Croft, Simon L

LSHTM Research Online

Indian J Med Res 128, July 2008, pp 10-11Post-kala-azar dermal leishmaniasis (PKDL) is acutaneous manifestation of visceral leishmaniasis (VL),characterized by skin lesions, nodules or papules,frequently on the face. It often appears 2-7 years afterthe apparently successful treatment of VL by antimonialdrugs. It has long been considered a curiousphenomenon, difficult to treat and difficult to explain.Recent studies have sought to determine parasite, hostand treatment factors that might explain the cause(s) ofPKDL.First, is there anything special about the parasite?PKDL is caused by Leishmania donovani in India andSudan, with a few cases reported to be caused by L.infantum / chagasi and historically by either species inChina. Recent molecular studies in India and Sudan onPKDL and VL clinical isolates have not identified ordefined any strains characteristically associated withthe problem1-3. It seems unlikely to be a parasitedetermined manifestation of leishmaniasis. Second, isthere anything different about PKDL patients, theirimmunological status, susceptibility or other factors?Clinical reports have not identified sex, age or racialorigin as defining factors4. A possibility that geneticdisposition might be involved was indicated in Sudanwhere genotypic studies identified linkage of theinterferon-γ (IFN-γ) receptor to PKDL and not to VL.But further studies are required to clearly definesusceptibility factors. The immunological status ofPKDL patients continues to be characterized but thepicture is complex with mixed T cell responses andelevated levels of interleukin-10 (IL-10) and tumournecrosis factor alpha (TNF-α)6-9.The last factor in the puzzle to be considered isdrug treatment. Although there have been reports ofPKDL in untreated patients, the generally accepted viewis that this cutaneous manifestation of VL appears onlyafter treatment. In their excellent review Zijstra and El-PKDL - a drug related phenomenon?Commentary10Hassan4 (2001) refer to the earliest cases of PKDLreported in Sudan by Christopherson in 1921 and inIndia by Brahmachari in 1922, a time when trivalentantimonial drugs (for example, antimony tartrate) werethe norm for treatment. The sporadic reports on PKDLin India and Sudan that were published in the followingdecades referred to disease following treatment withpentavalent antimonials, a form of drug seen now as apro-drug for trivalent antimonials10. Is PKDL onlyassociated with antimonial treatment? In Bihar, India,amphotericin B has been introduced as a front line drugfollowing the development of resistance to pentavalentantimonial treatment. There are now also alternativetreatments for VL in India following the registration ofmiltefosine in 200211 and paromomycin in 200612. It isnow possible to test whether PKDL is a specific resultof antimonial treatment. Thakur et al in this issue10present a retrospective analysis of data on the incidenceof PKDL following the wider use of amphotericin Band discuss the hypothesis that antimonial treatmentand PKDL are inextricably linked. We know fromrecent clinical and experimental studies that sodiumstibogluconate has specific and profound influence onthe immune response through effects on cell signalling,cytokines and on immune complex induced granulocytemacrophage colony stimulating factor (GM-CSF)levels14,15. More importantly, and directly related toThakur’s analysis, Saha et al16 have recently reported acomparative study showing that sodium stibogluconateand amphotericin B had contrasting effects on IL-10and transforming growth factor (TGF)-β levels in PKDLand VL patients, factors already implicated in thedevelopment of this intractable disease.Further studies are needed to get to the bottom ofthe PKDL phenomenon. Prospective clinical trials witha 2-3 year follow-up are required to really test thehypothesis that PKDL is a specific sequela of antimonialtreatment. However, the low incidence of PKDLreported by Thakur et al13 would challenge any trialdesign in India. The significantly higher incidence ofPKDL in Sudan makes this the obvious endemic regionto determine the impact of alternative treatments on theincidence of PKDL. Unfortunately we will have to waituntil miltefosine, paromomycin or AmBisome areshown to be effective against VL in Sudan before theirimpact on PKDL can be investigated. In the meantime,the elimination of VL is a priority for India, Nepal andBangladesh and the accompanying reduction in theincidence of PKDL will assist this effort by removing apotential human reservoir.Simon L. CroftDepartment of Infectious & Tropical DiseasesLondon School of Hygiene & Tropical MedicineKeppel Street, London WC1E 7HT, UKsimon.croft@lshtm.ac.ukReferences1. Dey A, Singh S. Genetic heterogeneity among visceral andpost-kala-azar dermal leishmaniasis strains from eastern India.Infect Genet Evol 2007; 7 : 219-22.2. Sreenivas G, Raju BV, Singh R, Selvapandiyan A, Duncan R,Sarkar D, et al. DNA polymorphism assay distinguishesisolates of Leishmania donovani that cause kala-azar fromthose that cause post-kala-azar dermal leishmaniasis inhumans. J Clin Microbiol 2004; 42 : 1739-41.3. Subba Raju BV, Singh R, Sreenivas G, Singh S, Salotra P.Genetic fingerprinting and identification of differentiallyexpressed genes in isolates of Leishmania donovani fromIndian patients of post-kala-azar dermal leishmaniasis.Parasitology 2008; 135 : 23-32.4. Zijlstra EE, el-Hassan AM. Leishmaniasis in Sudan. Post kala-azar dermal leishmaniasis. Trans R Soc Trop Med Hyg 2001;95 : S59-76.5. Mohamed HS, Ibrahim ME, Miller EN, Peacock CS, KhalilEA, Cordell HJ, et al. Genetic susceptibility to visceralleishmaniasis in The Sudan: linkage and association with IL4and IFNGR1. Genes Immun 2003; 4 : 351-5.6. Ansari NA, Ramesh V, Salotra P. Interferon (IFN)-gamma ,tumor necrosis factor-alpha, interleukin-6, and IFN-gammareceptor 1 are the major immunological determinantsassociated with post-kala-azar dermal leishmaniasis. J InfectDis 2006; 194 : 958-65.7. Ismail A, Gadir AF, Theander TG, Kharazmi A, El HassanAM. Pathology of post-kala-azar dermal leishmaniasis: a lightmicroscopical, immunohistochemical, and ultrastructural studyof skin lesions and draining lymph nodes. J Cutan Pathol2006; 33 : 778-87.8. Ganguly S, Das NK, Panja M, Pal S, Modak D, Rahaman M,et al. Increased levels of Interleukin-10 and IgG3 are hallmarksof Indian post-kala-azar dermal leishmaniasis. J Infect Dis2008; 197 : 1762-71.9. Ismail A, El Hassan AM, Kemp K, Gasim S, Kadaru AE,Moller T, et al. Immunopathology of post kala-azar dermalleishmaniasis (PKDL): T-cell phenotypes and cytokine profile.J Pathol 1999; 189 : 615-22.10. Denton H, McGregor JC, Coombs GH. Reduction of anti-leishmanial pentavalent antimonial drugs by a parasite-specificthiol-dependent reductase, TDR1. Biochem J 2004; 381 : 405-12.11. Ganguly NK. The potential impact of miltefosine on visceralleishmaniasis in India. TDR News No.68. Available from:http://www.int/tdr/publications/tdrnews/news68/miltefosine-india.htm12. http://www.oneworldhealth.org/diseases/leishmaniasis_next.php13. Thakur CP, Kumar A, Mitra G, Thakur S, Sinha PK, Das P,et al. Impact of amphotericin B in the treatment of kala-azaron the incidence of PKDL in Bihar, India. Indian J Med Res2008; 128 : 38-44.14. Pathak MK, Yi T. Sodium stibogluconate is a potent inhibitorof protein tyrosine phosphatases and augments cytokineresponses in hemopoietic cell lines. J Immunol 2001; 167 :3391-7.15. Elshafie AI, Ahlin E, Mathsson L, El Ghazali G, Rönnelid J.Circulating immune complexes (IC) and IC-induced levels ofGM-CSF are increased in Sudanese patients with acute visceralLeishmania donovani infection undergoing sodiumstibogluconate treatment: implications for diseasepathogenesis. J Immunol 2007; 178 : 5383-9.16. Saha S, Mondal S, Ravindran R, Bhowmick S, Modak D,Mallick S, et al. IL-10- and TGF-beta-mediated susceptibilityin kala-azar and post-kala-azar dermal leishmaniasis: thesignificance of amphotericin B in the control of Leishmaniadonovani infection in India. J Immunol 2007; 179 : 5592-603.CROFT: PKDL - A DRUG RELATED PHENOMENON 11

PKDL--a drug related phenomenon?

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PKDL--a drug related phenomenon?

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