Medical Science Publication No. 4, Volume II
LEPTOSPIROSES*
LIEUTENANT COLONELROBERT H. YAGER, VC
Members of the spirochetal genus Leptospira comprise a groupof antigenically distinct strains, globally distributed in enzootic proportionsamong many species of rodent as well as other mammalian populations (1).Although the infection in man is accidental, it presents a potential militaryhazard due to the exigencies and exactments of military personnel undercombat and training conditions. The enforced departure from normal sanitaryfacilities, coupled with the association and exposure of troops to particularenvironmental conditions, may bring into play all the epidemiologic factorsthat make up the links in the chain of transmission of leptospires fromanimal to man. No consideration of leptospirosis in military personnelis possible without a basic understanding of the multiple epidemiologiccharacteristics that must be present before humans can be infected (2,3).
Leptospires have been found, with rare exception, in every area of theworld in which they have been sought. Generally, most strains are associatedwith one or more mammalian hosts; however, a particular mammalian speciesmay serve as the primary host for a multiple number of leptospiral strains(4). The principal reservoirs involve numerous species of the rodentfamily and in recent years the widespread infection of domesticated animals,particularly among canine, bovine and porcine populations, has been demonstrated(5-7). Leptospires usually exhibit little or no pathogenicity fortheir natural rodent hosts, and even in severe infections of larger mammalstheir presence may be asymptomatic (1).
Of particular epidemiologic significance is the characteristic nestingability of these organisms within the host's tissue (2). Leptospiresare able to exist in the lumen of the convoluted tubules of the renal cortex,even in the presence of a large number of protective humoral antibodies.From this site they are discharged and excreted with the urine. The chronicityof leptospiruria may extend for months and in several instances has beenobserved to last for years in various natural hosts. The incidence of leptospirosisin the natural host varies with
*Presented 29 April 1954, to the Course on Recent Advances in Medicine and Surgery, Army Medical Service Graduate School, Walter Reed Army Medical Center, Washington, D. C.
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the species, its geographic location, and the infecting strain. Theresults of many surveys, conducted in diverse parts of the world, indicatethat infectivity rates in excess of 50 percent are not uncommon. It isinteresting to note that in several conducted surveys, the incidence ofhuman leptospirosis could be correlated to the relative frequency of leptospirosisin the natural hosts of the regions studied. This is not always the case,as evidenced by the rare appearance of Weil's disease in the United Stateswhere the infectivity rate in rats is high (8, 9). Obviously, thehygenic status of the American populace is a significant factor which contributesto the paucity of human leptospiral infections.
The existence of leptospires in waters contaminated by the urine ofhost-carriers is of fundamental importance to our knowledge of the epidemiologyof leptospirosis. The viability of these organisms outside their hostsdepends upon the salinity and acidity of the aquatic environment (3).These organisms do not tolerate brackish water and, consequently, no knowncases of leptospirosis are known to be associated with sea water. It hasbeen demonstrated that the low frequency rate of Weil's disease in NorthHolland as compared to the high frequency rate in South Holland is relatedto the salinity of the water in the former region. The inability of leptospiresto survive in water of low pH has been adequately established by differentinvestigators (3). Epidemiologic studies in Japan, Africa and Indonesiahave indicated that the difference in the prevalence of human leptospirosisin selected regions is associated with the acidity of the waters of theseareas (3). In addition, leptospires have been shown to retain theirviability and pathogenicity for as long as 22 days in surface waters ofpH 7.0 to 8.0 (2, 3). The epidemic outbreaks of human leptospirosishave usually occurred where there has been contact with contaminated waters,and such outbreaks are made possible by the remarkable pervasiveness ofleptospires.
The invasiveness of leptospires is unique with respect to the readinessand rapidity with which they penetrate mucous membranes. Upon intraperitonealinoculation of cultures in experimental animals, leptospires appear withinminutes in the circulating blood (3). The ability of these organismsto penetrate intact skin has not been conclusively demonstrated. The factthat leptospires can penetrate scarified skin has been repeatedly shownin experimental animals and has been utilized in the recovery of pathogenicstrains from contaminated waters. In man infections result from the penetrationof leptospires through the skin which is usually associated with thoseoccupations where the skin is readily injured or softened by prolongedexposure to water. The nasopharyngeal, buccal and esophageal mucosa, as
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well as the conjunctival membrane, are probably the more frequent sitesof entry (3).
The water ecology of leptospires, coupled with their ready penetrationof injured skin and mucosal surfaces, demonstrates the potential sourcesof infection in stagnant pools, slow-moving streams, swamps, wet trenches,etc., in an enzootic or epizootic area of leptospirosis, particularly inview of the marked susceptibility of human beings to these infections.Sex and age are not determining factors in the incidence of these diseasesin man, and seasonal factors are important only insofar as they are relatedto the occurrences of floods and abundant rainfall. Epidemiologic surveyssuggest that certain occupational or recreational practices afford greateropportunities for infection than the naturally occurring events previouslymentioned.
The medical significance of leptospirosis in military history cannotbe fully appreciated since the Weil's disease syndrome was not describeduntil 1886, and the etiologic agent of the disease was not recognized andisolated until 1916 by Inado and Ido in Japan (10). Since the medicalrecords of many campaigns, including the American Civil War, contain descriptionsof febrile disease outbreaks accompanied by jaundice, it is quite possiblethat some cases were due to leptospirosis. The military significance ofthis disease was definitely established by Uhlenhuth and Fromme (11)in World War I, while working in a field laboratory in France. They observedthe disease in German troops engaged in trench warfare. These and otherreports of leptospirosis in the German Army in 1915 were followed by similarreports among British troops the following year by Stokes, Ryle and coworkers(12). It was along the Ypres sector in Flanders that some of thebloodiest fighting in World War I took place, and the battle that beganas a series of offenses and counteroffenses in 1915 bogged down to a trenchwar that was characterized by violent activity but little change of position.In these sodden, rat-infested trenches a hundred cases of leptospirosisamong British soldiers were observed (13). Scattered outbreaks werealso reported in the French and Belgian armies along the Western front.Various European investigators confirmed the observation of Miyajima andother Japanese workers by demonstrating the significance of leptospiresin the urine of rats trapped in areas where human leptospirosis had occurred.The disease was also reported among Italian and Canadian forces in NorthernItaly.
It would be difficult, if not impossible, to give an accurate appraisalof the incidence of leptospirosis among military personnel in World WarII. This war was fought on so many fronts, and under such conditions asto make laboratory confirmation of sporadic cases un-
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feasible. However, an outbreak of leptospirosis with at least 100 clinicalcases was reported among British troops on the Normandy beachhead nearCaen (14).
One of the most notable outbreaks of leptospirosis occurred among theAmerican soldiers stationed on the military reservation of Fort Bragg,North Carolina, in 1942, and again in 1943 and 1944 (15). It issignificant that in this instance the diagnosis of leptospirosis was madein retrospect some 8 years following its last occurrence and that the infectingserotype was L. autumnalis, not previously reported in the UnitedStates.
Data obtained from Medical Statistics Division of the Office of TheSurgeon General indicate that a total of 115 cases of Weil's disease occurredin the United States Army in all theaters from 1942 to 1945 (16).This figure represents only cases of clinically diagnosed spirochetal jaundice(Weil's disease) and does not include cases of leptospirosis manifestedin other clinical forms. There is ample evidence to support the view thatmore cases of leptospirosis occurred in the United States Army during WorldWar II than the records indicate. Obviously an accurate estimate can neverbe obtained.
Numerous other instances of outbreaks of leptospirosis are recordedamong troops both in war and in peace. An outbreak of aseptic meningitisamong American soldiers on Okinawa in 1949 was diagnosed as leptospirosisin retrospect several years later (17). This outbreak as well asother epidemics have occurred among troops who swam and bathed in slow-movingstreams and ponds. More recently, leptospirosis has been implicated asone of the most serious infectious disease problems in units fighting inMalaya (18). Injection rates up to 10 percent have been experiencedamong jungle patrols forced into close contact with an environment contaminatedwith leptospires.
All too frequently the reported incidence of leptospirosis may varywith the general awareness of the disease, and unless adequate laboratorysupport is available, many cases of leptospirosis, other than those thatexhibit the symptoms of classical Weil's disease, may be overlooked. Armyarea laboratories and medical general laboratories are currently preparedto render serologic diagnoses of leptospirosis. These units are suppliedwith three sonic-vibrated complement-fixing antigens with a sufficientlybroad spectrum to detect leptospiral antibodies, regardless of the infectingstrain (19). Standard Kolmer qualitative technics are employed inexamining paired undiluted sera from suspected cases. The paired sera shouldconsist of one specimen drawn during the acute phase of the disease andanother drawn the tenth day or after. Since no information can be obtainedas to the infecting serotype on the basis of a positive complement fixationtest, such sera should be forwarded to the Army Medical Service Graduate
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School where the agglutination-lysis test is employed to confirm diagnosisand identify the etiologic serotype. A battery of selected distinct leptospiralserotypes are employed in our laboratory since it has been determined,on the basis of cross-agglutination studies, that such a combination ofantigens is essential in detecting an antibody response to any leptospiralserotype known to exist in the world (19).
Numerous technics have been described for the detection of leptospiresin blood, cerebrospinal fluid, urine and tissue emulsion. We have foundthat the direct dark-field examination of such material is unreliable initself. Too often artifacts resembling leptospires in size and behaviorare present, which may lead to a false-positive diagnosis. Conversely,the spirochetes may be present in such small numbers as to be undetectable,leading to a false-negative result. Leptospiral isolation attempts arebest made by the direct culturing into appropriate laboratory media ofpatients' blood or cerebrospinal fluid during the first week of diseaseand by the subsequent microscopic examination of the cultures at 2-weekintervals (20). Cultures are considered negative only after no leptospiresare detected after 4 weeks of incubation at 30° C. The leptospiruricphase of the disease commences usually about the fourteenth day, and theorganisms may be isolated from urine by inoculating freshly voided or catheterizedspecimens into small hamsters or guinea pigs and culturing their heart'sblood 4 to 6 days post-inoculation. The same procedures are then followedin handling these cultures as those used in the cultivation and identificationof direct isolations. Any leptospiral isolations made in Army Medical Serviceunits are forwarded to the Army Medical Service Graduate School for definitivetyping.
Almost all of the work done on leptospirosis in the Far Eastern Theaterwas done by the Japanese, and there is no paucity of information concerningthis disease in their home islands. The early work done by Inado and Idohas already been mentioned. Kitaoka has described the existence of eightleptospiral strains in Japan and Okinawa (21). In addition to Weil'sdisease, seven-day fever (Nanukayami) is widespread in Japan, and its etiologicagent is L. hebdomadis. So-called autumnal fever (Akiyami) has asit etiologic agent L. autumnalis, a strain closely related to theleptospires of Fort Bragg fever.
With the exception of the outbreak of leptospirosis on Okinawa in 1949,few cases have been recorded among military personnel in the Far EasternTheater of Operation since the end of World War II. The hazards of schistosomiasisin Japan and Okinawa, the military regulations placing fresh water lakesand streams off limits in endemic areas, can be considered as an importantfactor in reducing the potentiality of leptospirosis.
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Prior to 1951 little was known or at least recorded about the incidenceof leptospirosis in Korea. No cases of human leptospirosis had been reported,and there were no data available regarding surveys to determine possibleanimal host carriers of the organism. Less than a year after the outbreakof the Korean conflict there appeared among United Nations forces a maladypreviously unknown to the Western world. It was the disease now describedas hemorrhagic fever. Early reports, based on the detection of leptospira-likeorganisms in the blood of those with acute clinical cases, created a sharperinterest in leptospirosis in that country. Although it was subsequentlydemonstrated that hemorrhagic fever is not a leptospirosis, the interestcreated by these early but erroneous reports lead to leptospiral surveysof rodents trapped in Korea (22).
Why then, was leptospirosis not reported among United Nations personnelengaged in the Korean incident? Laboratory support was available in Japanand the United States for confirmation of any sporadic cases that mighthave occurred. It was definitely established that leptospirosis is enzooticin Korean rodents, as in rodents elsewhere.
One might still consider the possibility that leptospirosis did occurin Korea, and in keeping with its protean nature was classified as a feverof unknown origin. Confirmation, in either sense, could be obtained byscreening all such available sera from Korea. There is reason to believe,on the basis of past experience, that a few such cases might prove to beleptospirosis. Probably of greater significance in regard to the paucityof leptospirosis in Korea were the overall standards of military sanitationin our Army. The prevention of the transmission of leptospira from infectedrodent urine to man was made possible by the routine chlorination of drinkingwater, strict mess hall sanitation in permanent and semipermanent installations,and by the methods used to protect rations for front line units duringall stages of processing, shipping and utilization.
The intensive effort to curtail rodent population, because of theirpossible epidemiologic importance in hemorrhagic fever, probably is a factorin at least reducing the leptospiral contamination of streams, marshy areasand rice paddies. The climate of Korea cannot be described as being favorablefor the prolonged survival of leptospires in the free state. Korea hasbeen described as being either all dust or all mud. A dry spell may endwith a torrential rain, followed by a rapid runoff of surface water, quickdrying up of streams and ditches, and then a repetition of the cycle. Undersuch conditions leptospira would suffer the fate of either being dessicatedor washed into the sea.
Consideration must also be given to the nature of the conflict thatwas fought in Korea. Troop movements were generally made by
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road, even in the forward areas, and not by wading through rice paddiesand streams, such as the jungle patrols encountered in Malaya. The forwardobservation bunkers of Korea were placed mainly in elevated, better drainedpositions than the trenches in Flanders, where men were pinned down forlong periods of time in the mire of these trenches.
In summary, leptospirosis has been a major problem of preventive medicinein military history, and will remain so as long as wars are fought withlarge masses of men forced into intimate contact with the earth and itsanimal population.
On the basis of experience gained in Korea and in other conflicts, thechief weapons at our disposal in the control of leptospirosis are:
1. Strict adherence to the basic principles of military sanitation withparticular emphasis on chlorination of water, protection of food from contamination,rodent control and water discipline.
2. Constant awareness of its potentiality and an understanding of thebasic epidemiologic mechanisms involved.
3. Adequate and readily available laboratory support to military unitsin all parts of the world.
References
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2. Walch-Sorgdrager, B.: Leptospirosis. League of NationsBull. of the World Health Organ. 8 : 143-386, 1939.
3. Van Thiel, P. H.: The Leptospirosis. Universitairepers Leiden, 1948.
4. Gsell, O.: Epidemiology of the Leptospirosis. Symposiumon the Leptospiroses. Med. Sci. Pub. No. 1 : 34-56, U. S. GovernmentPrinting Office, Washington, 1953.
5. Rosenberg, B. L.: Canicola Fever. Review, with reportof two new cases. Am. J. Med. 11 : 75-91, 1951.
6. Wolff, J. W., and Bohlander, H.: Bovine Leptospirosis.A survey of the epidemiology and serology and an investigation on the possibleoccurrence in bovines in the Netherlands. Doc de Med. Geog. et Tropien.4 : 257-265, 1952.
7. Sippel, W. L., and Atwood, M. G.: Leptospirosis inSwine. Symposium on the Leptospiroses. Med. Sci. Pub. No. 1 : 143-151,U. S. Government Printing Office, Washington, 1953.
8. Larsen, Carl L.: The Public Health Significance ofthe Leptospirosis. Symposium on the Leptospiroses. Med. Sci. Pub. No. 1: 14-24, U. S. Government Printing Office, Washington, 1953.
9. Li, H. Y., and Davis, D. E.: The Prevalence of Carriersof Leptospira and Salmonella in Norway Rats of Baltimore. Am. J. Hyg. 56: 90-100, 1952.
10. Inada, R., Ido, Y., Koki, R., Kaneko, R., and Ito,H.: The Etiology, Mode of Infection, and Specific Therapy of Weil's Disease.J. Exp. Med. Hyg. 23 : 377, 1916.
11. Unlenhuth, P., and Fromme, W.: Experimentelle untersuchungenuber die sogenannte Weilsche Krankheit (Ansteckende Gelbsucht). Med. Kl.11 : 1202-1203, 1915.
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12. Stokes, A., and Ryle, J. A.: A Note on Weil's Disease(Spirochaetosis icterohemorrhagica) as it Occurred in the Army inFlanders. Br. Med. J. 2 : 413-417, 1916.
13. Stokes, A., Ryle, J. A., and Tyler, W. H.: Weil'sDisease (Spirochaetosis icterohemorrhagica) in the British Armyin Flanders. Lancet 1 : 142-155, 1917.
14. Bulmer, E.: Weil's Disease in Normandy. Its Treatmentwith Penicillin. Brit. Med. J. 1 : 113-114, 1945.
15. Gochenour, W. S., Jr., Smadel, J. E., Jackson, E.B., Evans, L. B., and Yager, R. H.: Leptospiral Etiology of Fort BraggFever. Pub. Health Reports 67 : 811-813, No. 8, Aug. 1952.
16. Data from the Medical Statistics Division, Officeof The Surgeon General.
17. Gauld, R. L., Crouch, W. L., Kaminsky, A. L., Hullinghorst,R. L., Gochenour, W. S., Jr., and Yager, R. H.: Leptospiral Meningitis.Report of Outbreak among American Troops on Okinawa. J. A. M. A. 149: 228-231, May 1952.
18. Ley, H. L., Jr., Gochenour, W. S., Jr., Wisseman,C. M., Pirrie, J. M., Patterson, P. Y., Smadel, J. E., and Hoag, W. G.:Leptospirosis in Malaya I. Human Disease Contracted in Jungle Areas. Inpreparation.
19. Gochenour, W. S., Jr., and Yager, R. H.: Classificationof North American Leptospiras. Proc. Am. Vet. Med. Assoc. 178-183, June1952.
20. Gochenour, W. S., Jr., Yager, R. H., Wetmore, P. W.,and Hightower, J. A.: Laboratory Diagnosis of Leptospirosis. Am. J. Pub.Health 43 : 405-410, 1953.
21. Kitaoka, M.: Classification of Leptospirosis. JapaneseMed. J. 4 : 181-214, 1951.
22. Monthly Technical Report: 406th Medical General Laboratory,Tokyo, September 1951.
