Article:New insights into leishmaniasis in the immunosuppressed. (5944929)

From ScienceSource
Revision as of 12:01, 15 April 2019 by Charles Matthews (talk | contribs) (Protected "Article:New insights into leishmaniasis in the immunosuppressed. (5944929)" ([Edit=Allow only administrators] (indefinite)))
(diff) ← Older revision | Latest revision (diff) | Newer revision → (diff)
Jump to: navigation, search

This page is the ScienceSource HTML version of the scholarly article described at https://www.wikidata.org/wiki/Q53683717. Its title is New insights into leishmaniasis in the immunosuppressed. and the publication date was 2018-05-10. The initial author is Hannah Akuffo.

Fuller metadata can be found in the Wikidata link, which lists all authors, and may have detailed items for some or all of them. There is further information on the article in the footer below. This page is a reference version, and is protected against editing.



Converted JATS paper:

Journal Information

Title: PLoS Neglected Tropical Diseases

New insights into leishmaniasis in the immunosuppressed

  • Hannah Akuffo
  • Carlos Costa
  • Johan van Griensven
  • Sakib Burza
  • Javier Moreno
  • Mercè Herrero

[1]Swedish International Development Agency (Sida), and Microbiology, Tumor and Cell biology (MTC), Karolinska Institutet, Solna, Sweden

[2]Federal University of Piauí, Teresina-PI, Brazil

[3]Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium

[4]Médecins Sans Frontières, New Delhi, India

[5]World Health Centre (WHO) Collaborating Centre for Leishmaniasis, National Centre for Microbiology, Instituto de Salud Carlos III, Madrid, Spain

[6]Leishmaniasis, IDM Unit, Neglected Tropical Diseases, WHO, Geneva, Switzerland

  • Sima Rafati (Editor)

Pasteur Institute of Iran, ISLAMIC REPUBLIC OF IRAN

Publication date (epub): 5/2018

Publication date (collection): 5/2018

Abstract

Immunosuppression contributes significantly to the caseload of visceral leishmaniasis (VL). HIV coinfection, solid organ transplantation, malnutrition, and helminth infections are the most important immunosuppression-related factors. This review briefly describes the challenges of these associations. East Africa and the Indian subcontinent are the places where HIV imposes the highest burden in VL. In the highlands of Northern Ethiopia, migrant rural workers are at a greater risk of coinfection and malnutrition, while in India, HIV reduces the sustainability of a successful elimination programme. As shown from a longitudinal cohort in Madrid, VL is an additional threat to solid organ transplantation. The association with malnutrition is more complex since it can be both a cause and a consequence of VL. Different regimes for therapy and secondary prevention are discussed as well as the role of nutrients on the prophylaxis of VL in poverty-stricken endemic areas.

Paper

Introduction

Immunosuppression is associated with leishmaniasis. It is more frequently described in association with visceral leishmaniasis (VL) as it is one of the consequences of the disease, especially in the latter stages. VL occurs both in the ‘Old World’ and in the ‘New World’, often in underresourced areas of conflict and instability. The causative agents of VL are those in the Leishmania donovaniL. infantum complex. However, other species of Leishmania that cause cutaneous or mucocutaneous leishmaniasis have also been described as resulting in immunosuppression.

Immunosuppression in leishmaniasis may stem from the leishmanial infection itself, but it can be further exacerbated by comorbidities involving coinfections with pathogens, such as Human Immunodeficiency Virus (HIV) and helminths, or through morbidity associated with malnutrition.

Methods

Treatment of VL is difficult in patients with certain comorbidities. This paper, developed after deliberations at a session on the subject at the WorldLeish 2017, discusses the value of antiretroviral treatment (ART) in VL–HIV patients, illustrates the contrasting picture of VL–HIV in East Africa and Asia, examines VL in immunosuppressed patients after transplantation, and considers the need for nutritional supplements as a treatment adjunct in VL-endemic countries with widespread malnutrition. We elaborate on how immunosuppression due to HIV coinfection and malnutrition exacerbates the symptoms of VL as well complicates treatment. We illustrate the many things that we do not understand to date but also other things where there remains a ‘know–do gap’, a gap between evidence and effective implementation.

Results

Helminths

Experimental coinfection with Schistosoma mansoni and L. donovani in mice showed that those with established S. mansoni infections fail to control L. donovani growth in the liver and spleen [[1]]. The influence of helminth coinfection on cutaneous leishmaniasis has also been presented in a number of studies but with conflicting results, which may be because the impact of helminth coinfection on leishmanial lesion growth appears to be time dependent [[2]].

Furthermore, helminth infections have been reported to influence the clinical course and the immune response to cutaneous leishmaniasis caused by L. braziliensis. Patients with L. braziliensis coinfected with helminths healed at a slower rate compared to patients without coinfection, suggesting a role for screening and treatment of helminths to improve the outcomes of L. braziliensis treatment and potentially reduce the risk of progression to mucosal disease [[3]]. However, subsequent randomised clinical trials showed that treating helminths did not make a difference in treatment outcomes [[4]].

HIV

HIV infection has been shown to appreciably increase the risk of developing VL in endemic areas, reduce the chances for adequate therapeutic response, and greatly increase the likelihood of relapse. In vitro studies showed that the addition of HIV to human mononuclear cell cultures altered the T helper cell cytokines induced in response to L. donovani stimulation [[5]].

Subsequent studies in Ethiopian HIV-coinfected VL patients demonstrated that the outcome of both conditions was worsened, with enhanced severity of the VL and acceleration of HIV progression.

The current picture of VL seen in East Africa and that in Asia differ considerably, with the picture in India, Nepal, and Bangladesh moving towards elimination of VL as a public health problem based on political commitment coupled with focused studies aimed at improving treatment. The measures taken in this elimination agenda has led to improved surveillance and, in turn, better identification of VL–HIV.

VL–HIV coinfection in East Africa

East Africa has an estimated VL caseload of around 30,000 cases annually. Several areas face high rates of HIV coinfection. This is most marked in Northwestern Ethiopia, where coinfection rates of approximately 20% have been reported [[6]]. In part, this relates to the high number of young seasonal workers migrating to the area from VL-nonendemic highlands [[6]].

As in the rest of the world, the standard of care for VL–HIV coinfected patients in East Africa consists of several components. Besides aiming to achieve parasitologically confirmed VL cure, early initiation of ART is vital. This should be followed by secondary prophylaxis, targeting those at highest risk of VL relapse [[6]].

Within East Africa, the first-line treatment in HIV-negative patients consists of parenteral administration of antimonials and paromomycin for 17 days. Overall, this combination therapy was found effective and safe, although the daily intramuscular injections can be painful [[6]]. For HIV patients, WHO guidelines recommend liposomal amphotericin B at a total dose of 40 mg/kg [[7]]. Although there are a number of commercially available preparations of lipidic and liposomal formulations of amphotericin B available, at present, the only liposomal preparation procured for use in VL by WHO is the liposomal formulation AmBisome (Gilead Sciences; San Dimas, California, United States of America). There are a number of noninferiority studies ongoing with other preparations; however, to date, safety and effectiveness results have not been encouraging [[8]]. Additionally, the lack of a clear regulatory pathway for the registration of these other formulations complicates the entry of new competitors on the markets [[8]]. As such, outside of nongovernmental organisation (NGO) settings, availability is often limited.

Regarding treatment of VL in HIV-positive patients, most drugs have proven disappointing (Table 1). The Médecins Sans Frontières (MSF) experience with a combination regimen consisting of AmBisome (Gilead Sciences; San Dimas, California, USA) 30 mg/kg and miltefosine for 28 days looks promising, with initial cure rates of 81% [[6]]. Based on this experience, Drugs for Neglected Diseases initiative (DNDi) is conducting a randomised controlled trial with two arms: (1) AmBisome 30 mg/kg combined with miltefosine for 28 days and (2) AmBisome 40 mg/kg in monotherapy [[9]]. Data are expected to be reported soon.

10.1371/journal.pntd.0006375.t001Table 1
Objective Status: Experience in Northwestern Ethiopia
Achieving parasitological cure Antimonials: toxicity, suboptimal efficacy [[10]]Miltefosine: safe but limited efficacy [[11]]AmBisome 30 mg/kg: safe but limited efficacy [[12]]• Initial treatment cure rate of 74% in primary VL and 38% in relapsed VL; overall cure rate 59%AmBisome 30 mg/kg IV + miltefosine PO for 28 days in compassionate use [[6]]• Initial cure rate of 81%
Early ART initiation Retrospective patient file review in one referral and one district hospital in Northwestern Ethiopia. Amongst newly diagnosed VL–HIV patients, ART uptake was 28% (13/47) at the district hospital and 61% (30/49) at the referral hospital [[13]]
Preventing VL relapse (secondary prophylaxis) Single-arm clinical trial evaluating monthly administration of pentamidine 4 mg/kg IV for a minimum of 12 months; a 6-month extension was given for those with CD4 counts ≤ 200 cells/μL by 12 months of pentamidine [[6], [14]]. No relapse after pentamidine discontinuation if CD4 counts > 200 cells/μL by 12 months of pentamidine (0/28)3 out of 17 relapses in those with CD4 counts ≤ 200 cells/μL by 12 months, despite a 6-month pentamidine extension
Preventing primary VL (primary prophylaxis) PreLeisH study (Northern Ethiopia): Multicentre observational cohort studyHIV patients in HIV care and living in a VL-endemic area will be followed for 2 years with clinical/laboratory evaluation every 3 months. The incidence of asymptomatic Leishmania infection will be determined, and a clinical prediction tool to predict the onset of VL will be developed [[15]].

Abbreviations: ART, antiretroviral treatment; CD4, cluster of differentiation 4; IV, intravenously; PO, per os (oral treatment); VL, visceral leishmaniasis.

Several studies from Ethiopia have shown the importance of ART initiation in VL–HIV coinfected patients to reduce mortality and relapse rates [[6], [16]]. However, studies looking at ART uptake in routine programme conditions are lacking. In a retrospective patient file review conducted in Northern Ethiopia, ART uptake—defined as documented proof of ART prescription in VL patients—in newly diagnosed VL–HIV patients was fair (61%) at the referral-hospital level but poor (28%) at the district hospital [[13]] (Table 1). This poor uptake could be due to many factors, including poor documentation and information exchange between referring and recipient facilities. Another factor is that VL–HIV coinfection predominantly occurs in highly mobile populations (e.g., seasonal migrants), who might move back to their place of origin for ART initiation. Alternatively, it is possible that a substantial proportion become lost to follow-up and never start ART, or with long delays.

Data on secondary prophylaxis of VL in HIV patients in anthroponotic (L. donovani) areas are limited to a single-arm trial, evaluating the use of monthly administration of pentamidine, a drug currently not in use for VL treatment in East Africa. Previously, the outcomes at 12 months of pentamidine use supporting the effectiveness, safety, and feasibility of this intervention have been reported [[17]]. Data on the risk of relapse after discontinuing 12 months of pentamidine have been published recently [[6], [14]]. For those reaching a cluster of differentiation 4 (CD4) count > 200 cells/μL at 12 months, no relapses were seen (Table 1). Those with a CD4 count ≤ 200 cells/μL remained at risk, suggesting that pentamidine continuation might be needed on a case-by-case basis until CD4 count levels have increased. The overall risk of VL relapse was 37% by 2 years after starting pentamidine, highest amongst those with low baseline CD4 counts and a history of (multiple) relapses. The Ethiopian national programme should therefore consider this intervention within their national guidelines.

An unexplored strategy to reduce the VL–HIV burden would entail the prevention of VL onset in HIV patients. The PreLeisH study, started in October 2017, aims to provide insights into the incidence of asymptomatic Leishmania infection in HIV patients living in VL-endemic areas and the identification of those at highest risk of VL [[15]]. This would constitute a first step towards a ‘screen and treat’ strategy [[18]].

VL–HIV coinfection in Asia

The incidence of VL has been decreasing in Asia over the last decade. India, Nepal, and Bangladesh used to carry over 50% of the global burden of VL; however, reported cases of VL are now substantially higher in East Africa than in the Indian subcontinent (ISC) [[19]]. The decline in cases is most likely due to the elimination efforts because in 2005, the three most affected countries entered into an agreement to eliminate VL as ‘a public health problem’ by 2015, which was later extended to 2017. This was considered feasible due to a myriad of factors, including the assumed purely anthroponotic nature of VL spread in the subcontinent, a single vector, availability of effective rapid diagnostic tests, and crucially, the availability of short-course effective treatments [[20]].

The East Indian state of Bihar has been the epicentre of VL for over a century. This populous state is also one of the few in India where the rate of new HIV infections is increasing [[21]], bringing together two diseases whose interaction is a well-established risk factor for poor outcomes [[22]]. However, until recently, there has been a dearth of data and evidence surrounding VL–HIV coinfection in the ISC. A 2014 single-centre study from Bihar reported 5.6% of 2,077 consecutive confirmed VL patients ≥14 years of age were found to be HIV positive; half of these were unaware of their HIV status [[23]]. With improved disease surveillance and reporting, including recommendations to offer all VL patients screening for HIV [[20]], the numbers of reported coinfected cases are increasing. With the overall falling incidence of VL, this means that at a state level, currently up to 7% of all reported VL patients ≥18 years of age are coinfected with HIV in 2017; however, in highly VL-endemic districts with reliable HIV screening, this is as high as 20% [[24]].

More recently, increasing numbers of coinfected cases are being reported following the introduction of routine HIV screening in Nepal, where 9 out of 48 VL cases presenting to a tertiary hospital catering to a wide VL-endemic area during 2016–2017 were coinfected with HIV [[24]]. Bangladesh remains a lacuna since HIV screening of VL patients has not yet been introduced, even in patients presenting with multiple relapses.

There remains a substantial number of issues in the diagnosis and management of coinfected patients in the ISC. Although the recombinant K39 (rK39) test has been shown to be highly sensitive and specific for patients not diagnosed with HIV, its accuracy in coinfected patients has not yet been established in the ISC. Additionally, no high-quality evidence-based treatment regimens exist for coinfection in the ISC; the current WHO and regional recommendation of 40 mg/kg of AmBisome over 38 days is based on evidence generated on a different strain (L. infantum) in southern Europe (Table 2). A clinical trial to establish the safety and effectiveness of this regimen and that of a shorter lower-dose combination of AmBisome and miltefosine in Bihar is nearing completion [[25]]. The main challenges for coinfection in the ISC are presented in Table 3.

10.1371/journal.pntd.0006375.t002Table 2

Current evidence for treatment of VL–HIV coinfection in the ISC.

Treatment of primary VL–HIV episode Result Limitations/Observations
40 mg/kg of liposomal amphotericin B in 10 divided doses on days 1–5, 10, 17, 24, 31, and 38 8 out of 10 relapsed within 7 months, 2 out of 10 defaulted. No patients on ART Prospective cohort study of 10 patients in southern Europe, pre-ART [[26]]. No data from ISC available
30 mg/kg AmBisome in 6 divided doses with 100 mg per day oral miltefosine over 14 days In patients taking ART, 6.4% relapse, 11.2% mortality at 12 months Observational data from Bihar, India [[27]]
20–25 mg/kg AmBisome in 4–5 divided doses over 4–5 days In patients taking ART, 16.2% relapse, 8.7% mortality at 12 months Observational data from Bihar, India [[28]]
Treatment of relapses or refractory cases
No evidence base currently exists  
Secondary prophylaxis
1 mg/kg amphotericin B deoxycholate or liposomal amphotericin B No relapse versus 75% relapse in nonprophylaxis arm at 6 months Retrospective study from West Bengal, India [[29]].

Abbreviations: ART, antiretroviral therapy; ISC, Indian subcontinent; VL, visceral leishmaniasis.

10.1371/journal.pntd.0006375.t003Table 3

Challenges in VL–HIV infection in Asia.

Epidemiological
    Limited evidence on prevalence of HIV in reported VL cases in endemic areas
    No established method of screening HIV patients in VL-endemic areas for VL
    No data on prevalence of asymptomatic VL infection in HIV patients in endemic areas
    No data on risk factors for progression from asymptomatic VL infection to symptomatic VL infection in patients with HIV
Diagnostic
    No evidence on the accuracy of existing RDTs for VL in coinfected patients
    Standard VL case definition unlikely to be appropriate for VL–HIV coinfected cases
    Improved biomarkers for confirming relapse need to be developed to reduce risk of repeated invasive biopsy
Treatment
    No evidence for 40 mg/kg WHO recommended dose for VL–HIV infection in ISC
    Only observational data for lower doses of AmBisome and combination treatment
    No evidence on primary prophylaxis
    Limited evidence on secondary prophylaxis
    Very limited therapeutic options for treatment of VL in coinfection
    Challenge of VL–HIV–TB triple infection emerging and poorly understood

Abbreviations: ISC, Indian subcontinent; RDT, rapid diagnostic test; TB, tuberculosis; VL, visceral leishmaniasis.

Late presentation of coinfected patients poses the most difficult obstacle in improving patient outcomes. Nearly half present with CD4 counts of under 100, with the majority under 200 [[28], [30]]. Concomitant infection with TB has become an additional challenge; with the use of cartridge-based nucleic amplification test (CB-NAAT) screening in VL–HIV coinfected patients, up to 20% are being identified with tuberculosis (TB) infection. These patients have the highest risk for mortality [[28]] and present therapeutic challenges with regards to timing and monitoring of concurrent treatment initiation (or continuation) for VL, TB, and HIV. As such, in endemic areas, VL should always be considered in addition to other opportunistic infections already highlighted by recent WHO guidelines on management of patients presenting with advanced HIV disease [[27]].

In the future, a better understanding of the epidemiology and progression of VL in patients with HIV through improved proxy biomarkers will be key in improving earlier detection and outcomes. The susceptibility of L. donovani in the ISC to low-dose liposomal amphotericin B may provide a unique opportunity for primary prophylaxis in asymptomatic VL–HIV coinfected patients, potentially reducing progression to symptomatic disease, and should be further explored.

Solid organ transplants (SOTs) and leishmaniasis

The worldwide number of cases of VL in recipients of SOTs has quadrupled since the 1990s, although VL is still a rare disease among transplant recipients [[29]]. Most of the clinical cases have been reported in the Mediterranean Basin, particularly in Spain, which is among the foremost in performing SOTs and is endemic for L. infantum transmission. In these patients, the immunosuppressive therapy to avoid graft rejection affects T cell lymphocytes, altering the mechanisms of defence against intracellular microorganisms as Leishmania, predisposing to manifestations of disease. However, the precise mechanism behind the VL risk has not been well defined.

The development of VL by SOT recipients is not related to the origin of the organ, the socioeconomic category of the patient, nor the type of transplant, although usually associated with renal transplants as they are the most frequent transplant (Table 4). It is much more dependent on the degree of exposure to infection. The higher incidence of VL in SOT recipients from Brazil compared to those from Spain has been explained as a consequence of the higher incidence and transmission of VL in the first place [[31]].

10.1371/journal.pntd.0006375.t004Table 4

Review of publications reporting cases of leishmaniasis in SOT recipients, describing the organ transplanted and the number of cases and the treatment options used for each type of leishmaniasis.

Type of leishmaniasis Type of SOT Cases reported References Treatments
Visceral leishmaniasis Kidney 119 [[31], [33], [38][58]] Primary: AmBisome, Antimonials, Amphotericin B, AllopurinolRelapses: AmBisome, Miltefosine
Liver 11 [[31], [56][60]]
Heart 9 [[31], [33], [58], [61], [62]]
Lung 4 [[31], [63], [64]]
Pancreas 2 [[65], [66]]
Visceral and cutaneous Kidney 2 [[67], [68]] AmBisome B, Antimonials
Liver 1 [[69]]
Cutaneous leishmaniasis Kidney 5 [[70][74]] Antimonials, Ambisome B, Allopurinol + fluconazole
Mucocutaneous leishmaniasis Kidney 3 [[75][77]] Antimonials
Liver 2 [[78], [79]] Amphotericin B, AmBisome
Asymptomatic leishmaniasis Kidney 42 [[35], [80]]
Liver 4 [[81]]

Abbreviation: SOT, solid organ transplant.

The recent outbreak of leishmaniasis in Fuenlabrada (southwest Madrid, Spain), with a mean incidence rate of 22.2 per 100,000 inhabitants in the general population [[32]], has allowed the study of a cohort of patients with SOT living in the area [[33]]. During the outbreak, a total of 7 VL cases were counted amongst the 68 SOT recipients included in the study, yielding an annual incidence of 2,997 cases per 100,000 population. This suggests that the susceptibility to develop VL is 135 times higher in these patients than shown by the immunocompetent individuals living in the same area. This study also confirms that the degree of exposure to infection, expressed as the distance from the patient’s residence to the focus of the outbreak, is a key risk factor, as has already been described for the general population [[34]]. Further, despite this higher risk of developing clinical leishmaniasis, Leishmania-specific cellular immunity analysis of the SOT-recipient cohort demonstrated asymptomatic infection in 12 out of the 57 evaluated, all of whom showed specific lymphoproliferation and interferon gamma (IFN-γ) production in response to the parasite antigens. Although the ratio clinical/subclinical appears to be high, parasite infection does not always lead to overt disease in these transplanted patients [[35]].

In SOT recipients, performance of diagnostic tests for VL is variable, and a combined approach of parasitological and molecular methods is recommended [[36]] since serological tests have shown a lower sensitivity [[31]].

The recommended therapy for VL in transplanted patients is the same as that for immunocompetent individuals: a total dose of 21 mg/kg of AmBisome; however, other therapies, such as antimonial, amphotericin b, or allopurinol, have also been used with varying success (Table 4). Relapse rates in these patients are low and can be resolved with AmBisome or miltefosine treatment (Table 4). Secondary prophylaxis is not usually required. The measurement of the cell-mediated immune response in SOT recipients may help to confirm recovery following VL treatment and to assess the risk of relapse and necessity of secondary prophylaxis. Analysis of Leishmania-specific cell immunity in 5 SOT recipients patients that remained relapse-free after VL treatment showed positive lymphoproliferation and IFN-γ production after in vitro cell stimulation [[35]], in a similar way to that reported for HIV-positive patients after VL treatment [[37]].

All these data highlight the need to assess previous exposure to the parasite in patients subjected to induced immunosuppression, to counsel recipients in endemic areas to reduce the risk of being bitten by sand flies, and to follow up SOT patients in areas with outbreaks of leishmaniasis.

Malnutrition and leishmaniasis

VL mostly affects poverty-stricken and often malnourished populations. Data from 29,570 VL patients divided over Brazil, East Africa, Nepal, and India showed that severe malnutrition in VL is frequent in South Asia and East Africa, while it is uncommon in Brazil [[82]]. The amastigote form of the Leishmania parasite attacks the reticuloendothelial system of naive people and causes an infection that either spontaneously resolves (in 90% of patients) or progresses over weeks to months to clinical VL and death, if untreated. Progression to disease depends on the condition of the host; genetic factors, immune suppression, malnutrition, and the presence of other infectious diseases all play a role [[83], [84]]. Observational studies have suggested that both protein malnutrition and micronutrient deficiencies may speed the progression of leishmaniasis infection [[85], [86]] and that VL itself worsens malnutrition [[87], [88]].

Protein malnutrition and VL

In a murine model of moderate childhood malnutrition, poly-nutrient deficiency led to a 4–5-fold increase in early visceralisation of L. donovani following infection and a 16-fold decrease in lymph node barrier function [[89]], while in a recent study in hamsters infected with L. infantum, well-nourished hamsters had stronger specific immune responses and lower parasite loads than their malnourished counterparts [[90]]. Hence, it is likely that malnourished people will have a greatly increased risk of developing VL. Indeed, in a study in Brazil, the parasite burden in children with severe and moderate malnutrition was almost three times higher than in nonmalnourished children [[91]].

Micronutrients and VL

Deficiencies of micronutrients such as iron, iodine, zinc, and vitamin A are known as ‘hidden hunger’ and in developing countries often go hand in hand with acute malnutrition. The poverty-stricken populations affected by VL habitually eat large amounts of staple food crops (maize, wheat, rice) high in calories but lacking sufficient micronutrients, leaving them susceptible to disease. In a study aiming to understand the link between micronutrient deficiencies and VL in Bangladesh, it was found that in a population with poor nutritional status, retinol and zinc levels were lower and C-reactive protein levels higher in patients who developed VL compared to those who remained symptomless after infection [[92]].

The reality in the field: Nutritional support for VL patients

Supportive treatment, like nutritional supplementation, before the start of therapy of VL is recommended both by WHO [[7]] and in national VL guidelines in most endemic countries. Ready-to-use therapeutic food (RUTF) is available in most hospitals in VL-endemic regions as part of well-financed programmes for the control of TB and HIV. But since VL remains a neglected disease, in practice, VL patients do not receive any nutritional therapy, unless they are less than five years of age and included in UNICEF programmes, coinfected with HIV and/or TB, or specifically supported by NGOs.

Populations affected by VL frequently suffer from malnutrition, including micronutrient deficiencies. Clinical experience suggests that VL patients recover more quickly with nutritional supplementation. There is a need of advocacy to governments and donors to understand the importance of nutrition in VL and include nutritional supplements as part of VL treatment. In Africa, RUTF, which is currently only used in TB and HIV programmes, needs to be available for VL patients as well. There is a need for policy change; WHO and partners should advocate for free nutritional support for VL patients to other agencies such as UNICEF or the World Food Programme (WFP).

Documenting malnutrition in VL is crucial for measuring the problem and acting, but VL control programmes often do not collect any anthropometric data. WHO has recently included anthropometric indicators as part of the global VL surveillance system and recommends countries to collect data on weight and height of all VL patients.

In a recent Cochrane protocol review [[93]] assessing the effects of oral nutritional supplements in people being treated with antileishmanial drug therapy for VL, the authors found no completed or ongoing studies. This absence of evidence should not be interpreted as the evidence of no effect for nutritional supplements in people with VL. It means that eligible research for this review has not been identified.

Discussion

Special attention should be paid to immunosuppression among persons at risk of exposure to the viscerotropic species of Leishmania in the ISC and East Africa and L. infantum scattered in Central Asia, the Middle East, Mediterranean Basin, and Latin America.

HIV-infected individuals, SOT patients (and, by extension, those taking immunosuppressive medications for other reasons), and malnourished populations are the most vulnerable. They may have a much higher risk of developing disease after being infected as compared to immunocompetent individuals.

Given the reliance on rK39 rapid diagnostic tests (RDTs) in many settings and given the poorer performance of serological testing in immunosuppressed patients, alternative noninvasive diagnostic methods, such as molecular testing or antigen detection, should be evaluated in immunosuppressed patients and adapted for field use. Such tests might also be better suited to monitor treatment response and to diagnose relapses.

Due to the clearer relationship and higher number of affected patients, HIV infection is the most critical threat. Migrant crop workers in Ethiopia pose a challenge due the temporal work that raises hurdles to HIV adherence and secondary prophylaxis for VL. Despite the rewarding efforts to control the transmission of VL in the ISC, there remains a substantial number of coinfected patients. Since patients with CD4 counts under 200 cells/mm3 appear to be at a higher risk of relapse, earlier diagnosis of HIV infection, specific biomarkers of relapse, and the development of improved treatment regimens and options for secondary prophylaxis are urgently needed. In Africa, monthly pentamidine and elsewhere weekly or biweekly liposomal amphotericin B, potentially combined with miltefosine, are the most promising regimes.

The VL epidemic in the urban settlement in Fuenlabrada, Madrid, showed clearly that VL can become an urban disease and poses an extremely high risk of disease among immunocompromised individuals living in the proximity of VL foci. Testing for exposure to Leishmania, preventing sand fly bites, and careful follow-up are measures that can reduce the harm of VL in solid transplant patients.

The effect of immunosupression caused by malnutrition needs to be studied more carefully, since most severely or moderately malnourished patients live in the most VL-affected, poverty-stricken regions. Malnutrition appears to be simultaneously a risk for the development of VL after infection and a consequence of the disease, possibly as part of the acute phase reaction of VL. Addressing nutrition in populations not covered by nutritional supplementation that are at risk of VL should be implemented. Studies on the specific components of nutrition associated with the risk of VL development, as well as their role as adjuvant therapy for patients, are needed.

This review has shown that the main impact of immunosuppression in persons exposed to Leishmania is increased risk of development of disease after exposure, higher risk of death, and relapse. While it is highly likely that Leishmania infection leads to parasite persistence due to the absence of sterilising immunity and that T-cell immune response impairment is the principal mechanism behind evolution of disease, the detailed mechanisms of immunosuppression and why some persons are at higher risk than others remain unclear. Moreover, the absence of effective human VL vaccines remains a critical gap in preventing disease and improving outcomes for this group of patients.

The lack of curative, sterilising therapy points the solution on the development of new, more effective, and less toxic oral drugs coupled with the finding of prognostic biomarkers for early detection of relapse. The development of safe immunotherapy, as recently proposed, seems to be an additional option [[94]]. Finally, the stabilisation and even increase of HIV transmission in many parts of the world, the advancements in organ transplantation techniques, the persistence of hunger and malnutrition in a scenario of globalisation and global warming, and the expansion and reemergence of VL in parts of the world like South America [[95]], Madrid [[32]], and Tbilisi [[96]] raise red flags and stress the priority to be given to this growing global health challenge.

Key learning points

Migrant rural workers in Ethiopia are at high risk of coinfection with HIV, malnutrition, and VL.

In the ISC, there are limited data on the prevalence of coinfection outside of India, making it a threat for sustained elimination of VL.

VL is a threat to SOT in endemic areas.

Nutrient supplementation can help to prevent and to treat VL in endemic poverty-stricken areas.

Top five papers

Alvar J, Aparicio P, Aseffa A, Den Boer M, Canavate C, Dedet JP, et al. The relationship between leishmaniasis and AIDS: the second 10 years. Clin Microbiol Rev. 2008;21(2):334–59.

Diro E, Ritmeijer K, Boelaert M, Alves F, Mohammed R, Abongomera C, Ravinetto R, De Crop M, Fikre H, Adera C, Colebunders R, van Loen H, Menten J, Lynen L, Hailu A, van Griensven J. Use of pentamidine as secondary prophylaxis to prevent Visceral Leishmaniasis relapse in HIV infected patients, the first twelve months of a prospective cohort study. PLoS Negl Trop Dis. 2015;9(10):e0004087.

Burza S, Mahajan R, Sanz MG, Sunyoto T, Kumar R, Mitra G, et al. HIV and visceral leishmaniasis coinfection in Bihar, India: an underrecognized and underdiagnosed threat against elimination. Clin Infect Dis. 2014;59(4):552–555.

Clemente W, Vidal E, Girão E, Ramos AS, Govedic F, Merino E, Muñoz P et al. Risk factors, clinical features and outcomes of visceral leishmaniasis in solid-organ transplant recipients: a retrospective multicenter case-control study. Clin Microbiol Infect. 2015;21(1):89–95.

Badaró R, Jones TC, Lorenço R, Cerf BJ, Sampaio D, Carvalho EM et al. A prospective study of visceral leishmaniasis in an endemic area of Brazil. J Infect Dis. 1986;154(4):639–49.

References

  1. MF Hassan, Y Zhang, CR Engwerda, PM Kaye, H Sharp, QD Bickle. The Schistosoma mansoni hepatic egg granuloma provides a favorable microenvironment for sustained growth of Leishmania donovani. Am J Pathol. 2006;169(3):943–53. Epub 2006/08/29. doi: 10.2353/ajpath.2006.051319 ; PubMed Central PMCID: PMCPMC1698825.16936268
  2. AC La Flamme, P Scott, EJ Pearce. Schistosomiasis delays lesion resolution during Leishmania major infection by impairing parasite killing by macrophages. Parasite Immunol. 2002;24(7):339–45. Epub 2002/08/08. .12164819
  3. SE O'Neal, LH Guimaraes, PR Machado, L Alcantara, DJ Morgan, S Passos, et alInfluence of helminth infections on the clinical course of and immune response to Leishmania braziliensis cutaneous leishmaniasis. J Infect Dis. 2007;195(1):142–8. Epub 2006/12/08. doi: 10.1086/509808 .17152018
  4. T Newlove, LH Guimaraes, DJ Morgan, L Alcantara, MJ Glesby, EM Carvalho, et alAntihelminthic therapy and antimony in cutaneous leishmaniasis: a randomized, double-blind, placebo-controlled trial in patients co-infected with helminths and Leishmania braziliensis. Am J Trop Med Hyg. 2011;84(4):551–5. Epub 2011/04/05. doi: 10.4269/ajtmh.2011.10-0423 ; PubMed Central PMCID: PMCPMC3062447.21460008
  5. D Wolday, N Berhe, S Britton, H Akuffo. HIV-1 alters T helper cytokines, interleukin-12 and interleukin-18 responses to the protozoan parasite Leishmania donovani. AIDS. 2000;14(8):921–9. Epub 2000/06/15. .10853973
  6. E Diro, L Lynen, K Ritmeijer, M Boelaert, A Hailu, J van Griensven. Visceral Leishmaniasis and HIV coinfection in East Africa. PLoS Negl Trop Dis. 2014;8(6):e2869doi: 10.1371/journal.pntd.0002869 ; PubMed Central PMCID: PMCPMC4072530.24968313
  7. World Health Organization. Control of the leishmaniasesWorld Health Organization technical report series. Geneva, Switzerland: WHO, 2010; 949: xii–xiii, 1–186. 2010.
  8. M Balasegaram, K Ritmeijer, MA Lima, S Burza, G Ortiz Genovese, B Milani, et alLiposomal amphotericin B as a treatment for human leishmaniasis. Expert Opin Emerg Drugs. 2012;17(4):493–510. Epub 2012/11/22. doi: 10.1517/14728214.2012.748036 ; PubMed Central PMCID: PMC3518293.23167833
  9. Diro E. Efficacy Trial of Ambisome Given Alone and Ambisome Given in Combination With Miltefosine for the Treatment of VL HIV Positive Ethiopian Patients. ClinicalTrials.gov registration number: NCT02011958.
  10. E Diro, L Lynen, R Mohammed, M Boelaert, A Hailu, J van Griensven. High parasitological failure rate of visceral leishmaniasis to sodium stibogluconate among HIV co-infected adults in Ethiopia.PLoS Negl Trop Dis. 2014;8(5):e2875doi: 10.1371/journal.pntd.0002875 ; PubMed Central PMCID: PMCPMC4031116.24854196
  11. K Ritmeijer, A Dejenie, Y Assefa, TB Hundie, J Mesure, G Boots, et alA comparison of miltefosine and sodium stibogluconate for treatment of visceral leishmaniasis in an Ethiopian population with high prevalence of HIV infection. Clin Infect Dis. 2006;43(3):357–64. Epub 2006/06/29. doi: 10.1086/505217 .16804852
  12. K Ritmeijer, R ter Horst, S Chane, EM Aderie, T Piening, SM Collin, et alLimited effectiveness of high-dose liposomal amphotericin B (AmBisome) for treatment of visceral leishmaniasis in an Ethiopian population with high HIV prevalence. Clin Infect Dis. 2011;53(12):e152–8. Epub 2011/10/22. doi: 10.1093/cid/cir674 .22016502
  13. J van Griensven, T Simegn, M Endris, E Diro. Visceral Leishmaniasis and HIV Co-Infection in Northwest Ethiopia: Antiretroviral Treatment and Burden of Disease among Patients Enrolled in HIV Care. Am J Trop Med Hyg. 2017 Epub 2017/12/07. doi: 10.4269/ajtmh.17-0142 .29210347
  14. E Diro, K Ritmeijer, M Boelaert, F Alves, R Mohammed, C Abongomera, et alLong-term clinical outcomes in visceral leishmaniasis-HIV co-infected patients during and after pentamidine secondary prophylaxis in Ethiopia: a single-arm clinical trial Authors and affiliations. Clin Infect Dis. 2017doi: 10.1093/cid/cix807 .29020217
  15. Predicting Visceral Leishmaniasis in HIV Infected Patients (PreLeisH) [Internet]. [cited August 28 2017]. Available from: https://clinicaltrials.gov/ct2/show/NCT03013673.
  16. R ter Horst, SM Collin, K Ritmeijer, A Bogale, RN Davidson. Concordant HIV infection and visceral leishmaniasis in Ethiopia: the influence of antiretroviral treatment and other factors on outcome. Clin Infect Dis. 2008;46(11):1702–9. Epub 2008/04/19. doi: 10.1086/587899 .18419422
  17. E Diro, K Ritmeijer, M Boelaert, F Alves, R Mohammed, C Abongomera, et alUse of Pentamidine As Secondary Prophylaxis to Prevent Visceral Leishmaniasis Relapse in HIV Infected Patients, the First Twelve Months of a Prospective Cohort Study. PLoS Negl Trop Dis. 2015;9(10):e0004087doi: 10.1371/journal.pntd.0004087 ; PubMed Central PMCID: PMCPMC4591988.26431253
  18. J van Griensven, E Diro, R Lopez-Velez, K Ritmeijer, M Boelaert, EE Zijlstra, et alA screen-and-treat strategy targeting visceral leishmaniasis in HIV-infected individuals in endemic East African countries: the way forward?PLoS Negl Trop Dis. 2014;8(8):e3011 Epub 2014/08/08. doi: 10.1371/journal.pntd.0003011 ; PubMed Central PMCID: PMCPMC4125108.25101627
  19. World Health Organization. Weekly Epidemiological Record: Leishmaniasis in high-burden countries: an epidemiological update based in data reported in 2014. P287. 2014.
  20. World Health Organization. Kala-Azar Elimination Programme, Report of a WHO consultation of partners, Geneva, Switzerland 10–11 February 2015, 1st ed. Geneva: WHO, 2015. 2015.
  21. Department of AIDS Control, NACO. Ministry of Health and family Welfare Government of India. State HIV Epidemic Fact Sheets. July 2014.
  22. J Alvar, P Aparicio, A Aseffa, M Den Boer, C Canavate, JP Dedet, et alThe relationship between leishmaniasis and AIDS: the second 10 years. Clin Microbiol Rev. 2008;21(2):334–59. Epub 2008/04/11. doi: 10.1128/CMR.00061-07 ; PubMed Central PMCID: PMC2292576.18400800
  23. S Burza, R Mahajan, MG Sanz, T Sunyoto, R Kumar, G Mitra, et alHIV and visceral leishmaniasis coinfection in Bihar, India: an underrecognized and underdiagnosed threat against elimination. Clin Infect Dis. 2014;59(4):552–5. Epub 2014/05/13. doi: 10.1093/cid/ciu333 .24814660
  24. Burza S, editor HIV-VL co-infection in Asia. Sixth World Leishmaniasis Conference; May 2017 August 20, 2017; Toledo, Spain.
  25. A Hailu, M Gramiccia, PA Kager. Visceral leishmaniasis in Aba-Roba, south-western Ethiopia: prevalence and incidence of active and subclinical infections. Ann Trop Med Parasitol. 2009;103(8):659–70. Epub 2009/12/25. doi: 10.1179/000349809X12554106963555 .20030990
  26. RP Goswami, RP Goswami, A Basu, Y Ray, M Rahman, SK Tripathi. Protective Efficacy of Secondary Prophylaxis Against Visceral Leishmaniasis in Human Immunodeficiency Virus Coinfected Patients Over the Past 10 Years in Eastern India. Am J Trop Med Hyg. 2017;96(2):285–91. Epub 2016/11/24. doi: 10.4269/ajtmh.16-0432 ; PubMed Central PMCID: PMCPMC5303025.27879457
  27. World Health Organization. Guidelines for managing advanced HIV disease and rapid initiation of antiretroviral therapy, July 2017Geneva: World Health Organization; 2017. Licence: CC BY-NC-SA 3.0 IGO. 2017.
  28. R Mahajan, P Das, P Isaakidis, T Sunyoto, KD Sagili, MA Lima, et alCombination Treatment for Visceral Leishmaniasis Patients Coinfected with Human Immunodeficiency Virus in India. Clin Infect Dis. 2015;61(8):1255–62. doi: 10.1093/cid/civ530 ; PubMed Central PMCID: PMCPMC4583582.26129756
  29. S Antinori, A Cascio, C Parravicini, R Bianchi, M Corbellino. Leishmaniasis among organ transplant recipients. Lancet Infect Dis. 2008;8(3):191–9. Epub 2008/02/23. doi: 10.1016/S1473-3099(08)70043-4 .18291340
  30. S Burza, R Mahajan, PK Sinha, J van Griensven, K Pandey, MA Lima, et alVisceral leishmaniasis and HIV co-infection in Bihar, India: long-term effectiveness and treatment outcomes with liposomal amphotericin B (AmBisome). PLoS Negl Trop Dis. 2014;8(8):e3053doi: 10.1371/journal.pntd.0003053 ; PubMed Central PMCID: PMCPMC4125300.25101665
  31. W Clemente, E Vidal, E Girao, AS Ramos, F Govedic, E Merino, et alRisk factors, clinical features and outcomes of visceral leishmaniasis in solid-organ transplant recipients: a retrospective multicenter case-control study. Clin Microbiol Infect. 2015;21(1):89–95. Epub 2015/02/01. doi: 10.1016/j.cmi.2014.09.002 .25636932
  32. A Arce, A Estirado, M Ordobas, S Sevilla, N Garcia, L Moratilla, et alRe-emergence of leishmaniasis in Spain: community outbreak in Madrid, Spain, 2009 to 2012. Euro Surveill. 2013;18(30):20546 Epub 2013/08/10. .23929177
  33. N Carrasco-Anton, F Lopez-Medrano, M Fernandez-Ruiz, E Carrillo, J Moreno, A Garcia-Reyne, et alEnvironmental Factors as Key Determinants for Visceral Leishmaniasis in Solid Organ Transplant Recipients, Madrid, Spain. Emerg Infect Dis. 2017;23(7):1155–9. Epub 2017/06/20. doi: 10.3201/eid2307.151251 ; PubMed Central PMCID: PMCPMC5512489.28628447
  34. AA Ruiz AE, GE Monzo mL, IA Calle, DFS Ureña, SMJ Zabalgogeazcoa, et alAnálisis espacial de un brote de leishmaniasis en el sur del Área metropolitana de la Comunidad de Madrid. 2009–2013. Rev salud ambient2014;14:39–53.
  35. E Carrillo, N Carrasco-Anton, F Lopez-Medrano, E Salto, L Fernandez, JV San Martin, et alCytokine Release Assays as Tests for Exposure to Leishmania, and for Confirming Cure from Leishmaniasis, in Solid Organ Transplant Recipients. PLoS Negl Trop Dis. 2015;9(10):e0004179 Epub 2015/10/27. doi: 10.1371/journal.pntd.0004179 ; PubMed Central PMCID: PMCPMC4619795.26496365
  36. J van Griensven, E Carrillo, R Lopez-Velez, L Lynen, J Moreno. Leishmaniasis in immunosuppressed individuals. Clin Microbiol Infect. 2014;20(4):286–99. Epub 2014/01/24. doi: 10.1111/1469-0691.12556 .24450618
  37. A Castro, E Carrillo, JV San Martin, L Botana, L Molina, B Matia, et alLymphoproliferative response after stimulation with soluble leishmania antigen (SLA) as a predictor of visceral leishmaniasis (VL) relapse in HIV+ patients. Acta Trop. 2016;164:345–51. doi: 10.1016/j.actatropica.2016.09.026 .27693332
  38. MA Perez-Jacoiste Asin, N Carrasco-Anton, M Fernandez-Ruiz, R San Juan, R Alonso-Moralejo, E Gonzalez, et alExperience with miltefosine for persistent or relapsing visceral leishmaniasis in solid organ transplant recipients: A case series from Spain. Transpl Infect Dis. 2017;19(1). Epub 2016/10/22. doi: 10.1111/tid.12623 .27768239
  39. A Silva Jde, M Araujo Ide, LC Pavanetti, LS Okamoto, M Dias. [Visceral leishmaniasis and pregnancy in renal transplanted patient: case report]. J Bras Nefrol. 2015;37(2):268–70. Epub 2015/07/15. doi: 10.5935/0101-2800.20150041 .26154649
  40. AA de Silva, A Pacheco e Silva Filho, Rde C Sesso, Rde M Esmeraldo, CM de Oliveira, PF Fernandes, et alEpidemiologic, clinical, diagnostic and therapeutic aspects of visceral leishmaniasis in renal transplant recipients: experience from thirty cases. BMC Infect Dis. 2015;15:96 Epub 2015/04/17. doi: 10.1186/s12879-015-0852-9 ; PubMed Central PMCID: PMCPMC4381535.25877483
  41. JA Pedroso, M Paola Salerno, G Spagnoletti, M Bertucci-Zoccali, G Zaccone, V Bianchi, et alElderly kidney transplant recipient with intermittent fever: a case report of leishmaniasis with acute kidney injury during liposomal amphotericin B therapy. Transplant Proc. 2014;46(7):2365–7. Epub 2014/09/23. doi: 10.1016/j.transproceed.2014.07.064 .25242789
  42. M Bouchekoua, S Trabelsi, T Ben Abdallah, S Khaled. Visceral leishmaniasis after kidney transplantation: Report of a new case and a review of the literature. Transplant Rev (Orlando). 2014;28(1):32–5. Epub 2013/12/11. doi: 10.1016/j.trre.2013.10.007 .24321305
  43. A Alves da Silva, A Pacheco-Silva, R de Castro Cintra Sesso, RM Esmeraldo, CM Costa de Oliveira, PF Fernandes, et alThe risk factors for and effects of visceral leishmaniasis in graft and renal transplant recipients. Transplantation. 2013;95(5):721–7. Epub 2013/02/08. doi: 10.1097/TP.0b013e31827c16e2 .23388734
  44. S Trabelsi, M Bouchekoua, D Aloui, A Sellami, M Bacha, E Abderrahim, et alVisceral leishmaniasis in renal transplant patient. Tunis Med. 2011;89(12):954 Epub 2011/12/27. .22198886
  45. I Simon, KM Wissing, V Del Marmol, S Antinori, M Remmelink, E Nilufer Broeders, et alRecurrent leishmaniasis in kidney transplant recipients: report of 2 cases and systematic review of the literature. Transpl Infect Dis. 2011;13(4):397–406. Epub 2011/02/02. doi: 10.1111/j.1399-3062.2011.00598.x .21281418
  46. M Veroux, D Corona, G Giuffrida, B Cacopardo, N Sinagra, T Tallarita, et alVisceral leishmaniasis in the early post-transplant period after kidney transplantation: clinical features and therapeutic management. Transpl Infect Dis. 2010;12(5):387–91. Epub 2010/06/11. doi: 10.1111/j.1399-3062.2010.00520.x .20534033
  47. S Dettwiler, T McKee, K Hadaya, F Chappuis, C van Delden, S Moll. Visceral leishmaniasis in a kidney transplant recipient: parasitic interstitial nephritis, a cause of renal dysfunction. Am J Transplant. 2010;10(6):1486–9. Epub 2010/05/22. doi: 10.1111/j.1600-6143.2010.03125.x .20486908
  48. K Harzallah, R Belhadj, B Jemli, M Haloues, N Berraies, S Gargouri, et alVisceral leishmaniasis in a renal transplant recipient treated with allopurinol. Saudi J Kidney Dis Transpl. 2010;21(1):105–8. Epub 2010/01/12. .20061702
  49. A Zumrutdal, E Erken, T Turunc, S Colakoglu, YZ Demiroglu, R Ozelsancak, et alDelayed and overlooked diagnosis of an unusual opportunistic infection in a renal transplant recipient: visceral leishmaniasis. Turkiye Parazitol Derg. 2010;34(4):183–5. Epub 2010/01/01. doi: 10.5152/tpd.2010.09 .21391189
  50. RA Oliveira, LS Silva, VP Carvalho, AF Coutinho, FG Pinheiro, CG Lima, et alVisceral leishmaniasis after renal transplantation: report of 4 cases in northeastern Brazil. Transpl Infect Dis. 2008;10(5):364–8. Epub 2008/05/30. doi: 10.1111/j.1399-3062.2008.00320.x .18507750
  51. CM Oliveira, ML Oliveira, SC Andrade, ES Girao, CN Ponte, MU Mota, et alVisceral leishmaniasis in renal transplant recipients: clinical aspects, diagnostic problems, and response to treatment. Transplant Proc. 2008;40(3):755–60. Epub 2008/05/06. doi: 10.1016/j.transproceed.2008.02.039 .18455008
  52. JN Boletis, A Pefanis, C Stathakis, H Helioti, A Kostakis, H Giamarellou. Visceral leishmaniasis in renal transplant recipients: successful treatment with liposomal amphotericin B (AmBisome). Clin Infect Dis. 1999;28(6):1308–9. Epub 1999/08/18. doi: 10.1086/514784 .10451172
  53. NV Sipsas, J Boletis. Fever, hepatosplenomegaly, and pancytopenia in a renal transplant recipient. Transpl Infect Dis. 2003;5(1):47–52. Epub 2003/06/07. .12791075
  54. M Sabbatini, A Pisani, A Ragosta, R Gallo, F Borrelli, B Cianciaruso. Visceral Leishmaniasis in renal transplant recipients: is it still a challenge to the nephrologist?Transplantation. 2002;73(2):299–301. Epub 2002/02/01. .11821748
  55. S Llorente, L Gimeno, MJ Navarro, S Moreno, M Rodriguez-Girones. Therapy of visceral leishmaniasis in renal transplant recipients intolerant to pentavalent antimonials. Transplantation. 2000;70(5):800–1. Epub 2000/09/26. .11003361
  56. MV Batista, LC Pierrotti, E Abdala, WT Clemente, ES Girao, DR Rosa, et alEndemic and opportunistic infections in Brazilian solid organ transplant recipients. Trop Med Int Health. 2011;16(9):1134–42. Epub 2011/06/23. doi: 10.1111/j.1365-3156.2011.02816.x .21692958
  57. D Basset, F Faraut, P Marty, J Dereure, E Rosenthal, C Mary, et alVisceral leishmaniasis in organ transplant recipients: 11 new cases and a review of the literature. Microbes Infect. 2005;7(13):1370–5. Epub 2005/07/28. doi: 10.1016/j.micinf.2005.06.002 .16046170
  58. J Hernandez-Perez, M Yebra-Bango, E Jimenez-Martinez, C Sanz-Moreno, V Cuervas-Mons, L Alonso Pulpon, et alVisceral leishmaniasis (kala-azar) in solid organ transplantation: report of five cases and review. Clin Infect Dis. 1999;29(4):918–21. Epub 1999/12/10. doi: 10.1086/520457 .10589910
  59. CM Pereira, HM Oliveira, V Lopes, J Gandara, S Ferreira, J Daniel, et alVisceral leishmaniasis after orthotopic liver transplantation: a rare cause of infection. Transpl Infect Dis. 2016;18(2):251–4. Epub 2016/02/21. doi: 10.1111/tid.12511 .26895697
  60. WT Clemente, LC Faria, RM Romanelli, SS Lima, JR Cortes, AP Oliveira, et alVisceral leishmaniasis in liver transplant recipients from an endemic area. Transplantation. 2011;91(7):806–8. Epub 2011/03/26. doi: 10.1097/TP.0b013e31820c4574 .21436655
  61. JM Frapier, B Abraham, J Dereure, B Albat. Fatal visceral leishmaniasis in a heart transplant recipient. J Heart Lung Transplant. 2001;20(8):912–3. Epub 2001/08/15. .11502416
  62. L Larocca, R La Rosa, A Montineri, C Iacobello, V Brisolese, F Fatuzzo, et alVisceral leishmaniasis in an Italian heart recipient: first case report. J Heart Lung Transplant. 2007;26(12):1347–8. Epub 2007/12/22. doi: 10.1016/j.healun.2007.09.005 .18096492
  63. P Morales, JJ Torres, M Salavert, J Peman, J Lacruz, A Sole. Visceral leishmaniasis in lung transplantation. Transplant Proc. 2003;35(5):2001–3. Epub 2003/09/10. .12962876
  64. O Opota, Z Balmpouzis, C Berutto, J Kaiser-Guignard, G Greub, JD Aubert, et alVisceral leishmaniasis in a lung transplant recipient: usefulness of highly sensitive real-time polymerase chain reaction for preemptive diagnosis. Transpl Infect Dis. 2016;18(5):801–4. Epub 2016/08/09. doi: 10.1111/tid.12585 .27495987
  65. N Colomo Rodriguez, MS De Adana Navas, S Gonzalez Romero, I Gonzalez Molero, JM Reguera Iglesias. [Visceral leishmaniasis in a type 1 diabetic patient with isolated pancreas transplant]. Endocrinol Nutr. 2011;58(7):375–7. Epub 2011/05/17. doi: 10.1016/j.endonu.2011.02.004 .21571598
  66. H Aardema, YW Sijpkens, LG Visser. Pancytopenia in a simultaneous pancreas and kidney transplant recipient: an unexpected cause—a case of visceral leishmaniasis in a transplant recipient. Clin Nephrol. 2009;71(4):460–2. Epub 2009/04/10. .19356384
  67. S Yucel, D Ozcan, D Seckin, AM Allahverdiyev, F Kayaselcuk, M Haberal. Visceral leishmaniasis with cutaneous dissemination in a renal transplant recipient. Eur J Dermatol. 2013;23(6):892–3. Epub 2013/11/15. doi: 10.1684/ejd.2013.2168 .24225071
  68. CM Gontijo, RS Pacheco, F Orefice, E Lasmar, ES Silva, MN Melo. Concurrent cutaneous, visceral and ocular leishmaniasis caused by Leishmania (Viannia) braziliensis in a kidney transplant patient. Mem Inst Oswaldo Cruz. 2002;97(5):751–3. Epub 2002/09/10. .12219147
  69. D Ozcan, D Seckin, AM Allahverdiyev, PJ Weina, H Aydin, F Ozcay, et alLiver transplant recipient with concomitant cutaneous and visceral leishmaniasis. Pediatr Transplant. 2007;11(2):228–32. Epub 2007/02/16. doi: 10.1111/j.1399-3046.2006.00660.x .17300508
  70. A Zandieh, B Zandieh, L Dastgheib. Dissemination of localized cutaneous leishmaniasis in an organ transplant recipient: case report and literature review. Int J Dermatol. 2013;52(1):59–62. Epub 2013/01/03. doi: 10.1111/j.1365-4632.2012.05615.x .23278609
  71. S Yaich, K Charfeddine, A Masmoudi, M Masmoudi, S Zaghdhane, H Turki, et alAtypical presentation of cutaneous leishmaniasis in a renal transplant recipient successfully treated with allopurinol and fluconazole. Ann Saudi Med. 2013;33(2):187–91. Epub 2012/07/04. doi: 10.5144/0256-4947.2012.01.7.1510 .22750767
  72. FA Vinhal, SR Afonso-Cardoso, AG Silva, CG Pereira, W Sousa, SM Botelho, et alA typical presentation of cutaneous leishmaniasis after renal transplantation. Nephrol Dial Transplant. 2007;22(12):3674 Epub 2007/07/31. doi: 10.1093/ndt/gfm520 .17660184
  73. M Mirzabeigi, U Farooq, S Baraniak, L Dowdy, G Ciancio, V Vincek. Reactivation of dormant cutaneous Leishmania infection in a kidney transplant patient. J Cutan Pathol. 2006;33(10):701–4. Epub 2006/10/10. doi: 10.1111/j.1600-0560.2006.00532.x .17026523
  74. IM Fernandes, MA Baptista, TR Barbon, JF Oliveira, RC Oliveira, NM Murai, et alCutaneous leishmaniasis in kidney transplant recipient. Transplant Proc. 2002;34(2):504–5. Epub 2002/05/16. .12009606
  75. FF Tuon, GM Bombonatto, ER Battaglin, MH Sakumoto, VS Amato, RA de Camargo, et alReactivation of mucosal and cutaneous leishmaniasis in a renal transplanted patient. Am J Trop Med Hyg. 2014;91(1):81–3. Epub 2014/04/16. doi: 10.4269/ajtmh.13-0578 ; PubMed Central PMCID: PMCPMC4080574.24732458
  76. F Borgia, M Vaccaro, F Guarneri, C Manfre, SP Cannavo, C Guarneri. Mucosal leishmaniasis occurring in a renal transplant recipient. Dermatology. 2001;202(3):266–7. Epub 2001/06/01. doi: 10.1159/000051651 .11385238
  77. F Baglieri, G Scuderi. A case of mucosal leishmaniasis of the tongue in a kidney transplant recipient. Int J Dermatol. 2012;51(5):597–600. Epub 2011/07/28. doi: 10.1111/j.1365-4632.2011.04981.x .21790554
  78. SA Araujo, TC Nascentes Queiroz, MM Demas Alvares Cabral. Colonic leishmaniasis followed by liver transplantation. Am J Trop Med Hyg. 2010;83(2):209 Epub 2010/08/05. doi: 10.4269/ajtmh.2010.09-0430 ; PubMed Central PMCID: PMCPMC2911159.20682856
  79. A Ramos, E Munez, J Garcia-Dominguez, R Martinez-Ruiz, C Chicharro, I Banos, et alMucosal leishmaniasis mimicking squamous cell carcinoma in a liver transplant recipient. Transpl Infect Dis. 2015;17(3):488–92. Epub 2015/03/31. doi: 10.1111/tid.12380 .25816835
  80. EK Elmahallawy, E Cuadros-Moronta, MC Liebana-Martos, JM Rodriguez-Granger, A Sampedro-Martinez, A Agil, et alSeroprevalence of Leishmania infection among asymptomatic renal transplant recipients from southern Spain. Transpl Infect Dis. 2015;17(6):795–9. Epub 2015/08/20. doi: 10.1111/tid.12444 .26288113
  81. WT Clemente, A Rabello, LC Faria, V Peruhype-Magalhaes, LI Gomes, TA da Silva, et alHigh prevalence of asymptomatic Leishmania spp. infection among liver transplant recipients and donors from an endemic area of Brazil. Am J Transplant. 2014;14(1):96–101. Epub 2013/12/26. doi: 10.1111/ajt.12521 .24369026
  82. MO Harhay, PL Olliaro, M Vaillant, F Chappuis, MA Lima, K Ritmeijer, et alWho is a typical patient with visceral leishmaniasis? Characterizing the demographic and nutritional profile of patients in Brazil, East Africa, and South Asia. Am J Trop Med Hyg. 2011;84(4):543–50. Epub 2011/04/05. doi: 10.4269/ajtmh.2011.10-0321 ; PubMed Central PMCID: PMC3062446.21460007
  83. R Badaro, TC Jones, R Lorenco, BJ Cerf, D Sampaio, EM Carvalho, et alA prospective study of visceral leishmaniasis in an endemic area of Brazil. J Infect Dis. 1986;154(4):639–49. Epub 1986/10/01. .3745974
  84. G Malafaia. Protein-energy malnutrition as a risk factor for visceral leishmaniasis: a review. Parasite Immunol. 2009;31(10):587–96. Epub 2009/09/16. doi: 10.1111/j.1365-3024.2009.01117.x .19751470
  85. GM Anstead, B Chandrasekar, W Zhao, J Yang, LE Perez, PC Melby. Malnutrition alters the innate immune response and increases early visceralization following Leishmania donovani infection. Infect Immun. 2001;69(8):4709–18. Epub 2001/07/12. doi: 10.1128/IAI.69.8.4709-4718.2001 ; PubMed Central PMCID: PMCPMC98556.11447142
  86. S Collin, R Davidson, K Ritmeijer, K Keus, Y Melaku, S Kipngetich, et alConflict and kala-azar: determinants of adverse outcomes of kala-azar among patients in southern Sudan. Clin Infect Dis. 2004;38(5):612–9. Epub 2004/02/27. doi: 10.1086/381203 .14986243
  87. KG Luz, RC Succi, E Torres. [Vitamin A serum level in children with visceral leishmaniasis]. Rev Soc Bras Med Trop. 2001;34(4):381–4. Epub 2001/09/20. .11562734
  88. J Van Weyenbergh, G Santana, A D'Oliveira Jr., AF Santos Jr., CH Costa, EM Carvalho, et alZinc/copper imbalance reflects immune dysfunction in human leishmaniasis: an ex vivo and in vitro study. BMC Infect Dis. 2004;4:50 Epub 2004/11/18. doi: 10.1186/1471-2334-4-50 ; PubMed Central PMCID: PMCPMC534101.15546498
  89. MK Ibrahim, JL Barnes, GM Anstead, F Jimenez, BL Travi, AG Peniche, et alThe malnutrition-related increase in early visceralization of Leishmania donovani is associated with a reduced number of lymph node phagocytes and altered conduit system flow. PLoS Negl Trop Dis. 2013;7(8):e2329 Epub 2013/08/24. doi: 10.1371/journal.pntd.0002329 ; PubMed Central PMCID: PMCPMC3744437.23967356
  90. E Carrillo, MA Jimenez, C Sanchez, J Cunha, CM Martins, A da Paixao Seva, et alProtein malnutrition impairs the immune response and influences the severity of infection in a hamster model of chronic visceral leishmaniasis. PLoS ONE. 2014;9(2):e89412 Epub 2014/03/04. doi: 10.1371/journal.pone.0089412 ; PubMed Central PMCID: PMCPMC3934886.24586759
  91. DA Zacarias, N Rolao, FA de Pinho, I Sene, JC Silva, TC Pereira, et alCauses and consequences of higher Leishmania infantum burden in patients with kala-azar: a study of 625 patients. Trop Med Int Health. 2017;22(6):679–87. Epub 2017/04/06. doi: 10.1111/tmi.12877 .28380279
  92. C Bern, R Haque, R Chowdhury, M Ali, KM Kurkjian, L Vaz, et alThe epidemiology of visceral leishmaniasis and asymptomatic leishmanial infection in a highly endemic Bangladeshi village. Am J Trop Med Hyg. 2007;76(5):909–14. Epub 2007/05/10. .17488915
  93. E HM Custodio, C Bouza, J López-Alcalde, A Benito, J Alvar. Nutritional supplements for patients being treated for active visceral leishmaniasis (Protocol). Cochrane Database of Systematic Reviews, 2016doi: 10.1002/14651858.CD012261
  94. Y Taslimi, F Zahedifard, S Rafati. Leishmaniasis and various immunotherapeutic approaches. Parasitology. 2016:1–11. Epub 2016/12/16. doi: 10.1017/S003118201600216X .27974063
  95. MO Harhay, PL Olliaro, DL Costa, CH Costa. Urban parasitology: visceral leishmaniasis in Brazil. Trends Parasitol. 2011;27(9):403–9. Epub 2011/05/21. doi: 10.1016/j.pt.2011.04.001 .21596622
  96. E Giorgobiani, N Chitadze, G Chanturya, M Grdzelidze, RC Jochim, A Machablishvili, et alEpidemiologic aspects of an emerging focus of visceral leishmaniasis in Tbilisi, Georgia. PLoS Negl Trop Dis. 2011;5(12):e1415 Epub 2011/12/20. doi: 10.1371/journal.pntd.0001415 ; PubMed Central PMCID: PMCPMC3236723.22180796
The underlying source XML for this text is taken from https://www.ebi.ac.uk/europepmc/webservices/rest/PMC5944929/fullTextXML. The license for the article is Creative Commons Attribution 4.0 International. The main subject has been identified as visceral leishmaniasis.