Post-kala-azar Dermal Leishmaniasis Incidence Research Articles

Relationship between treatment regimens for visceral leishmaniasis and development of post-kala-azar dermal leishmaniasis and visceral leishmaniasis relapse: A cohort study from Bangladesh.

BackgroundWe investigated the relationship of treatment regimens for visceral leishmaniasis (VL) with post-kala-azar dermal leishmaniasis (PKDL) and visceral leishmaniasis relapse (VLR) development.MethodsStudy 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.Findings974 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.InterpretationDevelopment 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.

Clinical and Immunological Aspects of Post–Kala-Azar Dermal Leishmaniasis in Bangladesh

We conducted active surveillance for kala-azar and post-kala-azar dermal leishmaniasis (PKDL) in a population of 24,814 individuals. Between 2002 and 2010, 1,002 kala-azar and 185 PKDL cases occurred. Median PKDL patient age was 12 years; 9% had no antecedent kala-azar. Cases per 10,000 person-years peaked at 90 for kala-azar (2005) and 28 for PKDL (2007). Cumulative PKDL incidence among kala-azar patients was 17% by 5 years. Kala-azar patients younger than 15 years were more likely than older patients to develop PKDL; no other risk factors were identified. The most common lesions were hypopigmented macules. Of 98 untreated PKDL patients, 48 (49%) patients had resolution, with median time of 19 months. Kala-azar patients showed elevated interferon-γ (IFNγ), tumor necrosis factor-α (TNFα), and interleukin 10 (IL-10). Matrix metalloproteinase 9 (MMP9) and MMP9/tissue inhibitor of matrix metalloproteinase-1 (TIMP1) ratio were significantly higher in PKDL patients than in other groups. PKDL is frequent in Bangladesh and poses a challenge to the current visceral leishmaniasis elimination initiative in the Indian subcontinent.

Clinical Epidemiologic Profile of a Cohort of Post–Kala-Azar Dermal Leishmaniasis Patients in Bihar, India

Post-kala-azar dermal leishmaniasis (PKDL) has important public health implications for transmission of visceral leishmaniasis (VL). Clinical and epidemiologic profiles of 102 PKDL patients showed that median age of males and females at the time of diagnosis was significantly different (P = 0.013). A significant association was observed between family history of VL and sex of PKDL patients (χ(2) = 5.72, P < 0.01). Nearly 33% of the patients showed development of PKDL within one year of VL treatment. The observed time (median = 12 months) between appearance of lesions and diagnosis is an important factor in VL transmission. A significant association was observed between type of lesions and duration of appearance after VL treatment (χ(2) = 6.59, P = 0.001). Because PKDL was observed during treatment with all currently used anti-leishmanial drugs, new drug regimens having high cure rates and potential to lower the PKDL incidence need to be investigated.

Recent advances in post-kala-azar dermal leishmaniasis

Post-kala-azar dermal leishmaniasis (PKDL) is a challenge for clinicians and researchers, because its burden is poorly investigated and pathogenesis is disputable. However, recent studies contributed to understanding of the pathogenesis of PKDL especially its association with host immunological factors, and also how to improve its diagnosis and treatment. This review focuses on recent advances in diagnosis, new insights into pathogenesis and case management. Information regarding the burden of PKDL, especially in Bangladesh, is now available. Association between skin parasite burden and different clinical forms of PKDL has been explored. The diagnostic importance of detection of Leishmania donovani DNA in the peripheral blood buffy coat and in skin specimens by PCR has been studied. Variable effects of different antileishmanial drugs on immune response have been observed. Finally, high efficacy of miltefosine for treatment of PKDL has been demonstrated. The incidence of PKDL is reducing in India after introduction of miltefosine and amphotericin B for treatment of visceral leishmaniasis. It remains higher in Bangladesh and in Sudan. Parasite burden is higher in nodular and papular forms of PKDL compared to the macular form of the disease. The demonstration of Leishmania DNA in peripheral blood buffy coat and in skin specimens can help to diagnose 40-75% clinically suspected PKDL individuals. An initial cure rate of 95% has been achieved with miltefosine for treatment of PKDL. However, the efficacy of combination therapy should be explored to reduce the treatment duration and hence to improve treatment compliance.

Post-Kala-Azar Dermal Leishmaniasis in Mymensingh, Bangladesh

A 50-year-old man from Mymensingh district, Bangladesh, presented with a 3-month history of non-pruritic, painless hypopigmented papules, and plaques, beginning on the face and subsequently spreading to the forearms, torso, and legs (Figures 1–4) Fifteen months before the onset of skin lesions, the patient had visceral leishmaniasis (kala-azar), successfully treated with 30 intramuscular injections of sodium stibogluconate (SSG). Polymerase chain reaction showed Leishmania donovani DNA in a buffy coat specimen. Figure 1. The patient has hypopigmented papules and plaques scattered over the face, most concentrated peri-orally and on the cheeks, common areas of involvement for post-kala-azar dermal leishmaniasis (PKDL). The patient consented to having his picture published ... Figure 4. The patient has hypopigmented papules and plaques on both forearms. The absence of sensorineural changes helps to distinguish post-kala-azar dermal leishmaniasis (PKDL) from leprosy, which commonly presents with hypopigmented macules or patches associated ... Figure 2. Hypopigmented papules are seen on the patient's back. The lesions are roughly symmetrical, a common characteristic of post-kala-azar dermal leishmaniasis (PKDL), and are painless and non- pruritic. Figure 3. Hypopigmented papules on the abdomen. Post-kala-azar dermal leishmaniasis (PKDL) is a chronic skin rash usually seen in apparently cured kala-azar patients in East Africa and South Asia. In the Indian subcontinent, the cumulative PKDL incidence after kala-azar is 5–10%.1 The PKDL usually presents with erythematous or hypopigmented papules or macules, sometimes progressing to plaques or nodules. Kala-azar patients treated with antimonial drugs may have poorer immune recovery and a higher risk of subsequent PKDL compared with those treated with amphotericin formulations.2 The only PKDL treatment regimens with proven efficacy in South Asia consist of 120 SSG injections over 6 months or miltefosine 2.5 mg/kg/day for 12 weeks. The PKDL patients are infectious to the sand fly vector and are thought to represent an important parasite reservoir in the anthroponotic transmission cycle of visceral leishmaniasis in South Asia.1

Increasing Incidence of Post–Kala‐Azar Dermal Leishmaniasis in a Population‐Based Study in Bangladesh

Post-kala-azar dermal leishmaniasis (PKDL) occurs after kala-azar treatment and acts as a durable infection reservoir. On the basis of active case finding among 22,699 respondents, 813 (3.6%) had had kala-azar since 2002, of whom 79 (9.7%) developed PKDL. Eight additional patients with PKDL had no history of kala-azar. Annual kala-azar incidence peaked at 85 cases per 10,000 person-years in 2004 and fell to 46 cases per 10,000 person-years in 2007, but PKDL incidence rose from 1 case per 10,000 person-years in 2002-2004 to 21 cases per 10,000 person-years in 2007. The rising PKDL incidence threatens the regional visceral leishmaniasis elimination initiative and underscores the urgent need for more effective PKDL diagnosis and treatment.

Consultation meeting on the development of therapeutic vaccines for post kala azar dermal leishmaniasis

BackgroundPost kala azar dermal leishmaniasis (PKDL) is a disease that appears after treatment of visceral leishmaniasis (VL). The highest incidence of PKDL in the world is in Sudan. Many patients heal spontaneously within 6 months but those who don't are difficult to treat, often requiring months of daily injections. These patients harbour parasite in their skin and are believed to be a source of infection and possibly epidemics. Present treatment modalities of PKDL are inadequate and impractical due to cost, duration of treatment required and side effects. New approach for treatment of PKDL is required. A joint meeting of the UNICEF/UNDP/World Bank/WHO Special Programme for research and training in Tropical Disease (TDR) and the Infectious Disease Research Institute (IDRI) Seattle, USA was held to review the progress of therapeutic vaccines and plan the development of treatment modalities for PKDL.MethodsThe history of leishmaniasis vaccine development for prophylaxis and therapy was reviewed. Other than previous infection – simulated by inoculation of live Leishmania as a vaccine (leishmanization), none of the preparations of killed parasite with or without adjuvants have shown significant prophylactic efficacy. Killed L. major absorbed with alum and mixed with BCG remains to be tested as a prophylactic vaccine.ResultsKilled parasite preparations i.e. L. mexicana mixed with BCG and L. amazonensis (combined with low dose of antimonial), have shown efficacy in immunotherapy and immuno-chemotherapy, respectively. In addition combined full antimonial plus alum-absorbed autoclaved L. major vaccine has been shown to significantly improve therapy of refractory PKDL patients. These are all crude preparations of parasites and are difficult to define and standardize. However, there is now a new, second generation vaccine, Leish-111f + MPL-SE, composed of a recombinant protein comprising three leishmanial antigens and a defined adjuvant in clinical development.Conclusion and recommendationsImmuno-chemotherapy has the potential of becoming a practical and affordable treatment modality for PKDL and other forms of leishmaniasis. The encouraging results with alum-autoclaved L. major + antimonial should be pursued. However, before further trials, availability of the vaccine and its production under Good Manufacturing Product, hence quality control must be assured. Following satisfactory safety profile of Leish-111f+MPL-SE, clinical trials using this vaccine initially with antimonials should be initiated. Similarly immunotherapy of VL should be considered with the view to controlling development of PKDL. Some immunological studies are required prior to initiation of immunotherapy in VL patients.

Endemic kala-azar in eastern Sudan: post-kala-azar dermal leishmaniasis.

In a longitudinal study between 1991 and 1993 in an endemic area in eastern Sudan, 85 cases of kala-azar (visceral leishmaniasis) were diagnosed, of whom 48 (56%) developed post-kala-azar dermal leishmaniasis (PKDL). Another four cases of PKDL had no clinical history of kala-azar. In children, PKDL was more frequent in the very young; seven of nine kala-azar cases (78%) in the group 0-1 years of age and 13 of 16 (81%) in the group 2-3 years of age developed PKDL. On the average, PKDL occurred 56 days (mean; range 0-180) after the end of treatment of kala-azar. To assess the severity of PKDL, a classification was developed using three grades of severity based on differences in density and distribution of lesions. In young children, PKDL was more severe. Incomplete treatment of kala-azar may be important in the pathogenesis of PKDL. Thirty-one patients were followed-up for at least six months; of these, 20 were not treated (17 healed, two improved, and in one, the condition was unchanged), three healed after incomplete treatment with sodium stibogluconate, and eight were cured after treatment but two required two courses. Considerable morbidity was caused by PKDL and should be taken into consideration in the management and follow-up of kala-azar patients. The high incidence of PKDL may have important implications in transmission.