Cell-mediated immunity during natural measles infection.

Natural measles causes prolonged depression of cell-mediated immunity yet little is known as to how the infection influences lymphocyte function. Therefore, we studied the properties and function of lymphocytes during and after measles. The number and proportion of circulating thymus-derived lymphocytes was low during the acute stage of measles, and at this time 37% of these cells showed positive immunofluorescent staining for measles virus after stimulation with phytohemagglutinin. 7% of B cells were shown to contain virus but their numbers did not alter during the infection. Acute-phase lymphocytes, when stimulated, yielded infective virus and half were killed on incubation with autologous serum and complement. In acute measles the increase in [(3)H]-thymidine uptake of lymphocytes when stimulated with an optimal dose of PHA was normal in media with 10% fetal calf serum and low in media containing 10% autologous serum: the mean values were 56.8+/-34.1 and 23.7+/-25.9 cpm x 10(3) per 10(6) lymphocytes, respectively. Stimulation of acute-phase lymphocytes by Candida antigen was also low in media containing autologous serum averaging 1.2 x 10(3) cpm per 10(6) lymphocytes. On recovery 4-6 wk later this rose significantly to 18.9+/-19.8. The mean migration index of leukocytes to heat-killed candida cells in acute measles was 0.84+/-SD 0.08, and this fell significantly to 0.75+/-SD 0.08 4 wk later. Thus, depletion of T cells, an inhibitor of lymphocyte proliferation in the serum and a possible defect in antigen processing, interacts to depress cell-mediated immunity in measles.

Miltefosine: issues to be addressed in the future.

Future issues that need to be addressed for miltefosine are efficacy against non-Indian visceral leishmaniasis, efficacy in HIV-coinfected patients, efficacy against the many forms of cutaneous and mucosal disease, effectiveness under clinical practice conditions, generation of drug resistance and the need to provide a second antileishmanial agent to protect against this disastrous event, and the ability to maintain reproductive contraceptive practices under routine clinical conditions.

Clinical features and diagnosis of 42 travellers with cutaneous leishmaniasis.

BACKGROUND: Leishmania species that occur within different geographical areas may cause different clinical manifestations, virulence and drug sensitivity. Patients/Methods. All patients with a clinical diagnosis of cutaneous leishmaniasis seen at the Hospital for Tropical Diseases from 1997 to 2000 were identified and clinical details recorded onto a database, with emphasis on clinical presentation, risk factors, travel history and laboratory diagnosis. RESULTS: Forty-two patients were identified, 23 of whom had travelled to New World and 19 to Old World countries. Clinical presentation typically consisted of a single nodule with ulceration. In 50% infection was caused by L. (Viannia) braziliensis. PCR was performed in specimens from 34 patients and species identification was possible in 32 cases (sensitivity 94%), the two PCR negative patients had amastigotes demonstrated by histology and culture. Patients were treated with established therapies. Seventy one percent were cured by treatment, 12% had a spontaneous cure, 7% were lost to follow-up and the remaining 10% required a second-line therapy. No relapses were reported during a mean follow-up period of 27 months. CONCLUSIONS: Our study highlights the need for comprehensive investigations and the advantages of PCR in the diagnosis of patients with suspected leishmaniasis in non-endemic regions of the world.

Visceral leishmaniasis (kala azar) in a patient with AIDS.

A patient with HIV infection presented with multiple cutaneous Kaposi's sarcomata. Biopsy of one of these showed the presence of amastigotes within an otherwise typical Kaposi's sarcoma. Further investigations proved the patient to have visceral leishmaniasis (kala azar). Visceral leishmaniasis has been reported in HIV infection but it is rare and this presentation is unique. The patient made a good response to a prolonged course of treatment with sodium stibogluconate and allopurinol.

Meningococcal antigen in diagnosis and treatment of group A meningococcal infections.

Meningococcal antigen was measured by countercurrent immunoelectrophoresis in the blood and cerebrospinal fluid of 200 patients with group A meningococcal meningitis. Antigen was detected in the blood of 27 (13.5 per cent) patients. These patients had a worse prognosis and a higher incidence of allergic complications, such as arthritis and vasculitis, about 5 days after the start of antibiotic treatment. Antigen was found in the CSF of 129 (67.5 per cent) patients); antigen often persisted in the cerebrospinal fluid despite antibiotic treatment before admission. A combination of immunoelectrophoresis and routine bacteriologic study was used in the diagnosis of 162 (84.8 per cent) patients with meningococcal meningitis. High levels of antigen and a slow antigen disappearance were associated with neurologic damage. The antigen is stable and may be detected from specimens of cerebrospinal fluid dried on filter paper.

Circulating immune complexes in subacute infective endocarditis and post-streptococcal glomerulonephritis.

Two out of five patients with subacute infective endocarditis and two patients with post-streptococcal glomerulonephritis had large amounts of soluble circulating immune complexes in their sera. The three others with endocarditis had less severe disease and minimal evidence of circulating immune complexes. Low serum complement was also found in two of the cases.

Quantitation of amastigotes of Leishmania donovani in smears of splenic aspirates from patients with visceral leishmaniasis.

During a 20-month period, more than 500 splenic aspirations were performed in 89 patients with suspected or proven visceral leishmaniasis. The two complications which occurred (intra-abdominal bleeding and penetration of the intestine in one patient each) both resolved with conservative management. Parasite density in splenic aspirate smears was graded on a logarithmic scale from 0 (no parasites in 1,000 microscopic fields) to 6+ (greater than 100 parasites per microscopic field). Among 46 newly diagnosed and 17 relapsed or drug-resistant patients with visceral leishmaniasis, the average initial parasite grade was 4.35 +/- 0.92 (mean +/- SD) and 4.15 +/- 1.37, respectively. The grading system was useful in measuring the speed of response to treatment, and in distinguishing slow responders from nonresponders. This was especially valuable for managing patients with drug-resistant visceral leishmaniasis. The system also provided a means of comparing the efficacy of different treatment regimens, and for calculating the optimum duration of treatment.

Comparison of microscopy and culture in the detection of Leishmania donovani from splenic aspirates.

Three culture media were compared with Giemsa-stained smears for the detection of Leishmania in splenic aspirates from Kenyan patients with visceral leishmaniasis. Ninety-nine splenic aspirates obtained from 26 patients at various times before, during, and after treatment were cultured in Schneider's Drosophila medium and RPMI medium 1640 (each supplemented with 20% fetal bovine serum) and McConnell's modification of Senekje's medium overlayed with 0.9% saline. From 13 splenic aspirates obtained before treatment, amastigotes were identified microscopically in all and promastigotes were cultured in 12. During and after treatment, Schneider's medium was the most sensitive method for detecting parasites, followed by microscopic examination of stained smears which was more sensitive than either of the other two media tested. Results indicate that, for initial diagnosis, both culture and direct microscopy of aspirates should be employed.

Fever as the presenting complaint of travellers returning from the tropics.

We investigated prospectively the cause of fever in patients requiring hospitalization after returning from the tropics. All consecutive admissions (n = 195) with oral temperature > 37.0 degrees C at the time of admission were enrolled. Final diagnosis as recorded on the discharge summary by the attending physician and results of any relevant laboratory or radiological investigations were recorded on standard proforma. Malaria accounted for 42% of admissions; two patients had returned to Britain more than 6 months before presentation. The second largest group was assumed to have a non-specific viral infection (25%). Cosmopolitan infections (urinary tract infection, community-acquired pneumonia, streptococcal sore throat, etc.) accounted for 9%. Coincidental infections (schistosomiasis, filariasis, intestinal helminths) were found in 16%. Serology was positive for HIV infection in 3%. The most useful investigation was a malaria film, which was positive in 45% of cases in which it was performed. The combination of thrombocytopaenia (platelet count < 100 x 10(9)) and hyperbilirubinaemia (bilirubin > 18 IU/ml) were useful predictive markers of malaria: all 23 patients with both abnormalities had positive malaria films. Malaria must be excluded in any febrile patient returning from the tropics. In the absence of a positive malaria film, the combination of a low platelet count and raised bilirubin may suggest the need for an empirical course of therapy.

Cutaneous leishmaniasis and leprosy.

Eight patients who had concomitant leprosy and leishmaniasis are described. Two patients with lepromatous leprosy had high resistance leishmaniasis, implying that the immune deficiency in lepromatous leprosy is specific to Mycobacterium leprae.

Treatment of 'Old World' cutaneous leishmaniasis with aminosidine ointment: results of an open study in London.

Five preparations of ointment containing aminosidine were used to treat lesions of 'Old World' cutaneous leishmaniasis. A preparation containing 12-15% aminosidine with 10% urea in white soft paraffin was nontoxic. 23 of 27 patients treated healed in a mean of 6.7 weeks, the ointment being applied daily for up to 12 weeks.

High-dose sodium stibogluconate treatment of cutaneous leishmaniasis in Kenya.

Cutaneous leishmaniasis caused by Leishmania aethiopica usually responds poorly to conventional doses of pentavalent antimonial drugs. We treated three patients with cutaneous leishmaniasis acquired in Kenya, presumed or documented to be caused by L. aethiopica, with intravenous sodium stibogluconate, 18 to 20 mg Sb/kg body-weight twice daily for 30 days. All patients had a good response to treatment, with disappearance of parasites from skin smears and cultures after 14 to 27 days, clinical healing of the lesions, and no recurrence during a three to 18-month follow-up. Side effects of treatment were minor. We conclude that this high dose sodium stibogluconate regimen is safe and effective for treating cutaneous leishmaniasis caused by L. aethiopica in Kenya.

Aminosidine and its combination with sodium stibogluconate in the treatment of diffuse cutaneous leishmaniasis caused by Leishmania aethiopica.

Treatment of diffuse cutaneous leishmaniasis (DCL) caused by Leishmania aethiopica remains unsatisfactory as the parasite is relatively insensitive to antimonial compounds. Reports of the clinical effectiveness of aminosidine sulphate, especially in combination with sodium stibogluconate, in visceral leishmaniasis and the finding that this antibiotic is potent against L. aethiopica in vitro, prompted us to evaluate its usefulness in DCL. Two patients with long-standing, active DCL were treated for 60 d with aminosidine sulphate, 14 mg/kg/d parenterally. The skin lesions resolved completely in both patients although they relapsed subsequently. Synergism between aminosidine and stibogluconate was demonstrated in vitro against parasites isolated from the patients. This led us to administer combined therapy, aminosidine sulphate 14 mg/kg/d and sodium stibogluconate 10 mg/kg/d, to the 2 patients in relapse and to another, third patient. Treatment was continued for 2 months beyond parasitological cure. Side effects were minimal. Following treatment, a return of specific cell-mediated immunity occurred, as expressed by a moderate infiltration of lymphocytes into the lesions and by lymphocyte proliferation in vitro in the presence of live Leishmania antigen, with synthesis of interleukin-2 and interferon gamma with one patient and interleukin 4 with the other. During follow-up periods of 2 to 21 months after treatment, no sign of relapse was seen.

Visceral leishmaniasis unresponsive to antimonial drugs. I. Clinical and immunological studies.

Ten Kenyan patients with visceral leishmaniasis, unresponsive to sodium stibogluconate at a dose of 16 to 20 mg Sb/kg/day 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 in 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.

Visceral leishmaniasis unresponsive to antimonial drugs. III. Successful treatment using a combination of sodium stibogluconate plus allopurinol.

Five patients with long-standing visceral leishmaniasis who were unresponsive to sodium stibogluconate, 20 mg antimony/kg body-weight once or twice daily, were treated for 14 to 54 days with a combination of sodium stibogluconate at the same dose plus allopurinol at a dose of 20 mg/kg body-weight per day in three divided doses. This combination was safe and effective. Negative splenic aspirate smears were obtained from all patients within 19 days, and none has relapsed in at least 12 months of follow-up.

Zoonotic cutaneous leishmaniasis in Saudi Arabia: lesions healing naturally in man followed by a second infection with the same zymodeme of Leishmania major.

A patient with a previous history of an infection with Leishmania b. braziliensis contracted zoonotic cutaneous leishmaniasis (ZCL) in the Al-Hassa oasis, Eastern Province, Saudi Arabia. Five lesions healed spontaneously over a period of 40 weeks without treatment. A year after acquiring ZCL he became infected again in the same focus. Isolates of parasites at both episodes were identified as L. major, zymodeme LON-4. Compared with the first infection of ZCL, parasites were fewer in the lesions on the second occasion, the lesions were smaller and healing was quicker (10 weeks). This work and a previous report of patients with active lesions and leishmanial scars suggest that second infections of L. major are not uncommon in the oasis where no autochthonous infections of other species of Leishmania have yet been recorded in man and only one species of Phlebotomus (P. papatasi) is known.

Aminosidine (paromomycin) in the treatment of leishmaniasis imported into the United Kingdom.

We report 11 patients with leishmaniasis from different endemic areas, treated in the UK with intravenous aminosidine alone or in combination with other drugs. Clinical and parasitological cures were achieved in all 7 patients from the Mediterranean zone who had visceral disease, with one relapse. Two of 4 patients with cutaneous or mucosal disease were cured; the other 2, from Iraq and Iran, did not respond. Toxic effects were high-tone deafness in 2 patients, one of whom had pre-existing renal impairment, and transient, mild elevation of serum creatinine in 3. Aminosidine is an effective, tolerable and relatively non-toxic alternative to existing antileishmanial drugs for the treatment of visceral leishmaniasis. Further studies will be needed to assess its place in cutaneous and mucosal disease.

Experience with mebendazole in the treatment of inoperable hydatid disease in England.

Eleven heterogeneous patients with inoperable hydatid disease were treated with high doses of oral mebendazole, up to 200 mg/kg/day for 16 to 48 weeks. Toxicity was not encountered. Despite careful assessment it proved difficult critically to evaluate the efficacy of mebendazole. In four patients chemotherapy appeared to have been at least partially successful and success seems to have correlated with serum levels in excess of 100 ng/ml one to three hours after dosage. The problems of assessment are discussed and the need for controlled trials of mebendazole in hydatid disease are stressed.

Leishmania infecting man and wild animals in Saudi Arabia. 8. The influence of prior infection with Leishmania arabica on challenge with L. major in man.

A clinical trial is described of an attempt to protect against Leishmania major by prior vaccination with live L. arabica. After a single, previously leishmanin-negative, adult male volunteer was bitten by 8 Phlebotomus papatasi infected with L. arabica, no infected lesions were observed. He remained leishmanin-negative and his lymphocytes reacted weakly to antigens of L. arabica or L. major. Subsequently he and 3 other leishmanin-negative adult male volunteers were vaccinated with cultures containing 4 x 10(6) promastigotes of L. arabica. All remained leishmanin-negative but their lymphocytes showed some response to both L. arabica and L. major antigens. 96 d after vaccination these 4, and another, non-vaccinated, volunteer were challenged with 2 x 10(6) promastigotes of L. major. Active cutaneous, ulcerated lesions developed in all 5 volunteers. The lesions in 3 vaccinated volunteers were associated with marked lymphadenitis and beading, but the lesions started to heal spontaneously within 120-250 d after challenge. The lesion in the fourth vaccinated volunteer was less severe and lymphadenitis was not observed. The lesion in the unvaccinated subject developed more slowly and was smaller, but more chronic, than those in the vaccinated individuals. Marked cross-reactivity in terms of lymphocyte proliferation and interferon-gamma production was observed between L. major and L. arabica in both directions in subjects exposed first to one or the other organism. Although the procedure followed in this trial failed to give protection against L. major, further studies in volunteers should be considered.

Visceral leishmaniasis unresponsive to antimonial drugs. II. Response to high dosage sodium stibogluconate or prolonged treatment with pentamidine.

Ten Kenyan patients with visceral leishmaniasis unresponsive to sodium stibogluconate, at a dose of 16 to 20 mg Sb/kg body-weight/day given for 30 to 98 days, were treated with 20 mg Sb/kg bw given every eight hours. This regimen was modified or abandoned in six patients because of suspected toxicity, although toxicity was difficult to assess because of intercurrent illness. Toxic effects included lethargy, anorexia, vomiting, electrocardiographic changes, fall in haemoglobin and rise in liver enzymes. One patient died, probably from a cardiac arrhythmia. Two patients were cured, four responded partially and four showed no response. Pentamidine, at a dose of 4 mg/kg body-weight given one to 3 times per week for 5 to 39 weeks, was given as initial treatment in one patient and after failure of sodium stibogluconate in seven. Toxic effects included nephritis, hepatitis, transient diabetes and subcutaneous abscesses. Two patients were cured, two responded partially, three showed no response and one, after apparent cure, relapsed and was unresponsive to additional pentamidine treatment. Low-frequency, long-duration pentamidine was often useful in maintaining any improvement made during treatment with the less well tolerated high-dose, high frequency sodium stibogluconate. We observed the step-wise development of resistance to both sodium stibogluconate and pentamidine. The problems of managing patients with visceral leishmaniasis which is unresponsive to conventional doses of pentavalent antimonials are discussed and some tentative suggestions put forward.