Carmen Cañavate

Leishmania and human immunodeficiency virus coinfection: the first 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.

The Relationship between Leishmaniasis and AIDS: the Second 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.

Spread of Vector-borne Diseases and Neglect of Leishmaniasis, Europe

Exotic vector-borne diseases are gaining attention at the expense of leishmaniasis.

A nested polymerase chain reaction (Ln-PCR) for diagnosing and monitoring Leishmania infantum infection in patients co-infected with human immunodeficiency virus

We investigated a Leishmania-specific nested polymerase chain reaction (Ln-PCR) for the diagnosis and treatment monitoring of L. infantum infections in patients co-infected with human immunodeficiency virus (HIV). Peripheral blood and bone marrow samples from 89 HIV patients in Spain suspected of having leishmaniasis were examined by different diagnostic techniques (Ln-PCR, microscopy, NNN culture and indirect fluorescent antibody test). The sensitivity of Ln-PCR compared with microscopy and culture of bone marrow was 95.45% using blood and 100% when using bone marrow. 38 of these patients with confirmed leishmaniasis were entered in a chemotherapy trial (reported elsewhere), and samples from them were collected before treatment, one month after treatment ended and during follow-up (1-20 months), and examined similarly. Ln-PCR was shown to be a good method for testing efficacy of treatment and for predicting relapses after treatment (relapses were predicted on average 5 months earlier than when using classical diagnostic techniques). We suggest that Ln-PCR (especially using peripheral blood) should be the technique of choice for diagnosis, monitoring the success of treatment, and predicting relapses in patients with HIV and suspected or confirmed L. infantum infection.

Comparison of New Diagnostic Tools for Management of Pediatric Mediterranean Visceral Leishmaniasis

ABSTRACT New techniques are available for diagnosing leishmaniasis, but their efficacy in the identification of pediatric visceral leishmaniasis (VL) has not been compared with that of traditional methods. Blood, bone marrow, and urine samples were taken from 25 children with VL during their first clinical episode, 22 days after the start of treatment with liposomal amphotericin B (3 mg/kg/day on 6 days over a 10-day period), and when a relapse was suspected during follow-up. The results obtained suggest that antibody detection techniques, the antigen detection in urine (KAtex kit), and Leishmania nested PCR (LnPCR) analysis of the blood could be used for diagnosis of the first clinical episode. After treatment, clinical improvement was associated with negativization of Novy-MacNeal-Nicolle culture and microscopy of bone marrow aspirate, KAtex test, and LnPCR blood analysis results. Interestingly, LnPCR analysis of the bone marrow aspirate showed that sterile cure was not achieved in eight patients, two of which suffered a relapse within 10 to 20 weeks. All of the new noninvasive techniques tested showed high diagnostic sensitivity. However, LnPCR analysis of the bone marrow was the most sensitive; this test was able to detect the persistence of parasites and predict potential relapses.

Leishmaniases in the Mediterranean in the era of molecular epidemiology

Molecular tools are used increasingly for descriptive epidemiological studies in different Mediterranean foci of visceral and cutaneous leishmaniases. Several molecular markers with different resolution levels have been developed to address key epidemiological questions related to the (re-)emergence and spread of leishmaniases, as well as its risk factors: environmental changes, immunosuppression and treatment failure. Typing and analytical tools are improving but are not yet addressing all epidemiological issues satisfactorily. There is an urgent need for better cooperation between laboratory scientists and epidemiologists and for regional epidemiological surveillance of these infectious diseases that affect all Mediterranean countries.

Differentiation and Gene Flow among European Populations of Leishmania infantum MON-1

Background Leishmania infantum is the causative agent of visceral and cutaneous leishmaniasis in the Mediterranean region, South America, and China. MON-1 L. infantum is the predominating zymodeme in all endemic regions, both in humans and dogs, the reservoir host. In order to answer important epidemiological questions it is essential to discriminate strains of MON-1. Methodology/Principal Findings We have used a set of 14 microsatellite markers to analyse 141 strains of L. infantum mainly from Spain, Portugal, and Greece of which 107 strains were typed by MLEE as MON-1. The highly variable microsatellites have the potential to discriminate MON-1 strains from other L. infantum zymodemes and even within MON-1 strains. Model- and distance-based analysis detected a considerable amount of structure within European L. infantum. Two major monophyletic groups—MON-1 and non-MON-1—could be distinguished, with non-MON-1 being more polymorphic. Strains of MON-98, 77, and 108 were always part of the MON-1 group. Among MON-1, three geographically determined and genetically differentiated populations could be identified: (1) Greece; (2) Spain islands–Majorca/Ibiza; (3) mainland Portugal/Spain. All four populations showed a predominantly clonal structure; however, there are indications of occasional recombination events and gene flow even between MON-1 and non-MON-1. Sand fly vectors seem to play an important role in sustaining genetic diversity. No correlation was observed between Leishmania genotypes, host specificity, and clinical manifestation. In the case of relapse/re-infection, only re-infections by a strain with a different MLMT profile can be unequivocally identified, since not all strains have individual MLMT profiles. Conclusion In the present study for the first time several key epidemiological questions could be addressed for the MON-1 zymodeme, because of the high discriminatory power of microsatellite markers, thus creating a basis for further epidemiological investigations.

Drug regimens for visceral leishmaniasis in Mediterranean countries

Until the early 1990s, pentavalent antimony was the only documented first‐line drug employed for the treatment of zoonotic visceral leishmaniasis (VL) in the Mediterranean, with reported cure rates exceeding 95% in immunocompetent patients. The emergence of antimony resistance in other endemic settings and the increase in drug options have stimulated re‐evaluation of the current therapeutic approaches and outcomes in Mediterranean countries. A scientific consortium (‘LeishMed’ network) collected updated information from collaborating clinical health centres of 11 endemic countries of Southern Europe, Northern Africa and the Middle East. In contrast with the previous situation, VL is now treated differently in the region, basically through three approaches: (1) In Northern Africa and in part of the Middle East, pentavalent antimony is still the mainstay for therapy, with no alternative drug options for treating relapses; (2) In some European countries and Israel, both pentavalent antimony and lipid‐associated amphotericin B (AmB) formulations are used as first‐line drugs, although in different patients’ categories; (3) In other countries of Europe, mainly liposomal AmB is employed. Importantly, cure rates exhibited by different drugs, including antimonials in areas where they are still in routine use, are similarly high (≥95%) in immunocompetent patients. Our findings show that antimony resistance is not an emerging problem in the Mediterranean. A country’s wealth affects the treatment choice, which represents a balance between drug efficacy, toxicity and cost, and costs associated with patient’s care.

Transfusional Chagas Disease: Parasitological and Serological Monitoring of an Infected Recipient and Blood Donor

Chagas disease is endemic to Latin America, but human migration is extending its distribution. This report describes the parasitological and serological course of disease in a Spanish patient fatally infected via a blood product transfusion, as well as the monitoring of the donor. Before undergoing immunosuppression, multitransfused patients should be screened for anti-Trypanosoma cruzi antibodies.

Variability of Leishmania (Leishmania) infantum among stocks from immunocompromised, immunocompetent patients and dogs in Spain

Leishmania (Leishmania) infantum is the causative agent of both the cutaneous and visceral forms of leishmaniasis in southwest Europe; the dog is the main reservoir. In order to identify the L. (L.) infantum zymodemes present in Spain, a total number of 85 Leishmania stocks isolated from dogs (31), HIV-positive patients (46) with visceral or cutaneous leishmaniasis, a patient with visceral leishmaniasis complicating renal transplantation (1) and immunocompetent patients (7) with visceral or cutaneous leishmaniasis, have been characterized by isoenzyme typing. All canine stocks were MON-1, which is the most widespread zymodeme in the Mediterranean area. In immunocompetent patients three zymodemes were found: MON-1 (2), MON-24 (2) and MON-34 (3). Nine different zymodemes were obtained in stocks from HIV co-infected patients, indicating a higher variability of L. (L.) infantum amongst them: MON-1 (in 21 stocks), MON-24 (7), MON-28 (1), MON-29 (3), MON-33 (7), MON-34 (1) and MON-183 (4). Two new zymodemes, MON-198 (1) and MON-199 (1), were described among HIV patients from Spain. The stock from the renal transplanted patient was MON-1. The exclusive presence of certain zymodemes in immunocompromised patients and their absence in typical cases of cutaneous and visceral leishmaniasis and in infected dogs suggests two possibilities: (i) an anthroponotic pattern of leishmaniasis where intravenous drug user-infected patients act as potential reservoir for these new zymodemes. In the latter, syringes could act as the vehicles for infected monocytes; (ii) the cellular immune system could select virulent from non-virulent zymodemes in immunocompetent visceral leishmaniasis patients.