FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W1967828232> ?p ?o ?g. }

• W1967828232 endingPage "74" @default.
• W1967828232 startingPage "65" @default.
• W1967828232 abstract "•Sodium antimony gluconate contributes towards the pathogenesis of PKDL.•UV light plays a pivotal role in the development of PKDL.•Development of PKDL can be viewed as a reinfection or activation of latent Leishmania parasites.•PKDL can be resolved by mounting an effective tissue-specific memory T cell response.•Host genetic factors play a contributory role. 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. 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. The leishmaniases comprise a diverse group of poverty-related neglected tropical diseases that have a major impact on health worldwide. Among the manifestations of leishmaniasis, post kala-azar dermal leishmaniasis (PKDL; see Glossary) caused by the protozoan parasite Leishmania donovani, is possibly the most intriguing clinically and scientifically, as it generally develops as a sequela after apparent successful cure from visceral leishmaniasis (VL; also known as kala-azar) [1Antinori S. et al.Post kala-azar dermal leishmaniasis as an immune reconstitution inflammatory syndrome in a patient with acquired immune deficiency syndrome.Br. J. Dermatol. 2007; 157: 1032-1036Crossref PubMed Scopus (46) Google Scholar, 2Ganguly S. et al.Post kala-azar dermal leishmaniasis – an overview.Int. J. Dermatol. 2010; 49: 921-931Crossref PubMed Scopus (63) Google Scholar]. The clinical presentation of VL and PKDL differ substantially; in VL, patients suffer from prolonged fever, hepatosplenomegaly, weight loss, and anaemia, whereas manifestations of PKDL are limited to macular, papular, or nodular lesions in the skin [2Ganguly S. et al.Post kala-azar dermal leishmaniasis – an overview.Int. J. Dermatol. 2010; 49: 921-931Crossref PubMed Scopus (63) Google Scholar]. PKDL is confined to two geographically distinct zones, namely South Asia (India, Nepal, and Bangladesh) and East Africa, mainly Sudan [2Ganguly S. et al.Post kala-azar dermal leishmaniasis – an overview.Int. J. Dermatol. 2010; 49: 921-931Crossref PubMed Scopus (63) Google Scholar, 3Desjeux P. Ramesh V. Post kala-azar dermal leishmaniasis: facing the challenge of eliminating kala-azar from South Asia.in: Jha T.K. Noiri E. Kala Azar in South Asia – Current Status and Challenges Ahead. Springer, 2011: 111-124Crossref Scopus (12) Google Scholar]. In the South Asian variant, polymorphic lesions (coexistence of macules/patches along with papulonodules) are prevalent, whereas the Sudanese variant has papular or nodular lesions. Although mortality from PKDL is low, it is a stigmatizing disease that carries a significant socioeconomic burden, further amplified by a reluctance to obtain treatment or due to noncompliance. Lesions, especially the papulonodules, are parasite-rich, driving speculation that PKDL plays a pivotal role in the inter-epidemic transmission of VL. Understanding the clinico-epidemiological aspects of PKDL would help define strategies for controlling VL, by providing further insights into L. donovani transmission dynamics. Most epidemiological studies with PKDL have reported no gender bias [4Zijlstra E.E. et al.Post kala-azar dermal leishmaniasis.Lancet Infect. Dis. 2003; 3: 87-98Abstract Full Text Full Text PDF PubMed Scopus (393) Google Scholar, 5Mondal D. Khan M.G. Recent advances in post kala-azar dermal leishmaniasis.Curr. Opin. Infect. Dis. 2011; 24: 418-422Crossref PubMed Scopus (32) Google Scholar, 6Rahman K.M. et al.Increasing incidence of post kala-azar dermal leishmaniasis in a population-based study in Bangladesh.Clin. Infect. Dis. 2010; 50: 73-76Crossref PubMed Scopus (66) Google Scholar, 7Uranw S. Post kala-azar dermal leishmaniasis in Nepal: a retrospective cohort study (2000-2010).PLoS Negl. Trop. Dis. 2011; 5: e1433Crossref PubMed Scopus (44) Google Scholar, 8Das V.N. et al.Clinical epidemiologic profile of a cohort of post kala-azar dermal leishmaniasis patients in Bihar, India.Am. J. Trop. Med. Hyg. 2012; 86: 959-961Crossref PubMed Scopus (29) Google Scholar], a notable exception being studies from our group where a male predominance was reported [9Ganguly S. et al.Enhanced lesional Foxp3 expression and peripheral anergic lymphocytes indicate a role for regulatory T cells in Indian post kala-azar dermal leishmaniasis.J. Invest. Dermatol. 2010; 130: 1013-1022Crossref PubMed Scopus (42) Google Scholar]. The age distribution of PKDL in South Asia and Sudan also differs, as in the former, young adults are more affected whereas in the latter, children are more affected [4Zijlstra E.E. et al.Post kala-azar dermal leishmaniasis.Lancet Infect. Dis. 2003; 3: 87-98Abstract Full Text Full Text PDF PubMed Scopus (393) Google Scholar]. A lag period ranging from 2 to 10 years exists between cure from VL and onset of PKDL, suggesting that PKDL echoes the epidemic of VL and can persist well after the epidemic. This is supported by an epidemiological study in Bangladesh where it was noted that the incidence of PKDL showed a steep rise from 1 case per 10 000 in 2002–2004 to 21 cases per 10 000 in 2007 [6Rahman K.M. et al.Increasing incidence of post kala-azar dermal leishmaniasis in a population-based study in Bangladesh.Clin. Infect. Dis. 2010; 50: 73-76Crossref PubMed Scopus (66) Google Scholar]. In India, the incidence of VL peaked in 1992 and a smaller rise was reported in 2007 (http://www.who.int/leishmaniasis/resources/INDIA.pdf). Therefore, extrapolating from the Bangladesh experience, the incidence of PKDL in India may well see a sharp rise in coming years. In South Asia, transmission of VL is anthroponotic, whereas in Sudan, it is zoonotic and anthroponotic; therefore, patients with PKDL are the proposed disease reservoir of VL in India [10Thakur C.P. et al.Impact of amphotericin-B in the treatment of kala-azar on the incidence of PKDL in Bihar, India.Indian J. Med. Res. 2008; 128: 38-44PubMed Google Scholar]. Accordingly, eradication of PKDL should be an essential component of the current VL elimination programme in South Asia that aims to bring down the annual incidence of VL to less than 1 per 10 000 population at a district or sub-district level by the end of 2015 (http://www.who.int/tdr/publications/documents/kala_azar_indicators.pdf). To achieve this goal, a greater understanding of the cause(s) of PKDL is essential. Many excellent reviews have covered the epidemiology, immunopathology, diagnosis, and treatment of PKDL; Box 1 and Figure 1 summarise our current knowledge of the immune responses observed in PKDL [2Ganguly S. et al.Post kala-azar dermal leishmaniasis – an overview.Int. J. Dermatol. 2010; 49: 921-931Crossref PubMed Scopus (63) Google Scholar, 4Zijlstra E.E. et al.Post kala-azar dermal leishmaniasis.Lancet Infect. Dis. 2003; 3: 87-98Abstract Full Text Full Text PDF PubMed Scopus (393) Google Scholar, 11Zijlstra E.E. el-Hassan A.M. Leishmaniasis in Sudan. Post kala-azar dermal leishmaniasis.Trans. R. Soc. Trop. Med. Hyg. 2001; 95: S59-S76Abstract Full Text PDF PubMed Google Scholar, 12Ramesh V. Mukherjee A. Post kala-azar dermal leishmaniasis.Int. J. Dermatol. 1995; 34: 85-91Crossref PubMed Scopus (120) Google Scholar, 13Salotra P. Singh R. Challenges in the diagnosis of post kala-azar dermal leishmaniasis.Indian J. Med. Res. 2006; 123: 295-310PubMed Google Scholar, 14Ramesh V. Treatment of post kala-azar dermal leishmaniasis.Int. J. Dermatol. 1994; 33: 153-156Crossref PubMed Scopus (13) Google Scholar]. Information regarding the aetiopathogenesis of PKDL is limited and, therefore, no consensus has emerged to explain what factors modify the behaviour of the normally viscerotropic L. donovani parasite to become dermatotropic and manifest as PKDL. In the following sections, we review key mechanisms suggested to be involved in the development of PKDL.Box 1Immunology of PKDLThe precise immune mechanisms of PKDL are still obscure and, interestingly, the immunobiology of the Sudanese and South Asian PKDL differ. Therefore, information from one is not extrapolatable to the other [2Ganguly S. et al.Post kala-azar dermal leishmaniasis – an overview.Int. J. Dermatol. 2010; 49: 921-931Crossref PubMed Scopus (63) Google Scholar]. In Sudanese PKDL, because of the shorter time lag between cure from VL and development of PKDL, the disease-associated immune involvement mimics the scenario of immune reactivation after cure from VL. PBMCs from Sudanese PKDL patients react and proliferate following induction by Leishmania antigens and secrete more IFN-γ, whereas IL-10 was produced primarily from CD4+ T cells [52Ismail A. et al.Immunopathology of post kala-azar dermal leishmaniasis (PKDL): T-cell phenotypes and cytokine profile.J. Pathol. 1999; 189: 615-622Crossref PubMed Scopus (56) Google Scholar]. By contrast, South Asian PKDL is more chronic due to the longer gap between cure from VL and disease onset. Here, CD8+ T cells predominated in lesions and circulation [53Rathi S.K. et al.Lesional T-cell subset in post kala-azar dermal leishmaniasis.Int. J. Dermatol. 2005; 44: 12-13Crossref PubMed Scopus (11) Google Scholar, 73Ganguly S. et al.Increased levels of interleukin-10 and IgG3 are hallmarks of Indian post kala-azar dermal leishmaniasis.J. Infect. Dis. 2008; 197: 1762-1771Crossref PubMed Scopus (63) Google Scholar]. Tregs also play an important role in the lesional immunology of South Asian PKDL, as evident by their elevated mRNA expression of FoxP3, CTLA-4, and CD25 [9Ganguly S. et al.Enhanced lesional Foxp3 expression and peripheral anergic lymphocytes indicate a role for regulatory T cells in Indian post kala-azar dermal leishmaniasis.J. Invest. Dermatol. 2010; 130: 1013-1022Crossref PubMed Scopus (42) Google Scholar, 43Katara G.K. et al.Foxp3 and IL-10 expression correlates with parasite burden in lesional tissues of post kala azar dermal leishmaniasis (PKDL) patients.PLoS Negl. Trop. Dis. 2011; 5: e1171Crossref PubMed Scopus (59) Google Scholar]. In addition to lesional immunology, systemic immune changes include increased antigen-induced IL-10 within circulating CD8+ T cells and impairment of antigen-induced proliferation. These cells were anergic in nature because they lost their surface co-stimulatory CD28 molecule [9Ganguly S. et al.Enhanced lesional Foxp3 expression and peripheral anergic lymphocytes indicate a role for regulatory T cells in Indian post kala-azar dermal leishmaniasis.J. Invest. Dermatol. 2010; 130: 1013-1022Crossref PubMed Scopus (42) Google Scholar, 73Ganguly S. et al.Increased levels of interleukin-10 and IgG3 are hallmarks of Indian post kala-azar dermal leishmaniasis.J. Infect. Dis. 2008; 197: 1762-1771Crossref PubMed Scopus (63) Google Scholar]. Furthermore, the interacting partner of CD28, known as B7.1 or CD86, on monocytes was decreased, suggesting that an immunosuppressive milieu occurs in circulation [21Mukhopadhyay D. et al.Miltefosine effectively modulates the cytokine milieu in Indian post kala-azar dermal leishmaniasis.J. Infect. Dis. 2011; 204: 1427-1436Crossref PubMed Scopus (38) Google Scholar]. Lesional immunology of PKDL was similar in South Asian and Sudanese PKDL with enhanced expression of IL-10, TGF-β, IFN-γ, and TNF-α. However, despite the higher levels of IFN-γ and TNF-α, the expression of IFN-γR and TNFR1 was lower in patients with PKDL in India and increased after treatment [37Ansari N.A. et al.Interferon (IFN)-γ, tumor necrosis factor-α, interleukin-6, and IFN-γ receptor 1 are the major immunological determinants associated with post kala azar dermal leishmaniasis.J. Infect. Dis. 2006; 194: 958-965Crossref PubMed Scopus (61) Google Scholar, 74Ansari N.A. et al.Evidence for involvement of TNFR1 and TIMPs in pathogenesis of post kala-azar dermal leishmaniasis.Clin. Exp. Immunol. 2008; 154: 391-398Crossref PubMed Scopus (19) Google Scholar]. Similarly, in the Sudanese variant, a genetic polymorphism was found in IFN-γR [63Salih M.A. et al.IFNG and IFNGR1 gene polymorphisms and susceptibility to post kala-azar dermal leishmaniasis in Sudan.Genes Immun. 2007; 8: 75-78Crossref PubMed Scopus (40) Google Scholar]. In Sudanese PKDL, expression of IL-10 from keratinocytes was considered as a key factor and a predictor for development of PKDL, particularly after cure from VL [4Zijlstra E.E. et al.Post kala-azar dermal leishmaniasis.Lancet Infect. Dis. 2003; 3: 87-98Abstract Full Text Full Text PDF PubMed Scopus (393) Google Scholar]. Moreover, the decreased presence of E-LCs plays a contributory role for immune suppression. Recently, elevated levels of IL-17, its transcription factor ROR-γt, and IL-22 in lesions and circulation (plasma and lymphocytes) were reported [75Katara G.K. et al.Evidence for involvement of Th17 type responses in post kala azar dermal leishmaniasis (PKDL).PLoS Negl. Trop. Dis. 2012; 6: e1703Crossref PubMed Scopus (46) Google Scholar]. Taken together, immunological studies conducted so far indicate that PKDL is not a localised disease, but involves systemic immunity. Figure 1 in main text summarises our current knowledge of the local immune response in patients with PKDL. The precise immune mechanisms of PKDL are still obscure and, interestingly, the immunobiology of the Sudanese and South Asian PKDL differ. Therefore, information from one is not extrapolatable to the other [2Ganguly S. et al.Post kala-azar dermal leishmaniasis – an overview.Int. J. Dermatol. 2010; 49: 921-931Crossref PubMed Scopus (63) Google Scholar]. In Sudanese PKDL, because of the shorter time lag between cure from VL and development of PKDL, the disease-associated immune involvement mimics the scenario of immune reactivation after cure from VL. PBMCs from Sudanese PKDL patients react and proliferate following induction by Leishmania antigens and secrete more IFN-γ, whereas IL-10 was produced primarily from CD4+ T cells [52Ismail A. et al.Immunopathology of post kala-azar dermal leishmaniasis (PKDL): T-cell phenotypes and cytokine profile.J. Pathol. 1999; 189: 615-622Crossref PubMed Scopus (56) Google Scholar]. By contrast, South Asian PKDL is more chronic due to the longer gap between cure from VL and disease onset. Here, CD8+ T cells predominated in lesions and circulation [53Rathi S.K. et al.Lesional T-cell subset in post kala-azar dermal leishmaniasis.Int. J. Dermatol. 2005; 44: 12-13Crossref PubMed Scopus (11) Google Scholar, 73Ganguly S. et al.Increased levels of interleukin-10 and IgG3 are hallmarks of Indian post kala-azar dermal leishmaniasis.J. Infect. Dis. 2008; 197: 1762-1771Crossref PubMed Scopus (63) Google Scholar]. Tregs also play an important role in the lesional immunology of South Asian PKDL, as evident by their elevated mRNA expression of FoxP3, CTLA-4, and CD25 [9Ganguly S. et al.Enhanced lesional Foxp3 expression and peripheral anergic lymphocytes indicate a role for regulatory T cells in Indian post kala-azar dermal leishmaniasis.J. Invest. Dermatol. 2010; 130: 1013-1022Crossref PubMed Scopus (42) Google Scholar, 43Katara G.K. et al.Foxp3 and IL-10 expression correlates with parasite burden in lesional tissues of post kala azar dermal leishmaniasis (PKDL) patients.PLoS Negl. Trop. Dis. 2011; 5: e1171Crossref PubMed Scopus (59) Google Scholar]. In addition to lesional immunology, systemic immune changes include increased antigen-induced IL-10 within circulating CD8+ T cells and impairment of antigen-induced proliferation. These cells were anergic in nature because they lost their surface co-stimulatory CD28 molecule [9Ganguly S. et al.Enhanced lesional Foxp3 expression and peripheral anergic lymphocytes indicate a role for regulatory T cells in Indian post kala-azar dermal leishmaniasis.J. Invest. Dermatol. 2010; 130: 1013-1022Crossref PubMed Scopus (42) Google Scholar, 73Ganguly S. et al.Increased levels of interleukin-10 and IgG3 are hallmarks of Indian post kala-azar dermal leishmaniasis.J. Infect. Dis. 2008; 197: 1762-1771Crossref PubMed Scopus (63) Google Scholar]. Furthermore, the interacting partner of CD28, known as B7.1 or CD86, on monocytes was decreased, suggesting that an immunosuppressive milieu occurs in circulation [21Mukhopadhyay D. et al.Miltefosine effectively modulates the cytokine milieu in Indian post kala-azar dermal leishmaniasis.J. Infect. Dis. 2011; 204: 1427-1436Crossref PubMed Scopus (38) Google Scholar]. Lesional immunology of PKDL was similar in South Asian and Sudanese PKDL with enhanced expression of IL-10, TGF-β, IFN-γ, and TNF-α. However, despite the higher levels of IFN-γ and TNF-α, the expression of IFN-γR and TNFR1 was lower in patients with PKDL in India and increased after treatment [37Ansari N.A. et al.Interferon (IFN)-γ, tumor necrosis factor-α, interleukin-6, and IFN-γ receptor 1 are the major immunological determinants associated with post kala azar dermal leishmaniasis.J. Infect. Dis. 2006; 194: 958-965Crossref PubMed Scopus (61) Google Scholar, 74Ansari N.A. et al.Evidence for involvement of TNFR1 and TIMPs in pathogenesis of post kala-azar dermal leishmaniasis.Clin. Exp. Immunol. 2008; 154: 391-398Crossref PubMed Scopus (19) Google Scholar]. Similarly, in the Sudanese variant, a genetic polymorphism was found in IFN-γR [63Salih M.A. et al.IFNG and IFNGR1 gene polymorphisms and susceptibility to post kala-azar dermal leishmaniasis in Sudan.Genes Immun. 2007; 8: 75-78Crossref PubMed Scopus (40) Google Scholar]. In Sudanese PKDL, expression of IL-10 from keratinocytes was considered as a key factor and a predictor for development of PKDL, particularly after cure from VL [4Zijlstra E.E. et al.Post kala-azar dermal leishmaniasis.Lancet Infect. Dis. 2003; 3: 87-98Abstract Full Text Full Text PDF PubMed Scopus (393) Google Scholar]. Moreover, the decreased presence of E-LCs plays a contributory role for immune suppression. Recently, elevated levels of IL-17, its transcription factor ROR-γt, and IL-22 in lesions and circulation (plasma and lymphocytes) were reported [75Katara G.K. et al.Evidence for involvement of Th17 type responses in post kala azar dermal leishmaniasis (PKDL).PLoS Negl. Trop. Dis. 2012; 6: e1703Crossref PubMed Scopus (46) Google Scholar]. Taken together, immunological studies conducted so far indicate that PKDL is not a localised disease, but involves systemic immunity. Figure 1 in main text summarises our current knowledge of the local immune response in patients with PKDL. Epidemiological data and clinical reports have strongly suggested a link between administration of sodium antimony gluconate (SAG) and subsequent development of PKDL [15Croft S.L. PKDL – a drug related phenomenon?.Indian J. Med. Res. 2008; 128: 100-111Google Scholar]. In India, 62 out of 85 (73%) patients with PKDL who were followed up for 9 years after cure from VL were treated with SAG for VL [8Das V.N. et al.Clinical epidemiologic profile of a cohort of post kala-azar dermal leishmaniasis patients in Bihar, India.Am. J. Trop. Med. Hyg. 2012; 86: 959-961Crossref PubMed Scopus (29) Google Scholar]. A minority (23/85, 27%) developed PKDL after being treated for VL with amphotericin B (n = 13), ambisome (n = 2), miltefosine (n = 2), miltefosine–amphotericin B (n = 1), or paromomycin (n = 5), respectively. In Sudan, Bangladesh, and Nepal, 100% of PKDL patients received SAG [4Zijlstra E.E. et al.Post kala-azar dermal leishmaniasis.Lancet Infect. Dis. 2003; 3: 87-98Abstract Full Text Full Text PDF PubMed Scopus (393) Google Scholar, 5Mondal D. Khan M.G. Recent advances in post kala-azar dermal leishmaniasis.Curr. Opin. Infect. Dis. 2011; 24: 418-422Crossref PubMed Scopus (32) Google Scholar, 6Rahman K.M. et al.Increasing incidence of post kala-azar dermal leishmaniasis in a population-based study in Bangladesh.Clin. Infect. Dis. 2010; 50: 73-76Crossref PubMed Scopus (66) Google Scholar, 7Uranw S. Post kala-azar dermal leishmaniasis in Nepal: a retrospective cohort study (2000-2010).PLoS Negl. Trop. Dis. 2011; 5: e1433Crossref PubMed Scopus (44) Google Scholar], suggesting that SAG could well influence the development of PKDL. A small subgroup of 15–20% of patients with PKDL gave no prior history of VL, attributable to subclinical infection and had therefore not received any drug during that period [8Das V.N. et al.Clinical epidemiologic profile of a cohort of post kala-azar dermal leishmaniasis patients in Bihar, India.Am. J. Trop. Med. Hyg. 2012; 86: 959-961Crossref PubMed Scopus (29) Google Scholar]. It is interesting, however, that SAG can and is still being used for the treatment of PKDL, although at a higher dose and for a prolonged period (20 mg/kg/day, intramuscular, for 4 months) than required for the treatment of VL (20 mg/kg/day for 3 weeks). It is also plausible that differences in systemic versus skin concentrations of antileishmanial drugs permit the survival of parasites in the latter. However, before incriminating SAG for the development of PKDL, further data are required on the frequency of PKDL in cured VL patients treated with other more recently introduced antileishmanial drug regimens. Due to the rise in antimony resistance, there is now a long history of using miltefosine and amphotericin B to treat patients with VL in India [16Sundar S. et al.Oral miltefosine for Indian visceral leishmaniasis.N. Engl. J. Med. 2002; 347: 1739-1746Crossref PubMed Scopus (630) Google Scholar]. As noted above, Thakur et al. reported that using amphotericin B (20 mg/kg) for the treatment of VL effectively minimised development of PKDL, whereas in individuals treated with lower doses of amphotericin B (15 mg/kg), PKDL was reported [10Thakur C.P. et al.Impact of amphotericin-B in the treatment of kala-azar on the incidence of PKDL in Bihar, India.Indian J. Med. Res. 2008; 128: 38-44PubMed Google Scholar]. Patients who received miltefosine, paromomycin, and a combination therapy of amphotericin B/miltefosine have rarely been found to develop PKDL [17Das V.N. et al.Development of post kala-azar dermal leishmaniasis (PKDL) in miltefosine-treated visceral leishmaniasis.Am. J. Trop. Med. Hyg. 2009; 80: 336-338PubMed Google Scholar, 18Kumar D. et al.Post kala-azar dermal leishmaniasis (PKDL) developing after treatment of visceral leishmaniasis with amphotericin B and miltefosine.Ann. Trop. Med. Parasitol. 2009; 103: 727-730Crossref PubMed Scopus (22) Google Scholar, 19Pandey K. et al.Post kala-azar dermal leishmaniasis in a patient treated with injectable paromomycin for visceral leishmaniasis in India.J. Clin. Microbiol. 2012; 50: 1478-1479Crossref PubMed Scopus (22) Google Scholar]. Collectively, available data strengthened the notion that SAG directly or indirectly influences the incidence of PKDL, but definitive evidence may require another decade, because in India, PKDL can develop 20–40 years after cure from VL [2Ganguly S. et al.Post kala-azar dermal leishmaniasis – an overview.Int. J. Dermatol. 2010; 49: 921-931Crossref PubMed Scopus (63) Google Scholar, 18Kumar D. et al.Post kala-azar dermal leishmaniasis (PKDL) developing after treatment of visceral leishmaniasis with amphotericin B and miltefosine.Ann. Trop. Med. Parasitol. 2009; 103: 727-730Crossref PubMed Scopus (22) Google Scholar]. Another speculation is that antileishmanial drugs used at lower doses and for a shorter duration eliminated parasites from the viscera, not from the skin, which required a higher dose. Hence, PKDL might not only be drug-related but could also result from a dose-related phenomenon (Hypothesis 1). A more formal understanding of drug pharmacokinetics/pharmacodynamics is clearly warranted. In addition to epidemiological evidence, immunological data also support this hypothesis, because levels of immunoregulatory cytokines transforming growth factor β (TGF-β) and interleukin 10 (IL-10), factors that support parasite persistence, remained high even after completion of treatment with SAG [20Saha S. et al.IL-10 and TGF-β-mediated susceptibility in kala-azar and post kala-azar dermal leishmaniasis: the significance of amphotericin B in the control of Leishmania donovani infection in India.J. Immunol. 2007; 179: 5592-5603Crossref PubMed Scopus (130) Google Scholar], whereas this was not the case with amphotericin B or miltefosine [20Saha S. et al.IL-10 and TGF-β-mediated susceptibility in kala-azar and post kala-azar dermal leishmaniasis: the significance of amphotericin B in the control of Leishmania donovani infection in India.J. Immunol. 2007; 179: 5592-5603Crossref PubMed Scopus (130) Google Scholar, 21Mukhopadhyay D. et al.Miltefosine effectively modulates the cytokine milieu in Indian post kala-azar dermal leishmaniasis.J. Infect. Dis. 2011; 204: 1427-1436Crossref PubMed Scopus (38) Google Scholar]. Furthermore, in an in vitro model, treatment of THP1 macrophages with SAG caused elevation of two anti-inflammatory, disease-sustaining molecules, namely haem oxygenase 1 (HO-1) and glutathione [22El Fadili K. et al.Modulation of gene expression in human macrophages treated with the anti-leishmania pentavalent antimonial drug sodium stibogluconate.Antimicrob. Agents Chemother. 2008; 52: 526-533Crossref PubMed Scopus (33) Google Scholar]. Another contributory factor is the inability of SAG to restore the peroxisome function of the host [23Gupta S. et al.Host peroxisomal properties are not restored to normal after treatment of visceral leishmaniasis with sodium antimony gluconate.Exp. Parasitol. 2009; 123: 140-150Crossref PubMed Scopus (5) Google Scholar]. Additionally, the failure of SAG to provide a sterile cure strongly indicates the possibility of drug-induced genetic alterations in resistant parasites; SAG-resistant parasites are proposed to have an enhanced degree of ‘fitness’ [24Vanaerschot M. et al.Antimonial resistance in Leishmania donovani is associated with increased in vivo parasite burden.PLoS ONE. 2011; 6: e23120Crossref PubMed Scopus (47) Google Scholar]. Another pertinent observation is that PKDL-causing strains expressed higher levels of promastigote surface antigen (PSA2) and glycoprotein 63 (gp63), molecules associated with dermatotropism; concomitantly, they had decreased expression of amastigote antigen 2 (A2), which is linked with enhanced viscerotropism [25Salotra P. et al.Upregulation of surface proteins in Leishmania donovani isolated from patients of post kala-azar dermal leishmaniasis.Microbes Infect. 2006; 8: 637-644Crossref PubMed Scopus (50) Google Scholar, 26McCall L.I. Matlashewski G. Involvement of the Leishmania donovani virulence factor A2 in protection against heat and oxidative stress.Exp. Parasitol. 2012; 132: 109-115Crossref PubMed Scopus (27) Google Scholar]. Given our recent understanding of the plasticity of the Leishmania genome [27Rogers M.B. et al.Chromosome and gene copy number variation allow major structural change between species and strains of Leishmania.Genome Res. 2011; 21: 2129-2142Crossref PubMed Scopus (310) Google Scholar], and improved capacity and cost reductions associated with parasite genome sequencing, future studies aimed at characterising PKDL isolates with various drug histories are now clearly essential and have become technically and financially achievable. Lesions of PKDL consistently appear on sun-exposed areas, particularly the face, ears, arms, etc., rather than unexposed areas, such as the scalp and chest. This supports the concept that exposure to UV light plays a contributory role in the pathogenesis of PKDL (Hypothesis 2) (Figure 2) [28Ismail A. et al.The pathogenesis of post kala-azar dermal leishmaniasis from the field to the molecule: does ultraviolet light (UVB) radiation play a role?.Med. Hypotheses. 2006; 66: 993-999Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar]. This role of UV light is further highlighted by the characteristic presence of photosensitivity in patients with PKDL. The potent immunosuppressive property of UV light is linked to its ability to damage the antigen presenting epidermal Langerhans cells (E-LCs) and inhibit contact hypersensitivity and alloantigen responses [29Clydesdale G.J. et al.Ultraviolet light induced injury: immunological and inflammatory effects.Immunol. Cell Biol. 2001; 79: 547-568Crossref PubMed Scopus (451) Google Scholar]. UVB light (280–320 nm)-induced immunosuppression can operate either through its chromophore cis-urocanic acid or via modulation of vitamin D3 (Figure 2) [30Amerio P. et al.UV induced skin immunosuppression.Anti-Inflamm. Anti-Allergy Agents Med. Chem. 2009; 8: 3-13Crossref Scopus (10) Google Scholar, 31Hart P.H. et al.Modulation of the immune system by UV radiation: more than just the ef" @default.
• W1967828232 created "2016-06-24" @default.
• W1967828232 creator A5015534998 @default.
• W1967828232 creator A5034613514 @default.
• W1967828232 creator A5055434787 @default.
• W1967828232 creator A5058753331 @default.
• W1967828232 date "2014-02-01" @default.
• W1967828232 modified "2023-10-11" @default.
• W1967828232 title "Post kala-azar dermal leishmaniasis: an unresolved mystery" @default.
• W1967828232 cites W1514702282 @default.
• W1967828232 cites W1525888996 @default.
• W1967828232 cites W1596604198 @default.
• W1967828232 cites W1866137602 @default.
• W1967828232 cites W1897049516 @default.
• W1967828232 cites W1941024190 @default.
• W1967828232 cites W1944631314 @default.
• W1967828232 cites W1965164933 @default.
• W1967828232 cites W1969821479 @default.
• W1967828232 cites W1976469493 @default.
• W1967828232 cites W1978892915 @default.
• W1967828232 cites W1980270838 @default.
• W1967828232 cites W1981711656 @default.
• W1967828232 cites W1992432991 @default.
• W1967828232 cites W1994412261 @default.
• W1967828232 cites W1999343644 @default.
• W1967828232 cites W2000845290 @default.
• W1967828232 cites W2004426423 @default.
• W1967828232 cites W2006679485 @default.
• W1967828232 cites W2007250728 @default.
• W1967828232 cites W2008087433 @default.
• W1967828232 cites W2011343303 @default.
• W1967828232 cites W2011867023 @default.
• W1967828232 cites W2016587111 @default.
• W1967828232 cites W2017335874 @default.
• W1967828232 cites W2020830292 @default.
• W1967828232 cites W2029057112 @default.
• W1967828232 cites W2031646342 @default.
• W1967828232 cites W2034057157 @default.
• W1967828232 cites W2036586400 @default.
• W1967828232 cites W2038275192 @default.
• W1967828232 cites W2040479272 @default.
• W1967828232 cites W2041538995 @default.
• W1967828232 cites W2047634773 @default.
• W1967828232 cites W2048663598 @default.
• W1967828232 cites W2050892758 @default.
• W1967828232 cites W2054408809 @default.
• W1967828232 cites W2057282948 @default.
• W1967828232 cites W2057498107 @default.
• W1967828232 cites W2058318327 @default.
• W1967828232 cites W2061933750 @default.
• W1967828232 cites W2067709645 @default.
• W1967828232 cites W2073104313 @default.
• W1967828232 cites W2074759202 @default.
• W1967828232 cites W2078555782 @default.
• W1967828232 cites W2078911014 @default.
• W1967828232 cites W2079396957 @default.
• W1967828232 cites W2091943843 @default.
• W1967828232 cites W2099206618 @default.
• W1967828232 cites W2099422482 @default.
• W1967828232 cites W2111819389 @default.
• W1967828232 cites W2113211906 @default.
• W1967828232 cites W2120509159 @default.
• W1967828232 cites W2123998716 @default.
• W1967828232 cites W2125274566 @default.
• W1967828232 cites W2128627731 @default.
• W1967828232 cites W2144756920 @default.
• W1967828232 cites W2145152098 @default.
• W1967828232 cites W2152438891 @default.
• W1967828232 cites W2153490452 @default.
• W1967828232 cites W2155792295 @default.
• W1967828232 cites W2158670312 @default.
• W1967828232 cites W2160003876 @default.
• W1967828232 cites W2161367264 @default.
• W1967828232 cites W2168057295 @default.
• W1967828232 cites W2171234521 @default.
• W1967828232 cites W2171530398 @default.
• W1967828232 cites W2188628209 @default.
• W1967828232 cites W2322032713 @default.
• W1967828232 cites W3216725099 @default.
• W1967828232 doi "https://doi.org/10.1016/j.pt.2013.12.004" @default.
• W1967828232 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3919212" @default.
• W1967828232 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/24388776" @default.
• W1967828232 hasPublicationYear "2014" @default.
• W1967828232 type Work @default.
• W1967828232 sameAs 1967828232 @default.
• W1967828232 citedByCount "107" @default.
• W1967828232 countsByYear W19678282322014 @default.
• W1967828232 countsByYear W19678282322015 @default.
• W1967828232 countsByYear W19678282322016 @default.
• W1967828232 countsByYear W19678282322017 @default.
• W1967828232 countsByYear W19678282322018 @default.
• W1967828232 countsByYear W19678282322019 @default.
• W1967828232 countsByYear W19678282322020 @default.
• W1967828232 countsByYear W19678282322021 @default.
• W1967828232 countsByYear W19678282322022 @default.
• W1967828232 countsByYear W19678282322023 @default.
• W1967828232 crossrefType "journal-article" @default.
• W1967828232 hasAuthorship W1967828232A5015534998 @default.

• next