Prevalence of post kala-azar dermal leishmaniasis (PKDL) and treatment seeking behavior of PKDL patients in Nepal.

BACKGROUND: In Nepal, the burden of post kala-azar dermal leishmaniasis (PKDL) is not known since there is no active case detection of PKDL by the national programme. PKDL patients could pose a challenge to sustain visceral leishmaniasis (VL) elimination. The objective of this study was to determine the prevalence of PKDL and assess PKDL patients' knowledge on VL and PKDL, and stigma associated with PKDL. METHODOLOGY/PRINCIPAL FINDINGS: Household surveys were conducted in 98 VL endemic villages of five districts that reported the highest number of VL cases within 2018-2021. A total of 6,821 households with 40373 individuals were screened for PKDL. Cases with skin lesions were referred to hospitals and examined by dermatologists. Suspected PKDL cases were tested with rK39 and smear microscopy from skin lesions. An integrated diagnostic approach was implemented in two hospitals with a focus on management of leprosy cases where cases with non-leprosy skin lesions were tested for PKDL with rK39. Confirmed PKDL patients were interviewed to assess knowledge and stigma associated with PKDL, using explanatory model interview catalogue (EMIC) with maximum score of 36. Among 147 cases with skin lesions in the survey, 9 (6.12%) were confirmed as PKDL by dermatologists at the hospital. The prevalence of PKDL was 2.23 per 10,000 population. Among these 9 PKDL cases, 5 had a past history of VL and 4 did not. PKDL cases without a past history of VL were detected among the "new foci", Surkhet but none in Palpa. None of the cases negative for leprosy were positive for PKDL. There was very limited knowledge of PKDL and VL among PKDL cases. PKDL patients suffered to some degree from social and psychological stigma (mean ± s.d. score = 17.89 ± 12.84). CONCLUSIONS/SIGNIFICANCE: Strengthening the programme in PKDL case detection and management would probably contribute to sustenance of VL elimination. Awareness raising activities to promote knowledge and reduce social stigma should be conducted in VL endemic areas.

Post kala azar dermal leishmaniasis and leprosy prevalence and distribution in the Muzaffarpur health and demographic surveillance site.

INTRODUCTION: Post-kala-azar dermal leishmaniasis (PKDL) is a skin manifestation that is a late clinical outcome of visceral leishmaniasis (VL). Its presentation is similar to leprosy, and the differential diagnosis is not always easy. In VL endemic rural areas of Bihar, India, both infectious diseases co-exist. This observational study aimed to determine the prevalence and distribution of both conditions in an area that had until recently been highly endemic for VL. METHODS: We conducted a door-to-door survey in an area that belongs to the Health and Demographic Surveillance Site (HDSS) of Muzaffarpur, Bihar, India. Within the HDSS we selected the villages that had reported the highest numbers of VL cases in preceding years. All consenting household members were screened for skin conditions, and minor conditions were treated on the spot. Upon completion of screening activities at the level of a few villages, a dermatology clinic ("skin camp") was conducted to which suspect leprosy and PKDL patients and other patients with skin conditions requiring expert advice were referred. We studied the association between distance from an index case of leprosy and the probability of disease in the neighborhood by fitting a Poisson model. RESULTS: We recorded a population of 33,319, out of which 25,686 (77.1%) were clinically screened. Participation in skin camps was excellent. Most common conditions were fungal infections, eczema, and scabies. There were three PKDL patients and 44 active leprosy patients, equivalent to a prevalence rate of leprosy of 17.1 per 10,000. Two out of three PKDL patients had a history of VL. Leprosy patients were widely spread across villages, but within villages, we found strong spatial clustering, with incidence rate ratios of 6.3 (95% C.I. 1.9-21.0) for household members and 3.6 (95% C.I. 1.3-10.2) for neighbors within 25 meters, with those living at more than 100 meters as the reference category. DISCUSSION: Even in this previously highly VL endemic area, PKDL is a rare condition. Nevertheless, even a single case can trigger a new VL outbreak. Leprosy is also a rare disease, but current prevalence is over 17 times the elimination threshold proclaimed by WHO. Both diseases require continued surveillance. Active case finding for leprosy can be recommended among household members and close neighbors of leprosy patients but would not be feasible for entire populations. Periodic skin camps may be a feasible and affordable alternative.

Integrating Case Detection of Visceral Leishmaniasis and Other Febrile Illness with Vector Control in the Post-Elimination Phase in Nepal.

Nepal has completed the attack phase of visceral leishmaniasis (VL) elimination and now needs active case detection (ACD) and vector control methods that are suitable to the consolidation and maintenance phases. We evaluated different ACD approaches and vector control methods in Saptari district. We assessed 1) mobile teams deployed in villages with VL cases in 2015 to conduct combined camps for fever and skin lesions to detect VL/PKDL (post-kala-azar dermal leishmaniasis) and other infections; 2) an incentive approach by trained female community health volunteers (FCHVs) in villages with no VL cases in 2015. Both were followed by house-to-house visits. For vector control, four villages were randomly allocated to insecticide impregnation of bednets, insecticide wall painting, indoor residual spraying (IRS), and control. Sandfly density (by CDC light traps, The John W. Hock Company, USA) and mortality (World Health Organization cone bioassay) were assessed in randomly selected households. One VL, three tuberculosis, one leprosy, and one malaria cases were identified among 395 febrile cases attending the camps. Post-camp house-to-house screening involving 7,211 households identified 679 chronic fever and 461 skin lesion cases but no additional VL/PKDL. No VL/PKDL case was found by FCHVs. The point prevalence of chronic fever in camp and FCHV villages was 242 and 2 per 10,000 populations, respectively. Indoor residual spraying and bednet impregnation were effective for 1 month versus 12 months with insecticidal wall paint. Twelve-month sandfly mortality was 23%, 26%, and 80%, respectively, on IRS, bednet impregnation, and insecticide wall painting. In Nepal, fever camps and insecticidal wall paint prove to be alternative, sustainable strategies in the VL post-elimination program.

Revisiting the role of the slit-skin smear in the diagnosis of Indian post-kala-azar dermal leishmaniasis.

BACKGROUND: Post kala azar dermal leishmaniasis (PKDL) is a neglected dermatosis that develops as a sequel to kala azar after apparent complete treatment. Being a non life threatening condition, patients often delay treatment thereby maintaining a reservoir of infection. The diagnosis of PKDL rests on the demonstration of the parasite in tissue smears, immune diagnosis by detection of parasite antigen or antibody in blood, or detection and quantitation of parasite DNA in tissue specimens. Sophisticated molecular tests are not only expensive but also need skilled hands and expensive equipment. To be useful, diagnostic methods must be accurate, simple and affordable for the population for which they are intended. AIMS: This study was designed to assess functionality and operational feasibility of slit-skin smear examination. METHODS: Sensitivity and specificity was evaluated by performing slit-skin smear and histo-pathological examination in 46 PKDL patients and the results were compared with the parasite load in both the slit aspirate and tissue biopsy specimens by performing quantitative Real-time PCR (Q-PCR). RESULTS: The slit-skin smear examination was more sensitive than tissue biopsy microscopy. The parasite loads significantly differed among various types of clinical lesions (P < 0.05). The threshold of parasite load for detection by SSS microscopy was 4 parasites/µl in slit aspirate and 60 parasites/µg tissue DNA in tissue biopsy while that for tissue microscopy was 63 parasites/µl and 502 parasites/µg tissue DNA respectively. As detection of Leishmania donovani bodies may be challenging in inexperienced hands, the microscopic structure of these has been detailed along with a comprehensive discussion of pre analytical, analytical and post analytical variables affecting its identification. To facilitate the diagnosis of PKDL, some scenarios have been suggested taking into consideration the clinical, epidemiological, immunological and microscopic aspects. CONCLUSION: Such evidence based medicine helps minimize intuition, systematize clinical experience and provides a diagnostic rationale as sufficient grounds for a clinical decision.

Socioeconomic Inequalities in Neglected Tropical Diseases: A Systematic Review.

BACKGROUND: Neglected tropical diseases (NTDs) are generally assumed to be concentrated in poor populations, but evidence on this remains scattered. We describe within-country socioeconomic inequalities in nine NTDs listed in the London Declaration for intensified control and/or elimination: lymphatic filariasis (LF), onchocerciasis, schistosomiasis, soil-transmitted helminthiasis (STH), trachoma, Chagas' disease, human African trypanosomiasis (HAT), leprosy, and visceral leishmaniasis (VL). METHODOLOGY: We conducted a systematic literature review, including publications between 2004-2013 found in Embase, Medline (OvidSP), Cochrane Central, Web of Science, Popline, Lilacs, and Scielo. We included publications in international peer-reviewed journals on studies concerning the top 20 countries in terms of the burden of the NTD under study. PRINCIPAL FINDINGS: We identified 5,516 publications, of which 93 met the inclusion criteria. Of these, 59 papers reported substantial and statistically significant socioeconomic inequalities in NTD distribution, with higher odds of infection or disease among poor and less-educated people compared with better-off groups. The findings were mixed in 23 studies, and 11 studies showed no substantial or statistically significant inequality. Most information was available for STH, VL, schistosomiasis, and, to a lesser extent, for trachoma. For the other NTDs, evidence on their socioeconomic distribution was scarce. The magnitude of inequality varied, but often, the odds of infection or disease were twice as high among socioeconomically disadvantaged groups compared with better-off strata. Inequalities often took the form of a gradient, with higher odds of infection or disease each step down the socioeconomic hierarchy. Notwithstanding these inequalities, the prevalence of some NTDs was sometimes also high among better-off groups in some highly endemic areas. CONCLUSIONS: While recent evidence on socioeconomic inequalities is scarce for most individual NTDs, for some, there is considerable evidence of substantially higher odds of infection or disease among socioeconomically disadvantaged groups. NTD control activities as proposed in the London Declaration, when set up in a way that they reach the most in need, will benefit the poorest populations in poor countries.

IL10 Variant g.5311A Is Associated with Visceral Leishmaniasis in Indian Population.

BACKGROUND: Visceral leishmaniasis (VL) is a multifactorial disease, where the host genetics play a significant role in determining the disease outcome. The immunological role of anti-inflammatory cytokine, Interleukin 10 (IL10), has been well-documented in parasite infections and considered as a key regulatory cytokine for VL. Although VL patients in India display high level of IL10 in blood serum, no genetic study has been conducted to assess the VL susceptibility / resistance. Therefore, the aim of this study is to investigate the role of IL10 variations in Indian VL; and to estimate the distribution of disease associated allele in diverse Indian populations. METHODOLOGY: All the exons and exon-intron boundaries of IL10 were sequenced in 184 VL patients along with 172 ethnically matched controls from VL endemic region of India. RESULT AND DISCUSSION: Our analysis revealed four variations; rs1518111 (2195 A>G, intron), rs1554286 (2607 C>T, intron), rs3024496 (4976 T>C, 3' UTR) and rs3024498 (5311 A>G, 3' UTR). Of these, a variant g.5311A is significantly associated with VL (χ2=18.87; p =0.00001). In silico approaches have shown that a putative micro RNA binding site (miR-4321) is lost in rs3024498 mRNA. Further, analysis of the above four variations in 1138 individuals from 34 ethnic populations, representing different social and linguistic groups who are inhabited in different geographical regions of India, showed variable frequency. Interestingly, we have found, majority of the tribal populations have low frequency of VL ('A' of rs3024498); and high frequency of leprosy ('T' of rs1554286), and Behcet's ('A' of rs1518111) associated alleles, whereas these were vice versa in castes. Our findings suggest that majority of tribal populations of India carry the protected / less severe allele against VL, while risk / more severe allele for leprosy and Behcet's disease. This study has potential implications in counseling and management of VL and other infectious diseases.

Feasibility of a combined camp approach for vector control together with active case detection of visceral leishmaniasis, post kala-azar dermal leishmaniasis, tuberculosis, leprosy and malaria in Bangladesh, India and Nepal: an exploratory study.

BACKGROUND: We assessed the feasibility and results of active case detection (ACD) of visceral leishmaniasis (VL), post kala-azar dermal leishmaniasis (PKDL) and other febrile diseases as well as of bednet impregnation for vector control. METHODS: Fever camps were organized and analyzed in twelve VL endemic villages in Bangladesh, India, and Nepal. VL, PKDL, tuberculosis, malaria and leprosy were screened among the febrile patients attending the camps, and existing bednets were impregnated with a slow release insecticide. RESULTS: Among the camp attendees one new VL case and two PKDL cases were detected in Bangladesh and one VL case in Nepal. Among suspected tuberculosis cases two were positive in India but none in the other countries. In India, two leprosy cases were found. No malaria cases were detected. Bednet impregnation coverage during fever camps was more than 80% in the three countries. Bednet impregnation led to a reduction of sandfly densities after 2 weeks by 86% and 32%, and after 4 weeks by 95% and 12% in India and Nepal respectively. The additional costs for the control programmes seem to be reasonable. CONCLUSION: It is feasible to combine ACD camps for VL and PKDL along with other febrile diseases, and vector control with bednet impregnation.

No evidence for association between SLC11A1 and visceral leishmaniasis in India.

BACKGROUND: SLC11A1 has pleiotropic effects on macrophage function and remains a strong candidate for infectious disease susceptibility. 5' and/or 3' polymorphisms have been associated with tuberculosis, leprosy, and visceral leishmaniasis (VL). Most studies undertaken to date were under-powered, and none has been replicated within a population. Association with tuberculosis has replicated variably across populations. Here we investigate SLC11A1 and VL in India. METHODS: Nine polymorphisms (rs34448891, rs7573065, rs2276631, rs3731865, rs17221959, rs2279015, rs17235409, rs17235416, rs17229009) that tag linkage disequilibrium blocks across SLC11A1 were genotyped in primary family-based (313 cases; 176 families) and replication (941 cases; 992 controls) samples. Family- and population-based analyses were performed to look for association between SLC11A1 variants and VL. Quantitative RT/PCR was used to compare SLC11A1 expression in mRNA from paired splenic aspirates taken before and after treatment from 24 VL patients carrying different genotypes at the functional promoter GTn polymorphism (rs34448891). RESULTS: No associations were observed between VL and polymorphisms at SLC11A1 that were either robust to correction for multiple testing or replicated across primary and replication samples. No differences in expression of SLC11A1 were observed when comparing pre- and post-treatment samples, or between individuals carrying different genotypes at the GTn repeat. CONCLUSIONS: This is the first well-powered study of SLC11A1 as a candidate for VL, which we conclude does not have a major role in regulating VL susceptibility in India.

Leishmaniasis / No disponible

La leishmaniasis es una enfermedad parasitaria causada por parásitos protozoarios del género Leishmania, transmitidos por la picadura de insectos flebotomineos hematófagos que se han alimentado previamente en un hospedero reservorio infectado. Existen dos presentaciones clínicas básicas: leishmaniasis visceral (LV) o “kala-azar” y leishmaniasis cutánea (LC). VL es el más grave y es mortal en casi todos los casos si no se tratan oportunamente, mientras que CL se asocia con una fuerte tendencia hacia la resolución espontánea, pero causa estigma social y psicológico importante en las personas afectadas. La leishmaniasis es una problema de salud pública importante en muchos regiones del mundo. A pesar de los avances de la ciencia básica, la leishmaniasis sigue siendo prevalente (y de aparición reciente) en muchas partes del mundo y el tratamiento eficaz y la prevención de la enfermedad sigue siendo un desafío. Se requieren nuevos tratamientos farmacológicos, especialmente aquellos que pueden ser de fácil administración y bajo costo. Así mismo, se requiere que la investigación en vacunas avance lo más rápidamente posible desde los estudios pre-clínicos a los estudios clínicos. Esta revisión destaca los aspectos más importantes en el estudio del parásito de la leishmaniasis en relación con la biología y la taxonomía, el ciclo de la vida y la patogénesis de la enfermedad, la respuesta inmune, las formas clínicas de la leishmaniasis, el diagnóstico, el tratamiento y las medidas de prevención (AU)

Leishmaniasis is a parasitic disease caused by protozoan parasites of the genus Leishmania, transmitted by the bite of blood suckling insects, sandflies, which have previously fe don an infected reservoir host. There are two basic clinical presentations: visceral leishmaniasis (VL) or “kala-azar” and cutaneous leishmaniasis (CL). VL is the most severe and is fatal in almost all cases if left untreated, while CL is associated with a strong tendency toward spontaneous resolutionbut causes important social and psychological stigma. The leishmaniaiss is a significant remains prevalent (and newly emerging) in many parts of the world, and the effective treatment and prevention of disease continues to be a challenge. New drug therapies, especially those that can be easily and inexpensively administered are needed. Vaccine research must move as quickly as possible form pre-clinical to clinical studies. This review highlights the most important aspects in the study of leishmaniasis related to parasite biology and taxonomy , life cycle and disease pathogenesis, immune response, clinical aspects, diagnosis treatment and prevention (AU)

Biology-based mapping of vector-borne parasites by geographic information systems and remote sensing.

Application of growing degree day-water budget analysis and satellite climatology to vector-borne parasites will be reviewed to demonstrate the value of using the unique thermal-hydrological preferences and limits of tolerance of individual parasite-vector systems to define the environmental niche of disease agents in the landscape by modern geospatial analysis methods. Applications of geospatial modeling will be illustrated by examples on fascioliasis, malaria, leprosy and leishmaniasis.

Sero-epidemiological study of kala-azar in a village of Varanasi district, India.

OBJECTIVE: To evaluate five kala-azar serological tests for field use. METHOD: Serological survey in Pandit Ka Purva village in Varanasi district, India, using Sia water test, aldehyde test, direct agglutination test (DAT), micro-enzyme-linked immunosorbent assay (ELISA) and dot-ELISA. RESULTS: The total population of the village was 518, 67 of whom showed typical clinical and parasitological features of kala-azar, including seven who died. The age distribution of kala-azar cases showed significant differences, being highest among the 45-54-year age group. The disease was more prevalent among males. Serum samples were collected from 498 persons (96% of total population) including 67 kala-azar cases and 40 disease controls (malaria, TB, leprosy, typhoid). Ten 10 serum samples from healthy controls living in endemic area were also collected. The test sensitivities were: Sia water test, 85.0%; aldehyde test, 62.7%; DAT, 94.0%; micro-ELISA, 91.0% and dot-ELISA, 97.0%. The test specificities were: Sia water test 92.5%, aldehyde test, 93.2%, DAT, 96.7; micro-ELISA, 97.6% and dot-ELISA, 98.4%. CONCLUSION: The dot-ELISA is highly sensitive and specific, cheap, and easy to interpret with the naked eye, making it a powerful screening test for the surveillance and diagnosis of Indian kala-azar at field level.

Leishmaniasis in Sudan. Post kala-azar dermal leishmaniasis.

Post kala-azar dermal leishmaniasis (PKDL) is increasingly recognized in Sudan as a complication of visceral leishmaniasis (VL), occurring in c. 55% of patients after, or during treatment of, VL. The development of PKDL seems to be restricted to parasites of the Leishmania donovani sensu stricto cluster; no particular zymodeme has been found to be associated with it. In contrast to PKDL in India, PKDL in Sudan occurs within 0-6 months after treatment for VL. The rash may be macular, maculo-papular or nodular, and spreads from the perioral area to other parts of the body, depending on grade of severity. Young children are particularly at risk of developing more severe disease. In 16% of PKDL patients, parasites can be demonstrated by microscopy in lymph node or bone marrow aspirates and, with the aid of the polymerase chain reaction (PCR), in lymph nodes of 81% of patients, possibly indicating persistent visceralized infection. Diagnosis can be made by demonstration of parasites in skin smears or biopsies in 20-30% of cases; newer techniques, using PCR with skin smears, have higher sensitivity (83%). Monoclonal antibodies against L. donovani can detect parasites in 88% of biopsies. Serological tests are of limited value. The leishmanin skin test is positive in 50-60% of cases; there is an inverse relationship between the skin test result and severity of PKDL. In differential diagnosis, miliaria rubra is the most common problem; differentiation from leprosy is the most difficult. In biopsies, hyperkeratosis, parakeratosis, acanthosis, follicular plugging and liquefaction degeneration of the basal layer may be found in the epidermis; in the dermis there are varying intensities of inflammation with scanty parasites and mainly lymphocytes; macrophages and epithelioid cells may also be found. In 20% of cases discrete granulomas may be found. After VL, the immune response shifts from a Th2-type to a mixed Th1/Th2-type. High levels of interleukin-10 in skin biopsies as well as in peripheral blood mononuclear cells and plasma in patients with VL predict the development of PKDL. Treatment is needed only for those who have severe and prolonged disease; sodium stibogluconate (20 mg/kg/d for 2 months) is usually sufficient. (Liposomal) amphotericin B is effective, whereas ketoconazole, terbinafine and itraconazole are not.

Post-kala-azar dermal leishmaniasis in the Sudan: clinical presentation and differential diagnosis.

Post-kala-azar dermal leishmaniasis (PKDL) is a common complication following kala-azar (visceral leishmaniasis). In a prospective study in a village in the endemic area for kala-azar in the Sudan, 105 of 183 (57%) kala-azar patients developed PKDL. There was a significantly higher PKDL rate (69%) in those who received inadequate and irregular treatment of kala-azar than in those who were treated with stibogluconate 20 mg kg-1 daily for 15 days (35%). The group of patients who developed PKDL did not differ from those who did not develop PKDL with regard to age and sex distribution, reduction in spleen size, and conversion in the leishmanin skin test (LST). In a clinical study, 416 PKDL patients were analysed and divided according to grade of severity. Severe PKDL was more frequent in younger age groups (P < 0.001); there was an inverse correlation between grade and conversion in the LST (P < 0.01). In 16% of patients tested, parasites were demonstrated in inguinal lymph node or bone marrow aspirates, indicating still visceral disease (para-kala-azar dermal leishmaniasis); there was no correlation between the presence of parasites and grade of severity. Conversion rates in the LST were lower than in those who did not have demonstrable parasites (11% and 37%, respectively; P < 0.01). In the absence of reliable and practical diagnostic tests, PKDL may be diagnosed on clinical grounds and differentiated from other conditions, of which miliaria rubra was the most common. Differentiation from leprosy was most difficult.

Diagnostic and prognostic potential of a competitive enzyme-linked immunosorbent assay for leishmaniasis in India.

A Leishmania donovani species-specific monoclonal antibody (monoclonal antibody D2) was evaluated for its diagnostic and prognostic potential by a competitive enzyme-linked immunosorbent assay (C-ELISA) in sera from Indian patients with visceral leishmaniasis (VL) and seven patients with post-kala-azar dermal leishmaniasis (PKDL). These results were compared with those obtained by microscopy with Giemsa-stained tissue smears and a direct enzyme-linked immunosorbent assay (direct ELISA) with crude parasite antigen. Of 121 patients with clinically diagnosed VL examined, 103 (85.1%) were positive and 11 (9.1%) were negative by all three methods. An additional 7 (5.8%) who were negative by microscopy were positive by both C-ELISA and direct ELISA. Seven PKDL patients were also examined and were found to be positive by all three methods. Analysis of the chemotherapeutic response to sodium antimony gluconate of these 110 serologically positive VL patients showed that 57 (51.8%) were drug responsive and 53 (48.2%) were drug resistant. The C-ELISA with sera from 20 longitudinally monitored VL patients before and after chemotherapy showed a significant decrease in percent inhibition of monoclonal antibody D2 in drug-responsive patients. However, in drug-unresponsive patients, the percent inhibition of D2 was unchanged or was slightly increased. Our results therefore indicate (i) the applicability of L. donovani species-specific monoclonal antibody D2 for sensitive and specific serodiagnosis by C-ELISA, (ii) that the C-ELISA is more sensitive than microscopy, especially for early diagnosis, (iii) that L. donovani is still the main causative agent of VL, irrespective of the chemotherapeutic response, and (iv) that the C-ELISA can be used to evaluate the success of drug treatment.

Outbreak of kala-azar in Bombay.

A chance diagnosis of kala-azar in a patient referred from Acworth Leprosy Home in Bombay was followed up, resulting in an investigation of a total of 25 patients (inpatients and residents) for the presence of the disease. 30.3% of the patients investigated were found to be suffering from the disease. This confirms the earlier suspicion that Bombay and especially the Acworth Leprosy Home is an endemic area for kala-azar.