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Post Kala-azar dermal leishmaniasis (PKDL), caused by Leishmania donovani is the dermal sequel of Visceral Leishmaniasis and importantly, is the proposed disease reservoir. The survival of Leishmania parasites within monocytes/macrophages hinges on its ability to effectively nullify immune activation mechanisms. Thus, delineating the disease-promoting immune mechanisms can facilitate development of immunotherapeutic strategies. Accordingly, in the absence of an animal model, this study aimed to delineate the status of CD8 + T-cells in patients with PKDL. At disease presentation, the absence of CD4 + T-cells at lesional sites was concomitant with an overwhelming infiltration of CD8 + T-cells that demonstrated an absence of Perforin, Granzyme and Zap-70, along with an enhanced expression of Programmed Death-1 (PD-1) and the skin-homing CCL17. Additionally, the lesional CCR4 + CD8 + population was associated with an enhanced expression of IL-10 and IL-5. In circulation, the enhanced CD8 + CCR4 + T-cell population and raised levels of CCL17/22 was associated with an increased frequency of PD-1, while CD127 was decreased. Taken together, in PKDL, the enhanced plasma and lesional CCL17 accounted for the dermal homing of CD8 + CCR4 + T-cells, that along with a concomitant upregulation of PD-1 and IL-10 mediated immune inactivation, emphasizing the need for designing immunotherapies capable of reinvigorating T-cell potency.

Post kala-azar dermal leishmaniasis (PKDL) is a mucocutaneous disease usually seen in apparently cured, inadequately treated or untreated cases of visceral leishmaniasis and is endemic to many parts of India, Nepal, Bangladesh, and eastern Africa (Sudan, Ethiopia, Kenya). The disease usually manifests as a variable combination of hypopigmented patches, erythematous succulent papulo-plaques, and nodular lesions on the face and upper body and sometimes extending on the extremities, genitalia, and tongue. Atypical morphology and presentations are not uncommon, especially in endemic areas, which include photosensitivity, verrucous, hypertrophic, xanthomatous, and ulcerative lesions. Recognition of spectrum of mucocutaneous changes helps physicians in early initiation of treatment and in reducing disease transmission in the community. The differential diagnosis depends on the pattern of manifestations, but lepromatous leprosy is the closest mimicker. Since PKDL does not cause significant morbidity, at least initially, but the affected patients continue to act as a reservoir of the disease, active case detection is required to identify cases early to control the disease transmission in the community.

Background. Post-kala-azar dermal leishmaniasis (PKDL), an established sequela of visceral leishmaniasis (VL), is proposed to facilitate anthroponotic transmission of VL, especially during interepidemic periods. Immunopathological mechanisms responsible for Indian PKDL are still poorly defined. Methods. Our study attempted to characterize the immune profiles of patients with PKDL or VL relative to that of healthy control subjects by immunophenotyping, intracellular cytokine staining of peripheral blood mononuclear cells, and enzyme-linked immunosorbent assay for serum cytokines and immunoglobulin G (IgG) subclasses. Results. Patients with PKDL had significantly raised percentages of peripheral CD3+CD8+ cells compared with control subjects, a difference that persisted after cure. Patients with PKDL showed an intact response to phytohemagglutinin, with the percentages of lymphocytes expressing interferon (IFN)-γ, interleukin (IL)-2, IL-4, and IL-10 being comparable to those in control subjects. Patients with VL had decreased IFN-γ and IL-2 expression, which was restored after cure, and increased IL-10 expression, which persisted after cure. In their response to Leishmania donovani antigen, patients with PKDL showed a 9.6-fold increase in the percentage of IL-10-expressing CD3+CD8+ lymphocytes compared with control subjects, and this percentage decreased with treatment. Patients with PKDL had raised levels of IgG3 and IgG1 (surrogate markers for IL-10), concomitant with increased serum levels of IL-10. Conclusions. IL-10-producing CD3+CD8+ lymphocytes are important protagonists in the immunopathogenesis of Indian PKDL.

The potential reservoirs of leishmaniasis in South Asia include relapsed cases of visceral leishmaniasis (VL), patients with post-kala-azar dermal leishmaniasis (PKDL), and an asymptomatically infected population. Therefore, assessment of cure in terms of parasite clearance, early detection of PKDL, and asymptomatic VL are pivotal for ensuring elimination. This study aimed to monitor the efficacy of miltefosine and liposomal amphotericin B (LAmB) in PKDL based on parasite load. Patients with PKDL were recruited from the dermatology outpatient departments or during active field surveys. Skin biopsies were collected at disease presentation, immediately at the end of treatment, and 6 months later. The presence of parasite DNA was assessed by internal transcribed spacer-1 polymerase chain reaction, and quantified by amplification of parasite kinetoplastid DNA. At disease presentation (n = 184), the median parasite load was 5229 (interquartile range [IQR], 896-50898)/μg genomic DNA (gDNA). Miltefosine cleared the parasites to <10 in the macular (n = 17) and polymorphic (n = 21) variants, and remained so up to 6 months later (<10 parasites). LAmB reduced the parasite burden substantially in macular (n = 34; 2128 [IQR, 544-5763]/µg gDNA) and polymorphic PKDL (n = 36; 2541 [IQR, 650-9073]/µg gDNA). Importantly, in patients who returned 6 months later (n = 38), a resurgence of parasites was evident, as the parasites increased to 5665 (IQR, 1840-17067)/µg gDNA. This study established that quantifying parasite load is an effective approach for monitoring patients with PKDL, wherein miltefosine demonstrated near-total parasite clearance and resolution of symptoms. However, in cases treated with LAmB, the persistence of parasites suggested treatment inadequacy. This needs immediate redressal in view of the leishmaniasis elimination program targeted for 2020.

Post Kala-azar Dermal Leishmaniasis (PKDL) develops in patients apparently cured of Visceral Leishmaniasis (VL), and is the strongest contender for being the disease reservoir. Therefore, existence of a few cases is sufficient to trigger an epidemic of VL in a given community, emphasizing the need for its active detection and in turn ensuring success of the current elimination program. This study explored the impact of active surveillance on the demographic profile of PKDL patients in West Bengal. Patients with PKDL were recruited through passive (2003-date, n = 100) and active surveillance (2015-date, n = 202), the former from outpatient departments of dermatology in medical colleges in West Bengal and the latter through an active door-to-door survey in four VL hyper-endemic districts of West Bengal. Passive surveillance indicated a male preponderance and a predominance of polymorphic lesions, whereas active surveillance indicated absence of any gender bias and more importantly, macular PKDL constituted almost 50% of the population burden. In terms of polymorphic vs. macular PKDL, the former appeared at a later age, their disease duration was longer and had a higher parasite burden. In the polymorphic variant, the lesional distribution was asymmetrical, comprised of papules/nodules/macules that were present mainly in sun-exposed areas whereas in macular cases, the hypopigmented patches were diffusely present all over the body. Active surveillance unraveled a disease component whose demographic profile showed important differences with PKDL cases who sought treatment in government hospitals. Detection of a higher proportion of macular cases indicates that this variant is not an uncommon presentation as conventionally stated in text books, and should be studied in greater detail to ensure success of the ongoing Leishmaniasis elimination programme.

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.

Post kala-azar dermal leishmaniasis (PKDL) is a neglected tropical disease, which has got the attention in recent times after the London Declaration on “Neglected Tropical Diseases” in 2012 set a target of 2020 to eliminate visceral leishmaniasis (VL) as a public health problem. [1,2] Understanding the fact that PKDL is the interepidemic reservoir of VL, this is needless to say that all efforts of elimination of VL would go in vain if PKDL is not simultaneously eliminated.[3] The symposium on PKDL is planned at a time when we are approaching the deadline for the target.

Post-kala-azar dermal Leishmaniasis (PKDL) is one of the important neglected tropical diseases, which has a tremendous epidemiological significance, being the reservoir of kala-azar. Relapse and resistance to treatment along with the lack of a drug of choice and consensus treatment guideline pose a significant problem in the management of PKDL. The aim of this article was to review the available therapeutic options for PKDL, with special emphasis on their pharmaco-dynamics, pharmaco-kinetics, effectiveness, safety, tolerability, and cost factor. A comprehensive English language literature search was done for therapeutic options in PKDL across multiple databases (PubMed, EMBASE, MEDLINE, and Cochrane) for keywords (alone and in combination). MeSH as well as non-MeSH terms such as \"Kala-azar,\" \"Leishmaniasis\" AND \"Treatment,\" \"Management,\" \"Antimony Sodium Gluconate,\" \"Meglumine Antimoniate,\" \"Amphotericin B,\" \"Paromomycin,\" \"Miltefosine\" were taken into consideration. Among 576 relevant articles, 15 were deemed relevant to this review. These articles were evaluated using \"Oxford Centre for Evidence-Based Medicine (OCEBM)\" AND \"strength of recommendation taxonomy\" (SORT) with respect to the level of evidence and grade of recommendation. The review includes 15 studies. The use of sodium stibogluconate is being discouraged because of multiple documented reports of treatment failure. Liposomal amphotericin B is emerging as a favorable option, owing to its superiority in terms of effectiveness and safety profile. Miltesfosine is the drug of choice in India because of the ease of oral administration and minimal risk of toxicity. Isolated Paromomycin alone is not effective in PKDL; however, combination therapy with sodium stibogluconate is found to be safe and effective. Combination of amphotericin B and miltefosine is one of the excellent options. Immunotherapy with combination of alum-precipitated autoclaved Leishmania major (Alum/ALM) vaccine + Bacille Calmette-Gu´erin (BCG) has shown promising results. Kala-azar continues to haunt the tropical countries and PKDL being its reservoir is threatening its elimination. With the availability of drugs such as liposomal amphotericin B and miltefosine, apart from the advent of immunotherapy, the future of treatment of this condition looks promising.

Ethics are the moral values of human behavior and the principles which govern these values. The situation becomes challenging for a doctor when he assumes the role of researcher. The doctor-researcher has to serve both the roles and at times the zeal of an investigator has the potential to cloud the morality of the physician inside. It is very important to realize that exploiting the faith of patients is an offence that tantamount to a crime. Medical science is one discipline where the advancement of knowledge is hugely guided by research and mankind has benefitted from many experiments. However benefit and risk are the two faces of the same coin. Various unethical human experiments made us realize that the whims of researchers need to be reined and led to the evolution of the first guidelines for researcher, the Nuremberg code. Thereafter the Good Clinical Practice guidelines serve as the guiding doctrine of clinical research. The principles of ethics rest on the four pillars of autonomy, beneficence, justice, non-maleficence and recently two more pillars are added which includes, confidentiality and honesty. Ethics committees serve as a guardian of these principles. The multidisciplinary Ethics Committee ensures a competent review of the ethical aspects of the project proposal submitted and does it free from any bias or external influence. Ethical review of clinical trial applications follows a decentralized process in India, and requires Ethics Committee approval for each trial site. All Ethics committees have to be registered with Drug Controller General of India (DCGI) without which they cannot approve any clinical trial protocol and has come into effect from 25th February 2013.

Background: Immunotherapy for wart employs ability of immune system to recognize certain viral, bacterial, and fungal antigens in previously sensitized individual inducing Type IV delayed-type hypersensitivity reaction (up-regulated Th1 cytokines IL-1, TNF-α, IFN-γ; down-regulated Th2 cytokines IL-10), not only to injected antigen but also against wart virus. Aims: To evaluate and compare the pattern of production of Th1 cytokines (IL-1, TNF-α, IFN-γ) and Th2 cytokines (IL-10) in patients receiving immunotherapy with purified-protein-derivative (PPD), Mycobacterium w (Mw), or mumps-measles-rubella (MMR) vaccine. Methods: The cohort study conducted on patients receiving immunotherapy with PPD, Mw, or MMR which was injected intradermally at baseline, repeated every 2 weeks for 6 doses?. Five-millilit?e?r blood was collected for evaluation of cytokines at baseline and 12 weeks of treatment. Blood was centrifuged to separate serum, stored at -80°C. Cytokines were measured by ELISA using a standard kit. Results: Nine participants in PPD group, 11 in Mw group, and 12 in MMR group completed the study. IL-1 was raised from baseline in all study arms and was significant in PPD group (P = 0.008). There was a predicted increase in IFN-γ in Mw and MMR groups but not in the PPD group. In the PPD group, IFN-γ was found to be down regulated. IL-10, a Th 2 cytokine was down regulated in all the groups at the study end from baseline, significantly so in the PPD group (P = 0.027) and MMR group (P = 0.001). TNF-α, being a Th1 cytokine was down regulated in all groups instead of an increase. In PPD group, IL-10 was significantly low at study end in patients who had complete resolution of warts. Limitations: Longer follow-up could not be done due to logistic issues. Conclusion: IL-1, TNF-α upregulation and IL-10 downregulation confirm that cytokine milieu plays an important role in wart immunotherapy. TNF-α has no contributory role. IL-10 can be used as a biomarker of complete response in PPD therapy.