MASSACHUSETTS • •HISTORICAL-SOCIETY ''msiitlBi|ifflfi|^^ With the complimeiits of the American Bed Cross Digitized by the Internet Archive in 2010 with funding from Boston Library Consortium IVIember Libraries http://www.archive.org/details/typhusfeverwithpstro TYPHUS FEVER WITH PARTICULAR REFERENCE TO THE SERBIAN EPIDEMIC BY RICHARD P. STRONG, M.D., S.D. DIRECTOR OF THE AMERICAN BED CROSS AND INTERNATIONAL SANITARY COMMISSIONS TO SERBIA PROFESSOR OF TROPICAL MEDICINE, HARVARD UNIVERSITY MEDICAL SCHOOL GEORGE C. SHATTUCK, A.M., M.D. A. W. SELLARDS, A.M., M.D. MEMBER OP THE AMERICAN RED CROSS SANITARY COMMISSION TO SERBIA GENERAL MEDICAL SECRETARY, LEAGUE OF RED CROSS SOCIETIES MEMBER OP THE AMERICAN RED CROSS SANITARY COMMISSION TO SERBIA ASSISTANT PROFESSOR OP TROPICAL MEDICINE HARVARD UNIVERSITY MEDICAL SCHOOL HANS ZINSSER, M.D. BACTERIOLOGIST OF THE AMERICAN RED CROSS SANITARY COMMISSION TO SERBIA PROFESSOR OF BACTERIOLOGY, COLUMBIA UNIVERSITT J. GARDNER HOPKINS, M.D. BACTERIOLOGIST OF THE AMERICAN RED CROSS SANITARY COMMISSION TO SERBIA PUBLISHED BY THE AMERICAN RED CROSS AT THE HARVARD UNIVERSITY PRESS CAMBRIDGE, MASS. 1920 /? C. / X w Pi < a < o K O Fig. 1. Filled cesspool Fig. 2. A typical Serbian town after eradication of typhus PLATE XX THE SERBIAN EPIDEMIC 39 shortly after the siege of Granada. Later (1557) it became known in Spain under the name of el tabardillo (the much dreaded red cloak); and in this country there were repeated epidemics. In a third epidemic in Italy in the second half of the sixteenth century, it is said to have destroyed more than one million people in Tuscany. In 1566 it became epidemic in the army of Maximilian II of Hungary and extended its ravages again over Europe, continuing for more than twenty-one years. In the seventeenth century typhus was again one of the dis- eases which caused the highest mortality. So great were the miseries engendered by it and by the other events in connection with the Thirty Years War, that Haeser, writing of this period with reference to districts formerly well populated, says that one could wander for miles without seeing a living soul, only dead bodies decomposing and partially devoured by wolves, dogs, and vultures, for want of a decent burial. Towards the close of this century Morton implies that practically every hos- pital in England was filled with typhus victims. The eight- eenth century saw no abatement of typhus epidemics, and there is scarcely a year during this century that one may not find references to epidemics of it. Hirsch, however, distinguishes four periods during which the disease was excessively prevalent; the first period was a con- tinuance of the outbreaks which had occurred in Germany and in Austria-Hungary as a result of the wars waged in those countries. The epidemics died out about the year 1720. Dur- ing the second period, 1734-44, the disease ravaged Central and Eastern Europe. It was first noticed among the Polish troops engaged in the war of the Polish succession. It spread throughout Russia, Prussia, Silesia, and the central German states and the Netherlands. The English and French troops engaged in these wars were also affected. The third period lasted from 1757-75. It owed its origin to the Seven Years War, starting in 1757 between England and France. The epidemic began in Prussia, extended all over Germany, and then spread to France and Spain. In 1764 and 1767 extensive epidemics occurred over most of Italy, it is said as a result of a total failure 40 TYPHUS FEVER of crops in each case. The fourth and most extensive period beg^n in 1789 in France during the Revolution, and from there spread over the whole of Europe. The disease persisted in epidemic form throughout the duration of the Napoleonic wars, and did not begin to subside until the conclusion of peace in 1815, after the Battle of Waterloo. This was said to be the severest epidemic of typhus fever ever recorded on the con- tinent. The disease was always most severe in those places where the various battles and sieges occurred, but it spread to many places far removed from the sites of war. The general poverty and distress, the results of war, evidently aided greatly in the spread of the disease in these localities. After this severe epidemic over the whole of Europe no gen- eral epidemic occurred until the years 1846 and 1847, when typhus fever became widespread again over the entire con- tinent; however, from 1816 to 1873 in Italy there were fifty-one epidemics, and in France, there were sixteen. In England there were definite references to epidemics from 1643. According to Creighton, in 1694 the fever deaths in Lon- don were 5036. In 1741, during a general epidemic of typhus, there were 7500. Another severe epidemic began in England in 1831, and continued its ravages there for more than ten years, being at its worst, however, between 1837-42. Another serious epidemic occurred between 1862-69, and particularly in London between 1863-65. In England and Wales during the period 1869-83 there were 23,702 deaths from typhus. During 1884-98 there were 2249, while during 1899-1913 there were only 390. Ireland had long been infected by typhus, and, particularly from 1708, this country was ravaged by one epidemic after another. At the beginning of the eighteenth century the popu- lation of Ireland was estimated at about seven million, and during 1846-47 the number of sick at one million, about one- seventh of the population. In Dublin alone there were 60,000 cases of the disease. Since 1815, apart from smaller epidemics, the disease has spread widely six times, the epidemic of 1846- 48 above referred to being one of the severest, and the last of these six severe epidemics being from 1862-64. THE SERBIAN EPIDEMIC 41 In Mexico the disease became epidemic in 1530, shortly after the conquest. Another outbreak occurred in 1570, being said to have been imported from Spain. In 1734-36, 189,000 people are reported to have died from typhus fever in Mexico. There have been numerous epidemics during the nineteenth century, one of the most serious in 1861. In the United States and Canada typhus also prevailed in certain centers in the early years of the nineteenth century, and there were severe epidemics following the Irish immigra- tions in 1846 and 1847. In South America typhus was probably imported from Spain to Peru at a very early period where it was well known under the Spanish name of tabardillo in 1821, 1825, and 1846. It also prevailed in Chili at the same period. The Napoleonic, Crimean, Russo-Turkish, and recent Balkan wars have all been accompanied by typhus. Early in the recent great war, typhus appeared in Germany among the Russian prisoners of war in Austria, and it also became epidemic among the Turkish troops in the Erzeroum district. It has not been my intention to attempt a complete sum- mary of the history of typhus fever in this Report, but merely to cite many of the important epidemics in order that it may be seen that in earlier years the disease apparently raged almost unrestrictedly. The epidemics often continued for a number of years at a time and were not limited to or by any particular season. Hirsch writes that out of 147 epidemics which occurred in the temperate and cold latitudes of the eastern and western hemi- spheres, and of which we have accurate data as to the time of their outbreak and their course, 30 reached their acme in spring, 28 in winter and spring, 21 in spring and summer, 19 in summer and autumn, 18 in autumn, 17 in summer, and 14 in autumn and winter. He concludes that even if there can be no doubt that the maximum of typhus cases falls distinctly in the colder months (winter and spring) yet it is proved that typhus is quite independent of season and weather in its development and epidemic diffusion; that neither the upper nor lower ex- tremities of temperature or moisture can further or hinder the 42 TYPHUS FEVER disease in its breaking out and progress, nor any other condi- tion of weather exert a perceptible influence in these respects. It is in this sense that almost all the authorities express them- selves. Osier has remarked that the gradual disappearance of the disease in Great Britain and on the continent has been one of the great triumphs of sanitation and this also proved to be the case in connection with the epidemic in Serbia. It will be re- called that this epidemic of typhus fever was the first extensive and serious one to occur since the demonstration of the method of the transmission of this disease by lice in 1909-10. It should be emphasized that the efforts of all of the physicians, sani- tarians, nurses, and particularly of the people generally in Ser- bia being directed against the spread of the disease by pediculi, the suppression of the epidemic by intensive work was accom- plished within a period of six months. Method of Transmission In connection with the Serbian epidemic, it is also important to refer to the method of transmission of the disease. As long ago as 1876, Murchison suggested, in addition to other measures in connection with the prevention of typhus, that in order to prevent an individual from acquiring such infection, it was necessary to protect him from lice. In 1903, at the International Sanitary Congress held in Paris,^ Dr. Cor- tezo made a statement based upon his experiences in an epi- demic at Madrid that typhus fever is transmitted by lice and fleas, but no data of speciflc experiments were supplied demon- strating these facts. It has been for a long time a well-recog- nized fact that epidemics of typhus fever and of relapsing fever occur side by side and under similar conditions, and the close association of these two diseases has indeed been noted since 1739. This fact and the work carried out upon relapsing fever by Sergent and Foley ^ and Mackie ^ and Smith ^ suggested 1 OflBcial abstracts of Proceedings of the Conference, p. 343. 2 Sergent and Foley: Bull. Soc. de path, exot., 1908, i, 174. 3 Mackie: Brit. Med. Jour., 1907, ii, 1706. ^ Smith: Medical Thesis (London), 1909, John Bale Sons and Danielson, Ltd. THE SERBIAN EPIDEMIC 43 that lice were also probably the transmitters of typhus fever. However, in 1909, NicoUe ^ working in Algiers showed by actual experiments that the chimpanzee could be infected with the typhus virus by the injection of a small amount of blood from a human active case of the disease. He then showed that lower monkeys could be similarly infected by the inoculation of the chimpanzee's blood, and that then the infection could be transmitted from monkey to monkey by means of the bites of infected body lice (Pediculus humanus var. corporis) . This work was shortly afterwards confirmed in the United States by Ricketts and Wilder ^ and by Anderson and Goldberger,^ who also showed that the lower monkeys might be infected directly with human typhus blood or by the bites of lice that had fed upon human cases of the disease. Later it was shown by dif- ferent investigators, Wilder,* Goldberger,* Prowazek,® Sergent,^ and Nicolle,^ that the disease may be transmitted to monkeys by inoculating them with the contents of crushed lice or with faeces of infected lice, the lice or their faeces becoming capable of conveying infection from two to eleven days after feeding upon typhus infected blood, and the blood in typhus fever cases being found infective from the third to the tenth day of the attack. A few experiments which have been undertaken with bedbugs and fleas seem to show that these insects do not transmit typhus fever. From other experimental work per- formed, first by Anderson and Goldberger ^ and more recently by Toepfer^*^ NicoUe ^^ and others, and from observations made ^ Nicolle: Compt. rend. Acad. d. sc, Paris, 1909, cxlix, 157; Ann. de I'Inst. Pasteur, 1910, xxiv, 243. 2 Ricketts and Wilder: Jour. Am. Med. Assn., 1910, liv, 463; Wilder: Jour. Infect. Dis., 1911, ix, 9. 3 Anderson and Goldberger: Pub. Health Rep., Wash., 1910, xxv, 177; also Bull. Hyg. Lab., U. S. P. H. S., Wash., 1912, Bull. No. 86, p. 13. ^ Wilder: loc. cit., 1911. 5 Goldberger: Pub. Health Rep., Wash., 1912, xxvii, 297; and Bull. Hyg. Lab., U. S. P. H. S., 1912, No. 86, p. 37. 6 Prowazek: Berl. klin. Wchnschr, 1913, 1, 2037. ' Sergent, Foley, and Vialatte: Compt. rend. Acad. d. sc, Paris, 1914, clviii, 964. ^ Nicolle, Blanc, and Conseil: ibid., clix, 661. 8 Anderson and Goldberger: loc. cit., 1912. 10 Toepfer: Deutsch. med. Wchnschr., 1916, xlii, 1251. 11 Nicolle: Bull, de I'Inst. Pasteur, 1920, xviii, 49. 44 TYPHUS FEVER by Foster in the Philippines ^ it seems not unhkely that Pedi- culus capitis, the head louse, may also sometimes transmit the disease. Further experimental work on this question, however, would appear desirable. Nuttall ^ apparently inclines to the belief that Goldberger's experiments are not entirely convinc- ing but NicoUe^ states that P. capitis uasiy convey the disease. It has also been suggested that infection may occur in man by the ova of infected lice being rubbed or scratched into abrasions of the skin, but it has not yet been definitely demon- strated if hereditary transmission of the typhus virus occurs in lice, the evidence on this question being contradictory. There have been no scientific and properly controlled actual experiments performed upon human beings which demonstrate that typhus is transmitted by lice, though Moczutowski in 1900 and Yersin and Vassal ^ and Ostero ^ demonstrated by human experiment that the disease could be transmitted by direct injection of typhus blood. However, in a few instances in which accidental infection or experiments in man were car- ried out in connection with transmission by lice, the evidence has been in favor of the view that the transmission of typhus is through this agency. These human experiments, however, had not been adequately controlled as is evidenced from the follow- ing summary of them.^ Sergent, Foley, and Vialatte,^ trying to prove the transmis- sion of recurrent fever by the louse, made lice who had fed on a patient of recurrent fever bite a man. Another man was inocu- lated with similar lice, and still another with eggs from such lice. All of them developed typhus. Sergent, Foley, and Vialatte explained this by assuming that the patient was suffering from typhus at the same time or was already infected with typhus. This seems not unlikely, as it is well known that both of these 1 Foster: Arch. Int. Med., 1915, xvi, 363. 2 Nuttall: Parasitology, 1917, x, 52. ^ Nicolle: loc. cit. ^ Yersin and Vassal: cited by Thoinot, Paris Med., 1915, Nos. 49-50, p. 473. ^ Ostero: cited by Vincent and Muratet, "Exanthematic Typhus," Univ. of London Press, 1917, p. 207. 6 Banus: Intern. Jour. Pub. Health, Geneva, 1920, i, 69. ^ Sergent, Foley, and Vialatte: Compt. rend. Acad. d. sc, 1914, clviii, 964. THE SERBIAN EPIDEMIC 45 diseases occur together in epidemic form, and Kirkovic and Alexieff ^ have reported thirty-three cases in which both dis- eases were present at the same time, and they state that in most of these cases the recurrent fever appeared first. Another instance of transmission to man is reported by Ussher,^ who states that a male nurse allowed himself to be bitten by an in- fected louse and developed typhus in five days. Nicolle, Blanc, and Conseil,^ tell of the case of the warder in the penitentiary at Tunis who caused infected lice to bite one of two workers coming from the outside and with no contact with any typhus patients. The bitten man developed typhus while the other did not. They describe, too, another case, that of a laboratory- assistant who was bitten accidentally by an infected louse and developed the disease. This experimental evidence on human beings alone of transmission of typhus by lice is obviously not strong enough to be entirely convincing and does not exclude the hypothesis of other means of transmission. A great many physicians of different nationalities have died from typhus during the war and a great many more have con- tracted the disease. In many instances these physicians were thoroughly cognizant of the method of transference of the dis- ease by lice and of the precautions to be taken in avoiding such infection. In a number of instances where particular care was taken to avoid contamination with lice, nevertheless, infection with typhus followed. For this reason it has been particularly urged that infection sometimes must occur in man by another manner than through the agency of pediculi, and it has been suggested that the droplet method of infection after coughing might sometimes occur in this disease. It is recognized that in the early stages of iyphus there are likely to be inflammatory conditions of the mouth, nose, and throat. A number of in- stances have been recently recorded in medical literature and evidence given which is sometimes in favor and sometimes op- posed to the idea of the possibility of droplet infection in ty- 1 Kirkovic and Alexieff: Arch. f. Schiffs- u. Tropen-Hyg., xxii, 289. 2 Ussher: Med. Rec, 1914, Ixxxvi, 509. ^ NicoUe, Blanc, and Conseil: Compt. rend. Acad. d. sc, 1914, clix, 661; Ann. de I'Inst. Pasteur, 1910, xxiv, 261. 46 TYPHUS FEVER phus fever. As yet there has been no experimental proof that the sputum or saliva in typhus fever contains the virus, but on the other hand there have been no careful experiments per- formed upon man in which the saliva or sputum have been em- ployed for infection. Also, even if typhus may sometimes be transmitted to man by droplet infection, the experimental proof of this fact might be very difficult. In this connection we have only to recall the negative experiments performed upon man by Rosenau and his associates ^ in connection with the transmission of influenza by the sputum and by droplet infec- tion. It must be borne in mind that the virus of typhus fever has repeatedly been shown to be present in the blood; that Moczutowski inoculated himself in this manner and suffered an attack of typhus fever after an incubation period of 18 days. Yersin and Vassal also inoculated two men with typhus blood who developed typhus after 14 and 21 days respectively. While the experimental transmission of typhus infection to monkeys and other animals is certainly sometimes very un- satisfactory,^ and the proof that the infection has been actually transmitted not always definite and convincing without the most minute study, nevertheless, practically all such transmis- sion experiments in animals are also in favor of the view that the virus of tjrphus is present in the circulating blood and that the blood is usually infected during the active period of the fever. As the virus is present in the blood it would not be sur- prising if some of the secretions also contained it. The experi- ments recently performed on man in demonstrating the method of transmission of trench fever are interesting in this connec- tion.^ A series of inoculations in man with urine or urinary sediments and with saliva or sputum from typhus cases might give further information on this question. While it seems evi- dent that the only common and important method of trans- mission of typhus is through the louse, and that epidemics of 1 Rosenau: Jour. Am. Med. Assn., 1919, Ixxiii, 311. 2 See in this connection, Friedberger, Ztschr. f. Immunitatsforsch. u. exper. Therap., 1920, Ixxix, 125, who states it is not possible to infect guinea pigs with typhus blood. ^ Trench Fever, Report of Commission Medical Research Committee, American Red Cross, Oxford University Press, 1918, p. 37. THE SERBIAN EPIDEMIC 47 the disease are due to this method of transmission alone, never- theless, several careful observers have the impression that exceptionally and rarely typhus may be transmitted to those who come into close intimacy and contact with patients by some other means. In cases of typhus in which there are abrasions of the mucous membranes of the mouth, nose, and throat, the possibility of infection through coughing should be borne in mind. A number of observers are in favor of this idea. Thus Kraus believes that there is some other means of trans- mission than by the body louse, and states that this was the belief of all the Galician doctors who based their views on the observation that if the rooms containing tjrphus patients were kept well ventilated, no infection occurred among the person- nel. Allan ^ is of the same opinion that, if a person not pro- tected by a previous attack remains some time in a close, stuffy room near the patient, he runs the risk of contracting the dis- ease although no lice may be present. Walter ^ suggests the danger of overlooking such a possibility and describes an epi- demic which he could not entirely explain on the assumption of transmission by the louse. Friedberger,^ in his account of the epidemic in Pomerania, expresses doubts as to whether the louse is the real carrier, because he found cases that he could not ascribe to louse bites, among which were those of four doctors who developed tj^phus without even having felt a louse bite, and that of a lady who only once for a short time had entered a room occupied by patients in order to give them some apples. The idea of droplet infection is also supported by Rondke,* who bases it on the evidence of the case of one nurse who de- veloped typhus when no new patients had been admitted for ten days, while all the sick people were free from lice. She had taken very carefully all the precautions advised, but did not wear a mask. A similar case is reported by Sellards ^ and Shat- 1 Allan: Brit. Med. Jour., 1915, ii, 841. 2 Walter: Berl. klin. Wchnschr., 1915, Hi, 851. ^ Friedberger: Ztschr. f. Hyg. u. Infectionskrankh., 1918, Ixxxvii, 475. ^ Rondke: Med. Klin., 1915, p. 1152. ^ Sellards: Part III in this Report. 48 TYPHUS FEVER tuck ^ in Serbia of a nurse who protected herself very carefully, wearing a louse-proof suit. She had to sponge and swab the throat of a very severe case with serious lung and mouth com- plications. The patient was free from lice but coughing fre- quently. The nurse developed typhus after two weeks. Of the same opinion are Flueggi, Gaertner, Bujwid; Kisskalt, Uhlen- huth, and Stroklosinski,^ Larrieu and Delarde and d'Halluin. Delarde and d'Halluin ^ believe that in some cases of typhus during the epidemic they studied in Germany, droplets of saliva expelled in coughing were infectious, and when inocu- lated to the mucosa produced the disease. They also report the case of a physician who was found to be free from lice and yet contracted typhus. One should not dismiss such evidence with the mere statement that the small larval stages of lice may well escape notice. It does not seem entirely improbable that some of the doctors and nurses, who came repeatedly into very close contact with typhus cases and who have lost their lives from this disease during the war, contracted the infection per- haps because they regarded the only possible means of trans- mission to be by body lice, and only took precautions against this means of infection. That typhus may be sometimes trans- mitted by some other means than by the louse is a view held by a considerable number of physicians who have had during the war an unusual experience during epidemics, though little cre- dence is given to this idea by some investigators who have no such experience and who have formed their judgment that the louse is the sole transmitter from the louse transmission ex- periments recorded in the literature. Granting that the spread of the disease in epidemics is due to louse transmission, and that our methods in combating success- fully this disease in epidemics need only be directed against such a means of transmission, nevertheless, it must be borne in 1 Shattuck, G. C. : Harvard Graduate Magazine. 2 Flueggi, Gaertrier, Bujwid, Kisskalt, Uhlenhuth, and Stroklosinski : Med. Klin., 1915, p. 586. 2 Larrieu and Delarde and d'Halluin: Bull, et mem. Soc. med. d. hop. de Paris, 1916, xxxii, 320. THE SERBIAN EPIDEMIC 49 mind that this does not exclude exceptional instances of infec- tion by other means. Typhus fever claims more victims in the medical profession than any other epidemic disease. The mortality among phy- sicians in epidemics is generally high. Osier states in a period of 25 years in Ireland, among 1230 physicians attached to institu- tions, 550 died of typhus. Minkine reports that out of 13 phy- sicians working at the tjrphus hospitals, 12 contracted the disease, and 6 of them died. Butler in connection with his typhus hospital unit states that of 6 physicians, 4 contracted it and 2 died. The mortality among the Serbian physicians, 126 out of 350, or 36 per cent, has already been referred to. More- over, some of these physicians were immune from previous attacks contracted before this epidemic. Friedberger,^ in re- porting an epidemic at Schutzen in 1915, states that 24 of the doctors were attacked and 14 died, a mortality of 58 per cent; that of 332 nurses, 71 fell ill of whom 15 died, a mortality of 21 per cent; at the same time the disease among the Russian prisoners showed only a mortality of 7.8 per cent. Why is in- fection with typhus so common and the mortality so high among physicians? Is there an opportunity of direct infection by some means in which the virulence of the infection (as in pneumonic plague) is uniformly greater than when it is trans- mitted through the intermediate host, in the case of typhus, the louse; and in bubonic plague, the flea? Aetiology Bacteriological investigations in regard to the aetiology of typhus were carried out during the Serbian epidemic in con- nection with several of the larger hospitals. In spite of the very large amount of experimental work that has been performed in relation to the causative organism of typhus, there is no general unanimity of opinion upon the na- ture of the virus. A number of different investigators working in different epidemics in various parts of the world have de- scribed species of cultivable bacteria as the cause; others 1 Friedberger: Ztschr. f. Hyg. u. Infectionskrankh., 1918, Ixxxvii, 475. 50 TYPHUS FEVER believe the disease owes its origin to a species of protozoa, and still others think that it is due to a filterable virus. Rocha-Lima ^ and a number of other investigators regard the so-called Rickettsia prowazeki as the cause. Different bacilli, each regarded as specific, have been reported, particularly by Horiuche ^ in 1909, Ricketts and Wilder in 1910,^ Plotz, 1914,^ Rabinowitsch,^ Arnheim,'^ Rudisjicinsky,"^ Petruschky, 1915,^ and Zeiss, 1917.^ Specific cocci have been regarded as the cause, particularly by Wilson, 1910,^° Proescher, 1915,^^ Penfold, 1916,^2 and Danielopolu, 1917,^^ while pleomorphic organisms (diplo- coccoid and bacillary forms) have been described by Prejet- chensky,^^ Fuerth, Mueller, Hort, and Ingram,^^ and Topley^^ and Gaston.^^ In addition to these claims Futaki (1915)^® has described a spirochaete, Goldstein ^^ a motile diplobacillus, and Milman ^° a non-motile diplobacillus as the cause of typhus. Wolbach and Todd^^ believe that the cause of Mexican typhus fever is due to a new parasite which they call Dermacentroxe- nus typhi: Weil and Felix,^^ Felix,^^ and Friedberger^^ have be- 1 Rocha-Lima: Arch. f. Schiffs- u. Tropen-Hyg., 1916, xx, 17; Berl. klin. Wchnschr., 1916, liii, 567. 2 Horiuche: cited by Ledingham, Lancet, 1920, i, 380. 3 Ricketts and Wilder: Jour. Am. Med. Assn., 1910, liv, 1373. 4 Plotz: ibid., 1914, Ixii, 1556. 5 Rabinowitsch: Berl. klin. Wchnschr., 1914, li, 1458. s Arnheim: Deutsch. med. Wchnschr., 1915, xli, 1060. ^ Rudisjicinsky: New York Med. Jour., 1915, cii, 1175. 8 Petruschky: Centralbl. f. BacterioL, 1914-1915, Orig., Abt. 1, Ixxv, 497. 9 Zeiss: Deutsch. med. Wchnschr., 1917, xliii, 1227. 1" Wilson: cited by Ledingham, Lancet, 1920, i, 380. 11 Proescher: Berl. klin. Wchnschr., 1915, lii, 805. 12 Penfold: Tr. Soc. Trop. Med. and Hyg., 1916, ix, 105. 13 Danielopolu: Presse med., 1917, xxix, 403. 1* Prejetchensky: Typhus Fever, cited by Cox, Commonwealth of Australia Quaran- tine Service, 1917, PubUcation No. 13, p. 30. 15 Fuerth, Mueller, Hort, and Ingram: cited by Cox, Commonwealth of Australia Quarantine Service, Publication No. 13, p. 31. 18 Topley: Jour. Roy. Army Med. Corps, 1915. I'' Gaston: Revue de med., 1915, xxxiv, 559. 18 Futaki: Brit. Med. Jour., 1917, pp. 265 and 491. 19 Goldstein: ibid., p. 167. 20 Milman: Jour. Am. Med. Assn., 1915, Ixv, 2203. 21 Wolbach and Todd: Ann. d. I'lnst. Pasteur, 1920, No. 3, p. 159. 22 Weil and Felix: Wien. khn. Wchnschr., 1916, xxix, 33; ibid., 1917, xxx, 393. 23 Fehx: Ztschr. f. Immunitatsforsch. u. exper. Therap., 1917, xxvi, 602. " Friedberger: Deutsch. med. Wchnschr., 1917, xHii, 1314. THE SERBIAN EPIDEMIC 51 lieved that Bacillus proteus X 19 possesses specific properties in connection with the disease, and Werner and Leoneanu ^ and Hilgermann and Arnoldi ^ have even made human inocula- tions for protection against typhus with this organism. On the other hand, Nicolle, Hort^ and others beheve that typhus is due to a filterable virus. On account of the attention that has been recently called to the Rickettsia in relation to the disease and the opportunities for the investigation of the aetiology of typhus which will undoubtedly occur in connection with the epidemics of this disease in Central and Eastern Europe, it seems advis- able to present here a detailed account of the investigations which have been already made in relation to the Rickettsia. The Significance of Rickettsia in Relation to Disease In 1916 Rocha-Lima called attention to the presence of very minute bodies which were found in lice which had fed upon pa- tients suffering from typhus fever. These bodies were present not only in the contents of the alimentary canal, but especially in the epithelial cells of the alimentary tract of these insects. He regarded them as very minute microorganisms. They were elliptical, oval, often found in pairs and bipolar in appearance. The smallest forms measured from about .3 to A ix and the larger ones, sometimes biscuit-shaped, from .4 to .9 m. They were best demonstrated by staining in Giemsa's solution. These organisms were not at first found in lice which had not fed upon cases of typhus fever. The lice were said to become parasitized only after ingesting infected blood. Rocha-Lima pointed out that while these bodies slightly resembled bacteria in their morphology, they were in other respects more like the Chlamydozoa-Strongyloplasmata. He therefore proposed for them the name of Rickettsia prowazeki (n.g. n.sp.) evidently choosing this name in memory of Ricketts and Prowazek, both of whom succumbed to typhus fever which they contracted 1 Werner and Leoneanu: Miinchen. med. Wchnschr., 1918, Ixv, 587. 2 Hilgermann and Arnoldi: Deutsch. med. Wchnschr., 1917, xhii, 1582. 3 Hort: Brit. Med. Jour., 1917, p. 265. 52 TYPHUS FEVER while pursuing their independent investigations upon this dis- ease. Subsequently, organisms having a similar appearance were found by other observers and also by Rocha-Lima in lice which had fed upon healthy individuals or on those suffering with various other diseases. For this second form Rocha-Lima proposed the name of Rickettsia pediculi. He believes that Rickettsia pediculi differs from Rickettsia prowazeki in that the former is found normally only in the lumen of the alimentary canal of the louse, and does not multiply in the cells of the in- sects' alimentary tract, or only does so exceptionally. It is of importance in considering the study of the Rickettsia to recall that the terms Chlamydozoa (Prowazek) ^ Strongylo- plasmata (Lipschuetz)^ were proposed to include a group of very minute pathogenic organisms or viruses which exhibited cer- tain common properties, while exercising specific peculiarities in each case. These viruses are believed during at least one stage of their development (that of the "elementary cor- puscles") to pass through bacterial filters without losing their virulence. Within the cells of the host the elementary cor- puscles are believed to grow into larger "initial bodies." The chief characteristics of the chlamydozoa ^ were said to be firstly, their minute size, smaller than any bacteria hitherto known, enabling them to pass the ordinary bacterial filters during one stage of their development; secondly, that they develop within cells, in the cytoplasm or nucleus, and produce characteristic reaction products and enclosures of the cell; thirdly, that they pass through a series of developmental stages and are specially characterized by their mode of division, which is not a simple process of splitting as in bacteria, but is effected with formation of a dumb-bell shaped figure as in the division of a centriole. Two dots are seen connected by a fine line like a centrodesmus, which becomes drawn out until it snaps across the middle, and its two halves are then retracted into the body. In appearance the chlamydozoa seem to consist primarily of merely a grain of chromatin without cytoplasm 1 Arch. f. Protistenkunde, 1907, x, 336. 2 Handbuch der Pathogenen Protozoen, Leipzig, 1911, Prowazek and others. ^ Minchen: Introduction to the Study of the Protozoa, London, 1917, p. 472. THE SERBIAN EPIDEMIC 53 and without a membrane of any kind. Hence they appear to represent the simplest form of Hving body. The chlamydozoa have not yet been successfully cultivated, but infections can be produced with pure colloid-filtrates free from bacteria, but containing the minute bodies themselves. They are char- acteristically parasites of epiblastic cells and tissues. The viruses of trachoma, vaccinia, scarlet fever, hydrophobia, mol- luscum contagiosum, and more recently of typhus fever, have been referred to the chlamydozoa. Previous to Rocha-Lima's observations, several investiga- tors had published articles describing microorganisms observed in lice which had fed upon typhus fever patients, and Ricketts described a somewhat similar organism in connection with Rocky Mountain fever. It, therefore, is advisable to consider these investigations in chronological order in connection with the discussion of this subject. In 1909 Ricketts ^ reported upon the occurrence of diplo- coccoid bodies and short bacillary forms in the blood of guinea pigs and monkeys which had been experimentally infected with blood from cases of Rocky Mountain spotted fever. These organisms were also seen, but not so frequently, in the blood of man. They were also encountered in the female tick (Derma- centor occidentalis) and in the eggs of these ticks which had fed upon infected guinea pigs. Ricketts describes his method of examination and the organism itself, as seen in the eggs, as fol- lows: "A number of eggs from the first day's laying were crushed on cover glasses, fixed in absolute alcohol and stained with Giemsa's solution. Each egg was found to be laden with astonishing numbers of an organism which appears typical as a bipolar staining bacillus of minute size, approximately that of the influenza bacillus. Although definite measurements have not yet been made, it is very common to find two organisms end to end with their poles stained deeply. In some instances thousands of these organisms were found, many staining faintly." Morphologically, the organism appeared to him to be , 1 Ricketts: Jour. Am. Med. Assn., 1909, lii, 379, and Med. Rec, N. Y., 1909, Ixxvi, 842. 54 TYPHUS FEVER a bacillus, and he points out that its resemblance to the bacillus of haemorrhagic septicaemia is striking, though he was not able to cultivate it. He suggests that the organism in question be called the bacillus of Rocky Mountain fever. Ricketts and Wilder ^ in 1910 described the organism of typhus fever, which disease they studied in Mexico. In prep- arations of the blood of patients taken from the seventh to the twelfth day of the disease, stained with Giemsa's solution, they invariably found a short bacillus which had roughly the mor- phology of those organisms belonging to the haemorrhagic septicaemia group. Usually, this bacillus appeared to stain solidly, but on minute examination an unstained or faintly stained bar was seen to extend across the middle. The exact measurements were not made, but when compared with the size of the erythrocyte, their length was estimated at hardly more than two micromillimeters and their diameter at about one-third of this figure. They also described involution forms of the organism. No active motility was observed in fresh preparations. These bipolar organisms were found in the de- jecta and in various organs of lice which had been infected by feeding on typhus patients. While they were also found oc- casionally in the faeces and intestinal contents of normal lice, they were present almost constantly and often in large numbers in lice from infected individuals. Gavin and Girard ^ found in the blood of patients in Mexico bacilliform bodies 2 ^u in length by 1.2 /^ in width, which when treated with Giemsa's solution exhibited at the extremities two small, deeply-stained masses united by a slightly stained portion. They regarded the significance of these bodies as obscure, and did not consider their aetiological significance demonstrated. In 1913 Prowazek,^ in the examination of the blood of 51 cases of typhus observed in Belgrade, found that the poly- morphonuclear leucocytes showed striking changes. The nu- 1 Ricketts and Wilder: Jour. Am. Med. Assn., 1910, liv, 1373. 2 Gavin and Girard: Publ. del Inst. bact. nacional, Mexico, 20 mai et 20 juin 1910; Bull, de rinst. Pasteur, 1910, viii, 841. ' Hegler and Prowazek: Berl. klin. Wchnschr., 1913, 1, 2035. THE SERBIAN EPIDEMIC 55 cleus showed signs of fragmentation and the whole leucocytes became filled with particles of chromatin. These cells stained intensely red with Giemsa's solution and were found to contain numerous rod-shaped and round bodies; diplococcus forms and frequently irregular granules were also observed. At the begin- ning of the infection many of the leucocytes were free from these bodies, but later more of them contained them. Pro- wazek, in discussing the nature of these bodies, inclined to the belief that they were related to the strongyloplasmata described by Lipschuetz, which belonged to the chlamydozoa. These bodies tended to disappear during the convalescence of the patient. In addition, he observed in the blood of a number of cases the curious double bodies similar to those first described by Ricketts and Wilder, but he remarks that the significance of these forms is still very obscure. In the examination of sections of organs of typhus cases, trachoma-like bodies were observed in the endothelial cells of the heart, lung, fiver, and kidney. Infected lice were carefully examined, and in one case small coccoid bodies and also diplococcus forms were observed. Sergent, Foley, and Vialatte ^ in 1914 working in Algeria found in lice living only on the sick — never in those living on healthy people or on people suffering from recurrent fever — an organism of which the following description is given: the microbe has the appearance of a coccobacillus. The staining of the poles though never very intense is more pronounced than that of the central portion, which is occasionally quite trans- parent. The length varies from 1-3 m and the thickness be- tween .5 and .8 m- Some of the small forms are shaped like seeds with a diameter of .7 /i. These organisms are frequently seen in pairs. When the germs are abundant they become elongated, forming chains with hardly distinguishable links. They were found in greater number in the bloody fiuid of the digestive tract of the lice than in smears of their organs after crushing. The organisms were few during the first days of ill- ness and could be observed only in a small proportion of the lice examined; but their number increased gradually and more ' Sergent, Foley, and Vialatte: Compt. rend. Soc. de Biol., 1914, Ixxvii, 101. 56 TYPHUS FEVER lice became infected. A number of such lice were fed on healthy individuals and the proportion of microbes seen be- came much larger. From the twentieth to the twenty-fifth day most of the lice showed signs of infection. The above-mentioned authors did not succeed in cultivating this microorganism on artificial media. They thought the microbe observed by them might be identical with that described by Ricketts and Wilder in the louse. They terminate their remarks with the conservative statement that if the coccobacillus described above does not constitute the virus of exanthematic typhus, it may, however, be supposed that, as is the case in a number of the pasteurella, it is a 'Hemoin" microbe which accompanies the true invisible infectious agent. Nicolle, Blanc, and Conseil ^ in 1914 found in Tunis the coccobacillus described by Sergent and his collaborators in five per cent of the lice collected in districts which had been free from typhus for two years. In consequence they considered that this germ could not be the agent which produces typhus. They found that lice fed on typhus cases did not become infec- tive before the eighth day, but are constantly infectious on the ninth and tenth days. Two attempts to filter the virus of typhus obtained by grinding up 140 and 155 infected lice both gave uncertain results and therefore they believed that the filterability of the causative agent of this disease cannot be regarded as certain. They could not detect any organism in the blood and organs of guinea pigs infected with typhus. Proescher in 1915 ^ examined blood smears from nine typhus cases after staining with one per cent solution of methylene- azur-carbonate. Endothelial cells from the blood-vessels were found containing very small diplococci and diplobacilH, meas- uring from .2 to .3 M- They were found either singly in short chains or in groups. Very few were seen in the plasma and in the polynuclear leucocytes. These bodies were not found in normal blood or in blood from cases of measles, mumps, scarlet fever, cholera, and relapsing fever. The author suggests that ' Nicolle, Blanc, and Conseil: Compt. rend. Acad. d. sc, 1914, clix, 661, and Arch. de I'Inst. Pasteur de Tunis, 1914, ix, 84.''^' => Proescher: Berl. khn. Wchnschr., 191S>;|ii, 805. THE SERBIAN EPIDEMIC 57 these minute bodies may be the cause of typhus, but he points out as they have not yet been cultivated this fact has not been demonstrated. He beheves the nature of the bodies described by Prowazek is still uncertain and states they are smaller than the diplococci and diplobacilli he has found. Whether they are quite different structures or cocci under- going phagocytosis degeneration products, or granules, is still doubtful. Dorendorf ^ in the examination of the blood of typhus fever cases in Serbia discovered in all cases examined during the febrile stage of the disease the organisms previously described by Prowazek. These bodies were found in the plasma, in the polymorphonuclear and mononuclear leucocytes, either singly or in pairs. Nuclear variations were a marked feature in the blood picture of the severe cases, and these changes were also seen in the mild cases at the height of the fever. Stempell ^ in 1916, in dissecting lice collected from sick people, found among the enigmatic parasites brownish bodies in the intestinal epithelium of the louse which he named Strickeria jungensi n.g. n.sp. He considered these organisms as the cause of typhus. Coccoid forms encountered were attrib- uted to the same parasite. Lipschuetz ^ observed in the polymorphonuclear leucocytes in blood from typhus cases bodies like those that Prowazek had described. Of 23 cases examined, 18 were positive and 5 nega- tive. These bodies were not found in control preparations from typhoid fever and variola cases, or in normal blood prepara- tions. He believes that while their nature is obscure they may be of service in the diagnosis of the disease. , Csernel ^ describes the bodies found in typhus blood which seem to be the causal agent of the disease. He gives illustra- tions of these bodies. They show two distinct phases. One a bipolar bacillus which he regards as the virulent form, and a long bacillus which he believes to be a saprophytic one. In three cases he detected flagella, and was unable to explain their presence. 1 Dorendorf: Deutsch. med. Wchnschr., 1916, xlii, 345. ? Stempell: ibid., 439. ' Lipschuetz: Wien. klin. Wchnschr., 1916, xxix, 549. * Csernel: ibid., 1643. 58 TYPHUS FEVER Zollenkopf ^ in describing a new disease resembling inter- mittent fever (probably Volhynia fever) found changes in the red cells, consisting of blue dots and rods, as many as eight or twelve in a corpuscule. These were not found in preparations taken after the fever, and the author thinks they may be only basophilic granules in the erythrocytes. Rocha-Lima and Prowazek ^ found during investigations carried out at the Prison Camp, Kottbus, that 95 per cent of the lice taken from sick people were infected by a parasitic microorganism. The organisms were found not only in the con- tents of the alimentary canal, but especially in the epithelial cells of the alimentary tract. They were not found in lice living on healthy subjects, but on the other hand non-infected lice placed on sick patients became infected with them. Refer- ence has already been made in the beginning of this article to the fact that Rocha-Lima believed that while these bodies were somewhat bacterial-like in appearance, they resembled more closely the chlamydozoa, and he therefore proposed the name of Rickettsia prowazeki for them — n.g. n.sp. He believed that this organism could penetrate the cells of the alimentary canal of the louse and multiply actively there. He observed that this parasite has been found in man only in the leucocytes. Rocha-Lim'a ^ in another publication points out that in December, 1914, in streak preparations made from lice which had fed on typhus cases, he found large numbers of bacillus- Hke bodies which stained red with Giemsa's solution. These organisms did not stain well with the usual bacteriological stains. When Prowazek arrived, he recognized that these bodies were the same as those already seen by him in 1913 in a preparation from an infected louse. By the examination of a number of sections of lice from typhus cases, and of normal lice, it was found that the bacillus-like bodies were present in large numbers in the cells of the alimentary canal and in the salivary glands of infected lice, but were not present in normal 1 Zollenkopf: Deutsch. med. Wchnschr., 1916, xlii, 1034. * Rocha-Lima and Prowazek: Berl. klin. Wchnschr., 1916, liii, 567. 3 Rocha-Lima: Arch. f. Schiffs- u. Tropen-Hyg., 1916, xx, 17. THE SERBIAN EPIDEMIC 59 lice. Of 18 lice taken from a sick patient, 17 were infected by this microorganism. The organism described by him appeared as a coccobacillus which could be easily stained by Giemsa's solution. In the beginning, the parasites were slightly elliptical in shape. Later, during the course of the division they became elongated. The two poles were deeply stained, and joined by a faintly tinted envelope. The organisms did not stain well with the usual reagents, and did not retain Gram's stain. In order to measure the microorganisms, he submitted them to a magnifi- cation of 3000 diameters. The smallest forms measured from .3 to .4 iJL, while the biscuit-shaped forms measured from .3 to .9 M- Only a similar picture regarding the occurrence of these bodies in infected Hce had he observed up to the present time in normal lice, and not an identical one. The Rickettsia made their appearance in the cells of the in- testine of lice on the fourth or fifth day after they had been placed on the patient, but they did not achieve their complete development before the eighth or ninth day. They developed rapidly at 32° but not below 23°. Rocha-Lima's experiments with respect to the filterability of the tj^hus virus did not give positive results, the Rickettsia appearing to remain in the Berkefeld V filter employed. At- tempts to cultivate the organism of tjrphus on various agar media with the addition of ascitic fluid, blood or extracts of the organs of rabbits or of lice were also unsuccessful. He refers to the fact that of all the bacteria described as the cause of typhus, the organism of Plotz might seem to be the most plausible. However, he remarks that the almost entirely negative results with animal experiments in an infection which is so easily trans- mitted to animals as typhus confirms our scepticism regarding it. He also refers to Petruschky 's ^ work, and points out that the organism he has described has only been demonstrated in the sputum, in which the virus has not been proven to be present. He believes that the bacillus described by Arnheim ^ evidently belongs to the pseudodiphtheria group of organisms. He con- 1 Petruschky: Centralbl. f. Backteriol., Orig., Abt. 1, 1914-15, Ixxv, 497. 2 Arnheim: Deutsch. med. Wchnschr., 1915, xli, 1060. 60 TYPHUS FEVER siders the bodies that he has described are really the aetiologic agents, because he has transmitted the disease to guinea pigs by the injection of lice containing these parasites, and the dis- ease produced was identical to that produced in animals in- oculated with the blood of typhus patients. In a third article Rocha-Lima ^ alludes to the fact that Ricketts and Wilder found polar staining organisms occasion- ally in the faeces and intestinal contents of normal lice, whereas they found them almost continuously and often in large num- bers in similar material from infected lice. In proposing the names of Rickettsia prowazeki for this organism as the cause of typhus, he points out that the Gram-positive diplobacillus of Rabinowitsch, the paratyphus-like bacillus of Horiuche, the aerobic, bipolar bacillus of Prejetchensky, as well as the Bacil- lus violentus parvus of Klodnitsky were even more strongly agglutinated with typhus fever serum than the strict anaerobic organism of Plotz. He showed that a louse which was fed upon a typhus patient on the fourth day of the disease showed the presence of Rickettsia infection four days afterwards. This louse was proved infective by animal experiment as well as by microscopical examination, the animal inoculated with it having contracted typhus infection. In still another publication Rocha-Lima ^ admits that it has not been conclusively proved that typhus fever is caused by Rickettsia prowazeki. He, however, alludes to the fact that organisms which are not dissimilar to the Rickettsia and which may be identical have been described in connection with typhus fever by Ricketts and Wilder, by Gavin and Girard and McCampbell in the blood serum, by Prowazek in the leuco- cytes, and by Rocha-Lima in the blood and organs and in sec- tions. He thinks, however, that the final proof is still wanting that these bodies are identical and are the cause of typhus, and the dimensions given by Rocha-Lima for these organisms are considerably below those given by Ricketts and by Sergent and his collaborators. He believes that the bodies described by Hanser in skin sections from cases of typhus fever are entirely 1 Rocha-Lima: Mtinchen. med. Wchnschr., 1916, Ixiii, 1381. ^ i^id., 1917, Mv, 33. THE SERBIAN EPIDEMIC 61 different from the Rickettsia, and that the organism described by Toepfer in typhus fever cases is not unlike the bacillus de- scribed by Rabinowitsch in 1909. Munk and Rocha-Lima ^ further describe the difficulties in distinguishing Rickettsia from other bodies such as elements of tissue, granulations or coagula, and point out that they can only be identified as microorganisms when in large numbers and when distinctly stained. They believe that it is really im- possible even for the experienced eye to identify Rickettsia prowazeki by its morphology alone, as has been demonstrated by finding similar microorganisms in lice not infectious. They em- phasize that the difference between Rickettsia prowazeki and the Rickettsia pediculi is that the former develops in the epithelial cells of the stomach and small intestine of the lice, while the latter lies in the lumen of the digestive tube. They point out that the Rickettsia found in lice taken from cases of Volhynia fever and from other patients, or even from healthy people, increase normally in the lumen of the alimentary canal and penetrate only exceptionally into the cells. They remark that Nicolle, Blanc, and Conseil found the same organism in a cer- tain percentage of normal lice, and that Toepfer and Jung- mann found the Rickettsia in lice from Volhynia fever cases, and that these Rickettsia also were intracellular. Rocha-Lima and Munk believe that the intracellular Rickettsia are excep- tional, except in connection with typhus, and are different from those observed in the lice fed on .Volhynia fever cases. In relation to the microscopical study of the blood in Vol- hynia fever, they remark that Jungmann, His, Toepfer, and Korbsch thought this disease was due to a diplobacillus, while Toepfer, Korbsch, and Riemer thought the cause was a spiro- chaete. Rocha-Lima and Munk found diplobacillus-like forms in the blood of Volhynia fever cases, but they also found the same forms in the blood taken from patients with other diseases or even from healthy people. For this reason, Toepfer and the authors came to the conclusion that the bodies described by the investigators named above, and by Jungmann and Ku- 1 Munk and Rocha-Lima: Miinchen med. Wchnschr., 1917, xliv, 1422. 62 TYPHUS FEVER czynski, were probably not the cause of Volhynia fever, and that this link in the chain of proof concerning the Rickettsia as the cause of typhus also is still lacking, particularly since morphologically the bodies found in normal blood cannot be differentiated from those found in typhus blood. Rocha-Lima and Munk were able to transmit Volhynia fever to guinea pigs by the injection of the blood, but not to mice as Jungmann and Kuczynski had done. From this, it would appear that they were not working with trench fever since this disease has not been communicated to guinea pigs. They were able to produce the disease in two guinea pigs inoculated with the urine from Volhynia fever cases, but a bacteriological examination of this urine did not reveal the cause of the disease. The question of the filterability of the virus of Volhynia fever they still consider doubtful. Munk and Rocha-Lima performed further experiments in cultivation of the Rickettsia, but these were not successful. In 70 experiments on patients of whom Munk had made the diagnosis of Volhynia fever, 51 gave a positive result with re- gard to the infection of one louse at least with Rickettsia pedi- culi, 11 remained negative, and 6 were doubtful. Among the negative instances were some typical cases which, although repeated, gave the same results. In 33 control tests of pa- tients whom Munk considered did not have this fever, 26 re- mained negative, and 6 infected in the same way as the lice from the Volhynia fever cases, while 1 test remained doubt- ful. These control tests were made on people in the hospital for other diseases, such as malaria, scarlet fever, measles, diph- theria, trichinosis, typhoid fever, tuberculosis, rheumatism, stomach and bladder diseases, and inguinal hernia. The 6 cases upon which the lice were fed, which later were positive for Rickettsia were — 3 with malaria, 1 with bladder disease, 1 with bronchitis, and 1 with inguinal hernia. One who had never suffered from any disease gave rise to particularly strongly infected lice. Among infected lice taken from 14 people, examined at Hamburg, the lice from 2 of these peo- ple were found severely infected by a microorganism which THE SERBIAN EPIDEMIC 63 could not be differentiated from Rickettsia pediculi either in .smears or in sections. One case was undiagnosed. The second was that of a workman who had never been ill, who did not leave Hamburg, and had never been in connection with soldiers at the front. These results confirm those formerly published. In all these cases the intracellular characteristic development of Rickettsia prowazeki was absent. The author states that one might think Rickettsia pediculi the cause of Volhynia fever, but the fallacy of such an idea is shown by the fact that these or- ganisms have been found in a number of control tests in lice from healthy people in a country free from Volhynia fever. The author admits that it is not impossible that the Rickettsia pediculi may be the cause of Volhynia fever, but it is impossible to differentiate this form for the present from that found in lice fed on healthy human beings. Rocha-Lima, however, does not believe that Rickettsia pediculi is the cause of Volhynia fever. He states, moreover, that it is only a supposition that this dis- ease is carried by lice. Both Korbsch and himself attempted the propagation of this disease with lice, but their experiments were not successful, although the lice were strongly infected. Noeller ^ believes in the pathogenic properties of Rickettsia prowazeki, though he gives no important evidence of the proof of this idea. He demonstrated in a series of experiments that lice from pigs transferred from infected guinea pigs to pig blood lived long enough for the Rickettsia to develop in them, and that the pig blood was not detrimental to the development of the Rickettsia. He did not think that the infection of the lice was hereditary with this organism. Toepfer and Schuessler ^ carried out investigations upon about 2000 lice taken from patients. In 400 lice which had fed on 35 patients, bacteria-like organisms were found in the in- fected hce. These organisms, whose form and appearance they say are characteristic, were constantly present in the intestinal canal of the lice removed from typhus fever patients. They were also often present in the cells of the alimentary tract. 1 Noeller: Berl. klin. Wchnschr., 1916, liii, 778. 2 Toepfer and Schuessler: Deutsch. med. Wchnschr., 1916, xlii, 1157. 64 TYPHUS FEVER Control lice fed on other individuals than those suffering with typhus fever remained free from these organisms. From mi- croscopical examination, the organisms seemed to be in pure culture in the infected lice. This organism was found only in lice which had been fed for some days on the blood of patients during the febrile period. Lice fed during the postfebrile period did not apparently become infective. The eggs and offspring of the infected lice were not found capable of producing infection. The parasites continued to develop in the intestine of the lice and apparently remained infective indefinitely. They were not able to cultivate the organism. The injection of the con- tents of the alimentary tract of an infected louse into a healthy guinea pig produced a febrile condition similar to that pro- duced by the injection of the blood of a typhus fever patient. In connection with Volhynia fever Toepfer ^ called attention to the presence of characteristic bodies in the blood in Volhynia fever. In three cases of this disease he observed spirochaetes.' In one instance, in a fresh specimen, the organism was motile. In lice taken from typhus fever patients he found bodies similar to those described by Rocha-Lima. He is unwilling to commit himself whether a connection exists between these bodies and the spirochaetes. In another paper relating to Volhynia fever,, Toepfer ^ ex- presses the opinion that the organisms described by His and Werner as the cause of this fever were accidental artefacts. He found in the blood smaU parasitic-like bodies, but did not con- sider that these were diagnostic. He, however, convinced him- self that the virus was circulating in the blood in this disease as he performed experiments by injecting five cubic centimeters of blood intraperitoneally into guinea pigs and obtained similar temperature curves to those which were injected with blood from tjrphus patients. He found that lice taken from typical cases of Volhynia fever contained in their alimentary tract bodies similar to the typhus fever organism. These bodies were fouriLd both free and inside the cells of the louse, and appeared 1 Toepfer: Berl.klin.Wch'nschr., 1916, liii, 323. ; 2 Ibid.: Muiichen med. Wchnschr., 1916, Ixiii, 1495. THE SERBIAN EPIDEMIC 65 as small short rods. Polar staining rods and diplobacilli forms were present. He believes these organisms to be bacilli and not protozoa, and considers that they are the cause of the disease. Toepfer ^ in a more recent work examined smears and sec- tions of 500 lice. He believes he has confirmed his former ob- servations regarding the presence of an organism in infected lice. He criticizes the name of Rickettsia prowazeki as giving a wrong impression of the nature of these organisms.^ He found the same parasite in lice {Pediculus capitis) taken from the heads of patients, and he was also able to artificially infect normal lice of this species by placing them upon the sick. Smears made from lice which had previously fed on the blood of patients infected with typhus fever were found to contain nearly pure cultures of the organisms. In another paper on the aetiology of typhus, Toepfer ^ de- scribes the organism found in tissues of typhus patients and in infected lice as intracellular diplobacilli. Hanser ^ reports that he has confirmed Toepfer's discovery of bacteria-like forms in the intestinal cells of lice fed on typhus fever patients. Toepfer^ in another article upon war nephritis describes similar organisms to those which he had observed in lice fed upon cases of typhus fever or of Volhynia fever. He regards this form of nephritis as a specific disease, probably transmit- ted by lice. He also considers it plausible that the virus circu- lates in the blood. Guinea pigs inoculated with blood from the nephritic cases grew lean and had bloody urine, but no rise in temperature. In the lice from the nephritic cases, especially those which had fed during the early stages of the disease, definite bacteria were found almost without exception. He also infected lice by feeding them on the nephritic cases, and in order to control these results he put lice of the same breed upon healthy people and these remained uninfected. These or- ^ Toepfer: Deutsch. med. Wchnschr., 1916, xlii, 1251. ^ Rocha-Lima (ibid., 1353) in a subsequent paper controverts the statement of Toepfer regarding the nature of Rickettsia prowazeki found in the intestinal cells of infected lice. 3 Toepfer: ibid., 1383. ^ Hanser: ibid., 1254. 6 Toepfer: Med. Klin., 1917, xiii, 678. 66 TYPHUS FEVER ganisms appeared to be identical with those he had found in lice from typhus and Volhynia fever cases. Anaerobic cultures of these bacteria were successful if the contents of the intes- tine of the lice were placed in dextrose agar, but the colonies were so small that they were of no value for specific reactions. Toepfer thought that the germs of the nephritic cases could be differentiated from. those seen in typhus fever by the fact that the latter developed more markedly in the intestine of the lice. He believed that the three different organisms appear in the epithelial cells of the louse. He states that the similarity iti appearance between the three forms of bacteria found in lice which he described as the cause of spotted fever, of Volhynia fever, and of nephritis cannot be regarded as an argument against their specificity, because in stained preparations the bacillus o£ typhoid fever cannot be differentiated from the colon bacillus and several other bacteria. Having found similar organisms in spotted fever, in Yolhynia fever, and in nephritis, the author believes that the three diseases, which are clinically so different, belong to the same group. The author thinks that not only from an aetiological standpoint is this true, but that between nephritis and spotted fever there are histological re- semblances which he observed in the study of sections of the skin of the oedematous tissue in nephritis cases, a general dis- turbance of the capillaries being present in both diseases, though in spotted fever the capillaries are much more affected. In the nephritic cases, the kidneys are obviously particularly affected. The author believes that the oedema and nephritis are only partial results of the infection, that the infection ex- tends from the capillaries over the whole body, and that the oedema and nephritis may b.e entirely lacking in some instances. In conclusion, he states that he believes that war nephritis is an infectious disease in which several organs are attacked, and that it is caused by an inflammatory and proliferative disturb- ance of the capillary endothelial cells, and as a result of this a disturbance of the circulation follows. - ' Otto and Dietrich ^ attempted to confirm the work of Rocha- ^ Otto and Dietrich: Deutsch. med. Wchnschr., 1917, xliii, 577. THE SERBIAN EPIDEMIC 67 Lima in relation to the Rickettsia to typhus fever. Lice en- closed in small cardboard boxes were covered with a fine layer of gauze and then placed on the under surface of the arm or in- side the thigh of typhus fever patients at various stages of the disease and for various periods. The lice placed on the patients during the febrile period became infected from the fourth day, 70 to 80 per cent being infected if they were allowed to feed during the period of seven to eight days. Of these lice placed on the patient towards the end of the disease, only a few be- came infected. The infection was never found to be heredi- tary. In addition to the usual bipolar staining organisms found, they also observed short, rodlike, and long, filamentous forms. The threadlike forms were noted in the case of a louse taken from a patient on the fourth day, and were absent in lice which had fed for nine days. They suggest that these forms may be transition stages in the life history of the parasite. They suc- ceeded in infecting lice with Rickettsia by feeding them on a case of typhus fever without the exanthem. Attempts to transmit the infection to guinea pigs by the injection of the gut contents of infected lice were only successful in a small percentage of the experiments. The authors endeavored to prove by agglutination tests with the serum of typhus cases and an emulsion of the gut contents of the infected lice, that the Rickettsia prowazeki is the causative agent of typhus. Wolbach ^ in the study of Rocky Mountain spotted fever points out that the essential lesions of spotted fever are found in the vascular system and that bacillary bodies are present in large numbers in the endothehal cells of guinea pigs infected with the virus of Rocky Mountain spotted fever through the bites of infected ticks. These bacillary bodies had some of the characteristics of those previously described by Ricketts, The endothelial cells accumulate in the vessel walls and around vessels and in the lymphatics. The organisms are diplobacilli in character and show polar staining. The staining, however, is not that commonly seen with most bacteria, and indicates ^ Wolbach: Jour. Med. Research, 1916, xxxiv, 121. 68 TYPHUS FEVER that the organisms have some of the characters of spirochaetes. All attempts at cultivating them have so far failed. In another paper Wolbach ^ reports the presence and distribution of this organism in experimentally infected ticks {Defmacentor venus- tus, Banks). In the infected ticks, parasites were found similar to those previously observed in the tissues of monkeys and guinea pigs, but never in non-infected ticks. The parasites were present most abundantly in the striped muscle, also in the malpighian tubes, salivary glands, and ducts and brain ganglia. They were numerous in the muscle fibers of the uterus and vagina, and have been seen in the spermatozoa. In a third paper Wolbach ^ gives the characteristics of these bodies as follows: ^'In guinea pigs and monkeys, in sections, a minute rod in pairs, often lanceolate and surrounded by a clear zone or halo and staining with difficulty, occurring in large mononuclear cells (endothelial cells) and smooth muscle cells. Larger and smaller forms were mentioned, the former lance- olate, the latter occurring in smooth muscle ceUs. In smear preparations from guinea pigs there were noted lanceolate paired forms, rods with irregular staining, and rods with chro- matoid granules. ^'In ticks, in sections (1) a lanceolate paired form, (2) a smaller, more slender rod-shaped form, and (3) a minute, oval- coccoid form; in size, just within the limits of resolution with the best optical equipment." He also describes in this last paper the presence of these bodies in the lesions of the blood-vessels in f atail human cases of Rocky Mountain spotted fever, and thinks they are forms of a new organism. Lopez ^ in a study of the blood in typhus fever found the intraleucocytal bodies discovered by Doehle ^ in cases of scarlatina and also recognized by Preisich and others in dif- ferent diseases. Lopez found these bodies in 77 out of 90 cases 1 Woibacii: Jour. Med. Research, 1916, xxxv, 147. 2 Ibid., 1918, xxxvii, 499. 'Lopez: Bol. de la Direction de Estudios Biol., 1917, ii, 92 (reviewed in Trop. Dis. Bull., 1918, xii, 108). * Doehle: Miinchen. med. Wchnschr., 1912, July 23, No. 30. THE SERBIAN EPIDEMIC 69 of tjq^hus fever examined by him. From one to three bodies were found in one leucocyte, and the percentage of leucocytes always polynuclear containing them varied from 3 to 80 per cent. They were best stained by Giemsa's method. He re- marks that the blood must be taken from well-marked cases of the disease and at the height of the fever from the sixth to the tenth day to contain these bodies. He thinks that they may be chlamydozoa, but does not express a decided opinion regarding their nature. Schmidt ^ found in three patients only out of many cases of five-day fever examined, almond or sickle-shaped organisms in the blood which showed one or two round chromatin bodies in the interior, situated either peripherally or centrally. They were best demonstrated by Giemsa's stain. The size varied, but is comparable with that of blood platelets. Jungmann and Kuczynski ^ found in the blood of typhus patients during the first days of the rash an organism which they believe to be identical with Rickettsia prowazeki which th'ey had also found in cases of trench fever. As they had never found this organism in other diseases, they conclude there must be a relation between typhus and trench fever. Werner and Benzler ^ in examining lice which had fed upon cases of febris quintana found in the stomach of some of them organisms resembling spirochaetes. In one, the stomach con- tents of the louse showed bodies which could not be distin- guished from those described by Rocha-Lima in typhus and by Toepfer in febris quintana, and which had previously been cultured by him anaerobically. Brumpt * studied 72 body lice {Pediculus corporis) taken from prisoners of war who had been living in France for some time, and whose state of health was quite satisfactory. No case of typhus fever had ever been reported among them. Twenty-seven lice from the head {Pediculus capitis) taken from a healthy child at Rennes were also studied. Of the 72 1 Schmidt: Deutsch. med. Wchnschr., 1917, xliii, 682, 2 Jungmann and Kuczynski: Ztschr. f. klin. Med., 1917, Ixxv, 251. 2 Werner and Benzler: Miinchen med. Wchnschr., 1917, Ixiv, 695. * Brumpt: Bull. Soc. de path, exot., 1918, ii, 249. 70 TYPHUS FEVER body lice from 7 healthy prisoners of war, 53 were found in- fected by the microorganism described by Rocha-Lima under the name of Rickettsia prowazeki, and considered by him to be the causative agent of typhus fever. Of the 53 Hce with para- sites, 18 were considerably infected. Their alimentary canal and a number of the cells contained what may be described as a pure culture of the microorganism in question. In the 35 remaining instances, the infection was slight. Herpetomonas pediculi was not observed. Brumpt's investigations are so im- portant that it is advisable to consider them in greater detail. A group of 16 lice taken from healthy prisoners of war were all found to be infected with Rickettsia. Infection was marked in 1 case, moderate in 13, and mild in 2. Twenty-four lice taken at the same time from these same men were fed upon the author himself once a day for three days and kept in the incubator at a temperature of 20° C. After the third day the surviving lice were dissected, and the following results were obtained: severe infection was found in 5 cases, moderate infection in 5, slight infection in 3, and no infection in 7. Lice from another healthy prisoner were fed upon the author. Thirteen of these surviv- ing hce were dissected, when 1 was found to be strongly in- fected, 5 moderately infected. In 2 the infection was shght, and 5 showed no signs of infection. Eighteen lice taken from another healthy person were fed on the author. In 4 of these, intense infection was found, in 1 moderate, 2 slight, and in 5, no infection was present. Lice were taken from another healthy subject and fed on the author. Of the 6 lice which survived, 5 showed severe infection, and 1 no infection. Lice taken from another healthy prisoner of war were fed on the author for four days. The 9 surviving lice were dissected with the result that in 2 instances a severe infection was present, in 2 a moderate one, and in 5 no infection was found. The microorganism in question was found practically as a pure culture in the dejecta of the louse. No sign of infection was found in the alimentary canal of 27 head hce taken from a healthy child. The germs found in 73 per cent of the lice taken from healthy individuals were either elliptical in shape, occasionally spherical, but THE SERBIAN EPIDEMIC 71 generally coccobacillary in form. There is always a predomin- ating shape in the Rickettsia encountered in one louse. They are either practically round or slightly elongated. The or- ganisms stained like spirochaetes in the blood. They showed intensely tinted poles, joined by a faintly stained central por- tion. The average dimensions of the organism varied between .4 and .6 /x for the round forms, 1.2 to 1.4 /x in length, .5 ju in width for the average forms, 1.65 m to 2 m long by .6 m wide for the largest forms. The last were seldom met with. The author never observed the parasites in chains. He concludes that his observations lead him to identify the organisms found in lice taken from healthy people with those previously described by Rocha-Lima under the name of Rickettsia prowazeki. Seventy of these lice were fed upon himself and 53 were found infected with the above described organism; but he remained healthy. The author points out that although this organism in question which has not been cultivated may be encountered in the blood or in the organs of some of the patients, it need not for this rea- son be considered the pathogenic agent of typhus fever as it may have been inoculated by the louse and have no path- ogenic action. The author points out that the lice infected by the coccobacilli retain the infection during their entire life. The lice carrying the typhus virus are active from the eighth to the tenth day. Arkwright, Bacot, and Duncan ^ reported that in their in- vestigations they used a clean stock of lice bred in captivity and kept under observation for over three years. They fed these normal lice on trench fever patients both during and after febrile periods. Either the feeding on the infected person was for one day only, followed by feeding on a healthy man, or after the first infecting meal the lice were fed regularly on the same or another infected man, and between the feedings the lice were kept in an incubator at a temperature of about 27° C, or in an inside pocket. They were later examined micro- scopically either by films made from the excreta, or from the gut contents, or in microscopic serial sections. The films were 1 Arkwrightj Bacot, and Duncan: Brit. Med. Jour., 1918, ii, 307. 72 TYPHUS FEVER treated with acid alcohol to fix and to remove haemoglobin debris, and were then stained with Giemsa's solution. The following conclusions were reached by them, confirming and extending the work of previous workers: 1. If a box of lice is fed on a trench fever patient, and the excreta collected after a period of about ten days, large num- bers of Rickettsia bodies can almost invariably be found in films. Smears of the guts of lice from such a box contain large numbers of these bodies after about the same interval of time. Of 253 specimens from boxes of lice which had been fed on trench fever patients at least five days previously, 150 showed Rickettsia bodies, 83 gave a negative result, and 20 a doubtful result. 2. The excreta from sixteen boxes of lice which were ex- amined daily after an infecting meal showed Rickettsia bodies for the first time twice on the fifth day, three times on the seventh, three times on the eighth, four times on the ninth, three times on the tenth, and once on the twelfth day from the first infecting meal. When first seen only small numbers were noted in the films, but three or four days later enormous num- bers appeared. These experiments show that after an infecting feed there is a period during which these bodies are not recog- nizable on account of their small numbers, or of some difference in form. When a box has once become infected with Rickettsia the excreta collected from it continue to show the bodies for two or three weeks, or till the lice which partook of the infect- ing feed are dead. 3. All lice from an infected box do not show Rickettsia; only a small proportion do so in the first week; the proportion increases until after two and a half to three weeks the great majority show these forms. Experiments at Hampstead have also made it probable that after the same time a considerable proportion of lice are infective. 4. Trench fever patients can infect lice with Rickettsia bodies during the fever, between the attacks, or even several weeks after an attack during a non-febrile period. 5. Normal lice, fed on persons who have not been exposed to THE SERBIAN EPIPEMIC 73 trench fever infection, have remained free from Rickettsia. Of 245 specimens from 22 boxes fed on seven healthy persons only one specimen of excreta was found to contain forms which closely resembled Rickettsia microscopically. It is not sur- prising, considering the difficulty in recognizing such small bodies by their morphology, that occasional errors should oc- cur. Four other specimens from two boxes showed these bodies, but they were being fed on a man who had been working with infected excreta in the laboratory for five weeks, and had also been feeding infected lice on himself for the same period. He developed trench fever three days after that upon which the first one of the four positive specimens was found. It is most probable, therefore, that he had been infected for some days before the bodies were observed in the lice. They further pointed out that Rickettsia bodies are very small and approach the limits of filterability of a Berkefeld filter. In their experiments the Rickettsia bodies did not make their appearance in lice till about the fifth to the twelfth day after an infecting meal. In 53 experimental inoculations of volunteers, the lice or excreta of lice used as the virus were also examined microscopically. In every case the lice had pre- viously been fed on a trench fever patient. Twenty-seven of the specimens showed Rickettsia bodies and caused trench fever; 10 specimens did not show Rickettsia bodies and did not cause trench fever; 1 specimen showed Rickettsia bodies but did not cause trench fever; 2 specimens did not show Rickettsia bodies but caused trench fever; 4 specimens gave doubtful results microscopically, or the inoculation was followed by fever of a doubtful nature; 9 specimens showed Rickettsia bodies but did not cause trench fever. The authors thought this was because the virus had been heated or treated with disinfectant, or because the volunteer inoculated had recently passed through an attack of trench fever and was probably immune. They believe the agreement between the demon- strable presence of the virus and the Rickettsia bodies is very close, and that a very close correlation has been shown to exist between the presence of Rickettsia bodies in lice or the excreta 74 TYPHUS FEVER of lice and the virulence of these materials when inoculated into man. Most of the observers so far mentioned in this article, who have regarded the Rickettsia as representing microorganisms, apparently have believed that they were either chlamydozoal or protozoal in character or at any rate were of a non-bacterial nature. Other investigators, however, have believed the bodies described as Rickettsia are really bacteria, and more recently it has been suggested that the bacillary forms are identical either with the bacillus described by Plotz as the cause of typhus fever or with the Bacillus proteus X 19, believed by others to be the cause of this disease. Rabinowitsch Mn 1914 refers to the fact that in 1908 he dis- covered the causative agent of typhus naming the organism Diplohacillus exanthematicus. In fresh cultures the organism practically always appeared as a diplobacillus. Degeneration forms only developed in old cultures. In fresh cultures, the organism was always Gram-positive, while in old ones it be- came Gram-negative. Cultures were best obtained the author says by using a medium consisting of equal parts of ascitic broth mixed with 4 per cent glycerin. One hundred c.c. of this mix- ture were to be inoculated with from 3 to 5 c.c. of the blood of a typhus patient obtained shortly before the crisis. After the crisis the organism seemed to disappear from the blood. He points out that guinea pigs can be infected both by the injec- tion of cultures and by the blood of typhus patients, the incuba- tion period varying from 5 to 37 days. He examined the blood of 58 typhus patients. In the films stained deeply with Giemsa's solution he found peculiar, very deeply staining leucocytes which had a very basophilic protoplasm. They often constituted from 3 to 8 per cent of the white cells. He thought that these might furnish a means of diagnosing the infection. Mueller ^ made bacteriological examinations of various cases of typhus occurring amongst the Bosnians in the Marine Hos- 1 Rabinowitsch: Berl. klin. Wchnschr., 1914, li, Part 2, 1458. 2 Mueller: Miinchen. med. Wchnschr., 1913, Ix, Part 1, 1364. THE SERBIAN EPIDEMIC 75 pital of San Bartolomeo, Trieste. In Giemsa-stained prepa- rations, diplococci, cocci, and ovoid rod-shaped bodies were found present in the blood of all the cases of typhus examined, and also in four patients that no longer showed any fever. The cultural examination of the blood of eleven patients gave five positive results, in each case a diplobacillus developing in the broth. Attempts to cultivate the organisms on ascitic agar succeeded only three times. The isolated cultures seemed to be identical with those obtained by Fuerth from cases of typhus in Tsingtau. The organisms were non-motile rods which readily round off into coccoid forms in the various culture media. The pathogenicity of the culture organism towards animals was only very slight. When mice were inoculated with enormous doses, they succumbed within 24 hours, and the diplobacilli were found in every part of the body. A rabbit showed a single parasite after an incubation period of seven days. On the other hand, three monkeys inoculated with the cultures remained normal. According to the author there can be no doubt that this diplobacillus isolated at San Bartolomeo is identical with the organism described by Rabinowitsch and others. Olitsky, Denzer, and Husk ^ state it is their opinion that the Bacillus typhi exanthematici described by Plotz corresponds to the organism described by Rocha-Lima as Rickettsia pro- wazeki. They point out that while Rocha-Lima found the Rickettsia to be Gram-negative, and that the bacillus described by Plotz was Gram-positive, that the organism described by Plotz may be sometimes Gram-negative ^ in the first subcul- tures made from lice or in smears made directly from typhus infected lice, as has been shown by Baehr and Plotz, ^ and Baehr and Plotz have reported the occurrence of the Plotz or- ganism in infected lice and have ^own it under anaerobic conditions. They have also produced typhus fever by the in- jection of infected lice. For these reasons they think the Rickettsia and the Plotz bacillus are identical. They think the 1 Olitsky, Denzer, and Husk: Jour. Am. Med. Assn., 1917, Ixviii, 1165. 2 Baehr and Plotz: Jour. Infect. Dis., 1917, xx, 201. ^ Olitsky, Denzer, and Husk: ibid., 1916, xix, 811. 76 TYPHUS FEVER reason that the bodies described under the name of Rickettsia have not been cultivated by other observers is owing to the fact that improper methods have been used. Popoff ^ beUeves that the Rickettsia prowazeki described by Rocha-Lima is the same organism as the bacillus described by Plotz as the cause of typhus fever. Kuczynski ^ carried out his experiments with a view to determining the role played by Bacillus proteus Xl9m typhus fever. Seventy-two body lice were artificially infected with a pure culture of this organism. After examining the lice which survived for 72 hours, he came to the conclusion that Bacil- lus X 19 and Rickettsia are not identical, and that it is possible that infection with Rickettsia prevents the development of X 19 under natural conditions. He found that X 19 developed in the louse and believes that the rod and threadlike forms de- scribed by other authors as developmental stages of Rickettsia are probably stages in the development of X 19. He fed these experimental lice upon himself and as he remained healthy he came to the conclusion that X 19 is not pathogenic. In another paper ^ he made histological investigations upon material from typhus fever cases. . . , In the petechiae of typhus he, was not able to find anything which appeared definitely to be the causative organism. In the investigation of sections of the liver in the endothelial cells of the capillaries and in free phagocytic cells, two different micro- organisms were found. First, large bacilli-like bacteria which appeared similar in appearance to the proteus bacillus; and second, bodies in sections stained by Giemsa's solution, re- sembling the Rickettsia as described by Rocha-Lima in the intestinal cells of lice. The author believes he could differen- tiate these bodies from other histologic elements by their intracellular position, their spherical grouping, and their inten- sive stain. 1 Popoff: Med. KUn., 1917, No. 14, p. 397. 2 Kuczynski: Arch. f. Protistenkunde, 1918, xxxviii, 376. 3 Ibid. : Centralbl. f. allg. Path. u. path. Anat., 1918, xxix, 279. • THE SERBIAN EPIDEMIC 77 The following table summarizes the reports of different in- vestigators with reference to Rickettsia bodies in connection with disease. Year Investigator 1909 Ricketts 1910 Ricketts and Wilder 1910 Gavin and Girard 1912 Doehle Preisich 1913 Prowazek 1913 MueUer 1914 Sergent, Foley, and Vialatte 1914 Nicolle, Blanc, and Conseil 1914 Rabinowitsch 1915 Proescher 1916 Dorendorf Rickettsia bodies or organisms resembling them found in Bacilli in blood of guinea pigs and monkeys infected with blood from Rocky Mountain spotted fever cases. Also seen in blood of man, and in female tick (Dermacent&r occidentalis) and in eggs of these ticks fed upon infected guinea pigs. Studies in Mexico. Bacilli in blood of typhus pa- tients. Also in dejecta and various organs of lice fed on typhus patients. Occasionally found in faeces and intestinal contents of normal lice. Blood of patients in Mexico. Significance of bodies obscure. Discovered intraleucocytal bodies in scarlatina cases. Recognized same bodies in other diseases. Blood of 51 typhus cases in Belgrade. In examina- tion of sections of organs of typhus cases, tra- choma-like bodies observed in endothelial cells of heart, lung, liver, kidney. One infected louse con- tained coccoid bodies and diplococcus forms. Blood of typhus fever cases. Inoculated mice and rabbit. Lice living only on the sick, never in hce living on healthy people, or recurrent fever patients, in Algeria. Found especially in bloody fluid of diges- tive tract of the lice. A number of such lice fed on healthy individuals and proportion of microbes seen became much larger. Could not cultivate microorganism on artificial media. Tunis, in 5 per cent of lice collected in districts free from typhus for two years. Lice fed on typhus cases are constantly infectious on ninth and tenth day, not before the eighth. Organisms not detected in blood and organs* of guinea pigs infected with typhus. In 1908 discovered Diplobacillus exanthematicus as the causative agent of typhus. Organism found in blood of typhus patients. Blood smears from nine typhus cases showed bodies in endothelial cells from blood-vessels. Very few seen in plasma and in polynuclear leucocj^tes. These bodies not found in normal blood or in blood from cases of measles, mumps, scarlet fever, cholera, relapsing fever. Blood of typhus fever cases in Serbia examined, and organisn^s described by Prowazek discovered in all cases examined during febrile stage — found in plasma and in polymorphonuclear and mononu- clear leucocytes. 78 TYPHUS FEVER Year Investigator 1916 Stempell 1916 Lipschuetz 1916 Csernel 1916 ZoUenkopf 1916 Rocha-Lima and Prowazek 1916 Rocha-Lima 1916 Wolbach 1916 Wolbach 1916 Noeller Rickettsia bodies or organisms resembling them found in Among the enigmatic parasites in the intestinal epithelium in dissected lice collected frohi sick people. Polymorphonuclear leucocytes in blood from typhus cases; twenty-three examined, eighteen were posi- tive. These bodies not found in control prepara- tions from typhoid fever and variola cases, or in normal blood preparations. Typhus blood. In describing a new disease resembling intermittent fever (probably Volhynia fever) found changes in red cells. Not found in preparations taken after the fever. Investigations at Prison Camp, Kottbus, 95 per cent of lice taken from sick people were infected by parasitic microorganism. Organisms found in contents of alimentary canal, and especially in epithelial cells of alimentary tract. Not found in lice living on healthy subjects. Non-infected lice placed on sick patients became infected. This parasite found in man only in the leucocytes. In 1914 (December) in streak preparations made from lice fed on typhus cases, found large numbers of bodies. Recognized by Prowazek as the same as seen by him in 1913 in preparation from in- fected louse. In examination of sections of lice from typhus cases, and of normal lice, bodies found in large numbers in cells of alimentary canal and in salivary glands of infected lice; not in normal lice. Seventeen out of eighteen lice from a sick patient were infected. Rickettsia appeared in cells of intestine of lice on fourth or fifth day. Louse fed on typhus patient showed Rickettsia four days afterwards. Bacillary bodies are present in large numbers in en- dothelial cells of guinea pigs infected with the virus of Rocky Mountain spotted fever through the bites of infected ticks. Organism found in experimentally infected ticks, similar to those previously seen in tissues of mon- keys and guinea pigs, but never in non-infected ticks. Parasites most abundant in striped muscle, malpighian tubes, salivary glands, and ducts and brain ganglia. Numerous in muscle fibers of uterus and vagina, and seen in the spermatozoa. Also in lesions of blood-vessels in fatal human cases of Rocky Mountain spotted fever. Lice from pigs transferred from infected guinea pigs to pig blood. THE SERBIAN EPIDEMIC 79 Year Investigator 1916 Toepfer 1916 Toepfer 1916 Hanser 1917 Munk and Rocha- Lima 1917 Toepfer and Schues- sler 1917 Toepfer 1917 Otto and Dietrich Rickettsia bodies or organisms resembling them found in Blood of Volhynia fever. Also in lice from typhus fever patients. Lice from typical Volhjaiia fever contained bodies in alimentary tract similar to typhus fever organism. Bodies both free and inside the cells. Examined smears and sections of 500 lice. Con- firmed his former observations regarding organism in infected hce. Same parasite found in lice from heads of patients and in artificially infected normal lice of this spe- cies by placing them upon the sick. Smears from lice fed on typhus blood contained organism. Described intracellular diplobaciUi in tissues of typhus patients. Confirms Toepfer's discovery of forms in intestinal cells of lice fed on typhus patients. Found diplobacillus in blood of Volhynia fever cases, but also found same in blood from patients with other diseases or even from healthy ones. Munk made 70 experiments on patients diagnosed as Volhynia fever cases, — 51 positive for R. pediculi, 11 negative, 6 doubtful. Among nega- tives were some typical cases. Among 33 control tests, 26 were negative and 6 in- fected same as lice from Volhynia fever cases. These 6 cases upon which the lice were fed which proved positive for Rickettsia were 3 malaria, 1 bladder disease, 1 bronchitis, 1 inguinal hernia. One normal gave rise to strongly infected lice. Rocha-Lima and Korbsch attempted propagation of Volhynia fever with lice, but not successful although lice were strongly infected. In 400 lice which had fed on 35 patients, bacteria- like organisms were found in the infected Hce. Organisms found constantly in intestinal canal of lice removed frpm typhus patients and often in cells of alimentary tract. Control lice fed on other ■ . individuals than those suffering with tj^phus fever remained free. Organism found only in lice fed on blood of typhus patients during febrile (not post- febrile) period. In article on war nephritis describes similar or- ganisms to those seen in lice fed on cases of typhus or Volhynia fever. Found similar organisms in 3 diseases, i. e., spotted fever, Volhynia fever, and nephritis. In lice placed on patients. Infection not hereditary. They infected lice with Rickettsia by feeding them on a case of typhus fever without the exanthem. 80 TYPHUS FEVER Year Investigator Rickettsia bodies or organisms resembling them found in 1917 Lopez Blood of typhus fever, found same intraleucocyi;al bodies, in 77 out of 90 cases. Blood must be taken from well-marked cases and at the height of the fever, to contain these bodies. 1917 Schmidt Organisms found in 3 cases only, out of many cases of five-day fever examined. 1917 Jungmann and Blood of typhus patients during first days of the Kuczynski rash, and also in trench fever. Had never found organism in other diseases. 1917 Werner and Benzler In the stomach of lice fed upon cases of fehris quintana. 1918 Brumpt 53 out of 72 body lice taken from healthy prisoners of war, pure culture found in the alimentary canal and in some cells. 16 lice from healthy prisoners of war were all in- fected, etc. 1918 Arkwright, Bacot, Lice fed on trench fever patients. Normal lice fed on and Duncan persons not exposed to trench fever infection re- mained free from Rickettsia. 1918 KuCzynski In the petechiae of typhus cases, in sections of liver in the endothelial cells of the capillaries, and in free phagocytic cells. Our studies regarding the occurrence of Rickettsia bodies in lice which have fed upon healthy persons have confirmed those of a number of observers already referred to. Lice collected from healthy men in different parts of France, where neither typhus fever nor trench fever were present, were often found to contain Rickettsia in their dejecta: from 20 to 40 per cent of such lice examined, collected in different groups, revealing these bodies. In some of these normal lice, microscopical examina- tion of the excreta or material from the alimentary tract showed them to be severely infected with Rickettsia bodies. Others were only moderately or very slightly infected, while in the remaining no definite Rickettsia were observed. Obviously from a microscopical examination, it is sometimes extremely difficult to say whether these bodies are not present in small numbers in the lice. Plate XXI, Figures 1 and 2, demonstrate the Rickettsia bodies in the excrement of normal lice.^ There 1 These photomicrographs were kindly made at the Pasteur Institute by Dr. P. Jeantet, who is in charge of the photomicrographic work of this Institute. I wish to ex- press my thanks to both Dr. Roux, the Director of the Pasteur Institute, and to Dr. Jeantet, for this courtesy. Figs. 1 and 2. Rickettsia bodies in the excrement OP NORMAL lice {Reprinted with permission of Paul B. Hoeber, Publisher of Osier Anniversary Volume) PLATE XXI THE SERBIAN EPIDEMIC 81 was not opportunity to search for them in the intestinal epi- thelium. The lice are referred to as normal because they pro- duced no disease either in their original host from which they were collected, or when they were placed upon or fed upon other healthy individuals. A critical examination of the literature regarding the relation of Rickettsia to disease reveals the fact that these bodies have been found in lice which have fed upon cases of typhus fever, Volhynia fever, trench fever, war nephritis, malaria, bron- chitis, inflammation of the bladder, and inguinal hernia, as well as in a large number of lice collected in different parts of the world which have fed only on healthy people in whom they produced no disease. Rocha-Lima maintains that in lice, Rickettsia prowazeki, which is regarded by him as the prob- able cause of typhus fever, differs from Rickettsia pediculi (which is found in lice not infected with the virus of typhus) in that the latter does not occur normally in the epithelium of the alimentary canal of the louse. However, Toepf er, Brumpt, and others have reported the presence of Rickettsia in the intesti- nal epithelial cells of lice fed upon healthy individuals or in those fed upon Volhynia fever cases, or cases of war ne- phritis. Rickettsia have also been found in ticks that have fed upon cases of Rocky Mountain spotted fever. They have in addition been observed in the blood of man in a number of dis- eases, for example, in typhus fever, in Rocky Mountain spotted fever, in Volhynia fever, and trench fever. Rocha-Lima also believes that he has seen in the blood of healthy persons similar bodies to those observed in the blood of Volhynia fever by other investigators, and described by them under the name of Rickettsia. Further, when we come to consider the aetiological signifi- cance of Rickettsia in human disease, it is apparent from the evidence already presented in this article that not one of the three classical postulates regarded necessary for the proof of the aetiological factor of an infectious disease has yet been demonstrated for the Rickettsia. (1) They have not been found in every case of the disease they have been said to be the 82 TYPHUS FEVER cause of; moreover they have been found in connection with other diseases than the one it is maintained they give rise to. (2) They have not been isolated and grown in pure culture.^ (3) The disease which they are said to be the cause of has not been produced by the inoculation of such culture. It seems very probable that the Rickettsia bodies are micro- 'organisms, but as they have been found in lice from patients with so many different diseases, as well as in lice from healthy individuals, obviously no specificity for them could be justly claimed without further investigation. It is true that Rocha- Lima, Toepfer, and Olitsky, Denzer and Husk report the pro- duction of typhus infection in animals by the inoculation of the contents of the alimentary tract of infected lice. In this con- nection Rocha-Lima claimed that the disease developed in the inoculated animal because the Rickettsia were present in the lice used for the injections, while on the other hand, Olitsky, Denzer, and Husk claim the disease developed because the Plotz baciUus was present in the lice used in the inoculation of the animals. Obviously we can draw no definite conclusions from these experiments save that the infecting agent visible or invisible was present in the lice. Nothing can be said from them regarding the definite nature of the infecting agent. Sergent, Foley, Vialatte, and Brumpt all pointed out that the Rickett- sia might merely accompany the infectious agent. Observations and experiments recently made in connection with trench fever may be of interest in the study of Rickettsia. In relation to the aetiology of trench fever, as has been the case in the history of most infectious diseases, a number of widely differing microorganisms have previously been described as its cause, but none of these claims have been substantiated, and although very extensive studies have been made by a large number of observers, it is still a question whether the organism causing trench fever has yet been definitely seen in man either with the microscope or the ultramicroscope. Our experiments 1 Kuczynski (Med. Klin., 1920, xvi, pp. 706, 733, 759) has since reported to have cul- tivated R. prowazeki in blood plasma modified to resemble human tissue Ijrmph in cel- loidin capsules in the abdominal cavity of guinea pigs. He has also claimed to have pro- duced typhus infection in guinea pigs with such cultures. THE SERBIAN EPIDEMIC 83 carried on in relation to the aetiology of trench fever have since shown that the causative organism of this disease is under cer- tain circumstances filterable and that it bears some resem- blance in its behavior to the filterable virus of hog cholera.^ Our work regarding the filterable qualities of the virus of trench fever has recently been confirmed by Major General Sir John Rose Bradford, Captain E. F. Bashford, and Captain J. A. Wilson.^ The organism causing trench fever being so minute is obviously separated only with great difficulty from the sur- rounding structures in the media in which it occurs naturally. Thus, while we have demonstrated that the virus of trench fever is present in the plasma of the blood of trench fever cases, in the febrile stages of the disease it is frequently very difficult to separate it from the blood corpuscles themselves by repeated washings of these with saline solution.^ Also in the alimentary canal of the louse fed upon trench fever cases and in infected louse excrement, the virus on account of its minute size must be closely intermingled with other cellular struc- tures present. We have also seen that in different examinations of lice fed only upon healthy individuals, the Rickettsia have been dem- onstrated in from 20 to 74 per cent of them. Knowing these facts let us suppose that lice already containing such sapro- phytic Rickettsia in variable number had been fed upon trench fever cases and had become infected with the virus of trench fever, and such lice (containing the Rickettsia which may in the meantime have multiplied or increased in number) were then placed upon healthy human beings whom they subsequently infected with trench fever, obviously then erroneous con- clusions might be drawn that the Rickettsia were themselves the aetiological factor of trench fever. It is evident that great difficulty would be experienced in a separation of the virus of trench fever from such bodies under the circumstances de- scribed above. Probably only by successful filtration ex- 1 Trench Fever: Report of Commission of American Red Cross Research Committee, Oxford University Press, 1918. 2 Bradford, Bashford, and Wilson: Brit. Med. Jour., 1919, i, 127. ^ Loc. cit. : Trench Fever Report, p. 27. 84 TYPHUS FEVER periments, such as we have performed with lice excrement in connection with trench fever, could the separation be accomplished. It of course may be argued that Rickettsia have a filter- able stage as have other so-called chlamydozoa, and this idea receives some support from the fact that the virus of trench fever is under some circumstances filterable with difficulty, and attempts to infect human beings with the filtrates of infected material are often unsuccessful. Thus in ten filtration exper- iments performed with infected blood and urine from trench fever cases, and infected louse excrement, only three with urine gave undoubted positive results. The temperature charts of two cases of trench fever experimentally produced by the in- jection of the filtered trench fever virus are illustrated in Plate XXII. Bradford, Bashford, and Wilson ^ have since reported upon the cultivation of the trench fever virus from filtrates which have previously passed through porcelain filters and have also shown by human experiments that such filtrates contain the infectious agent. It is conceivable that the Rickettsia, whether they possess a filterable stage or not, may be parasites of lice and not path- ogenic for man, and Brumpt has suggested that the finding of them in human blood may simply be an indication that the individual has been previously infested with lice. On the other hand, there is the possibility that the bodies sometimes de- scribed as Rickettsia may constitute products of degenerated cells, for example, basophilic granules, which are more numer- ous in the blood in certain febrile diseases, in which case they would also increase in number in the lice fed upon such cases, and might then merely accompany the very minute or invisible aetiological factor of the disease. Finally, there may be at least three distinct species of Rickettsia, — R. prowazeki, R. Volhynia, and the third form either intra or extracellular, found in lice, and non-pathogenic for man.^ 1 Bradford, Bashford, and Wilson: loc. cit. 2 Rocha-Lima: Deutsch. med. Wchnschr., 1919, p. 732. -S i.._^ ■■"■^"'^jt ""S' E Is' S E ir::::::--.:. "K '"■"''^■■■Tt"n""{i'' VfT rt - OS ||;;|;;|:|j!;p _, _ I- F :;;;;;:;;;;;;:;;;:• ii II ) r Iftt " ! 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'■■ !::: :::::: fl '.I '..:..:::: -- ;;;;;;;;;':;■,;:;;::' 1^ ii -- |;ii::;iiii::i!!i; : ^'« ::;::;. :i:::S:::;;:: .- ■■H-± J f h__ g,,,:: ::i^ + :::.: Ttii 1 1 r,n 8p I;;: ii:::::: 1!: « 1 1 1 k-.j S e ::-|H' m \\\\\ if :::: :i s V. 7- - -1 ; :::::::::::::::::::::: ii :::::::::::::::"■": rsi ' < *^ Sg]::::. :.::;!}:::: 5e m flWi ;; ste S^Ht^ t » _j "M+/ Tl^osVTT '^ ;-iStl ■f" Q. 1 a * 35 30 25 \ fl / '\ -^ / y »> ^ ^ 15 '•s ^ \ ^ % > / »^ TJ,^ ^ :i d W£ L Wi_ 16 th Series Number 1. Typhus fever moderately se- vere; with mild, acute nephritis. Admitted to hospital April 23, 1915. Haemoglobin estimations, red counts, white counts, and blood-pressure are recorded on the chart first-sound is obscured by a systolic murmur which is not transmitted to the axilla. Blood-pressure, 120/S.-65/D. Urine: Normal in color, neutral, sp. gr. 1012, no albumen, rare hyaline casts. May IS. The first-sound is still blurred. Blood-pressure, 125/S.-65/D. Haemoglobin (Tallquist), 65 per £^nt. The eruption is pale pinkish brown in color. CASES OF TYPHUS FEVER WITH RECOVERY 181 May 16. The Widal test and agglutination tests for paratyphoid A and B were negative in dilutions of 1 to 25 and 1 to 50. The patient was discharged from the hospital in excellent condition. Series Number 9. Diagnosis: Typhus fever, severe, with nephritis apparently becoming chronic. Qlinical Notes Serbian, age 30, admitted to hospital on April 26. April 27 . Present Illness: The patient says that he has been ill for three days. The color of the rash suggests that he has been ill at least a week but he may have worked until three days ago. Physical Examination: The patient is moderately emaciated, the face browned by the sun, the malar region flushed, the eyes hollow, the nose sharp and the facies typical of typhus. The skin is dry, and the conjunc- tivae are moderately injected. The tongue has a slight brown coat. The nostrils move with respiration and the breathing is rapid and rather deep. Muscular twitching of the hands is frequent. The eruption is scanty on trunk and legs and more marked on the arms and hips. It is macular and punctiform in character and purple in color. The face, the backs of the hands and those of the feet show no spots. April 28. Heart: The action is rapid and regular. All heart sounds are accentuated. No murmurs are heard. The pulse is small and weak. Lungs: Many fine rales are heard in the back, especially at the bases. There is no dulness and the breath sounds are normal. The abdomen is concave and soft. The abdominal reflexes are lively and the knee-jerks are very sluggish. The neck is moderately stiff and Kernig's sign is present to a slight degree. The muscles of the left calf are sensitive to pressure. There is muttering delirium at times and the patient is not fully con- scious. The facial expression is that of pain. Gestures indicate pain in the forehead and in the legs. The breathing is very rapid. The Urine is of normal color, acid, sp. gr. 1015, and shows a trace of al- bumen. The test for sugar is negative. Thesediment shows many granular and fatty casts. April 29. The body is emaciated and the skin is dry. Heart: The sounds this morning are of poor quality, and the pulse is very weak. The systolic blood-pressure is 70 mm. The patient is conscious but mentality clouded and his movements are tremulous. He has a frequent, dry cough. This morning about 720 cc. of salt solution were given intravenously. The pulse rate dropped from 140 to 120 while the first 500 cc. were going in and the pulse improved much in quality at the same time. The injection 182 CASES OF TYPHUS FEVER WITH RECOVERY was terminated later because the pulse rate rose again to 130, and its qual- ity deteriorated. The heart sounds, however, remained excellent. At 5 p.m. the heart sounds were clear, the action regular, and the rate 134. The blood- pressure was 75/S.-60/D., and the pulse small and weak. At 6 p.m. salt solution was again administered. The pulse improved much at first during the injection, but after about '480 cc had been given the patient coughed repeatedly, the heart sounds which had been abnormally loud became less so, and the pulse deteriorated again. The patient did not look quite so well and seemed rather prostrated. Therefore the injection was dis- continued. The blood examination made one hour after the first infusion of salt solution showed a haemoglobin (Sahli) of 125 per cent, a red count of 5,500,000, a white count of 4000, and a color index of 1.13. April 30. This morning the patient is weaker and semicomatose. He slept better, however. The pulse is of very poor quality but the heart sounds are fairly good. In the afternoon the pulse was much stronger for a time, but weakened again later. Salt solution was administered at 6 p.m. and again at midnight in small amounts with good effect. May 1 . The pulse is of fair quality this morning and the heart sounds are good. ■ The temperature has dropped abruptly to normd,l and the pulse rate has fallen to 92. Muscular twitching persists. May 3. This morning the patient is semicomatose and can only be roused with difficulty. The pulse is very weak and irregular in force. After about 720 c.c. of salt solution had been given intravenously at 11 a.m. the heart sounds became loud. The blood-pressure was then 95/S.-70/D. May 4. The patient looks rather dried up this morning, but feels well enough to smile. The heart sounds are loud and the pulse is of fair quality, the rate being 70. The temperature has remained normal for 24 hours. The respiration rate has varied from 20 to 24 during the past three days. May 6. Patient passed only about 15 c.c. of urine today. The bowels moved once today and three times freely yesterday. The abdomen is markedly distended and is tympanitic. It shows slight general tenderness. There is no dulness in the region of the bladder. The nurse says that the patient frequently takes from 240 to 300 cc. of liquid at a time. She reports also that at times the pulse is slciw and of poor quality. Since the administration of a little brandy one hour ago it has been excellent. The heart sounds are now of good quality and the rate moderate. Digitalis was then prescribed. . The patient seems mentally dull and physically weak. CASES OF TYPHUS FEVER WITH RECOVERY 183 Shortly after the time mentioned in the last note an enema was given with little effect on the bowels but soon the patient voided about 720 c.c. of urine and the abdominal distention nearly disappeared. May 6. The patient is better this morning. For the past three days he has been asking for bread. The pulse is of good quality and the blood-pressure is 90/S.-60/D. There is no distention. Patient is taking 240 cc. of water every two hours and eating well. His face is less emaciated. Haemoglobin (Tallquist), 90 per cent. The urine is acid, the sp. gr. 1025, and the diazo-reaction is negative. The sediment shows many hyaline and granular casts, some of them with fat and cells adherent. In the afternoon the left side of the face on which the patient had been lying was distinctly ©edematous . May 7. The face and eyelids are slightly swollen and there is slight oedema of left leg. The patient is very drowsy. Muscular twitching and cough have stopped. Limitation of the ingestion of liquid was prescribed. Digitalis was discontinued on account of bradycardia. May 9. The right side of the face is still slightly swollen. The patient is weak and drowsy. The bladder is distended nearly to the umbilicus. The patient was, therefore, catheterized. Haemoglobin (Tallquist), 90 per cent. Blood-pressure, 100/S.-80/D. May 11. The patient now urinates normally. He is gaining strength. There is no oedema. The ingestion of liquids has been limited to 1000 cc. in 24 hours. The aortic second-sound is accentuated, and is louder than the pulmonic second-sound. The first-sound is faint and blurred. Blood-pressure, 105/S.- 65/D.* May 14- The patient is passing more urine and his condition is improv- ing steadily. The heart action is slow and regular, the pulmonic second-sound is ac- centuated and louder than the aortic second-sound. The second-sound at the apex is accentuated, and the first-sound is nearly replaced by a systolic murmur which is heard equally well in the pulmonic and mitral areas, and is not transmitted to the axilla. Blood-pressure, 105/S.-70/D. Haemoglobin (Tallquist), 75 per cent. May 26. The Widal test and the paratyphoid A and B agglutination tests are negative in dilutions of 1-25 and 1-50. May 30. The urine is normal in color, the sp. gr. 1008, and there is no albumen. The general condition of the patient is good. The fingers were almost completely paralyzed for a time but their strength is returning. -• 184 CASES OF TYPHUS FEVER WITH RECOVERY June 2. The second-sounds of the heart are now of good quahty. The puhnonic second-sound is louder than the aortic second-sound. The first- sound is blurred by a systolic murmur which is heard all over the precordia. It is loudest in the mitral area and is not transmitted to the axilla. It dis- appears when the patient sits up. The cardiac dulness is slightly increased CUNICAL CHART N,*M6.._S,c3-,i.e,s...,Jl9._ MEDICAL RECORD -BOOK, VOl , — PAGE.._ BED NO. 0ATE.Ap,VjJ_Sf-M.CLy-131S., .DISEASE l^..p.liu.£_^-e.«e.r. ._ — ., Zfe 27 28 Z5 30 1 ^ "3 4 5 i. 7 8 9 ~ dS^ I "1 t Z z z s I e a. E ■J £ E £ S 3 \ i z I i 1 s 107' 106 105' 1 Ol- ios 102 lor 100 99 U' 9? 96- 95' ISO 140 1,30 120 MO 100 80 70 50 45 40 35 25 20 15 " ' ' " M t " ' M t " ' " ' " • M t / --\ J A ^ u ^ A , /] I \'^ , / ,/ ^ ■^ h J P) sl \/ / o i-v v» O t^ l/l V J -^7 1 1 1 1 r\ y i/\ o 8, td ^ CL \ . : ? = : pa >^ = i 2 : 3 ^ ^ ¥ H Tl ^ «J K c - ^ \ \, / \ \ \ V \ A V •^ "^ L _ k ict ar \fl J il J id Series Number 9. Typhus fevere severe. Ne- phritis apparently becoming chronic. Admitted to hospital April 26. Haemoglobin estimations, red counts, white counts, and blood-pressure are recorded on the chart to the left and the apex impulse, when the patient lies on the left side, is felt in the mid-axillary line. Its force is greater than normal. Blood-pressure, 115/S.-75/D. The lungs are negative. The skin and mucous membranes are abnor- mally pale. Haemoglobin (Tallquist), 75 per cent. The patient is much stronger. He was discharged today, advice having been given about diet with regard to signs of nephritis. CASES OF TYPHUS FEVER WITH RECOVERY 185 Series Number 10. Diagnosis: Typhus fever moderately severe with marked irregularity of the pulse. Clinical Notes Serbian, age 37, admitted to hospital on April 26. April 27 . The patient is said to have been sick for three days, but more probably he has been so for a week. Physical Examination: The patient lies on the side. He is apathetic but mentally clear when aroused. He then becomes nervous and excitable. There is a malar flush, the eyes are sunken, the conjunctivae are injected, there is moderate emaciation, and the skin is dry. The pupils are large, equal, and react to light. The tongue shows a white coat. The throat is red. There is no glandular enlargement. The eruption consists of scattered pink or purple macules on the chest, abdomen, and back. The face, the arms and the legs show no eruption. The pink spots disappear on pressure, and the purple ones fade, but do not disappear. Heart: The dulness is normal and the action regular but slightly rapid. The aortic second-sound is muffled and the pulmonic second-sound is faint. The sounds at the apex are of poor quality and the pulse is soft. The Lungs are negative. The Abdomen is concave, soft, and not tender. The liver and spleen are not palpable. Reflexes: The abdominal reflexes are absent, but the knee-jerks are present. The neck is moderately stiff and there is a slight Kernig's sign. The calf muscles are not sensitive to pressure. On the left hip is a purple spot about 6 cm. in diameter, due probably to pressure. Treatment: Ordinary care and cathartics were prescribed. April 28. The face which is much browned by the sun has a tinge of cyanosis. The patient is fully conscious but drowsy. The palms of the hands are bright yellow in color and the soles of the feet are slightly yellow. The systolic blood-pressure is 80 by palpation. By auscultation it varied from 90 to 70 but there were heart beats which gave no sound in the artery which shows a marked irregularity of force. The haemoglobin (Tallquist) was considerably above 100 per cent. Urine: Color high, acid, sp. gr. 1016, albumen a very slight trace, diazo- reaction strongly positive. April 29. Temperature falling. General condition about the same, pulse weak. Haemoglobin (Sahli), 130 per cent, red count, 5,900,000, color index, 1.10, white count, 16,600, platelets scarce; differential count: polymor- 186 CASES OF TYPHUS FEVER WITH RECOVERY phonuclears, 72 per cent, lymphocytes, 8 per cent, large mononuclears, 17 per cent, transitional cells, 2 per cent, unclassified, 1 per cent. April 30. Lungs clear. Sputum frothy, white, very viscid. Pulse of poor quality in the morning, better in the afternoon. Salt solution was admin- istered by rectum. May 1 . The heart sounds are of poor quality. The aortic second-sound is very indistinct but the second-sound at the apex is fairly loud. May 2. The patient is better this morning. The pulse has been irregular in force and rhythm ever since admission and the heart sounds have been of poor quality most of the time. This evening at 6 p.m. the pulse rate at the wrist had risen from 110 to 120. The heart rate at the same time was 132. The face was markedly flushed and there was slight cyanosis of ears, face, and finger nails. Heart dulness to the right was slightly increased. The patient has been getting salt solution by rectum every six hours and had 720 cc. yesterday afternoon intravenously. It was administered be- cause the skin was very dry and the body emaciated as if in need of liquid. Last night 240 cc. of salt solution were given intravenously, but the in- fusion was then stopped because the heart sounds had become faint, and because the pulse rate had not diminished. The pulse had improved, how- ever, in quality. Shortly after the infusion the patient had a slight rigor. Nothing of this sort followed the first infusion. Blood: White count, 14,200, haemoglobin (Sahli), 100 per cent, red count, 5,900,000. May 3. This morning the patient is decidedly better. The aortic second-sound is faint, but the pulmonic second-sound is good. The first and second-sounds at the apex are excellent. Blood-pressure, 85/S.-55/D. May Jf. The patient is much brighter. The heart sounds are of good quality. Blood-pressure, 90/S.-60/D. There is considerable cough with scanty, viscid expectoration. The conjunctivae are still injected. The tongue is clean. White count, 9700. May 5. Urine: Color normal, sp. gr. 1017, albumen a very slight trace. May 6. A few days ago the patient complained of pain in the tip of the right middle finger. A small, red, purpuric spot was seen under the skin. Following this there was swelling of the finger tip. Yesterday a little pus was evacuated by incision. The general condition of the patient is improving steadily. The entire face and ears have been flushed and are so still. The conjunctivae are no longer injected. Herpes appeared on the ear several days ago. Blood-pressure, 85/S.-60/D. Haemoglobin (Tallquist), 80 per cent. White count, 6300. CASES OF TYPHUS FEVER WITH RECOVERY 187 May 7. Haemoglobin (Sahli), 100 per cent. Red count, 4,700,000. May 8. Urine: Color high, acid, sp. gr. 1023, albumen a slight trace. May 9. The heart action is regular, and slow. The aortic second-sound is louder than the pulmonic second-sound. The first-sound is blurred by a faint systolic murmur. Blood-pressure, 95/S.-60/D. White count, 5700. CUNICAL CHART ..Seiies * 10-. _OATE J p.ril ,«..B,av .1915." MEDICAL RECORD BOOK, VOL. -. PAGE _ DISEASE .Ty.p.haS {:e.V.e.r....... Dayiof Month Zfe Z7 28 19 30 1 2. 3 4- 5 e 7 8 9 10 11 11 13 14- 15 1-6 Days of Disease 3 » fc I z I b D < z li 3 Z z \ -1 i z i I 1 \ 107' 105' 104' 103' " " ' " ' " ' " ' ^ 1 U v^ /' M lor 100' ^ \^ , v' ■■ L r ._ 1 ±:a -A ^- _ . -/- ^,' " 1 98' 97' " ~ ~ ~ ~" "s^ ^ ^ t v" u^ ^ / V ^ ISO 140 130 120 no 100 90 70 50 35 30 15 10 n A vS o o A oi /^ / W-. / I, 00 1 i ^ iJ \^ ^ y ^ \ § ^ 9 PJ ^- = i PQ l?1 = = \h ^ V V^ ^ \ V '-^ -s 1 \ '"' K •~~ 1 \ r- \ ^ ^ •^ ^ ►-* / ^ '-' _ _ 5i ,ch aT e.c / Va 3 Ith _ _ _ _ Series Number 10. Typhus fever, moderately- severe with marked irregularity of the pulse. Ad- mitted to hospital April 26. Haemoglobin, red counts, white counts, and blood-pressure are re- corded on the chart Digitalis was omitted yesterday morning, and the brandy which the patient had been having for several days was omitted a few days earlier. May 11. Haemoglobin (Tallquist), 100 per cent. The heart sounds are of good quality. The pulmonic second-sound is louder than the aortic second-sound. A systolic murmur is heard over the precordia, loudest in the mitral area, and not transmitted to the axilla. Blood-pressure, 105/S.-50/D. 188 CASES OF TYPHUS FEVER WITH RECOVERY May 13. The face is desquamating. The pulse is of good volume and tension. The pulmonic second-sound is louder than the aortic second-sound and both are accentuated. The first- sound is blurred by a systolic murmur. The second-sound at the apex is ac- centuated. Blood-pressure, 100/S.-55/D. Today the patient was out of bed for the first time. May 19. The patient's condition is improving rapidly. The heart action is slow and the sounds are of good quality except the first-sound which is faint. The pulse is small. Blood-pressure, 100/S.- 60/D. Haemoglobin (Tallquist), 80 per cent. May 30. The urine is normal in color, sp. gr. 1018, no albumen. The patient was discharged today in excellent condition. Series Number 36. Diagnosis: Mild typhus. Bradycardia, no drugs used. Clinical Notes Serbian, age 26, admitted on April 26. April 26. Said to have been ill ten days. April 28. Urine: Normal in color, acid, sp. gr. 1017, no sugar, albumen a slight trace. The sediment shows a rare hyaline cast. Eruption Present: A complete examina- tion was not made because the condition of the patient was satisfactory and other work pressing. May 8. The tongue is clean. The con- junctivae are injected on the right side of each eye but not on the left side. The skin shows a few spots of doubtful nature. The patient is gaining rapidly in strength and his state of nutrition is good but he looks anaemic. Haemoglobin (Tallquist), 80 per cent. Blood-pressure, 120/S.-55/D. May 1 1 . The patient was discharged as cured. Series Number 48. Diagnosis: Typhus fever; with chronic cervical adenitis and hysteria during conva- lescence. CUNICAL CHART - DATE April T A ay 1315 MEDICAL RECORD BOOK. VOL.... DISEASE T-yph u.a t- i..e.r 1 D.jsol Month Z8 IS 30 1- 2 3 4 5 t 7 B 3 10 11 3 I X z I § I s 5 z i I z i z f 107 r06 105 104 103 102 101 100 99 "5f 97' ISO 130 120 110 00 90 80 70 " " " " " " ' - — ^ \ / 1/ \ \ /" '^ .^ ,^ ~ -^ ^ r~ \ \ /' ^ K A ^ ■,^ 50 45 <0 35 30 25 20 V * l^ r? ' X ^ ^ "v ^ "1 h A 1 J "\ '\ r^ *"' \'' %. , , Di; di xr( = w el ^ = t. ur £ IS- J Series Number 49. Typhus fever — a typical case of moderate severity. Haemoglobin, white count, and blood-pressure are recorded on the chart first-sound is loud but blurred. The second-sound at the apex is accen- tuated. Cardiac dulness is normal. Blood-pressure, 105/S.-50/D. Lungs: A few coarse rales are heard. Abdomen is soft and shows slight, general sensitiveness. The spleen is not palpable but splenic dulness is increased. The knee-jerks are present. The calf muscles and hamstring muscles are sensitive to pressure. Kernig's test causes pain. The neck is very slightly stiff. Haemoglobin (Tallquist), 85 per cent. 192 CASES OF TYPHUS FEVER WITH RECOVERY May 15. The eruption is beginning to turn purple but most of the spots are still pink. The heart sounds are all of good quality, the aortic second-sound equals the pulmonic second-sound and the pulse is of the bounding type. Blood- pressure, 105/S.-60/D. Haemoglobin (Tallquist), 70 per cent. May 16. White count, 12,800. May 19. There has been a rapid fall of temperature associated with steady improvement in the condition of the patient. The nutrition is well maintained. The eruption is turning brown. The leg muscles are no longer sensitive. The second-sounds are accentuated, especially the pulmonic second- sound. The first-sound is of fair quality, the pulse is full and soft, and the blood-pressure is 110/S.-70/D. Haemoglobin (Tallquist), 95 per cent. May 21. The patient is doing well. Blood-pressure, 110/S.-70/D. Haemoglobin (Tallquist), 75 per cent. May 26. The convalescence is rapid. Blood-pressure, 110/S.-60/D. Haemoglobin (Tallquist), 90 per cent. The Widal test in dilution of 1-25 is positive but in that of 1-50 it is negative. Agglutination tests for para- typhoid A and B are negative at 1-25 and 1-50. The patient was discharged well about June 1 . Series Number 57. Diagnosis: Typhus fever; persistent vomiting in convalescence, and bradycardia. Four-hourly tem- perature chart, showing crisis. Clinical Notes May 17. A Serbian, age 20, admitted yesterday afternoon; and said to have been sick twelve or thirteen days. Physical Examination: The patient lies on his side sleeping comfortably. The breathing is rather rapid and deep but the nostrils do not move. When aroused the patient grunts occasionally when breathing. The face is brown and slightly flushed especially in the malar region. The ears are particularly red. The pupils are equal and of normal size, the conjunctivae moderately in- jected, the tongue shows a white coat, and the throat is slightly red. The Eruption is macular. The spots are irregular in shape and of various sizes. Their color is purplish or bluish pink. There are a few spots on the neck, legs, and back, and many on the shoulders, upper chest, flanks, and abdomen. The face, mucous membranes, hands and feet show no spots. The Heart Action is regular and not rapid. The aortic second-sound is accentuated, and the pulmonic second-sound much accentuated and louder CASES OF TYPHUS FEVER WITH RECOVERY 193 thaD the aortic second-sound. The first-sound is blurred by a systolic mur- mur which is heard also in the pulmonic area but is not transmitted to the axilla. The second -sound at the apex is slightly accentuated. There is a MiMe-Sariea— *52 CUNICAL CHART _WARO_ .DATE .&om li>,.B15 Series Number 57. Typhus fever; four-hourly chart showing crisis marked pulsation in the neck. An excessive pulsation is seen in the second and fourth interspaces over the heart. The heart impulse is increased in force and is best felt in the fourth interspace in the mid-clavicular Hne. When the patient lies on the left side an excessive impulse is felt in the fourth interspace in the mid-axillary line. No murmurs are heard. Blood-pressure, 110/S.-85/D. The Lungs are negative . The Abdomen is flat, soft, and not sensitive. Pressure causes gurgling, especially in the right ihac fossa. The liver and spleen are not palpable and the splenic dulness is not increased. 194 CASES OF TYPHUS FEVER WITH RECOVERY The neck is slightly stiff and there is a slight Kernig's sign but the test does not cause pain. The leg muscles are not sensitive. The knee-jerks are present. Haemoglobin (Sahli), 110 per cent, red count, 4,600,000, white count, 7800, color index, approximately 1.30. Treatment: Routine without drugs. CUNICAL CHART HAME,„ ,S,e.ri e.s.-.,* .S.,7.. MEDICAL RECORD BOOK, VOL.. _.- PAGE DISEASE _1^.p.ku-E,_.f:i _DATE .An )!..»- .lanciaiS Days of Month 16 17 18 19 20 21 22 23 24- X5 2fe 27 28 29 30 31 1 2 3 + 5 I'S^ 1 !^ a £ I z c X s u c z t: id £ I DC is: I m °- z i e SI E C 07 05- W 03' 02' 100 Is' 9/ y t " ' " ^ " ^ . ^ ;i l\ /I 1 l/ 1/ j ' , ^ / ^ \^ *., / ^ / ^ / ' ^ '-, 150 HO 130 120 100 80 60 o 00 Ln -0 to ■~.o ^ •^ 1 1 1 1 o 3 o 0-) 3 a pu - : CP c r ; . V r" v^ -^ , V W-, / ^ / ^ ^ ^= z ^ ir ■\ / 7 V *"• 45 40 35 30 25 y \ \ \ / •n ^ y w„ \ ^ »-• -- -- v* — ' c _ D. .cl ar ge L lu = L2 ^ _ _ _ Series Number 57. Typhus fever; persistent vomiting in convalescence, bradycardia, crisis May 19. All the second-sounds are accentuated and especially the puhnonic second-sound. The pulse is full, and the blood-pressure, 105/S.- 65/D. The eruption is fading and turning brown. Haemoglobin (Tallquist), 95 percent. May 22. The patient is very thin. He has vomited frequently. (No drugs have been used.) CASES OF TYPHUS FEVER WITH RECOVERY 195 The second-sounds are accentuated, especially the pulmonic second- sound. The first-sound is of fair quality. The second -sound at the apex is accentuated and the pulse is of fair quality. Blood-pressure, 90/S.-65/D. Haemoglobin (Tallquist), 90 per cent. May 23. The patient still vomits everything. Examination of the ab- domen is negative. Calomel was prescribed yesterday in small, repeated doses and feeding was attempted in very small quantities every hour but the patient vomited even water. Nutritive enemata and salt solution by rectum were prescribed. May 26. The patient has not retained the salt solution well and has con- tinued to vomit until yesterday afternoon when he was able to keep down a little water. This morning he has taken 240 c.c. of liquid nourishment and looks better. The heart sounds are of good quality, the pulmonic second-sound is ac- centuated and louder than the aortic second-sound. The second -sound at the apex is accentuated and the first-sound is of good quality. Blood-pres- sure, 105/S.-65/D. June 2. Improvement is marked and rapid. June 11. There is now no stiffness of neck or legs. The patient is very thin, but is fairly strong. Blood-pressure, 120/S.-65/D. He will be dis- charged tomorrow. Series Number 59. Diagnosis: Typhus fever; diarrhoea, crisis, pulmonary gangrene in convalescence. Clinical Notes May 19. Serbian, age 22. He says that his left eye became inflamed about twenty days ago and that he has had fever for seven days. There has been no pain except in the eye. Physical Examination: The patient is well developed and fairly well nourished. He is fully conscious and mentally clear. The face is brownish, the cheeks moderately flushed, and the forehead slightly so. The ears and nose are red. The right pupil is very large, but it reacts to light. The left eye is in- flamed and sticky. The tongue shows a whitish coat, the throat is red, and the tonsils are slightly enlarged. The glands in the axillae are enlarged but the posterial auricular glands are not palpable. Eruption: The face and mucous membranes are free from spots. There are a few spots of doubtful nature on the neck. On the arms, the chest, and the backs of the hands there are a few typical, pink spots which disappear on pressure. On the abdomen there are a few macules and 196 CASES OF TYPHUS FEVER WITH RECOVERY papules. Macules are seen faintly outlined on the legs and feet. The back shows many reddish papules of doubtful nature. The Heart Action is regular and rapid. The pulmonic second-sound is accentuated, and louder than the aortic second-sound. The second-sound at the apex is accentuated. The first-sound is blurred by a systolic murmur which is loudest in the pulmonic area and is not transmitted to the axilla. The pulse is of the bounding type. There is excessive pulsation in the neck. The arteries are soft. Blood-pressure, 125/S.-45/D. The Lungs are negative. The Abdomen is soft, full, and not sensitive. The spleen is palpable about 4 cm. below the costal margin and the splenic dulness is much increased. The Neck is decidedly stiff but an attempt at flexion does not cause pain. The neck muscles are not sensitive. There is a definite Kernig's sign with- out sensitiveness of calf or thigh muscles. The knee-jerks are present. Haemoglobin (Tallquist), 95 per cent. Routine treatment and brandy in small quantities were prescribed. May 21. White count, 3900. May 22. The patient is losing weight rapidly although taking nourish- ment well. His color is not good, the pulse is of poor quality. Blood-pres- sure, 105/S.-50/D. Haemoglobin (Tallquist), 75 per cent. Digitalis and extra diet were prescribed. May 23. The patient is taking nourishment well but continues to lose weight and strength. His condition is critical. The eruption has become profuse all over the body and limbs, and is turning purple. Nutrient enema of syrup, 60 cc. in 480 cc. of water were administered every six hours. May 26. Urine: Color high, neutral, sp. gr. 1012, no albumen, diazo- reaction strongly positive. May 28. The patient began to have diarrhoea yesterday and it became profuse to day. The stools are of the pea soup variety, and not offensive. There is incontinence of the bowels. The mouth has been very foul. The nurse says it has required cleaning hourly. The patient is mildly delirious, picks at the bedclothes, and is extremely weak. The pulse has remained full and of good quality. Blood-pressure at 6 p.m. 95/S.-45/D. The aortic second-sound is faint and the pulmonic second- sound of fair quality. The first-sound is faint and second-sound at the apex is accentuated. May 29. The patient's condition was so bad yesterday evening that he was not expected to live through the night. He was extremely weak and seemed too tired to breathe, but the pulse continued pretty good. Salt solution, 480 cc, was given intravenously in the evening with benefit. CASES OF TYPHUS FEVER WITH RECOVERY 197 This morning after the crisis, the patient's condition is still bad. Although the pulse was satisfactory, salt solution was given again intravenously to make up for fluid lost by diarrhoea. Fifteen minutes after the infusion the pulse became very weak and irregular, and the patient seemed about to die. CUNICAL CHART NAME, Sei-ie.3 ...^..Sa.. MEDICAL RECORD BOOK, VOL., BED NO - DISEASE J^phuS-fe -DATE .tt.a^'».XLi.ne..l9lS. _.,pulmo,n.a.r.^aajic|r«ne,. So'Ak"' 13 2.0 ii 2: 23 Z4 X51 IJi? zs: sbo 31 1 J 3 TT sk 7 8 .1^' «t. s t I z X s i < E 1- 1 - 3 i E i I Z o 1 107 106 105 104 103 "98' 97' 95 ISO 130 120 110 100 80 70 60 50 " " ' ' '" ' ■" " "" ■ •s, 1 if \ 1 1 /\ !• ^ / ■ ^ V 7" V \ \ « 1/ t f / ;/ « /' l/^ — — — — -^ ^- r^ / 1/ — — — — f*^ ^ i/-' -^ / o '^ lO U >o ■i) A I as been gradually increasing irregular fever with slight constitutional symptoms. About the time of the crisis and for several days the patient was ex- tremely sensitive all over. Any motion or attempt at motion caused great pain. Examination today with the patient lying on the left side shows a few rales at the left base behind and slight sensitiveness in the right flank with- out spasm. The patient's appearance suggests tuberculosis. He has been raising much sputum which is frothy and tenacious.. June 12. Urine: High colored, sp. gr. 1013, no albumen or bile. June 24. The sputum became foul about a week ago and a small area of dulness with a few rales was found at the right base in the axilla. The rales at the left base meanwhile disappeared. Moderate elevation of temperature persists. The sputum continues to be raised in considerable quantity and is foul at times. More often it is frothy and inoffensive. Microscopic examination shows no tubercle bacilli. There are great numbers of Gram-negative influenza-Uke bacilli, besides bacteria of many kinds, and a few pneumococci and spirochaetae. The patient remained in the hospital on account of these pukaonary symptoms and had periods of improvement followed by exacerbations. He was last seen about the end of August still in the hospital. Series Number 60. Diagnosis: Typhus fever. Mild paro- titis in convalescence. Clinical Notes May 19. Physical Examination: The patient is too dull and confused to reply to questions rationally. The face is much tanned and the cheeks are slightly flushed. The pupils are equal and of normal size. The tongue shows a brownish coat. The throat is negative and the mucous membranes are free from spots. The Eruption is scanty on the neck and hands and indefinite on the legs. The chest, flanks, abdomen, back, and arms are profusely covered with small purplish-brown spots. There are a few minute purple spots on the forearms and elsewhere. Evidently they are flea bites. Heart: The puhnonic second-sound is accentuated and occasionally redupHcated. It is louder than the aortic second-sound. The second-sound at the apex is accentuated. The first-sound is faint, and blurred by a soft, systoHc murmur which is best heard in the puhnonic area. Blood-pressure, 90/S.-50/D. The Lungs are negative. CASES OF TYPHUS FEVER WITH RECOVERY 199 The Abdomen is flat, soft, and not tender. The liver and spleen are not palpable and the splenic dulness is not increased. The neck is very slightly stiff, but the neck muscles are not sensitive. Kernig's sign is present, slight in degree. The test causes no pain. The muscles are not sensitive to pressure. Treatment consisted of routine measures without drugs. May 22. The right cheek began to swell yesterday in the region of the parotid gland. The temperature rose a little. Cold compresses were applied locally. June 2. The tenderness and swelling of the parotid have never been great. The swelling diminished markedly two days ago after poulticing. Now there is no tenderness and no pain. The swelling which remains is slight, and very hard. There is slight, irregular fever, but the patient looks and feels well. June 10. Discharged well except for slight, hard swelling of the parotid gland. Series Number 61. Diagnosis: Typhus fever; severe case, eruption peculiar, delirium violent. Clinical Notes May 20. Patient was admitted yesterday. Physical Examination: The patient is drowsy but rational. The entire face is flushed, especially the cheeks and ears. The pupils are small, equal, and react to light. The conjunctivae are red. The tongue shows a brownish coat, the throat is slightly red, and the mucous membranes are free from spots. Eruption: The lower part of the neck, the chest, and the arms show many rose-pink macules which disappear entirely on pressure and which are not elevated. There are a few macules on the abdomen, legs, and feet. The flanks show a few papules which are redder in color than the macules- and which do not disappear entirely on pressure. The face and hands are free from spots. Extensive pink mottling is seen on the back and there are blotches of irregular outline and considerable size scattered over the trunk. They re- semble pityriasis rosea. Heart: Dulness is normal in extent. The sounds are of good quality except the aortic second-sound which is rather faint. The pulse is of good volume and tension. The Lungs are negative. The Abdomen is very soft and tympanitic. It shows considerable general tenderness without spasm. The spleen is palpable on deep breathing and^ the splenic dulness is increased. 200 CASES OF TYPHUS FEVER WITH RECOVERY The neck muscles are very sensitive to pressure and the neck is stiff. The hamstring and calf muscles are very sensitive, and the thigh muscle in front is less so, and the biceps is still less sensitive. Kernig's sign is positive but slight in degree. The test causes pain. Routine treatment prescribed. May SI. White count, 8C00. May 26. The patient has been delirious since admission. At first he would get up and try to leave the ward. The night before last the deUrium became so violent that the patient had to be tied in bed. This morning he was quiet but mentally confused. The face has become several shades darker in color. The conjunctivae are still deeply injected. The patient lies on his back and dozes with eyes half open. Heart: The pulmonic second -sound is accentuated and louder than the aortic second-sound. The first-sound is of good quality. The pulse is of good volume. Blood-pressure, 95/S.-65/D. Haemoglobin (Tallquist), 75 per cent. May 27. The pupils remain contracted. June 12. This patient has been very ill and has gained strength slowly. He has been drowsy and lethargic but now looks decidedly better. For several days his bed was put out of doors but for the past three days he has been able to walk out. Today he returned complaining of headache. The weather has been very hot. Three days ago white spots, like thrush, appeared in the throat. They are clearing up now. Examination of the heart shows the first-sound short but louder than the second-sound and the pulmonic second-sound louder than the aortic second-sound which is faint. Blood-pressure, 125/S.-60/D. The skin and mucous membranes are pale. Haemoglobin (Tallquist), 90 per cent. An iron tonic and small doses of digitalis were prescribed. June 18. The patient is rather pale and lethargic. His condition is otherwise satisfactory. He will be discharged tomorrow. Sekies Number 83. Diagnosis: Typhus fever. Bradycardia; heartblock (?). Digitalis used. Clinical Notes May 25. The patient says he was ill for a week before admission. Physical Examination: The patient is mentally clear and alert. The tongue shows a brownish coat. CASES OF TYPHUS FEVER WITH RECOVERY 201 The Heart Action is regular, the sounds at the base are of good quaHty but at the apex they are faint. The pulmonic second-sound is accentuated and louder than the aortic second -sound . The pulse is small and rapid. CUNICAL CHART WAME,_jS.e.ri f S » fl?l WARO BED HO., _ OATC . rto y .»• Ju « E. 131." ' ' 1 Month 15 2.6 xi ■X& 29 30 31 L 2 3 4- s 6 7 8 9 10 11 12 13 14 8 I Z z a: 1 u e 1 a. X : z i i i i a z 1 E 107 106' 105 104- 103 102' 101- 100 99 ■98' 97' 96- 95 ISO 140 130 120 110 100 90 eo 70 60 50 45 40 35 30 25 20 15 10 " ' " ' " ■ ' ' " ' " ■ " ' " ' ■ ' " ■ ^ / •^ Vl l^ J / 7 \ n * \^ \ ^ "N ,-« u V— ^ ^> 'n (-> tQ tO r CL - PQ 5 / A \ fl V^ « \ V / f \ /^ ^ / / / / / w V L 1 V '' ir i-\ / J ^ / V^ K ^ V ^ — 1 ^ / ^ \ ^ ^ ^ y v' iA L= D^ ch an y _j 4.n( _2 Ot T_ _^ Series Number 83. Typhus fever. Bradycardia, heart-block (?). Digitahs used T^e Lung's are negative. The Abdomen is negative. The spleen is not palpable but splenic dulness is increased. The neck is not stiff and Kernig's sign is absent. The knee-jerks are sluggish. Digitalis was prescribed. May 26. (Morning.) The soft palate and the pharynx are red. On the palate is a single minute red spot. The entire face is flushed and especially the cheeks and ears. The conjunctivae are much injected. The pupils are small. There are a few spots on the neck. The chest, the back, the abdomen, and the backs of the feet and hands are profusely sprinkled with spots. 202 CASES OF TYPHUS FEVER WITH RECOVERY The neck is not stiff or sensitive. There is a shght bilateral Kernig's sign more definite on the right. Performance of the test causes pain in the ham- string muscles. They are slightly sensitive to pressure. The patient is rational but rather dull. The pulse has been of poor quality since admission. Blood-pressure, 75/S.-55/D. The condition of the patient is otherwise excellent. Haemoglobin (Tall- quist), 90 per cent. The urine is high colored. Increased ingestion of water was prescribed and a small dose of strych- nin every four hours. May 26. (Afternoon.) Every third or fourth heart beat is skipped. The sounds are loud. The pulse is now of good volume and tension. Digitalis omitted. The doses taken since admission have not been large. May 27. The cardiac irregularity is less pronounced but the pulse rate continues to fall. June 12. Haemoglobin (Tallquist), 90 per cent. The heart action is rapid again and regular. The pulmonic second-sound is louder than the aortic second-sound. The first-sound is louder than the second-sound at the apex. In the aortic region a short, scratchy systolic murmur resembling a pericardial friction rub is heard. Blood-pressure, 115/S.-75/D. Digitalis was prescribed again. June 13. Because the pulse rate fell markedly and irregularity recurred the digitalis was omitted this morning. In the afternoon the pulse was again more rapid and there was no arrhythmia. The patient had been walking about the ward a little. Blood-pressure, 120/S.-80/D. June 20. Discharged in good condition. Series Number 92. Diagnosis: Typhus fever in an old man; mild; premature systoles. Clinical Notes June 11. Nationality Turkish, age 60. Present Illness: Admitted yesterday having been "sick eight days." The patient was incontinent last night and is so today. He was stuporous yesterday but is brighter today. He is taking nourishment fairly well in small quantities. There is no cough or expectoration. Physical Examination: The patient is very drowsy, but when aroused replies intelhgently. He lies most of the time with the eyes half closed and the mouth open, grunts occasionally but breathes easily and does not cough. The skin is rough and dry. The body is well developed but ema- ciated and dried up. The face is very brown but markedly flushed. The hyperaemia extends over the forehead and neck and down on to the upper part of the sternum. CASES OF TYPHUS FEVER WITH RECOVERY 203 The conjunctivae are moderately injected. The pupils are equal, of moder- ate size, and react to light. The tongue shows a heavy brownish coat. It is dry and fissured. The throat is red and sticky mucus adheres to it. Eruption: The chest, arms, abdomen, and back show many spots midway between the pink and purple stages. The spots are macular, and CUNICAL CHART •UME..-.S tr.Le. s„.* 9 a_. WARD BED NO DATE-XuJie-lQ,.iaiS~ DICAL RECORD BOOK. VOI PAGE DISEASE...!^ ph..lJLa..-_|-ty.£X.___. -_ . Dnyiof Monlh 10 11 12 M 14 15 Ife 17 L8 19 20 ■xt 2.2 23 24 !! rf I X z c z s D t I — £ c £ S s X I g K S c 107 106 105' 104' 103 102 lor 100' » "S' 97 96 95 ISO 140 130 120 " ' " ■ " ' " ' « . " ■ ' ' " ' " " A A r V \l \/ J ' \/ I ^ u '-^ / ■ /" f V v- y V 90 SO 70 A ^ J M ^ r / ^ v' 'i / ^ V V \ r-r / >/ |rV\ / 50 45 40 35 30 20 15 10 V V" ^ / ^ , , _ V* ^ ^ _ Dl ch ar |ec I J U£ . a 5_t \ __ __ _ _ Series Number 92. Typhus fever in an old man; mild; premature systoles they nearly disappear on pressure. The legs, backs of the forearms, hands and feet and face are free from spots. The heart's action is regular. The aortic second-sound is slightly ac- centuated and the pulmonic second-sound is faint. The second-sound at the apex is accentuated and the first-sound has a valvular quality. Blood-pres- sure, 85 /S. -65 /D. The Lungs are negative. The Abdomen is soft and is not sensitive. Peristalsis is visible. The liver and spleen are not palpable and splenic dulness is not increased. 204 CASES OF TYPHUS FEVER WITH RECOVERY The neck cannot be bent forward at all, but rotation is free. There is no sensitiveness of the neck muscles. The Kernig's sign is present and this test causes pain. The knee-jerks are present, but very sluggish. The ab- dominal and plantar reflexes are present and lively. Haemoglobin (Tall- quist), 85 per cent. Prescribed brandy, 15.0 cc. and digitalis, 0.6 gm. every four hours. June 15. The heart sounds are of fair quality. Single or double prema- ture systoles are heard occasionally. The pulse is of good volume and fair tension. Blood-pressure, 90/S.-55/D. The eruption is fading. Only a few pale, brown spots remain. The patient sleeps a great deal. He has always taken nourishment well and seems to be improving. He has given no cause for alarm. Constipation is very obstinate. June 18. The aortic second-sound is faint, the pulmonic second-sound is of fair quality, and the first-sound is short. The second-sound at the apex is good. Blood-pressure, 90/S.-55/D. June 25. Discharged in good condition. Series Number 93. Diagnosis: Typhus fever; broncho- pneumonia; dry pleurisy. Clinical Notes Present Illness: Serbian, age 40, admitted to the wards of a colleague June 5 and transferred to the writer on June 8. The patient is said to have been ill eight days before admission and to have had an eruption which first appeared nine days ago. June 11. Physical Examination: The patient is drowsy, but easily aroused and is then apprehensive because every movement which involves the shoulder causes pain. He appears to be rational. The respiration is rapid and shallow and the nostrils move. The face is very brown and there is a slight malar flush. The pupils are equal, of medium size, and react to light. The tongue shows a heavy brown- ish coat. The throat is reddish and there is sticky mucus adherent. The skin is dry and rough. The eruption is profuse, purple, blotchy, and is beginning to turn brown. It is abundant on the chest, abdomen, and back, and less so on the arms and thighs. The forearms, lower legs, feet, and hands are free from it or nearly so. :: - The heart action is very rapid but regular. The aortic second-sound is louder than the pulmonic second-sound. The second-sound at the apex is accentuated. The first-sound is short and has a valvular quality. The pulse is small and of low tension. Blood-pressure, 80/S.-60/D. CASES OF TYPHUS FEVER WITH RECOVERY 205 The Lungs are negative. The Abdomen is soft and seems to be acutely sensitive all over. Pressure anywhere on the abdomen causes the patient's face to show signs of pain. The spleen is not palpable and the splenic dulness is not increased. - The neck is very stiff and the neck muscles are sensitive. The head ro- tates freely but cannot be bent forward. The Kernig's sign is well marked. The muscles of the thighs and calves appear to be very sensitive to pres- sure. For three days the patient has been receiving 0.6 gm.^of digitalis and 15.0 cc of brandy every four hours. The night before last salt solution by rectum every six hours was prescribed. At first it was all retained, but how some of it is being lost. The bowels became incontinent yesterday. The patient coughs much but expels the secretion with great difficulty because he is very weak and the sputum is extremely viscid. It frequently causes a rattle in the throat. The nourishment was well taken until last night. The pulse is more rapid and becomes bad whenever the patient is dis- turbed. The blood-pressure at 11.30 a.m. was 75/S.-65/D. The aortic second-sound was of fair quality. The pulmonic second-sound and the first-sound were faint. At 5 p.m. the blood-pressure was 80/S.-65/D., and the heart sounds as before. The pulse was very weak. The area of heart dulness was less than normal. (Front of chest hyperresohant.) The Lungs were practically clear and the breathing easy but rapid. At 5.30, about 480 cc of salt solution were administered intravenously. During the injection the pulse improved in quality, and the heart sounds became stronger; the blood-pressure after the injection was 83/S.-60/D. Half an hour before the injection the pulse rate was 140. Immediately after the injection it was varied between 132 and 136. About 15 or 20 minutes after the infusion the patient had a prolonged and severe rigor during which his color became dusky and the pulse scarcely perceptible. The rigor lasted about 15 minutes and the patient's condition afterward Wap much the same as before the infusion. Haemoglobin (Tallquist), 100 per cent. June 13. The temperature is falhng and the condition has improved. June 16. Yesterday afternoon the patient's condition again became critical. He was given tea last night. He rallied again this morning and now seems decidedly better. The eruption is fading. Blood-pressure at noon, 90/S.-75/D. For the past three days he has been taking nourishment poorly. June 17. There has been severe diarrhoea for several days. Opium and an astringent mixture were given to check it. Last night the circulatory condition was unsatisfactory. Salt solution, about 360 cc, were given intravenously. There was no rigor. The pulse is of fair quality this morning. 206 CASES OF TYPHUS FEVER WITH RECOVERY There is a good deal of cough and a considerable quantity of thick, whitish expectoration. Nourishment is taken better this morning. Urine: Normal color, sp. gr. 1016, no albumen, no bile. The pulse in the afternoon became poor in quality. The rate was 104. Salt solution was prepared in the most careful way, the temperature care- ^ - * q^ CUNICAL CHART 5ATE TiLfl MEDICAL RECORD BOOK. VOL_ - DISEASE .T^.phjji_.f.e.v.e.r.... _ y D.,19JA . PAGE DISEASE Typhus feVftt". Days of Month 3 + 5 fe 7 8 9 10 11 12 13 14 15 Ifc 17 18 19 2,0 =11 Da,, of — r^ 8 t X z I ? E 3 i I i i z E IC o z o I CL c 107' 106 105' 103' 100' 99' ?i' 97' 96' " ' " ' " ^ " "■ " ' . ■ A h r ; \ i \/ Vl . / \ j \ M \ I V y j\ y / I 1 / \ .- — - -- ^-- — — — L L '/ - __ — - ^ / ^ 150 140 130 120 110 100 SO 70 50 40 35 25 20 15 10 /^ \\ / w^" p / i p \l \ h / ^ J ^ \ 1 J / =/i A V (D V D- (M / ' r / y / \ 1 J \ ; \l 1 \ -» / H I / * ^ A ab = : S A \ Autopsy Number 25. Typhus fever. Inhalation pneumonia and a haK after the infusion he had a severe chill. The salt solution had been freshly prepared with care. June 17. The delirium is quieter today, and the patient weaker. A small abscess on the buttock was opened yesterday, and today another appeared on the thigh. In the afternoon the patient was very weak and the pulse was of poor quality. Salt solution, 450 cc, was given intravenously. Fifteen minutes later the delirium increased and the patient had a chill. A small dose of TYPHUS FEVER — FATAL CASES — AUTOPSY 231 morphine was given subcutaneously after which the pulse improved much and the patient slept well. The pulse remained good in the evening. The salt solution was used because the patient was taking practically nothing by mouth and fought off attempts to feed him with the nasal tube. June 18. Thismorning the patient's condition is about the same. He is delirious, apathetic, and weak, but the pulse is of fair quality. He takes nourishment better. Corneal ulceration began several days ago. June 19. The patient is semicomatose and the pulse extremely bad. June 20. For the last two days the patient's condition has been getting worse. Symptoms suggested pulmonary lesions, but no definite signs have been found. The lungs were not examined yesterday. The abscess of the buttock became a slough and is increasing. The stiffness of the neck continues slight this morning and the patient is practically pulseless and comatose. He died about 9 a.m. Autopsy Findings Postmortem performed one hour after death. Body much emaciated. Heart: There is a milk-patch on the anterior surface of the heart. The left ventricle is firmly contracted. The right ventricle is flabby and perhaps a Kttle dilated. The heart muscle is apparently in good condition. The aortic, mitral, and tricuspid valves show slight fibrous thickening. There are a few minute yellowish spots on the aorta. Lungs: The left pleural cavity contains about 30 cc. of pus. The pleural surface of the lung is cloudy and shows several small patches of fibrin. The right pleural cavity contains no pus but the surface of the lung is like that of the left except that the changes are less marked. In both lungs are numerous small, hard nodules, some of which, on section, yield pus. At the left base there is atelectasis. In the right lung a bright red, narrow area of consolidation follows the posterior margin. Abdomen: The intestines appear normal externally. Liver: Shows slight nutmeg markings. Spleen: Firm, and slightly enlarged. Kidneys: Capsules adherent in places, cortex variable in width, markings indistinct, color rather pale. Specimens: Pieces of organs. TYPHUS FEVER, FATAL CASES NO AUTOPSY Series Number 87. Patient of Dr. Holmes. Diagnosis: Typhus fever. Died during the stage of nervous depression. Apparent Cause of Death: Severe toxaemia with general sjrmptoms. Clinical Notes A Russian physician, admitted May 21. A slight eruption was first observed on that day. May 27 . Physical Examination: The apparent age is about 23. The patiejnt hes on the back propped up. He is conscious but the mind is clouded. The eyes are closed, the respiration is rapid and shallow. The cheeks and eyelids are brightly flushed and the ears are bright red. The arms twitch occasionally, the hands move aimlessly and pick at the bed- clothes. The eruption is profuse on the chest, and dull red in color. The color partly disappears on pressure. The spots are irregular in size and shape. Most of them are macular but on very close inspection a few are seen to be slightly elevated. The elevation is more easily appreciated by palpation. The rash is clearly seen on the backs of the hands, and is abundant on the arms, abdomen, and legs. On the abdomen are a few maculopapules which are darker red and more elevated than the others. From these the color does not disappear on pressure. The rash as a whole is beginning to assume a purple tinge. The Heart Action is rapid and regular. The first- sound is faint and the second-sounds are accentuated. The pulse is large and of the bounding type. Lungs: No rales are heard in front. The backs were not examined. There is an occasional cough like that of bronchitis. June 1 . The patient's condition has been critical for several days. The respiration is very rapid and the pulse is very rapid and of poor quality. There is shght cyanosis. When the patient coughs there is rattHng in the throat but he is unable to raise anything. Three days ago he grabbed his chart and carefully examined it. Yester- day he was too sick to do this. He lies most of the time with eyes closed and when approached looks nervously from side to side. 232 TYPHUS FEVER — FATAL CASES — NO AUTOPSY 233 The chin twitches most of the time and the other muscles of the face move continually. The hands move convulsively and in a futile manner. The eruption is purple and is beginning to fade. The bases of the lungs are free from rales. There is no dulness or bronchial breathing. Nourish- ment is taken fairly well. There is considerable perspiration. Abdominal distention is now very marked. The colon can be felt through the abdominal wall. The distention can be reduced temporarily by enemata and the pulse rate then falls but the distention returns in a short time and then the pulse rate rises again. The temperature remains high. June 2. The patient died last night. Series Number 21. Patient of Dr. Holmes. Diagnosis: Typhus fever. Died during the stage of nervous depression. Apparent Cause of Death: Pulmonary oedema, sudden as- phyxia. Clinical Notes May 1 . Present Illness: A Serbian officer, said to have been ill six days before admission. He complains of pain around the eyes and in the back of the head, but not in the legs. There is cough and a little expectoration. Physical Examination: The apparent age is about 35. The patient is well developed and nourished. The face is much tanned, the ears are red, and the hands are slightly so. The tongue shows a white coat. The con- junctivae are not injected. The pupils are equal and of normal size. The Eruption is profuse and consists of pink macules on chest, abdomen, and arms. The hands, face and neck are free from spots. The Heart Action is rapid and regular. The sounds are of good quality and there are no murmurs. A few coarse rales are heard at the apices behind. The Abdomen is negative. The spleen is not palpable and splenic dulness is not increased. The Neck is slightly stiff. There is a slight Kernig's sign associated with muscular spasm but no pain. The calves are not tender. May 3. The diazo-reaction is mildly positive. May 5. The severity of the illness is increasing. The patient is men- tally dull and confused but recognizes people. There was epistaxis today, moderate in amount. The expectoration is considerable in quantity and very tenacious. The breathing is rapid and shallow. Many rales, most of which are of the coarse, dry variety, are scattered throughout the lungs. 234 TYPHUS FEVER — FATAL CASES— NO AUTOPSY The rash is fading and turning brown. Blood-pressure, 90/S -55/D. Haemoglobin, 85 per cent. May 7. There is an occasional spasm of hiccough. The patient is cyanotic. The breathing is rapid and makes a whistling sound at the nose. The nostrils move with respiration and there is a rattle in the throat. The cheeks are flushed. The forehead, which was very white on admission, is now slightly pigmented. The heart sounds are obscured by coarse rales. Blood-pressure, 110/S.- 55 /D. The patient takes food badly but water and lemonade freely. May 9. This afternoon, in the absence of the physician in charge of the ward, the patient was reported to me as being in a dangerous condition. When seen within a few minutes he was found gasping and unconscious but with a full, strong pulse which was not rapid. There was a loud rattle in the throat. The patient was quickly turned on his side and the jaws held open. He then began to draw deep breaths at long intervals but in two or three minutes the pulse and respiration both stopped and the patient died. PROBLEMS IN DIAGNOSIS The three following cases, Autopsies Nos. 2, 11, and 26, illustrate either errors of diagnosis or interesting complications of typhus fever. Autopsy Number 2. Patient of Dr. . Clinical Diagnosis: Typhus fever. Pathological Diagnosis: Malignant endocarditis. Autopsy Number 11. Patient of Dr. . Clinical Diagnosis: Typhus fever. Pathological Diagnosis: Typhoid fever with perforation of the intestine. Autopsy Number 26. Patient of Dr. Smith. Clinical Diagnosis: Typhus fever (?)'. Pathological Diagnosis: Endocarditis, typhus fever (?). Clinical Notes The patient was admitted June 14. His age was 30 and he is said to have been ill four days. No eruption was seen on admission or later. The patient was conscious at first and became comatose later. The breathing was noisy and difficult. There was muscular twitching. The general appearance of this patient suggested typhus fever. On June 22 the neck was markedly stiff and there was a slight Kernig's sign. The patient died at 3.40 p.m. Autopsy Findings Postmortem performed five hours after death. Body fairly well nour- ished. Heart: There is a large milk-patch on the anterior surface. The left ventricle is firmly contracted, and there is no dilatation of any of the cham- bers. The mitral valve shows a continuous row of small, pearly white, soft vegetations along the edge. Beneath the endocardium a little above one of the cusps is a small area of haemorrhage. There is no ulceration. The other valves are natural. The intima of the aorta shows a few very small yel- lowish patches. The coronary openings are free. 235 236 PROBLEMS IN DIAGNOSIS Lungs: The left shows much oedema, especially at the base. The base of the right is oedematous and atelectatic. Abdomen: The intestines are normal in appearance. The lower part of the ileum was opened and no ulceration or swelling was found but the mucous membrane showed many minute red dots. Li2;er; Much congested, ASpZeew; Normal in size, rather firm. ; Kidneys: Extremely congested. ♦ Brain: Shows whitish streaks along some of the larger arteries on the upper and lateral surfaces of the hemispheres. No pus on the meninges. Cranial fluid perhaps a little in excess. Meninges not oedematous. Base of brain natural. Lateral ventricles contain a pale and slightly turbid fluid. Lumbar puncture after death showed that the fluid was not under tension. Several cubic centimeters were removed with a syringe. The fluid was clear and greenish yellow in color. ' Series Number 33. Diagnosis: Scabies, typhus iever (7). Clinical Notes ■ May 8. Serbian, apparent age about 20. The patient says he has had typhus for a month which probably means, that he has had scabies for a month. Physical Examination: The patient is well developed and nourished. The skin and mucous membranes are pale. The conjunctivae are slightly injected. The skin of the body and face is somewhat pigmented and shows many brown macules of various sizes. There are many excoriated papules upon the front of the chest, abdomen, upper arms^ axillae, groins, wrists^ and genitals. There are no such papules below the knees. The forearms, wrists, and hands show many crusted papules of moderate size and there are^ similar ones on the lower legs. On the chest there are &Jew pink macwZes which might be interpreted as a scanty eruption in a mild case of typhus. The other lesions, clearly, are due to scabies. Heart and Lungs: Negative, Abdomen: Soft, not tender. Spleen not palpable; splenic dulness not increased. i, Knee-jerks present. No stiffness of neck or legs. Haemoglobin (Tallquist), 100 per cent +. Blood-pressure, 105/S.- 65/D. _ ■ '[ ' ' '^ " ."" '. , May 13. Throat slightly red. Heart, lungs, and abdomen negative. PROBLEMS IN DIAGNOSIS 237 May 14. Skin improving under treatment for scabies. Few brown spots remain. Junel. Patient discharged well. Note : The temperature curve in this case points to an acute infection of some sort and the small amount of local infection of the skin lesions can- CUNICAL CHART NAME._Se.rie S *33 ward bed no date May 8, 1315. MEDICAL RECORD BOOK. VOL. .. PASE DISEASE.Sc.Q.bl fi-S ...'>t-Ty ph LI S feVCl-? Day. Mont Ts 9 10 11 12 13 14 15 Ife 17 18 13 2.C XI x-x :i3 p 25 26 2" M Days \ < t ' r 1 z X 1- 3 5 13 E 5 12 V' 3 I » 7 5 i , i Q. z 1 " " " " ' ' V 1 )1 s ^ /" ^ f ■A 1 '^ / '4 j V \ ;1 i I' \i j / 1 \n - .- — — \h- F 4 _ _ 8' h V N; *^ 7* 9^ *"*■ ~ V- " ■' . . j / V ° \ I L % A I J / / \ \ 1 / V \y % 1 V. y ^ "^ w. / r " / \ k' / ^ / ^^ / \ ^ ■> >_^ ■" ^^ J \. ' w^ / _ _ Bi ^ OJ d d\ we II. rm e.. _sj Series Number 33. Scabies, (?) typhus fever ' not explain it. Although more irregular than the curve usually is in typhus the chart suggests this disease and the pink macules above mentioned strengthen such an hypothesis. Series Number 33a. Diagnosis: Gangrene of foot and leg, probably a sequel of typhus fever. 238 PROBLEMS IN DIAGNOSIS Clinical Notes April 26. A Serbian. Brought in with a number of typhus patients that arrived together on a train. Said that he had been ill eight days. Spots were seen which may have been a fading typhus rash, but which were not sufficiently definite for a positive diagnosis. At the time of admission there was pronounced discoloration of the left foot and of the leg halfway to the knee, a line of demarcation existed at the "point of election." May 5. The patient was transferred to a surgical hospital for amputa- tion of the leg. Note : This case illustrates the difficulty of satisfactory diagnosis after the eruption has faded . Series Number 88. Diagnosis: Pappataci fever (?). Abortive typhus (??). Clinical Notes May 26. The patient has been sick two days. He complains of pain in the temples, thighs, and back. Physical Examination: The patient is rather drowsy, but mentally clear and alert when aroused. The pupils are equal and of moderate size. The conjunctivae are moderately injected. The tongue shows a thin, white coat. The throat, the soft palate, the pillars of the fauces, and the pharynx are red. There are no spots on the mucous membranes. The Heart is negative, the pulse of good quality, and the blood-pressure, 90/S.-60/D. Haemoglobin, 80 per cent. The Lungs and Abdomen are negative. The splenic dulness is not in- creased and the spleen is not palpable. The knee-jerks are present. There is no stiffness of the neck or legs. The thigh muscles are slightly sensitive to firm pressure. Skin: The face is covered with a red flush which extends two-thirds of the way down the neck and, in front, covers a V-shaped area extending on to the sternum. A slighter flush extends over the lower part of the neck to the shoulders and over the clavicles to the second ribs where it gives place to rose-colored macules. The ears are very red. On the sides of the chest, the flanks, and the abdomen there are a few bright red, clearly defined spots the size of a pinhead and a few purplish spots of about the same size which do not disappear on pressure. (Old flea bites?) On the inner aspects of the arms and of the flanks " taches bleuatres " are numerous. In the center of some of these is a bright red, circumscribed spot like those already described on the sides of the chest and flanks. These spots are believed to have been caused by bites. PROBLEMS IN DIAGNOSIS 239 On the hips and on the backs of the hands are a considerable number of maculopapules some of which are capped by a small vesicle. The nature of these spots is uncertain. They resemble acne more than anything else. June 2. On the day after admission of the patient the temperature dropped to normal. On the same day a rash consisting of groups of very CUNICAL CHART NAME. - Sen e a * 8 B date I\ ay x5, 1915. MEDICAL RECORD BOOK, VOL. DISEASE ry.pku S faveV. -. Days of 25 2.( n 28 Z9 3C 31 Days of I t Z Z z ? IE 1 1 |i ■d '3 Z £ I I ? 3 i z i S 10 z o F < 1 106' 105' I04' 103' 101- "if 97' 95' 150 130 120 110 90 eo 70 50 45 40 35 30 " ' " ' " ' " ' M I- — A / .__ — V — — ,_. — -^ -^ — ^ ^ / ^ /^ \ > A / U- ^ \ •"^ ^ "•"^ •"• _ _ u scl QP ^= J J un tl Lt| Series Number 88. Pappataci fever (?). Abortive typhus (??) small, irregular papules was found on the flanks and sides in the morning. In the afternoon it had nearly disappeared and in the evening there was no sign of it. The patient's condition today is excellent. June 11 . With the exception of a rise of temperature to 99" on one day, there has been no recurrence of fever. The patient is to be discharged tomorrow. Note : The probability in this case seems in favor of the diagnosis of pappataci fever. 240 PROBLEMS IN DIAGNOSIS Series Number 100. Diagnosis: Pneumococcus bronchitis. Typhus fever (??). Clinical Notes June 21. Admitted to hospital today. Duration of illness ten days. Physical Examination: The face is flushed and the conjunctivae are in- jected. There is pink mottling of the skin on the chest and abdomen but CUNICAL CHART NAME, .Sen eS * lOQ ..ward bed no.. _oate Jan e.-SJ., 1915. MEDICAL RECORD BOOK, VOU «fc.PAG - DisEASE.,_..Xy.pKu5 ^.cv.ey.. Day. of Month 2.1 22 Xb X'\ 25 Zk ;i7 ZQ X9 30 ■ Days of Disease t X z I < £ 1- ul 1- Z E (C a. ? 3 I I z. i E Z O 5 a. c 107 106 105' 104' 103 102' 100' 99' " ' " ' " *■ " ' ' ' " ■ " ' ■ ' " ' " ' /' ■^ r V V \ \ s 97' 96' 95' 150 130 120 110 100 90 80 70 60 50 45 40 35 30 25 U. ^ / ^/ ^ - ->. \ f y *^ ^ A / ^ p-^ y' / i- \ ^ A ■v V '-> ^ ■^' *"• ,0 _ _ _ Series Number 100. Pneumococcus bronchitis. Typhus fever (??) there are no macules or papules. The tongue shows a brown coat. The mind is cleair and the general condition is good. The spleen is not palpable. June 24. There is profuse purulent expectoration. The face is still a- Uttle flushed and a band of injection extends across the conjunctivae. The lungs were negative yesterday and today. . . ^ PROBLEMS IN DIAGNOSIS 241 The patient is improving and does not look seriously sick. Micro- scopical examination of the sputum shows pneumococci in great numbers and few other bacteria. No tubercle bacilli were found. Note : The most probable diagnosis seems to be bronchitis caused by the pneumococcus. The ''mottling" on the chest may have been due to the appHcation of a counterirritant of some sort. There seems no reason for believing the case to be one of typhus fever although the patient was sent in as such. PART III LABORATORY EXAMINATIONS IN TYPHUS FEVER By ANDREW WATSON SELLARDS Intkoduction In order to complete the arrangements of the commission for conducting sanitary work, a central laboratory was organized by Dr. Hans Zinsser in Skoplje at the Lady Paget Hospital. The scope of this laboratory included the preparation of various vaccines, the sanitary examination of water supplies, and more particularly, special investigations of typhus fever. The op- portunity was afforded me to carry out clinical laboratory examinations on typhus fever patients. The general findings in typhus fever were observed with the special object of differentiating this disease from other infec- tions which were prevalent and in which an early clinical di- agnosis could not be made. Of the acute infections which gave rise to confusion, the two most troublesome ones were typhoid and relapsing fever. Indeed the clinical similarity in the onset of these three diseases gave rise to a local custom in the Balkan States of designating them all by the one name "typhus." It was often only by the context that one could determine whether reference was made to typhus exanthematicus, typhus recurrens, or typhus abdominalis. The rapid clinical differen- tiation of typhus and relapsing fever would have been advan- tageous since, in the management of the sanitary work, it had seemed desirable to the authorities to reserve the Lady Paget Hospital solely for typhus cases. Once the cases had been ad- mitted, the prompt diagnosis was important to prevent, as far as possible, the development of cross infections in the hospitals. 243 .... 244 EXAMINATION OF THE BLOOD IN TYPHUS FEVER Examination of the Blood in Typhus Fever In the literature on the cHnical microscopy of the blood in ty- phus fever certain important statements occur which, for the most part, have remained unconfirmed. Even as regards the actual blood counts, and the morphology of the blood-cells, the statements are somewhat conflicting. In searching for para- sites, Ricketts and Wilder ^ in a preliminary note reported the finding of bacteria in blood films stained by Giemsa's method; with similar preparations Prowazek ^ noted the occurrence in the white cells of inclusion bodies of the general character of the chlamydozoa. Red Blood-Cells Prompt confirmation was obtained of the high count of red blood-cells, figures of 5,500,000 and 6,000,000 being common, the haemoglobin content being increased often in greater pro- portion than could be accounted for by the increase in the number of red cells. The percentage of haemoglobin was de- termined with a Sahli apparatus standardizing the instrument by comparing it with several normal healthy adults and con- sidering this value as 100 per cent. The blood examined was taken in all cases from the ear. This increase in cell count and haemoglobin was most marked at the height of the infection. With the progress of the disease, the count usually fell to nor- mal or even to slightly subnormal values; a definite anaemia did not develop in typical cases. Some of the conditions bearing on this increased count were considered. Clinically, there was no increase in the size of the spleen in contrast to the spleno- megaly which sometimes accompanies polycythaemia. Many of these patients showed the effects of depletion in their supply of fluids. The explanation of this lay not in an excessive loss of fluid due to any effect of the typhus infection, but to the in- ability of the patients to obtain water during their long journey to the hospital. In order to determine in how far the poly- 1 Ricketts and Wilder: Jour. Am. Med. Assn., 1910, liv, 1373. 2 Prowazek: Med. Rec, N. Y., 1915, Ixxxviii, 21; Beitr. z. Klinik d. Infections, u. z. Immunitatsforsch., iv, No. 1. TYPHUS IN SERBIA 245 cythaemia was due to deprivation of water, a series of counts was made upon selected cases in whom the therapeutic injec- tion of salt solution was required. These injections were made intravenously, in quantities of one-half to three-fourths of a liter. The first injection often showed surprisingly little effect upon the blood-count; repeated injections usually reduced the red count and the haemoglobin considerably. The values often remained slightly higher than normal even after sufficient fluid had been injected to restore the tissues approximately to their normal condition. Signs of this restoration consisted chiefly in the return of the elasticity of the skin, the improve- ment of the pulse, and the free secretion of urine. It seemed justifiable to conclude that the deprivation of water was re- sponsible in a large measure for the high red counts and high haemoglobin, though one could not exclude the possibihty that other factors may play a minor role. In fresh preparations and in stained smears the red cells were essentially ^ normal. In a small proportion of the cases the red cells showed coarse basophihc stippling and occasionally polychromatophilia. This feature occurred indifferently both in the cases with moderately low counts and also in some in- stances in which the red cell count was as high as 6,000,000. White Blood-Cells In regard to the white blood-cells there is a prevalent opinion that a leucocytosis of high grade often occurs late in the dis- ease, characteristic large mononuclear cells appearing in the blood. The total number of white cells was found to be rather variable. Often the count was normal or a little high. In a few instances a marked leucopoenia was present. These leuco- poenias, however, were rather transient instead of persisting over a period of days or weeks as in typhoid fever. Occasionally a striking leucocytosis developed during the second week of the disease. Thorough examination often revealed some focus of 1 The Giemsa stain was used exclusively, partly because this stain kefeps very well in warm climates and also because the work of Ricketts and Prowazek is based upon smears stained with Giemsa's method. 246 EXAMINATION OF THE BLOOD IN TYPHUS FEVER secondary infection. Two patients with high counts in whom no compHcations could be found developed, after a few days, a small patch of pneumonia. A few cases developed leuco- cytosis, however, in which no suggestion of secondary infection could be detected. The differential counts showed considerable variation. Fre- quently the mononuclear cells were increased at the expense of the polymorphonuclears and often the large non-granular mononuclear cells were unusually prominent. These cells were often difficult to classify. Polymorphonuclear cells that ap- peared to be rather young were seen not infrequently. An occasional neutrophilic myelocyte was seen in the peripheral blood. These were rare being by no means as frequent as in some of the high grade bacterial leucocytoses. A thorough examination of the blood in ten active cases of the disease failed to reveal either the bacilli described by Ricketts or the inclusion bodies of Prowazek. Most of these patients were examined for the first time at about the fourth or fifth day of the disease and subsequently throughout the re- mainder of the course at intervals of two or three days. The platelets were abundant in the blood smears and they were normal in appearance. The bleeding time and the coagu- lation time were within normal limits. The latter was deter- mined by drawing the blood in a syringe from a vein and noting the time required for coagulation in a test tube. It is not infrequently stated that the blood of typhus cases is very prone to give the reactions of agglutination and comple- ment fixation with various antigens. Cameron ^ has empha- sized the occurrence of positive Widal reactions with the sera of typhus patients. In view of his observations, some macro- scopic agglutination tests were carried out in the Lady Paget Hospital using B. typhosus and the two paratyphoid strains, A and B. Twenty typhus- cases were examined three of which were active and the others were convalescent. No positive re- actions were obtained with either of the two strains of para- typhoid. With the typhoid strain there were five cases which 1 Cameron: Brit. Med. Jour., 1915, i, 785., TYPHUS IN SERBIA 247 TABLE I. —BLOOD COUNTS AND HAEMOGLOBIN DETERMINATIONS ON TYPHUS CASES UPON ADMISSION Case no. Day of disease Red cell counts Millions per c.mm. White blood-cells Number per c.mm. Haemoglobin Sahli 1 4 4,0 12,000 120 3 8 6,0 6,000 135 8 10? 5,6 5,000 95 9 8 5,5 4,600 125 10 8 5,9 16,600 130 11 5 4,0 6,000 90 15 14* 4,0 7,200 100 16 18* 4,1 3,200 110 17 14* 5,6 6,000 120 18 5 4,7 1,500 95 19 5 4,4 8,800 105 20 16* 3,9 4,800 85 21 6 3,5 3,900 110 35 5 4,5 7,600 110 41 6 4,7 3,700 110 45 8? 5,0 4,000 115 46 2 5,1 10,600 115 47 7 4,9 4,800 115 53 ? 5,6 4,300 130 55 4 6,2 5,800 145 56 6 5,2 10,200 115 57 12 4,6 7,800 110 58 10 5,0 15,000 115 * These are patients who reported themselves ill from some unknown cause and in whom typhus fever developed as an intercurrent infection. gave good agglutination at a dilution of 1 : 25, but not at 1 : 50. In the entire series there was but one case which gave agglu- tination at 1 : 50 and the clinical diagnosis of typhoid fever had already been made in this patient. In the cases agglutinating at 1 : 25 no record was available in regard to their previous history of typhoid fever and of antityphoid vaccination; con- sequently, even if an occasional positive Widal had been ob- tained in the typhus cases it would not have been of any especial significance. For completeness sake some of the data of the blood counts are appended. The data in regard to the time of onset of the disease are extremely unsatisfactory. Many patients were too 248 EXAMINATION OF THE BLOOD IN TYPHUS FEVER ill to give a reliable history; others did not consider themselves ill unless a rash or high fever developed. The data for the '' day of the disease" as given in Table I are compiled in part from the history of the patient and in some cases from the apparent stage of the disease as judged by the clinical findings. In ten additional cases occurring toward the close of the epidemic and showing no complications, the white count dur- ing the first week of the disease varied from 3800 to 13,000. In Table II some typical differential counts are recorded. TABLE II. — DIFFERENTIAL COUNTS ON TYPHUS CASES Day of Total Polymor- phonuc- Large and Large Transi- tional Unclassi- Eosinophiles disease count lear neut- rophiles phocytes nuclears cells fied cells Number seen 1 4 12,000 92% 3% 4% 0% 1% None 3 8 6,000 77 13 10 One cell 8 10? 5,000 72 18 6 2 2 Two cells 9 8 4,600 82 8 6 4 None 10 8 16,600 72 17 8 2 1 One cell 11 5 6,000 72 20 6 1 1 None 17 ? 6,000 72 20 4 2 2 18 5 1,500 47 31 15 3 3 None 19 5 8,800 73 17 2 5 3 None 20 ? 4,800 76 18 2 2 2 Two cells 21 6 3,900 70 18 6 3 3 None 87 4 12,000 76 21 2 1 None These percentages are based upon counts of 300 cells. The eosinophiles were unexpectedly scarce, never being as high as one per cent. An attempt was made to follow the blood-counts from the onset of the disease throughout its course in a small group of uncomplicated cases. The effort to secure such a series was not very successful. In Table III, although the exact day of the on- set is not accurately known, still the figures give a very fair idea of the stage of the disease. These counts were made from uncomplicated cases or at least the patients were free from complications at the time these observations were made. As regards the effect of complications there seemed to be a com- paratively large proportion of cases in which pyogenic ab- scesses failed to produce a polymorphonuclear leucocytosis. >i >s >a >J >3 >5 >i >. >i b >J (U Cr tH ^^ M t- tH tH tH u ^ Ut 4J > > > > > !> rSi > > M > > o o o o o o O *i o -M o o = 0) o o s o t> o o s* o cS o o g« OJ 0) v 4> 0) « lU o O o «5 o o o o o o 00 o o CO «o' oT go" o 1> o »-( »» !> ^ o o ^ o vO oo o^ o l-H -*" go" co" o o o lO o o o i-H ■* 50 o H «5 «5 as" o o tc •<1< o o »c 05_ C CD C6 ic" oT o -< r^ o Q 1-H go" o O o o o r-i ^ ®1 GC <-H oo" >* go" o o o o o o o o O o 05 «c GO '^ v> oo" Oj" go" o o 0\ o o o o o o o o o o o 00 TjT GO o o o o o I> o o o o o o o o vO 05 go' of o" o o o o o o o in . GO 05 o GO 05 o 1—1 GO ^ CO <© 00 t 1 o IS I— 1 (N o< Ol ©< »o 00 00 so TYPHUS IN SERBIA " 249 Examination of the Urine Examination of the urine showed an almost constant and early development of some inflammation of the kidney. Mod- erate amounts of albumin were present and granular casts were fairly numerous. These signs were usually transient, clearing up promptly with the drop in temperature. In one instance only, a severe nephritis developed during the height of the disease which did not entirely clear up during convalescence; in this case a preexisting nephritis could not be excluded. The diazo-reaction was found to be almost constantly pres- ent and usually very strong. However, it did not occur early in the disease and it was not of definite value in the differentia- tion of early or doubtful cases. Differential Diagnosis We do not at present possess routine methods which are ade- quate for the recognition of atypical cases of typhus fever or for the early diagnosis before the typical clinical picture has de- veloped. Among the French physicians a high percentage of cases are frequently diagnosed as typhus "sin exanthem"; while this type may occur more or less frequently, it is a di- agnosis which is extremely difficult to establish. The more common laboratory procedures give evidence in typhus which is essentially negative in character. Of the few positive find- ings, the occurrence of the diazo-reaction in the urine and the tendency of the mononuclear cells of the blood to increase were .of only very minor assistance. The diagnosis of typhus by the laboratory findings must be made by exclusion. This is fre- quently unsatisfactory for its differentiation both from typhoid and from relapsing fever. The application to typhus fever of some of the mOre elabo- rate experimental procedures gives results which are char- acteristic. The inoculation of the virus of typhus fever into monkeys and guinea pigs often gives rise to a characteristic temperature curve; studies of complement fixation and agglu- tination to B. typhi exanthematici have in the hands of Plotz, 250 CULTURES IN TYPHUS FEVER Olitsky, and Baehr ^ given results of diagnostic value. The transmission of the virus to lower animals is at present out of consideration as a diagnostic method; the results are so inconstant that the procedure is suitable only for the labora- tory study of typhus. Jahlous ^ reports that there is a general tendency of the serum of typhus cases to give non-specific com- plement fixation with the Wassermann antigens. This possi- bility in typhus fever should be taken into consideration in any diagnostic methods involving complement fixation. Olitsky ^ finds that an antigen of B. typhi exanthematici fixes comple- ment readily with the sera of typhus cases but not with other sera. Furthermore, antigens prepared from other bacilli fail to fix complement with typhus sera. Olitsky's results though very striking have not yet received any wide confirmation. The final establishment of diagnostic aids by the use of comple- ment fixation either with a specific or a non-specific antigen requires an enormous amount of empirical work carried out preferably in a number of different laboratories. Bacteriological Cultures in Typhus Fever In the search for the specific organism of typhus fever, the blood is the most suitable material for examination. Injection of blood from typhus patients into normal men reproduces the disease, thereby demonstrating that the virus occurs in the circulating blood. Numerous bacteriological cultures have proven that the virus as it occurs in the blood is practically pure. Of the many organisms that have been described as the specific aetiologic factor in typhus fever there is none on which so much work has been done or for which so much favorable evidence has been offered as in the case of the anaerobic bacil- lus described by Plotz and his associates. The following at- tempts at the confirmation of this organism were made in Belgrade and its vicinity. The technique described by Plotz 1 Plotz, Olitsky, and Baehr: Jour. Infect. Dis., 1915, xvii, 1. 2 Jahlous: Jour. Med. Research, 1914, xxx, 131; Delta, Centfalbl, f. Bakteriol., I, Abt., Orig. 1915, Bd. Ixxvi, 50. TYPHUS IN SERBIA 251 was followed carefully but in view of the proportionately large number of negative results obtained by Dr. Zinsser in Skoplje some additional cultures were made with certain minor modifications of the Plotz technique. These consisted in an en- richment of the medium and an increase in the degree of anaero- biosis. Three samples of ascitic fluid were used. They were free from bile and the specific gravity varied from 1.015 to 1.018, but in view of the possibility that they might not be en- tirely suitable for the growth of the Plotz bacillus pieces of kidney tissue were added in some instances. This procedure had given successful results in Plotz 's experience but was re- garded by him as an unnecessary refinement. Some of the Plotz cultures to which kidriey tissue had been added were given a higher degree of anaerobiosis by placing the tubes in a jar from which the oxygen had been absorbed by yellow phosphorus. In the selection of cases, only those patients were chosen from whom cultures could be made some time during the first half of the period of the exanthem, except in one instance when a fulminating case was cultured who died eight hours later. The cultures from this patient developed numerous colonies, some cocci growing aerobically, and some bacilli growing an- aerobically; the latter were longer and coarser than the or- ganism described by Plotz. Cultures from twelve additional cases remained sterile for one month with the exception of an occasional mould or coarse coccus growing on the surfaces of the media toward the end of this period. No anaerobic growth occurred either in the cultures made by Plotz 's technique or in those tubes to which kidney tissue was added some of which were placed in an anaerobic jar. Five of these twelve cases were cultured either on the first or second day of the appear- ance of the rash. Moreover, the work was done under very favorable conditions. The laboratory at Belgrade was housed in a substantial building and was well equipped with modern French apparatus. In Serbian Macedonia it had been neces- sary to work practically under field conditions with a labora- tory set up in what was formerly a Turkish artillery shed, where 252 CULTURES IN TYPHUS FEVER the exposure to dust storms added greatly to the difficulty of the work. It is hard to understand this failure to obtain the Plotz bacillus under favorable conditions in view of the practically constant recovery of the organism from acute cases by Plotz and his associates. Although it is exceedingly treacherous to work with unheated and unsterilized media, yet in a large series of control blood cultures Plotz failed to obtain this or- ganism in a single instance. It is evidently a highly parasitic organism but I am not yet convinced that it occurs only in typhus fever or that it is pathogenic for man. Although Plotz has collected a large amount of evidence in favor of this organism, there are still some serious objections to its acceptance. Anderson has pointed out that the cultures on injection into animals give rise to a transient fever which does not especially resemble the temperature curve of typhus fever; moreover these animals on subsequent injection with typhus fever virus may react with a typical rise in temperature. If a liberal dose of the living organism fails to protect an animal against typhus virus, some doubt is raised as to whether the usual small vac- cinating dose would give efficient protection in man. In addition to the failure to obtain the anaerobic bacillus isolated by Plotz, I was likewise unable to confirm the work of Topley.^ In kidney tissue ascitic fluid agar, Topley reports the clouding of the media due to the growth of minute cocci or bacilli. On this medium, cultures of a diplococcal organism were obtained in each of eight cases. As regards the bacteriological examination of the urine no confirmation could be obtained of the smaU coccobacillus re- ported by Hort and Ingram.^ Specific biologic reactions such as agglutination and com- plement fixation were not attempted in view of the negative results in these cultures and the inabihty to secure a strain of Plotz 's organism at this time. 1 Topley: Jour. Roy. Army Med. Corps, 1915, xxv, 215. 2 Hort and Ingram: Brit. Med. Jour., 1914, ii, 15. TYPHUS IN SERBIA . 253 Animal Experimentation The reported transmission of typhus to animals, especially to guinea pigs, has given rise to considerable confusion. The recognition of the disease depends almost wholly on the tem- perature reaction. The highest febrile reaction produced by the typhus virus is usually not greater than the maximal nor- mal temperature of the guinea pig. However, after a definite incubation period, this maximal temperature is sustained s-teadily over a period of several days without remissions such as occur in normal animals. There may be considerable doubt about the specific nature of the rather transitory rises in tem- perature following the injection of the virus of measles and scarlet fever into lower animals. However, in the case of ty- phus fever it would seem that guinea pigs are definitely suscep- tible and permit the growth and multiplication of the virus for a time. However, not all individuals react. Indeed, there is every gradation between a typical febrile curve and no reac- tion. Since the normal temperature of the guinea pig varies considerably, it is often impossible to interpret mild reactions. Indeed, some of the important statements in the literature are based upon the interpretation as positive of reactions which in no way differ from normal fluctuations in temperature. In the following work, the animals were inoculated from cases of typhus during the first or second day after the appear- ance of the rash. Guinea pigs were injected intraperitoneally with 3 to 5 c.c. of blood from several typical cases but the reac- tions which followed were not satisfactory. Moreover, after a period of incubation subinoculation from the first guinea pig to a second one was likewise unsuccessful. A reaction in guinea pigs corresponding to those described by French and American authors was obtained, however, by passing the virus first through a monkey and then through a guinea pig, analogous to the method for securing the infection of rats with relapsing fever. The reaction in a monkey produced by an injection of blood from a human case is illustrated in the accompanying chart, together with the chart of a control animal. Blood cul- 254 EXAMINATION OF THE BLOOD IN TYPHUS FEVER tures taken from this monkey on the second day of the fever were negative. Such a shght rise of temperature over a short period of time is, in a single instance, without significance. The evidence, 1 TEMPERATURE, CFAHRENHEITS SCALE) 5? 1 o \o ^o i£>5:vo o o o oo o o o a»^ ^ 00 s r iD O^ — „ ^O W -tfc, Cn^ O^ -^^^ / Inj< .ch d ■ VlK s tK hu. bl ooc s - P 1 \ ^ hJ -a n \ \, „ Oo P > s -1^ o != \ I u. 1- -i \ s 0) „ >o (T) ^ \ .„ OO P ^ ? P ^- / „ Ui C/5 r^ „ cr^ 0) „ '^, P / s S ^ I Cp \ s o however, that the virus of typhus multipUes in the monkey and guinea pigs and is responsible for this rise in temperature lies in the fact that one can in a certain proportion of cases duplicate these results; moreover the monkeys appear dis- tinctly ill during the febrile period. In contrast to this febrile reaction, an instance was observed of natural immunity in the monkey, a feature that was emphasized by Anderson and Gold- berger. The frequency of the occurrence of immune animals TYPHUS IN SERBIA 255 and of indefinite reactions renders the procedure extremely tedious and treacherous as a laboratory method. It is con- sidered that one of the most essential features for further prog- ress in animal experimentation is the development of some TEMPERATURE, tFAHRENHEITS SCALE) II S ^ gng 8 2 S S 2 S i. ^. i In jec tior f- o F ! \ t\ Drrr J bio acL £ - i . ^ X) i < s W B rr c ^ s -^ -i ! C/1 -s \ ; 0^ -t- p \ s. ^ vj zr- o > • ! CX) o 3 O 1 / ; <^ P i 1 < s o 0- o 3 • ; "-* o o -s o < s N:! C- 1 ) £ w 3 o / S 1— II ^ \ 5 C/1 \ ^ o \ S -0 p j £ ^ { =£ 1-^ 1' ' \ £ O means for the recognition of typhus in animals. This is espe- cially necessary in view of the great importance attached to the experiments on the louse transmission of typhus in the lower animals. 256 TRANSMISSION OF TYPHUS FEVER Question of the Mode of Transmission op Typhus Fever Some of the cardinal features concerning the mode of trans- mission of typhus fever are still undetermined. In the case of malaria and yellow fever it is not only proven that these dis- eases are commonly transmitted in man by mosquitoes but it is clearly established that they are not propagated in any other manner. This, of course, is an extremely fortunate circum- stance in the management of these two diseases. In typhus fever there is ground to believe that it may be transmitted either by droplet infection or by the louse. The evidence re- gai-ding louse transmission is in a somewhat confused condi- tion. The transmission of typhus to monkeys by the human body louse has been investigated by three groups of authors, namely, Nicolle and his associates,^ Ricketts and Wilder,^ and Ander- son and Goldberger.^ These authors have all arrived at the same conclusion : namely, that typhus is transmissible to the monkey by the body louse. However, it is very striking that the data and the fundamental premises of the various authors frequently vary widely and even conflict seriously. Thus the results on which one group of authors base their conclusions would frequently be unacceptable to the other two. Ricketts and Wilder considered that all normal monkeys are susceptible whereas Anderson and Goldberger frequently found natural immunity in monkeys. Nicolle found that monkeys which were bitten by lice without developing fever were subse- quently susceptible to the injection of virulent blood, whereas Ricketts obtained the opposite result. Nicolle as well as An- derson and Goldberger determined infection in the monkey by the febrile reaction whereas Ricketts in his experiments on 1 Nicolle, Comte, and Conseil: Ann. de Flnst. Pasteur, 1910, xxiv, 261; Nicolle and Conseil: ibid., 1911, xxv, 109; Nicolle, Blanc, and Conseil: Compt. rend. Acad. d. sc, 1914, clix, 663. 2 Ricketts and Wilder: Jour. Am. Med. Assn., 1910, liv, 1304; ibid., Iv, 309; Wilder: Jour. Inf. Dis., 1911, ix, 9. 3 Anderson and Goldberger: Bull. Hyg. Lab., U. S. P. H. S., 1912, No. 86. TYPHUS IN SERBIA 257 louse transmission did not obtain a sufficiently definite rise in temperature to permit of a positive diagnosis; reliance was placed primarily on the appearance of malaise and on the immunity test. NicoUe in contrast to the other authors found that monkeys infected by the bites of lice showed two distinct febrile periods. The accompanying outHne gives a summary of the results of these authors. EXPERIMENTAL TRANSMISSION OF TYPHUS TO MONKEYS BY THE BODY LOUSE Feeding experiments Injection of emulsions of lice Positive Negative Doubtful Positive Negative Doubtful By Nicolle and His Collaborators No. of experiments 4a 3* 4 %<^ Anderson and Goldberger ^ No. of experiments 1« 2 I 4 1 RiCKETTS AND WiLDER No. of experibaents 7/ 3 ■2 1 (o) These animals are regarded as positive by the authors on account of their tempera ture reactions but three of the four might more critically be considered doubtful or negative. (6) Two of these three negative animals were bitten by lice which had fed on typhus patients only four days previously. (c) These animals were injected with lice which had their infecting feeding two to seven days previously. {d) Anderson and Goldberger obtained positive results also with head lice. (e) The temperature reaction in this animal was not very convincing. (/) Typical temperature reactions were not obtained but typhus was diagnosed be- cause these animals appeared ill. Some evidence is also available in regard to the transmission by the louse in man. Two of NicoUe's laboratory attendants in Africa were accidentally bitten by lice that had fed on infected 258 TRANSMISSION OF TYPHUS FEVER monkeys. These attendants did not develop typhus fever. In another instance an attendant in a jail in Africa transferred lice from a typhus patient to a healthy individual. This in- dividual developed typhus after the usual incubation period. While this patient was presumably not exposed to typhus in any other way the conditions were not under control and no definite conclusions are permissible. While no direct experiments on man have been undertaken, some data were obtained by Sergent, Foley, and Vialatte ^ in the course of some work on relapsing fever. A normal man, who was bitten by lice that had fed upon a case of relapsing fever, developed as a consequence typhus fever. A second individual injected with lice that had fed on this case of relapsing fever and a third man injected with eggs of these lice also developed typhus fever. Apparently none of these individuals developed relapsing fever, although the lice contained large numbers of spirochaetes. These authors conclude that the case of relaps- ing fever must have been infected also with typhus fever and that the latter was transmitted by the bites and by the injec- tion of the lice. Although there is considerable confusion in the data of the experimental transmission of typhus to monkeys, still there is good reason to accept the idea of louse transmission of the dis- ease both experimentally in animals and in man under natural conditions. Such circumstantial evidence as we were able to obtain in Serbia was in full accord with the theory of louse transmission. Certainly the vast majority of all patients had been bitten repeatedly by lice. However, with the approach of hot weather the incidence of typhus and of relapsing fever ap- peared to diminish more rapidly than the disappearance of lice. It should be emphasized that the establishment of louse transmission does not militate against the possibiHty of the disease being transmitted by other methods also. Indeed the possibility of droplet infection in typhus must be considered 1 Sergent, Foley, and Vialatte: Compt. rend. Acad. d. sc, 1914, clviii, 964. TYPHUS IN SERBIA 259 seriously. A few cases of typhus developed in the Lady Paget Hospital among the staff under circumstances which per- mitted careful observation. Some of these cases seemed to be directly traceable to louse infestation; others could not readily be explained on this basis. This was especially true in the case of a nurse who protected herself carefully against insects in all of her hospital work. Toward the end of the epidemic, the ward under her charge had been free from active cases for about ten days when a patient extremely ill with typhus was admitted. It happened that this case had developed serious mouth, throat, and lung complications, necessitating frequent sponging and swabbing, the cleansing process often provoking more or less coughing. It is significant that both this patient and presumably the ward itself were free from lice, that the nurse also wore an effective louse-proof suit, that at no time had she any reason to suspect louse contamination, but that she did not wear the gauze masks providing for protection against droplet infection. No further typhus cases came under the care of this nurse; about two weeks later in Belgrade, while en route to England, in surroundings perfectly free from ty- phus, she developed a typical attack of the disease. While none of those instances occurring spontaneously under natural conditions can afford any exact proof, nevertheless they are sufficiently striking to merit consideration. The members of the Commission working in the hospital with typhus cases adopted precautions both against insects and against droplet infection, although some authorities advise against the employment of precautions for droplet infection. The precautions taken against the louse were twofold in their nature, consisting in the destruction, as far as possible, of the lice and the wearing of the louse-proof uniforms. In the first place, the entire hospital was theoretically free from lice, all patients being carefully cleansed before admission. Practi- cally, it was impossible to keep the wards absolutely and con- stantly free from lice though the living quarters of the staff were always free from such contamination. Accordingly the louse-proof suits were worn only in the wards and were then 260 TRANSMISSION OF TYPHUS FEVER left in a changing room and were never worn in the staff quar- ters. This regime necessitated the use of a fresh uniform at each visit to the wards. The uniforms for each day were col- lected and exposed overnight to chloroform vapor and were then ready for use the next morning. This procedure for de- stroying Hce was suggested by Dr. C. T. Brues of Harvard University and it proved to be very simple and effective. In addition to the use of these uniforms, antiseptic baths were taken at the end of each day's work. An ordinary surgeon's mask was used for protection against droplet infection. Essentially no other precautions were adopted. Boston, Mass., Deqember, 1915. PART IV REPORT OF BACTERIOLOGIST OF THE AMERICAN RED CROSS SANITARY COMMISSION TO SERBIA By HANS ZINSSER The bacteriological supplies were shipped on March 19, and the writer- left with the main party of ten on the Ducca d'Ahruzzi, on April 3. He arrived at Uskub (Skoplje) on the evening of May 1, where a general survey of the contents of the hospitals was made. After consultation with Dr. Strong it was decided that the bacteriological work should begin at Skoplje, since there seemed to be a greater concentration of typhus material here than in other places. Accordingly, about a week after arrival at Skoplje the writer, together with Doc- tors Shattuck and Sellards, moved out to the Sixth Reserve or Lady Paget Hospital, situated on the heights along the Var- dar, about two kilometers outside of the town. There were said to be at that time a few more than 400 cases of typhus fever at the hospital. There was a very small room which the British unit were using as a laboratory, equipped only for the simplest clinical tests, available at the time, but such as it was, the full courtesies of everything at hand were extended by the British physicians. The writer wishes to lay stress at this place upon the generosity and uniform courtesy with which the officials of the Serbian government and the British hospital received and treated the American workers at Uskub throughout their stay. Establishment of Laboratory The first task, of course, was the establishment of a bac- teriological laboratory in which suitably controlled work could be done, the writer conceiving it as his mission not only to work 261 262 REPORT OF BACTERIOLOGIST on typhus, but to attempt the estabhshment of a laboratory to which the general bacteriological and sanitary work of the Commission could be referred. Although the suppHes shipped from New York had not arrived, and did not arrive at Skoplje until May 17, the interval was spent in becoming famihar with typhus in its clinical aspects, the preparation of a laboratory space and autopsy room, and the performance of autopsies. By the courtesy of the Serbian government, a portion of the main artillery shed next to the Administration Building was placed at the disposal of the Commission for the establishment of a laboratory. A partition had been put up in this shed, but otherwise it consisted of a bare cement floor, with windows unsuitable for microscopic work, without running water, with- out electricity, and without gas. The labor of several Austrian prisoners and of a local carpenter were placed at the disposal of the bacteriologist, and the space was divided into a smaller autopsy room and a main laboratory room. Windows were broken through the walls, another door was broken through, cement sinks were put in, and a pipe was run from a well, in the yard, to the laboratory. A tin tank of about four cubic feet capacity was found and placed on the partition between the autopsy room and the laboratory, and from this, pipes were run to the sinks. When the supplies arrived it was found that the box containing thermometers, syringes, and the more expensive smaller apparatus — platinum wire, etc. — had been lost in transit. The electrical apparatus taken along, as well as that requiring gas, could not, of course, be used. Fortunately, a petroleum lamp incubator had been taken, and Primus kero- sene stoves were bought. The British laboratory worker. Dr. Dalyell, permitted the transfer of all her available apparatus to this laboratory, joining forces with the American laboratory. Without this aid and cooperation the work of the Commission would have been very seriously hampered, because of the fact that so much of the apparatus brought was not suitable for the conditions encountered. Finally the apparatus was put in place and the laboratory was in suitable working condition by about the twenty-fifth of May. TYPHUS IN SERBIA 263 During the period preceding this, the writer thought that although not all the criteria for properly controlled bacteriology could be fulfilled under the circumstances, it would be better to begin work with what was available. Fortunately, by the fore- sight of Doctors Shattuck and Sellards, some extra supplies had been taken with the party of ten, some of which duplicated the special bacteriological orders, and with these, together with what was borrowed from the British, work was begun. An Austrian prisoner, placed at the disposal of the bacteriologist, was trained as a laboratory assistant, was taught to make agar, broth, sterilize, etc. Autopsies were done on most of the cases of typhus that died during this time, and smear studies were made from the spleen and organs. Bacteriological Examinations Cultures also were made, from the spleen and heart's blood and other organs, but one or two of these only were of any great value, since most of the cases that died at this time, died very late in the disease, after the temperature had been normal for anjnA^^here from two to ten or twelve days, and secondary invaders, such as streptococci and Gram-negative bacilli, were often found in these cultures. Blood cultures were made at this time on many of the living patients, although few of the cases were in the early stage of the disease when they came under observation at the hospital. The large majority of the cases that came in were well along in the disease, having often been brought in from considerable dis- tances under conditions that did not permit speed of trans- portation. In none of these early cultures was it possible to fulfill the criteria laid down by Plotz for the cultivation of his organism. Ascitic fluid was hard to obtain, since at this time almost. all the patients in the hospitals were either typhus or relapsing fever, and small specimens of chest fluid only could be obtained. These were often not sterile, and in no case during this early period did we obtain an ascitic fluid of 1015 specific gravity or over, which could be used in the unheated and unfiltered condition as required for the Plotz method. 264 REPORT OF BACTERIOLOGIST During this period, blood culture "5," taken with one of the specimens of chest fluid, which showed no growth in the con- trols, showed in a high tube in glucose agar a colony about two inches from the top, not gas-forming, with a white halo about it due to acid formation, which on fishing showed a short bacil- lus, slightly diphtheroid in form, morphologically correspond- ing roughly to the organism of Dr. Plotz. Comparing smears from an old culture of the Plotz bacillus with this organism, great similarity was seen, except that our organism appeared to be very slightly larger than the Plotz organism and a little more irregular in form. We were not successful in carrying this cul- ture to the second generation, probably because we were at that time not in possession of suitable ascitic fluid. We wish to em- phasize distinctly that we did not, at this time, consider our blood culture "5" of great scientific value because the ascitic fluid with which it had been taken had not been sufficiently controlled before use. When our own supplies arrived it was found that all the ascitic fluid shipped from New York was either contaminated or probably because of aging and shaking had settled out, so that its specific gravity in no case exceeded 1012. However, by this time (the end of May) cases of ascites appeared at the hos- pital, and these were tapped. From two cases, ascitic fluids "X" and '^Y" were obtained, fluids which we thought more nearly approximated the conditions set down by Plotz. With these fluids a number of blood cultures were taken, ^'X" hav- ing been well tested for sterility. In some blood cultures both fluids were used. From blood culture "5" to blood culture ''35" no repetition of the diphtheroid anaerobic organism was obtained; a majority of these cultures were negative when the control tubes were negative, in two of them streptococci were obtained, and, in several others, large Gram-positive bacilli were present, which were taken to be evidences of contamina- tion. It may be said that all blood cultures which showed any evidence of contamination were indiscriminately thrown out. It should also be stated that during this period hardly any of the cultures could be taken before what we would consider at TYPHUS IN SERBIA 265 least the eighth or ninth day of the disease, and most cases were older than this. In blood cultures "35" and "38," one of which (38) had developed in the hospital, early blood cul- tures were obtained, most of the tubes being taken with ascitic fluid "X." In one tube of each of these a number of heavy colonies containing small Gram-positive diphtheroid baciUi were found, but these diphtheroid organisms showed great similarity to contaminating diphtheroids found in control tubes with one of the other ascitic fluids. These colonies, there- fore, were not considered to have any significance. In blood culture "41," another early case which had developed in the hospital, the blood culture was taken on what we assumed to be the third or fourth day of the disease. In this case ascitic fluids "X" and "Y" were employed in different tubes. This blood culture was taken on June 12. By the twentieth two of the tubes taken with ascitic fluid "Y" were grossly contami- nated. On one tube with "X" ascitic fluid which had shown no contaminations in controls, a suspicious colony appeared, which showed small Gram-positive bacilli, which were trans- planted on ascitic agar slants in Buchner tubes and in ascitic glucose agar stabs in Buchner tubes. Two of the transplants grew. This culture, in the original appearance of the colonies, in the appearance of the transplants, their anaerobic growth requirements, and their morphology and staining properties corresponded to the Plotz organism. We may briefly summarize the results of something over forty blood cultures on cases of unquestionable typhus by stating that only two of these showed organisms which corresponded to the Plotz bacillus. Cultures from the older cases showed oc- casional streptococci and Gram-negative bacilli, as did many of the cultures taken from recently dead bodies at autopsy, and these we regarded as secondary invaders. Indeed, we obtained the general impression that secondary bacterial invasion of the blood stream was not uncommon in typhus fever. It did not seem to the writer that his own experience justified drawing definite conclusions about the Plotz bacillus. His opinion was against the aetiological significance of this organ- 266 REPORT OF BACTERIOLOGIST ism because of the rarity with which it had been found, and because of the fact that the necessity of using unfiltered and unsterihzed ascitic fluid in these cultures made it impossible to exclude absolutely that the organisms had originated in the ascitic fluid rather than in the case. While the difficulty under the circumstances of adhering accurately to the criteria set down by Plotz for the cultivation of his organism did not per- mit the writer to draw definitely negative conclusions concern- ing this organism, yet he felt that his work as a whole was more against it than in its favor. The laboratory meanwhile had been, we consider, well or- ganized, and it had been possible to extend its facilities to Dr. Castellani, who, with his personal assistant, used it during this period to make large quantities of cholera and typhoid vaccines for the use of the Commission for the Serbian army. Autopsies had been done on typhus cases and on other cases which interested the various physicians at the hospital whether or not typhus, and the laboratory was made as generally useful to the hospital as a whole as was possible at the time. During this time also it was used by Dr. Sellards in the pursuit of his special studies until his departure for Belgrade. Guinea pig work was necessarily limited since three guinea pigs only survived, of the fifty taken from New York, probably owing to the rough weather and cold on the way over, which took pretty nearly a month, with many changes of weather and many transshipments en route. Five further guinea pigs were obtained at the end of May by the great courtesy of Dr. Kopanaris, sanitary chief of Greek Macedonia, in Salonika. Inoculations into these, intraperitoneally, of blood directly from the patient were made immediately after arrival at the hospital, and one of these after twelve days showed what we considered a typical rise in temperature. A transfer from this pig to another resulted in a temperature suggestive of typhus, though it did not exceed 104°C. at any time. Trans- fers from this one were also made, but showed no temperature reaction. TYPHUS IN SERBIA 267 When the Kopanaris pigs arrived, all of them were injected from patients at various times, and in a number of them the peritoneal cavity was punctured by the Pfeiffer method, two, three, and six days after inoculation with the typhus blood, and cultures and smears made from the puncture fluid. In one of these pigs small Gram-positive bacilh were seen on the third day after inoculation with typhus blood. Smears of this pig were studied very carefully, both by the writer and by Dr. Cas- tellani, and both beheved that they were in a general way similar to the Plotz organism, but none of the other pigs showed such organisms, and cultures from the pigs with the materials used both aerobically anaerobically were entirely negative. Two of the pigs were injected rather a short time before leaving in the hope that the virus might be kept going for Dr. Hopkins on his arrival. Vaccination At about this time the question arose whether or not the Serbian troops should be vaccinated with the Plotz organism. The question was put to the bacteriologist by the director, Dr. Strong, and, as may be easily seen from the above report, the writer was not yet in a position at this time to either con- firm or deny the aetiological importance of the Plotz organism. The isolated apparently positive findings in the blood cultures described above were not deemed by him sufficient basis for advising extensive vaccination which would subject the Ser- bian government to much administrative trouble, to expense, and difficulties of mobihzation at a time of critical military necessities. Moreover, the epidemic was distinctly on the wane at this time, the decHne being progressively more rapid as the weather turned warmer. The writer, therefore, dis- tinctly advised the director that there was no information at his disposal at this time to justify a general vaccination of Serbian troops and population. This statement is made in order to make clear that in omitting a vaccination order at this time the director of the expedition asked the advice of the writer and obtained the above negative reply. 268 REPORT OF BACTERIOLOGIST The writer started South on the twenty-ninth of June after turning over his material to Dr. Sellards and leaving the lab- oratory under the direction of Dr. Castellani. Dr. Sellards took charge of the typhus materials and the culture of the supposed Plotz organism isolated from the case above de- scribed, which he turned over to Dr. Hopkins who came over shortly after to continue the work. PART V SUPPLEMENTARY BACTERIOLOGICAL REPORT OF THE AMERICAN RED CROSS SANITARY COMMISSION TO SERBIA By J. GARDNER HOPKINS The writer left New York on the steamship Thessalonica on June 19 and arrived at Skoplje on July 19. Typhus had been for some time on the decrease, and by this time there were very few acute cases available for study. On arrival at Skoplje, however, it was found that a dozen cases from the civil jail at Cavadara had recently been brought to the Sixth Reserve (Lady Paget) Hospital, five of which were in the acute stage of the disease, and the writer proceeded at once to the hospital to study these cases. He found there a well-equipped bac- teriological laboratory, which had been organized by Dr. Zins- ser and his coworkers, which was then being used by Dr. Castellani of the American Commission for the preparation of typhoid, paratyphoid, and cholera vaccines for the Serbian army. There were two Austrian prisoners, assigned to labora- torj^ duty, whom Dr. Zinsser had trained in the work. The use of the laboratory was put entirely at the disposal of the bacteriologist, and he was also given full charge of the typhus cases through the courtesy of Dr. Maitland, the chief physician of the Lady Paget Hospital. Cultures were made from one case with materials at hand in the laboratory, and as soon as agar, pleural fluid, and blood serum could be prepared, cul- tures were taken on other acute cases. Two days later an addi- tional case in the acute stage of the disease was brought in from Cavadara. Blood Culture Studies Cultures were made by the method described by Plotz, the blood being taken from the arm vein with a sterilized syringe, and mixed with 2 per cent glucose agar, to which ascitic fluid or 269 270 SUPPLEMENTARY REPORT OF BACTERIOLOGIST human blood serum was added. The mixtures were made in deep tubes, and some of the tubes from each of the first eight cultures were placed in Buchner tubes before the agar had solidified. Considerable emphasis has been laid by Plotz on the specific gravity of the ascitic fluid used in the culture, and some difficulty was found in obtaining fluid which answered the re- quirement, that is, in which the specific gravity was over 1015. The only fluids available at the hospital were those obtained from cases of pleurisy with effusion, in which the specific grav- ity ranged from 1011 to 1018. In one culture a specimen of ascitic fluid was employed which had been kindly furnished by Dr. Plotz and had been found satisfactory in his work at Mount Sinai Hospital. In other cultures blood serum obtained by venesection in cases of nephritis was used, as it seemed that this must have all the advantages of a specimen of ascitic fluid with high protein content. Other specimens of ascitic fluid of lower specific gravity which had been brought from New York were also used. The cases from which the cultures were made were all con- sidered by the physicians who had studied the typhus epidemic in Serbia to be typical cases of typhus. They had high, con- tinuous fever, ranging from 102° to 105° and profuse rash ap- pearing, in some cases, on the palms of the hands. The cultures were all made during the febrile period, from the seventh to the eighteenth day of the disease, as nearly as could be ascertained from the history. Twelve cultures in all were taken from the six cases available, and were observed for at least three weeks' incubation. The tubes before being discarded were emptied into sterile Petri dishes and the cylinder of agar cut into thin slices in order to detect any small colonies which might have escaped observa- tion in the rather opaque medium. A number of tubes showed surface contaminations, due probably to the fact that the wards in the hospital were exceedingly drafty and it was impossible to avoid occasional contaminations from dust. In only one in- stance, however, was a deep growth obtained which in any way resembled the organism described by Dr. Plotz. TYPHUS IN SERBIA 271 This one positive culture, No. 10, was obtained on the fifteenth day of the disease from a patient who died the follow- ing night. The temperature at the time of the blood culture was 102°. Two tubes from this culture showed each a single large colony in the depth of the medium, which appeared after ten days of incubation. The colonies were surrounded by a zone of precipitated albumen and showed morphologically srnall Gram-positive bacilli, strongly resembling those in the culture which had been furnished by Dr. Plotz. On subculture the organism proved to be an obligate anaerobe, until it had been preserved on artificial media for nearly two months, after which very faint growth in aerobic cultures was obtained. Like the Plotz organism it rapidly produces acid in glucose serum media as shown by the precipitation of the protein. It grows somewhat more heavily than the cultures of Dr. Plotz which the writer has seen, and produces deep yellow pigment, at times with a pinkish tinge. Inoculation of the culture in the third generation into a guinea pig was without result. Since this organism showed no pathogenicity, did not give the agglutination reaction described by Plotz and Olitsky, and resembled organisms described by Torrey as occurring as sapro- phytes in pathological lymph-nodes, it could not be regarded as significant. Agglutination Studies As the patient from whom the culture was obtained died before recovery of the bacillus, it was impossible to test the organism against his own serum. Macroscopic and micro- scopic agglutination tests were, however, carried out with the serum of convalescent typhus cases in the hospital which had had a normal temperature for a period of ten days to several weeks. Later, on going to Nish, a case was found which had had a normal temperature for only five days, and serum ob- tained through the courtesy of the Russian Red Cross phy- sician in charge was also tested against the organism in question. None of the typhus sera gave definite agglutination in excess of that obtained in normal controls. 272 SUPPLEMENTARY REPORT OF BACTERIOLOGIST Autopsies Autopsies were performed on three cases of typhus that died during the febrile period. Cultures made from the spleen were negative except for post-mortem contaminations. Guinea Pig Inoculations Two guinea pigs were inoculated from acute cases in the Lady Paget Hospital, and one from an emulsion of spleen of a typhus case obtained at autopsy, but no typical reactions were obtained. Later Cases As no further cases of typhus were available at the Sixth Reserve Hospital, attempts were made to locate cases suitable for study in other parts of the country. On a rumor that cases were developing in GaHcnik, on the Albanian frontier, a trip was made to this place with a bacteriological outfit in the hope of obtaining specimens, but the rumor turned out to be false. Later two cases were located at Mladinowatz. These were mild cases, and were seen in conjunction with Dr. Sellards, Dr. Baehr, and Dr. Plotz. Dr. Baehr and Dr. Plotz made cul- tures from these cases, and Dr. Sellards and the bacteriologist inoculated a monkey and four guinea pigs, all of which failed to react. Other guinea pigs injected from these animals at a time when reaction might have been expected also failed to show any characteristic rise of temperature. Two cases of probable typhus were also visited at the Serbian military hospital at Ralja. Blood cultures taken from these cases were negative. Although they were considered typhus by the physician in charge, they were certainly not outspoken cases. Results Of six outspoken cases of typhus studied in the acute stage, all gave negative blood cultures except one. From this an organism resembling the Plotz bacillus was obtained, but, as it failed to agglutinate in serum of typhus patients and failed TYPHUS IN SERBIA 273 to produce any typical reaction in a guinea pig, it was dis- carded. The results of these studies were not conclusive on account of the few cases available for study. However, the failure to isolate an organism corresponding to that described by Plotz, from the typical cases studied, has a certain value as negative evidence. While these experiments are too limited to be considered as disproving the reports of Plotz and his cowork- ers as to the aetiology of typhus, they failed to confirm these results, and the writer so reported to the chief of the commis- sion, Dr. Strong. As there seemed little likelihood of obtaining further suitable material for study, the writer left Serbia on the fifteenth of September. In conclusion, acknowledgment should be made of the hospitality and courtesy extended by Lady Paget 's British unit in charge of the Sixth Reserve Hospital and the invariable courtesy of the Serbian physicians and officials. PRINTED AT THE HABVARD UNIVERSITY PRESS GAMBHIDGE, MASS., TJ. S. A. DATE DUE - ■' '' MAR 27 'm^ f.»rL.CF,o PHINTEO IN US A BOSTON COLLEGE l_ 3 9031 01497791 2 ^ T e Boston College Library Chestnut Hill 67, Mass. Books may be kept for two weeks unless a shorter period is specified. If you cannot find what you want, inquire at the circulation desk for assistance.