700 TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE(1985) 79, 700-704 Visceral leishmaniasis unresponsive to antimonial drugs I. Clinical and immunological studies A. D. M. BRYCESON,” J. D. CHLJLAY,‘~~” MAY Ho,~+++ M. MUGAMBII,’ J. B. WERE,’ R. MUIGAI,’ C. CHUNGE,’ G. GACHIHI,’ J. MEME,~ G. ANABWANI~ AND S. M. BHATT’ ‘Clinical Research Centre, Kenya Medical Research Institute, P.O. Box 20778, Nairobi, Kenya; ‘US Army Medical Research Unit-Kenya; 3Division of Geographic Medicine, Case Western Reserve University Medical School, Cleveland, Ohio, USA, and Division of Disease Control Ministry of Health, Nairobi, Kenya; 4Department of Paediatrics, University of Nairobi Medical School. Abstract Ten Kenyan patients with visceral leishmaniasis, unresponsive to sodium stibogluconate at a dose of 16 to 20 mg Sblkgiday given for 30 to 98 days, have been studied clinically and immunologically and compared with 57 antimony-responsive patients. Pulmonary tuberculosis and previous treatment with antimonial drugs were the only factors which were more common in unresponsive patients. The degree of immunosuppression and rate of recovery of immunoreactivity did not differ between antimony-responsive and -unresponsive patients. Only one patient had never been treated before (primary unresponsiveness). In the other nine patients secondary unresponsiveness occurred after one or more treatment courses, suggesting that the parasite developed resistance to antimony. Antimony-unresponsiveness m visceral leishmaniasis is a serious problem numerically, clinically and economically. A plea is made that the initial treatment of visceral leishmaniasis should be adequate in dose and duration. Introduction Most patients with visceral leishmaniasis respond well to treatment with pentavalent antimonials given in the dose range 10 to 20 mg antimony (Sb)/kg body-weight (bw) daily for 6 to 30 days, although a variable proportion relapse (BRYCESON, 1985). A few patients are, or become during relapse, unresponsive to such doses of antimonial drugs and pose several problems. Second line drugs (pentamidine and amphotericin B) are toxic, difficult to administer and expensive, and the disease tends to respond slowly to them. Unresponsive patients, who are commonly children, may remain in hospital for many months or years, miss their schooling, and drain precious health resources. Understanding of the problem of unre- sponsiveness has been hampered by the loose use of terms such as resistant, refractory and relapsed, and there has not been a study of unresponsive patients as a group. The present study of ten patients with visceral leishmaniasis unresponsive to conventional doses of antimonial drugs was undertaken in order to define the nature of the problem and to evaluate host and parasite factors which may contribute to unrespon- siveness. We report here the results of clinical and immunological studies on these patients. Patients and Methods During the two-year period August 1980-July 1982, 67 patients with visceral leishmaniasis were treated at the Clinical Research Centre (CRC!, Nairobi. Ten of these patients were unresponsive to antimony and are the subjects of this study. In all casesdiagnosis was confirmed by the demonstratibn of amastigotes-in splenic aspirate smears (CHIJLAY & BRYCESON, 1983). Certain terms used m this paper are defined as follows. Initial cure: improvement in clinical and laboratory abnorma- lities plus disappearance of parasites from splenic aspirates or disappearanceof splenomegaly. Primaty unresponsiveness: no clinical or parasitological improvement at the end of the first defined course of treatment. Secondaty unresponsiveness: no clinical or parasitological improvement at the end of a defined course-of treat&em in a patient who has relapsed after initial cure. Partial response: clinical and parasitological improvement, but with persistence of parasites, at the end of a defined course of treatment; response may be at the expected rate or slow. Relapse: reappearance of parasitologi- callv confirmed disease after initial cure: relause is not di&guished from reinfection. I . The criterion for admission to this study was that a patient should have persistent clinical and parasitological disease af the end of a course of treatment with sodium stibogluconate given in a dose of at least 20 mg Sb/kg bw daily for at least 30 days. It will be seen from Table I that six patients met this criterion fully on admission. The other four had either received a slightly lower dose, but for 60 days (patient 7), or had relapsed for the fourth, third or first time after receiving 20 mg Sb/kg bw for 60, 84 and 89 days, respectively (patients 3, 5 and 6). These latter four patients were all subsequently unresponsive fo antimony at a dose of 20 mg Sbikg bw given eight-hourly (BRYCESON et al., 1985). Iniestigaiions included physical examination, measure- ment of weight and height, spleen size (measured from the left costal margin in the mid-axillary line to the tip), haemoglobin, white cell count, reticulocyte count, platelet count, alanine aminotransferase, asparate aminotransferase, albumin,, globulin, prothrombin time, blood urea nitrogen, urinalysis, chest radiograph, electrocardiogram, and skin tests for delayed hypersensitivity to leishmanin, tuberculin (PPD), streptokinaseistreptodornase (SKSD), and Candidu *Present address: Hospital for Tropical Diseases, 4 St. Pancras Way, London NW1 OPE. **Present address: Department of Immunology, Walter Reed Army Institute of Research, Washington, DC 20307-5100, USA. ***Present address: Facultv of Tronical Medicine. Mahidol University, 42016 Rajvifhi Road, Bangkok 4, Thailand. The views of the authors do not purport to reflect the position of the US Department of the Army or the US Department of Defense.