; the fulfilment of this condition usually necessitates a slightly longer period being allowed between inoculations than would be allowed if the raising of tolerance were the sole objective — in other words, the intervals may have to be five to seven days instead of three to five days. On the other hand, if tolerance is adequate, as shown by the absence of auto-inoculatory phenomena, the necessity for rapid increase of 2 24 THE BACTERIAL DISEASES OF RESPIRATION. dosage does not exist, and so long as a certain dosage produces a satis- factory focal reaction there is no need to go beyond it. As a rule it will be found that after three or four doses of a given magnitude focal reaction begins to fail : this is the signal for immediate increase of dosage. A very satisfactory scale for dosage is that employed by Bandelier and Roepke, viz. i, 1*5, 2, 3, 5, 7, 10, 15, 20 and so on; this will serve for the great majority of cases, but will need modifying to meet individual peculiarities. It should be remembered that if at any time increased dosage produces an excessive reaction or undesirable constitutional effects in any way, prolonged rise of temperature or of pulse-rate and loss of weight being the most important symptoms under this category, return should at once be made to that dosage which failed to give rise to these ill- results, and any subsequent increase is to be made with especial care and caution. The temperatures which should be taken for control purposes are best determined experimentally for every case, for some have their highest temperatures at one hour of the day, others at a totally different hour. Before treatment is ever begun it is therefore wise to send the patient to bed, in order that rectal temperatures may be taken every three or even every two hours, and that careful clinical study may be made of the patient as an individual. Thereafter it will, as a rule, suffice to take the temperature at such times as correspond to the usual daily maximum and minimum, and if there is any great objection to rectal temperatures, mouth temperatures, or, better, those taken in the stream of urine, may be substituted. During the twenty-four hours following an inoculation three-hourly temperatures are, however, most desirable. Under this scheme of treatment it will be seen that primarily atten- tion is focussed upon the changes induced at the foci of infection, secondarily upon the general reaction and constitutional effects, and thirdly upon all the signs and symptoms that can give any indication of the progress of immunisation, such as the sputum, urine, appetite, body-weight and feeling of general well-being. The near completion of a course of treatment is indicated by : (i) The complete disappearance of all signs and symptoms ; (2) A failure to incite auto-inoculatory phenomena by hard exercise or work ; and perhaps — (3) the failure of such dosages as o'l to o"2 c.c. of old tuberculin, tuberculin Beraneck, or Denys' bouillon filtre to produce either a focal or a general reaction. After this stage has been reached it is well to continue treatment with a few further doses of the patient's optimal maximum strength, i.e., of that dosage which produces the best clinical results, given at THE BACTERIAL DISEASES OF RESPIRATION. 225 lengthening intervals such as one week, two weeks, three weeks, and finally one month. No matter how complete a cure may appear to be it is highly desirable that the patient should return every four to six months for careful re-examination of the chest and general condition. The physi- cian should then also determine whether auto-inoculation can be induced, and also estimate the degree of tolerance by means of cutaneous tests with such dilutions of tuberculin as 5 per cent., 10 per cent., 25 per cent., 50 per cent., and 100 per cent. Should any suspicion of relapse exist a fresh course of immunisation is to be strongly urged upon the patient. Difficulties in the course of treatment are almost sure to arise, but the number and magnitude of these may be reduced by the proper selection of cases. They arise at any time — at the beginning, near the end, or in the middle of treatment. When they occur at the beginning they are, as a rule, due to the high reactivity of the tissues to tuberculin, i.e. to a high degree of sensitiveness, and are especially liable to be encountered in very early cases and in those that have reacted strongly to a diagnostic dose of tuberculin. In one instance, a very early case indeed reacted to a diagnostic dose of "oooi c.c. of old tuberculin in a very violent manner. After two months' waiting I endeavoured to begin tuberculin treatment, but doses even of '000001 c.c. of P.T. and P.T.O. induced such marked constitutional upsets, including loss of weight of 4^-1 lb. per week, that it was thought almost hopeless to continue specific therapy in-'the face of such extreme sensitiveness. Difficulties in the middle of treatment are more likely to arise from the onset of mixed infection or from a revival or re-exacerbation of a mixed infection which prior vaccine treatment had failed to eradicate entirely than from any other cause. Sometimes it will originate from the non-correspondence of the optimal therapeutic dosage with that which the patient can then tolerate ; his tissues may be able to tolerate far larger doses than they are actually receiving ; general reactions may be therefore conspicuous by their absence, focal reactions may be very difficult of detection, and accordingly the limits of dosage best suited to the needs of the patient are exceeded, little or no indica- tion being given, for some time that such is the case. The clue will usually be afforded by a process of exclusion, and by such symptoms as slight loss of appetite and weight, depression and feeling of not being so well taking the place of previously perfectly satisfactory ones, and this in the absence of any unfavourable signs at the foci of infection. The suspension of the treatment for a couple of weeks and resumption then with dosages reduced to one third or one fourth will do little harm whenever suspicion exists of such a state of things^ and may be productive of much good. 15 2 26 THE BACTERIAL DISEASES OF RESPIRATION. The difficulties which may arise towards the end of treatment are concerned chiefly with the determination of ultimate dosage and the time for suspending further treatment. It is a mistake to fix any maximum or minimum limits to the final dosage. Some authorities endeavour always to reach i c.c. of old tuberculin ; others are content with a tenth or less of this amount. In all cases where auto-inoculatory symptoms have been marked and where tolerance has shown a tendency to rapid fall it is very desirable to establish a high degree of tolerance by reaching a dosage of i c.c. of undiluted tuberculin if possible. In other cases the lower limit of o*i c.c. may be ample or it may even be unnecessarily high. This will be determined by the general features of the case and its behaviour during the course of specific treatment. Objection may be taken to my scheme for the conduct of treatment on the grounds that it requires too great individual attention, and occupies more time than can possibly be devoted to any case. My reply to this is that too great attention cannot possibly be given to the individual peculiarities of any case, and that a false conception may easily be formed of the time occupied in the examinations ; while it is true that at the beginning of the course repeated examinations have to be made at short intervals, it is also true that once an accurate estimate has been formed of the .reactive powers of the individual it is possible to predict with almost unerring accuracy the response that will be made to any dose; it therefore follows that just as clinical practice enables one to make a careful stethoscopic examination with greatly increased speed, so experience of the patient enables one to foretell the appropriate times for such examinations to be made. I will now pass on to a brief description of the methods which I consider to be less scientific and less productive of clinical benefit than the foregoing, viz. those methods wherein the guidance utilised is that afforded by the general reaction or where little control upon dosage is made use of other than the general condition of the patient. In this connection three different schools exist : (i) That including Sahli, Denys and Wolff - Eisner, who aim at the avoidance of all general reactions. (2) That including Bandelier and Roepke and many workers in this country and America, who aim at avoiding all excessive reactions but at utilising mild ones. (3) That including Gotsch, Moller, Lowen- stein and Wilkinson, who pay little or no regard to strong reactions, and regard them as inevitable and as useful stepping-stones to the attainment of a very high degree of tolerance. The first of these schools hold that time is of little consequence in the treatment of a disease like pulmonary tuberculosis, which, as a rule, progresses so slowly. They are still more or less obsessed by the memory of the disasters of early days, and would avoid any possibility of producing a THE BACTERIAL DISEASES OF RESPIRATION. 22/ reaction which might have even the most temporary ill-effects, oblivious of the fact that improvement in some cases dates only from the time at which a general reaction of moderate degree was first excited, and that improvement in most of their cases begins with that dosage which just fails to produce a general reaction ; in other words, with a dosage that in the great majority of cases produces that definite focal reaction which was not excited by some or many of the preceding smaller doses. Their view that focal reactions are not induced under their scheme of treatment is explicable only on the assumptions that their stethoscopic observations are not sufficiently complete or painstaking, not continued as the dosage rises, or not conducted at appropriate intervals after the administration of the tuberculin. In these particulars exception is to be taken to Sahli's methods, and many will not agree that the loss of time, whereby a course of treatment is drawn out to one, two or more years, is a negligible consideration ; otherwise much is to be said for a practice wherein great regard is paid otherwise to individual peculiarities in reactivity and wherein danger of ill-effects is reduced to a minimum. The plan of treatment is to begin with the smallest dose of one of the weakest solutions [e.g. '05 c.c. of an 8ig2-fold or even greater dilution of Beraneck's tuberculin), which will always prove harmless, and then the dose is raised quite gradually in such a way that no manifest toxic actions (so-called reactions) ever occur, or if these are not to be avoided entirely they must be reduced to a minimum. As soon as any such phenomena occur, be they ever so insignificant, one must wait till they entirely disappear, and reduce the next dose to at least one half of that which last failed to produce any reaction ; the interval between the doses must also be increased and the treatment subsequently conducted with greater precautions. Inoculations are given not oftener than twice a week with the concentrations up to the 32-fold dilution ; thereafter only once a week till the maximum dose is reached, when they are given only once a fortnight. The dosage is gradually raised by yV or w c.c. of each dilution till one reaches either the absolute maximum dose of i c.c. of undiluted tuberculin, or if the sensitiveness of the patient will net permit of this, till the individual maximum dose is attained. This must be found for each separate case ; it will be one that can be tolerated without any ill-effects, but cannot be exceeded without producing unfavourable results. When this individual maximum dose has once been reached, it is repeated at certain intervals but not exceeded. By making a series of dilutions in multiples of 2, in such numbers that a dilution of 65,536 times is ultimately reached, and by means of the device of using only the upper half of the syringe in passing from one dilution to another, so that, for instance, the next dose following I5§ 228 THE BACTERIAL DISEASES OF RESPIRATION. I c.c. of dilution Y^-g- is 0*55 c.c. of dilution J^, Sahli has devised a very carefully graduated scheme for dosage, which certainly has advantage over the decimal system of dilution usually employed. Bandelier and Roepke and the other members of the second school, while not failing to recognise that the observance of symptoms must also be supplemented by physical examination of the chest, and that focal reactions are more easily produced than general ones, yet fail to utilise this knowledge to the full advantage. Thus, after pointing out that "the view must be entirely put on one side that the curative process in tuberculin treatment takes place only with objective signs of reaction," and that " clinical observation teaches that a local effect on the focus of disease may make itself evident without a subjective feeling of illness or appreciable rise of temperature," Bandelier and Roepke state that " the common practice of observing the temperature curve only is quite sufficient for the purpose," i. e. of controlling of tuberculin inoculations. They hold that " the maxim to remain as close as possible to the reaction limit without well-marked or severe reactions occurring coincides with the experience that the most evident results have been obtained with slight reactions up to 38° C. or a little over. The principle of the production of slight reactions will be more in place and easier to<:arry out in slighter and more limited cases of disease, in the slowly progressive forms associated with fibrosis, where nutrition and appetite are good, where weight is being put on and the temperature normal, and where susceptibility to tuberculin is slight. But in these cases the possibility of an overdose must still be borne in mind." And again, " It must be constantly kept in mind that the curative effect for the individual is dependent, not on the absolute, but on the relative size of the dose, i. e. that quantity of tuberculin is most advantageous which can at anytime be just borne without (general) reaction. . . . Time must be allowed for the increase of dosage, and the same dose repeated, if necessary, several times if reaction occurs, with increase of the interval ; or better, a return made to a smaller dose, increased again more slowly. The thought guiding action must be that any dose associated with fever is too high for the individual concerned, and that the smaller dose borne without reaction not merely suffices for thera- peutic action but is actually of more value. Tolerance cannot be attained by violence but only by patiently persisting." The obvious criticism of all this is that while strongly upholding the advisability of a dosage which just falls short of a reaction in practice they fail to follow out their own precepts, and only determine the magnitude of their dosage by producing such reactions — at all events from time to time. Were more attention paid in the way I have indicated to the resulting focal reactions, which they themselves admit are produced by THE BACTERIAL DISEASES OF RESPIRATION. 229 dosages which fail to excite general reactions, guess-work and improper experimental determinations would be no longer necessary. In practice the determination of the dosage just short of that which will produce a general reaction is facilitated by the observation that a definite flattening of the temperature is coincident with the approach of the limit of tolerance. As regards the conclusion of treatment they write : " It must be our aim to attain to the highest possible doses of tuberculin, to reach the maximal dose. In slight cases a cure will be effected in this way. If the limit of apparently possible improvement is not then reached the maximal dose is to be repeated at increasing intervals as long as improvement continues, in order to retain the toxic immunity as long as may be, to stimulate the production of antibodies and to assist the healing processes. This injection of the absolute maximum we have ourselves prolonged for many months." Sahli well points out how utterly illogical is this artificial creation of a maximum dose at the containing capacity of the ordinary syringe, for this alone is the real reason why the maximum of dosage has been fixed at i c.c. The objection is, however, deprived of most of its sting in virtue of the fact that most members of this school stop considerably short of i c.c. as the maximum dose. The procedures of the third school, that which ignores reactions and regards them as an incidental inevitable to a course of tuberculin, are based on the following considerations : (i) that the constitutional disturbances of the disease are due to lack of toxin tolerance on the part of the tissues ; (2) that general reactions, like the constitutional disturbances, are unwelcome, and are obstacles to the attainment of the desired tolerance ; (3) that therefore they are to be swept aside and overcome by brute force, as they have found can be done by the administration of massive doses, which must act by paralysing the mechanism of reactivity. They therefore waste no time, but begin with doses of "0002 c.c. of old tuberculin, increase the dosage, if neces- sary, till a general reaction is the result ; when this occurs they repeat that dosage till the reaction begins to fail, when once more the dosage is increased. Some stop at a maximal dose of i c.c, others do not hesitate to go beyond this limit. In the case of some of this school the treatment is begun with P.T.O. ; when a dosage of i c.c. has been attained with this, P.T. is substituted for it, treatment being concluded with a course of old tuberculin. The objections to this method are several: (i) it is really only applicable to those whose general condition warrants such severe and oft-repeated constitutional disturbances ; (2) that even in these the reactions may become more than the sufferers can bear, and treatment is abandoned ; (3) that cases of mixed infection are considered to be 230 THE BACTERIAL DISEASES OF RESPIRATION. unsuited to the treatment, and these comprise a very considerable proportion of the phthisical ; (4) in advanced cases with pyrexia more harm than good may result. There are other means of moving a heavy rock than by means of a cumbrous crane — a lever will do the same work with much less ex- penditure of energy and sometimes more expeditiously; similarly there are ways of raising tolerance than by the sledge-hammer-like blows of massive dosage. On the other hand, there is at least one class of case to which this method is the more applicable, namely, those cases of good general condition who, despite moderate degrees of pyrexia, have to go about their daily work, means of undergoing a careful course of immunisation in sanatorium or their own home being quite beyond them. Such cases are undergoing constant auto- inoculation with varying doses of tuberculin at irregular intervals. The rest in bed which would control these being denied the patient, it becomes urgently necessary to overwhelm these irregular disturbances, which are unsuitable as stimuli for the establishment of immunity, under the greater and regulated waves set up by massive doses of tuberculin. That this objective is by no means impossible of attain- ment is certainly shown by the statistics of Wilkinson, Lowenstein and Gotsch, and if this method be regarded as one to be employed in the lack of opportunity to the employment of a better, a definite sphere of usefulness can be assigned to it ; it may even be regarded as the method of election for use on ambulatory patients, adapted to the needs and requirements, not of the classes, but of the masses. Treatment by the Induction of Auto-inoculations. Inman and Paterson have carefully investigated the relationship of the temperature curve to that of the opsonic content of the serum in pyrexial cases of phthisis. They found that the two curves roughly correspond but move in reverse directions. From this it may be inferred that rise of temperature corresponds to fall in content of the immune bodies generally of the blood, and that control of the temperature oscillations would result in the main- tenance of the defensive mechanism at a steadier level. This has been confirmed by clinical observation ; cases of irregular pyrexia wh ich are taking a downhill course improve markedly when the pyrexia is controlled by rest in bed. Sometimes ordinary rest will achieve this end ; sometimes absolute or " typhoid" rest is essential ; occasionally no degree of rest will control the irregular auto-inoculations. The thought suggested itself to Paterson whether it would not be better to utilise inoculations with the patient's own tuberculin produced by THE BACTERIAL DISEASES OF RESPIRATION. 23 I increasing the vascular supply to the infected foci by means of care- fully ordered exercise than to introduce tuberculin from without. The very large percentage of the human race who do successfully auto- inoculate themselves lends an a priori support to an affirmative answer. Paterson has therefore given an extensive trial to the treatment of cases of pulmonary tuberculosis by carefully graduated rest and exercise. Cases with pyrexia are sent to bed and kept at rest, ordinary or "typhoid," until their pyrexia is under complete control ; they are then allowed up and given carefully graduated exercise. If the exercise results in a rise of temperature to over 99° F. they are kept at rest until the tem- perature has steadied itself once more, when exercise is again per- mitted, and so on. In this way it is found that the organism can be accustomed to more and more exercise, until finally a hard day's manual labour may fail to elicit an immunising response as evidenced by rise of temperature beyond the patient's normal. The treatment has been found to be especially beneficial to cases which show little pyrexia and fail to improve beyond a certain point. Paterson reports excellent results from this form of treatment, but there are several objections to be taken to it : (i) It necessitates great individual attention and con- siderable care and judgment on the part of the physician in the assign- ment of the exercise to be taken by each patient. (2) It can only be carried out in a well-ordered sanatorium where the opportunity exists for furnishing the necessary tasks to the patients. (3) Auto-inocula- tions are induced the most easily when they are least desired, and are most difficult to induce when they are the most to be desired ; i. e. as treatment advances, and arrest and cure are the more nearly reached, the organism gradually accustoms itself to stimuli, so that to keep up a high degree of immunity stimuli of increasing strength must needs be applied. On the other hand, as healing of the foci proceeds the difficulty of inducing hypersemia in them increases, and the quantum of bacilli and their products which are carried into the circulation shows a corre- sponding decrease. It thus comes about that while it is easy to bring about marked relief of constitutional S3'mptoms and rise in tolerance, it is rather more difficult to bring about arrest and much more difficult to bring about a cure. It is much to be regretted that Paterson appears to have contented himself with an imperfect ideal, that he is content with having produced that degree of improvement which will enable the patient to return to his daily task, however severe this may be, without any resultant con- stitutional disturbance. To the disappearance of all bacilli from the sputum, to the precise condition of the infected foci and consequently to the chance of permanence o£ the results obtained he appears to have paid too little 232 THE BACTERIAL DISEASES OF RESPIRATION. heed. The procedure is based on sound reasoning and sound observation, and the introduction into it of suitable modifications, such as the addition of stimuH from without as those from within begin to fail, would tend to widen its applicability and increase its value. Whether auto-inoculatory procedures can be conducted with benefit in cases of mixed infection is very doubtful and must be left to the future to decide. Residts. Upon this question I propose to say but little. Mere statistics are of little help in aiding the formation of a true estimate of the value of tuberculin in the treatment of pulmonary tuberculosis. The disease is often a very chronic one, and one of its worst features is its crippling effect on man's power of work and of production, and the consequent casting of his maintenance upon the shoulders of others. From the economic standpoint it is therefore even more important that recovery should be expedited in those who are destined in any case to recover, than that a certain additional percentage should be preserved to lead a life of semi-invalidism. One of the most striking testimonies to the value of tuberculin treatment is the complete change of front in regard to its use which has once more come over the medical men throughout the world. Riviere and Morland point out, that whereas the percentage of sanatoria and public institutions in Germany which combined specific with hygienic treatment was only 29 in 1905, it had risen to 57 in 1907 and to about 70 in 1910. Many lung specialists who formerly were utterly opposed to it now use it extensively. Bandelier and Roepke cite the remarkable instance of Ritter, who, prejudiced against tuberculin, wished to collect evidence of its inefficacy. He therefore treated at his sanatorium a number of cases which had already undergone treatment without avail. The result is seen in the views he expressed in 1908, that sanatorium physicians are not merely justified, but in a certain sense bound to make the widest possible use of tuberculin in the treatment of pulmonary tuberculosis. Sahli says as regards himself: " Blind enthusiasm for tuberculin treatment can hardly be laid to my charge, but I honestly believe that it is the best weapon of modern times in the fight against tuberculosis." The greater the experience of most specialists, not necessarily in the uses of tuberculin, but in the manifold aspects of the disease itself, the stronger as a rule is their advocacy of the remedy ; the greater the experience of any specialist in tuberculin treatment itself the stronger as a rule is their advocacy, not that its use should be confined to THE BACTERIAL DISEASES OF RESPIRATION. 233 specialists like themselves, but that it should be extended, and that all general practitioners should learn to avail themselves of its help. Thus Sahli, Bandelier and Roepke and Wilkinson each voice this sentiment, and Lenhartz expressed much the same view when he said : " It is a defect in practice when tuberculin is not employed." Riviere and Morland sum up the case for tuberculin succinctly and well in the following words : " But statistics apart, certain results may be said to be well established by clinical experience. The first and most striking of these is that phthisis treated with tuberculin before it has become open remains closed. The importance of this fact, in which there is practically unanimous opinion, can hardly be exaggerated. It is true that the same result has been claimed for hygienic treatment ; it is also true that the vis medicatrix naturcB unfettered by art would have had the same result in a large proportion of cases ; but there remains a proportion — it may be small — of closed pulmonary tuberculoses which will not get well, and with these tuber- culin has been shown to be competent to deal. Early diagnosis — that is to say, really early diagnosis, before tubercle bacilli appear in the sputum — combined with specific treatment, insures completely against a breakdown. We believe that statistics have already shown the ability of tuberculin to increase the percentage of those who lose their sputum, or the tubercle bacilli contained in it, during hygienic treat- ment, and to extend the expectation of working efficiency after hygienic treatment ; but we are content to leave this to a more rigid demonstra- tion. Of all these matters the tubercular patient is the final judge, and misled as he was by the disasters of i8go-gi, there is no doubt that his experience of tuberculin under the new conditions is making him willing, and sometimes even anxious, to submit himself to treatment with the remedy." It is with the earnest hope that the many hours of patient work which I have bestowed upon the various forms of bacterial invasion of the respiratory tract may not have failed to cast some light upon the origin, prophylaxis and treatment of the various distressing manifesta- tions of infection and of pulmonary tuberculosis in particular, and thereby may have contributed in some small measure to the relief of human suffering, that I leave this record to the kindly consideration of the reader. INDEX. Abscess of lung, 119 Accessory sinuses, bacteriology of, 47 — — treatment of, 87 Albumen test, 12 AUergie, 202 Antiformin method, 20 Antral disease, bacteriology of, 47 — — treatment of, 87 Asthma, bacteriology of, 52 — treatment of, 97 Auto-inoculation in phthisis, 230 Bacillus, Bordet-Gengou, 31 — coli communis, 40 — diphtherise, 32 — ■ Friedlander's, 38 — Hoffmann's, 32 — influenzae, 31, 74 — Koch-Weeks', 31 — proteus, 39 — pyocyaneus, 39 — septus, 32 — tuberculosis, 20, 25, 192 — typhosus, 40 — xerosis, 32 Bacteriology of asthma, 52 — bronchitis, 52 — catarrh, nasal, 44 — — post-nasal, 46 — common cold, 44 — laryngitis, 51 — ozsena, 137 — phthisis, 55, 145 — pneumonia, 104 — rhinoscleroma, 139 — sinusitis, 47 — tracheitis, 51 — whooping-cough, 55, 122 Blister test. Woodcock's, 204 Blood-agar, 23 Blood cultures, 106 Bronchitis, bacteriology of, 52 — treatment of, 90 Broncho-pneumonia, 119 Calmette's test, 206 Capsule staining, 21 Catarrh, Eustachian, 50 — general treatment of, 82 — post-nasal, 46 — nasal, 44 — vaccine treatment of, 71, 79 Cells of sputum, 13 Chemical examination of sputum, ii Cultural methods, 23 Diphtheria bacillus, 32 — treatment of, 123 Dosage, control of, 65, Bo, 91, 156 Empyema, 119 Flagella staining, 21 Focal reaction, 210 Friedlander's bacillus, 38, 73 Fusiform bacillus, 41 Gram's method of staining, 18 Hay-fever, 134 Influenza bacillus, 31, 74 Inhalations, 188 Intervals, control of, 65, 91 Intra-dermal test, 203 Intra-tracheal injection, 189 Koch-Weeks' bacillus, 31 Laryngitis, 51, 83 Leishman's stain, 13, 20 Lung abscess, 119 — puncture 10 236 INDEX. Media, 23 Meningococcus, 35 Methods of collecting material, 8 — of staining, 12, 17 Micrococcus catarrhalis, 33, 72 — paratetragenus, 37, 72 — tetragenus, 37 Mixed infection, import of, 141, 147 — — prevention of, 180 treatment of, 160, 170 Morro's test, 204 Nasal catarrh, bacteriology of, 44 — — treatment of, 71, 79 Ophthalmo-test, 206 Opsonic index in diagnosis, 214 Ozasna, bacteriology of, 137 — treatment of, 138 Percutaneous test, 204 Phthisis, bacteriology of, 55, 145 — mixed infections of, 55, 141 — treatment of , 140, 192 Pneumococcus, 30, 73 Pneumonia, bacteriplogy of, 104 — pathology of, 107 — prophylaxis of, 107 — treatment of, 103 Post-nasal catarrh, bacteriology of, 46 • — — treatment of, 84 Preparation of vaccine, 75 Prophylaxis of catarrhs, 84, 180, 1S7 — of pneumonia, 107 Pyorrhoea alveolaris, bacteriology of, 41 — — importance of, 61, 125 — — treatment of, 124 Reactions, 69, 80, 91, 156 — table of, 69 — to tuberculin, 202 Reactivity, 202, 211 Rhinoscleroma, bacteriology of, 139 — treatment of, 139 Salicylate test, 1 1 Sero-albuminous contents of sputum, 16 Sinusitis, bacteriology of, 47 — treatment of, 87 Spengler's staining methods, 19 Sputum, cells of, 13 — chemical examination of, 11 — method of collecting, 9 Staphylococcus, 27 Streptococcus, 28, 74 Streptothrix, 25 Subcutaneous test, 207 Swabs, method of taking, 8 Tonsillitis, bacteriology of, 41 — treatment of, 62 Tracheitis, 51 Tubercle bacillus, cultivation of, 25 — — isolation of, 20, 25 — — staining of, 18 Tuberculin, choice of, 219 — in diagnosis, 202 — in treatment, 221 — reaction, 207 Tuberculins, the, 199 Tuberculosis, defensive mechanism against, 196 — mixed infection in, 56, 140, 160, 170, 180, — treatment of, 140, 192 Unna's methylene-blue, 13 Vaccine, administration of, 77 — preparation of, 75 — treatment of asthma, 97 — — of bronchitis, 90 ■ — — of catarrhs, 71, 79 — — of diphtheria, 123 — — of hay-fever, 134 — — of mixed infections, 160, 170 — — of ozasna, 138 of phthisis, 140, 192 — — of pneumonia, 103 of pyorrhoea alveolaris, 124 of rhinoscleroma, 139 — — of sinusitis, 87 — — of whooping-cough, 121 — — preliminaries to, 58 — — rationale of, 62 Von Pirquet test, 202 Whooping-cough, bacteriology of, 55, 122 — treatment of 121 Woodcock's blister test, 204 Ziehl-Neilsen's staining method, 18.