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Chapter 5

Contents

CHAPTER V

Leptospirosis

Thomas B. Turner, M.D., and Hugh Tatlock, M.D.

Part I. General and Leptospiral Jaundice (Weil's Disease)

Leptospirosis is the collective term applied to a group of diseases caused by micro-organisms of the Leptospira genus. The best known of these clinical and etiological entities is Weil's disease or leptospiral jaundice, the etiological agent of which is usually Leptospira icterohaemorrhagiae. However, at least six other species of Leptospira are known to produce disease in man, and evidence indicates that these infections are much more common than is generally supposed.1

Throughout the period of World War II, clinical and laboratory interest in leptospirosis was focused largely on leptospiral jaundice. Although the specific etiological nature of the disease has been known since 1914, both before and since that period leptospiral jaundice has been confused frequently with other diseases in which jaundice is a prominent feature. Weil's disease itself was not an important cause of illness among military personnel in World War II, but the frequency with which it became involved in problems of differential diagnosis makes it worthy of special consideration.

Epidemics of jaundice have occurred in every great war. It seems probable that most of these were epidemics of infectious hepatitis, a disease of viral origin.

1As indicated by Yager and Gochenour (Yager, R. H., and Gochenour, W. S., Jr. : Leptospirosis in North America . Am. J. Trop. Med. 1 : 457-461, May 1952) and by Murphy and Alexander (Murphy, L. C., and Alexander, A. D.: Significance of Leptospiroses in Military Medicine. Mil. Med. 121 : 1-10, July 1957), knowledge of the different forms of leptospirosis has expanded considerably since World War II. In addition to leptospiral jaundice, disease phenomena in man, usually without jaundice, can be produced by Leptospira canicola, which seems to be primarily a disease of dogs; by Leptospira pomona, the cause of swineherd's disease, which has been recognized among swine, cattle, and horses, and occasionally in man; and by Leptospira ballum, Leptospira bataviae, Leptospira pyrogenes, and Leptospira hebdomadis, each of which has been implicated occasionally in human disease.
Of particular interest in this connection are developments in knowledge of Fort Bragg fever (p. 41). This disease, which was first recognized and described as a clinical entity by Daniels and Grennan (Daniels, W. B., and Grennan, H. A.: Pretibial Fever, an Obscure Disease. J.A.M.A. 122: 361-365, June 1943), occurred as an epidemic among soldiers at Fort Bragg, N.C., in 1943. Through the happy circumstances, compounded of good clinical and epidemiological practice, that acute and convalescent serums from many of these patients were collected and preserved and that infective material was maintained in animals, it was possible nearly 10 years later for Gochenour and coworkers (Gochenour, W. S., Jr., Smadel, J. E., Jackson, E. B., Evans, L. B., and Yager, R. H.: Leptospiral Etiology of Fort Bragg Fever. Pub. Health Rep. 67: 811-813, August 1952) to determine on the basis of serologic and bacteriological evidence that this disease was due to infection with Leptospira autumnalis, an organism which was not known to have occurred previously in the United States.


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The U.S. Army reported a total of 452 admissions of spirochetal jaundice during World War I, with a resultant loss of 9,251 days and 15 deaths. Thirty-five of the admissions occurred among officers and were not reported by geographic area ; of the 417 admissions among enlisted men, 279 occurred in the United States, 108 in Europe, and 30 elsewhere. To these original admissions must be added 80 instances in which the same malady occurred concurrently with other diseases, making a grand total of 532 cases.2 The disease also occurred in the British, French, and German Armies on the Western Front during World War I.3

In World War II, viral hepatitis was endemic throughout the war and reached epidemic proportions at one time or another in several theaters. In addition, a great epidemic of homologous serum jaundice, which is also of viral origin, developed from the administration of yellow fever vaccine that contained small amounts of infective human serum; sporadic cases of homologous serum jaundice were also observed following transfusions of whole blood and blood plasma. While the relationship of infectious hepatitis to homologous serum jaundice is still unsettled, approximately 182,000 admissions for one or the other of the two diseases were recorded among military personnel during World War II. Suffice it to say that the widespread occurrence of these diseases, in which jaundice is an objective sign, created a vexing diagnostic problem with respect to the differentiation of Weil's disease.

Incidence.-The foregoing statements concerning the confusion existing in the differential diagnosis of cases in which fever and jaundice occur are emphasized by the circumstance that tabulations of the individual medical records for Army personnel from 1942 to 1945, inclusive, show a total of 8,167 cases of Weil's disease. For the year 1942 alone, 6,949 cases of Weil's disease were recorded on individual medical records.

Interpretation of these conflicting data must rest largely on collateral evidence, but, when all of this is reviewed, the conclusion is reached that the true incidence was relatively small. More than three-fourths of all the cases reported on the individual medical records were recorded for 1942. This was the year of the great epidemic of homologous serum jaundice from yellow fever vaccine ; undoubtedly, before medical officers became aware of this virtually new clinical syndrome, Weil's disease was erroneously assigned as the tentative diagnosis in many instances. The most reliable statistics appear to be those for the year 1944-45, during which about 60 cases of Weil's disease were reported in the total Army; 10 in the continental United States, 20 in Europe, 5 in the China-Burma-India theater, and 25 in the Pacific. The Office of the Surgeon General has for many years recognized this overstatement in the medical records.

2The Medical Department of the United States Army in the World War. Washington : U.S. Government Printing Office, 1928, vol. IX, p. 483.  
3Official History of the Great War Based on Official Documents. Medical Services. Diseases of the War. London : His Majesty's Stationery Office [1922], vol. I, p. 378.  


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It must be recalled that in civilian practice a substantial proportion of cases of leptospiral jaundice is probably overlooked, since at different times and places when the disease has been particularly sought for, an increased number of cases has usually been found.4 It is probable, therefore, that the actual number of cases occurring among military personnel during World War II was approximately 200.

A few cases of leptospirosis were recognized among war dogs during World War II. A serologic survey for leptospirosis among 4,368 war dogs yielded positive results in 58 (1.3 percent) and questionable results in 136 (3.1 percent).5 There is no record of transmission of leptospirosis from war dogs to military personnel.

Epidemiological features.-It is known that wild rats and mice, particularly the Norway rat (Rattus norvegicus), are a common carrier of Lept. ieterohaemorrhagiae, which they eliminate in the urine; it is believed that these animal species are the principal natural reservoir of the infection. Among civilians, Weil's disease is encountered largely in individuals whose occupation brings them into contact with water that has been contaminated with rat urine. Thus, sewer workers, miners, fishmongers, and poultry dressers are groups with a relatively high risk of infection.

Military operations frequently create conditions which would appear to be particularly conducive to acquisition of this disease, and it is surprising that more authenticated cases of Weil's disease were not observed in World War II.

Of the 19 cases reported on the statistical health reports, 11 occurred in the European theater, 1 in the Africa-Middle East area, 6 in the Pacific, and 1 in the United States. Of the cases reported from the European theater, 4 occurred in 1944 and 7 in 1945. While few details are available concerning the circumstances of infection in these cases, scattered reports in the literature suggest that wet shellholes and sluggishly moving streams, both doubtless contaminated with rat urine, provided the most likely places of infection.6 At least 39 cases occurred in the British Army in France, and 17 additional cases were reported from British forces in Italy.

4(1) Yager, R. H., and Gochenour, W. S., Jr. : Leptospirosis in North America. Am. J. Med. 1 : 457-461, May 1952. (2) Havens, W. P., Bucher, C. J., and Reiman, H. A.: Leptospirosis : A Public Health Hazard ; Report of a Small Outbreak of Weil's Disease in Bathers. J.A.M.A. 116: 289-291, January 1941. (3) Ward, T. G., and Turner, T. B.: Study of Certain Epidemiological Features of Leptospiral Jaundice in Baltimore. Am. J. Hyg. 35: 122-133, January 1942. (4) Beeson, P. B., and Hankey, D. D.: "Benign Aseptic Meningitis" as a Manifestation of Leptospiral Infection. Tr. A. Am. Physicians 63: 130-135, May 1950. (5) Gauld, R. L., Crouch, W. L., Kaminsky, A. L., Hullinghorst, R. L., Gochenour, W. S., Jr., and Yager, R. H.: Leptospiral Meningitis : Report of an Outbreak Among American Troops on Okinawa. J.A.M.A. 149: 228-231, May 1952.
5Miller, Everett B. : The Medical Department of the United States in World War II, Army Veterinary Service. [In preparation.]
6(1) Semiannual Report of Medical Services, European Theater of Operations, Chief Consultant in Medicine, 1 January-30 June 1945 ; Exhibit I, Anglo-American Consultants Conference Medical Programme, pp. 7-12. (2) Bulmer, E. : Weil's Disease in Normandy : Its Treatment With Penicillin. Brit. M.J. 1: 113-115, 27 Jan. 1945. (3) Hutchison, J. H., Pippard, J. S., Gleeson-White, M. H., and Sheehan, H. L. : Outbreak of Weil's Disease in the British Army in Italy. Trop. Dis. Bull. 43 : 338, April 1946.


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The extent of occurrence of other clinical syndromes due to Leptospira during World War II is difficult to determine, since in most of these jaundice is not a prominent feature and during the war diagnostic antigens for the other species of Leptospira were not available. The episode of Fort Bragg fever is discussed by Dr. Tatlock in part II of this chapter. Other outbreaks of mild disease may well have been due to unrecognized infection with one or another species of Leptospira.

Problems of diagnosis.-Despite the alternate designation of Weil's disease as leptospiral jaundice, jaundice occurs only late in the course of the disease and may not occur at all in about half the cases. Abrupt onset, fever, muscle pain, headache (often with meningismus), cutaneous and scleral hemorrhages, and albuminuria are common early symptoms, which makes the disease difficult to distinguish from many other acute infections, notably influenza. At times, meningeal symptoms are predominant.7

While the disease may therefore be suspected on clinical grounds, definitive diagnosis must be made on the basis of laboratory tests. These tests are isolation of the causative organisms from blood or urine, by inoculation of the young guinea pig or hamster and also by culture, and demonstration of specific antibody rise by the agglutination test. These are well-known procedures, but it is often not practicable to carry them out under field conditions, either because of the unavailability of young guinea pigs or hamsters or of living cultures of Lept. icterohaemorrhagiae for agglutination tests. A simpler laboratory test would greatly facilitate differential diagnosis. The importance of including antigenically different species of Leptospira in the diagnostic procedures has already been noted.

Attention should be directed to a frequent source of error in laboratory diagnosis. It is virtually never possible to demonstrate Leptospira in the blood of patients by microscopic examination, either in stained films or by dark field. Yet, over and over again, strands shed from red blood corpuscles have been mistakenly identified as Leptospira under the dark-field microscope; this happens repeatedly in civilian practice and was often a cause of confusion in military practice in World War II.

Typical of other episodes involving diagnostic confusion was the so-called Alaskan epidemic.8 In February 1945, cases of jaundice began to occur at Whittier in the Alaskan Department; they reached epidemic proportions during March. Cases listed according to date of onset of symptoms were as follows:

Period:

Number of cases

    

Feb. 12-28

7

    

Mar. 1-10

56

    

Mar. 10-20

5

7See footnote 4 (4) and (5), p. 39.  
8Letter, Office of the Surgeon, Alaskan Department, to Office of the Surgeon General, 15 Mar. 1946, subject : Medical History, Alaskan Dept. for the Year 1945.  


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The disease was characterized by sudden onset with nausea, epigastric distress, chilliness, backache, and mild generalized myalgia. Only an occasional patient had clinically recognizable jaundice, while in a few additional patients there was an elevated icterus index.

Because one of the first patients had jaundice, Weil's disease was suspected. Leptospirae were said to have been observed on dark-field examination of blood smears in this patient, and similar "organisms," which formed the basis of the diagnosis of Weil's disease, were observed in a total of 198 persons, of whom 68 had symptoms and 130 were not sick. The post was quarantined, and most of the sick persons were given either penicillin or Mapharsen (oxophenarsine hydrochloride).

Upon request of the Surgeon of the Alaskan Department to The Surgeon General, Capt. Sidney S. Gellis, MC, of the Army Epidemiological Board was dispatched to Alaska to investigate the outbreak. It was determined that the so-called Leptospirae were in fact pseudospirochetes arising from red blood cells, that no Leptospirae were recovered by animal inoculation, and, subsequently, that none of the patients had agglutinins for Lept. ieterohaemorrhagiae.

While the nature of the outbreak was not conclusively determined, it was believed to have been one of infectious hepatitis.

Summary.-Leptospiral jaundice, or Weil's disease, was not an important cause of illness among military personnel during World War II. It presented, however, a diagnostic problem in the differentiation of other infectious diseases in which jaundice is a prominent feature, notably infectious hepatitis and homologous serum jaundice, both of viral origin. Simplification of laboratory methods for the diagnosis of leptospirosis would go far toward solving this problem of differential diagnosis.

Leptospirosis remains a potential problem in future military operations wherever personnel must come into contact with stagnant water likely to be contaminated with rat excreta. Field mice and other small mammals, as well as swine, cattle, horses, and dogs, are also natural or aberrant hosts of Leptospira and may, under special circumstances, serve as sources of infection for military personnel. The common modes of transmission of these species of Leptospira are not well known.

THOMAS B. TURNER, M.D.

Part II. Leptospiral Pretibial Fever (Fort Bragg Fever)

Among the new diseases first described during World War II was one designated Fort Bragg fever. It was originally thought to be due to a virus but was later shown to be caused by Leptospira autumnalis.9 The investigation of this disease was accomplished by means of facilities and personnel

9Gochenour, W. S., Jr., Smadel, J. E., Jackson, E. B., Evans, LaR. B., and Yager, R. H.: Leptospiral Etiology of Fort Bragg Fever. Pub. Health Rep. 67: 811-813, August 1952.


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furnished by the Preventive Medicine Service, Office of the Surgeon General. The research laboratory built, equipped, and maintained for the Commission on Respiratory Diseases at Fort Bragg did much to implement the difficult research. No immunologic relationships have been shown between the causative agents of Fort Bragg fever and of sandfly fever and dengue, which it somewhat resembled.

Incidence.-An outbreak of Fort Bragg fever occurred at Fort Bragg, N.C., during the summer of 1942. As the clinical characteristics became apparent during the course of the epidemic, attention was called to the description of an outbreak of a similar disease in Wrens, Ga., in 1940.10 With this exception, nothing could be found in the professional literature to indicate that the disease had been recognized in the past. The outbreak was studied in detail from a clinical point of view by Lt. Col. (later Col.) Worth B. Daniels, MC, and Capt. H. Arthur Grennan, MC, who reported 40 cases between 29 July and 1 September 1942.11 It seemed probable that the true incidence of the disease was considerably higher because many more individuals experienced similar illness without rash at a time when the seasonal incidence of respiratory tract disease, including influenza, was low. Similar outbreaks of an illness that was strongly suspected of being the same disease occurred at the same season during the next 2 years. It was noteworthy that the cases all occurred in the same area of the post.

Epidemiology.-Toward the end of the 1942 epidemic at Fort Bragg, The Surgeon General assigned a commission to study the disease. The members of the commission were Dr. Norman H. Topping, of the U.S. Public Health Service; Maj. (later Col.) Cornelius B. Philip, entomologist in the Sanitary Corps; and Dr. John R. Paul, School of Medicine, Yale University.

Data accumulated by this commission, in collaboration with Colonel Daniels and his staff, led to the belief that some local environmental factor, perhaps an insect vector, was responsible for the spread of the disease. All the cases came from the northern third of the reservation near a small stream and its tributaries. In the Wrens epidemic, known locally as Brushy Creek fever, all of the patients had gone swimming in a neighboring stream. Patients at Fort Bragg had not been swimming. Furthermore, no one insect found in the Fort Bragg area seemed to be a likely vector. Circumstantial evidence suggested that the incubation period of the disease was rather long, perhaps 10 days or longer, but no definite conclusion could be reached on this point. There was no evidence to suggest spread by personal contact, and isolation of cases was considered unnecessary. The commission concluded 12 that (1) a nonexanthematous form of the disease exists and (2) that, if all forms of the disease are considered, it can appear in explosive epidemic form so that within a period of 2 weeks almost 10 percent of the officers and men

10Bowdoin, C. D.: A New Disease Entity (?) J.M.A. Georgia, 31 : 437-438, December 1942.  
11Daniels, W. B., and Grennan, H. A.: Pretibial Fever, and Obscure Diseases. J.A.M.A., 122: 361-365, 5 June 1943.  
12Topping, N. H., Philip, C. B., and Paul, J. R. : Report of the Commission for the Study of an Unidentified Disease at Fort Bragg, N.C., 3 Sept. 1942-11 Sept. 1942.  


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in a given company can be infected. No means of control was found, since the mode of transmission of the disease was unknown.

Clinical description.-The onset of the disease was usually sudden, with pronounced constitutional symptoms. The temperature curve was characteristically spiking, often with two or more peaks up to 103 or 104 F. in the course of 24 hours. The fever lasted about 5 days with rapid defervescence, and there was usually no recurrence. No complications were seen, and most of the soldiers affected were back on duty in about 10 days. Treatment was symptomatic.

Headache was a prominent symptom. In 3 cases with meningismus, spinal fluid findings were negative. Minor respiratory symptoms were seen in a third of the cases in the early stage of the disease. Splenomegaly appeared in most of the cases, but lymphadenopathy was not observed. The distinctive feature of the disease was the appearance of a rash confined to the pretibial area in 60 percent of the cases, with scattered lesions elsewhere on the body in an additional 20 percent of the cases. The lesions consisted of erythematous localized blushes with irregular borders, varying from 2 to 5 cm. in diameter. They felt warm, were slightly indurated, and were often tender to touch. Though the lesions were suggestive of erythema nodosum, they were less distinct. The rash generally lasted about 2 days and could not be ascribed to drug reaction or to insect bites. A leukopenia with normal differential count was usually seen. The diagnosis depended entirely on recognition of this clinical picture in conjunction with the epidemiological findings. Exclusion of other types of short fevers by appropriate means was obviously necessary. Bacteriological and serologic tests were found to be negative for a variety of diseases.

Etiology.13-The members of the special commission attempted to isolate the etiological agent of the disease from frozen specimens of blood, nasal washings, and urine from the few patients available during the time of their study and from flies and mosquitoes collected locally. They concluded "* * all tests on this material proved negative insofar as isolating, or determining the nature of, the infectious agent responsible for this disease was concerned."

In August 1944, an unidentified nonbacterial agent was recovered from guinea pigs inoculated with freshly drawn blood from a soldier with Fort Bragg fever. Preliminary tests suggested that the agent was filterable. After prolonged passage of the probable virus in animals and eggs, inoculation of
human volunteers with this virus reproduced the clinical picture of the disease with rash in some of the subjects. This was thought to constitute strong but not conclusive evidence that the etiological agent had been found. This work was carried out by the author, a member of the Commission on Acute Respiratory Diseases of the Army Epidemiological Board, which was resident as a group at Fort Bragg at the time. This commission, through another of

13(1) See footnotes 1, p. 37; and 4, p. 39. (2) Tatlock, H.: Studies on a Virus From a Patient With Fort Bragg Fever (Pretibial Fever). J. Clin. Investigation 26: 287-297, March 1947.


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its members, Dr. Albert B. Sabin, provided the subjects for and financed the human transmission experiments.

Preliminary tests to determine the biological characteristics of the etiological agents suggested that its infectivity was destroyed by the freezing and thawing of blood known to contain the agent. During the human transmission experiments in 1946, blood shown to be infectious when freshly drawn had lost its capacity to infect after only 10 days' storage at -70 C. In 1942 and 1943, the members of the special commission had failed to transmit the disease to human subjects by use of frozen and thawed blood drawn from patients in the acute febrile stage. The liability of the virus to freezing was thought by the author to be a probable explanation for the failure of the first set of human transmission experiments. In tests on the appearance of the agent in the blood of the human volunteers, it was found that the infectious stage occurred shortly before the onset of fever and disappeared promptly; furthermore, the titer of the agent in the human blood was very low, a 1 to 10 dilution being ineffective where undiluted blood or serum killed hamsters. No attempts were made to detect the agent in other human tissues or secretions.

From cross-immunity tests in human beings, the new agent was shown to have neither a group relationship with the known dengue viruses nor any relationship with one strain of sandfly-fever virus. It appeared to be unrelated in its serologic and other properties to the agents of lymphocytic choriomeningitis, Q fever, and Rocky Mountain spotted fever. Details concerning the properties of the agent and the cross-immunity test may be found in the author's article.14

Summary.-It is evident that Fort Bragg fever presented no considerable military problem during the war; it occurred in a localized area of one large Army post in the Southern United States. There was nothing to indicate a potentially high degree of infectivity or a rapid rate of spread of the disease, though circumstantial evidence suggested that 10 percent of a population might become infected. Recognition of the disease was based solely on clinical and epidemiological considerations, there being no serologic or other specific test to confirm the diagnosis. The course of the disease was benign, and soldiers were disabled by it for a period of only a week or 10 days, at the end of which time they returned to full duty. There were no special problems in the management of cases. No means of control was found, since the mode of transmission could not be established. Apparently, a hitherto undescribed agent was isolated from the blood of a soldier with the disease. Finally, it was shown by Gochenour15 and others in 1952 that the etiological agent was Leptospira autumnalis.

HUGH TATLOCK, M.D.
14See footnote 13(2), p. 43.  
15See footnote 1, p. 37.

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