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Chapter I

Contents

CHAPTER I

Leishmaniasis

Harry Most, M.D.

Part I. Cutaneous Leishmaniasis

Cutaneous leishmaniasis did not constitute an important or a disabling medical problem in World War II, and the effective troop strength in the areas involved was not appreciably altered. An estimated 1,000 to 1,500 cases occurred, and all but the few reported from Latin America,1 North Africa,2 and Panama3 originated in 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 result of special attention to the problem of cutaneous leishmaniasis, that is, by altering dispensary officers to the appearance of the lesion and by establishing a central area for the administration of treatment, 630 cases were reported within the next 3 months. The peak incidence was over by 1 February 1944, and during 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, Quarry Camp, Ahvāz, based on an analysis of 499 cases, detailed information was furnished concerning the clinical aspects of cutaneous leishmaniasis in American military personnel.5 White and Negro enlisted personnel as well as male and female officers were involved.

Incubation Period

The incubation period for the development of cutaneous leishmaniasis, based on human inoculation experiments with cultures or material from

1Report, Medical Statistics Division, Office of The Surgeon General, U.S. Army, 15 Dec. 1945.
2Kranes, A.: Leishmaniasis Among American Troops in the Mediterranean Theater of Operations. (One case of cutaneous leishmaniasis proved by biopsy at the 17th General Hospital.) [Unpublished; official paper.]
3Kean, B. H.: Cutaneous Leishmaniasis on the Isthmus of Panama. 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 Medical Data, 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 rates for cutaneous leishmaniasis in Persian Gulf Command, U.S. Army, 1943-45

proved ulcers, is known to vary from a few weeks to 56 months.6 In the group of 499 cases just mentioned, the disease developed in one patient within 10 days of exposure; in others, presumably infected while in India, it developed within 3 weeks after arrival in Iran. The maximum incubation period for the latter group, which had spent about a month in India and about 10 days en route to Iran, would be approximately 6 weeks. Of interest in regard to the prolonged incubation period in some instances was the development of cutaneous leishmaniasis in military personnel following their return to the United 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 thin crust, becoming slightly dimpled. Ulceration occurred in the center and formed a thick, rough crust or scab which was difficult to remove. The ulcer, from 1 to 1

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 from 4 to 29 in 193 patients. The majority of the lesions occurred on the extremities, 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 the majority of patients. A stained smear of material removed from beneath the crust provided the most valuable diagnostic information. In 387 cases, the first smear was found to contain Leishmania tropica; in 9 cases, 2 smears were necessary; and in 1 case, 3 smears were made before L. tropica could be demonstrated. Fifty-three patients with a clinical diagnosis of cutaneous leishmaniasis had two or three negative smears and were not treated. In 49 of these patients, spontaneous healing occurred in an average time of 7.3 weeks. It was assumed that these patients were in the healing stage when first seen. Treatment was almost entirely carried out in dispensaries, and those affected could perform their usual military functions. No patients were returned to the United States because of this infection, and no patient was given a medical discharge because of it.

TREATMENT

The average age of the lesions when treatment was begun was 9.7 weeks. Sixty-five patients with one to four noninfected lesions were treated with ethyl chloride spray every 5 days. Fifty-seven of these showed no evidence of healing in an average of 3 weeks, and only eight patients were cured in an average of 5.5 weeks. Only small young lesions were amenable to freezing with ethyl chloride, and this form of treatment failed in 87.7 percent of the patients 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 an average of 5.5 weeks, 31.8 percent of these patients failed to respond to the treatment. The interval to cure, after treatment with acid berberine sulfate alone, was 6.8 weeks and was 4.5 weeks after prior failure with ethyl chloride spray.

Neostam (stibamine glucoside) was given intravenously to 221 patients of whom 155 had had no prior therapy. The others had previously been treated without success with ethyl chloride, acid berberine sulfate, Neostam locally, or X-ray. Cure was accomplished in all cases in 2 to 20 weeks (average 14.5). Toxic manifestations of nausea, vomiting, diarrhea, and collapse were encountered in 5 percent of the patients who initially received Neostam in maximum single doses of 0.2 gram. Reduction in maximum doses to 0.15 gm. given at least 5 hours after a meal diminished


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the incidence of toxic symptoms to 0.83 percent in the last 950 injections. The initial dose was 0.5 gm. and subsequent doses, 0.1 and 0.15 gram. Injections of 0.15 gm. were given twice weekly and continued until cure was accomplished. Healing began with as little as 0.7 gm. total dosage of Neostam and was manifested by disappearance of the redness of the lesion, by the development of a copper-colored area around the lesion, and by the formation of new epithelium when the crust fell off. The average amount of Neostam to accomplish cure was 1.14 grams.

Neostam (1-2 cc. of a 2-percent solution) was administered locally at weekly intervals in 35 cases, and in 32, cures resulted in an average of 3.3 weeks, the shortest interval for cure of any group.

Of 10 patients treated locally with roentgen radiation and adequately followed, 9 were cured in an average of 8.3 weeks after the last exposure to X-ray therapy. The initial X-ray dose was 60 R. (roentgen), and three subsequent doses of 75 R. were given at 4-day intervals. One patient failed 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 5 days of therapy, and apparently viable parasites were still found in the tissues 8 days after completion of treatment.7

In summarizing the results of treatment, it appeared that ethyl chloride spray and acid berberine sulfate locally were not highly effective in the treatment of cutaneous leishmaniasis. Neostam locally injected into noninfected lesions cured 90 percent of them in a month. X-ray treatment was effective in selected cases. Neostam, intravenously, was effective in all cases but produced considerable toxicity unless the maximum dose was not greater than 0.15 gram. Neostibosan (ethyistibamine), a less toxic drug than Neostam, which can be given at short intervals (daily) in relatively large amounts is more effective in the treatment of leishmaniasis. Unfortunately, its use was not recommended in 1941,8 and although recommended for use in 1943,9 its designation as a standard item was not approved until 1944.

Complications occurred in 0.7 percent of the patients with proved cutaneous leishmaniasis and consisted of such infections as cellulitis, lymphangitis, and thrombophlebitis. It was observed that 35 percent of these secondary infections occurred in patients who were receiving local injections of acid berberine sulfate. The patients with these complicating infections were hospitalized for periods from 5 to 93 days (average 25). Only one recurrence or reinfection was observed in the group of patients discussed in this chapter. No deforming scars remained after treatment.

7Snow, J. S.: The Unsuccessful Treatment of American Leishmaniasis With Penicillin; Report of Case. Arch. Dermat. & Syph. 50: 324-325, November 1944.
8Circular Letter No. 56, Office of The Surgeon General, War Department, 9 June 1941, subject: Notes on the Treatment and Control of Certain Tropical Diseases.
9Circular Letter No. 33, Office of The Surgeon General, War Department, 2 Feb. 1943, subject: Treatment and Control of Certain Tropical Diseases.


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An interesting observation by local health authorities with regard to control measures of reservoir hosts and the effect of such measures on the rate of infection in the natives in known endemic areas was cited in the report from the 113th General Hospital. In one such area, 60 percent of the gerbils (burrowing rodents related to the mouse, native to Africa and Asia) were found infected. Intensive rodent destruction with chloropicrin resulted in a reduction of the incidence of leishmaniasis in the natives in the area from 70 to 0.4 percent.

Part II. Visceral Leishmaniasis

Visceral leishmaniasis, or kala-azar, was not a serious problem in troops of the United States. In all, an estimated 50 to 75 cases occurred in military personnel from North Africa, Sicily, southern Italy, the Riviera, and India. The individual case, however, often posed a problem in diagnosis to medical officers, owing chiefly to lack of prior experience. In the United States before World War II, cases of kala-azar were rare, with the disease occurring in persons who had resided in India, China, or countries bordering the Mediterranean Sea.10 Many medical officers were unaware of the possibility of encountering kala-azar in American troops stationed in areas where the disease was endemic. This frequently resulted in a long delay in diagnosis and in inadequate or inappropriate treatment.

As many of these patients were hospitalized early, and for long continued periods, for unexplained chills and fever and other symptoms, and as many patients were sent for specialized study to the Zone of Interior, the opportunity was presented to observe the entire course of the disease and its response to treatment. Some studies on individual cases were reported.11 A 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 discussed here, with a few case histories (pp. 42-48). The case numbers used in the Most and 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 Visceral Leishmaniasis (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 been reported as a result of kala-azar. Subsequently, one death occurred 66 months after the diagnosis of kala-azar, complicated by nephritis, had been established (Case 23). As the incubation period, though indeterminate, is frequently long, a small number of cases occurred in the United States; the disease developed in men who had previously served in endemic areas, in some, after separation from military service.13 In a few patients, there was slight residual splenomegaly. Posttreatment cutaneous leishmaniasis did not develop in any of the patients, and only the one (Case 23) who died had suffered relapse after return to civilian life.

In the present series of 30 cases, the average interval from the onset of acute symptoms to definitive diagnosis and specific treatment was 10 weeks, varying from 2 to 23 weeks. In 50 percent of the cases, the disease was active and under observation in a military hospital for 3 months or more before diagnosis was made, and in only five patients was the diagnosis established within a month after onset. In six patients, the disease was continuously active during 4 to 6 months of uninterrupted hospitalization before the correct diagnosis of kala-azar was proved. Most of these men lost a year or more of active duty.

From this experience, it may be hoped that, if troops are again exposed to infection by Leishmania donovani, they will have suitable protection14 against the vector, the sandfly of the genus Phlebotomus, and, if cases do occur, that early diagnosis will be made and appropriate, intensive therapy given promptly.

PRECLINICAL HISTORY

Age and occupation.-Of the 30 patients, 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 enlisted men and 2 officers. One of the officers was attached to an air forces headquarters in India, and the other was an infantry platoon commander, also in India.

Geographic origin of infection.-Of the 30 cases, 15 originated in India and 15 in the Mediterranean theater, with the infected soldiers having spent enough time in North Africa, Sicily, and southern Italy to make more exact localization impossible, with one exception. This patient, stationed near Paris, France, had a 1-week furlough in Nice, 3 weeks before

13A review, in 1951, of records of veterans drawing compensation from the Veterans' Administration and carrying leishmaniasis as a major discharge diagnosis, disclosed no significant disability attributable to kala-azar.-H. M.
14The extensive research program which the Office of The Surgeon General, U.S. Army, instituted in 1941 for improved insecticides and insect repellants led to the discovery of the insecticide DDT and such insect repellants as Indalone (butopyronoxyl), dimethyl phthalate, and Formula No. 612 of Rutgers University. All of these were tested, not only against mosquitoes but also against the Phlebotomus sandfly of kala-azar and the tsetse fly of African sleeping sickness and found quite effective. However, their full-scale production did not become available until the latter part of 1943 and early 1944.-A. L. A.


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the onset of symptoms. It is reasonably certain that his infection was acquired in the vicinity of Nice.

Mode of infection-Several species of Phlebotomus are known to act as vectors in the transmission of leishmaniasis. The 30 patients all said that they had been bitten by mosquitoes and other "insects and bugs," but they were not specifically aware of the sandfly. This is not surprising, since Phlebotomus is only from 1.5 to 2.5 mm. in length, and the local irritation caused by its bite may easily be attributed to the more readily visible arthropods.

Kala-azar occurs mostly in native villages and frequently is a household infection. One patient was one of three officers sharing an apartment in Calcutta, India, in two of whom leishmaniasis developed. Three patients were from the same company quartered at an airbase on the outskirts of Calcutta. Six patients said they had occupied native huts in a village recently vacated. One patient, a truckdriver, slept repeatedly in a stable on the outskirts of a village. Five other truckdrivers traveled at night along the coast of North Africa and often had to sleep in their trucks in towns or villages. In the majority of the 30 patients, there was thus ample opportunity for acquiring infection in or near native villages, but for some of the patients, there was no history obtained of time spent in native huts or villages.

Incubation period.-The incubation period is not definitely known and apparently varies widely, instances being reported in which it was as short as 2 weeks and as long as 18 months. In the patient who became ill 3 weeks after spending a week at Nice, it is fairly certain that the incubation period was 3 weeks, since previously this man had been on duty only in England and Paris. In two of the cases, the incubation period, based on the interval between the last possible exposure in an endemic area and the development of the clinical disease in the United States, was at least 2 months. The longest possible incubation period, as indicated by the interval between arrival in an endemic area and the onset of symptoms, was 33 months. Our attention has been called15 to a soldier who had served in North Africa, Sicily, and Italy. In Italy, in February 1944, he was taken prisoner and sent to Germany where he remained until his liberation and subsequent return to the United States. He was discharged from the Army in August 1945. Symptoms developed insidiously during the next 2 months, and the patient was finally hospitalized in December 1945. The last possible exposure was in Italy, in early February 1944, and the shortest possible incubation period extended from his arrival in Germany until he became ill in the United States, an interval of 19 months. Accordingly, when there are suggestive clinical 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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FIGURE 1.-Types of fever in untreated kala-azar and response to specific therapy. A. Daily intermittent fever before treatment. Note double daily peaks. This type of fever was present in this patient for almost 3 months before treatment. Note prompt control of fever after institution of specific therapy (200 cc. stibanose). No relapse occurred during 6 months' observation. B. Note control of fever in this patient within 6 days after institution of specific treatment (Neostibosan, 5.0 gm.). Before treatment, two rises in temperature (101-105 F.) occurred daily for 4 months. The tertian periodicity that occurred during treatment may also occur in untreated patients and may simulate the form of malaria caused by Plasmodium vivax. C. Period of sustained fever simulating typhoid. Note characteristic double peaks later. D. Spontaneous remission and exacerbation of fever without treatment simulating undulant fever.


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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 of sufficient severity to warrant their seeking medical attention. 

In the acute phase of the disease, the fever was intermittent, with one or two daily temperature rises to 101 to 106 F. The phenomenon of double peaks in daily temperature was observed in 50 percent of the patients (fig. 1A). Although this may be seen in other infections, it occurs so frequently in kala-azar as to suggest this possible diagnosis in cases of prolonged fever. The second rise may occur late at night and may be overlooked unless temperature readings are taken every 2 or 3 hours, day and night, and are charted graphically.

In some patients, the maximum rise occurs at approximately the same time every day. In a few patients, there may be an exact tertian periodicity of chills and fever, recurring on alternate days for several days and weeks, and suggesting the form of malaria caused by Plasmodium vivax (fig. 1B). Occasionally, the temperature, although intermittent, may show very irregular variations in the height as well as in the hour of each maximum rise. Intercurrent infection may alter the temperature curve with periods of sustained high fever, which may be confusing in evaluating response to treatment. A typhoidlike fever early in the disease occurs commonly in China, but this was observed in only one patient whose high fever was sustained for 10 days before it became intermittent (fig. 1C). Recurring febrile waves resembling the temperature pattern in brucellosis have been described in kala-azar, particularly when its course is prolonged (fig. 1D), but this was not a characteristic curve even in patients who were febrile as long as 6 months before diagnosis or treatment. It occurred in four patients; after from 10 to 30 days, it subsided gradually, and a period of from 10 days to 6 weeks elapsed before it recurred. In only one patient was fever entirely absent throughout the observed course of the disease.

Many patients had one or more chills daily, for weeks at a time, and all but three had chills at some time during the disease. The aching in the back and the extremities and the vomiting that frequently occur following a 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 physical finding in most patients. In 27 (90 percent), the spleen was found enlarged on first examination, and in the 3 others, it became enlarged later. The liver was enlarged in 73 percent on first examination or subsequently. No patient had hepatomegaly without splenomegaly, and in all patients, the spleen was enlarged much more than the liver, varying in size from an edge readily palpable just below the costal margin to a gross mass below


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the level of the umbilicus. The edge of the spleen was usually firm and smooth and, often, tender. The spleen often enlarged with remarkable speed. 

Cervical adenopathy-Cervical adenopathy was prominent in seven patients. There was also slight to moderate generalized lymphadenopathy in these patients, which, together with coexisting splenomegaly and hematological changes, helped to establish the differential diagnosis. In lymph node biopsies, L. donovani were demonstrated in six of these patients, either on first examination or on review of the sections. In still another patient, the only complaint at onset and throughout the whole course of the disease was painless progressive enlargement of lymph nodes of the neck.

Other complaints-Other complaints at onset, aside from chills and fever, were remarkably few. In practically every patient, there was loss of weight, usually evident when first seen, but only two complained of weakness. Many observers noted that these patients usually did not seem acutely ill-"toxic" or "septic"-even after prolonged periods of chills and high temperature. The skin was warm and dry except following a paroxysm or during the profuse 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 unproductive cough for 3 weeks, but physical and roentgenographic examinations of the chest were negative in all patients except two with intercurrent pneumonia. Blood pressures were normal, or below normal, in all patients but one. This patient had hypertension associated with acute nephritis (Case 23). This may or may not have been related to the onset of kala-azar. The pulse averaged about 80 per minute except during fever, when it ranged from 100 to 120 per minute. There were no disturbances in cardiac rhythm or in electrocardiograms made before treatment.

In one patient (Case 27), hospitalized because of jaundice, presumably infectious hepatitis, kala-azar was suspected and was later confirmed by the clinical and laboratory findings. This patient had slight icterus of the skin 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. In one patient (Case 11), the chief complaint was bleeding from the gums, which were spongy, infected, and receded from the teeth.

One patient (Case 23), hospitalized because of edema of the lower extremities, had hypertension, azotemia, and hematuria. A bone marrow examination performed in an attempt to explain the persistent leukopenia in this case of diffuse glomerulonephritis led to the diagnosis of kala-azar.

DIFFERENTIAL DIAGNOSIS

Various acute or chronic infections and neoplastic diseases were sometimes suspected in this group of patients. Intermittent fever, spleno-


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megaly, and hematological changes were suggestive, early in the clinical course, of acute infection and, later, of some primary disease of the hematopoietic organs. Frequently, there were intensive studies directed along these lines and numerous therapeutic trials with antimalarial drugs, sulfonamides, and penicillin. These remedies are of no benefit in kala-azar except to control intercurrent infections. The diagnoses most frequently made are discussed here briefly and in more detail in the article by Most and Lavietes (p. 5).

Differentiation from other infections.-In almost every case, malaria had been suspected at onset, suggested by the chills and fever and other findings and by the fact of military service in areas endemic for malaria. Invariably, however, repeated blood smears were negative for Plasmodia, and antimalarial drugs were ineffective.

Brucellosis had been seriously considered in five patients from the Mediterranean theater and one from India, but blood cultures were sterile and agglutination tests negative for Brucella. In brucellosis, there are usually no double peaks in daily temperature; the white count is rarely so depressed and the spleen rarely becomes so huge as in leishmaniasis.

Subacute bacterial endocarditis was suspected in one patient but was not confirmed. Military tuberculosis was suspected in one patient, a Negro, but was not found in roentgenograms. Dengue was suspected in two patients. Amebiasis was seriously considered in three cases, but there was no leukocytosis, and specific therapy was ineffective. Fortunately, these patients were not subjected either to laparotomy or to aspiration.

Typhoid fever or typhus was considered for several weeks in five patients. In one of these, the temperature was very suggestive of typhoid fever during the first 10 days. However, the blood, urine, or stool cultures, and the Widal reaction, characteristic for typhoid fever, are negative in kala-azar.

Pneumonia may complicate leishmaniasis, particularly in poorly nourished natives. The diagnosis of pneumonia was made early in the course of kala-azar in two patients, one of whom in fact had pneumonia, with leukocytosis. It is of interest that intercurrent bacterial infection in the course of kala-azar is frequently associated with leukocytosis. Proper treatment of the intercurrent infection may result in clinical improvement but as a rule the temperature curve follows the pattern and the white blood count falls to the leukopenic levels of kala-azar.

Infectious hepatitis was suspected in two patients. One may have had hepatitis with kala-azar, an unusual combination. One case was suspected of being histoplasmosis, which may be difficult to differentiate clinically from leishmaniasis since leukopenia, anemia, lymphadenopathy, splenomegaly, and remittent fever occur in both, and the diagnosis ultimately depends 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 (Case 23), there undoubtedly was an acute glomerulonephritis. Although its coexistence with kala-azar may have been a coincidence, the two may be related, for the association has been commented on in the literature.16 In Case 23, as noted, bone marrow examination was done to explain the persistent leukopenia and anemia. Proteinuria is a common occurrence in leishmaniasis.

Of the 30 patients, 9 were transferred to general hospitals under the classification F.U.O. (fever of undetermined origin).

Differentiation from diseases of the hematopoietic organs-In approximately 50 percent of the cases of kala-azar, Hodgkin's disease, acute aleukemic leukemia, aplastic anemia, and infectious mononucleosis were seriously considered, and in some, one of these diagnoses was regarded as tenable for at least 3 months. In kala-azar, the peripheral blood picture does in fact resemble aplastic anemia, but the presence of reticulocytes and young white cells indicates continuous regeneration of the blood. Further comparison with these several conditions is discussed elsewhere.17

It should be emphasized that progressive, painless enlargement of lymph nodes without fever, splenomegaly, or blood changes may occur in visceral leishmaniasis. This condition has been reported from China and Brazil and more recently in two American soldiers.18 One case was observed in the present series. The diagnosis is made by finding L. donovani in smears and sections of lymph nodes. Accordingly, this diagnosis should be considered in patients presenting progressive cervical adenopathy together with a history of residence or sojourn in a region where visceral leishmaniasis is endemic.

Certainly, it should not be inferred that kala-azar is the correct diagnosis in all febrile cases associated with such findings as leukopenia, splenomegaly, or lymphadenopathy, but only that the possibility should not be overlooked. In a general hospital in the United States, splenectomy was performed on an Italian prisoner of war more than a year after his arrival in the United States.19 This man had fever, leukopenia, anemia, hyperglobulinemia, and splenomegaly. The spleen, after operation, weighed 1,660 gm. and contained large numbers of L. donovani. Before operation, various hematological, neoplastic, and infectious diseases (including kala-azar) were considered. Bone marrow smears examined at the hospital were negative, but Leishmania were reported in specimens submitted to the Army Institute of Pathology (now Armed Forces Institute of 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's Diagnosis, Prevention and Treatment of Tropical Diseases. 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) Simulating Splenic Anemia. J.A.M.A. 128: 1020, 4 Aug. 1945.


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Awareness of this disease should not interfere with studies designed to establish other possible diagnoses but may materially shorten the interval from clinical onset to correct diagnosis. Early diagnosis is important in kala-azar because adequate therapy is dramatically effective and in most patients results in complete cure.

DIAGNOSIS

The diagnosis of leishmaniasis is suggested by a history of possible 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 serum globulin. The diagnosis is established by demonstration of L. donovani in smears, sections, cultures (on N.N.N. medium), or by hamster inoculation of material from spleen, liver, bone marrow, lymph nodes, or blood. These sources are listed in the order of relative abundance with which the parasites are said to occur in them.

The results of various diagnostic procedures in the 30 cases are summarized in table 1. The micro-organisms were found in the blood in only one case in which the diagnosis was previously unsuspected. In another series of 300 proved cases, there were positive smears in only 3, and in a series of 23 cases, there were 9 positive smears.20

Sternal marrow aspiration was done in 29 patients of the present series. Of 49 punctures, only 21 were positive. The diagnosis was established with one puncture in 14 cases, with a second puncture in 3, and with a third puncture in 4 cases, leaving 8 undiagnosed by this method. The average age of the disease was the same (10 weeks) in those with negative, and in those with positive, bone marrow smears.

In the four sternal punctures in this series that were done at the Moore General Hospital, Leishmania were demonstrated by smear and culture but in small numbers compared with the numbers seen in splenic preparations. Bone marrow material may be negative on smear, but positive after culture on N.N.N. medium. Cultures should not be discarded before 1 month, as growth may be slow.

Splenic puncture was performed in 18 cases and gave positive results in all. Three positive specimens of splenic material produced the infection in inoculated hamsters. The age of the disease when diagnosis was made by this means varied from 2 to 23 weeks (averaging 10 weeks).

Lymph node biopsy was done on seven patients with prominent lymphadenopathy. In three, the initial biopsy report was negative, but in two of these, Leishmania were found when the sections were reviewed because of

20Henderson (1936) and Wang (1938), cited by Strong, Richard P., in Stitt's Diagnosis, Prevention and Treatment of Tropical Diseases, 7th edition. Philadelphia: The Blakiston Co., 1944, vol. I, p. 277.


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TABLE 1.-Results of diagnostic procedures1 in 30 cases of proved kala-azar

additional clinical and laboratory evidence. In four, the diagnosis was established from smears or sections of lymph nodes, making a total of six out of seven. However, Leishmania may easily be overlooked, unless search for them is directed by a record of stay in endemic areas.


15

Notes on Technique

Puncture of the spleen-As this proved to be the most reliable procedure in this series and as it is not widely used in the United States, a general description of the technique of spleen puncture is presented in the paragraph which is to follow and is described in detail elsewhere.21 The procedure is simple and safe, if done carefully. It should be performed only when kala-azar is suspected from a history of possible exposure, supported by clinical evidence, and only when the edge of the spleen is well below the costal margin. The blood-clotting time and bleeding time should be determined beforehand, and transfusions of whole blood should be given if required.

One hour before puncture, 0.1 gm. pentobarbital sodium is given by mouth. The patient is placed on an abdominal binder and the site of puncture selected. This should be midway between the edge of the spleen and the costal margin, never immediately below the costal margin or between the ribs. A 1-percent procaine hydrochloride solution is injected so as to produce a wheal in the skin about 2 cm. in diameter. The patient is told to breathe deeply in and out 10 times, and a dry sterile needle (17 to 19 gage and 1 inch long) is then thrust deeply into the spleen. It should be held firmly but not rigidly. If a 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 sterile pad is applied for a few minutes with gentle pressure to the site of injection, then the abdominal binder is closed. The patient should stay in bed and his pulse and blood pressure should be watched closely for 24 hours.

Smears.-Material from tissue puncture should be spread as thin as possible and allowed to dry. After staining with Giemsa's or Wright's stain, it should be painstakingly examined under an oil immersion lens, with care not to confuse blood platelets and Leishman-Donovan bodies that have been liberated from broken mononuclears.

From blood specimens, both thick and thin smears should be made. The latter require special attention to the edges and ends of the smear where aggregations of white cells may include parasitized mononuclears. Here again, 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. Sections should be examined under an oil immersion lens, to avoid overlooking parasites which shrink in fixation.

Summary

Bone marrow smears and cultures may be diagnostic in 60 to 75 percent of cases if suitable specimens (marrow material rather than blood) are obtained and if sufficient care is taken in the search for parasites. These methods failing, splenic puncture remains the most reliable, with due care

21See footnote 12, p. 5.


16

given to the technique of this procedure. Delays in diagnosis were caused not so much by the difficulty in finding the micro-organisms as by the failure to look for them. Of 14 cases reported to The Surgeon General from India22 during 1944 and the first 5 months of 1945, 8 were studied at the 142d General Hospital in 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 materially shortened. Other cases were also reported from the North African and India-Burma theaters.23

TREATMENT AND RESPONSE

Specific treatment with antimony compounds was instituted as soon as the diagnosis was made. The results of treatment and the relative efficiency of the drugs used are presented in tables 2 and 3.

The response was frequently dramatic. Fever, which may have been hectic for months, in some cases subsided within a few days after the first dose.

Comparative effectiveness.-Two patients had previously been treated, without benefit, with the trivalent compound Fuadin (stibophen). All were ultimately treated with Neostam (stibamine glucoside), Neostibosan (ethylstibamine), or stibanose (sodium antimony gluconate, 20 mg. antimony per centimeter) in one or more courses of one or more of these pentavalent compounds. Two failures were re-treated, successfully, with stilbamidine (4, 4'-diamidinostilbene isethionate).

Neostam was slower in bringing down fever (average 22 days) than Neostibosan (average 12 days) even when the total dosage was as high. The majority of patients reacted to Neostam with toxic symptoms, principally severe nausea and vomiting, and one patient had shock and convulsions after a single dose of 0.3 gram.

Stibanose eliminated fever rapidly, and no toxic symptoms were observed in four patients in whom it was used for kala-azar, in four others 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 be superior to Neostibosan.

Stilbamidine, a potentially dangerous drug, is effective in treating antimony-resistant strains (from the Sudan) as well as the more readily susceptible strains (from India, China, and Mediterranean countries).

22Blumgart, Herrman L., and Pike, George M.: In Medical Department, United States Army. Internal Medicine in World War II. Volume I. Activities of Medical Consultants. Washington: U.S. Government Printing Office, 1961, p. 796.
23(1) Essential Technical Medical Data, North African Theater of Operations, U.S. Army, for April 1944. (2) Essential Technical Medical Data, U.S. Forces, India-Burma Theater, 1 July 1945.


17

TABLE 2.-Results of treatment in 30 cases of proved 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 of drugs used in treatment of 30 proved cases of kala-azar


Drug

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 no toxic symptoms. In another case (Case 16), however subsequent to a course of 3.9 gm. of Neostibosan, there developed a kidney lesion characterized 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 9 months. This is a very uncommon manifestation of antimony toxicity. It may be encountered during or after treatment either with trivalent or pentavalent compounds.

Failures in treatment (p. 22) have been principally the result of the use of Neostam overseas or in a few hospitals in the United States or to inadequate dosage with Neostibosan.

Neostam was recommended for the treatment of leishmaniasis in 1941.24 Previously, the chairman of the Subcommittee on Tropical Medicine of the National Research Council had pointed out that Neostibosan was a superior drug; however, not having been approved by the Food and Drug Administration, Neostibosan was not recommended until 2 February 1943,25 and its standardization was not approved until 1 June 1944. As a result, this drug did not become available as a standard item of medical supply until most of the patients had already been treated with Neostam 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 several patients, failure or relapse resulted from the use of inadequate amounts of Neostibosan. Antimony refractoriness was the probable explanation for repeated relapse in one patient (Case 19) after each of two intensive courses of Neostibosan (5.0 and 10.0 gm., respectively) and one course of 240 cc. of stibanose. Previous treatment with small amounts of Fuadin, Neostam and Neostibosan had produced only temporary improvement after the latter two. Ultimately, cure followed administration of 4.0 gm. of stilbamidine. The treatment and response to various drugs in this patient is shown in figure 2.

24See footnote 8, p. 4.
25See footnote 9, p. 4.


19

Treatment.-Neostibosan, a light brownish powder containing 42 percent antimony, is available in ampules of 0.3 gram. It is dissolved as a 5-percent solution in sterile, saline, or distilled water and is administered intravenously. 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 adjuvant therapy is prescribed. Complications are not an indication for the discontinuance of the specific therapy, unless there should be evidence of a causal relation, which was not seen in the 30 patients of this series. Penicillin or sulfonamides, or both, may be given to control bacterial infections

FIGURE 2.-Response of temperature to four courses of treatment in the same patient (Case 19). Note that fever subsided promptly after each therapeutic course but recurred after each course but the last. This patient had received, before the first course shown in the figure, small noncurative amounts of Fuadin, Neostibosan, and Neostam and, as a result, may have developed an antimony-resistant strain of Leishmania. Relapse occurred even after 10.0 gm. of Neostibosan. Stilbamidine is recommended only after relapse, following adequate amounts of antimony. The necessity of prolonged observation after treatment is apparent from this case.

during a course of Neostibosan. In the 30 patients, the anemia of kala-azar responded to Neostibosan therapy, and no patient required any blood transfusions.

Stilbamidine, a nonmetallic organic compound, may produce shock, hemolysis, hepatic necrosis, and severe neuritis. It should be used with caution only after failure with several intensive courses of Neostibosan. Of the 30 patients, only 2 were treated with this drug. It is given intravenously in at least 200 cc. fluid, beginning with 25 mg. and increasing by 24 mg. daily until 300 mg. are given at one time. The total dose in the patients was 4.0 gm., 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 if the solutions are prepared daily before use.


20

FIGURE 3.-Enlargement of liver and spleen in patients with kala-azar, and response to treatment. Note marked diminution in size of liver and spleen within a month after completion of treatment. Note also improved nutritional state.


21

FIGURE 3.-Continued.

Clinical response to Neostibosan treatment-Symptomatic improvement is frequently noted within a few days after beginning treatment. Most patients have a normal temperature when about half of the total amount of Neostibosan has been given, although a few may still have a low-grade fever 7 to 10 days after completion of treatment. In some, the maximum daily temperature becomes progressively lower each day during treatment until it is normal. In others, chills and high fever continue daily for the first 5 to 8 days of treatment, and then the temperature suddenly becomes, and remains, normal. A striking response to treatment is shown in figures 1A and B and 2.

With subsidence of fever and chills, appetite improves. One patient gained 30 pounds during the first 5 weeks of treatment, and most patients have regained normal weight in from 3 to 8 weeks after completion of treatment.

The spleen frequently shrinks very rapidly and, in practically all the patients, was no longer palpable within 2 months after completion of treatment. In one patient, who had been ill for 6 months before institution of therapy, the spleen, whose edge was in the pelvis at the start of treatment, was barely palpable 1 month thereafter. Typical changes in the size of the spleen and liver after treatment are shown in figure 3.


22

Correction of the accompanying anemia is seen in the frequently striking reticulocyte response and in the gradual increase in the number of leukocytes to normal within, usually, a month. The typical alterations in serum proteins may take 6 months to return to a normal balance. Hematological and biochemical changes observed in these cases of kala-azar before, during, and after treatment are discussed fully in the report by Most and Lavietes and briefly in this chapter.

Complications.-Whether related to treatment or to other infections, complications were infrequent in the patients in this series. Pneumonia developed in one before the diagnosis of kala-azar was established, and in two others, it occurred during or shortly after the course of antimony therapy. Another patient, while being treated with Neostibosan, developed an acute exacerbation of a previous otitis media. Penicillin brought these intercurrent infections promptly under control without interruption of the Neostibosan schedule. In another patient, a gluteal abscess, which had developed overseas following injection of liver extract, was controlled by incision, drainage, and penicillin. Intercurrent infections were associated with a leukocyte count of 13,000 to 20,000 which returned to the previously low level characteristic of kala-azar when the infection was controlled.

No ulcerative stomatitis occurred in this series, possibly because of the relatively healthy condition of the mouth of the American patient as compared to the native in whom this complication does occur. Acute agranulocytosis was not observed. This rare complication has been described26 and may be recognized clinically and by leukocyte and differential counts. If it occurs during antimony treatment, such treatment is suspended until the complication has been overcome by blood transfusions, penicillin, and crude liver extract. Treatment with antimony is then reinstituted.

Relapse.-Treatment failures, observed in the United States and occurring overseas, fall into two categories. In one group, there is seen little or no effect on fever, anemia, enlargement of liver and spleen, and leukopenia during treatment or for a month after its completion. Such failures occurred with Fuadin and in many cases with Neostam. In the second group of failures, there is a satisfactory response to treatment, but after an interval of several weeks or months, fever recurs and there is clinical and laboratory evidence of relapse.

The average interval to relapse was 5.8 weeks (range 4 to 13 weeks) after Neostibosan treatment and 5.2 weeks (range 1 to 16 weeks) after Neostam. In this series, all patients were observed for more than 16 weeks after completion of therapy, the average being 6 months. In most cases, relapse is apparent within 2 months of treatment, but in some it may occur later. Relapses were suspected in 2 of the 30 cases only after 4 months of continued observation. One patient (Case 30) was clinically well at this

26(1) Huang, C. H.: Acute Agranulocytosis 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 Occurrence as a Complication of Kala-azar. Am. J.M. Sc. 188: 5, November 1934.


23

time, but discharge was not advised because leukopenia persisted. 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 still subnormal. Sternal puncture done 3 weeks later revealed viable Leishmania. These patients were re-treated, and one of them (Case 23) relapsed again with kala-azar and nephritis, eventually becoming the only fatality reported in American troops.

In this series of cases, splenic punctures were performed in all relapses and were invariably found positive. However, a positive splenic puncture 1 or 2 months after treatment is, by itself, not proof of failure or relapse since, in several instances, viable Leishmania were obtained from the spleen from 4 to 8 weeks after treatment; these patients were cured without any further treatment. Nevertheless, splenic puncture is important in excluding suspected relapse especially if no Leishmania are found on smear or culture of material from other tissues. Negative results indicate a search for a cause 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 relapse has 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 the same drug (0.5 gm. daily for 20 days). Relapse after 10.0 gm. should be treated with stilbamidine. In the event of repeated relapse following intensive therapy with Neostibosan and other pentavalent compounds, or when other drugs are not available, a trial of tartar emetic (potassium or sodium antimony tartrate) 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 a total of 360 cc. (1.8 gm.) has been given. Toxic manifestations consist of a hacking cough immediately after an injection; severe aching in joints and muscles, beginning 6 to 12 hours after the injection and lasting for about 12 hours; nausea; and electrocardiographic changes (principally inversion of T waves). Severe cough can be minimized or avoided by giving the 30-cc. doses in two injections of 15 cc. each, with an interval of 1 hour between the two. The rate of injection should not be more rapid than 1 cc. per 15 seconds.

Failure following intensive pentavalent and trivalent antimony and stilbamidine treatment of kala-azar is rare. Careful clinical and laboratory studies are necessary to determine whether some other condition is responsible for continued illness. A patient with kala-azar unsuccessfully treated with several intensive courses of pentavalent antimony compounds and stilbamidine was submitted to splenectomy (p. 44). A dramatic clinical and hematological response followed. Splenectomy must, therefore, be considered as a last resort if all other attempts at treatment have failed.


24

BLOOD STUDIES

Serum Proteins

Before treatment-Data on serum proteins available in 19 cases before specific therapy, and within from 1 to 5 months after onset of symptoms, are presented in table 4.

Briefly, it is seen that a fall in albumin and rise in globulin are regularly manifested within 2 months of the clinical onset. Hyperglobulinemia became marked, but hypoalbuminemia never became severe in this series, although more extreme values have been reported.27

TABLE 4.-Serum proteins before any specific therapy in 19 cases of proved kala-azar

Case No.


Albumin 
(gm. percent)

Globulin
(gm. percent) 

Time from onset of symptoms (days)

10

4.1
4.2
3.8

2.1
2.2
2.0

9
27
37

16

2.8
3.1

5.2
6.2

152
168

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
2.7
2.9

3.9
3.9
4.2

83
115
117

20

3.8

3.7

77

12

4.8

8.9

81

1

3.2

3.8

56

13

4.9
4.5
4.0

3.1
3.5
5.9

39
186
223

14

3.1

2.9

61

6

4.8
3.4

2.7
6.8

62
120


27(1) Ling, S. M.: Distribution of Protein Fractions In the Serum of Kala-azar Patients. Proc. Soc. Exper. Biol. & Med. 27: 247, January 1930. (2) Chung, H. L.: The Sedimentation Rate of the Blood of Patients With Kala-azar. Chinese M.J. 48: 1101, November 1934.


25

FIGURE 4.-Course of serum proteins, with results of formol-gel test and cephalin flocculation before, during, and after specific antimony treatment in individual cases. Note slow fall of globulin, persistence of positive results in cephalin flocculation test, and more prompt reversion of serum albumin and formol-gel to normal.

Response to treatment-Data before beginning treatment and at monthly intervals thereafter are presented in table 5. With few exceptions, serum albumin rises to exceed 4 percent in 1 to 2 months, usually reaching maximum values 3 months after the start of therapy. Serum globulin returns to normal more slowly, remaining above normal, in the majority of cases, even after 5 months. The course of serum proteins, in three cases, in relation to the onset of symptoms and to therapy is shown in figure 4. Note the slow descent of globulin into the normal range, the reversion of the formol-gel reaction to normal shortly after treatment, and the prolonged persistence of positive cephalin flocculations.


26

TABLE 5.-Serum proteins in relation to start of successful therapy, in leishmaniasis


27

In Case 3, the fall in serum albumin during the first few days is not exceptional. In six of eight cases, a fall in albumin of 0.4 percent or more was noted between the second and seventh day of treatment. This is probably not due to blood dilution, although at this time the hemoglobin and erythrocyte count also usually fall, for the globulin usually increases, and the leukocytes and platelets may decrease disproportionately. It seems probable that these changes are all related to an initial stimulation ofLeishmania.

Phenomena due to hyperglobulinemia-Phenomena dependent largely upon hyperglobulinemia were studied as used diagnostically, as follows: A flocculation of protein from blood or serum by dilution with water; B flocculation from serum by solutions of pentavalent antimony compounds, and C opalescent gel formation when 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 same serum in 14 cases, with agreement between them in 12. In one case, A was negative while C was positive; in another, B was negative while A and C were positive. The formol-gel test, done 31 times in untreated cases, was positive 8 times, doubtful twice, and negative 7 times in the first 3 months after onset of symptoms; positive 12 times, and negative only twice, after 3 months.

As the formol-gel test depends primarily upon hyperglobulinemia,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 after completion of successful treatment, when serum albumin had increased considerably before serum globulin had fallen markedly. Occasionally, a doubtful positive becomes definitely positive during treatment,29 as it did in Cases 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 opalescence of the formol-gel reaction in the serum of patients with kala-azar is obtained only in hyperglobulinemia in the presence of hypoalbuminemia. Opalescent gels may be obtained with normal euglobulin in physiologic saline solution. Gel formation is common in serum with elevated globulin content in conditions other than kala-azar, but is rarely as opalescent, despite equal reduction in albumin concentration. This suggests that the globulin in kala-azar yields stronger 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

FIGURE 5.-Correlation of serum globulin and result of formol-gel test. Note that, when the serum globulin is 4.2 gm. percent or above, the formol-gel test is positive in most instances. Note also that the serum globulin may be elevated for as long as 6 months after completion of successful treatment although the formol-gel test becomes negative within a month after treatment.

centration has fallen to normal range, suggesting that some of 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 the euglobulin fraction. Curves of electrophoretic studies (fig. 7) made in 2 of the 30 cases indicate an increase in gamma globulin without abnormal concentration of alpha or beta globulin.

A cold precipitable serum protein which redissolves readily on return to room temperature has been described31 and was found in approximately one-third of the active cases. In one, 1.9 gm. of protein per 100 cc. came out of solution at 5 centigrade.

The globulin in leishmaniasis serum binds subnormal amounts of calcium. Total serum calcium was in the lower normal range in the presence of marked hyperproteinemia, but ultrafilterable calcium was within normal

30See footnote 27, p. 24.
31Wertheimer, E., and Stein, L.: Cold-Susceptible Globulin Fraction of Pathologic Sera. J. Lab. & Clin. Med. 29: 1082-1089, October 1944.


29

limits (table 6). Hyperglobulinemia of certain other diseases has likewise been shown to possess subnormal base-binding power.32

The globulin peculiar to leishmaniasis is, in summary, a sparingly soluble gamma globulin which binds subnormal amounts of calcium (and presumably of total base as well). It probably arises in an immune reaction or, conceivably, from continuous destruction of parasitized reticuloendothelial cells.

FIGURE 6.-Effect of albumin on the formol-gel reaction. Serum from Case 23 was diluted I (20 percent), II (30 percent), III (40 percent), IV (50 percent), and V (60 percent) with A (17 percent solution of normal human albumin in physiologic saline solution), B (normal serum), and C (physiologic saline solution). One-half cc. portions of the diluted serum were mixed with 1 drop of commercial formalin in 8-mm. tubes. Photographs were made with the samples lying on a black background after 24 hours. Note marked diminution of opalescence in I-A, its almost complete disappearance in II-A, and loss of gelation as well in IV-A. This is in striking contrast to the gelation and intense opalescence after even greater dilution with physiologic saline in V-C. The dilution with normal serum gives intermediate results.

32Gutman, A. B., and Gutman, E. B.: Calcium-Protein Relation in Hyperproteinemia: Total and Diffusible Serum Calcium in Lymphogranuloma Inguinale and Myeloma. Proc. Soc. Exper. Biol. & Med. 35: 511-515, December 1936.


30

TABLE 6.-Calcium in serum and in ultrafiltrate of serum, in leishmaniasis

Case No.

Serum albumin
(gm. percent)

Serum globulin 
(gm. percent)
-

Serum calcium
(mg. percent)

Ultrafiltrate
calcium
(mg. percent)

 

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


FIGURE 7.-Electrophoretic pattern of sera from two cases of active kala-azar. In both instances, gamma globulin makes up more than half of the total protein and albumin, little over one-fourth of the total. (A, albumin; γ, gamma globulin; , beta globulin; a, alpha globulin (1 and 2)). There is no significant change during or immediately after completion of treatment in Case 21 (200 cc. stibanose during 10 days). (These studies were made by Mrs. M. Costello and Dr. Dan Moore, Department of Anatomy, College of Physicians and Surgeons, Columbia University, New York, N.Y.)

Leukopenia

Leukopenia is an early and striking manifestation of leishmaniasis. Counts done early in the course of most of these cases are available and are summarized in table 7.


31

FIGURE 8.-Early changes in the red and white blood counts in active kala-azar. Note rapid development of anemia and leukopenia in patients under observation shortly after onset of symptoms.

TABLE 7.-Leukocyte counts in 28 cases of proved kala-azar

Number of cases


Days after onset of symptoms


Number of patients with leukocyte counts of-

Polymorphonuclear cells, <3,000


<4,000

<6,000

>7,000

11

<10
<30

3
9

7
2

1
---

4

9

11-30
30+

5
9

4
---

---

2

8

>30
>44

7
8

1
---

---
---

 

 


32

TABLE 8.-Blood counts before and after successful treatment of leishmaniasis in Moore General Hospital

Case No.


Before treatment

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
(thousands)

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 Moore General Hospital given because in these two cases transfusions were given shortly before transfer.

NOTE:-A: indicates antimony therapy; T: indicates that transfusions were given in the preceding month.


33

Thus, only 2 of 20 cases observed in the first month after onset of symptoms failed to develop a leukocyte count of less than 4,000, and 1 of these had a mild persistent granulopenia. Another patient was noted as having both leukopenia and anemia in the first month of clinical illness but is not included in the analysis because the early data are not available. The speed with which leukopenia may develop is illustrated in figure 8.

The data obtained in active cases before (and after) successful treatment at the Moore General Hospital are shown in table 8. During spontaneous remissions of the disease, the blood count reverts to or toward normal.33 There are no observations during remissions in this series. In two cases, leukocytosis developed with the occurrence of pyogenic complications (otitis media and pneumococcic pneumonia).

Anemia

A common early symptom of kala-azar is a lowered erythrocyte count. Observations made soon after the onset of symptoms are presented in table 9.

At or near the time of first observation, 16 of 26 cases had erythrocyte counts of 4.0 million or less. In 13 of 17 patients with counts done during the first month 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 3.7 million, range from 2.4 to 4.6. For the 28 cases as a whole, the minimal pretreatment count had a median of 3.2, range from 2.2 to 4.5. Pretreatment counts at the Moore General Hospital, recorded in table 8, range from 2.9 to 3.9, median 3.4, in close agreement with pretreatment data from other hospitalizations.

Color indices (Sahli's technique) in the active cases were rarely less than 0.90, and in several exceeded 1.00 (table 10), again in close agreement

TABLE 9.-Erythrocyte counts in 26 cases of proved kala-azar

Number of cases

Days after onset of symptoms


Number of patients with erythrocytes

 


>4.8
(millions)

>4.0
(millions)

>2.8
(millions)

6

<10
<30

---
---

5
2

1
4

11

11-30
30

---
---

3
2

8
9

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 and 1.00, 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 of erythrocytes (color index) but more marked hypochromia in relation to cell volume (mean corpuscular hemoglobin concentration); that is, the red cells were often abnormally large and pale, as was readily apparent in some of the smears.

Other findings included reticulocyte counts, before treatment, of 0.5 percent or less in six active cases and of 1.0 and 1.4 percent in two active cases. Normal values had been noted elsewhere in three of these patients and in one other. The test for erythrocyte fragility to hypotonic saline made in four active cases gave normal results. The icterus index was normal in all active cases upon admission. In early determinations in 15 patients, it was within normal range in all except 1 patient who probably had concurrent hepatitis, 2 who had single observations of 9 and 11 shortly after transfusions, and 2 with unexplained single observations of 9 and 18. In blood smears, normoblasts were not observed; metamyelocytes were present in normal numbers, and no younger forms of leukocytes 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; +, positive result.

These findings indicate that the changes in the blood observed in kala-azar are not characterized by excessive blood destruction or by increased blood formation.

Clotting Mechanism

The clotting mechanism was studied during active disease in all 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 clot was often poor, and clot retraction was occasionally retarded; none being apparent at 2 hours in four patients and none at 24 hours in one, in which bleeding from the gums had occurred in its course (Case 11).

Thrombocytopenia developed early and regularly in the 30 patients but never became extreme. Platelet counts made before treatment (table 8) were uniformly subnormal, the lowest being in the case with the poorest clot retraction. In Case 23, with nosebleed at the onset of illness, platelets were 105,000 only 12 days thereafter; in Cases 11 and 7, they numbered 132,000 and 159,000, 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 onset of symptoms. The occasional defect in clot retraction was presumably due to thrombocytopenia. That the hyperglobulinemia was not responsible is suggested by the fact that globulin from patients with kala-azar added to normal serum did not prevent normal clot retraction.

Although total serum calcium was in the lower normal range (table 6), normal values for ultrafilterable calcium showed that an abnormally high portion of total calcium was not bound to protein, as might have been expected in view of the hyperglobulinemia.

Fibrinogen, measured in three patients, was normal, as in previously reported cases.34 Prothrombin time, determined in four active cases, was within normal limits. In one patient (Case 14), who was successfully treated before admission, the prothrombin time was 56 percent before treatment, with slow reversion to normal subsequently.

Deficiency in calcium, fibrinogen, or prothrombin cannot have been responsible for the bleeding observed in this disease. The thrombocytopenia, although occurring regularly, was not of the degree seen in purpura. In previous observations, also, a lack of correlation between bleeding and platelet counts has been noted.35 Only the two patients in this series had any abnormal bleeding, the one (Case 11), from his gums early in his disease; the other (Case 23), from the nose at the onset of illness and again during an exacerbation 4 months after treatment with stibanose. During this relapse, examination of the anterior nares revealed some areas of hyperemia, superficial ulceration, and crusting. The bleeding of kala-azar may be due, in part at least, to actual leishmanial lesions of the mucous membranes.

Response of Blood Count to Treatment

Circulating erythrocytes and leukocytes usually decreased during the first week of treatment. A progressive rise ensued, which was usually well marked within 1 month of beginning treatment. The counts after approximately 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 and Epidemiology in China and Clinical Observations on 585 Cases. Ann. Int. Med. 21: 607, October 1944.


36

FIGURE 9.-Hematological response to treatment. Note reticulocyte rise and reversion of red blood cells, white blood cells, and hemoglobin toward normal.

Available data on patients treated before admission showed a similar trend. Red cell count and hemoglobin usually became entirely normal in the 30 cases only 3 to 4 months after start of treatment. No medication was given for the anemia per se. Platelets were followed through treatment in only one patient (Case 28). The pretreatment level was 169,000, with fall to 115,000 on the 7th day of treatment and return to 171,000 on the 14th day. This is in accord with previous observations.36 Frequent reticulocyte counts during treatment in six cases invariably showed a significant rise, in three of them occurring 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 response is 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 of the leukocyte count to normal is not related to the ultimate outcome, although one should suspect therapeutic failure or relapse if leukopenia is prolonged for several 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

FIGURE 10.-White blood counts before and after treatment. Composite chart of all white blood counts in 25 cases. Note the marked and maintained leukopenia before treatment and the response after therapy.

TABLE 11.Reticulocyte response to specific treatment in proved cases of kala-azar

Case No.


Before treatment

Maximal reticulocyte count

Red blood count (millions)

Reticulocytes 
(percent)

Days from first injection

Level 
(percent)

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 been described37 and is usually so great that, in blood from untreated cases, the cells 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 is usually, but not necessarily, elevated during active disease. The following cases are illustrative:

Case 11.-This patient had had a sedimentation of 35 mm. before treatment with a small dose of antimony, which produced a brief remission. On admission to Moore General Hospital, 7 weeks later, he was febrile and splenic puncture was positive, yet the sedimentation rate was 2 mm. per hour.

Case 23.-This patient, with marked elevation of sedimentation rate before treatment, had a rate of 9 mm. per hour 19 weeks after treatment with stibanose. Because this patient failed to gain weight and strength, splenic puncture was done and viable Leishmania were recovered. Activity of the disease in this patient could not be predicted by the sedimentation rate.

TABLE 12.-Pretreatment sedimentation rate (millimeter per hour) in 19 cases of proved kala-azar

Number of cases


Pretreatment sedimentation rate (mm. per hour) after onset of symptoms


2 weeks

3 weeks

7 weeks

>8 weeks

4

25
---
---
---

30
20
26
32

---
---
---
---

---
---
---
---

13

---

---

---

>normal

11

---

---

8

---

12

---

---

---

34


1Case 7.
2Case 13.
332 weeks after onset of symptoms but only 1 week after spontaneous remission of 3 weeks.

Other Tests

Agglutination of group 0 erythrocytes in the cold by serum from patients with kala-azar has been reported.38 Of 5 of the 30 cases tested, 3 were negative and 2 were positive in low titer (1:5, 1:4). Complement fixation tests were more often negative than positive in the active cases.

Bone marrow smears were examined in only four active cases. Prior reports in most instances had noted only the presence or absence of Leishmania. In 7 cases, 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 average cellularity 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 cell fragility and icterus index are normal. There is no deficiency of antianemic principle, since the bone marrow is not megaloblastic nor the anemia hyperchromic. Liver extract was used before admission in several of the 30 patients, without therapeutic effect. The hematological disturbance is not nutritional in the ordinary sense, since it may develop with extreme rapidity, is associated with marked leukopenia, and is characterized by only minimal hyperchromia.

The peripheral blood picture is that of aplastic anemia, but the bone marrow is not morphologically aplastic. The anemia and leukopenia have been described as myelophthistic, a hypothesis which seems hardly tenable in view of the cellular marrow and relative paucity of Leishman-Donovan bodies. The picture in the periphery and in the marrow resembled that described in benzol and other poisoning.39 It seems quite possible that the anemia of kala-azar is likewise toxic either in the sense that a metabolic product of Leishmania interferes with cell production or that the metabolic needs of rapidly dividing Leishmania or rapid formation and destruction of reticuloendothelial cells deprive the marrow of essential nutrients. The early appearance of reticulocytes when the temperature falls during antimony treatment, while viable Leishmania are still present in abundance in spleen and marrow, is compatible with this hypothesis.

LIVER FUNCTION

There is no indication that liver function has suffered significantly in the 30 patients of this series. The icterus index was normal in all of the cases that were active on arrival in Moore General Hospital and in 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. Dye retention was only between 2 and 10 percent. The strongly positive cephalin flocculation and thymol turbidity probably were not indicative of liver damage but were rather a manifestation of the marked hyperglobulinemia.

Icterus index, serum bilirubin, and BSP (Bromsulphalein) excretion were determined during and after treatment with Neostibosan or stilbamidine in several instances, but no evidence of liver damage 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 from apparent infectious hepatitis fell from 31 to 20 in 4 days of febrile kala-azar immediately before treatment with antimony and to 10 during the first 2 weeks of treatment. On admission to Moore General Hospital, 3 months later, the icterus index was 4.

RENAL COMPLICATIONS

There were only two patients with clinically important renal complications in this series. One, Case 16, an instance of chronic renal insufficiency following successful treatment of kala-azar with Neostibosan, will be discussed later (p. 41). The other, Case 23 (p. 46), developed classical acute glomerulonephritis at approximately the same time as the onset of kala-azar. At the time of first observation, 2 weeks after the onset of symptoms, marked leukopenia was already present in addition to the edema, hypertension, azotemia, albuminuria, and hematuria of acute nephritis. Since leukopenia rarely develops in less than 2 weeks from the clinical onset in kala-azar, this disease was probably of at least 2 weeks' duration. That it was not much longer than this is indicated by the fact that splenomegaly and lymphadenopathy developed 1 week after the initial observation and that serum protein rose from 6.2 to 6.9 gm. percent in the first 10 days and to 10.4, 2 months later. Coincident onset does not, of course, indicate a causal relationship between the two diseases. In fact, progressive improvement in the nephritis was marked before treatment of the kala-azar, and the subsequent course to apparent cure was not inconsistent with the natural history of the ordinary severe acute nephritis. The very few cases of acute nephritis that have been reported in connection with kala-azar may be of an accidental association.

Incidence and course of albuminuria and hematuria in the patients of this series during the course of kala-azar are summarized as follows:

Of 25 patients, 16 were observed to have albuminuria during active kala-azar, and 12 were known to have microscopic hematuria. The albuminuria was usually slight and the hematuria usually mild. In only one case were many red blood cells reported with urinary findings so prominent that renal function tests and intravenous pyelograms were made; both were normal. In most cases, hematuria was observed on several occasions. Many specimens contained from 3 to 10 leukocytes per high-power field without relation to other urinary findings and usually without change following treatment. With the exception of Case 23, none of the patients had hypertension, edema, azotemia, and all were able to concentrate urine and to excrete phenolsulfonphthalein.

Hematuria, albuminuria, and cylindruria disappeared during treatment or within a few days thereafter. Neither albuminuria nor hematuria was constantly present during fever. The frequency of hematuria in the


41

patients of this series suggests that the albuminuria of leishmaniasis is due to focal leishmanial lesions, analogous to focal nephritis in bacteremias, and not to fever. In fatal cases, parasitized macrophages may be seen in the interstitial tissues of the kidneys.40

The other patient (Case 16) developed chronic renal insufficiency during convalescence from kala-azar, presumably from toxic effect of Neostibosan. Previous data in this case are scant. Urinalysis 12 weeks from onset of symptoms of kala-azar was normal. Four weeks later, from six to eight red blood cells per high-power field were reported. Five weeks after this, just before treatment, urinalysis showed specific gravity of 1.023, no albumin, and no formed elements. Clinical response to treatment with 3.9 gm. of Neostibosan in 23 days was prompt and satisfactory with no untoward reactions noted. Unfortunately, the urine was not examined during treatment or for 10 weeks thereafter. Casual urine specimens then showed low specific gravity, and concentration tests revealed marked hyposthenuria. Excretion of P.S.P. was only 22.5 percent in 15 minutes (normal 25 to 50 percent) and the BUN. was elevated to 22 mg. percent. The urine contained no albumin or formed elements. There was no hypertension or edema, and serum albumin was normal. For 9 months after completion of treatment, urine concentration was never greater than specific gravity 1.015, P.S.P. excretion ranged between 17.5 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 remained asymptomatic, except for slight nocturia, with normal blood pressure and without albumin or formed elements in the urine. In summary, this man had a diffuse, nonprogressive lesion with marked reduction of renal function but without signs of inflammation. This was presumably due to toxicity from antimony, although documentation is admittedly poor.

In all other cases in this series, urine examinations and renal function were normal at the end of the observation period. Therapy with the various pentavalent antimony preparations did not affect normal urines, and those with initially abnormal findings cleared during treatment. Excretion of P.S.P. was determined shortly after completion of treatment in many instances and urea clearance in four instances; all were within normal limits. In one patient (Case 19), during treatment with stilbamidine, slight albuminuria developed without other abnormality. Three consecutive specimens before treatment and repeated specimens after the last day of treatment were all negative. Routine urinalysis before, during, and after treatment had specific gravity in excess of 1.024. No appreciable change in slight albuminuria present before treatment was observed in the course of treating Case 23 with stilbamidine.

40Strong, Richard P.: Stitt's Diagnosis, Prevention and Treatment 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 in this section. Three (Case 22, Case 19, and Case 23) are from the series of cases discussed in the preceding sections of this chapter. One (Case 5c) is from another series, and one (unnumbered) is of a patient who was seen at the Walter Reed General Hospital, Washington, D.C.

Case 22.-Prolonged interval to diagnosis; leukemia considered for 2 months; prompt response to 5.0 gm. Neostibosan; no relapse.

This patient, white, 23 years old, a carpenter, had served in the Mediterranean theater (north Africa and Italy) from 13 May 1943 to 24 March 1945. Onset of illness in December 1944 was gradual, with progressive enlargement of the abdomen, with pallor, and, in January, with chills, fever, sweats, and anorexia. Admitted to the 81st Station Hospital, Leghorn, Italy, on 16 February 1945, he had lost 38 pounds; the liver and spleen were enlarged four fingers' breadth below the costal margin; there was generalized adenopathy; leukopenia (3.3) but no anemia; cephalin flocculation, 4 plus. Presumptive diagnoses were Hodgkin's disease, aleukemic leukemia, or kala-azar. Sternal puncture, blood culture, stool examinations, and malaria smears were all negative. An excised axillary lymph node showed nothing specific. Fever, with one or two chills daily, showed a temperature rise as high as 105 F. The liver and spleen continued to enlarge.

He was transferred to the 64th General Hospital, Ardenza, Italy, on 10 March 1945. Symptoms became progressively worse. A second sternal puncture 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 April 1945 to 10 May 1945. Pallor and emaciation became more severe; the splenomegaly, hepatomegaly, and adenopathy persisted; and anemia was discovered. Total serum proteins were elevated. Sternal puncture and biopsy of an axillary node did not reveal parasites. A splenic puncture was performed, but the slides were lost. Temperature rose daily to 104 F. The patient was transferred to the Moore General Hospital on 10 May 1945.

Physical examination.-Pallor; weight, 132 pounds; * * * generalized adenopathy involving the anterior cervical, the occipital, the epitrochlear, the axillary, and the inguinal glands. In the left axilla, there was a hard gland of moderate size, freely movable, not tender. The spleen was nine fingers' breadth below the costal margin and descended further with respiration; it was tender to touch. The liver was six fingers' breadth below the costal margin. The clinical impression was kala-azar.

Admission laboratory findings.-RBC, 3.6 million; Hb. 71 percent; WBC, 1.8; serum albumin, 2.5, serum globulin, 4.6 gm. percent; cephalin flocculation test, 4 plus; formolgel test, 4 plus; clotting time (Lee and White method), 16 minutes; bleeding time, 2.5 minutes; platelets, 106,430.

Hospital course.-A transfusion of 500 cc. blood was given on 13 May 1945. Splenic puncture on the following day showed Leishman-Donovan bodies. A course of 5.0 gm. Neostibosan was begun on 15 May and completed on 2 June 1945. In 10 days, the temperature became normal for the 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. Cephalin flocculation was 4 plus.

Returning from a 30-day furlough, the patient reported feeling fairly well except for some pain in the left upper quadrant of the abdomen. His spleen was no longer palpable, and all laboratory findings were normal except for a positive cephalin floccula-


43

tion. Seen again in September, he complained only of tiring easily. He weighed 165 pounds, and neither liver or spleen was palpable. Bilateral hernias were repaired on 3 October 1945, and the patient was discharged as completely well in December 1945. The serum proteins were normal, the red and white blood counts were normal, and the cephalin flocculation test was negative. Microscopic hematuria and albuminuria, which had been repeatedly observed, cleared completely after treatment.

Comment.-The interval to diagnosis from the onset of symptoms was at least 4 months. The consensus at several hospitals was that the patient had leukemia. The correct diagnosis was established by splenic puncture, and complete recovery followed treatment with 5.0 gm. Neostibosan. No relapse occurred 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 in various parts of India from 17 May 1942 to 25 August 1944, in contact with natives and quartered sometimes in barracks and sometimes in tents. Acute clinical onset, on 16 August 1944, with chills, fever, generalized aching, and headache. 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.-Negative except for enlargement of the spleen shown by X-ray.

Laboratory findings.-WBC, on admission 5,200, fell gradually and subsequently remained between 2 and 3 thousand; RBC 2.8, Hb. 60 percent. Formol-gel tests negative during the first 4 months of illness. On 29 December 1944, serum albumin 2.7, globulin 4.1 gm. percent. Presumptive diagnoses during this time were dengue, malaria, amebiasis, and finally unexplained fever. On 30 December 1944, smears from sternal marrow were positive for Leishmania.

Treatment (30 December 1944-20 January 1945), 42.5 cc. Fuadin, with no effect on fever, anemia, and leukopenia; Neostibosan, 2.7 gm. (5 February-24 February 1945), with temporary clinical response. Fever absent for 1 month; recurred on 29 March 1945. Anemia, leukopenia, and splenomegaly persisted. Neostam, 0.75 gm. (31 March-14 April 1945), with temporary slight lowering of fever; no change in blood picture.

The patient was evacuated to the United States. On admission to Moore General Hospital on 6 May 1945, he was moderately undernourished; the spleen was palpable eight fingers' breadth below the left costal margin. In the 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 in temperature daily, 104 to 105.6 F. RBC 2.9; Hb. 65 percent; WBC 1.8; serum albumin 3.0 and globulin 6.6 gm. percent; formol-gel and cephalin flocculation tests positive; platelets 134,000. Spleen puncture on 17 May 1945 positive for Leishmania by smear and culture.

Hospital course.-Treatment (17 May-4 June 1945) with Neostibosan 5.0 grams. Temperature normal on 15th day of treatment. Spleen receded somewhat. RBC 3.2; WBC 3.9. After a 30-day furlough, the patient returned with a history of chills, fever, loss of weight, and intermittent pain in left upper quadrant of the abdomen. The spleen had enlarged. Splenic puncture 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 fever recurred. 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 1945 again positive by smear and culture. Treatment with 10.0 gm. Neostibosan (24 October-12 November 1945), with prompt control of fever. Reticulocytosis, 13.9 percent, on last day of treatment. Relapse within 1 month, with spleen well into the pelvis; WBC 2.6; recurrence of fever. Spleen puncture on 10 January 1946 again positive.

Treatment (12 January 1946-2 February 1946) with stilbamidine. The dosage, initially 0.025 gm., was increased gradually to daily injections of 0.300 gram. Toxic symptoms included mild flushing of the skin, with some formication and burning; local venous irritation with resultant thromboses; moderate exacerbation of daily temperature peaks up to 102 F.; and moderate 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 mildly depressed; thereafter, all rose progressively. Reticulocytosis 5.3 percent on 7 February. Red blood count, hemoglobin, and white blood count rose progressively to peaks of 4.74 million, 84 percent, and 7.40, respectively, 22 days after cessation of treatment. Temperature (3 February) became and remained normal. The spleen, which enlarged during the early part of treatment, by the 15th day after its completion was only three fingers' breadth below the left costal margin. There was no relapse during observation continued for 5 months.

Comment.-The interval to diagnosis from onset of symptoms was 4 months. This patient had several courses of small amounts of antimony overseas. Subsequently, curative amounts of 5 and 10 gm. of Neostibosan and 240 cc. of stibanose were ineffective. The strain of Leishmania in this patient may possibly have developed resistance to antimony. Cure was ultimately accomplished with stilbamidine.

Patient seen at Walter Reed General Hospital.-Protracted illness; repeated failures with antimony and stilbamidine; cure with splenectomy.

The clinical record reads substantially as follows:

The patient began his current hospitalization on 27 February 1944 with fever, weakness, malaise, headache, and with laboratory findings: RBC 1.9 million, Hb. 40 percent, WBC 1500. * * * diagnosis of kala-azar was made 15 April 1944 by splenic puncture. * * * specific treatment between April 1944 and December 1945 consisted of inadequate dosages in three courses of Neostibosan, in one course of Anthiomaline (lithium antimony thiomalate), in one of Solustibosan, in four of diamidinostilbene, and in one of antimony by iontophoresis, and adequate dosage in two courses of diamidinostilbene, and in one of solustibanose.

Discussion as of 1 December 1945:

The problem, whether or not to remove this patient's spleen, has three aspects: The leishmaniasis, the anemia, and the general discomfort from this tremendously enlarged spleen.

The recent fever, increase in size of spleen on cessation of treatment, leukopenia, reversal of albumin globulin ratio, strongly positive aldehyde test, and the apparent temporary response to diamidinostilbene therapy all point to continued leishmanial infection despite three negative splenic punctures and one sternal puncture which appears to be negative so far. Physical examination has not disclosed any extraneous cause of fever and 10 blood 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 this picture except possibly Hodgkin's and the lymphomas, neither of which have been ruled out by gland biopsies as yet. If this patient has continuing leishmanial infection despite his more than adequate treatment, it may well be that the organisms lying deep in this enormous spleen are not reached by concentrations of drug adequate to destroy them completely.


45

The anemia is severe and 83 transfusions of 500 cc. each have been needed in the past 22 months to maintain him 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 3.0 million and the highest Hb. revealed is 8.1 grams. Other blood studies have shown reticulocytes of 10 to 25 percent * * *, which would tend to rule out aplastic anemia * * *, and an osmotic fragility which is increased with hemolysis beginning at 0.48 percent, whereas control blood began at 0.42 percent. No sickling trait has been found * * *. The icteric index has varied from 5 to 12 for the past 3 months with one level of 25 in July 1945. The serum proteins have been consistently elevated with reversal of A/G [albumin/globulin] ratio, * * *. Last week the patient was given 4,000 cc. of compatible group A blood all less than 72 hours old but 3 days later the hematocrit was only 24 percent, RBC 2.4 and Hb. 6.7 Gm.

All these data point to an anemia of the hemolytic type. The leishmaniasis * * * provided two factors which might contribute to the hemolysis: The first would be the opportunity for pooling of blood in the enlarged spleen; second, the tremendous increase in the globulin fraction of the serum proteins may well be due at least in part to the tremendous increase in reticuloendothelial tissue in the spleen. 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 complained of moderately severe pain over this region and a definite rub could be heard. The present distention interferes with his eating and makes maintenance of body weight difficult.

Realizing that the risk of splenectomy in this patient may be considerable, I still feel that with adequate pre- and post-operative transfusions the procedure * * * offers the only chance of cure.

Basis of diagnosis:

1.     14 April 1944. Splenic puncture showed Leishmania donovani in smear.

2.     25 July 1944. Sternal puncture showed inclusion bodies in R. E. cells suggestive of Leishman-Donovan bodies. Culture consistent with Leishmania.

3.     2 October and 24 October 1945. Splenic punctures failed to show Leishmania in smear, culture, or in hamsters.

4.     9 November 1945. Sternal puncture failed to show Leishmania in 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 hamsters was demonstrated by culture.

Formol-gel test before splenectomy was repeatedly positive in less than 5 minutes. Thereafter, for 3 weeks, it was positive in less than 1 minute, and then at increasing long intervals, until by 13 March 1946 it was positive 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):


Total proteins

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 to improve. He had gained 40 lbs. since the splenectomy; his proteins had continued to improve; he was asymptomatic; his RBC and WBC had been improving slowly and his formol-gel test was less positive. We feel this procedure saved the patient's life but that it was not necessarily a specific cure for his residual leishmaniasis.

Comment.-This case is most unusual. Repeated courses of treatment with small amounts of antimony and stilbamidine may have produced resistance of the Leishmania to these drugs. An underlying hemolytic disease or abnormal lesion in the spleen may have contributed to the continued anemia and illness of this patient.

Case 23.-Onset associated with acute nephritis. Diagnosis made incidentally by splenic puncture in attempt to explain the leukopenia in a case of nephritis; death 66 months later, the only fatality in a serviceman with kala-azar (see fig. 6).

The patient, 36 years old, Negro, a Quartermaster ration-dump worker, with service in north Africa and Italy, had had scarlet fever in childhood, when he was bedridden for 6 months with a complication of unknown nature. 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, dragging sensation in the abdomen, swelling of the legs, dizziness, and lethargy. He had had a productive cough for 1 week and daily nosebleeds for 2 weeks. On examination, there was some bleeding from the left nostril; a soft systolic mitral murmur; blood pressure 155/95; moist rales heard at the bases of both 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 to the 33d General Hospital, Leghorn, Italy, on 20 June 1945. There he was dyspneic on exertion; blood pressure was 142/92 and 180/108; RBC 3.0 million with proportionate reduction in hemoglobulin; WBC 5,400 to 5,000; 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, and urea 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 was evacuated to the United States and admitted to the Fletcher General Hospital, Cambridge, Ohio, on 13 August 1945, with a transfer diagnosis of chronic glomerulonephritis. He was in some distress from a recent tooth extraction. There was a large discoid lesion on the shaft of the penis with several satellite sores. The systolic apical murmur persisted; blood pressure was 132/86. There was mild generalized adenopathy. There were daily elevations of temperature, finally reaching 104.6 F., on 23 August 1945. A course of penicillin, totaling 2,400,000 units, was begun, and within 24 hours the temperature fell abruptly and remained normal for 10 days. However, on 12 September, a low grade fever reappeared and con-


47

tinued throughout the rest of his hospital course. RBC 3.0 million; 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 an attempt to explain the leukopenia (ranging from 3,600 to 5,600) occurring in a case of nephritis, and numerous Leishman-Donovan bodies were found. Repeated dark-field examinations of the penile lesion were negative, and smears disclosed no Leishmania. Sedimentation rate was 65 mm. per hour. Electrocardiogram showed low voltage of T waves. Roentgenogram of the chest showed pleural thickening in the right costophrenic angle.

The patient was admitted to the Moore General Hospital for treatment, on 4 October 1945, with a transfer diagnosis of (1) leishmaniasis, (2) chronic glomerular nephritis, (3) herpes progenitalis.

Physical examination.-Examination confirmed previous findings, including mild narrowing of retinal arteries, slight cardiac enlargement with an apical systolic murmur, generalized enlargement of lymph nodes, about 1.5 cm. in diameter, not tender.

Laboratory findings.-RBC 3.61 million; Hb. 71 percent, WBC 4,700. Urine contained a heavy trace of albumin, 5 to 6 WBC, and a specific gravity of 1.018. P.S.P. test: 20.5 percent excretion in 1 hour, formol-gel test 4 plus; total protein 8.8 gm., albumin 3.0, globulin 5.8; clotting and bleeding time within normal limits; platelets 165,000.

Treatment.-In view of this patient's chronic glomerular nephritis, it was decided to treat his kala-azar with stibanose. A total of 200 cc. stibanose was given from 22 October to 1 November 1945. On the eighth day of treatment, the patient became, and remained, essentially afebrile. There was no apparent aggravation of the nephritic abnormalities. On return from convalescent furlough on 26 January 1946, he had intermittent irregular low grade fever, and the spleen was still down two fingers' 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 cephalin flocculation tests 4 plus. He lost 5 pounds during the next month, and sternal puncture on 1 March 1946 was positive for Leishman-Donovan bodies. Treated with 4.0 gm. stilbamidine from 18 March to 7 April, with no untoward effect except mild phlebitis and transitory flushing and tingling during injections. WBC rose from 3,350 to 6,000 during treatment. Excretion of BSP and P.S.P. both normal at the 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. After another furlough, he returned on 23 May with fever, chills, genital lesion, marked inguinal adenopathy; WBC 8,200; Frei test strongly positive. Fever subsided during treatment with sulfathiazole, but red cell count and hemoglobin fell, and serum globulin rose again following this episode. Subsequent convalescence was uneventful, with apparent cure of the kala-azar and with marked improvement in the kidney lesion.

Subsequent history and comment.-This is the only known case in which further relapse occurred after the patient was separated from military service. He continued to have periodic parasitic and clinical relapses despite all forms of chemotherapy, including trivalent and pentavalent antimony compounds in large amounts, various stilbene derivatives, and splenectomy. Bilateral optic atrophy, nephritis, and severe intractable anemia developed, and the patient died 66 months after the diagnosis of kala-azar was established. He was hospitalized almost continuously during his entire illness and received all known specific and symptomatic treatment. Autopsy disclosed an overwhelming parasitization of the reticuloendothelial cells in all tissues examined. Apparently, this strain of micro-organism was resistant to the available drugs used against this infection. Fortunately,


48

this was the only death recorded as the result of kala-azar in American military personnel during or after World War II.

Case 5c.-Onset by lymphadenopathy; no other positive clinical or laboratory findings, Leishmania demonstrated in lymph nodes.

This patient had been in northern Africa for 4 months before his arrival in Sicily, in September 1943, where he spent the next 5 months before coming to England. He had been in excellent health until about 1 January 1944, at which time he noted a slight swelling, without tenderness, of the posterior cervical and postauricular lymph nodes. These increased gradually in 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 for the enlarged suboccipital, postauricular and posterior cervical lymph nodes. The largest of these, in the left posterior cervical chain, measured 1.5 by 2.0 centimeters. Roentgenograms of the chest and neck revealed nothing significant. The blood counts were normal, and Kahn, Widal heterophile, and undulant fever agglutination tests were done, with negative results. Typical Leishmania were found in sections from a biopsy of a large node stained with Giemsa's stain.

He was transferred to the Moore General Hospital, on 23 March 1944, with a diagnosis of leishmaniasis. No history could be obtained of chills, fever, night sweats, loss of weight, diarrhea, or slowly healing sores.

Physical examination.-Examination showed a well-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 in the postauricular and suboccipital regions; they were not tender. The epitrochlear nodes were just palpable, and a few small, discrete axillary nodes were palpable but not tender. The liver descended 2 cm. below the costal margin on deep inspiration and was slightly tender. The spleen could not be felt. Otherwise the physical examination was essentially negative.

Laboratory studies.-RBC 4,800,000, Hb. 96 percent, WBC 5,000, with 68 percent polymorphonuclear leukocytes and no abnormal cells. Total serum proteins were 6.5 gm., albumin 4.8, globulin 1.7. The aldehyde test of Napier was negative. Smears of sternal marrow and material aspirated from lymph nodes were negative, and cultures of these materials on N.N.N. medium showed no leptomonad forms after 21 days' incubation at room temperature. A second biopsy of an enlarged cervical node, however, showed typical Leishmania parasites in smears, microscopic sections, and culture. Despite the patient's apparently excellent health, antimony therapy was started on the basis of the incontestable diagnosis of lymph node leishmaniasis. Fifteen daily injections of 6 cc. of solution of sodium antimony gluconate, representing 1,800 mg. antimony, were given. At the completion of this series, he was discharged to duty, with instructions to return in one month for further evaluation of results.

Comments.-This case is of unusual interest because the only symptom or finding was lymphadenopathy. It emphasizes the importance of Leishmania in the differential diagnosis of adenopathy in patients from endemic areas.

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