CHAPTER I
Leishmaniasis
Harry Most, M.D.
Part I. Cutaneous Leishmaniasis
Cutaneous leishmaniasis did not constitute an important or adisabling medical problem in World War II, and the effective troop strength inthe areas involved was not appreciably altered. An estimated 1,000 to 1,500cases occurred, and all but the few reported from Latin America,1North Africa,2 and Panama3originatedin stations of the Persian Gulf Command, mainly in the vicinity of Ahvāz, Iran.In this command, the first case was discovered in October 1943, and as a resultof special attention to the problem of cutaneous leishmaniasis, that is, byaltering dispensary officers to the appearance of the lesion and by establishinga central area for the administration of treatment, 630 cases were reportedwithin the next 3 months. The peak incidence was over by 1 February 1944, andduring the next 12 months, the average number of new cases was only 23 per month4(chart 1).
CLINICAL ASPECTS
In a report from the 113th General Hospital, QuarryCamp, Ahvāz, based on an analysis of 499 cases, detailed information was furnishedconcerning the clinical aspects of cutaneous leishmaniasis in American militarypersonnel.5 White and Negro enlisted personnel as well as male andfemale officers were involved.
Incubation Period
The incubation period for the development of cutaneousleishmaniasis, based on human inoculation experiments with cultures or materialfrom
1Report, Medical Statistics Division, Office of The SurgeonGeneral, U.S. Army, 15 Dec. 1945.
2Kranes, A.: Leishmaniasis AmongAmerican Troops in the Mediterranean Theater of Operations. (One case ofcutaneous leishmaniasis proved by biopsy at the 17th General Hospital.)[Unpublished; official paper.]
3Kean, B. H.: Cutaneous Leishmaniasis on the Isthmus ofPanama. Arch. Dermat, & Syph. 50: 237-238, October 1944.
4(1) Essential Technical Medical Data, Persian Gulf Command,U.S. Army, for March 1944, dated 15 Apr. 1944. (2) Essential Technical MedicalData, Persian Gulf Command. U.S. Army, for December 1944, dated 19 Jan. 1945.
5Ball, D., and Ryan, R. C.: Cutaneous Leishmaniasis. Bull.U.S. Army M. Dept. No. 79, 65-73, August 1944.
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CHART 1.-Incidence ratesfor cutaneous leishmaniasis in Persian Gulf Command, U.S. Army, 1943-45
proved ulcers, is known to vary from a few weeks to 56months.6 In the group of 499 cases just mentioned, the disease developed in onepatient within 10 days of exposure; in others, presumably infected while inIndia, it developed within 3 weeks after arrival in Iran. The maximum incubationperiod for the latter group, which had spent about a month in India and about 10days en route to Iran, would be approximately 6 weeks. Of interest in regard tothe prolonged incubation period in some instances was the development ofcutaneous leishmaniasis in military personnel following their return to theUnited States after having served in endemic areas.
Lesion
The characteristic lesion at onset was an indolent papule,resembling an insect bite. At first, it was painless and did not itch.Subsequently, the small red papule enlarged and the center developed a thincrust, becoming slightly dimpled. Ulceration occurred in the center and formed athick, rough crust or scab which was difficult to remove. The ulcer, from 1 to1?
6Berberian, D. A.: Cutaneous Leishmaniasis(Oriental Sore); Incubation Period. Arch. Dermat. & Syph. 50: 231-232, October 1944.
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inches in diameter, was surrounded by a raised red, firm,liplike edge. The number of lesions ranged from 1 to 3 in 204 patients and from4 to 29 in 193 patients. The majority of the lesions occurred on theextremities, but the face, ears, and neck were also involved. In two patients,lesions were present on the penis.
DIAGNOSIS
The diagnosis was established without difficulty in themajority of patients. A stained smear of material removed from beneath the crustprovided the most valuable diagnostic information. In 387 cases, the first smearwas found to contain Leishmania tropica; in 9 cases, 2 smears werenecessary; and in 1 case, 3 smears were made before L. tropica could be demonstrated. Fifty-three patients with aclinical diagnosis of cutaneous leishmaniasis had two or three negative smearsand were not treated. In 49 of these patients, spontaneous healing occurred inan average time of 7.3 weeks. It was assumed that these patients were in thehealing stage when first seen. Treatment was almost entirely carried out indispensaries, and those affected could perform their usual military functions.No patients were returned to the United States because of this infection, and nopatient was given a medical discharge because of it.
TREATMENT
The average age of the lesions when treatment was begun was9.7 weeks. Sixty-five patients with one to four noninfected lesions were treatedwith ethyl chloride spray every 5 days. Fifty-seven of these showed no evidenceof healing in an average of 3 weeks, and only eight patients were cured in anaverage of 5.5 weeks. Only small young lesions were amenable to freezing withethyl chloride, and this form of treatment failed in 87.7 percent of thepatients for whom it was used. Injections of acid berberine sulfate, 1-2 cc.of a 1-percent solution, were given once a week to 138 patients. After anaverage of 5.5 weeks, 31.8 percent of these patients failed to respond to thetreatment. The interval to cure, after treatment with acid berberine sulfatealone, was 6.8 weeks and was 4.5 weeks after prior failure with ethyl chloridespray.
Neostam (stibamine glucoside) was given intravenously to 221patients of whom 155 had had no prior therapy. The others had previously beentreated without success with ethyl chloride, acid berberine sulfate, Neostamlocally, or X-ray. Cure was accomplished in all cases in 2 to 20 weeks (average14.5). Toxic manifestations of nausea, vomiting, diarrhea, and collapse wereencountered in 5 percent of the patients who initially received Neostam inmaximum single doses of 0.2 gram. Reduction in maximum doses to 0.15 gm. givenat least 5 hours after a meal diminished
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the incidence of toxic symptoms to 0.83 percent in the last950 injections. The initial dose was 0.5 gm. and subsequent doses, 0.1 and 0.15gram. Injections of 0.15 gm. were given twice weekly and continued until curewas accomplished. Healing began with as little as 0.7 gm. total dosage ofNeostam and was manifested by disappearance of the redness of the lesion, by thedevelopment of a copper-colored area around the lesion, and by the formation ofnew epithelium when the crust fell off. The average amount of Neostam toaccomplish cure was 1.14 grams.
Neostam (1-2 cc. of a 2-percent solution) was administeredlocally at weekly intervals in 35 cases, and in 32, cures resulted in an averageof 3.3 weeks, the shortestinterval for cure of any group.
Of 10 patients treated locally with roentgen radiation andadequately followed, 9 were cured in an average of 8.3 weeks after the lastexposure to X-ray therapy. The initial X-ray dose was 60 R. (roentgen), andthree subsequent doses of 75 R. were given at 4-day intervals. One patientfailed to respond to this course of treatment.
Penicillin was ineffective in one patient treated, in Panama,for cutaneous leishmaniasis of the face. No clinical response was noted during 5days of therapy, and apparently viable parasites were still found in the tissues8 days after completion of treatment.7
In summarizing the results of treatment, it appeared thatethyl chloride spray and acid berberine sulfate locally were not highlyeffective in the treatment of cutaneous leishmaniasis. Neostam locally injectedinto noninfected lesions cured 90 percent of them in a month. X-ray treatmentwas effective in selected cases. Neostam, intravenously, was effective in allcases but produced considerable toxicity unless the maximum dose was not greaterthan 0.15 gram. Neostibosan (ethyistibamine), a less toxic drug than Neostam,which can be given at short intervals (daily) in relatively large amounts ismore effective in the treatment of leishmaniasis. Unfortunately, its use was notrecommended in 1941,8 and although recommended for use in1943,9 its designationas a standard item was not approved until 1944.
Complications occurred in 0.7 percent of the patients withproved cutaneous leishmaniasis and consisted of such infections as cellulitis,lymphangitis, and thrombophlebitis. It was observed that 35 percent of thesesecondary infections occurred in patients who were receiving local injections ofacid berberine sulfate. The patients with these complicating infections werehospitalized for periods from 5 to 93 days (average 25). Only one recurrence orreinfection was observed in the group of patients discussed in this chapter. Nodeforming scars remained after treatment.
7Snow, J. S.: The Unsuccessful Treatment of AmericanLeishmaniasis With Penicillin; Report of Case. Arch. Dermat. & Syph. 50: 324-325,November 1944.
8Circular Letter No. 56, Office of The Surgeon General, WarDepartment, 9 June 1941, subject: Notes on the Treatment and Control of CertainTropical Diseases.
9Circular Letter No. 33, Office of The Surgeon General, WarDepartment, 2 Feb. 1943, subject: Treatment and Control of Certain TropicalDiseases.
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An interesting observation by local health authorities withregard to control measures of reservoir hosts and the effect of such measures onthe rate of infection in the natives in known endemic areas was cited in thereport from the 113th General Hospital. In one such area, 60 percent of thegerbils (burrowing rodents related to the mouse, native to Africa and Asia) werefound infected. Intensive rodent destruction with chloropicrin resulted in areduction of the incidence of leishmaniasis in the natives in the area from 70to 0.4 percent.
Part II. Visceral Leishmaniasis
Visceral leishmaniasis, or kala-azar, was not a seriousproblem in troops of the United States. In all, an estimated 50 to 75 casesoccurred in military personnel from North Africa, Sicily, southern Italy, theRiviera, and India. The individual case, however, often posed a problem indiagnosis to medical officers, owing chiefly to lack of prior experience. In theUnited States before World War II, cases of kala-azar were rare, with thedisease occurring in persons who had resided in India, China, or countriesbordering the Mediterranean Sea.10 Many medical officers were unaware of thepossibility of encountering kala-azar in American troops stationed in areaswhere the disease was endemic. This frequently resulted in a long delay indiagnosis and in inadequate or inappropriate treatment.
As many of these patients were hospitalized early, and forlong continued periods, for unexplained chills and fever and other symptoms, andas many patients were sent for specialized study to the Zone of Interior, theopportunity was presented to observe the entire course of the disease and itsresponse to treatment. Some studies on individual cases were reported.11A group of 30 patients were admitted to the Moore General Hospital, Swannanoa,N.C., for diagnosis, institution of treatment, re-treatment, or observation.Clinical, biochemical, and hematological studies were made. The observations,reported by Most and Lavietes,12 will be summarized and discussedhere, with a few case histories (pp. 42-48). The case numbers used in the Mostand Lavietes report have been retained in this chapter.
10(1) Price, F, L., and Myer,R. A.: Kala-azar (A Case). J.A.M.A. 125: 490, 1944. (2) Munter, E. J., and Packchanian, A.: Two Exogenous Cases of VisceralLeishmaniasis (Kala-azar) in the United States With Notes on Cultivation of Leishmania-Donovani in Vitro.Am. J. Trop. Med. 25: 507, November 1945. (3) Rose, H. M.: Cold Hemagglutinins in Visceral Leishmaniasis (Kala-azar). Proc. Soc. Exper. Biol. & Med. 58: 93, January 1945. (4) Mathieson, D. R., and Watson,B. A.: Kala-azar. J.A.M.A. 112: 309, January 1939.
11(1) Kaminsky, F., and Wever, G.K.: Visceral Leishmaniasis. New York State J. Med. 46: 522-525, 1 Mar. 1946. (2) Marple, C. D.: Visceral Leishmaniasis (Kala-azar):Report of a Case. Ann. Int. Med. 26: 787-795, May 1947. (3) Burchenal, J. H., and Woods, R. P.: Visceral Leishmaniasis; Report of 3 Cases of Its Occurrence in Members of Armed Forces of United States.War Med. 7: 173-177, March 1945. (4) Kranes, A.: Leishmaniasis Among American Troops in the Mediterranean Theater of Operations, (Report of 5 Cases Submitted to The Surgeon General's Office.)[Unpublished; official paper.]
12Most, H., and Lavietes, P. H.:Kala-azar in American Military Personnel; Report of 30 Cases. Medicine 26: 221-284, September 1947.
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By the end of World War II, not a single death had beenreported as a result of kala-azar. Subsequently, one death occurred 66 monthsafter the diagnosis of kala-azar, complicated by nephritis, had been established(Case 23). As the incubation period, though indeterminate, is frequently long, asmall number of cases occurred in the United States; the disease developed inmen who had previously served in endemic areas, in some, after separation frommilitary service.13 In a few patients, there was slight residualsplenomegaly. Posttreatment cutaneous leishmaniasis did not develop in any ofthe patients, and only the one (Case 23) who diedhad suffered relapse after return to civilian life.
In the present series of 30 cases, the average interval fromthe onset of acute symptoms to definitive diagnosis and specific treatment was10 weeks, varying from 2 to 23 weeks. In 50 percent of the cases, the diseasewas active and under observation in a military hospital for 3 months or morebefore diagnosis was made, and in only five patients was the diagnosisestablished within a month after onset. In six patients, the disease wascontinuously active during 4 to 6 months of uninterrupted hospitalization beforethe correct diagnosis of kala-azar was proved. Most of these men lost a year ormore of active duty.
From this experience, it may be hoped that, if troops areagain exposed to infection by Leishmania donovani, they will havesuitable protection14 againstthe vector, the sandfly of the genus Phlebotomus, and, if cases dooccur, that early diagnosis will be made and appropriate, intensive therapygiven promptly.
PRECLINICAL HISTORY
Age and occupation.-Of the 30patients, 13 were from 21 to 25 years of age; 12,from 26 to 30; 2, from 31 to 35; and 3, from 36 to 40. There were 28 enlistedmen and 2 officers. One of the officers was attached to an air forcesheadquarters in India, and the other was an infantry platoon commander, also inIndia.
Geographic origin of infection.-Of the30 cases, 15 originated in India and 15 in the Mediterranean theater, with theinfected soldiers having spent enough time in North Africa, Sicily, and southernItaly to make more exact localization impossible, with one exception. Thispatient, stationed near Paris, France, had a 1-week furlough in Nice, 3 weeksbefore
13A review, in 1951, of recordsof veterans drawing compensation from the Veterans' Administration andcarrying leishmaniasis as a major discharge diagnosis, disclosed no significantdisability attributable to kala-azar.-H. M.
14The extensive research programwhich the Office of The Surgeon General, U.S. Army, instituted in 1941 forimproved insecticides and insect repellants led to the discovery of theinsecticide DDT and such insect repellants as Indalone (butopyronoxyl), dimethylphthalate, and Formula No. 612 of Rutgers University. All of these were tested,not only against mosquitoes but also against the Phlebotomus sandfly ofkala-azar and the tsetse fly of African sleeping sickness and found quiteeffective. However, their full-scale production did not become available untilthe latter part of 1943 and early 1944.-A. L. A.
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the onset of symptoms. It is reasonably certain that hisinfection was acquired in the vicinity of Nice.
Mode of infection-Severalspecies of Phlebotomus are known to act as vectors in the transmission ofleishmaniasis. The 30 patients all said that they had been bitten by mosquitoesand other "insects and bugs," but they were not specifically aware ofthe sandfly. This is not surprising, since Phlebotomus is only from 1.5to 2.5 mm. in length, and the local irritation caused by its bite may easily beattributed to the more readily visible arthropods.
Kala-azar occurs mostly in native villages and frequently isa household infection. One patient was one of three officers sharing anapartment in Calcutta, India, in two of whom leishmaniasis developed. Threepatients were from the same company quartered at an airbase on the outskirts ofCalcutta. Six patients said they had occupied native huts in a village recentlyvacated. One patient, a truckdriver, slept repeatedly in a stable on theoutskirts of a village. Five other truckdrivers traveled at night along thecoast of North Africa and often had to sleep in their trucks in towns orvillages. In the majority of the 30 patients, there was thus ample opportunityfor acquiring infection in or near native villages, but for some of thepatients, there was no history obtained of time spent in native huts orvillages.
Incubation period.-The incubation period is not definitelyknown and apparently varies widely, instances being reported in which it was asshort as 2 weeks and as long as 18 months. In the patient who became ill 3 weeksafter spending a week at Nice, it is fairly certain that the incubation periodwas 3 weeks, since previously this man had been on duty only in England andParis. In two of the cases, the incubation period, based on the interval betweenthe last possible exposure in an endemic area and the development of theclinical disease in the United States, was at least 2 months. The longestpossible incubation period, as indicated by the interval between arrival in anendemic area and the onset of symptoms, was 33 months. Our attention has beencalled15 to a soldier whohad served in North Africa, Sicily, and Italy. In Italy, in February 1944, hewas taken prisoner and sent to Germany where he remained until his liberationand subsequent return to the United States. He was discharged from the Army inAugust 1945. Symptoms developed insidiously during the next 2 months, and thepatient was finally hospitalized in December 1945. The last possible exposurewas in Italy, in early February 1944, and the shortest possible incubationperiod extended from his arrival in Germany until he became ill in the UnitedStates, an interval of 19 months. Accordingly, when there are suggestiveclinical and laboratory findings, a diagnosis of kala-azar should be considered,even if the patient has long since left the endemic area.
15Hayman, J. H., Jr.: Personal communication.
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CLINICAL ASPECTS AT ONSET
Fever.-In this group of 30 patients, the onset of fever was abrupt.In 29 (96 percent) of them, the first symptom was fever, with a chill ofsufficient severity to warrant their seeking medical attention.
In the acute phase of the disease, the fever was intermittent, with one ortwo daily temperature rises to 101? to 106? F. Thephenomenon of double peaks in daily temperature was observed in 50 percent ofthe patients (fig. 1A). Although this may be seen in other infections, it occursso frequently in kala-azar as to suggest this possible diagnosis in cases ofprolonged fever. The second rise may occur late at night and may be overlooked unlesstemperature readings are taken every 2 or 3 hours, day and night, and arecharted graphically.
In some patients, the maximum rise occurs at approximatelythe same time every day. In a few patients, there may be an exact tertianperiodicity of chills and fever, recurring on alternate days for several daysand weeks, and suggesting the form of malaria caused by Plasmodium vivax (fig.1B). Occasionally, the temperature, although intermittent, may show veryirregular variations in the height as well as in the hour of each maximum rise.Intercurrent infection may alter the temperature curve with periods of sustainedhigh fever, which may be confusing in evaluating response to treatment. Atyphoidlike fever early in the disease occurs commonly in China, but this wasobserved in only one patient whose high fever was sustained for 10 days beforeit became intermittent (fig. 1C). Recurring febrile waves resembling thetemperature pattern in brucellosis have been described in kala-azar,particularly when its course is prolonged (fig. 1D), but this was not acharacteristic curve even in patients who were febrile as long as 6 monthsbefore diagnosis or treatment. It occurred in four patients; after from 10 to 30days, it subsided gradually, and a period of from 10 days to 6 weeks elapsedbefore it recurred. In only one patient was fever entirely absent throughout theobserved course of the disease.
Many patients had one or more chills daily, for weeks at atime, and all but three had chills at some time during the disease. The achingin the back and the extremities and the vomiting that frequently occur followinga paroxysm of malaria were not noted with the chill or fever of kala-azar.Profuse sweating followed the chill.
Splenomegaly.-Splenomegaly was the most prominent physicalfinding in most patients. In 27 (90 percent), the spleen was found enlarged onfirst examination, and in the 3 others, it became enlarged later. The liver wasenlarged in 73 percent on first examination or subsequently. No patient hadhepatomegaly without splenomegaly, and in all patients, the spleen was enlargedmuch more than the liver, varying in size from an edge readily palpable justbelow the costal margin to a gross mass below
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the level of the umbilicus. The edge of the spleen wasusually firm and smooth and, often, tender. The spleen often enlarged withremarkable speed.
Cervical adenopathy-Cervical adenopathywas prominent in seven patients. There was also slight to moderate generalizedlymphadenopathy in these patients, which, together with coexisting splenomegalyand hematological changes, helped to establish the differential diagnosis. Inlymph node biopsies, L. donovani were demonstrated in sixof these patients, either on first examination or on review of the sections. Instill another patient, the only complaint at onset and throughout the wholecourse of the disease was painless progressive enlargement of lymph nodes of theneck.
Other complaints-Othercomplaints at onset, aside from chills and fever, were remarkably few. Inpractically every patient, there was loss of weight, usually evident when firstseen, but only two complained of weakness. Many observers noted that thesepatients usually did not seem acutely ill-"toxic" or"septic"-even after prolonged periods of chills and hightemperature. The skin was warm and dry except following a paroxysm or during theprofuse sweating of defervescence.
No striking changes were found in the heart and the lungs.One patient, admitted with chills and fever, had a history of an unproductivecough for 3 weeks, but physical and roentgenographic examinations of the chestwere negative in all patients except two with intercurrent pneumonia. Bloodpressures were normal, or below normal, in all patients but one. This patienthad hypertension associated with acute nephritis (Case 23). This may or may nothave been related to the onset of kala-azar. The pulse averaged about 80 perminute except during fever, when it ranged from 100 to 120 per minute. Therewere no disturbances in cardiac rhythm or in electrocardiograms made beforetreatment.
In one patient (Case 27), hospitalized because of jaundice,presumably infectious hepatitis, kala-azar was suspected and was later confirmedby the clinical and laboratory findings. This patient had slight icterus of theskin and sclerae. Otherwise, the eyes and fundi were normal in all patients;there were no pigmentary changes in the skin; and no purpura was observed. Inone patient (Case 11), the chief complaint was bleeding from the gums, whichwere spongy, infected, and receded from the teeth.
One patient (Case 23), hospitalized because of edema of thelower extremities, had hypertension, azotemia, and hematuria. A bone marrowexamination performed in an attempt to explain the persistent leukopenia in thiscase of diffuse glomerulonephritis led to the diagnosis of kala-azar.
DIFFERENTIAL DIAGNOSIS
Various acute or chronic infections and neoplastic diseaseswere sometimes suspected in this group of patients. Intermittent fever, spleno-
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megaly, and hematological changes were suggestive, early inthe clinical course, of acute infection and, later, of some primary disease ofthe hematopoietic organs. Frequently, there were intensive studies directedalong these lines and numerous therapeutic trials with antimalarial drugs,sulfonamides, and penicillin. These remedies are of no benefit in kala-azarexcept to control intercurrent infections. The diagnoses most frequently madeare discussed here briefly and in more detail in the article by Most andLavietes (p. 5).
Differentiation from other infections.-Inalmost every case, malaria had been suspected at onset, suggested by the chillsand fever and other findings and by the fact of military service in areasendemic for malaria. Invariably, however, repeated blood smears were negativefor Plasmodia, and antimalarial drugs were ineffective.
Brucellosis had been seriously considered in five patientsfrom the Mediterranean theater and one from India, but blood cultures weresterile and agglutination tests negative for Brucella. In brucellosis,there are usually no double peaks in daily temperature; the white count israrely so depressed and the spleen rarely becomes so huge as in leishmaniasis.
Subacute bacterial endocarditis was suspected in one patientbut was not confirmed. Military tuberculosis was suspected in one patient, aNegro, but was not found in roentgenograms. Dengue was suspected in twopatients. Amebiasis was seriously considered in three cases, but there was noleukocytosis, and specific therapy was ineffective. Fortunately, these patientswere not subjected either to laparotomy or to aspiration.
Typhoid fever or typhus was considered for several weeks infive patients. In one of these, the temperature was very suggestive of typhoidfever during the first 10 days. However, the blood, urine, or stool cultures,and the Widal reaction, characteristic for typhoid fever, are negative inkala-azar.
Pneumonia may complicate leishmaniasis, particularly inpoorly nourished natives. The diagnosis of pneumonia was made early in thecourse of kala-azar in two patients, one of whom in fact had pneumonia, withleukocytosis. It is of interest that intercurrent bacterial infection in thecourse of kala-azar is frequently associated with leukocytosis. Proper treatmentof the intercurrent infection may result in clinical improvement but as a rulethe temperature curve follows the pattern and the white blood count falls to theleukopenic levels of kala-azar.
Infectious hepatitis was suspected in two patients. One mayhave had hepatitis with kala-azar, an unusual combination. One case wassuspected of being histoplasmosis, which may be difficult to differentiateclinically from leishmaniasis since leukopenia, anemia, lymphadenopathy,splenomegaly, and remittent fever occur in both, and the diagnosis ultimatelydepends upon demonstration of Histoplasma capsulatum in smears,cultures, or sections of tissue.
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Nephritis was suspected in two patients, and in one (Case23), there undoubtedly was an acute glomerulonephritis. Although its coexistencewith kala-azar may have been a coincidence, the two may be related, for theassociation has been commented on in the literature.16In Case 23, asnoted, bone marrow examination was done to explain the persistent leukopenia andanemia. Proteinuria is a common occurrence in leishmaniasis.
Of the 30 patients, 9 were transferred to general hospitalsunder the classification F.U.O. (fever of undetermined origin).
Differentiation from diseases of the hematopoietic organs-Inapproximately 50 percent of the cases of kala-azar,Hodgkin's disease, acute aleukemic leukemia, aplastic anemia, and infectiousmononucleosis were seriously considered, and in some, one of these diagnoses wasregarded as tenable for at least 3 months. In kala-azar, the peripheral bloodpicture does in fact resemble aplastic anemia, but the presence of reticulocytesand young white cells indicates continuous regeneration of the blood. Furthercomparison with these several conditions is discussed elsewhere.17
It should be emphasized that progressive, painlessenlargement of lymph nodes without fever, splenomegaly, or blood changes mayoccur in visceral leishmaniasis. This condition has been reported from China andBrazil and more recently in two American soldiers.18 One case was observed inthe present series. The diagnosis is made by finding L. donovani in smears and sections of lymphnodes. Accordingly, this diagnosis should be considered in patients presentingprogressive cervical adenopathy together with a history of residence orsojourn in a region where visceral leishmaniasis is endemic.
Certainly, it should not be inferred that kala-azar is thecorrect diagnosis in all febrile cases associated with such findings asleukopenia, splenomegaly, or lymphadenopathy,but only that the possibility should not be overlooked. In a general hospitalin the United States, splenectomy was performed on an Italian prisoner ofwar more than a year after his arrival in the United States.19 This man hadfever,leukopenia, anemia, hyperglobulinemia, and splenomegaly. The spleen, afteroperation, weighed 1,660 gm. and contained large numbers of L. donovani. Beforeoperation, various hematological, neoplastic, and infectiousdiseases (including kala-azar) were considered. Bone marrow smears examined atthe hospital were negative, but Leishmania were reported in specimenssubmitted to the Army Institute of Pathology (now Armed Forces Instituteof Pathology), Washington, D.C.
16(1) Lee, C. U., and Chung, H.L.: A Clinical Study of the Early Manifestations of Chinese Kalaazar,Chinese M.J. 49: 1281, December 1935. (2) Knowles, R., cited by Strong,Richard P., in Stitt'sDiagnosis, Prevention and Treatment of TropicalDiseases. 7th edition. Philadelphia: The Blakiston Co., 1944, vol. I.
17See footnote 12, p. 5.
18Angevine, D. M., Hamilton, T. R., Wallace, F. G.,and Hazard, J. B.: Lymph Nodes in Leishmaniasis. Am. J.M. Sc. 210: 33, July 1945.
19Sweeney, J. S., Friedlander,R. D., and Queen, F. B.: Kala-azar (Visceral Leishmaniasis) SimulatingSplenic Anemia. J.A.M.A. 128: 1020, 4 Aug. 1945.
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Awareness of this disease should not interfere with studiesdesigned to establish other possible diagnoses but may materially shorten theinterval from clinical onset to correct diagnosis. Early diagnosis isimportant in kala-azar because adequate therapy is dramatically effective and inmost patients results in complete cure.
DIAGNOSIS
The diagnosis of leishmaniasis is suggested by a history ofpossible exposure in endemic areas and by such clinical manifestations as (1)prolonged intermittent fever, frequently with double daily peaks; (2)enlargement of the spleen or lymph nodes or both with, in some cases,enlargement of the liver; (3) leukopenia; (4) anemia; and (5) elevation of serumglobulin. The diagnosis is established by demonstration of L. donovani in smears, sections, cultures (on N.N.N. medium), or by hamster inoculationof material from spleen, liver, bone marrow, lymph nodes, or blood. Thesesources are listed in the order of relative abundance with which the parasitesare said to occur in them.
The results of various diagnostic procedures in the 30 casesare summarized in table 1. The micro-organisms were found in the blood in onlyone case in which the diagnosis was previously unsuspected. In another series of300 proved cases, there were positive smears in only 3, and in a series of 23cases, there were 9 positive smears.20
Sternal marrow aspiration was done in 29 patients of thepresent series. Of 49 punctures, only 21 were positive. The diagnosis wasestablished with one puncture in 14 cases, with a second puncture in 3, and witha third puncture in 4 cases, leaving 8 undiagnosed by this method. The averageage of the disease was the same (10 weeks) in those with negative, and in thosewith positive, bone marrow smears.
In the four sternal punctures in this series that were doneat the Moore General Hospital, Leishmania were demonstrated by smear andculture but in small numbers compared with the numbers seen in splenicpreparations. Bone marrow material may be negative on smear, but positive afterculture on N.N.N. medium. Cultures should not be discarded before 1 month, asgrowth may be slow.
Splenic puncture was performed in 18 cases and gave positiveresults in all. Three positive specimens of splenic material produced theinfection in inoculated hamsters. The age of the disease when diagnosis was madeby this means varied from 2 to 23 weeks (averaging 10 weeks).
Lymph node biopsy was done on seven patients with prominentlymphadenopathy. In three, the initial biopsy report was negative, but in two ofthese, Leishmania were found when the sections were reviewed because of
20Henderson (1936) and Wang (1938), cited by Strong,Richard P., in Stitt's Diagnosis, Preventionand Treatment of Tropical Diseases, 7th edition. Philadelphia: The BlakistonCo., 1944, vol. I, p. 277.
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TABLE 1.-Results ofdiagnostic procedures1 in 30cases of proved kala-azar
additional clinical and laboratory evidence. In four, the diagnosis wasestablished from smears or sections of lymph nodes, making a total of six out ofseven. However, Leishmania may easily be overlooked, unless search forthem is directed by a record of stay in endemic areas.
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Notes on Technique
Puncture of the spleen-As thisproved to be the most reliable procedure in this series and as it is not widelyused in the United States, a general description of the technique of spleenpuncture is presented in the paragraph which is to follow and is described indetail elsewhere.21 The procedure is simple and safe, if donecarefully. It should be performed only when kala-azar is suspected from ahistory of possible exposure, supported by clinical evidence, and only when theedge of the spleen is well below the costal margin. The blood-clotting time andbleeding time should be determined beforehand, and transfusions of whole bloodshould be given if required.
One hour before puncture, 0.1 gm. pentobarbital sodium isgiven by mouth. The patient is placed on an abdominal binder and the site ofpuncture selected. This should be midway between the edge of the spleen and thecostal margin, never immediately below the costal margin or between the ribs.A 1-percent procaine hydrochloride solution is injected so as to produce a whealin the skin about 2 cm. in diameter. The patient is told to breathe deeply inand out 10 times, and a dry sterile needle (17 to 19 gage and 1? inch long) isthen thrust deeply into the spleen. It should be held firmly but not rigidly. Ifa stylet has been used, it is withdrawn, and a sterile, airtight 5 cc.syringe attached. Suction is produced, and a little blood enters the syringe.The plunger is then gently released and the needle withdrawn quickly. A sterilepad is applied for a few minutes with gentle pressure to the site ofinjection, then the abdominal binder is closed. The patient should stay in bedand his pulse and blood pressure should be watched closely for 24 hours.
Smears.-Material from tissue puncture should be spread asthin as possible and allowed to dry. After staining with Giemsa's or Wright'sstain, it should be painstakingly examined under an oil immersion lens, withcare not to confuse blood platelets and Leishman-Donovan bodies that have beenliberated from broken mononuclears.
From blood specimens, both thick and thin smears should bemade. The latter require special attention to the edges and ends of the smearwhere aggregations of white cells may include parasitized mononuclears. Hereagain, platelets and free parasites may be confused.
If lymph nodes are enlarged, one may be aspirated or removed,and smears and thin sections made, also cultures on N.N.N. medium. Sectionsshould be examined under an oil immersion lens, to avoid overlooking parasiteswhich shrink in fixation.
SummaryBone marrow smears and cultures may be diagnostic in 60 to 75percent of cases if suitable specimens (marrow material rather than blood) areobtained and if sufficient care is taken in the search for parasites. Thesemethods failing, splenic puncture remains the most reliable, with due care
21See footnote 12, p. 5.
16
given to the technique of this procedure. Delays indiagnosis were caused not so much by the difficulty in finding themicro-organisms as by the failure to look for them. Of 14 cases reported to TheSurgeon General from India22 during1944 and the first 5 months of 1945, 8 were studied at the 142d General Hospitalin Calcutta. The interval to diagnosis ranged from 12 to 121 days (average 2?months). Following presentation of one or two cases at staff conferences, the"index of suspicion" was raised, and delay in diagnosis was materiallyshortened. Other cases were also reported from the North African and India-Burmatheaters.23
TREATMENT AND RESPONSE
Specific treatment with antimony compounds was instituted assoon as the diagnosis was made. The results of treatment and the relativeefficiency of the drugs used are presented in tables 2 and 3.
The response was frequently dramatic. Fever, which may havebeen hectic for months, in some cases subsided within a few days after the firstdose.
Comparative effectiveness.-Two patients had previously beentreated, without benefit, with the trivalent compound Fuadin (stibophen). Allwere ultimately treated with Neostam (stibamine glucoside), Neostibosan(ethylstibamine), or stibanose (sodium antimony gluconate, 20 mg. antimony percentimeter) in one or more courses of one or more of these pentavalentcompounds. Two failures were re-treated, successfully, with stilbamidine(4, 4'-diamidinostilbene isethionate).
Neostam was slower in bringing down fever (average 22days) than Neostibosan (average 12 days) even when the total dosage was ashigh. The majority of patients reacted to Neostam with toxic symptoms, principallysevere nausea and vomiting, and one patient had shock and convulsions after asingle dose of 0.3 gram.
Stibanose eliminated fever rapidly, and no toxic symptomswere observed in four patients in whom it was used for kala-azar, in fourothers who were given 200 cc. experimentally for schistosomiasis japonica,and in one patient, with Bancroft's filariasis, who was given 400 cc.within 20 days. Two patients, one of whom had failed of cure with Neostibosan,were not, however, cured with stibanose. Stibanose was not found to besuperior to Neostibosan.
Stilbamidine, a potentially dangerous drug, is effectivein treating antimony-resistant strains (from the Sudan) as well as the morereadily susceptible strains (from India, China, and Mediterranean countries).
22Blumgart, Herrman L., and Pike,George M.: In Medical Department, UnitedStates Army. Internal Medicine in World War II. Volume I. Activities ofMedical Consultants. Washington: U.S. Government Printing Office, 1961,p. 796.
23(1) Essential Technical Medical Data, North AfricanTheater of Operations, U.S. Army, for April 1944. (2) Essential TechnicalMedical Data, U.S. Forces, India-Burma Theater, 1 July 1945.
17
TABLE 2.-Results of treatment in 30 cases ofproved kala-azar
In general, Neostibosan proved to be the drug of choice in these cases, regardless of their origin (Indian or Mediterranean), duration before diagnosis, or previous medication. Fever was controlled promptly; hematological recovery was complete. The optimum total dosage appeared to be 4.0 gm. or more, although several patients were cured with less. In 18
18
TABLE 3.-Summary of relative efficiency ofdrugs used in treatment of 30 proved cases of kala-azar
| Patients treated | Number of treatments | Percent treatment cures | Percent patients cured |
Fuadin | 2 | 2 | 0 | 0 |
Neostam | 14 | 15 | 40 | 42 |
Stibanose | 4 | 4 | 50 | 50 |
Neostibosan | 18 | 23 | 74 | 95 |
Stilbamidine | 2 | 2 | 100 | 100 |
patients, one given 0.5 gm. daily for 20 consecutive days, there were notoxic symptoms. In another case (Case 16), however subsequentto a course of 3.9 gm. of Neostibosan, there developed a kidney lesioncharacterized by fixed urinary specific gravity, diminished output of P.S.P.(phenolsulfonphthalein), and constantly elevated BUN. (blood urea nitrogen)without hypertension or proteinuria. These changes persisted for 9months. This is a very uncommon manifestation of antimony toxicity. It may beencountered during or after treatment eitherwith trivalent or pentavalent compounds.
Failures in treatment (p. 22) have been principally the result of the use ofNeostam overseas or in a few hospitals in the United States or to inadequatedosage with Neostibosan.
Neostam was recommended for the treatment of leishmaniasis in 1941.24Previously, the chairman of the Subcommittee on Tropical Medicine of the NationalResearch Council had pointed out that Neostibosan was a superior drug; however,not having been approved by the Food and Drug Administration, Neostibosan was notrecommended until 2 February 1943,25 and itsstandardization was not approveduntil 1 June 1944. As a result, this drug did not become available as a standarditem of medical supply until most of the patients had already been treated withNeostam at least once.
Of these, in the present series, relapse occurred in more than 50 percent,irrespective of the total dosage of Neostam that had been given. In severalpatients, failure or relapse resulted from the use of inadequate amounts ofNeostibosan. Antimony refractoriness was the probable explanation forrepeated relapse in one patient (Case 19) after each of two intensive coursesof Neostibosan (5.0 and 10.0 gm., respectively)and one course of 240 cc. of stibanose. Previous treatment with small amounts ofFuadin, Neostam and Neostibosan had produced only temporary improvement afterthe latter two. Ultimately, cure followed administration of 4.0 gm. ofstilbamidine. The treatment and response to various drugs in this patient isshown in figure 2.
24See footnote 8, p. 4.
25See footnote 9, p. 4.
19
Treatment.-Neostibosan, a light brownish powder containing42 percent antimony, is available in ampules of 0.3 gram. It is dissolved as a5-percent solution in sterile, saline, or distilled water and is administeredintravenously. A total of 5.0 gm. over a period of 17 days is usually given,although in several patients 0.5 gm. daily for 10 days gave excellent results.Liberal fluid intake and diet are encouraged during treatment. No adjuvanttherapy is prescribed. Complications are not an indication for thediscontinuance of the specific therapy, unless there should be evidence of acausal relation, which was not seen in the 30 patients of this series.Penicillin or sulfonamides, or both, may be given to control bacterialinfections
during a course of Neostibosan. In the 30 patients, theanemia of kala-azar responded to Neostibosan therapy, and no patient requiredany blood transfusions.
Stilbamidine, a nonmetallic organic compound, may produceshock, hemolysis, hepatic necrosis, and severe neuritis. It should be used withcaution only after failure with several intensive courses of Neostibosan. Ofthe 30 patients, only 2 were treated with this drug. It is given intravenouslyin at least 200 cc. fluid, beginning with 25 mg. and increasing by 24 mg. dailyuntil 300 mg. are given at one time. The total dose in the patients was 4.0gm., although the usual curative dosage is said to be between 1 and 2 grams.There is some indication that the more severe toxic reactions do not occur ifthe solutions are prepared daily before use.
20
21
Clinical response to Neostibosan treatment-Symptomatic improvement is frequently noted within a few daysafter beginning treatment. Most patients have a normal temperature when abouthalf of the total amount of Neostibosan has been given, although a few may stillhave a low-grade fever 7 to 10 days after completion of treatment. In some, themaximum daily temperature becomes progressively lower each day during treatmentuntil it is normal. In others, chills and high fever continue daily for thefirst 5 to 8 days of treatment, and then the temperature suddenly becomes, andremains, normal. A striking response to treatment is shown in figures 1A and Band 2.
With subsidence of fever and chills, appetite improves. Onepatient gained 30 pounds during the first 5 weeksof treatment, and most patients have regained normal weight in from 3 to 8 weeksafter completion of treatment.
The spleen frequently shrinks very rapidly and, inpractically all the patients, was no longer palpable within 2 months aftercompletion of treatment. In one patient, who hadbeen ill for 6 months before institution of therapy,the spleen, whose edge was in thepelvis at the start of treatment, was barely palpable 1 month thereafter. Typical changes in the size of thespleen and liver after treatment are shown in figure 3.
22
Correction of the accompanying anemia is seen in thefrequently striking reticulocyte response and in the gradual increase in thenumber of leukocytes to normal within, usually, a month.The typical alterations in serum proteins may take 6 months to return to a normal balance. Hematologicaland biochemical changes observed in these cases of kala-azar before, during, andafter treatment are discussed fully in the report by Most and Lavietes andbriefly in this chapter.
Complications.-Whether related to treatment or to otherinfections, complications were infrequent in the patients in this series.Pneumonia developed in one before the diagnosis ofkala-azar was established, and in two others, it occurredduring or shortly after the course of antimony therapy. Another patient, whilebeing treated with Neostibosan, developed an acute exacerbation of a previousotitis media. Penicillin brought these intercurrent infections promptly undercontrol without interruption of the Neostibosan schedule. In another patient, agluteal abscess, which had developed overseas followinginjection of liver extract, was controlled by incision,drainage, and penicillin. Intercurrent infections were associated with aleukocyte count of 13,000 to 20,000 which returned to the previously low levelcharacteristic of kala-azar when the infection was controlled.
No ulcerative stomatitis occurred in this series, possiblybecause of the relatively healthy condition of the mouth of the American patientas compared to the native in whom this complication does occur. Acuteagranulocytosis was not observed. This rare complication has been described26and may be recognized clinically and by leukocyte anddifferential counts. If it occurs during antimony treatment, such treatment issuspended until the complication has been overcome by blood transfusions,penicillin, and crude liver extract. Treatment withantimony is then reinstituted.
Relapse.-Treatment failures, observed in the United Statesand occurring overseas, fall into two categories. In one group, there is seenlittle or no effect on fever, anemia, enlargement of liver and spleen, andleukopenia during treatment or for a month after its completion. Such failuresoccurred with Fuadin and in many cases with Neostam. In the second group offailures, there is a satisfactory response to treatment, but after an intervalof several weeks or months, fever recurs and there is clinical and laboratoryevidence of relapse.
The average interval to relapse was 5.8 weeks (range 4 to 13weeks) after Neostibosan treatment and 5.2 weeks (range 1 to 16 weeks) afterNeostam. In this series, all patients were observed for more than 16 weeks aftercompletion of therapy, the average being 6 months. In most cases, relapse isapparent within 2 months of treatment, but in some it may occur later. Relapseswere suspected in 2 of the 30 cases only after 4 months of continuedobservation. One patient (Case 30) was clinically well at this
26(1) Huang, C. H.: AcuteAgranulocytosis in Kala-azar. Chinese M.J. 57: 119, February 1940. (2) Zia, L.S., and Forkner, C. E.: The Syndrome of Acute Agranulocytosis and Its Occurrenceas a Complication of Kala-azar. Am. J.M. Sc. 188: 5, November 1934.
23
time, but discharge was not advised because leukopeniapersisted. In the next 2 weeks, he lost 10 pounds. The other patient (Case 23)was improved in all respects at 4 months, but weight and strength were stillsubnormal. Sternal puncture done 3 weeks later revealed viable Leishmania. Thesepatients were re-treated, and one of them (Case 23) relapsed again withkala-azar and nephritis, eventually becoming the only fatality reported inAmerican troops.
In this series of cases, splenic punctures were performed inall relapses and were invariably found positive. However, a positive splenicpuncture 1 or 2 months after treatment is, by itself, not proof of failure orrelapse since, in several instances, viable Leishmania were obtained fromthe spleen from 4 to 8 weeks after treatment; these patients were cured withoutany further treatment. Nevertheless, splenic puncture is important in excludingsuspected relapse especially if no Leishmania are found on smear orculture of material from other tissues. Negative results indicate a search for acause other than active kala-azar to explain the symptoms or signs in question,before additional antimony or other therapy is contemplated.
Treatment of relapse-If relapsehas followed treatment with Neostam, or with less than 5.0 gm. of Neostibosan,at least 5.0 gm. of Neostibosan should be administered as has been outlined (p.19). Relapse after 5.0 gm. of Neostibosan can be treated with 10.0 gm. of thesame drug (0.5 gm. daily for 20 days). Relapse after 10.0 gm. should betreated with stilbamidine. In the event of repeated relapse following intensivetherapy with Neostibosan and other pentavalent compounds, or when other drugsare not available, a trial of tartar emetic (potassium or sodium antimonytartrate) may be attempted. A satisfactory dose schedule is as follows: First day, 10 cc. of freshly prepared 0.5 percent solution;third day, 20 cc.; fifth day, 30 cc., and this repeated every other day until atotal of 360 cc. (1.8 gm.) has been given. Toxic manifestations consist of ahacking cough immediately after an injection; severe aching in joints andmuscles, beginning 6 to 12 hours after the injection and lasting for about 12hours; nausea; and electrocardiographic changes (principally inversion of T waves). Severe cough can be minimized or avoided bygiving the 30-cc. doses in two injections of 15 cc. each, with an interval of 1hour between the two. The rate of injection should not be more rapid than 1 cc.per 15 seconds.
Failure following intensive pentavalent and trivalentantimony and stilbamidine treatment of kala-azar is rare. Careful clinical andlaboratory studies are necessary to determine whether some other condition isresponsible for continued illness. A patient with kala-azar unsuccessfullytreated with several intensive courses of pentavalent antimony compounds andstilbamidine was submitted to splenectomy (p. 44). A dramatic clinical andhematological response followed. Splenectomy must, therefore, be considered as alast resort if all other attempts at treatment have failed.
24
BLOOD STUDIES
Serum ProteinsBefore treatment-Data on serum proteinsavailable in 19 cases before specific therapy, and within from 1 to 5 monthsafter onset of symptoms, are presented in table 4.
Briefly, it is seen that a fall in albumin and rise in globulin are regularlymanifested within 2 months of the clinical onset. Hyperglobulinemia becamemarked, but hypoalbuminemia never became severe in this series, although moreextreme values have been reported.27
TABLE 4.-Serum proteins before any specifictherapy in 19 cases of proved kala-azar
Case No. |
| Globulin | Time from onset of symptoms (days) |
10 | 4.1 | 2.1 | 9 |
16 | 2.8 | 5.2 | 152 |
24 | 3.1 | 4.6 | 61 |
28 | 3.9 | 5.1 | 40 |
30 | 3.4 | 4.5 | 54 |
22 | 3.5 | 3.5 | 70 |
18 | 5.7 | 4.0 | 59 |
27 | 3.2 | 4.1 | 18 |
11 | 3.2 | 3.6 | 53 |
23 | 3.0 | 5.8 | 123 |
19 | 3.7 | 4.1 | 134 |
4 | 4.1 | 3.1 | 97 |
9 | 3.5 | 3.9 | 83 |
20 | 3.8 | 3.7 | 77 |
12 | 4.8 | 8.9 | 81 |
1 | 3.2 | 3.8 | 56 |
13 | 4.9 | 3.1 | 39 |
14 | 3.1 | 2.9 | 61 |
6 | 4.8 | 2.7 | 62 |
27(1) Ling, S. M.: Distribution of Protein Fractions In the Serum ofKala-azar Patients. Proc. Soc. Exper. Biol. & Med. 27: 247, January 1930. (2) Chung, H. L.: TheSedimentation Rate of the Blood of Patients With Kala-azar. Chinese M.J. 48: 1101, November 1934.
25
Response to treatment-Data before beginning treatment andat monthly intervals thereafter are presented in table 5. Withfew exceptions, serum albumin rises to exceed 4 percent in 1 to 2 months,usually reaching maximum values 3 months after the start of therapy. Serumglobulin returns to normal more slowly, remaining above normal, in the majorityof cases, even after 5 months. The course of serum proteins, in three cases, inrelation to the onset of symptoms and to therapy is shown in figure 4. Note theslow descent of globulin into the normal range, the reversion of the formol-gelreaction to normal shortly after treatment, and the prolonged persistence ofpositive cephalin flocculations.
26
TABLE 5.-Serum proteins in relation tostart of successful therapy, in leishmaniasis
27
In Case 3, the fall in serum albumin during the first fewdays is not exceptional. In six of eight cases, a fall in albumin of 0.4 percentor more was noted between the second and seventh day of treatment. This isprobably not due to blood dilution, although at this time the hemoglobin anderythrocyte count also usually fall, for the globulin usually increases, andthe leukocytes and platelets may decrease disproportionately. It seemsprobable that these changes are all related to an initial stimulation ofLeishmania.
Phenomena due to hyperglobulinemia-Phenomena dependentlargely upon hyperglobulinemia were studied as used diagnostically,as follows: A flocculation of protein from blood or serum bydilution with water; B flocculation from serum by solutions ofpentavalent antimony compounds, and C opalescent gel formationwhen two drops of 40 percent formalin are mixed with 1 percent of serum(Napier's formol-gel test). Two or more of these tests were run on the sameserum in 14 cases, with agreement between them in 12. In one case, A wasnegative while C was positive; in another, B was negativewhile A and C were positive. The formol-gel test, done 31 times inuntreated cases, was positive 8 times, doubtful twice, and negative 7 times inthe first 3 months after onset of symptoms; positive 12 times, and negative onlytwice, after 3 months.
As the formol-gel test depends primarily uponhyperglobulinemia,28 it is not specific for leishmaniasis. In the 30 patients,the result was usually positive when serum globulin was 4.2 percent or more(fig. 5) but sometimes was negative, usually within a month or two aftercompletion of successful treatment, when serum albumin had increasedconsiderably before serum globulin had fallen markedly. Occasionally, a doubtfulpositive becomes definitely positive during treatment,29 as it did inCases 3 and 19 on the third and fourth days of treatment.
These observations suggested, and in vitro experiments (fig.6) described by Most and Lavietes confirmed the suggestion, that the opalescenceof the formol-gel reaction in the serum of patients with kala-azar is obtainedonly in hyperglobulinemia in the presence of hypoalbuminemia. Opalescent gelsmay be obtained with normal euglobulin in physiologic saline solution. Gelformation is common in serum with elevated globulin content in conditions otherthan kala-azar, but is rarely as opalescent, despite equal reduction inalbumin concentration. This suggests that the globulin in kala-azar yieldsstronger opalescence than that in other conditions with hyperglobulinemia.
The cephalin flocculation and thymol turbidity tests are dependent upon hyperglobulinemia primarily and, the former at least, upon hypoalbuminemia secondarily. Both are strongly positive in active cases. They remain positive for months after successful treatment, even after the globulin con-
28Wise, C. R., and Gutman, A. B.: Formol-Gel Reaction: Convenient Preliminary Test for Hyperglobulinemia. Am. J.M. Sc. 194: 263, August 1937.
29See footnote 16 (1), p. 12.
28
centration has fallen to normal range, suggesting that someof the serum globulin peculiar to leishmaniasis is still present at this time.Test of liver function (p. 39)showed no evidence of damage.
Nature of the hyperglobulinemia-The increase in globulin,as in previously reported cases,30 was chiefly in theeuglobulin fraction. Curves of electrophoretic studies (fig. 7) made in 2 of the30 cases indicate an increase in gamma globulin without abnormal concentrationof alpha or beta globulin.
A cold precipitable serum protein which redissolves readilyon return to room temperature has been described31and was found inapproximately one-third of the active cases. In one, 1.9 gm. of protein per 100cc. came out of solution at 5? centigrade.
The globulin in leishmaniasis serum binds subnormal amountsof calcium. Total serum calcium was in the lower normal range in the presence ofmarked hyperproteinemia, but ultrafilterable calcium was within normal
30See footnote 27, p. 24.
31Wertheimer, E., and Stein, L.: Cold-SusceptibleGlobulin Fraction of Pathologic Sera. J. Lab. & Clin. Med. 29: 1082-1089, October 1944.
29
limits (table 6). Hyperglobulinemia of certain other diseaseshas likewise been shown to possess subnormal base-binding power.32
The globulin peculiar to leishmaniasis is, in summary, asparingly soluble gamma globulin which binds subnormal amounts of calcium (andpresumably of total base as well). It probably arises in an immune reaction or,conceivably, from continuous destruction of parasitized reticuloendothelial cells.
32Gutman, A. B., and Gutman, E. B.: Calcium-Protein Relationin Hyperproteinemia: Total and Diffusible Serum Calcium in LymphogranulomaInguinale and Myeloma. Proc. Soc. Exper. Biol. & Med. 35: 511-515,December 1936.
30
TABLE 6.-Calcium in serum andin ultrafiltrate of serum, in leishmaniasis
| Case No. | Serum albumin | Serum globulin | Serum calcium | Ultrafiltrate | |
| 15 | 3.3 | 7.0 | 9.5 | --- | |
| 11 | --- | --- | 9.2 | --- | |
| 9 | 2.5 | 6.1 | 9.0 | --- | |
| 12 | 4.8 | 8.9 | 10.0 | --- | |
| 19 | 3.6 | 6.4 | 9.7 | 5.4 | |
| 21 | 3.9 | 5.3 | 10.4 | 6.2 | |
| 23 | 3.1 | 6.1 | 9.0 | 5.7 | |
| 28 | 2.5 | 6.4 | 10.3 | 6.3 |
Leukopenia
Leukopenia is an early and striking manifestation ofleishmaniasis. Counts done early in the course of most of these cases areavailable and are summarized in table 7.
31
TABLE 7.-Leukocyte counts in 28 cases of proved kala-azar
Number of cases |
|
| Polymorphonuclear cells, <3,000 | |||
| <6,000 | >7,000 | ||||
11 | <10 | 3 | 7 | 1 | 4 | |
9 | 11-30 | 5 | 4 | --- | 2 | |
8 | >30 | 7 | 1 | --- |
|
|
32
Case No. |
| After treatment1 | ||||||||||||
Time from onset of symptoms (weeks) | Previous treatment | Red blood count (millions) | Hemoglobin (percent) | Color index | White blood count (thousands) | Neutrophils (percent) | Platelets | Red blood count | White blood count | |||||
3 days | 1 week | 1 month | 3 days | 1 week | 1 month | |||||||||
3 | 31 | A (T) | 3.03 | 56 | 0.93 | 1.8 | --- | 160 | 2.73 | 2.69 | 4.30 | 1.65 | 2.50 | 5.50 |
10 | 5 | --- | 3.75 | 68 | .90 | 1.85 | 33 | 119 | 3.56 | 3.63 | 4.28 | 1.35 | 2.05 | 5.10 |
16 | 24 | --- | 3.22 | 54 | .84 | 3.7 | --- | --- | 2.80 | 3.42 | 4.50 | 4.60 | 4.75 | 5.85 |
17 | 27 | A | 3.22 | 62 | .97 | 2.9 | 45 | 184 | --- | 3.86 | --- | --- | 3.15 | 4.65 |
282 | 7 | A | 2.91 | 48 | .83 | 2.05 | 44 | --- | --- | --- | --- | --- | --- | --- |
28 | 13 | T | 3.39 | 61 | .90 | 2.8 | 49 | 169 | 3.01 | 2.87 | 4.09 | 3.00 | 2.55 | 4.45 |
222 | 16 | --- | 2.88 | 55 | .96 | 1.75 | 50 | 82 | --- | --- | --- | --- | --- | --- |
22 | 20 | T | 3.67 | 71 | .97 | 1.8 | 38 | 106 | --- | --- | 3.51 | --- | --- | 6.00 |
21 | 24 | A | 3.30 | 62 | .94 | 2.1 | 36 | 180 | --- | 2.80 | 3.60 | 2.55 | 2.88 | 3.40 |
18 | 15 | A | 3.78 | 68 | .90 | 4.65 | 46 | --- | 4.05 | 4.10 | --- | 3.00 | 7.20 | --- |
11 | 19 | --- | 3.60 | 77 | 1.07 | 2.9 | --- | 69 | --- | 3.69 | 3.90 | 3.40 | 2.75 | 5.75 |
23 | 39 | A | 3.62 | 70 | .97 | 3.25 | --- | --- | 3.74 | 3.64 | 4.36 | 6.85 | 6.0 | --- |
19 | 72 | A | 3.28 | 56 | .86 | 2.60 | --- | --- | 2.90 | 3.02 | 4.14 | 2.20 | 1.95 | 4.60 |
4 | 13 | --- | 3.50 | 71 | 1.01 | 2.1 | 51 | 101 | --- | 4.08 | 4.15 | 3.45 | 4.60 | 5.15 |
9 | 16 | --- | 3.63 | 68 | .94 | 4.8 | 35 | --- | 3.56 | 3.70 | 4.20 | 1.85 | 2.40 | 6.80 |
20 | 33 | A | 3.86 | 65 | .84 | 2.85 | 40 | 165 | --- | --- | 4.07 | --- | 1.80 | 7.10 |
1 | 26 | A | 3.00 | 62 | 1.03 | 2.9 | 34 | 136 | --- | 3.60 | 4.00 | --- | 4.40 | 5.60 |
13 | 31 | --- | 3.50 | 71 | 1.01 | 4.0 | 46 | 148 | 2.70 | --- | 3.90 | 2.50 | --- | 3.50 |
7 | 21 | A | 3.65 | 74 | 1.01 | 4.85 | 63 | 102 | 4.58 | --- | --- | 7.00 | --- | --- |
6 | 24 | A (T) | 3.36 | 65 | .97 | 5.7 | 56 | 148 | 3.35 | 3.3 | --- | 3.90 | 3.40 | --- |
1Data presented, where available,at 3 ?1 days, 7 ?2 days, and 30 ?5 days.
2Data from hospitalization immediately before admission to MooreGeneral Hospital given because in these two cases transfusions were givenshortly before transfer.
NOTE:-A: indicates antimony therapy; T:indicates that transfusions were given in the preceding month.
33
Thus, only 2 of 20 casesobserved in the first month after onset of symptoms failed to develop aleukocyte count of less than 4,000, and 1 of these had a mild persistentgranulopenia. Another patient was noted as having both leukopenia and anemia inthe first month of clinical illness but is not included in the analysis becausethe early data are not available. The speed with which leukopenia may develop isillustrated in figure 8.
The data obtained in active cases before (and after)successful treatment at the Moore General Hospital are shown in table 8. Duringspontaneous remissions of the disease, the blood count reverts to or towardnormal.33 There are no observations during remissions in this series.In two cases, leukocytosis developed with the occurrence of pyogeniccomplications (otitis media and pneumococcic pneumonia).
Anemia
A common early symptom of kala-azar is a lowered erythrocytecount. Observations made soon after the onset of symptoms are presented in table9.
At or near the time of firstobservation, 16 of 26 cases had erythrocyte countsof 4.0 million or less. In 13 of 17 patients with counts done during the firstmonth after the clinical onset, the red cells fell to 4.0 or less.
In this series, anemia never progressed to extreme levels.The median count in 16 patients during the first month of symptoms was 3.7million, range from 2.4 to 4.6. For the 28 cases as a whole, the minimalpretreatment count had a median of 3.2, range from 2.2 to 4.5. Pretreatmentcounts at the Moore General Hospital, recorded in table 8, range from 2.9 to3.9, median 3.4, in close agreement with pretreatment data from otherhospitalizations.
Color indices (Sahli's technique) in the active cases wererarely less than 0.90, and in several exceeded 1.00 (table 10), again in closeagreement
TABLE 9.-Erythrocyte counts in 26 cases of proved kala-azar
Number of cases | Days after onset of symptoms |
| ||
| >4.0 | >2.8 | ||
6 | <10 | --- | 5 | 1 |
11 | 11-30 | --- | 3 | 8 |
9 | >30 | --- | 2 | 7 |
33See footnote 16 (1), p. 12.
34
with hemoglobin determinations made before admission,technique not specified. In these, color indices were usually between 0.90 and1.00, rarely below 0.85 and never below 0.82, with a few between 1.00 and 1.10.As a rule, there was but slight hypochromia in relation to the number oferythrocytes (color index) but more marked hypochromia in relation to cellvolume (mean corpuscular hemoglobin concentration); that is, the red cells wereoften abnormally large and pale, as was readily apparent in some of the smears.
Other findings included reticulocyte counts, beforetreatment, of 0.5 percent or less in six active cases and of 1.0 and 1.4 percentin two active cases. Normal values had been noted elsewhere in three of thesepatients and in one other. The test for erythrocyte fragility to hypotonicsaline made in four active cases gave normal results. The icterus index wasnormal in all active cases upon admission. In early determinations in 15patients, it was within normal range in all except 1 patient who probably hadconcurrent hepatitis, 2 who had single observations of 9 and 11 shortly after transfusions, and 2 with unexplained singleobservations of 9 and 18. In blood smears, normoblasts were not observed;metamyelocytes were present in normal numbers, and no younger forms ofleukocytes were found in the peripheral blood.
TABLE 10.-Hematological observations in seven cases of active kala-azar
Case No. | Previous treatment (antimony) | Time from onset of symptoms (weeks) | Red blood count (millions) | Hemoglobin (percent) | Hematocrit volumes (percent) | Color index | Mean corpuscular volume (cubic microns) | Mean corpuscular hemoglobin concentration (percent) |
10 | 0 | 5 | 3.46 | 68 | 28 | 0.98 | 81 | 35.2 |
28 | + | 19 | 3.03 | 57 | 27 | .94 | 89 | 30.6 |
22 | 0 | 17 | 2.88 | 55 | 27 | .96 | 94 | 29.5 |
11 | + | 22 | 3.67 | 77 | 36 | 1.05 | 98 | 32.1 |
23 | 0 | 32 | 3.62 | 70 | 36 | .97 | 100 | 28.2 |
9 | 0 | 16 | 3.63 | 68 | 33 | .95 | 91 | 29.9 |
16 | 0 | 12 | 2.65 | 54 | 26 | 1.02 | 98 | 30.0 |
NOTE.--0, negative result; +, positiveresult.
These findings indicate that the changes in the bloodobserved in kala-azar are not characterized by excessive blood destruction orby increased blood formation.
Clotting Mechanism
The clotting mechanism was studied during active disease inall but two cases. Bleeding time was 4 minutes or less, with rare exceptions,and never exceeded 5 minutes. Clotting time was usually in the upper normal
35
range, with none definitely abnormal. The quality of the clotwas often poor, and clot retraction was occasionally retarded; none beingapparent at 2 hours in four patients and none at 24 hours in one, in whichbleeding from the gums had occurred in its course (Case 11).
Thrombocytopenia developed early and regularly in the 30patients but never became extreme. Platelet counts made before treatment (table8) were uniformly subnormal, the lowest being in the case with the poorest clotretraction. In Case 23, with nosebleed at the onset of illness, platelets were105,000 only 12 days thereafter; in Cases 11 and 7, they numbered 132,000 and159,000, respectively, 5 and 7 weeks from clinical onset; and in Cases 3 and 22,they were 70,000 and 63,000, respectively, at approximately 20 weeks from onsetof symptoms. The occasional defect in clot retraction was presumably due tothrombocytopenia. That the hyperglobulinemia was not responsible is suggested bythe fact that globulin from patients with kala-azar added to normal serum did notprevent normal clot retraction.
Although total serum calcium was in the lower normal range(table 6), normal values for ultrafilterable calcium showed that an abnormallyhigh portion of total calcium was not bound to protein, as might have beenexpected in view of the hyperglobulinemia.
Fibrinogen, measured in three patients, was normal, as inpreviously reported cases.34 Prothrombin time, determined in fouractive cases, was within normal limits. In one patient (Case 14), who wassuccessfully treated before admission, the prothrombin time was 56 percentbefore treatment, with slow reversion to normal subsequently.
Deficiency in calcium, fibrinogen, or prothrombin cannot havebeen responsible for the bleeding observed in this disease. Thethrombocytopenia, although occurring regularly, was not of the degree seen inpurpura. In previous observations, also, a lack of correlation between bleedingand platelet counts has been noted.35 Only the two patients in thisseries had any abnormal bleeding, the one (Case 11), from his gums early in hisdisease; the other (Case 23), from the nose at the onset of illness and againduring an exacerbation 4 months after treatment with stibanose. During thisrelapse, examination of the anterior nares revealed some areas of hyperemia,superficial ulceration, and crusting. The bleeding of kala-azar may be due, inpart at least, to actual leishmanial lesions of the mucous membranes.
Response of Blood Count to Treatment
Circulating erythrocytes and leukocytes usually decreasedduring the first week of treatment. A progressive rise ensued, which was usuallywell marked within 1 month of beginning treatment. The counts afterapproximately 3 days, 1 week, and 1 month of therapy are presented in table 8.
34See footnote 27 (2), p. 24.
35Scovel, F. G.: Kala-azar: A Review of Its Incidence andEpidemiology in China and Clinical Observations on 585 Cases. Ann. Int. Med. 21: 607, October 1944.
36
Available data on patients treated before admission showed asimilar trend. Red cell count and hemoglobin usually became entirely normal inthe 30 cases only 3 to 4 months after start of treatment. No medication wasgiven for the anemia per se. Platelets were followed through treatment in onlyone patient (Case 28). The pretreatment level was 169,000, with fall to115,000 on the 7th day of treatment and return to 171,000 on the 14th day. Thisis in accord with previous observations.36 Frequent reticulocyte counts duringtreatment in six cases invariably showed a significant rise, in three of themoccurring within 2 days after the first injection. The peak (up to 15 percent)was reached in approximately 2 weeks in most instances (table 11). A typical hematological responseis shown in figure 9, and a composite chart of the leukocyte counts before,during, and after treatment is shown in figure 10. The speed of restoration ofthe leukocyte count to normal is not related to the ultimate outcome, althoughone should suspect therapeutic failure or relapse if leukopenia is prolonged forseveral months after treatment.
36Yang, C. S., and Ch'en, K. T.:Blood Platelets in Kala-azar. Nat. Med. J. China 16: 34-42, February 1930.
37
TABLE 11.Reticulocyte response to specifictreatment in proved cases of kala-azar
Case No. |
| Maximal reticulocyte count | ||
Red blood count (millions) | Reticulocytes | Days from first injection | Level | |
3 | 3.03 | --- | 13 | 15.0 |
191 (a) | --- | --- | 13 | 9.4 |
| (b) | --- | --- | 18 | 3.9 |
| (c) | --- | 1.0 | 27 | 5.3 |
4 | 3.50 | --- | 7 | 4.6 |
21 | 3.3 | --- | 18 | 14.8 |
28 | 3.39 | .5 | 15 | 7.0 |
18 | 3.78 | .5 | 15 | 3.4 |
1Response to 3 different courses of treatment,as follows: Relapse after (a) 10.0 gm. Neostibosan and (b) 240 cc. stibanose and cure after (c) 4.0 gm.stilbamidine.
38
Erythrocyte Sedimentation Rate
Regular increase in sedimentation rate in kala-azar has beendescribed37 and is usually so great that, in blood from untreated cases, thecells settle out to a large degree before clotting occurs. Sedimentation rates,determined by the method of Wintrobe in 19 of 30 cases before specific therapy,are summarized in table 12. It is apparent that the sedimentation rate isusually, but not necessarily, elevated during active disease. The followingcases are illustrative:
Case 11.-This patient had had a sedimentation of 35 mm.before treatment with a small dose of antimony, which produced a briefremission. On admission to Moore General Hospital, 7 weeks later, he was febrileand splenic puncture was positive, yet the sedimentation rate was 2 mm. perhour.
Case 23.-This patient, with marked elevation ofsedimentation rate before treatment, had a rate of 9 mm. per hour 19 weeksafter treatment with stibanose. Because this patient failed to gain weight andstrength, splenic puncture was done and viable Leishmania were recovered.Activity of the disease in this patient could not be predictedby the sedimentation rate.
TABLE 12.-Pretreatmentsedimentation rate (millimeter per hour) in 19 cases of proved kala-azar
Number of cases |
| |||
| 3 weeks | 7 weeks | >8 weeks | |
4 | 25 | 30 | --- | --- |
13 | --- | --- | --- | >normal |
11 | --- | --- | 8 | --- |
12 | --- | --- | --- | 34 |
1Case 7.
2Case 13.
332 weeks after onsetof symptoms but only 1 week after spontaneous remission of 3 weeks.
Other Tests
Agglutination of group 0 erythrocytes in the cold by serum from patientswith kala-azar has been reported.38 Of 5 of the 30 cases tested, 3were negative and 2 were positive in low titer (1:5, 1:4). Complement fixationtests were more often negative than positive in the active cases.
Bone marrow smears were examined in only four active cases. Prior reports inmost instances had noted only the presence or absence of Leishmania. In 7cases, however, in which complete examinations were recorded
37See footnote 27 (2), p. 24.
38See footnote 10 (3), p. 5.
39
and in 4 of the 30 of this series, marrow of averagecellularity and differential count was observed. In this cellular marrow,Leishman-Donovan bodies usually were sparsely scattered.
Nature of the Hematological Disturbance
There is no apparent hemolytic component, since red cellfragility and icterus index are normal. There is no deficiency ofantianemic principle, since the bone marrow is not megaloblastic nor the anemiahyperchromic. Liver extract was used before admission in several of the 30patients, without therapeutic effect. The hematological disturbance is notnutritional in the ordinary sense, since it may develop with extreme rapidity,is associated with marked leukopenia, and is characterized by only minimalhyperchromia.
The peripheral blood picture is that of aplastic anemia, butthe bone marrow is not morphologically aplastic. The anemia and leukopenia havebeen described as myelophthistic, a hypothesis which seems hardly tenable inview of the cellular marrow and relative paucity of Leishman-Donovan bodies. Thepicture in the periphery and in the marrow resembled that described in benzoland other poisoning.39 It seems quite possible that the anemia of kala-azar islikewise toxic either in the sense that a metabolic product of Leishmaniainterferes with cell production or that the metabolic needs of rapidlydividing Leishmania or rapid formation and destruction ofreticuloendothelial cells deprive the marrow of essential nutrients. The earlyappearance of reticulocytes when the temperature falls during antimonytreatment, while viable Leishmania are still present in abundance inspleen and marrow, is compatible with this hypothesis.
LIVER FUNCTION
There is no indication that liver function has sufferedsignificantly in the 30 patients of this series. The icterus index was normal inall of the cases that were active on arrival in Moore General Hospital andin almost all observations made before hospitalization here. Bromsulphalein (sulfobromophthalein)excretion was studied in six active febrile cases,using the 5 mg. per kilogram dose and the 45-minute interval. Dyeretention was only between 2 and 10 percent. The strongly positive cephalinflocculation and thymol turbidity probably were not indicative of liverdamage but were rather a manifestation of the marked hyperglobulinemia.
Icterus index, serum bilirubin, and BSP (Bromsulphalein) excretion were determined during and after treatment withNeostibosan or stilbamidine in several instances, but no evidence of liverdamage was found. The
39Rhoads, C. P., and Miller, D. K.: Histology of the Bone Marrow in Aplastic Anemia. Arch. Path. 26: 648-663, September 1938.
40
icterus index in the patient (Case 27) convalescent fromapparent infectious hepatitis fell from 31 to 20 in 4 days of febrile kala-azarimmediately before treatment with antimony and to 10 during the first 2 weeks oftreatment. On admission to Moore General Hospital, 3 months later, the icterusindex was 4.
RENAL COMPLICATIONS
There were only two patients with clinically important renalcomplications in this series. One, Case 16, an instance of chronic renalinsufficiency following successful treatment of kala-azar with Neostibosan, willbe discussed later (p. 41). The other, Case 23 (p. 46), developed classicalacute glomerulonephritis at approximately the same time as the onset ofkala-azar. At the time of first observation, 2 weeks after the onset ofsymptoms, marked leukopenia was already present in addition to the edema,hypertension, azotemia, albuminuria, and hematuria of acute nephritis. Sinceleukopenia rarely develops in less than 2 weeks from the clinical onset inkala-azar, this disease was probably of at least 2 weeks' duration. That itwas not much longer than this is indicated by the fact that splenomegaly andlymphadenopathy developed 1 week after the initial observation and that serumprotein rose from 6.2 to 6.9 gm. percent in the first 10 days and to 10.4, 2months later. Coincident onset does not, of course, indicate a causalrelationship between the two diseases. In fact, progressive improvement in thenephritis was marked before treatment of the kala-azar, and the subsequentcourse to apparent cure was not inconsistent with the natural history of theordinary severe acute nephritis. The very few cases of acute nephritis thathave been reported in connection with kala-azar may be of an accidentalassociation.
Incidence and course of albuminuria and hematuria in thepatients of this series during the course of kala-azar are summarized asfollows:
Of 25 patients, 16 were observed to have albuminuria duringactive kala-azar, and 12 were known to have microscopic hematuria. Thealbuminuria was usually slight and the hematuria usually mild. In only one casewere many red blood cells reported with urinary findings so prominent that renalfunction tests and intravenous pyelograms were made; both were normal. In mostcases, hematuria was observed on several occasions. Many specimens contained from3 to 10 leukocytes per high-power field without relation to other urinaryfindings and usually without change following treatment. With the exception ofCase 23, none of the patients had hypertension, edema, azotemia, and all wereable to concentrate urine and to excrete phenolsulfonphthalein.
Hematuria, albuminuria, and cylindruria disappeared duringtreatment or within a few days thereafter. Neither albuminuria nor hematuria wasconstantly present during fever. The frequency of hematuria in the
41
patients of this series suggests that the albuminuria ofleishmaniasis is due to focal leishmanial lesions, analogous to focal nephritisin bacteremias, and not to fever. In fatal cases, parasitized macrophages may beseen in the interstitial tissues of the kidneys.40
The other patient (Case 16) developed chronic renalinsufficiency during convalescence from kala-azar, presumably from toxic effectof Neostibosan. Previous data in this case are scant. Urinalysis 12 weeks fromonset of symptoms of kala-azar was normal. Four weeks later, from six to eightred blood cells per high-power field were reported. Five weeks after this, justbefore treatment, urinalysis showed specific gravity of 1.023, no albumin, andno formed elements. Clinical response to treatment with 3.9 gm. of Neostibosanin 23 days was prompt and satisfactory with no untoward reactions noted.Unfortunately, the urine was not examined during treatment or for 10 weeksthereafter. Casual urine specimens then showed low specific gravity, andconcentration tests revealed marked hyposthenuria. Excretion of P.S.P. was only22.5 percent in 15 minutes (normal 25 to 50 percent) and the BUN. was elevatedto 22 mg. percent. The urine contained no albumin or formed elements. There wasno hypertension or edema, and serum albumin was normal. For 9? months after completion of treatment, urine concentrationwas never greater than specific gravity 1.015, P.S.P. excretion ranged between17.5 and 20 percent in 15 minutes, BUN. varied between 21 and 27 mg. percent,and maximal urea clearance was only 38 cc. per minute. The patient remainedasymptomatic, except for slight nocturia, with normal blood pressure and withoutalbumin or formed elements in the urine. In summary, this man had a diffuse,nonprogressive lesion with marked reduction of renal function but without signsof inflammation. This was presumably due to toxicity from antimony, althoughdocumentation is admittedly poor.
In all other cases in this series, urine examinations andrenal function were normal at the end of the observation period. Therapy withthe various pentavalent antimony preparations did not affect normal urines, andthose with initially abnormal findings cleared during treatment. Excretion ofP.S.P. was determined shortly after completion of treatment in many instancesand urea clearance in four instances; all were within normal limits. In onepatient (Case 19), during treatment with stilbamidine, slight albuminuriadeveloped without other abnormality. Three consecutive specimens beforetreatment and repeated specimens after the last day of treatment were allnegative. Routine urinalysis before, during, and after treatment had specificgravity in excess of 1.024. No appreciable change in slight albuminuria presentbefore treatment was observed in the course of treating Case 23 withstilbamidine.
40Strong, Richard P.: Stitt's Diagnosis, Prevention andTreatment of Tropical Diseases. 7th edition. Philadelphia: The Blakiston Co., 1944. vol. I, p. 256.
42
CASE HISTORIES
Five case histories, of unusual interest, are presented inthis section. Three (Case 22, Case 19, and Case 23) are from the series of casesdiscussed in the preceding sections of this chapter. One (Case 5c) is fromanother series, and one (unnumbered) is of a patient who was seen at the WalterReed General Hospital, Washington, D.C.
Case 22.-Prolonged interval to diagnosis; leukemiaconsidered for 2 months; prompt response to 5.0 gm. Neostibosan; no relapse.
This patient, white, 23 years old, a carpenter, hadservedin the Mediterranean theater (north Africa and Italy) from 13 May 1943 to 24March 1945. Onset of illness inDecember 1944 was gradual, with progressive enlargement of the abdomen, withpallor, and, in January, with chills, fever, sweats, and anorexia. Admittedto the 81st Station Hospital, Leghorn, Italy, on 16 February 1945, he had lost38 pounds; the liver and spleen were enlarged four fingers' breadthbelow the costal margin; there was generalized adenopathy; leukopenia (3.3) butno anemia; cephalin flocculation, 4 plus. Presumptive diagnoses were Hodgkin'sdisease, aleukemic leukemia, or kala-azar. Sternal puncture, blood culture,stool examinations, and malaria smears were all negative. An excised axillarylymph node showed nothing specific. Fever, with one or two chills daily, showeda temperature rise as high as 105? F. The liver and spleen continued toenlarge.
He was transferred to the 64th General Hospital, Ardenza,Italy, on 10 March 1945. Symptoms became progressively worse. A second sternalpuncture was reported negative for kala-azar. An inguinal hernia developed.Evacuated to the United States with a transfer diagnosis of aleukemic leukemia,he was a patient at the Foster General Hospital, Jackson, Miss., from 19 April1945 to 10 May 1945. Pallor and emaciation became more severe; the splenomegaly,hepatomegaly, and adenopathy persisted; and anemia was discovered. Total serumproteins were elevated. Sternal puncture and biopsy of an axillary node did notreveal parasites. A splenic puncture was performed, but the slides were lost.Temperature rose daily to 104? F. The patient was transferred to the MooreGeneral Hospital on 10 May 1945.
Physical examination.-Pallor;weight, 132 pounds; * * * generalized adenopathy involving the anterior cervical, the occipital, theepitrochlear, the axillary, and the inguinal glands. In the left axilla, therewas a hard gland of moderate size, freely movable, not tender. The spleen wasnine fingers' breadth below the costal margin and descended further withrespiration; it was tender to touch. The liver was six fingers' breadth belowthe costal margin. The clinical impression was kala-azar.
Admission laboratory findings.-RBC, 3.6 million; Hb. 71percent; WBC, 1.8; serum albumin, 2.5, serum globulin, 4.6 gm. percent; cephalinflocculation test, 4 plus; formolgel test, 4 plus; clotting time (Lee and Whitemethod), 16 minutes; bleeding time, 2.5 minutes; platelets, 106,430.
Hospital course.-Atransfusion of 500 cc. blood wasgiven on 13 May 1945. Splenic puncture on the following day showedLeishman-Donovan bodies. A course of 5.0 gm. Neostibosan was begun on 15May and completed on 2 June 1945. In 10 days, the temperature became normal forthe first time in 5 months. By 18 June 1945, the patient had gained 24 pounds,his spleen was only three fingers' breadth and his liver four fingers'breadth below the costal margin. The erythrocyte count had risen to 4.2 million,Hb. 84 percent, leukocyte count to 5,500. The formol-gel test was negative.Total serum proteins were normal at 7.4, albumin 4.8 and globulin 2.6. Cephalinflocculation was 4 plus.
Returning from a 30-day furlough, the patient reportedfeeling fairly well except for some pain in the left upper quadrant of theabdomen. His spleen was no longer palpable, and all laboratory findings werenormal except for a positive cephalin floccula-
43
tion. Seen again in September, he complained only oftiring easily. He weighed 165 pounds, and neither liver or spleen waspalpable. Bilateral hernias were repaired on 3 October 1945, and the patient wasdischarged as completely well in December 1945. The serum proteins were normal,the red and white blood counts were normal, and the cephalin flocculation testwas negative. Microscopic hematuria and albuminuria, which had been repeatedlyobserved, cleared completely after treatment.
Comment.-The interval to diagnosis from the onset ofsymptoms was at least 4 months. The consensus at several hospitals was that thepatient had leukemia. The correct diagnosis was established by splenic puncture,and complete recovery followed treatment with 5.0 gm. Neostibosan. No relapseoccurred during 6 months' observation following treatment.
Case 19.-Protracted illness; long interval to diagnosis;repeated failure with antimony; cure with stilbamidine (see fig. 2).
The patient, white, 27 years old, a file clerk, served invarious parts of India from 17 May 1942 to 25 August 1944, in contact withnatives and quartered sometimes in barracks and sometimes in tents. Acuteclinical onset, on 16 August 1944, with chills, fever, generalized aching, andheadache. Admitted to the 263d General Hospital, Calcutta, India, on 25 August.One or two temperature elevations with chills daily. Treatment with quinine,Atabrine (quinacrine hydrochloride), sulfonamides, and penicillin had no effect on symptoms.
Physical examination.-Negativeexcept for enlargementof the spleen shown by X-ray.
Laboratory findings.-WBC, on admission 5,200, fellgradually and subsequently remained between 2 and 3 thousand; RBC 2.8, Hb. 60percent. Formol-gel tests negative during the first 4 months of illness. On 29December 1944, serum albumin 2.7, globulin 4.1 gm. percent. Presumptivediagnoses during this time were dengue, malaria, amebiasis, and finallyunexplained fever. On 30 December 1944, smears from sternal marrow were positivefor Leishmania.
Treatment (30 December 1944-20 January 1945), 42.5 cc.Fuadin, with no effect on fever, anemia, and leukopenia; Neostibosan, 2.7 gm. (5February-24 February 1945), with temporary clinical response. Fever absent for1 month; recurred on 29 March 1945. Anemia, leukopenia, and splenomegalypersisted. Neostam, 0.75 gm. (31 March-14 April 1945), with temporary slightlowering of fever; no change in blood picture.
The patient was evacuated to the United States. On admissionto Moore General Hospital on 6 May 1945, he was moderately undernourished; thespleen was palpable eight fingers' breadth below the left costal margin. Inthe axillae and the right epitrochlear region, there were palpable nodes, small(0.5-1.0 cm.), firm, discrete, freely movable, not tender. One or two rises intemperature daily, 104? to 105.6? F. RBC 2.9; Hb. 65 percent; WBC 1.8; serumalbumin 3.0 and globulin 6.6 gm. percent; formol-gel and cephalin flocculationtests positive; platelets 134,000. Spleen puncture on 17 May 1945 positive for Leishmaniaby smear and culture.
Hospital course.-Treatment (17 May-4 June 1945) withNeostibosan 5.0 grams. Temperature normal on 15th day of treatment. Spleenreceded somewhat. RBC 3.2; WBC 3.9. After a 30-day furlough, the patientreturned with a history of chills, fever, loss of weight, and intermittentpain in left upper quadrant of the abdomen. The spleen had enlarged. Splenicpuncture was again positive. Treatment (6 August-16 August 1945) with 240 cc.stibanose, with temperature becoming normal 1 day after completion of treatment;reticulocytosis 9.4 percent; rise of RBC to 3.9 and of WBC to 4.9. The patient,asymptomatic, was again given a 30-day furlough, during which chills and feverrecurred. On readmission, the spleen was found to be still larger; RBC 2.8; WBC
44
2.8; serum globulin 6.6. Spleen puncture on 21 August 1945again positive by smear and culture. Treatment with 10.0 gm. Neostibosan (24October-12 November 1945), with prompt control of fever. Reticulocytosis, 13.9percent, on last day of treatment. Relapse within 1 month, with spleen well intothe pelvis; WBC 2.6; recurrence of fever. Spleen puncture on 10 January 1946again positive.
Treatment (12 January 1946-2 February 1946) withstilbamidine. The dosage, initially 0.025 gm., was increased gradually to dailyinjections of 0.300 gram. Toxic symptoms included mild flushing of the skin,with some formication and burning; local venous irritation with resultantthromboses; moderate exacerbation of daily temperature peaks up to 102? F.; andmoderate malaise with nausea, lasting from 4 to 6 hours after each injection.During the first 16 days of this therapy, all elements of the blood were mildlydepressed; thereafter, all rose progressively. Reticulocytosis 5.3 percent on 7February. Red blood count, hemoglobin, and white blood count rose progressivelyto peaks of 4.74 million, 84 percent, and 7.40, respectively, 22 days aftercessation of treatment. Temperature (3 February) became and remained normal. Thespleen, which enlarged during the early part of treatment, by the 15th dayafter its completion was only three fingers' breadth below the left costalmargin. There was no relapse during observation continued for 5 months.
Comment.-The interval to diagnosis from onset of symptomswas 4 months. This patient had several courses of small amounts of antimonyoverseas. Subsequently, curative amounts of 5 and 10 gm. of Neostibosan and 240cc. of stibanose were ineffective. The strain of Leishmania in thispatient may possibly have developed resistance to antimony. Cure was ultimatelyaccomplished with stilbamidine.
Patient seen at Walter Reed GeneralHospital.-Protracted illness; repeated failures with antimony andstilbamidine; cure with splenectomy.
The clinical record reads substantially as follows:
The patient began his current hospitalization on 27February 1944 with fever, weakness, malaise, headache, and with laboratoryfindings: RBC 1.9 million, Hb. 40 percent, WBC 1500. * * * diagnosis of kala-azar was made 15 April 1944by splenic puncture. * * * specifictreatment between April 1944 and December 1945 consisted of inadequatedosages in three courses of Neostibosan, in one course of Anthiomaline (lithiumantimony thiomalate), in one of Solustibosan, in four of diamidinostilbene, andin one of antimony by iontophoresis, and adequate dosage in two courses ofdiamidinostilbene, and in one of solustibanose.
Discussion as of 1 December 1945:
The problem, whether or not to remove this patient'sspleen, has three aspects: The leishmaniasis, the anemia, and the generaldiscomfort from this tremendously enlarged spleen.
The recent fever, increase in size of spleen on cessationof treatment, leukopenia, reversal of albumin globulin ratio, strongly positivealdehyde test, and the apparent temporary response to diamidinostilbenetherapy all point to continued leishmanial infection despite three negativesplenic punctures and one sternal puncture which appears to be negative so far.Physical examination has not disclosed any extraneous cause of fever and 10blood cultures, both routine and under carbon dioxide, have shown no growth.Chest X-ray is negative. I know of no other disease which could produce thispicture except possibly Hodgkin's and the lymphomas, neither of which havebeen ruled out by gland biopsies as yet. If this patient has continuingleishmanial infection despite his more than adequate treatment, it may well bethat the organisms lying deep in this enormous spleen are not reached byconcentrations of drug adequate to destroy them completely.
45
The anemia is severe and 83transfusions of 500 cc. each have been needed in the past 22 months to maintainhim at a level of 1.5-3.0 million RBC. Of these 83 transfusions 69,representing 39,500 cc. of whole blood, have been given in the past 6 months.Even under such intensive transfusion therapy his RBC rose only to 3.0million and the highest Hb. revealed is 8.1 grams. Other blood studieshave shown reticulocytes of 10 to 25 percent * * *, which would tendto rule out aplastic anemia * * *, andan osmotic fragility which is increased with hemolysis beginning at 0.48percent, whereas control blood began at 0.42 percent. No sickling trait hasbeen found * * *. Theicteric index has varied from 5 to 12 for the past 3 months with one level of 25in July 1945. The serum proteins have been consistently elevated with reversalof A/G [albumin/globulin] ratio, * * *.Lastweek the patient was given 4,000 cc. of compatible group A blood all less than72 hours old but 3 days later the hematocrit was only 24 percent, RBC 2.4and Hb. 6.7 Gm.
All these data point to an anemia of the hemolytic type. Theleishmaniasis * * * providedtwo factors which might contribute to the hemolysis: The first would be theopportunity for pooling of blood in the enlarged spleen; second, the tremendousincrease in the globulin fraction of the serum proteins may well be due atleast in part to the tremendous increase in reticuloendothelial tissue in thespleen. From this point of view I feel splenectomy is advisable * * *.
From the point of view of the patient's present comfort** * there have been many episodes when he complainedof moderately severe pain over this region and a definite rub could beheard. The present distention interferes with his eating and makesmaintenance of body weight difficult.
Realizing that the risk of splenectomy in this patient may beconsiderable, I still feel that with adequate pre- and post-operative transfusionsthe procedure * * * offersthe only chance of cure.
Basis of diagnosis:
1. 14 April 1944. Splenicpuncture showed Leishmaniadonovani in smear.
2. 25 July 1944. Sternal puncture showed inclusion bodies inR. ?E. cellssuggestive of Leishman-Donovan bodies. Culture consistent with Leishmania.
3. 2 October and 24 October 1945. Splenic punctures failedto show Leishmania in smear, culture, or in hamsters.
4. 9 November 1945. Sternal puncture failed to showLeishmaniain smear, culture, or in hamsters.
5. 11 December 1945. Splenectomy.
a. Leishmania donovani found in smear from spleen.
b. Leishmania donovani cultured and growth in hamsterswas demonstrated by culture.
Formol-gel test before splenectomy was repeatedly positive inless than 5 minutes. Thereafter, for 3 weeks, it was positive in less than 1minute, and then at increasing long intervals, until by 13 March 1946 it waspositive only after 5 hours.
Course of red and white blood counts (selected samples):
| RBC | WBC |
18 Aug. 1944 | 2,100,000 | 2,050 |
21 Dec. 1944 | 1,900,000 | 3,050 |
17 May 1945 | 1,890,000 | 3,500 |
19 Oct. 1945 | 1,700,000 | 2,400 |
24 Nov. 1945 | 3,150,000 | 2,800 |
11 Dec. 1945 | Splenectomy |
|
21 Dec. 1945 | 3,150,000 | 9,000 |
23 Feb. 1946 | 3,950,000 | 10,900 |
13 Mar. 1946 | --- | 9,350 |
46
Course of proteins (selected samples): |
| A/G ratio |
16 Aug. 1944 | 11.60 | 1/2.18 |
25 Oct. 1945 | 8.73 | 1/2.28 |
3 Nov. 1945 | 8.4 | 1/1.372 |
11 Dec. 1945 | Splenectomy |
|
12 Jan. 1946 | 8.30 | 1/1.22 |
19 Jan. 1946 | 7.96 | 1/1.08 |
2 Feb. 1946 | 7.7 | 1.08/1 |
13 Mar. 1946 | 8.00 | 1.09/1 |
By 1 April 1946, the patient had steadily continued toimprove. He had gained 40 lbs. since the splenectomy; his proteins had continuedto improve; he was asymptomatic; his RBC and WBC had been improving slowly andhis formol-gel test was less positive. We feel this procedure saved the patient'slife but that it was not necessarily a specific cure for his residualleishmaniasis.
Comment.-This case is most unusual.Repeated courses of treatment with small amounts of antimony and stilbamidinemay have produced resistance of the Leishmania to these drugs. Anunderlying hemolytic disease or abnormal lesion in the spleen may havecontributed to the continued anemia and illness of this patient.
Case 23.-Onset associated with acute nephritis. Diagnosismade incidentally by splenic puncture in attempt to explain the leukopenia in acase of nephritis; death 66 months later, the only fatality in a serviceman withkala-azar (see fig. 6).
The patient, 36 years old, Negro, a Quartermaster ration-dumpworker, with service in north Africa and Italy, had had scarlet fever inchildhood, when he was bedridden for 6 months with a complication of unknownnature. His health was good in service, until he was admitted, on 10 June 1945,to the 8th Evacuation Hospital with a 5-day history of dyspnea, draggingsensation in the abdomen, swelling of the legs, dizziness, and lethargy. He hadhad a productive cough for 1 week and daily nosebleeds for 2 weeks. Onexamination, there was some bleeding from the left nostril; a soft systolicmitral murmur; blood pressure 155/95; moist rales heard at the bases ofboth lungs; and edema of both legs. The urine contained red cells, white cells,and casts.
Improved after 10 days in bed, the patient was evacuated tothe 33d General Hospital, Leghorn, Italy, on 20 June 1945. There he was dyspneicon exertion; blood pressure was 142/92 and 180/108; RBC 3.0 million withproportionate reduction in hemoglobulin; WBC 5,400 to5,000; red cells, white cells, and casts in urine; serum albumin 3.2,globulin 3.7 on 25 June; N.P.N. (nonprotein nitrogen) 54 mg. percent, andurea nitrogen 33.4 percent. Temperature elevations reaching a peak of 102.8?F., began on 1 July. Anemia and a moderate leukopenia developed.
Improved with rest and transfusions, the patient wasevacuated to the United States and admitted to the Fletcher General Hospital,Cambridge, Ohio, on 13 August 1945, with a transfer diagnosis of chronicglomerulonephritis. He was in some distress from a recent tooth extraction. Therewas a large discoid lesion on the shaft of the penis with several satellitesores. The systolic apical murmur persisted; blood pressure was 132/86. Therewas mild generalized adenopathy. There were daily elevations oftemperature, finally reaching 104.6? F., on 23 August 1945. A course ofpenicillin, totaling 2,400,000 units, was begun, and within 24 hours thetemperature fell abruptly and remained normal for 10 days. However, on 12September, a low grade fever reappeared and con-
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tinued throughout the rest of his hospital course. RBC 3.0million; WBC 3.6; N.P.N. 41 mg. percent; serum albumin 3.8; globulin 6.6.
On 25 September 1945, a sternal puncture was done in anattempt to explain the leukopenia (ranging from 3,600 to 5,600) occurring in acase of nephritis, and numerous Leishman-Donovan bodies were found. Repeateddark-field examinations of the penile lesion were negative, and smears disclosedno Leishmania. Sedimentation rate was 65 mm. per hour. Electrocardiogramshowed low voltage of T waves. Roentgenogram of the chest showed pleuralthickening in the right costophrenic angle.
The patient was admitted to the Moore General Hospital fortreatment, on 4 October 1945, with a transfer diagnosis of (1) leishmaniasis,(2) chronic glomerular nephritis, (3) herpes progenitalis.
Physical examination.-Examinationconfirmed previousfindings, including mild narrowing of retinal arteries, slight cardiacenlargement with an apical systolic murmur, generalized enlargement of lymphnodes, about 1.5 cm. in diameter, not tender.
Laboratory findings.-RBC3.61 million; Hb. 71 percent,WBC 4,700. Urine contained a heavy trace of albumin, 5 to 6 WBC, and a specificgravity of 1.018. P.S.P. test: 20.5 percent excretion in 1 hour, formol-gel test4 plus; total protein 8.8 gm., albumin 3.0, globulin 5.8; clotting and bleedingtime within normal limits; platelets 165,000.
Treatment.-In view of thispatient's chronic glomerular nephritis, it was decided to treat his kala-azarwith stibanose. A total of 200 cc. stibanose was given from 22 October to 1November 1945. On the eighth day of treatment, the patient became, and remained,essentially afebrile. There was no apparent aggravation of the nephriticabnormalities. On return from convalescent furlough on 26 January 1946, he hadintermittent irregular low grade fever, and the spleen was still down twofingers' breadth below the left costal margin; BUN 12; RBC 2.7 million; Hb.6.1; WBC 4,350; serum albumin 3.1, globulin 6.1; formol-gel and cephalinflocculation tests 4 plus. He lost 5 pounds during the next month, and sternalpuncture on 1 March 1946 was positive for Leishman-Donovan bodies. Treated with4.0 gm. stilbamidine from 18 March to 7 April, with no untoward effect exceptmild phlebitis and transitory flushing and tingling during injections. WBC rosefrom 3,350 to 6,000 during treatment. Excretion of BSP and P.S.P. both normal atthe end of treatment. He was asymptomatic on return from furlough on 29 April;WBC 5,900; RBC 4.2; Hb. 82 percent; serum albumin 3.9, globulin 4.7. Afteranother furlough, he returned on 23 May with fever, chills, genital lesion,marked inguinal adenopathy; WBC 8,200; Frei test strongly positive. Feversubsided during treatment with sulfathiazole, but red cell count and hemoglobinfell, and serum globulin rose again following this episode. Subsequentconvalescence was uneventful, with apparent cure of the kala-azar and withmarked improvement in the kidney lesion.
Subsequent history and comment.-This is the only known casein which further relapse occurred after the patient wasseparated from military service. He continued to have periodic parasitic andclinical relapses despite all forms of chemotherapy, including trivalent andpentavalent antimony compounds in large amounts, various stilbene derivatives,and splenectomy. Bilateral optic atrophy, nephritis, and severe intractableanemia developed, and the patient died 66 months after the diagnosis of kala-azarwas established. He was hospitalized almost continuously during his entireillness and received all known specific and symptomatic treatment. Autopsydisclosed an overwhelming parasitization of the reticuloendothelial cells in alltissues examined. Apparently, this strain of micro-organism was resistant to theavailable drugs used against this infection. Fortunately,
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this was the only death recorded as the result of kala-azarin American military personnel during or after World War II.
Case 5c.-Onset by lymphadenopathy; noother positive clinical or laboratory findings, Leishmania demonstratedin lymph nodes.
This patient had been in northern Africa for 4 months beforehis arrival in Sicily, in September 1943, where he spent the next 5 monthsbefore coming to England. He had been in excellent health until about 1 January1944, at which time he noted a slight swelling, without tenderness, of theposterior cervical and postauricular lymph nodes. These increased graduallyin size until the largest was plainly visible. There were no other complaints,and he was admitted to a station hospital only for study of the enlarged nodes.There the physical examination revealed essentially normal conditions except forthe enlarged suboccipital, postauricular and posterior cervical lymph nodes. Thelargest of these, in the left posterior cervical chain, measured 1.5 by 2.0centimeters. Roentgenograms of the chest and neck revealed nothing significant.The blood counts were normal, and Kahn, Widal heterophile, and undulant feveragglutination tests were done, with negative results. Typical Leishmaniawere found in sections from a biopsy of a large node stained with Giemsa'sstain.
He was transferred to the Moore General Hospital, on 23 March1944, with a diagnosis ofleishmaniasis. No history could be obtained of chills, fever, night sweats,loss of weight, diarrhea, or slowly healing sores.
Physical examination.-Examinationshowed awell-nourished man of 23, apparently in excellent health. The skin was clear.Small pea-sized lymph nodes were found in the posterior cervical chain and inthe postauricular and suboccipital regions; they were not tender. The epitrochlearnodes were just palpable, and a few small, discrete axillary nodes werepalpable but not tender. The liver descended 2 cm. below the costal margin ondeep inspiration and was slightly tender. The spleen could not be felt. Otherwisethe physical examination was essentially negative.
Laboratory studies.-RBC4,800,000, Hb. 96 percent, WBC5,000, with 68 percent polymorphonuclear leukocytes and no abnormal cells.Total serum proteins were 6.5 gm., albumin 4.8, globulin 1.7. The aldehydetest of Napier was negative. Smears of sternal marrow and material aspiratedfrom lymph nodes were negative, and cultures of these materials on N.N.N.medium showed no leptomonad forms after 21 days' incubation at roomtemperature. A second biopsy of an enlarged cervical node, however, showedtypical Leishmania parasites in smears, microscopic sections, andculture. Despite the patient's apparently excellent health, antimony therapywas started on the basis of the incontestable diagnosis of lymph nodeleishmaniasis. Fifteen daily injections of 6 cc. of solution of sodium antimonygluconate, representing 1,800 mg. antimony, were given. At the completion ofthis series, he was discharged to duty, with instructions to return in onemonth for further evaluation of results.
Comments.-This case is of unusual interest because the onlysymptom or finding was lymphadenopathy. It emphasizes the importance of Leishmaniain the differential diagnosis of adenopathy in patients from endemic areas.
