• Bangladesh
• Knowledge
• Post kala-azar dermal leishmaniasis
• Prevalence
• Stigma

• Humans
• Leishmaniasis, Visceral/epidemiology
• Male
• Female
• Cross-Sectional Studies
• Adult
• Leishmaniasis, Cutaneous/epidemiology
• Adolescent
• Child
• Bangladesh/epidemiology
• Young Adult
• Middle Aged
• Endemic Diseases
• Child, Preschool
• Infant
• Social Stigma
• Patient Acceptance of Health Care
• Aged

• 001 World Health Organization

Leishmaniasis is a vector-borne parasitic disease affecting millions of people worldwide. However, in the last decade, the number of cases has been reduced from well-documented endemic parts, but sporadic cases have been reported widely from various non-endemic areas, especially from the southern Himalayan zone. This raises concerns about the emergence of new ecological niches. This warrants a critical evaluation of key factors causing this rapid spread and possibly indigenous transmission. This mini-review article is aimed to briefly address the parasite, the vector, and the environmental aspects in the transmission of leishmaniasis in these new foci against a background of worldwide endemic leishmaniasis with a special focus on the southern Himalayan zone. As the lack of knowledge about the causative parasites, vectors, reservoir hosts, atypical presentations, and their management make the problem serious and may lead to the emergence of public health issues. The present works also reviewed the existing information regarding clinical variations, diagnostic methods, treatment, its outcome, and ignite for further research in these aspects of the disease.

• Anthroponosis
• Kala azar sandfly
• Sporadic transmission
• Southern Himalaya

• Cutaneous leishmaniasis
• Intracellular parasite
• Kala-azar
• Kinetoplastids
• Phagolysosome

Control of visceral leishmaniasis (VL) on the Indian subcontinent relies on prompt detection and treatment of symptomatic cases. Detection efforts influence the observed VL incidence and how well it reflects the underlying true incidence. As control targets are defined in terms of observed cases, there is an urgent need to understand how changes in detection delay and population coverage of improved detection affect VL control.

Using a mathematical model for transmission and control of VL, we predict the impact of reduced detection delays and/or increased population coverage of the detection programs on observed and true VL incidence and mortality.

Improved case detection, either by higher coverage or reduced detection delay, causes an initial rise in observed VL incidence before a reduction. Relaxation of improved detection may lead to an apparent temporary (1 year) reduction in VL incidence, but comes with a high risk of resurging infection levels. Duration of symptoms in detected cases shows an unequivocal association with detection effort.

VL incidence on its own is not a reliable indicator of the performance of case detection programs. Duration of symptoms in detected cases can be used as an additional marker of the performance of case detection programs.

• improved case detection
• mathematical modeling
• mortality
• resurgence
• transmission dynamics
• visceral leishmaniasis

Post-kala-azar dermal leishmaniasis (PKDL) is a cutaneous sequel of visceral leishmaniasis (VL) or kala-azar and has become an entity of epidemiological significance by virtue of its ability to maintain the disease in circulation during inter-epidemic periods. PKDL has been identified as one of the epidemiological marker of “kala-azar elimination programme.” Data obtained in 2018 showed PKDL distribution primarily concentrated in 6 countries, which includes India, Sudan, south Sudan, Bangladesh, Ethiopia, and Nepal in decreasing order of case-burden. In India, PKDL cases are mainly found in 54 districts, of which 33 are in Bihar, 11 in West Bengal, 4 in Jharkhand, and 6 in Uttar Pradesh. In West Bengal the districts reporting cases of PKDL cases include Darjeeling, Uttar Dinajpur, Dakshin Dinajpur, Malda, and Murshidabad. The vulnerability on the young age is documented in various studies. The studies also highlights a male predominance of the disease but recent active surveillance suggested that macular form of PKDL shows female-predominance. It is recommended that along with passive case detection, active survey helps in early identification of cases, thus reducing disease transmission in the community. The Accelerated plan for Kala-azar elimination in 2017 introduced by Government of India with the goal to eliminate Kala-azar as a public health problem, targets to reduceing annual incidence <1/10,000. Leishmania donovani is the established causative agent, but others like L. tropica or L. infantum may occasionally lead to the disease, especially with HIV-co-infection. Dermal tropism of the parasite has been attributed to overexpression of parasite surface receptors (like gp 63, gp46). Various host factors are also identified to contribute to the development of the disease, including high pretreatment IL 10 and parasite level, inadequate dose and duration of treatment, malnutrition, immuno-suppression, decreased interferon-gamma receptor 1 gene, etc. PKDL is mostly concentrated in the plains below an altitude of 600 mts which is attributed to the environment conducive for the vector sand fly (Phlebotumus). Risk factors are also linked to the habitat of the sand fly. Keeping these things in mind “Integrated vector control” is adopted under National vector borne disease control programme as one of the strategies to bring down the disease burden.

• Disease burden
• epidemiology
• leishmania
• phlebotumus
• post Kala-azar dermal leishmaniasis
• sand fly
• vector control

• Cytokines
• Immune responses
• Leishmania donovani
• Post-kala-azar dermal leishmaniasis
• T cells

This article describes an atypical case of post-kala-azar dermal leishmaniasis associated with complications due to delayed diagnosis and poor case management. The grave consequences of the prolonged disease process that continued for over 2 decades with eventual healing included facial disfigurement, visual impairment, and mental distress both to the patient and the family. The persistent infection within the skin over a lengthy period with likely increased risk of infection spread in the community highlights its potential negative impact on the ongoing leishmaniasis elimination program in the Indian subcontinent. Bhutan is a member of the leishmaniasis elimination network in Asia, and the government continues to invest in maintenance of the national healthcare system. The case study reveals the gaps in the healthcare system with hardships faced by a patient to access quality healthcare and poor patient outcome used as proxy indicators. It also points to the need to enhance access to healthcare to ensure early diagnosis and effective treatment for leishmaniasis patients including those who live in remote areas, in order to achieve the planned disease elimination targets. It also points towards the key challenges faced by a resource poor nation such as Bhutan in achieving universal health coverage and reaching the set goals for disease elimination. The findings underscore the need for a careful review of the national health care system and to address the deficiencies.

Few prospective data exist on incidence of post kala-azar dermal leishmaniasis (PKDL) and visceral leishmaniasis (VL) relapse after different treatment regimens.

A Phase IV trial included 1761 VL patients treated between 2012–2014 with single dose AmBisome (SDA; N = 891), miltefosine-paromomycin (Milt-PM; n = 512), or AmBisome-miltefosine (AmB-Milt; n = 358). Follow-up for PKDL and VL relapse was scheduled for 6, 12 and 24 months after treatment, lasting until 2017. Patients with lesions consistent with PKDL were tested by rK39 rapid test, and if positive, underwent skin-snip sampling, smear microscopy and PCR. Probable PKDL was defined by consistent lesions and positive rK39; confirmed PKDL required additional positive microscopy or PCR. PKDL and relapse incidence density were calculated by VL treatment and risk factors evaluated in Cox proportional hazards models.

Among 1,750 patients who completed treatment, 79 had relapse and 104 PKDL. Relapse incidence density was 1.58, 2.08 and 0.40 per 1000 person-months for SDA, AmB-Milt and Milt-PM, respectively. PKDL incidence density was 1.29, 1.45 and 2.65 per 1000 person-months for SDA, AmB-Milt and Milt-PM. In multivariable models, patients treated with Milt-PM had lower relapse but higher PKDL incidence than those treated with SDA; AmB-Milt rates were not significantly different from those for SDA. Children <12 years were at higher risk for both outcomes; females had a higher risk of PKDL but not relapse.

Active surveillance for PKDL and relapse, followed by timely treatment, is essential to sustain the achievements of VL elimination programs in the Indian sub-continent.

Efforts to eliminate visceral leishmaniasis (VL) in the Indian subcontinent have had an unprecedented impact on the number of cases over the past decade, however, the disease is known to be cyclical and previous periods of low incidence have been followed by a major resurgence. The disease is thought to be maintained between epidemics as post-kala-azar dermal leishmaniasis (PKDL), a skin disease affecting 5 to 15% of apparently cured VL patients in the Indian subcontinent. PKDL is difficult to cure and since PKDL patients are not systemically ill, they seldom seek treatment, meaning that PKDL is likely to be a major obstacle to elimination. A key question is how different VL treatment regimens affect the risk of subsequent PKDL. We followed-up a cohort of more than 1700 patients treated with three different drug regimens in an effectiveness trial in Bihar and found that patients treated with miltefosine-paromomycin had a lower risk of relapse but higher PKDL incidence, while AmBisome treated patients had the reverse pattern. In order to sustain the gains already made, active surveillance for PKDL and relapse is essential, along with timely treatment, and new VL treatment regimens that avoid future PKDL are needed.

• Antimony Sodium Gluconate/adverse effects
• Biomarkers
• Genetic Predisposition to Disease
• Humans
• Immunologic Memory
• Leishmaniasis, Cutaneous/diagnosis
• Leishmaniasis, Cutaneous/etiology
• Leishmaniasis, Cutaneous/genetics
• Leishmaniasis, Cutaneous/prevention & control
• Leishmaniasis, Visceral/complications
• Leishmaniasis, Visceral/drug therapy

• U19 AI074321 NIAID NIH HHS

• clinico-epidemiological
• diagnosis
• post kala-azar dermal leishmaniasis (PKDL)
• surveillance
• trained field workers (TFW's)
• visceral leishmaniasis (VL)

The 5th Post-Kala-Azar Dermal Leishmaniasis (PKDL) Consortium meeting brought together PKDL experts from all endemic areas to review and discuss existing and new data on PKDL. This report summarizes the presentations and discussions and provides the overall conclusions and recommendations.

• Diagnosis
• Epidemiology
• Immunology
• Parasitology
• Post-kala-azar dermal leishmaniasis
• Recommendations
• Treatment

We investigated the relationship of treatment regimens for visceral leishmaniasis (VL) with post-kala-azar dermal leishmaniasis (PKDL) and visceral leishmaniasis relapse (VLR) development.

Study subjects included cohorts of patients cured of VL since treatment with monotherapy by sodium stibogluconate (SSG), miltefosine (MF), paromomycin intramuscular injection (PMIM), liposomal amphotericin B [AmBisome (AMB)] in a single dose (SDAMB) and in multidose (MDAMB), and combination therapies by AMB+PMIM, AMB+MF, and PMIM+MF. Follow up period was 4 years after treatment. Cohorts were prospective except SSG (retrospective) and MF (partially retrospective). We compared incidence proportion and rate in 100-person-4year of PKDL and VLR by treatment regimens using univariate and multivariate analysis.

974 of 984 enrolled participants completed the study. Overall incidence proportion for PKDL and VLR was 12.3% (95% CI, 10.4%–14.5%) and 7.0% (95% CI, 5.6%–8.8%) respectively. The incidence rate (95% CI) of PKDL and VLR was 14.0 (8.6–22.7) and 7.6 (4.1–14.7) accordingly. SSG cohort had the lowest incidence rate of PKDL at 3.0 (1.3–7.3) and VLR at 1.8 (0.6–5.6), followed by MDAMB at 8.2 (4.3–15.7) for PKDL and at 2.7 (0.9–8.4) for VLR.

Development of PKDL and VLR is related with treatment regimens for VL. SSG and MDAMB resulted in less incidence of PKDL and VLR compared to other treatment regimens. MDAMB should be considered for VL as a first step for prevention of PKDL and VLR since SSG is highly toxic and not recommended for VL.

Post-kala-azar Dermal Leishmaniasis (PKDL), a sequale of visceral leishmaniasis (VL), and reappearance VL (visceral leishmaniasis relapse, VLR) are intra-epidemic reservoirs of VL and threats control of VL in long run. Currently there is no strategy for prevention of PKDL and VLR. If a relationship between treatment for VL and development of PKDL and VLR is there, and then selection of proper treatment regimen for VL should prevent PKDL and VLR. So far no study has been carried out to investigate the relationship between treatment regimens for VL and development of PKDL and VLR. The study demonstrated that multi-dose liposomal amphotericin B (AmBisome) defined as MDAMB herein for VL results in least PKDL and VLR among all existing and recommended by WHO treatment regimens for VL. We recommend adaptation of MDAMB in the national visceral leishmaniasis elimination program for VL cases management during subsequent phases of the national program when VL burden is low and hospitalization of VL patients for 3-5-days is now feasible.

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Antiprotozoal Agents/therapeutic use
• Bangladesh/epidemiology
• Drug Therapy/methods
• Drug Therapy, Combination/methods
• Female
• Humans
• Incidence
• Injections, Intramuscular
• Leishmaniasis, Cutaneous/epidemiology
• Leishmaniasis, Visceral/complications
• Leishmaniasis, Visceral/drug therapy
• Male
• Middle Aged
• Prospective Studies
• Recurrence
• Retrospective Studies
• Treatment Outcome
• Young Adult

• Bill and Melinda Gates Foundation

Post-kala-azar dermal leishmaniasis (PKDL) is a skin manifestation of visceral leishmaniasis (VL) which develops after apparent cure in some patients. PKDL is considered as the potential reservoir for the VL infection. Molecular epidemiological characterization of L. donovani isolates obtained from VL and PKDL isolates is essentially required in order to understand the transmission dynamics of the VL infection. To date, genetic variation among the VL and PKDL L. donovani isolates was not fully elucidated. Therefore, 14 clinical isolates from VL and 4 clinical isolates from PKDL were speciated by hsp70 and rDNA genes. Further characterization of L. donovani by haspB PCR demonstrates two different genotypes. All PKDL isolates have the same genetic structure. kDNA PCR-RFLP assay revealed 18 different genotypes; however, structural analysis showed the two distinct kDNA genotype population (k = 2). The kDNA fingerprint patterns of parasites from hilly districts were clustered separately from low-land districts. Therefore, further study with a large number of samples is urgently required for systematic characterization of the clinical isolates to track the molecular epidemiology of the Leishmania donovani causing VL and the role of PKDL as a reservoir.

• Adolescent
• Adult
• Epidemiological Monitoring
• Female
• Humans
• India/epidemiology
• Leishmaniasis, Cutaneous/epidemiology
• Leishmaniasis, Cutaneous/pathology
• Leishmaniasis, Visceral/complications
• Male
• Risk Factors
• Sex Factors
• Skin/pathology
• Young Adult

• Indian Council of Medical Research
• Department of Health Research, Govt. of India
• Fund for Improvement of S&T infrastructure in Universities and Higher Educational Institutions (FIST) Program, Dept. of Science & Technology, Govt. of India
• Department of Science and Technology, Government of West Bengal

• Kala-azar
• Nepal
• Népal
• comportement de recherche de santé
• delay periods
• délais de retard
• health seeking behaviour
• leishmaniose viscérale
• private sector
• report
• reporting
• secteur privé
• surveillance
• visceral leishmaniasis

Background: There is a recognized need for an improved diagnostic test to assess post-chemotherapeutic treatment outcome in visceral leishmaniasis (VL) and to diagnose post kala-azar dermal leishmaniasis (PKDL). We previously demonstrated by ELISA and a prototype novel rapid diagnostic test (RDT), that high anti-Leishmania IgG1 is associated with post-treatment relapse versus cure in VL.

Methodology: Here, we further evaluate this novel, low-cost RDT, named VL Sero K-SeT, and ELISA for monitoring IgG1 levels in VL patients after treatment. IgG1 levels against L. donovani lysate were determined. We applied these assays to Indian sera from cured VL at 6 months post treatment as well as to relapse and PKDL patients. Sudanese sera from pre- and post-treatment and relapse were also tested.

Results: Of 104 paired Indian sera taken before and after treatment for VL, when deemed clinically cured, 81 (77.9%) were positive by VL Sero K-SeT before treatment; by 6 months, 68 of these 81 (84.0%) had a negative or reduced RDT test line intensity. ELISAs differed in positivity rate between pre- and post-treatment (p = 0.0162). Twenty eight of 33 (84.8%) Indian samples taken at diagnosis of relapse were RDT positive. A comparison of Indian VL Sero K-SeT data from patients deemed cured and relapsed confirmed that there was a significant difference (p < 0.0001) in positivity rate for the two groups using this RDT. Ten of 17 (58.8%) Sudanese sera went from positive to negative or decreased VL Sero K-SeT at the end of 11–30 days of treatment. Forty nine of 63 (77.8%) PKDL samples from India were positive by VL Sero K-SeT.

Conclusion: We have further shown the relevance of IgG1 in determining clinical status in VL patients. A positive VL Sero K-SeT may also be helpful in supporting diagnosis of PKDL. With further refinement, such as the use of specific antigens, the VL Sero K-SeT and/or IgG1 ELISA may be adjuncts to current VL control programmes.

• IgG1
• PKDL
• RDT
• cure
• relapse
• serology
• treatment
• visceral leishmaniasis

• Animals
• Antiprotozoal Agents/therapeutic use
• Coinfection/complications
• Disease Vectors
• Global Health
• HIV Infections/complications
• Humans
• Leishmania
• Leishmaniasis, Cutaneous/diagnosis
• Leishmaniasis, Cutaneous/drug therapy
• Leishmaniasis, Cutaneous/epidemiology
• Leishmaniasis, Cutaneous/physiopathology
• Leishmaniasis, Visceral/diagnosis
• Leishmaniasis, Visceral/drug therapy
• Leishmaniasis, Visceral/epidemiology
• Leishmaniasis, Visceral/physiopathology

The South-East Asia Region Kala-azar Elimination Programme (KAEP) is expected to enter the consolidation phase in 2017, which focuses on case detection, vector control, and identifying potential sources of infection. Post-kala-azar dermal leishmaniasis (PKDL) is thought to play a role in the recurrence of visceral leishmaniasis (VL)/kala-azar outbreaks, and control of PKDL is among the priorities of the KAEP.

We reviewed the literature with regard to PKDL in Asia and interpreted the findings in relation to current intervention methods in the KAEP in order to make recommendations. There is a considerable knowledge gap regarding the pathophysiology of VL and PKDL, especially the underlying immune responses. Risk factors (of which previous VL treatments may be most important) are poorly understood and need to be better defined. The role of PKDL patients in transmission is largely unknown, and there is insufficient information about the importance of duration, distribution and severity of the rash, time of onset, and self-healing. Current intervention methods focus on active case detection and treatment of all PKDL cases with miltefosine while there is increasing drug resistance. The prevention of PKDL by improved VL treatment currently receives insufficient attention.

PKDL is a heterogeneous and dynamic condition, and patients differ with regard to time of onset after VL, chronicity, and distribution and appearance of the rash, as well as immune responses (including tendency to self-heal), all of which may vary over time. It is essential to fully describe the pathophysiology in order to make informed decisions on the most cost-effective approach. Emphasis should be on early detection of those who contribute to transmission and those who are in need of treatment, for whom short-course, effective, and safe drug regimens should be available. The prevention of PKDL should be emphasised by innovative and improved treatment for VL, which may include immunomodulation.

• Asia, Southeastern/epidemiology
• Disease Eradication/organization & administration
• Disease Outbreaks/prevention & control
• Female
• Humans
• India/epidemiology
• Leishmania donovani/isolation & purification
• Leishmaniasis, Cutaneous/epidemiology
• Leishmaniasis, Cutaneous/parasitology
• Leishmaniasis, Visceral/drug therapy
• Leishmaniasis, Visceral/epidemiology
• Leishmaniasis, Visceral/parasitology
• Leishmaniasis, Visceral/prevention & control
• Male
• Prevalence
• Preventive Health Services
• Recurrence
• Risk Factors

Quantitation of the nonlinear heterogeneities in Leishmania parasites, sand fly vectors, and mammalian host relationships provides insights to better understand leishmanial transmission epidemiology towards improving its control. The parasite manipulates the sand fly via production of promastigote secretory gel (PSG), leading to the “blocked sand fly” phenotype, persistent feeding attempts, and feeding on multiple hosts. PSG is injected into the mammalian host with the parasite and promotes the establishment of infection. Animal models demonstrate that sand flies with the highest parasite loads and percent metacyclic promastigotes transmit more parasites with greater frequency, resulting in higher load infections that are more likely to be both symptomatic and efficient reservoirs. The existence of mammalian and sand fly “super-spreaders” provides a biological basis for the spatial and temporal clustering of clinical leishmanial disease. Sand fly blood-feeding behavior will determine the efficacies of indoor residual spraying, topical insecticides, and bed nets. Interventions need to have sufficient coverage to include transmission hot spots, especially in the absence of field tools to assess infectiousness. Interventions that reduce sand fly densities in the absence of elimination could have negative consequences, for example, by interfering with partial immunity conferred by exposure to sand fly saliva. A deeper understanding of both sand fly and host biology and behavior is essential to ensuring effectiveness of vector interventions.

We review recent research that sheds light on the quantitative biology of leishmanial transmission between sand flies and mammalian hosts and use these insights to better understand transmission, the observed epidemiology of the disease, and their implications in choice of control strategy. Using animal models, we show how the parasite-induced processes manipulate sand fly blood-feeding behavior and the infectious metacyclic dose to promote host infection and to differentially regulate the onward transmission potential of individual vectors and hosts. The existence of subpopulations of mammalian and sand fly “super-spreaders” provides a biological basis for the spatial and temporal clustering of clinical leishmanial disease. While tools are unavailable to distinguish these individuals in mixed populations, blanket interventions will be necessary to ensure inclusion of transmission hot spots. Interventions that reduce sand fly densities without elimination could interfere with vector—host dynamics and conferred partial immunity to host populations.

• Animals
• Host-Pathogen Interactions/immunology
• Humans
• Insect Vectors/parasitology
• Leishmania/parasitology
• Leishmaniasis/epidemiology
• Leishmaniasis/parasitology
• Leishmaniasis/transmission
• Parasites/parasitology
• Parasites/pathogenicity
• Psychodidae/parasitology

• Wellcome Trust
• BB/H022406/1 Biotechnology and Biological Sciences Research Council

• Dynamical modeling
• Kala-azar
• Leishmaniasis
• Mathematical model
• Risk-factors

• Detection and treatment
• Elimination
• Indian subcontinent
• Indoor residual spraying
• Kala-azar
• Mathematical modelling
• Neglected tropical disease
• Predictions
• Sandfly
• Transmission dynamics
• Visceral leishmaniasis

• Antiprotozoal Agents/therapeutic use
• Disease Eradication
• Humans
• Incidence
• India/epidemiology
• Insecticides
• Leishmaniasis, Visceral/epidemiology
• Leishmaniasis, Visceral/prevention & control
• Leishmaniasis, Visceral/transmission
• Models, Theoretical

Visceral Leishmaniasis (VL) is a neglected tropical disease that afflicts some of the poorest populations in the world including people living in the Bihar state of India. Due to efforts from local governments, NGOs and international organizations, the number of VL cases has declined in recent years. Despite this progress, the reservoir for transmission remains to be clearly defined since it is unknown what role post kala-azar dermal leishmaniasis (PKDL) and asymptomatic infections play in transmission. This information is vital to establish effective surveillance and monitoring to sustainably eliminate VL.

We performed a longitudinal study over a 24-month period to examine VL transmission and seroconversion in households with VL, PKDL and asymptomatic infections in the Saran and Muzaffarpur districts of Bihar. During the initial screening of 5,144 people in 16 highly endemic villages, 195 cases of recently treated VL, 116 healthy rK39 positive cases and 31 PKDL cases were identified. Approximately half of the rK39-positive healthy cases identified during the initial 6-month screening period were from households (HHs) where a VL case had been identified. During the 18-month follow-up period, seroconversion of family members in the HHs with VL cases, PKDL cases, and rK39-positive individuals was similar to control HHs. Therefore, seroconversion was highest in HHs closest to the time of VL disease of a household member and there was no evidence of higher transmission in households with PKDL or healthy rK39-positive HHs. Moreover, within the PKDL HHs, (the initial 31 PKDL cases plus an additional 66 PKDL cases), there were no cases of VL identified during the initial screen or the 18-month follow-up. Notably, 23% of the PKDL cases had no prior history of VL suggesting that infection resulting directly in PKDL is more common than previously estimated.

These observations argue that acute VL cases represent the major reservoir for transmission in these villages and early identification and treatment of VL cases should remain a priority for VL elimination. We were unable to obtain evidence that transmission occurs in HHs with a PKDL case.

Visceral leishmaniasis (also known as kala-azar) caused by infection with L. donovani is a deadly parasitic disease that afflicts some of world’s poorest populations, including the people of the northern Bihar State of India. Once transmitted to a human by an infected sandfly, the L. donovani parasite migrates from the site of the sandfly bite throughout the reticuloendothelial system, resulting in high levels of infection in the spleen, liver and bone marrow that eventually lead to organ failure and death if not treated effectively. India, Nepal and Bangladesh are currently engaged in a program to eliminate visceral leishmaniasis, principally through early case detection, treatment and vector control. As humans are the only reservoir for L. donovani, it is necessary to understand how the disease is transmitted and specifically what role acute visceral leishmaniasis (VL) cases, asymptomatic infections and post kala-azar dermal leishmaniasis (PKDL) cases play in transmission. We therefore performed a study to determine seroconversion for antibodies against the L. donovani rK39 antigen as a surrogate for transmission in households with VL cases, asymptomatic infections and PKDL cases in 16 highly endemic villages over a 2-year period in Bihar, India. We observed that most transmission occurred in the VL households and further that it occurred closest to the time of acute disease. We were unable to confirm that transmission occurred in the households with either asymptomatic infections or PKDL cases. These observations argue that active surveillance to diagnose and treat VL cases as soon as possible to reduce transmission should remain a priority for VL elimination.

• Adolescent
• Adult
• Antiprotozoal Agents/therapeutic use
• Asymptomatic Infections/epidemiology
• Child
• Child, Preschool
• Disease Reservoirs/parasitology
• Family Characteristics
• Female
• Humans
• India/epidemiology
• Infant
• Leishmaniasis, Cutaneous/complications
• Leishmaniasis, Cutaneous/drug therapy
• Leishmaniasis, Cutaneous/transmission
• Leishmaniasis, Visceral/complications
• Leishmaniasis, Visceral/epidemiology
• Leishmaniasis, Visceral/parasitology
• Leishmaniasis, Visceral/transmission
• Longitudinal Studies
• Male
• Middle Aged
• Neglected Diseases/epidemiology
• Neglected Diseases/parasitology
• Seroconversion
• Young Adult

• Grand Challenges Canada

• Kala-azar
• Leishmania
• Mathematical modelling
• Neglected tropical disease
• PKDL
• Sandflies
• Vector-borne transmission
• Visceral leishmaniasis

As Bangladesh, India and Nepal progress towards visceral leishmaniasis (VL) elimination, it is important to understand the role of asymptomatic Leishmania infection (ALI), VL treatment relapse and post kala-azar dermal leishmaniasis (PKDL) in transmission.

We reviewed evidence systematically on ALI, relapse and PKDL. We searched multiple databases to include studies on burden, risk factors, biomarkers, natural history, and infectiveness of ALI, PKDL and relapse. After screening 292 papers, 98 were included covering the years 1942 through 2016. ALI, PKDL and relapse studies lacked a reference standard and appropriate biomarker. The prevalence of ALI was 4–17-fold that of VL. The risk of ALI was higher in VL case contacts. Most infections remained asymptomatic or resolved spontaneously. The proportion of ALI that progressed to VL disease within a year was 1.5–23%, and was higher amongst those with high antibody titres. The natural history of PKDL showed variability; 3.8–28.6% had no past history of VL treatment. The infectiveness of PKDL was 32–53%. The risk of VL relapse was higher with HIV co-infection. Modelling studies predicted a range of scenarios. One model predicted VL elimination was unlikely in the long term with early diagnosis. Another model estimated that ALI contributed to 82% of the overall transmission, VL to 10% and PKDL to 8%. Another model predicted that VL cases were the main driver for transmission. Different models predicted VL elimination if the sandfly density was reduced by 67% by killing the sandfly or by 79% by reducing their breeding sites, or with 4–6y of optimal IRS or 10y of sub-optimal IRS and only in low endemic setting.

There is a need for xenodiagnostic and longitudinal studies to understand the potential of ALI and PKDL as reservoirs of infection.

The role of asymptomatic Leishmania infection (ALI), PKDL and VL relapse in transmission is unclear as VL elimination is achieved in the Indian subcontinent. ALI, PKDL and relapse studies lacked a reference standard and appropriate biomarker. ALI was 4–17-fold more prevalent than VL. The risk of ALI was higher in VL case contacts. Most infections remained asymptomatic or resolved spontaneously. The natural history of PKDL showed variability. Twenty nine percent had no past history of VL treatment. The risk of VL relapse was higher with HIV co-infection. Modelling studies predicted different effects. Early diagnosis was unlikely to eliminate VL in the long term. ALI was predicted to contribute to 82% of the overall transmission, VL to 10% and PKDL to 8%. Another model predicted that VL cases were the main driver for transmission. VL elimination was predicted if the sandfly density was reduced by 67% by killing the sandfly or by 79% by reducing their breeding sites, or with 4–6y of optimal IRS or 10y of sub-optimal IRS and only in low endemic setting. There is a need for more studies to fully understand the potential of ALI and PKDL as reservoirs of infection.

Visceral leishmaniasis (VL) is a neglected tropical disease transmitted by sandflies. On the Indian subcontinent (ISC), VL is targeted for elimination as a public health problem by 2017. In the context of VL, the elimination target is defined as an annual VL incidence of <1 per 10,000 capita at (sub-)district level. Interventions focus on vector control, surveillance and on diagnosing and treating VL cases. Many endemic areas have not yet achieved optimal control due to logistical, biological as well as technical challenges. We used mathematical modelling to quantify VL transmission dynamics and predict the feasibility of achieving the VL elimination target with current control strategies under varying assumptions about the reservoir of infection in humans.

We developed three deterministic age-structured transmission models with different main reservoirs of infection in humans: asymptomatic infections (model 1), reactivation of infection after initial infection (model 2), and post kala-azar dermal leishmaniasis (PKDL; model 3). For each model, we defined four sub-variants based on different assumptions about the duration of immunity and age-patterns in exposure to sandflies. All 12 model sub-variants were fitted to data from the KalaNet study in Bihar (India) and Nepal, and the best sub-variant was selected per model. Predictions were made for optimal and sub-optimal indoor residual spraying (IRS) effectiveness for three different levels of VL endemicity.

Structurally different models explained the KalaNet data equally well. However, the predicted impact of IRS varied substantially between models, such that a conclusion about reaching the VL elimination targets for the ISC heavily depends on assumptions about the main reservoir of infection in humans: asymptomatic cases, recovered (immune) individuals that reactivate, or PKDL cases.

Available data on the impact of IRS so far suggest one model is probably closest to reality (model 1). According to this model, elimination of VL (incidence of <1 per 10,000) by 2017 is only feasible in low and medium endemic settings with optimal IRS. In highly endemic settings and settings with sub-optimal IRS, additional interventions will be required.

The online version of this article (doi:10.1186/s13071-016-1292-0) contains supplementary material, which is available to authorized users.

Post Kala-azar Dermal Leishmaniasis (PKDL) is a chronic but not life-threatening disease; patients generally do not demand treatment, deserve much more attention because PKDL is highly relevant in the context of Visceral Leishmaniasis (VL) elimination. There is no standard guideline for diagnosis and treatment for PKDL. A species-specific PCR on slit skin smear demonstrated a sensitivity of 93.8%, but it has not been applied for routine diagnostic purpose. The study was conducted to determine the actual disease burden in an endemic area of Malda district, West Bengal, comparison of the three diagnostic tools for PKDL case detection and pattern of lesion regression after treatment. The prevalence of PKDL was determined by active surveillance and confirmed by PCR based diagnosis. Patients were treated with either sodium stibogluconate (SSG) or oral miltefosine and followed up for two years to observe lesion regression period. Twenty six PKDL cases were detected with a prevalence rate of 27.5% among the antileishmanial antibody positive cases. Among three diagnostic methods used, PCR is highly sensitive (88.46%) for case confirmation. In majority of the cases skin lesions persisted after treatment completion which gradually disappeared during 6–12 months post treatment period. Reappearance of lesions noted in two cases after 1.5 years of miltefosine treatment. A significant number of PKDL patients would remain undiagnosed without active mass surveys. Such surveys are required in other endemic areas to attain the ultimate goal of eliminating Kala-azar. PCR-based method is helpful in confirming diagnosis of PKDL, referral laboratory at district or state level can achieve it. So a well-designed study with higher number of samples is essential to establish when/whether PKDL patients are free from parasite after treatment and to determine which PKDL patients need treatment for longer period.

A significant number of PKDL patients have been detected in the endemic areas of Malda who would remain undiagnosed without active mass surveys. Such active survey is required in other endemic areas of the country to attain the ultimate goal of eliminating Kala-azar from this part of the world by reducing the source of infection. PCR-based method is helpful in confirming diagnosis of PKDL, which is not applicable at field level. A referral laboratory at district or state level can be a solution to the problem. Since PKDL cases do not have a fatal outcome, treatment administration of these cases can be deferred until confirmed results are obtained, which requires about 7 days’ time. The detection of leishmanial DNA in skin lesions during successive treatment courses is essential to establish whether/ when PKDL patients are parasite free during/after treatment and to determine which PKDL patients need treatment for a longer period.

• Administration, Oral
• Adolescent
• Adult
• Animals
• Antimony Sodium Gluconate/administration & dosage
• Antiprotozoal Agents/administration & dosage
• Child
• Child, Preschool
• Disease Transmission, Infectious
• Epidemiological Monitoring
• Female
• Humans
• India/epidemiology
• Leishmaniasis, Cutaneous/diagnosis
• Leishmaniasis, Cutaneous/drug therapy
• Leishmaniasis, Cutaneous/epidemiology
• Leishmaniasis, Cutaneous/transmission
• Leishmaniasis, Visceral/complications
• Male
• Phosphorylcholine/administration & dosage
• Phosphorylcholine/analogs & derivatives
• Polymerase Chain Reaction
• Prevalence
• Recurrence
• Rural Population
• Young Adult

• Indian subcontinent
• kala-azar
• mathematical model
• review
• visceral leishmaniasis

The elimination of infectious diseases requires reducing transmission below a certain threshold. The Visceral Leishmaniasis (VL) Elimination Initiative in Southeast Asia aims to reduce the annual VL incidence rate below 1 case per 10,000 inhabitants in endemic areas by 2015 via a combination of case management and vector control. Using a previously developed VL transmission model, we investigated transmission thresholds dependent on measures reducing the sand fly density either by killing sand flies (e.g., indoor residual spraying and long-lasting insecticidal nets) or by destroying breeding sites (e.g., environmental management).

Model simulations suggest that elimination of VL is possible if the sand fly density can be reduced by 67% through killing sand flies, or if the number of breeding sites can be reduced by more than 79% through measures of environmental management.

These results were compared to data from two recent cluster randomised controlled trials conducted in India, Nepal and Bangladesh showing a 72% reduction in sand fly density after indoor residual spraying, a 44% and 25% reduction through the use of long-lasting insecticidal nets and a 42% reduction after environmental management.

Based on model predictions, we identified the parameters within the transmission cycle of VL that predominantly determine the prospects of intervention success. We suggest further research to refine model-based predictions into the elimination of VL.

Visceral leishmaniasis is suspected to be the second largest parasitic killer in the world after malaria. On the Indian subcontinent, the vector-borne disease is caused by the protozoan flagellate Leishmania donovani and transmitted by the sand fly Phlebotomus argentipes. The regional elimination programme has suggested as a target line to reduce the annual incidence below 1 case in 10,000 by 2015. Using a previously developed mathematical model, we investigated to what extent the sand fly population must be controlled to achieve elimination. These calculated thresholds were compared to data from two recent trials conducted in India, Nepal and Bangladesh to evaluate the efficacy of different vector control measures. Our results indicate that elimination should be feasible because the evaluated effect of indoor residual spraying exceeds the threshold. However, emerging insecticide resistance may compromise the effectiveness of this measure. The observed effects of long lasting insecticidal nets and environmental management do not seem to be sufficient to reach either threshold. Integrated vector management based on indoor residual spraying combined with long lasting insecticidal nets and more effective environmental management may allow overcoming the limitations of the current vector control methods and should also prevent re-emergence of the infection after local extinction.

•

Sodium antimony gluconate contributes towards the pathogenesis of PKDL.

Post kala-azar dermal leishmaniasis (PKDL), a cutaneous sequela of visceral leishmaniasis (VL), develops in some patients alongside but more commonly after apparent cure from VL. In view of the pivotal role of PKDL patients in the transmission of VL, here we review clinical, epidemiological, parasitological, and immunological perspectives of this disease, focusing on five hypotheses to explain the development of PKDL: (i) the role of antimonial drugs; (ii) UV-induced skin damage; (iii) reinfection; (iv) organ specific failure of memory T cell responses; and (v) genetic susceptibility of the host. This review will enable researchers and clinicians to explore the unresolved mystery of PKDL and provide a framework for future application of ‘omic’ approaches for the control and eventual elimination of VL.

• UV light
• antimony
• post kala-azar dermal leishmaniasis (PKDL)
• regulatory T cells
• vitamin D

The skin disorder Post Kala-Azar Dermal Leishmaniasis (PKDL) occurs in up to 10% of patients treated for visceral leishmaniasis (VL) in India. The pathogenesis of PKDL is not yet fully understood. Cases have been reported in India following therapy with most available treatments, but rarely in those treated with liposomal amphotericin B (Ambisome). Between July 2007 and August 2012 with the support of the Rajendra Memorial Research Institute (RMRI), Médecins Sans Frontières (MSF) supported a VL treatment programme in Bihar, India—an area highly endemic for Leishmania donovani—in which 8749 patients received 20 mg/kg intravenous Ambisome as first-line treatment. This study describes the characteristics of patients who returned to the MSF supported treatment programme with PKDL.

Over a 5-year period, Ambisome was administered to 8749 patients with laboratory-confirmed VL (clinical signs, rK39 positive, with/without parasite confirmation) in four intravenous doses of 5 mg/kg to a total of 20 mg/kg, with a high initial-cure rate (99.3%) and low default rate (0.3%). All patients received health education highlighting the possibility and symptoms of developing PKDL, and advice to return to the MSF programme if these symptoms developed. This is an observational retrospective cohort study of the programme outcomes. Of the 8311 patients completing treatment for their first episode of VL, 24 (0.3%) returned passively to the programme complaining of symptoms subsequently confirmed as PKDL, diagnosed from clinical history, appearance consistent with PKDL, and slit-skin smear examination. Of the 24 patients, 89% had macular lesions, with a median time (interquartile range) to development of 1.2 (0.8–2.2) years following treatment. Comparison of the demographic and clinical characteristics of the VL patients treated with Ambisome who later developed PKDL, with those of the remaining cohort did not identify any significant risk factors for PKDL. However, the time to developing PKDL was significantly shorter with Ambisome than in a subset of patients presenting to the programme with PKDL following previous sodium stibogluconate treatment for VL.

In this large cohort of patients with VL in Bihar who were treated with 20 mg/kg Ambisome, PKDL following treatment appears to be infrequent with no predictive risk factors. The shorter median time to developing symptoms of PKDL compared with that after conventional VL treatments should be taken into account when counseling patients treated with regimens including Ambisome.

Visceral leishmaniasis (VL), also known as Kala-azar, is caused by the parasite L.donovani. Half of cases worldwide occur in India, with up to 90% of these in Bihar state. Post Kala-azar dermal leishmaniasis (PKDL) is a difficult to treat skin condition that develops in up to 10% of VL cases following treatment in the Indian subcontinent. Although often mild, PKDL can be severe and disfiguring. Patients are otherwise healthy. PKDL is considered a reservoir of L.donovani and requires treating to support disease elimination. Between 2007–2012, 8311 patients diagnosed with a first episode of VL completed treatment with 20 mg/kg intravenous liposomal amphotericin B (Ambisome) in a Médecins Sans Frontières (MSF) programme supported by the Rajendra Memorial Research Institute (RMRI) in Bihar. Ambisome is a safe and effective treatment that is recommended by the WHO for first-line use in the Indian subcontinent; although not yet included in the Indian guidelines. PKDL has been described following all VL treatments, but so far in only two patients treated with Ambisome. Here, we describe 24 patients treated with Ambisome who returned to the MSF treatment programme with confirmed PKDL. We found no risk factors for PKDL following treatment; however, the average time to development of PKDL was much shorter than that seen following older treatments.

• Adolescent
• Adult
• Amphotericin B/administration & dosage
• Antiprotozoal Agents/administration & dosage
• Child
• Child, Preschool
• Cohort Studies
• Female
• Humans
• India
• Infant
• Leishmania donovani/isolation & purification
• Leishmaniasis, Cutaneous/diagnosis
• Leishmaniasis, Visceral/drug therapy
• Male
• Middle Aged
• Recurrence
• Retrospective Studies
• Treatment Failure
• Young Adult

Post kala-azar dermal leishmaniasis (PKDL) is a neglected complication of visceral leishmaniasis (VL)―a deadly, infectious disease that claims approximately 20,000 to 40,000 lives every year. PKDL is thought to be a reservoir for transmission of VL, thus, adequate control of PKDL plays a key role in the ongoing effort to eliminate VL. Over the past few years, several expert meetings have recommended that a greater focus on PKDL was needed, especially in South Asia. This report summarizes the Post Kala-Azar Dermal Leishmaniasis Consortium Meeting held in New Delhi, India, 27–29 June 2012. The PKDL Consortium is committed to promote and facilitate activities that lead to better understanding of all aspects of PKDL that are needed for improved clinical management and to achieve control of PKDL and VL. Fifty clinicians, scientists, policy makers, and advocates came together to discuss issues relating to PKDL epidemiology, diagnosis, pathogenesis, clinical presentation, treatment, and control. Colleagues who were unable to attend participated during drafting of the consortium meeting report.

Pentavalent antimonials have been the mainstay of antileishmanial therapy for decades, but increasing failure rates under antimonial treatment have challenged further use of these drugs in the Indian subcontinent. Experimental evidence has suggested that parasites which are resistant against antimonials have superior survival skills than sensitive ones even in the absence of antimonial treatment.

We use simulation studies based on a mathematical L. donovani transmission model to identify parameters which can explain why treatment failure rates under antimonial treatment increased up to 65% in Bihar between 1980 and 1997. Model analyses suggest that resistance to treatment alone cannot explain the observed treatment failure rates. We explore two hypotheses referring to an increased fitness of antimony-resistant parasites: the additional fitness is (i) disease-related, by causing more clinical cases (higher pathogenicity) or more severe disease (higher virulence), or (ii) is transmission-related, by increasing the transmissibility from sand flies to humans or vice versa.

Both hypotheses can potentially explain the Bihar observations. However, increased transmissibility as an explanation appears more plausible because it can occur in the background of asymptomatically transmitted infection whereas disease-related factors would most probably be observable. Irrespective of the cause of fitness, parasites with a higher fitness will finally replace sensitive parasites, even if antimonials are replaced by another drug.

The protozoan flagellate Leishmania donovani causes the neglected, life-threatening disease visceral leishmaniasis. Parasites are transmitted from man to man by the bite of the sand fly Phlebotomus argentipes, the vector of the disease. Pentavalent antimonials have been the mainstay of antileishmanial therapy for decades but rapidly increasing failure rates up to 65% observed between 1980 and 1997 in the state of Bihar, India, have challenged further use of these drugs. Comparative in vitro and in vivo experiments indicate that antimony-resistant parasites have a higher fitness than antimony-sensitive ones even in the absence of antimonial treatment. Simulation studies based on a previously published mathematical L. donovani transmission model suggest that resistance to antimonial treatment alone cannot explain the Bihar observations but that resistance together with higher fitness offers the potential to explain the data. After an antimony-resistant parasite with higher fitness has emerged, it will finally replace the antimony-sensitive ones, even in complete absence of antimonial treatment.

• Animals
• Antimony/administration & dosage
• Antimony/pharmacology
• Antiprotozoal Agents/administration & dosage
• Antiprotozoal Agents/pharmacology
• Drug Resistance
• Humans
• India
• Leishmaniasis, Visceral/drug therapy
• Leishmaniasis, Visceral/transmission
• Models, Theoretical
• Psychodidae
• Treatment Failure

• Bihar
• LCPK
• Leishmania donovani
• PKDL
• PKLD
• Post‐kala‐azar dermal leishmaniasis
• kala azar
• kala‐azar
• leishmaniasis cutánea post‐kala‐azar
• leishmaniasis visceral
• leishmaniose cutanée post kala‐azar
• leishmaniose viscérale
• visceral leishmaniasis