Visceral Leishmaniasis in Human Immunodeficiency Virus (HIV)-Infected and Non-HIV-Infected Patients

Introduction Visceral leishmaniasis (VL) is a severe disease associated with considerable morbidity, characterized by fever, hepatosplenomegaly, pancytopenia, and hypergammaglobulinemia, caused by intracellular protozoa of the genus Leishmania(27, 32, 122). VL is usually observed in immunocompetent hosts in endemic areas, but it occasionally occurs as a rare complication of immunodeficiency states and autoimmune diseases (4, 16, 22, 31, 60, 74, 96). Since the mid-1980s, VL has been recognized as a common complication of patients infected with the human immunodeficiency virus (HIV) in southern Europe (23, 35, 85, 93, 105, 113, 114, 138, 141, 144), where between 1.5% and 9% of patients with acquired immunodeficiency syndrome (AIDS) suffer from newly acquired or reactivated VL (70, 163). All reports regarding VL in HIV-infected patients concur in pointing out that this infection occurs in profoundly immunodepressed patients and may pre-sent with typical and atypical features (8, 11, 23, 93, 124, 128, 129, 163). Until recently, no comparative studies about the clinical presentation and outcome of VL in HIV-infected and immunocompetent patients have been reported (137). Regarding diagnostic procedures, a constant finding in HIV-infected individuals with VL has been the low sensitivity of the serologic studies; more than 50% of these patients show no detectable levels of antileishmanial antibodies (11, 64, 104, 164). However, there is still debate regarding the different yield of visualization techniques, which has led some authors to recommend the routine performance of bone marrow culture for Leishmania in this population (23, 93, 163). The best drug, the optimal doses, and the duration of treatment of AIDS-associated VL are still unknown, and much controversy persists regarding the selection of antimonial agents or amphotericin B. A clinical response is achieved in 38%–81% of HIV-infected patients (87, 93, 113, 141), but relapses typically occur in 25%–60% of cases (11, 124). Different maintenance regimens have been used to prevent relapses, with variable results (125, 139). In this paper we report the results of a comparative study on the epidemiology, clinical presentation, diagnostic procedures, response to treatment, relapses, and outcome of VL in a series of 80 HIV-infected and 40 non-HIV-infected patients. We describe the largest series of patients with HIV-Leishmania coinfection studied at a single institution, with a historic perspective of the major changes of the epidemiology and outcome of the disease from the beginning of the epidemic until the recent introduction of the new antiretroviral therapies. Methods Hospital setting and population of study This retrospective study was performed from January 1974 to December 1997 in a 1,750-bed general, teaching and referral hospital serving a population of 650,000 inhabitants in Madrid, Spain. The hospital has medical, surgical, pediatric, and obstetric units and, since 1991, the hospital has had a very active HIV program. Diagnostic procedures and microbiologic techniques Antileishmanial antibodies were assayed by indirect immunofluorescence (IIF) (Leishmania Indirect Immunofluorescence Antibody Test, Mardx Diagnostics, Scotch Plains, NJ). Titers ≥1:80 were considered significant. In a few patients, antibodies were measured by hemagglutination (Boehringerwerke AG, Marburg, Germany) and titers ≥1:8 were considered significant. Testing for HIV antibodies was performed using an enzyme-linked immunosorbent assay (ELISA) and was confirmed by Western blot. Leishmania cultures were made by inoculating the tissue specimens or the buffy coat layer of peripheral blood onto Schneider Drosophila Medium (Gibco, Paisley, Scotland, UK) supplemented with 30% inactivated fetal bovine serum (Flow Laboratories, Irvine, Scotland, and or the All cultures were at to and for were with or and studies were performed by and were measured by and of leishmaniasis of VL was confirmed by of Leishmania in tissue or by of in In a few patients with no the was made in the of clinical features and serologic and response to treatment, in of a bone marrow and of was as a new of by of the a response to the treatment of the VL was considered the was for HIV at the of the of The of HIV infection and the of were in with the of the for and and of the have been as of in since January and are as of in Europe and these were used in the study active for Leishmania was in patients to the hospital with of patients with VL between 1974 and 1997 were The were by the clinical of the of and for HIV or clinical presentation, of of VL and serologic antileishmanial treatment, response to treatment, antiretroviral antileishmanial and was as a than and were as a and than and The outcome and the were at the of the for cases in the study between 1974 and The of the cases and the population by hospital was used as the for the of response and The treatment regimens were The was that was in some cases with or The was amphotericin or amphotericin The was for patients were with a of with or for The clinical response was as clinical a of treatment the was with of the and hepatosplenomegaly, and was the of was as the of clinical of and the response was considered the treatment, or was for in the A study culture of bone was performed on some this study was made in the the of treatment in was as the of culture of bone marrow was by the of on culture of bone marrow or The response was the clinical and response was considered there was a clinical and there was a clinical and the clinical response was In patients in the response was the response was considered there was clinical of was out by the clinical of the patients. The were considered as a in that blood in the of serum and in serum was to some patients had a of had with and was on an variable was performed with the a the was The study of the was performed with the with the or the were using the between were using the that or relapses, a was All were and of or were considered significant. The was used for the and and the study newly cases of VL were observed in the population by the cases were and observed in was associated with HIV the of this we new cases of of which were in patients with HIV The of cases by of and HIV is in of cases of leishmaniasis in HIV-infected and non-HIV-infected individuals by an in the of VL in from cases in the of the study to cases in the of VL in patients has constant the study cases may the of VL observed in the In the of the study individuals with HIV infection of had been with were at that of the patients had from In the for new of VL in an new cases were in patients. In the of VL patients is than clinical was for of the patients with diseases associated with VL were HIV infection in 80 patients immunodeficiency states in of and of and diseases in and patients had had an of leishmaniasis in and in the of reports with different clinical of VL are in the patients were and were The was patients than in patients but this was significant. was in the than in the patients of of VL cases is in the of cases of leishmaniasis in HIV-infected and non-HIV-infected individuals by of the clinical and of patients. for HIV infection in in in and in The of in patients with VL was to that of cases at features in 80 patients with leishmaniasis and HIV clinical for were or at the of of VL in of the patients. in these patients were as or infection infection and In the was in of the patients. clinical about the of VL was for patients individuals had the typical clinical features of and were the VL as of in of The clinical presentation of VL was in and However, individuals had a of than patients of the was in HIV-infected patients, but in of the patients features of the of leishmaniasis in are in was observed in and of the and patients, and were more in than in In the of and were in than in patients The of was in patients, the was in and in of the was and the was A to was observed in of of the of leishmaniasis in procedures was confirmed in of The was made by of bone marrow in cases had a bone marrow by bone marrow culture in by of in and by blood culture in the yield of the different diagnostic marrow study was the and was performed on patients. culture of the buffy coat was out in Diagnostic of Leishmania infection in patients diagnostic was the of the bone marrow in of by bone marrow culture in of and in The sensitivity of serologic studies was in than in patients was no in the of the diagnostic between The diagnostic yield of bone marrow and was the cases with bone marrow the had been in is that bone marrow culture was the in the for of the made by bone marrow The diagnostic yield of bone marrow and was and response was to patients to The regimens used and the response to are in patients were with or to and patients, were at of of a of in for in patients. was in cases and in was at a of for in patients to treatment of the of leishmaniasis in in of the This complication was observed in of the patients and in of the patients The of was as In was observed in and was in and were the observed in patients with to were more in than in was to an in and of the and the of of was with than with was achieved in of patients. individuals had a of response than patients patients have a clinical more as is in A study was out in of the this study was performed the the of in of A was achieved in of the patients and in the patients in the study was This was significant. the response was considered in of the patients. patients had a of response than individuals In patients it was to the response of treatment, or for was observed in the response of patients or the of the individuals were with of or the and of a response was achieved in and patients, and a response was achieved in of the was to this treatment was the of VL in or with was used in and studied in the had the of active antiretroviral with regimens was to patients for a of about antiretroviral were for patients. treatment of the VL was observed in 40 The was in than in patients The patients to and were for at was had had relapses, had and had The of the was and from the to the was individuals had a the A of the clinical diagnostic and response to of the and the of VL is in presentation was to that of the but the duration of was in relapses A of relapses as of with the were observed in the or in the yield of the different diagnostic and of and were more in the relapses, but the response was to that of the diagnostic procedures, and response to treatment of the and the of leishmaniasis in HIV-infected patients for a of was used in in in and in patients with response to treatment and with at of the patients of the and patients of the VL that the variable that had a on VL was the of with or the clinical of HIV infection at the blood and the of antileishmanial the antiretroviral were to the patients there were relapses and new cases of VL the introduction of this and In December at of by the patients, were were and were for individuals were for a In a of patients the as a of was a in the between and individuals the of VL in of the patients and the treatment of a in patients. active VL have to in these patients, leishmaniasis was the of in of was to or clinical in than of individuals had severe that were the of the of the patients clinical for The was in than in patients as in which the of of leishmaniasis in of 80 HIV-infected and 40 non-HIV-infected patients with that the that had a on the of patients were a low and the of for VL with or The by the was in patients with than in patients with as in The in patients for VL was than in patients had a on The was in patients or no treatment than in patients there were no in the of patients this variable was in the of or VL the of HIV-infected patients with leishmaniasis with a and than of 80 HIV-infected patients with leishmaniasis and for of 80 HIV-infected patients with leishmaniasis and with active antiretroviral and is a disease to infection with of the genus VL is endemic in the and usually immunocompetent 164). However, in recent VL has been recognized as an infection associated with some immunodeficiency states as and (4, 16, 22, 31, 60, 74, 96). Since the mid-1980s, VL has been reported as a complication of from of southern Europe as and (11, 93, 113, has been reported from of the (11, and the of cases in to the of diseases and is a of Since VL is the on is has been that between 1.5% and 9% of patients in southern Europe VL but a was in We have observed that the of VL has in the the of VL the population has AIDS-associated VL to this VL usually in patients with studies have reported that between and of patients have the of VL 105, 113, 128, 138, and that the is than in of patients (11, 163). In VL was the severe infection in of the a reported in of patients in series 113, The of presentation of VL is of the and VL usually in (11, 128, the disease is more in and the immunocompetent population We have observed in the between the but in of coinfection is that the response the outcome of Leishmania and, a of infected individuals disease have been to the between VL and HIV to clinical the of a infection (11, the of the active disease Leishmania infection The of a of a infection is on the of a of leishmaniasis in of HIV-infected and the of VL in patients in areas, to endemic 16, 23, 113, The of an of disease infection is on the of VL the of patients in some reports that a of of the with This as and has been by this as the of patients was different patients with and This the cases of VL by of 141), the of new of the (11, and the by in HIV-infected patients. it has been that VL in hosts different clinical or study the of reports that the clinical features of leishmaniasis in individuals in immunocompetent hosts 138, 164). The between the in series was the of in as reported (23, 35, 124). in VL is to and it has been that the in to the of the response finding of study was the presentation of VL as of which in of patients. We reported that VL was the of this syndrome in of patients studied at A of atypical of infection has been reported in this 138, and We that of of VL are to observed in immunocompetent patients. of the of leishmaniasis in patients in this the have been with variable in immunocompetent is a of VL in the population 32, 122). study has that and were more in than in HIV infection is associated with a of and as and may this finding We have observed no in the of in of to is a finding in VL and HIV infection and the of has a diagnostic in patients with patients had at the of of and a low and a to was observed in patients. Diagnostic procedures marrow and are the used diagnostic procedures for VL in immunocompetent individuals 32, 122). In bone marrow and culture are used the diagnostic yield with no between and patients. The yield of the bone marrow in HIV-infected individuals by the bone marrow in HIV infection In a we reported the diagnostic yield of bone marrow culture in individuals which has been confirmed by authors 93, in the series the sensitivity of the culture was than the we that bone marrow for as by the finding that about of the patients had cultures The have been in these cases cultures for Leishmania had been In with reports 124, 141, we the diagnostic for VL to bone marrow with since VL but of of in individuals reports have the sensitivity of the in HIV-infected patients 93, 164). However, occur in than of the associated with this is a of studies have reported the diagnostic yield of the of peripheral blood and of the culture in VL 93, However, we that the sensitivity of blood culture was in The diagnostic of culture of clinical specimens in study to the low of The sensitivity of and in HIV-infected patients has been in studies 105, 113, 114, 164). The low yield of serologic studies is of the of 50% of patients a at results have been reported in in which the of was 93, 105, 113, 141, This is in to the in immunocompetent or of where titers are usually 22, 32, 60, The of to HIV infection in the of an response to Leishmania as for results have been reported in recent studies with the of techniques, as 141, Western and The of or more serologic techniques may the sensitivity of 141), and some have this in patients with VL 164). indirect with of peripheral blood and has been to the of VL in and with to treatment regimens by the immunocompetent patients with VL a response However, of the of VL is the response to studies have reported that of patients a clinical response (8, 23, 35, 93, 138, 141), and that a response is observed in 38%–81% of cases (8, 35, 93, study has confirmed the results of in of clinical and of the patients to In of patients to more than patients with VL have been the of the best and the duration of have been (11, 163). The treatment with antimonial of with a of in to for HIV-infected patients. of of with no on the have been for immunocompetent patients and these more in patients 124). has been used as a treatment for a of patients and some studies have reported results (8, 93, The results of a with have that the of regimens is in VL was in and of the patients with and In of patients, the response to the treatment with and was and in with to the of the patients, there were few to A response has been reported occasionally with these in and individuals but no comparative studies on the and have been reported to recommend the of therapies. The treatment patients the for therapies. A of has been used in this as 35, in with or in with and with variable has been used in patients with results However, the results with a response than studies that patients in the reports have that HIV may the response to antileishmanial and it may that a response to this treatment HIV is with antiretroviral We that an for VL in immunocompetent In with antimonial or for at in VL (11, about the is a for VL in We an and treatment for at are few reports that the of of VL (87, In a recent study the of of and was and We have observed a of with the different The of severe of and was and and it is that the was of an in about of the patients these of the features of with VL in the is to observed in of patients. In some patients a with relapses 93, 113, 124, 138, The that of patients a is since this is in than of cases in in immunocompetent patients A has been observed in patients and of VL are a common in immunocompetent individuals in some endemic of the This to or and of the but there is that it may to have been with of antimonial and The observed in patients is to the of leishmaniasis caused by the of the to the infection but the of out in some is that the of of Leishmania from some individuals has that to the that are to relapses and to In patients, the clinical presentation, the sensitivity of diagnostic procedures, and the response to treatment of relapses is to that of 93, 138, However, the of clinical about the the in relapses, the duration of the disease was and the of patients with of was than in the studies have an between the of antibodies or the of a with the of However, we that the of was the that had on the in patients. This has to the of different maintenance regimens in but the optimal has been and have been used as with variable the of for VL in patients 93, as is the for However, are to the of different as VL and The different clinical of VL in patients with that in immunocompetent individuals is the of We have observed that the is in and we that of patients in the of usually from A of has been reported (11, 23, 85, 93, 113, 124). patients from it is that leishmaniasis to the outcome by or by HIV reports have that HIV may the response to in VL and that active leishmaniasis is associated with and in individuals the that coinfection an in the and disease of infection may the of HIV infection as by the that between and of patients with in the the of VL 113, The in patients with VL from to 35, 113, 124, 163). study has confirmed that the is with that of immunocompetent The of the in this was the of with the of new reports have some that may the as the of 93, 113, 124, the the of at the of of and the In the of the of for and the were the for has been used in HIV-infected patients since and this treatment has led to a in and patients The of has been in some as and In with these study has a in of HIV-Leishmania patients series and some recent reports have a of VL in patients the of studies are to may the of VL patients. and the of are the reported for study has confirmed the of the in patients. The of on of patients with VL has been and this leishmaniasis diagnostic in patients with HIV The and the different clinical HIV-infected individuals have some and the of the to the of VL the diagnostic (8, 93, 113, 138, 163). The used to an disease as have been the of a with HIV presentation in the of the different clinical and the and of the disease associated with the HIV infection We have that VL as an infection in and that the are in AIDS-associated VL considered as an and in the to as HIV In leishmaniasis in clinical of the for and and considered the diseases of in HIV-infected Visceral leishmaniasis is an endemic infection in where it has a complication of acquired immunodeficiency syndrome The of leishmaniasis is in to human virus but some of epidemiology, clinical and In no comparative clinical studies about the disease in HIV-infected and non-HIV-infected patients have been a cases of leishmaniasis were at and 80 were associated with HIV The at was in HIV-infected that in non-HIV-infected patients but the was in The for HIV infection was The clinical presentation of leishmaniasis was in but HIV-infected patients had a of than individuals HIV-infected patients had a and of and of were profoundly at the of of and had The sensitivity of serologic studies for Leishmania was in HIV-infected than in non-HIV-infected patients but the diagnostic yield of bone marrow and bone marrow culture was in treatment, the response was in HIV-infected than in non-HIV-infected individuals The was and with antimonial or amphotericin to in relapses in HIV-infected patients. The was and the in patients than in leishmaniasis to in a of HIV-infected patients, it was the of in a few of The and the of active antiretroviral and for leishmaniasis were the for in patients. Visceral leishmaniasis as an infection in HIV-infected individuals and considered as an We reports of VL in HIV-infected patients to the clinical of disease associated with The the typical clinical of to that in immunocompetent The has an atypical clinical characterized by a of and clinical A to the hospital in with a and for HIV had had fever, and for had a of 40 and were and serum for Leishmania was with a of marrow and cultures of blood and bone marrow of Leishmania for HIV was and the was was in The a of with of and of clinical the and were but a bone marrow culture to Leishmania was maintenance treatment with and and until the in clinical A in with a of fever, and and were and for HIV was and the was The antileishmanial was Leishmania were in bone marrow and a of and was in clinical treatment was and a bone marrow and culture were for in in January with and The and The and Leishmania were from blood The was in clinical and no treatment was the few and and to the hospital in with The were and in and on the and The a and were from the was with and with of and of pancytopenia, and The treatment was until the was for a of and were of leishmaniasis was by bone marrow and This treatment was of but the and in was The diagnostic of bone marrow and blood cultures The cases of VL the diagnostic of bone marrow and blood patients had a clinical of VL but the routine diagnostic procedures were in was by bone marrow culture the in results of the bone marrow and This had a a few cultures were but the bone marrow studies and were by bone marrow culture A with was in January of of was an and had been with and had had for and had and and and the were and was were for were on a of the bone marrow and but Leishmania were a of with of the and of clinical the bone marrow Leishmania and the culture was for with clinical had relapses of leishmaniasis that were by blood bone marrow bone marrow The serologic were the of the in from treatment for the by blood culture A was in December with a and had been a and was with HIV infection and of fever, and and a of a of a of and a serum of The antileishmanial was and the was The bone marrow and culture were for but Leishmania were from blood was with for with clinical was for and and A marrow with culture was for was with and for with of clinical was for fever, and and the bone marrow and Leishmania and were cultures were for a of and and was with a of with clinical The bone marrow and culture were at the of treatment and was in clinical in from treatment for a of The the typical occasionally in these The had relapses of VL a of that in of of with and and as as with A with a of was to the hospital in had had a for and the a of a of and a of The antileishmanial was marrow of Leishmania but the culture was for for HIV was and the was was in a clinical and was with and for with clinical to the hospital in with and of marrow of Leishmania but the culture was cultures of Leishmania a of and was in clinical In January the was and was in of fever, and had and severe marrow but the culture was was with a of and with of clinical was as clinical was by and was in with of and and the The and the had clinical A bone marrow Leishmania and was In the was as and was clinical and the were in was This was in by the of We of of for with of for about and for with the We the of the of the Hospital for and of the patients.