The current interest in leishmaniasis stems from the importance of this disease with respect to travel medicine, veterans of Operation Desert Storm, humanitarian concerns, and infection with human immunodeficiency virus. Herein, I review aspects of leishmaniasis that are of practical value to practitioners, including presentation, diagnosis, and chemotherapy; I will emphasize advances in chemotherapy over the last 10 years. Amphotericin B and its new lipid formulations are now competitive with pentavalent antimony as primary therapy for visceral leishmaniasis. Pentamidine, paromomycin, and adjunctive therapy with interferon-gamma are secondary regimens for the treatment of this condition. High-dose long-term regimens of antimony have been shown to be highly effective for the treatment of cutaneous leishmaniasis. Preliminary evidence of efficacy has been observed with short courses of pentamidine for the treatment of Leishmania braziliensis complex disease and topical paromomycin/methylbenzethonium chloride for the treatment of Leishmania major disease.

Human leishmaniasis: clinical, diagnostic, and chemotherapeutic developments in the last 10 years.

Summary: To date, most Leishmania and human immunodeficiency virus (HIV) coinfection cases reported to WHO come from Southern Europe. Up to the year 2001, nearly 2,000 cases of coinfection were identified, of which 90% were from Spain, Italy, France, and Portugal. However, these figures are misleading because they do not account for the large proportion of cases in many African and Asian countries that are missed due to a lack of diagnostic facilities and poor reporting systems. Most cases of coinfection in the Americas are reported in Brazil, where the incidence of leishmaniasis has spread in recent years due to overlap with major areas of HIV transmission. In some areas of Africa, the number of coinfection cases has increased dramatically due to social phenomena such as mass migration and wars. In northwest Ethiopia, up to 30% of all visceral leishmaniasis patients are also infected with HIV. In Asia, coinfections are increasingly being reported in India, which also has the highest global burden of leishmaniasis and a high rate of resistance to antimonial drugs. Based on the previous experience of 20 years of coinfection in Europe, this review focuses on the management of Leishmania-HIV-coinfected patients in low-income countries where leishmaniasis is endemic.

https://www.who.int/leishmaniasis/burden/hiv_coinfection/Clinical_Microbiology_Reviews_2008.pdf

The Relationship between Leishmaniasis and AIDS: the Second 10 Years

Over 850 Leishmania-human immunodeficiency virus (HIV) coinfection cases have been recorded, the majority in Europe, where 7 to 17% of HIV-positive individuals with fever have amastigotes, suggesting that Leishmania-infected individuals without symptoms will express symptoms of leishmaniasis if they become immunosuppressed. However, there are indirect reasons and statistical data demonstrating that intravenous drug addiction plays a specific role in Leishmania infantum transmission: an anthroponotic cycle complementary to the zoonotic one has been suggested. Due to anergy in patients with coinfection, L. infantum dermotropic zymodemes are isolated from patient viscera and a higher L. infantum phenotypic variability is seen. Moreover, insect trypanosomatids that are currently considered nonpathogenic have been isolated from coinfected patients. HIV infection and Leishmania infection each induce important analogous immunological changes whose effects are multiplied if they occur concomitantly, such as a Th1-to-Th2 response switch; however, the consequences of the viral infection predominate. In fact, a large proportion of coinfected patients have no detectable anti-Leishmania antibodies. The microorganisms share target cells, and it has been demonstrated in vitro how L. infantum induces the expression of latent HIV-1. Bone marrow culture is the most useful diagnostic technique, but it is invasive. Blood smears and culture are good alternatives. PCR, xenodiagnosis, and circulating-antigen detection are available only in specialized laboratories. The relationship with low levels of CD4+ cells conditions the clinical presentation and evolution of disease. Most patients have visceral leishmaniasis, but asymptomatic, cutaneous, mucocutaneous, diffuse cutaneous, and post-kala-azar dermal leishmaniasis can be produced by L. infantum. The digestive and respiratory tracts are frequently parasitized. The course of coinfection is marked by a high relapse rate. There is a lack of randomized prospective treatment trials; therefore, coinfected patients are treated by conventional regimens. Prophylactic therapy is suggested to be helpful in preventing relapses.

Leishmania and human immunodeficiency virus coinfection: the first 10 years.

From the early 1900s, visceral leishmaniasis (VL; kala-azar) has been among the most important health problems in Sudan, particularly in the main endemic area in the eastern and central regions. Several major epidemics have occurred, the most recent--in Western Upper Nile province in southern Sudan, detected in 1988--claiming over 100,000 lives. The disease spread to other areas that were previously not known to be endemic for VL. A major upsurge in the number of cases was noted in the endemic area. These events triggered renewed interest in the disease. Epidemiological and entomological studies confirmed Phlebotomus orientalis as the vector in several parts of the country, typically associated with Acacia seyal and Balanites aegyptiaca vegetation. Infection rates with Leishmania were high, but subject to seasonal variation, as were the numbers of sand flies. Parasites isolated from humans and sand flies belonged to three zymodemes (MON-18, MON-30 and MON-82), which all belong to the L. donovani sensu lato cluster. Transmission dynamics have not been elucidated fully; heavy transmission in relatively scarcely populated areas such as Dinder national park suggested zoonotic transmission whereas the large numbers of patients with post kala-azar dermal leishmaniasis (PKDL) in heavily affected villages may indicate a human reservoir and anthroponotic transmission. Clinical presentation in adults and in children did not differ significantly, except that children were more anaemic. Fever, weight loss, hepato-splenomegaly and lymphadenopathy were the most common findings. PKDL was much more common than expected (56% of patients with VL developed PKDL), but other post-VL manifestations were also found affecting the eyes (uveitis, conjunctivitis, blepharitis), nasal and/or oral mucosa. Evaluation of diagnostic methods showed that parasitological diagnosis should still be the mainstay in diagnosis, with sensitivities for lymph node, bone marrow and spleen aspirates of 58%, 70% and 96%, respectively. Simple, cheap serological tests are needed. The direct agglutination test (DAT) had a sensitivity of 72%, specificity of 94%, positive predictive value of 78% and negative predictive value of 92%. As with other serological tests, the DAT cannot distinguish between active disease, subclinical infection or past infection. The introduction of freeze-dried antigen and control sera greatly improved the practicality and accuracy of the DAT in the field. An enzyme-linked immunosorbent assay using recombinant K39 antigen had higher sensitivity than DAT (93%). The polymerase chain reaction using peripheral blood gave a sensitivity of 70-93% and was more sensitive than microscopy of lymph node or bone marrow aspirates in patients with suspected VL. The leishmanin skin test (LST) was typically negative during active VL and converted to positive in c. 80% of patients 6 months after treatment. Immunological studies showed that both Th1 and Th2 cell responses could be demonstrated in lymph nodes from VL patients as evidenced by the presence of messenger ribonucleic acid for interleukin (IL)-10, interferon gamma and IL-2. Treatment of peripheral blood mononuclear cells from VL patients with IL-12 was found to drive the immune response toward a Th1 type response with the production of interferon gamma, indicating a potential therapeutic role for IL-12. VL responded well to treatment with sodium stibogluconate, which is still the first line drug at a dose of 20 mg/kg intravenously or intramuscularly per day for 15-30 d. Side effects and resistance were rare. Liposomal amphotericin B was effective, with few side effects. Control measures have not been implemented. Based on observations that VL does not occur in individuals who have a positive LST, probably because of previous cutaneous leishmaniasis, a vaccine containing heat-killed L. major promastigotes is currently undergoing a phase III trial.

Leishmaniasis in Sudan. 3. Visceral leishmaniasis

As the AIDS pandemic spreads to rural areas and human visceral leishmaniasis (VL) becomes more common in suburban areas, there is an ever greater degree of overlap between the geographical distributions of the two diseases and, in consequence, an increasing incidence of Leishmania/HIV co-infection. Cases of the co-infection have been reported from 35 countries around the world but most have been recorded in south-western Europe. There has been a total of 1911 cases detected in Spain, France, Italy and Portugal. The incidence of Leishmania/HIV co-infection is expected to continue increasing in eastern Africa but to fall in south-western Europe as increasing numbers of HIV-positives in the latter region are given the new, highly active, antiretroviral therapy (HAART). In 1998, a world-wide network of surveillance for the co-infection, which now includes 28 member institutions, was established by the World Health Organization (WHO) and the Joint United Nations Programme on HIV/AIDS (UNAIDS). In south-western Europe, the surveillance system is based on 16 institutions and is already well established. The systematic use of standardized and recently computerized case-report forms, a central international registry at the WHO's headquarters in Geneva, and the use of a geographical information system (GIS) for mapping and monitoring the co-infections have together improved the overall quality of the epidemiological data-gathering. All member institutions of the global network report to the WHO on an annual basis. The data collected are then analysed and periodically disseminated through international publications. The GIS allows the relevant epidemiological and demographic data-sets to be integrated and permits all detected cases of co-infection to be mapped down to locality level. The system also allows the spatial distribution of cases to be visualised and analysed and the geographical spread of the co-infection to be monitored over time. The risk posed by co-infected patients, as a source of Leishmania infection for the sandflies feeding on them, has recently been confirmed. The parasites and HIV may also be transmitted as the result of needle-sharing among intravenous-drug users.

https://www.who.int/leishmaniasis/burden/hiv_coinfection/en/ATMP1.pdf

Leishmania/HIV co-infections: epidemiology in Europe.

The authors sought to compare the clinical and laboratory features of visceral leishmaniasis (kala-azar) in HIV-infected and noninfected subjects and to determine the presence of Leishmania amastigotes in circulating leukocytes using peripheral blood smears. 28 HIV-infected and 6 HIV-negative adult patients diagnoses as having kala-azar and presenting at one institution over a 7-year period were studied by performing a retrospective review of their clinical charts and a reexamination of their peripheral blood smears. There were no significant differences in the clinical presentation and laboratory features of HIV-positive and HIV-negative patients. However Leishmania amastigotes were observed in circulating leukocytes in 8 of 17 available peripheral blood smears (15 from HIV-infected patients). All 8 individuals presenting with Leishmania in peripheral blood leukocytes were HIV-positive. The authors concluded that direct visualization of Leishmania amastigotes in leukocytes on peripheral blood smears enabled the diagnosis of kala-azar in a high proportion (8 of 15; 53%) of the HIV-infected patients. (authors modified)

Diagnosis of visceral leishmaniasis in HIV-infected individuals using peripheral blood smears.

Pyomyositis in patients with HIV infection.

BACKGROUND The rate of progression to AIDS in HIV-1 infected subjects is variable, and circumstances associated with more rapid or slow development of severe immunodeficiency might be grouped in three categories; environmental cofactors, host features, and particular virulence of the virus itself Currently, it is not yet clear the the relative impact of each one PATIENTS AND METHODS A cross-sectional study was done in a cohort of 1,783 IV-1 infected persons from three centers located in Madrid, mainly devoted to attend persons at risks for HIV infection Long-term nonprogressors (LTNP) were defined as those with more than 8 years of confirmed HIV seropositivity, and CD4+ T-cell count above 500 x 10(6)/I in the absence of antiretroviral therapy or symptoms suggesting immunodeficiency Rapid progressors (RP) were those with less than 5 years from seroconversion and repeatedly current CD4+ T-cell count below 200 x 10(6)/I An analysis of different epidemiological, immunological and virological features was performed comparing LTNP and RP RESULTS Among 1,783 HIV (+) subjects studied, 100 (56%) fulfilled criteria for LTNP and 12 (07%) for RP Among LTNP, stabilized CD4 slope was seen in 16 (33%) out of 48 after more than 8 years of infection Variables statistically associated with LTNP were: past history of intravenous drug addiction (80% of them), male gender (79% of them), high alcohol intake (48% of them), HIV-1 non-syncitium inducing viral phenotype, and very low or undetectable HIV-1 plasma viremia In contrast, variables associated with RP were: infection by sexual contact (75% of cases), female gender (50% of them), syncitium-inducing viral plenotype, and high titers of plasma viremia The CD4/CD8 ratio below 1 was seen in all RP and in 88% of LTNP However, a preferent depletion of CD4+ cell occurred in the first group, instead of an enhancement of the CD8 T-cell count in LTNP The prevalence of serological markers for hepatotropic viruses and other potential infectious cofactors was not higher in RP CONCLUSIONS Multiple factors seems to account for the different rate of disease progression observed in HIV-1 infected persons The dynamic equilibrium between the immune system and the virulence of the virus seem to be influenced--but not determined--by environmental infectious or non infectious cofactors

Rapid and slow progression of the infection by the type 1 human immunodeficiency virus in a population of seropositive subjects in Madrid

BACKGROUND Methicillin-resistant Staphylococcus aureus (MRSA) frequently occurs with nosocomial infections. Although human immunodeficiency virus (HIV) infected subjects spend a long time in hospital, the transmission of MRSA nosocomial infections in this group of patients has not been previously reported previously. PATIENTS AND METHODS A clinical sample of 14 HIV infected patients from an Infectious Diseases Unit, in whom MRSA had been isolated, were evaluated as part of a 6 months prospective study. The measures employed in assessing infectivity were the prospective surveillance of all those isolated and the search for carriers in associated health-workers. RESULTS The potential index case was a patient with an isolated MRSA pneumonia. From him, it was transmitted to his cohabitors and to the rest of the Unit. All the patients had AIDS and 13 presented with MRSA-associated symptoms. Five were admitted 30 days previously and 12 had intravenous catheters. The mean time for the appearance of the infection was 16 days. In the antibiotic investigations multiresistance was confirmed and in the 13 symptomatic cases systemic treatment with vancomycin was indicated requiring replacement by teicoplanin in 50% due to adverse reactions. Two years later, the 14 patients had died but only one in relation to MRSA. Of the health-workers, one carrier was detected. The line of decolonization with mupirocin was efficatious. CONCLUSIONS The MRSA nosocomial infection in HIV infected patients took place in subjects who were immunodepressed and had a prolonged mean time of hospitalization. The treatment with vancomycin and/or teicoplanin was effective in the majority of the cases.

Nosocomial infection with methicillin resistant Staphylococcus aureus in 14 human immunodeficiency virus infected patients

BACKGROUND Infections in subjects with HIV-1 infection are a frequent cause of hospital admission. Knowledge of the entities which most often motivate hospitalization may aid in designing the most appropriate diagnostic and prophylactic strategies. The causes of hospital admission in individuals with risk practices for HIV-1 infection attended in a Department of Infectious Diseases in Madrid over a period of 4 years were analyzed. METHODS The records of the patients admitted from 1989 to 1992 were retrospectively reviewed. The principal and associated diagnoses which led to hospitalization were considered. The admissions of the two years were compared. RESULTS Bacterial pneumonias were the principal cause of hospitalization in the 2 years studied. Forty-five percent of the infections leading to hospital admission were not included among those defining AIDS. Tuberculosis was the most frequent opportunistic infection. Admissions due to pulmonary pneumocystosis, tuberculosis, toxoplasmosis, esophageal candidiasis and Kaposi's sarcoma decreased from 1989-1992. To the contrary, disseminated Mycobacterium avium complex infection and systemic infection by cytomegalovirus significantly increased over the same period. The incidence of other diseases such as endocarditis or leishmaniasis remained stable. More than half of the diseases were diagnosed in association with another entity during the same admission. Likewise, an increase in atypical forms of infections thus making diagnosis and treatment more difficult was observed. The first cases of multiresistant tuberculosis, all of rapidly fatal evolution, were identified in 1992. Mean hospital stay increased 30% and the rate of mortality was of 9% in 1989 and rose to 20% in 1992. CONCLUSIONS The spectrum of infections which led to hospital admission of patients with HIV-1 infection has significantly modified over the last 4 years being related with the generalization of prophylactic medication for some opportunistic infections, the improvement of certain diagnostic techniques and more frequent ambulatory treatment of some diseases. The mean length of stay and hospital mortality have increased in the HIV+ population.

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Papers

Diagnosis of visceral leishmaniasis in HIV-infected individuals using peripheral blood smears.

Pyomyositis in patients with HIV infection.

Rapid and slow progression of the infection by the type 1 human immunodeficiency virus in a population of seropositive subjects in Madrid

Nosocomial infection with methicillin resistant Staphylococcus aureus in 14 human immunodeficiency virus infected patients

Changes in the spectrum of the diseases in patients hospitalized with HIV infection