The Post Kala-Azar Dermal Leishmaniasis (PKDL) Atlas a Manual for Health Workers WHO Library Cataloguing-In-Publication Data

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The Post Kala-azar Dermal Leishmaniasis (PKDL) Atlas A Manual for Health Workers WHO Library Cataloguing-in-Publication Data

The Post Kala-azar Dermal Leishmaniasis (PKDL) atlas: a manual for health workers.

1. Leishmaniasis, Visceral - diagnosis. 2. Leishmaniasis, Cutaneous – diagnosis. 3. Health personnel – education. 4. Handbooks. I. World Health Organization.

ISBN 978 92 4 150410 2 (NLM classification: WC 715)

WHO/HTM/NTD/IDM/2012.4

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Printed in Spain Printed by: BSD Design: José Mª Ropero The Post Kala-azar Dermal Leishmaniasis (PKDL) Atlas A Manual for Health Workers

Eduard E. Zijlstra Rotterdam Centre for Tropical Medicine Jorge Alvar WHO/NTD/IDM-Leishmaniasis Programme

Table of contents

Preface 1. Introduction [pag. 9]

2. PKDL in Africa: clinical presentation and differential diagnosis [pag. 13] a. PKDL in Sudan [pag. 17] • Macular PKDL [pag. 17] • Macular PKDL and differential diagnosis [pag. 21] • Papular and nodular PKDL [pag. 33] • PKDL grading system [pag. 54] • Severe PKDL [pag. 68] • Differential diagnosis of papular and nodular PKDL [pag. 80] • Chronic PKDL [pag. 106] • Other post-kala-azar manifestations [pag. 109] • Evolution [pag. 113] b. PKDL in Ethiopia [pag. 117] • Various examples [pag. 117] • Differential diagnosis [pag. 123]

3. PKDL in Asia: clinical presentation and differential diagnosis [pag. 127] a. PKDL in India: hospital-based experience [pag. 130] b. PKDL in Bangladesh: community-based experience [pag. 148]

4. PKDL in other areas [pag. 171] a. PKDL in China [pag. 173] b. PKDL in Brazil [pag. 174]

5. PKDL in immunocompromised patients and other skin manifestations of Leishmania in HIV-positive patients [pag. 175]

6. Other forms of leishmaniasis that resemble PKDL or that may be found in the same endemic area [pag. 187]

7. Literature [pag. 207]

8. Acknowledgements/List of contributors [pag. 211] Table of contents of Table

in theteaching of healthworkers at alllevels. . PKDL bythosewhowork inthefield remote areas. Itmay alsobe of use good clinicalassessment bywhichdifferential diagnosescanbe excluded. diagnosis of PKDLcanbemadeonclinicalgrounds onlyonthebasis of a and thelist of differential diagnosesis extensive. We believe a reasonable recognizing PKDLandmakingafirmdiagnosis.Theclinicalspectrum varies an epidemiologicalpoint of view. Thisispartlycausedbythedifficultyin riments insandflies. Yet, PKDLhasbeenneglected both from aclinicaland been suggested many years agoandthiswassupported byfeeding expe- the transmission of kala-azar inparticulartheinterepidemic periodshas where Leishmania donovani isthecausative parasite. Itspotential role in since thebeginningof the20 cation of visceral leishmaniasis (VL) orkala-azar. Ithasbeendescribed Post Kala-azardermalleishmaniasis(PKDL)isawell-recognized compli- Preface area are presented. other areas onlythemost common conditions encountered orconditions specific for that cular andpapular/nodular PKDLisdiscussedextensively inthe chapter onPKDLinSudan.For As PKDL is common in Sudan and has been well described, the differential diagnosis of ma- diagnosis. that canbeusedunder field conditions. Thesame would of course apply to thedifferential lop andto evaluate aclinicalalgorithmfor PKDLandto develop simpleandaccurate tools this atlas reflects current clinicalpractice. There isagreat need for further studies to deve- confirmed, in others itisaclinicaldiagnosisbasedon experience. Despite this, we feel that While thediagnosisof PKDLandtheconditions shown inthedifferential diagnosiswas often Note This manualaimsto beaguideto better andearlierrecognition of th century both inAsiaandAfrica, inareas Geneva, August 2012

7 Preface

1. Introduction Map. Visceral Leishmaniasis endemic countries and occurrence of PKDL co-infected patients co-infected

Leishmania Endemic countries with no PKDL or sporadic cases only. with no PKDL or sporadic Endemic countries ≤ 5% PKDL rate 6-10% PKDL rate 11-20% PKDL rate > 20% PKDL rate in HIV- PKDL reported

Design: J. Alvar-Beltrán. Post-kala-azar dermal leishmaniasis (PKDL) is a complication of visceral leishmaniasis (VL) or kala-azar. It is common in areas endemic for VL caused by L. donovani. These include countries in Africa in particular Sudan and in Asia, Bangladesh and to a lesser extent India. PKDL may also spora- dically occur in L. infantum or L. chagasi endemic areas, mainly the Medite- rranean countries and Latin America. The condition is characterized by the occurrence of a skin rash after an episode of VL; the interval varies according to the endemic area. The rash is usually in the face, from which it may or may not spread to other parts of the body. In contrast to VL, the patient is not ill and PKDL is not fatal. In the Sudanese type, self cure is the rule while in Bangladesh and India, all cases are treated. Risk factors for PKDL are not well known; previous treatment of VL with inadequate dosage of drug and the drug used, malnutrition, HIV infection and young age may play a role. The importance of PKDL is twofold: • Clinical: patients develop a rash that may last for weeks or months; in particular in small children, the rash may become generalized and severe with mucosal lesions in the mouth, causing general dis- comfort. • Epidemiological: smears or biopsies taken from the lesions may show Leishmania parasites and there is evidence that the sandfly vector may take up these parasites while taking a blood meal and thus PKDL patients may play an important role in transmission (anthroponotic transmission). It is thought that VL occurs in cycles with epidemics of thousands of cases, followed by a period of seemingly low transmission. It is likely that chronic PKDL patients who harbour parasites may play an important role in subsequent upsurges in VL cases. Diagnosis is usually clinical by the triad of the typical rash, its distribution and the previous episode of VL. There are however, often difficulties and exceptions: many patients do not have a previous episode of VL and the rash may mimic other common skin conditions. In addition, the presentation in Africa and Asia is quite different with the maculopapular form and typical spread being the most common in Sudan and the macular form being much more common in Bangladesh, often with a more atypical distribution. Parasites may be found in the lesions but this requires a skin smear or biopsy; in papular or nodular PKDL the parasites can usually be demonstrated but in the macular type they are scanty. Serological diagnosis is not very helpful as most patients will have a previous history of VL and antibodies may persist as a result and therefore a positive test may be

difficult to interpret. 1. Introduction

11 12 The PKDL Atlas. A Manual for Health Workers changes from aTh 1 continent Table 1:Differences between PKDLinSudanandtheIndiansub- who needs treatment and shorter, more effective and cheaper regimens. cheaper and effective more shorter, and treatment needs who B isthebest drug.For allareas there isaneedfor better identification of promised patients isalways treated andprobably liposomalamphotericin days of SSGinjectionsand 10days drugfree period).PKDLinimmunocom- (SSG). InBangladeshallcasesare treated with6cycles of monthly SSG(20 most severe are treated usuallywith6-8weeks of sodiumstibogluconate dulator to drugtreatment, thuspromoting cure. immune response may befurthermanipulated byaddinganimmunomo - under theinfluence of drugtreatment orspontaneously. Thischangein adapted from ref 1. Mucosal lesions Genital lesions (uveitis, conjunctivitis) May have other post KAmanifestations May occurwhileonRxfor VL May occurwithoutprevious VL May occurwithvisceralized disease Spontaneous cure Typical distribution Most common presentation Clinical Interval after VL Maximum reported PKDLrate after VL Highest rate reported infieldstudy Epidemiology Sun-exposed areas Face-arms/chest-legs The management of PKDL differs: inSudanmost casesselfheal;the PKDL occurswhentheimmuneresponse to Introduction 1

2 dominated response to amixed Th rare uncommon yes yes yes yes yes yes yes polymorphic, papular 0-6 months 60% 4.8/100 Sudan not uncommon common yes no yes no no yes face andbody, facenearlyalways polymorphic, papulonodular, macular 0-3 years 10-20% 4.8/1000 Indian subcontinent Leishmania 1 /Th 2 parasites response 2. PKDL in Africa: clinical presentation and differential diagnosis a. PKDL in Sudan • Macular PKDL • Macular PKDL and differential diagnosis • Papular and nodular PKDL • PKDL grading system • Severe PKDL • Differential diagnosis of papular and nodular PKDL • Chronic PKDL • Other post-kala-azar manifestations • Evolution b. PKDL in Ethiopia • Papular rash • Differential diagnosis

may become quite drywithscaling. parts of theskin;incaseof mucosal involvement ulcersmay form. Theskin Ulceration isnot afeature, butthere may besloughingof heavily affected sentations includeapatchy distribution of plaquesandtheverrucous type. classical spread asinthepapulonodularform. Othermore uncommon pre- common ase.g.inBangladesh.Themacularrash seemsnot to follow the lesions. Patients may present withamacularrash only, butthisismuchless me confluent. PKDLis often describedin3grades of densityandspread of measles; others increase insize andmay becallednodules;thesemay beco- occurring on a macular background. Thepapules may be smallresembling face. Themost common presentation isamaculopapularrash withpapules these increase innumberandsize andspread furtherto cover most of the The initialpresentation isusuallywithsomepapulesaround the mouth; In contrast withVL,thepatient isgenerally well, except insevere cases. Clinical presentation VL andprobably hadsubclinicalVLinfection. months after treatment. Somepatients donot have aprevious history of portance. Upto 50-60%of VLcasesdevelop PKDL,usuallywithin0-6 the parasite or the genetic background of the population may be of im- Ethiopia, Kenya or Uganda. The reason for this is not clear; differences in In Africa, PKDLbyfarmostly occursinSudan.Itismuchlesscommon in Table 2:Differential diagnosis of PKDLin Africa Psoriasis Infantile eczema Mycosis fungoides Tuberous sclerosis Keloids African histoplasmosis Mollusca contagiosa Lichen planus Granuloma annulare Granuloma multiforme Discoid lupuserythematosus Scabies Darier’ disease Urticaria pigmentosa/ mastocytosis Neurofibromatosis Acne Measles andother viral infections Lupus vulgaris Leprosy Miliaria rubra (pricklyheat) Mucosal leishmaniasis Diffuse CutaneousLeishmaniasis (DCL) Leishmaniasis recidivans Cutaneous leishmaniasis Papular/nodular rash Chloasma Pellagra Birth marks Burn scars Onchocerciasis Discoid lupuserythematosus Pityriasis alba Tinea barbae Tinea corporis Pityriasis versicolor Vitiligo Leprosy Macular rash 15 2. PKDL in Africa: clinical presentation and differential diagnosis 16 The PKDL Atlas. A Manual for Health Workers larly, post-kala-azar mucosal leishmaniasis in the nose has been described. developing immuneresponse causesinflammation anddestruction. Simi- ness. AsinPKDL,parasites persist intheeye for unknown reasons andthe mon. Theseconditions are often not recognized andmay leadto blind- mitantly withPKDL;of these uveitis andconjunctivitis are themost com- Similarly, PKDLmay coincide withleishmanioma. maniasis. Thesecasesmay beclinicallyill,withfever, splenomegaly etc. sent withvisceralized disease. Thisiscalledpara-kala-azar dermalleish- depressed scarsmay develop ortheskinmay become fibrotic . without scarring.Inthosewhohave chronic PKDL,often for many years, There are other post-kala-azar manifestations that may occurconco- PKDL may develop whilestill ontreatment for VLorpatients may pre- As arule,after treatment orspontaneous cure, theskinfullyrecovers

1-5 Macular PKDLmainlyaround themouthandspread to other partsof theface. PKDL inSudan 3 2 17 2. PKDL in Africa: clinical presentation and differential diagnosis 18 The PKDL Atlas. A Manual for Health Workers PKDL inSudan Macular PKDL 5 4 Macular PKDL 7 Symmetrical hypopigmented patches resembling lepromatous leprosy (seealsofig.131). 6

Macular rash affecting the“butterfly” area. 19 2. PKDL in Africa: clinical presentation and differential diagnosis 20 The PKDL Atlas. A Manual for Health Workers 10 Same patient; lesionsontheupperlegs. PKDL inSudan Macular PKDL mainly onthetrunk. 8 Macular lesions

9 Close-up of theabdomen. Macular PKDLanddifferential diagnosis This patient alsohadVLand 11 Pityriasisalba. Usually more common inthe increased susceptibility for 13 Pityriasisversicolor. for VLonly, suggesting an the rash disappeared with stibogluconate treatment this fungalskininfection trunk thanintheface. during VL. patches. hypopigmented Scattered corporis. 12 Tinea 21 2. PKDL in Africa: clinical presentation and differential diagnosis 22 The PKDL Atlas. A Manual for Health Workers PKDL inSudan healed scarsonboth cheeks andupperlip erythematosus; Discoid lupus (14, 15,16) Macular PKDLanddifferential diagnosis 15 16 14 Macular PKDLanddifferential diagnosis area andarms(17,18). Symmetrical depigmented inflammatory lesionsinthebutterfly Discoid LupusErythematosus.

17 18 23 2. PKDL in Africa: clinical presentation and differential diagnosis 24 The PKDL Atlas. A Manual for Health Workers PKDL inSudan lesions may co-exist. Hypopigmented and 20 Discoid lupus erythematosus. hyperpigmented Macular PKDLanddifferential diagnosis lesions. Hypopigmented erythematosus. 19 Discoid lupus 21 Lupusvulgaris. plaque withatrophic Macular PKDLanddifferential diagnosis infiltrated ulcerating scarring inthe Violaceous center. Depigmented irregular scarscausedbyprevious burninjury. 22 Burnscars. 25 2. PKDL in Africa: clinical presentation and differential diagnosis 26 The PKDL Atlas. A Manual for Health Workers Table 3:Differential diagnosis of macularPKDLandvitiligo Predilection Family members (axillae, inguinalarea) Sparing of most pigmented areas Other skinabnormalities Bordering skin Appearance face acra central back PKDL inSudan 24 Macular PKDLanddifferential diagnosis Macular PKDL yes similar exposure to VL yes no yes tous; papules,nodules macules may beerythema - normal hypopigmented affected yes genetic yes Vitiligo yes no none sometimes hyperpigmented depigmented sparing central back 23 cheeks are tribalmarkings. The darkvertical linesonboth occur inyounger patients. dermatome(s). Thistypemay in thedistribution of a lesions, asymmetrical Clinical clues:Depigmented vitiligo. Segmental orzosteriform Macular PKDLanddifferential diagnosis patient alsosuggests vitiligo,rather than as inPKDL(seeTable 3).Theageof the depigmented andnot hypopigmented PKDL. Note that someof hairsinthe beard andmoustache are white. Clinical clues:Themaculesare Vitiligo. 25 25 26 26 28 28 27 27 27 2. PKDL in Africa: clinical presentation and differential diagnosis 28 The PKDL Atlas. A Manual for Health Workers 31 Symmetrical hypopigmented lesions, PKDL inSudan taut skin,reduced mouthopening, impairment inmovement of the Macular PKDLanddifferential diagnosis Scleroderma. Clinicalclues: fingers. 30

29 29 Macular PKDLanddifferential diagnosis 34 34 33 (34, arrow) andscratch macules (32,33);look for onchocercomata Onchocerciasis. leopard skinwith hypopigmented lncl clues: Clinical marks (35). 32 32 35 35 29 2. PKDL in Africa: clinical presentation and differential diagnosis 30 The PKDL Atlas. A Manual for Health Workers Clinical clues:lookfor other signsof leprosy: anaesthetic patches, thickened nerves. SeeTable 4. Note theraised edge,thearea of hypopigmentation with central repigmentation. 36 Borderline leprosy. M macules,Ppapules, Nnodules. Table 4:Differential diagnosis of PKDLandleprosy Self-cure Management Skin slitsmear Diagnosis Predilection sunexposed parts Madarosis Lobulation of ears - pathological - clinical Neurological features Single lesion Uniform insize Symmetrical lesions Lesions Clinical Frequency inendemicareas Most important agegroup Epidemiology PKDL inSudan Macular PKDLanddifferential diagnosis no (Asia) yes (theruleinSudan) (Giemsa stain) PKDL Leishmania yes no yes neuritis incutaneousnerves none uncommon yes yes M, P, N,plaques common young children amastigotes no (modified ZNstain) acid-fast bacilli Leprosy no (cooler parts) yes yes id sweating nerves, nerve palsies,lossof anaesthetic patches, thickened tuberculoid leprosy common inundetermined and no lepromatous: yes indeterminate, tuberculoid: no M, P, N,plaques uncommon older individuals

Macular PKDLanddifferential diagnosis The longitudinalscarsonthecheekare tribalmarkings. Hyperpigmented depressed scarsof previous cutaneousleishmaniasisulcers. 37 Cutaneousleishmaniasisscars. Note thehyperpigmentation ontheforehead caused by frequent pressure exerted whilepraying. 38 Prayer marksinamuslimman. 31 2. PKDL in Africa: clinical presentation and differential diagnosis 32 The PKDL Atlas. A Manual for Health Workers could beremoved withwater andsoap. PKDL inSudan discoloration wascausedbydirtand confirmed kala-azar cases, theblack in Sudanesepatients. Inthese2 hyperpigmentation is not found “black disease”, whichrefers to hyperpigmentation of theskin Although kala-azar meansthe found inIndiankala-azar, this Pseudomelanosis. Macular PKDLanddifferential diagnosis 40 39 PKDL inSudan:Papular andnodularPKDL around themouthis initial localization various stages of development and various sizes; the 43 density andof Papules in typical. 41 41 42 33 2. PKDL in Africa: clinical presentation and differential diagnosis 34 The PKDL Atlas. A Manual for Health Workers PKDL inSudan Papular andnodularPKDL 44 Micropapular rash.

Papular andnodularPKDL 45 Macropapular rash. 35 2. PKDL in Africa: clinical presentation and differential diagnosis 36 The PKDL Atlas. A Manual for Health Workers 47 47 Further spread of thelesions to thenose,around theeyes and theforehead. PKDL inSudan Papular andnodularPKDL 46 46 Papular andnodularPKDL 48 Further spread of thelesionsto thenose,around theeyes andtheforehead.

37 2. PKDL in Africa: clinical presentation and differential diagnosis 38 The PKDL Atlas. A Manual for Health Workers 51 51 PKDL inSudan Papular andnodularPKDL increasing density. Papular rash with 52 52 49 49 50 55 55 Papular andnodularPKDL 56 56 Maculopapular rash. 53 54 39 2. PKDL in Africa: clinical presentation and differential diagnosis 40 The PKDL Atlas. A Manual for Health Workers 57 Maculopapular rash. PKDL inSudan Papular andnodularPKDL Papular andnodularPKDL 58 Papular PKDL,covering thewholeface. 41 2. PKDL in Africa: clinical presentation and differential diagnosis 42 The PKDL Atlas. A Manual for Health Workers PKDL inSudan Papular andnodularPKDL 60 to develop. fibrotic changes may prevent PKDLpapules horizontal linesare tribalmarkings and Note absenceof lesionsonforehead: the Nuer tribesmanfrom SouthSudan. 61

over eyebrows (60). Note verrucous plaques covering thewholeface. Papular PKDL, 59

Papular andnodularPKDL 63 63 Micropapular rash, measles-like. 62

43 2. PKDL in Africa: clinical presentation and differential diagnosis 44 The PKDL Atlas. A Manual for Health Workers 64 Hyperpigmented PKDL inSudan papules. 65 Papular andnodularPKDL 66 Papular andnodularPKDL Nodular lesions. 45 2. PKDL in Africa: clinical presentation and differential diagnosis 46 The PKDL Atlas. A Manual for Health Workers 67 PKDL inSudan Papular andnodularPKDL Nodular lesions. 69 68 Papular andnodularPKDL 70 Papules andnodules 72 become confluent to form plaques. 71

47 2. PKDL in Africa: clinical presentation and differential diagnosis 48 The PKDL Atlas. A Manual for Health Workers 74 Patient withthree solitaryplaquesonforehead (73),chin(74)andearlobe(121). PKDL inSudan Papular andnodularPKDL 73 73 Papular andnodularPKDL 75 Plaques intheface(Figures 75-79). 49 2. PKDL in Africa: clinical presentation and differential diagnosis 50 The PKDL Atlas. A Manual for Health Workers 76 PKDL inSudan Papular andnodularPKDL Papular andnodularPKDL 77 51 2. PKDL in Africa: clinical presentation and differential diagnosis 52 The PKDL Atlas. A Manual for Health Workers 78 PKDL inSudan Papular andnodularPKDL Papular andnodularPKDL 79 53 2. PKDL in Africa: clinical presentation and differential diagnosis 54 The PKDL Atlas. A Manual for Health Workers Table 5:Grading system of PKDLin Sudan with normalskininbetween. Grade 1.1 80 Grade 3 Grade 2 Grade 1 PKDL inSudan Lesions onlyinthefaceandrestricted to area around thenoseandmouth all over body;includinghands andfeet hands andfeet free affected, gradually becoming less distally; face, upperpartsof trunk, armsandlegs arms face mainlywithsomelesionsontrunkand Distribution PKDL grading system between moderate densitywithnormalskinin scattered lesions Density PKDL grading system on theface. Dense maculopapularrash, butmainly Grade 1.3. 83 (Figures 81-82). Transition into Grade 1.2 Grade 1.1. 81 82 55 2. PKDL in Africa: clinical presentation and differential diagnosis 56 The PKDL Atlas. A Manual for Health Workers 85 PKDL inSudan Grade 1.3Thewholefaceisaffected withadensepapular rash (84)and PKDL grading system macular rash (85)withfew papulesinother areas 84 PKDL grading system Papular rash. Most parts of thebody rash isdensebut skin canbeseen. are affected; the Grade 2.2. still normal 87

of VL. no previous history patient there was (arrows). Inthis leishmaniomas Papular rash and Grade 2.1 86 57 2. PKDL in Africa: clinical presentation and differential diagnosis 58 The PKDL Atlas. A Manual for Health Workers of thetrunkisalso Grade 2.2.Most PKDL inSudan involved. 88 PKDL grading system 89 PKDL grading system 91 Macular rash. Grade 3.2. 90 and papularrash. Combined macular Grade 3.2. 59 2. PKDL in Africa: clinical presentation and differential diagnosis 60 The PKDL Atlas. A Manual for Health Workers 92 Grade 3.2Maculopapularrash . PKDL inSudan PKDL grading system PKDL grading system 94 93 Mainly hyperpigmented papules. Grade 3.3. 61 2. PKDL in Africa: clinical presentation and differential diagnosis 62 The PKDL Atlas. A Manual for Health Workers PKDL inSudan lower armsmay beaffected nodular PKDL.Thefaceand does not follow thenormal Grade 3macularPKDL. distribution asinpapular/ with littleinvolvement of In macularPKDL,therash the trunk(95,96). PKDL grading system 96 95 PKDL grading system 98 is therefore difficult. and arms(97,98).Grading or nolesionsontheface may beaffected withfew Alternatively, thetrunk Grade 3macularrash. 97 63 2. PKDL in Africa: clinical presentation and differential diagnosis 64 The PKDL Atlas. A Manual for Health Workers Maculopapular rash. Grade 3.3 99 PKDL inSudan PKDL grading system PKDL grading system 100 Grade 3.3.Papulonodular rash. 65 2. PKDL in Africa: clinical presentation and differential diagnosis 66 The PKDL Atlas. A Manual for Health Workers 101 Grade 3.3Micropapular rash. PKDL inSudan PKDL grading system PKDL grading system around themouth andon All partsof thebodyare involved withplaques Papulonodular rash. Grade 3.3 eyebrows. 103

maculopapular rash. Close-up: dense Grade 3.3 102 67 2. PKDL in Africa: clinical presentation and differential diagnosis 68 The PKDL Atlas. A Manual for Health Workers 104 Severe PKDLgrade 3inthefacewithcrusts andsloughing of theskin. PKDL inSudan Severe PKDL Severe PKDL 106 grade 3intheface with crusts and Severe PKDL of theskin. sloughing 105 69 2. PKDL in Africa: clinical presentation and differential diagnosis 70 The PKDL Atlas. A Manual for Health Workers 107 Severe PKDLgrade 3.(Figures 107-112). PKDL inSudan Severe PKDL Severe PKDL 108 109 71 2. PKDL in Africa: clinical presentation and differential diagnosis 72 The PKDL Atlas. A Manual for Health Workers 110 PKDL inSudan Severe PKDL Severe PKDL 111 73 2. PKDL in Africa: clinical presentation and differential diagnosis 74 The PKDL Atlas. A Manual for Health Workers 112 PKDL inSudan Severe PKDL Severe PKDL 113 Desquamation of theskin. Grade 3. 114 115 75 2. PKDL in Africa: clinical presentation and differential diagnosis 76 The PKDL Atlas. A Manual for Health Workers 116 affects the PKDL also PKDL inSudan (back and Grade 3. 117 hands palm).

Severe PKDL 118 PKDL affecting theearlobe. Severe PKDL 119 77 2. PKDL in Africa: clinical presentation and differential diagnosis 78 The PKDL Atlas. A Manual for Health Workers 121 PKDL inSudan 120 PKDL affecting theearlobe; 123 Severe PKDL see alsofig.85. 122

Severe PKDL 124 leishmaniomas. lesions may be area. Theulcerative PKDL inthegenital 126 125 79 2. PKDL in Africa: clinical presentation and differential diagnosis 80 The PKDL Atlas. A Manual for Health Workers for comparison *Note that some photographs included in this chapter are from other countries than Sudan 128 wrapped inmany layers of cloth, despite hot weather conditions; PKDL inSudan the forehead andnot around Clinical clues:young child, typically tiny papuleson the mouthasinPKDL; Miliaria rubra. Differential diagnosis of papularandnodularPKDL* may beitchy. 127

with white head). greasy skin,comedones (papules different stages of development, Clinical clues:adolescent age, Acne. 129 Differential diagnosis of papularandnodularPKDL See alsoTable 4. hand. Bottom: collapse of thenose;not seeninPKDL. Middle left: wrist drop anddestruction of phalanges.Middleright: wrist drop andclaw Top right: tuberculoid leprosy: thegreat auricular nerve isclearlyvisibleandpalpable. Top middle:lepromatous leprosy (cf. Fig7). Top left: thevariation insize of papules,nodulesandplaques isnot seen inPKDL. with destruction of phalanges. peripheral nerve palsies,suchasclawhand(ulnarnerve) andwrist drop (radial nerve) Clinical clues:anaesthetic skinpatches, thickened nerves, e.g.greater auricularnerve, 130, 131,132,133,134,135.Leprosy.

81 2. PKDL in Africa: clinical presentation and differential diagnosis 82 The PKDL Atlas. A Manual for Health Workers cooler bodyparts:upperarms rather thanlower armsthat are exposed to sunlight. Elderly person,madarosis, lesions indifferent stages of development, preference for Clinical clues: 136 Lepromatous leprosy. PKDL inSudan Differential diagnosis of papularandnodularPKDL Differential diagnosis of papularandnodularPKDL Details of Fig136. Lepromatous leprosy. 138 137 83 2. PKDL in Africa: clinical presentation and differential diagnosis 84 The PKDL Atlas. A Manual for Health Workers History of genitalulcer;asinPKDL,palmsandsolesmay be involved. Clinical clues: Lues stage II. 139 PKDL inSudan Differential diagnosis of papularandnodularPKDL Differential diagnosis of papularandnodularPKDL 140 There isthickening of theskin scar. Surgical removal usually due to fibrosis, typicallyina results ina(more severe) Clinical clues: Keloids. relapse. 141 142 85 2. PKDL in Africa: clinical presentation and differential diagnosis 86 The PKDL Atlas. A Manual for Health Workers of HIVinfection are seenthat may break down. Itiscommon inAfrica inyoung peopleasanearlysign vesicles onanerythematous background inawhite skin;inablackskin,mainlyvesicles Herpes zoster. Clinicalclues:Thisistypicalinadermatome andmay present with 144 143 Herpes zoster scarinophthalmic branch of thetrigeminalnerve. Herpes zoster inakala-azar patient. PKDL inSudan Differential diagnosis of papularandnodularPKDL 146 Differential diagnosis of papularandnodularPKDL skin structure, thevesicles are less likely to break down. (147,148). Herpes zoster intheblackskin; because of thedifferent on erythematous background. Herpes zoster inwhite skin;vesicles 145 days. over evolves development; stages of in various Vesicles Clinical clues: (chickenpox). 148 Varicella 147 87 2. PKDL in Africa: clinical presentation and differential diagnosis 88 The PKDL Atlas. A Manual for Health Workers childhood; now presents with part of face;may runin Predilection for central cylindroma, syringoma, brother hadthesame tricho-epitheliomas tricho-epitheliomas families: thepatient’s differential diagnosis: adenoma sebaceum). (presumed diagnosis; Keloid after varicella in PKDL inSudan herpes zoster scar. condition. Multiple 150 Differential diagnosis of papularandnodularPKDL

151

adolescence. with age;starts during of papulesincrease and temples. Numbers part of face,cheeks skin, mostly inupper Common intheblack nigra. Dermatosis papulosa 149 Differential diagnosis of papularandnodularPKDL Mollusca contagiosa inanHIV-positive patient. 152 89 2. PKDL in Africa: clinical presentation and differential diagnosis 90 The PKDL Atlas. A Manual for Health Workers note thesplenomegaly. Noma orcancrumorisinaVLpatient whohadrelapsed after treatment; PKDL inSudan Differential diagnosis of papularandnodularPKDL

153 154 157 Measles-like PKDL. 155 Differential diagnosis of papularandnodularPKDL The micropapular rash is difficult to distinguish from PKDL. Measles. 156 91 2. PKDL in Africa: clinical presentation and differential diagnosis 92 The PKDL Atlas. A Manual for Health Workers 160 of pusprobably asaresult of desquamate (159)(seealso a perforated eardrum, 161). Clinical clues:lookfor other In measles,therash canbe and otitis media(discharge from themicropapular rash fever, cough, conjunctivitis in PKDL.Therash may also (158), Koplik’s spots (160) virtually indistinguishable signs of measlessuch as PKDL inSudan 113-115). Measles. Differential diagnosis of papularandnodularPKDL 158 159 161 Differential diagnosis of papularandnodularPKDL 163 162 Scabies Typical interdigital lesions(162); may alsobemore widespread (163). 93 2. PKDL in Africa: clinical presentation and differential diagnosis 94 The PKDL Atlas. A Manual for Health Workers 164 PKDL inSudan Differential diagnosis of papularandnodularPKDL African histoplasmosis. Differential diagnosis of papularandnodularPKDL The noseandearlobesremain free. Note different sizes, alsoaffecting thescalp. Chronic slowly progressing. Nodulesin grandmother, father andhis2siblings the multipleandgiant nodulesonthe also hadthediseasecompatible with abdomen; thisisnot seeninPKDL. autosomal dominant inheritance. Family history: inthiscase,his Neurofibromatosis. Clinical clues: 165 166 167 95 2. PKDL in Africa: clinical presentation and differential diagnosis 96 The PKDL Atlas. A Manual for Health Workers 169 PKDL inSudan Differential diagnosis of papularandnodularPKDL 170 168 gangosa. 171 leaving chest clear. and extremities, distribution onface of Congo) Note atypical Democratic Republic nodular (from the 169, 170Yaws, raised edge. macular lesionswith 168 Endemicsyphilis, 171 Late yaws :

Differential diagnosis of papularandnodularPKDL 173 elevated asplaques; Kaposi’s sarcoma They usuallybegin as macularlesions in thefaceandon positive patients. the chest inHIV typically purple that become in color. 172

97 2. PKDL in Africa: clinical presentation and differential diagnosis 98 The PKDL Atlas. A Manual for Health Workers PKDL inSudan Differential diagnosis of papularandnodularPKDL of PKDL. it isnot afeature leishmaniasis, in cutaneous this isalsoseen lymphatics. While Spread alongthe Sporotrichosis. 174

175

177 Nuer tribe. Differential diagnosis of papularandnodularPKDL Shilluk tribe. markings. Tribal 176 99 2. PKDL in Africa: clinical presentation and differential diagnosis 100 The PKDL Atlas. A Manual for Health Workers PKDL inSudan Differential diagnosis of papularandnodularPKDL 178 the markings. between occurring PKDL papules markings, with Nuer tribal

179 181 Differential diagnosis of papularandnodularPKDL appear ontheforehead, perhaps Nuer tribe.Thepapulesdonot because of fibrosis causedby 182 scarring. 180 on thecheeksandnose. scarring, butwithlessdensitythan found ontheforehead despite the Nuer tribe.Here thepapulesare also

101 2. PKDL in Africa: clinical presentation and differential diagnosis 102 The PKDL Atlas. A Manual for Health Workers PKDL inSudan Differential diagnosis of papularandnodularPKDL 183, 184Psoriasis. 185 Differential diagnosis of papularandnodularPKDL case, buttheappearance and thepatient’s agemay suggest Burkitt’s lymphoma. Swelling of thefaceisnot afeature of PKDL;nodiagnosiswasmade inthis PKDL.

103 2. PKDL in Africa: clinical presentation and differential diagnosis 104 The PKDL Atlas. A Manual for Health Workers 187 PKDL inSudan Differential diagnosis of papularandnodularPKDL invisible again. and thescarsbecame the lesionsdisappeared after treatment of PKDL, lesions appeared inthem; became visibleasPKDL for anunknown illness, traditional scarification scars, causedby In thischild,previous Köbner’s phenomenon. 186 188 distribution which is otherwise unusual inPKDL. Note thepreferential localization of thepapules inthescarscausinganasymmetrical 189 Köbner’s phenomenon. Differential diagnosis of papularandnodularPKDL 105 2. PKDL in Africa: clinical presentation and differential diagnosis 106 The PKDL Atlas. A Manual for Health Workers 190 Depressed scarsdeveloping after longstanding PKDL. PKDL inSudan Chronic PKDL Chronic PKDL 192 Depressed scarsdeveloping after longstanding PKDL. 191 107 2. PKDL in Africa: clinical presentation and differential diagnosis 108 The PKDL Atlas. A Manual for Health Workers 193 PKDL inSudan in longstanding PKDL. Fibrosis of theskin Chronic PKDL 194 195

196 Post kala-azar manifestations 197 treated for VLin The patient was Post-kala-azar the recent past infection inthe conjunctivitis swelling of the not diagnosed but developed loss of vision. and uveitis. as related to eyes andled to complete These were Leishmanial eyelids and increasing persistent blindness. 199 198 109 2. PKDL in Africa: clinical presentation and differential diagnosis 110 The PKDL Atlas. A Manual for Health Workers conjunctivitis (top) and post-kala-azar Concomitant PKDL and blepharitis PKDL inSudan (bottom). 200

Post kala-azar manifestations 201 Left: inversion of eyelids. Right: after eyelid surgery; thecornea isopaque. Trachoma (below). 204 202 Post-kala-azar uveitis. Note theirregular pupilandnodules. Post kala-azar manifestations 205 irregular pupil. Right: uveitis; cornea (pannus). of overgrowth of Left: beginning (middle). Onchocerciasis 203 diagnosis: Differential 111 2. PKDL in Africa: clinical presentation and differential diagnosis 112 The PKDL Atlas. A Manual for Health Workers 206 Mucosal lesionsinsevere PKDL. PKDL inSudan Post kala-azar manifestations Other post kala-azar manifestations VL (confirmed inalymphnodeaspirate) andconcomitant micropapular PKDL. 207 Para-kala-azar dermalleishmaniasis. (conjunctivitis, uveitis, mucosal) 113 2. PKDL in Africa: clinical presentation and differential diagnosis 114 The PKDL Atlas. A Manual for Health Workers PKDL inSudan Evolution of PKDL after treatment. indeed becamelighter of thefigures, hisskin difference inbrightness In spite of the treatment (210,211). days of stibogluconate (208, 209)andafter 30 Nuer tribesmanbefore 209 211 208 210 Evolution of PKDL 212 after 6weeks (215). (212, 213),after 30 with SSG(214)and days of treatment Before treatment 215 214 213 115 2. PKDL in Africa: clinical presentation and differential diagnosis 116 The PKDL Atlas. A Manual for Health Workers 218 216 PKDL inSudan after treatment (216), 2weeks later (217)and presentation Evolution of PKDL (218). Initial 217 219 PKDL inEthiopia.Various examples 221 rash, mainlyaround themouth. Various examples of papular PKDL inEthiopia 220 117 2. PKDL in Africa: clinical presentation and differential diagnosis 118 The PKDL Atlas. A Manual for Health Workers 222 Papular rash, covering most of theface. PKDL inEthiopia PKDL inEthiopia.Various examples 223 PKDL inEthiopia.Various examples Papular rash. 224 119 2. PKDL in Africa: clinical presentation and differential diagnosis 120 The PKDL Atlas. A Manual for Health Workers PKDL inEthiopia PKDL inEthiopia.Various examples 226 Papular rash. 225 227 PKDL inEthiopia.Various examples Papular rash with plaques (228). 228 121 2. PKDL in Africa: clinical presentation and differential diagnosis 122 The PKDL Atlas. A Manual for Health Workers PKDL inEthiopia to form nodules(229); nodules confluent Papules confluent to form plaques (230, 231) PKDL inEthiopia.Various examples 231

230 229 Differential diagnosis 233 The lesionsresemble thoseof Kaposi’s sarcoma. The samestrain wasisolated from thespleenandfrom theskin. para-kala-azar dermalleishmaniasis. Subcutaneous nodularlesionsinanHIVco-infected VLpatient: Kaposi’s sarcoma inanHIV+ve patient. 234 232 123 2. PKDL in Africa: clinical presentation and differential diagnosis 124 The PKDL Atlas. A Manual for Health Workers PKDL inEthiopia 236 Differential diagnosis Diffuse CutaneousLeishmaniasis; thelesionshadbeen there for 3years andwere never treated. 235 and treated withzincointment (not anaccepted treatment for PKDL). Discoid LupusErythematosus. Thepatient wasinitiallydiagnosedasPKDL Differential diagnosis 237 125 2. PKDL in Africa: clinical presentation and differential diagnosis

3. PKDL in Asia: clinical presentation and differential diagnosis a. PKDL in India: hospital-based experience b. PKDL in Bangladesh: community-based experience

PKDL in Asia is much different from Africa. There are few longitudinal studies with active follow-up of VL cases and most reports are on cases that present with chronic PKDL. PKDL is increasingly reported from Bangladesh as more field studies are conducted. The interval between VL and PKDL is usually 2-3 years; however, patients may report a shorter interval. In one study with active follow-up 40% of cases developed PKDL within 12 months of VL.

Clinical presentation The currently available data do not permit a general description that is applicable to all areas (India, Bangladesh, Nepal); data from field studies are different from hospital –based studies; whether these differences are the result of patient delay, reporting bias or true differences related to parasite involved, genetic background, treatment received etc. is unknown. Hospital-based studies in India: The polymorphic form showing hypopigmented or erythematous macules with papules and/or nodules is the commonest. A monomorphic presentation with only papulonodules may be seen, the monomorphic form macular form being uncommon. Both of these monomorphic forms can mimic leprosy. In addition vitiligo is also an important differential diagnosis for macular PKDL. Verrucous lesions may be seen, though uncommon. A generalized redness of the face and body with scattered papules and plaques indicates the rare erythematous form of PKDL. Field studies in Bangladesh: The macular form is by far the most common presentation. While the face is usually involved the spread to other parts of the body does not always follow the classical pattern described for Sudan. Most cases in Bangladesh present with longstanding lesions that seem to spread and remain macular; sometimes concomitant papules may be found in the face. Up to 10% of cases present without a previous history of VL. In the Indian subcontinent all cases are treated as they are considered chronic cases also given the long interval after VL; while the skin returns to normal, repigmentation may take time and cannot be taken as a para- meter for cure. Other post-kala-azar manifestations have been described such as post-kala-azar uveitis. The main differential diagnosis for the macular form is vitiligo (Table 3) and for all forms leprosy (Table 4). 3. PKDL in Asia: clinical presentation and differential diagnosis and differential 3. PKDL in Asia: clinical presentation

129 130 The PKDL Atlas. A Manual for Health Workers 238 Macular lesionson thelegs. PKDL inIndia PKDL inIndia PKDL in India 3. PKDL in Asia: clinical presentation and differential diagnosis and differential 3. PKDL in Asia: clinical presentation 239 Macules and small papules. 131 132 The PKDL Atlas. A Manual for Health Workers PKDL inIndia Macules onarms and legs,butfacetrunkrelatively spared. 240

PKDL in India

241

Macules on limbs and face with some small papules on the nose. 3. PKDL in Asia: clinical presentation and differential diagnosis and differential 3. PKDL in Asia: clinical presentation 242 133 134 The PKDL Atlas. A Manual for Health Workers PKDL inIndia Nodules ontheface; maculesontherest of the bodywithvirtually total hypopigmentation sparingaxillae andinguinalareas. 243

PKDL in India

244 245 246

Hypopigmentation in the face with few papules/nodules; nearly total hypopigmentation of the back sparing the central area where some normal skin can be seen as irregular macules; lesions on the tongue and hypopigmentation of the hand palms.

247 3. PKDL in Asia: clinical presentation and differential diagnosis and differential 3. PKDL in Asia: clinical presentation

135 136 The PKDL Atlas. A Manual for Health Workers PKDL inIndia Hypopigmented patches intheface,typicallyaround themouth. 248 PKDL in India

249

Hypopigmented lesions involving the whole face sparing the neck; this is only appreciated in a lateral view. The lesions on the back spare the mid back and elbows (the arrow indicates the site of a biopsy). 3. PKDL in Asia: clinical presentation and differential diagnosis and differential 3. PKDL in Asia: clinical presentation 250 137 138 The PKDL Atlas. A Manual for Health Workers 251 penis andpapulesontipof glanspenis. Hypopigmentation of thethighswithnodularplaquesonscrotum, PKDL inIndia Macular lesionsininguinalarea, penisshaft andglans.

252 253 PKDL in India

254 PKDL: papules and nodules on inner thighs, scrotum and penis. 3. PKDL in Asia: clinical presentation and differential diagnosis and differential 3. PKDL in Asia: clinical presentation

139 140 The PKDL Atlas. A Manual for Health Workers 255 Papules andnodules on thetongue and buccal mucosa. PKDL inIndia sparing of theaxillae.Therest of thebodyisalsofaintly erythematous. 256 Erythrodermic PKDL.Thisisuncommon; there isfacialerythemaand PKDL in India

257 Papules and nodules on the tongue. 3. PKDL in Asia: clinical presentation and differential diagnosis and differential 3. PKDL in Asia: clinical presentation

141 142 The PKDL Atlas. A Manual for Health Workers chin andnose(260) crops of noduleson on chin(258,259); Discrete papules PKDL inIndia 258 260 259 PKDL in India

261 Verrucous or hypertrophic form. 3. PKDL in Asia: clinical presentation and differential diagnosis and differential 3. PKDL in Asia: clinical presentation

143 144 The PKDL Atlas. A Manual for Health Workers 263 262 PKDL inIndia Tumor-like nodulesonface(note sparingof eyebrows). Tumor-like; there isaspontaneous furrow. Differential diagnosis

264 Vitiligo. Note the total loss of pigment (depigmentation) 265 and the involvement of the central part of the trunk.

266 Lepromatous leprosy. 267 Lesions are prominent on the forehead and the cheeks while

the central part of the face is spared. The patient on the right diagnosis and differential 3. PKDL in Asia: clinical presentation has madarosis. All these are not features of PKDL. 145 146 The PKDL Atlas. A Manual for Health Workers Red, raised plaquesonthefaceandlimbs,note sparingareas around thenoseandmouth. PKDL inIndia Differential diagnosis Borderline leprosy. 268 Differential diagnosis

269 Borderline tuberculoid leprosy; the nose and chin are free; note the madarosis. 3. PKDL in Asia: clinical presentation and differential diagnosis and differential 3. PKDL in Asia: clinical presentation

147 148 The PKDL Atlas. A Manual for Health Workers PKDL inBangladesh PKDL inBangladesh Macular lesions. 270

PKDL in Bangladesh

271 Macular lesions. 3. PKDL in Asia: clinical presentation and differential diagnosis and differential 3. PKDL in Asia: clinical presentation 272 149 150 The PKDL Atlas. A Manual for Health Workers PKDL inBangladesh 274 273 Large areas of confluent maculesleaving someislandsof normalskin PKDL: macularlesions,someare confluent. PKDL in Bangladesh

275

Combined confluent macular lesions on the arms (275) and papulonodular lesions on the face (276). 3. PKDL in Asia: clinical presentation and differential diagnosis and differential 3. PKDL in Asia: clinical presentation 276 151 152 The PKDL Atlas. A Manual for Health Workers PKDL inBangladesh 278 little normalskin. on thebackandfaceleaving Extensive confluent macules 277 PKDL in Bangladesh

279 Extensive confluent macules on the back. 3. PKDL in Asia: clinical presentation and differential diagnosis and differential 3. PKDL in Asia: clinical presentation

153 154 The PKDL Atlas. A Manual for Health Workers PKDL inBangladesh 283 Mostly macularrash withpapularrash ontheshin. 280 284 282 281 PKDL in Bangladesh

285 diagnosis and differential 3. PKDL in Asia: clinical presentation Maculopapular rash. 155 156 The PKDL Atlas. A Manual for Health Workers PKDL inBangladesh 286 skin inparticularon Nodular rash with infiltration of the the nose. 287 PKDL in Bangladesh

288

Macular lesions on chest and nodular lesions on arms and fingers.

289 3. PKDL in Asia: clinical presentation and differential diagnosis and differential 3. PKDL in Asia: clinical presentation

157 158 The PKDL Atlas. A Manual for Health Workers 292 PKDL inBangladesh 290 or indicate treatment failure; for thelatter another diagnosisshouldalsobeconsidered. is difficultto assessiftheselesionswillfurtherheal,leave residual hypopigmentation patients thisleadsto cure within12months; inothers therash isslow to disappear. It treated withliposomalamphotericine B5mg/kgtwiceweekly for three weeks. Insome Figures 290-318:Inthissection,anumberof figures are shown of patients whowere Response to treatment response canbenoted. and after 6weeks; no Macular rash before 293 291 Response to treatment

294 295

Macular rash before and after 6 weeks, 4 months and 7 months; note the slow recovery (e.g. around the mouth).

296 297 3. PKDL in Asia: clinical presentation and differential diagnosis and differential 3. PKDL in Asia: clinical presentation

159 160 The PKDL Atlas. A Manual for Health Workers PKDL inBangladesh 300 298 Residual lesionscanbeseen10-11months after treatment (301). Response to treatment 301 302 299 Response to treatment

303 304

Almost complete disappearance of lesions 4 months after treatment 3. PKDL in Asia: clinical presentation and differential diagnosis and differential 3. PKDL in Asia: clinical presentation 305 161 162 The PKDL Atlas. A Manual for Health Workers PKDL inBangladesh 306 Response to treatment 308 treatment. 7 months after Good response 307 Response to treatment

309

Good response of nodular lesions 6 weeks after start of treatment. 3. PKDL in Asia: clinical presentation and differential diagnosis and differential 3. PKDL in Asia: clinical presentation 310 163 164 The PKDL Atlas. A Manual for Health Workers PKDL inBangladesh 311 Response to treatment 313 treatment. after start of lesions 5months Clear residual 312 Response to treatment

314

Poor response to treatment; lesions are virtually unchanged. 3. PKDL in Asia: clinical presentation and differential diagnosis and differential 3. PKDL in Asia: clinical presentation 315 165 166 The PKDL Atlas. A Manual for Health Workers PKDL inBangladesh 316 Response to treatment 318 start of treatment 9 months after the macularlesions disappearance of Gradual 317 Differential diagnosis

Table 6: Differential diagnosis of PKDL in Asia (most important) Macular rash Papulonodular Leprosy Leprosy Chronic arsenic poisoning Neurofibromatosis Pityriasis versicolor Secondary syphilis Vitiligo Pityriasis alba

Chronic arsenicosis. Hypopigmented and hyperpigmented lesions resembling PKDL. Common in Bangladesh; although epidemiologically the endemic areas do not overlap, this condition may be confused with PKDL. 319 3. PKDL in Asia: clinical presentation and differential diagnosis and differential 3. PKDL in Asia: clinical presentation

167 168 The PKDL Atlas. A Manual for Health Workers PKDL inBangladesh 321 complications are not seenin lentigo simplex (323).These arsenicosis: solarelastosis Complications of chronic carcinoma (321,322)and (320), squamouscell 320 chronic PKDL. Differential diagnosis 323 322 Differential diagnosis

324

Chronic arsenicosis Papulonodular lesions on lower limbs and warty hyperkeratotic lesions on the soles (324); psoriatic plaques on the right shin and palmoplantar warty hyperkeratosis (325). The presence of these lesions are useful to differentiate from PKDL. 3. PKDL in Asia: clinical presentation and differential diagnosis and differential 3. PKDL in Asia: clinical presentation 325 169

4. PKDL in other areas a. PKDL in China b. PKDL in Brazil

PKDL in China

326

Advanced nodular PKDL. The patients are from Taiwan but they contracted VL on mainland China. 327 328 4. PKDL in other areas 4. PKDL in other

173 174 The PKDL Atlas. A Manual for Health Workers was isolated from thebonemarrow. PKDL inBrazil Amastigotes were seeninabiopsy second episodeof VL; Presented withskinlesionsafter There were nofaciallesions;the 329 patient wasHIVnegative. from theskinlesions. PKDL from Brazil. L. infantum L. PKDL inBrazil 330

5. PKDL in immunocompromised patients and other skin manifestations of Leishmania in HIV-positive patients

PKDL may occur in immunocompromised patients; most cases have been described among HIV infected patients. Other conditions include bone marrow transplant patients and patients with immunosuppressive therapy. In HIV infected patients with VL, a variety of skin lesions has been described and these may occur before, during or after VL. They are sometimes referred to as atypical (disseminated) cutaneous lesions or diffuse cutaneous leishmaniasis in the course of VL, but these may basically be the result of the same pathophysiological mechanism that underlies PKDL: an immune reaction to Leishmania parasites in the skin with subsequent clinical manifestations. Although most evidence is anecdotal, one study found PKDL to be more common and more severe in patients who were HIV positive than in HIV negative patients. The clinical presentation and characteristics may differ from those found in immunocompetent patients; the most important differences are the atypical distribution and evolution and the abundance of parasites in mainly nodular lesions (Table 7).

Table 7: Differences between PKDL in immunocompetent and immunocompromised patients Immunocompetent Immunocompromised Parasite L. donovani mainly Also L. chagasi/ L. infantum Frequency (reference) more frequent, more severe Main clinical presentation macular or maculopapular nodular Other post KA manifestations yes, uveitis yes, uveitis Post or para KDL post>>para para>>post Parasites numbers scanty abundant Parasites found in skin <60% 90% Ulcerating no genital ulcers described Face affected the rule not always Acra involved no often; symmetrical Evolution typical atypical

Table 8: Clinical entities in HIV infection with disseminated cutaneous Leishmania lesions, parasites isolated and areas from where reported Disseminated cutaneous leishmaniasis without VL (history or present): L. tropica (India) L. chagasi / L. infantum (Nicaragua) Disseminated cutaneous lesions preceding VL: L. infantum (France) Disseminated cutaneous lesions with concomitant VL L. donovani (Ethiopia) L. infantum + L. donovani (Brazil) L. infantum (France) Disseminated cutaneous lesions after VL: L. donovani (Ethiopia) L. infantum (France, Italy, Greece) L. chagasi / L. infantum (Brazil) L. major (Burkina Faso) patients 5. PKDL in immunocompromised

177 PKDL inimmunocompromised patients 178 The PKDL Atlas. A Manual for Health Workers Mild papularrash inanHIV-positive patient from Spain,whohadmultiplerelapses. 331 L. infantum L. wasisolated from theskin. Nodules andplaquesinanHIV-positive patient.

332 PKDL in immunocompromised patients

PKDL in an Italian HIV patient a. At presentation; Leishmania PCR from a skin biopsy was positive. b. After 3 cycles of miltefosine. c. After liposomal amphotericine.

333

334 5. PKDL in immunocompromised patients 5. PKDL in immunocompromised 335 179 PKDL inimmunocompromised patients 180 The PKDL Atlas. A Manual for Health Workers 336 There isacompact inflammatory infiltrate ondeepdermisunderanormalepidermis Brazil. Cutaneous dissemination of visceral leishmaniasisinanHIV-positive patient from Leishmania 339 338 parasites were isolated inaspirates from bonemarrow andskin. (338; arrows); numerous amastigotes canbeseen(339,arrow). 337 PKDL in immunocompromised patients

340

PKDL in 2 HIV positive patients from Spain. Dermatomyositis-like presentation showing erythematous plaques with periungual erythema on dorsum of hands (340) and in the face particularly on the upper eyelids (341).

341

342 Diffuse infiltration around the nose. 5. PKDL in immunocompromised patients 5. PKDL in immunocompromised

181 PKDL inimmunocompromised patients 182 The PKDL Atlas. A Manual for Health Workers Amastigotes were demonstrated inspleenaspirate andslitskinsmear. HIV-positive withpapulesandnodulesintheface,abdomenextremities. Three patients from Ethiopia. found inaskinscraping. on thelower legs;amastigotes were sarcoma-like lesions HIV-positive andPKDLwithKaposi’s 348 345 343

346 demonstrated from bonemarrow andskin HIV-positive withamastigotes scrapings. 349 347 344 Disseminated cutaneous lesions and mucosal lesions in HIV infection without VL

350 351

352

353

Cutaneous and mucosal lesions in an HIV- positive patient from Bolivia; L. (V)

braziliensis was isolated from the skin. The ulceration shown (352, 353) is not a patients 5. PKDL in immunocompromised feature of PKDL. 183 PKDL inimmunocompromised patients 184 The PKDL Atlas. A Manual for Health Workers 354 showed amastigotes. There on thehands(354) on theindex finger are nodular lesions India withlow CD4 the left wrist and Two HIV-positive of theright hand from thelesions nose, dorsumof previous history in eachpatient plaques onthe of VL.Asmear counts andno and infiltrated patients from Leishmania (355). 355

lesions inHIVinfection withoutVL Disseminated cutaneouslesionsandmucosal Disseminated cutaneous lesions and mucosal lesions in HIV infection without VL

356 357 358

Diffuse cutaneous leishmaniasis in a patient who was HIV-positive patient for 8 years and on antiretroviral therapy. This patient was from Kerala, South India. There was no previous history of VL. Leishmania amastigotes were demonstrated in a smear. 5. PKDL in immunocompromised patients 5. PKDL in immunocompromised 359 185 PKDL inimmunocompromised patients 186 The PKDL Atlas. A Manual for Health Workers 360 lesions inHIVinfection withoutVL Disseminated cutaneouslesionsandmucosal 364 lesions dueto from IndiawithmultipleCL Three HIVpositive patients 363 362 L. tropica L. . 361 6. Other forms of leishmaniasis that resemble PKDL or that may be found in the same endemic area

Note The conditions shown do not necessarily overlap in epidemiology with PKDL.

Leishmanioma in Sudanese patients

365

The presence of leishmania parasites was confirmed by PCR (L. donovani) (367). The lesion cured spontaneously and a scar was seen 6 months later (368).

366 Other forms of leishmaniasis that resemble PKDL or that may be found in the same endemic area be found may PKDL or that resemble leishmaniasis that of Other forms 6.

189 190 The PKDL Atlas. A Manual for Health Workers Other forms Leishmanioma inSudanesepatients 367 368 in leishmanialPCR. lesion waspositive A smearfrom the close-up (368). PKDL (367); in apatient with Leishmanioma leishmanioma . Healed 369

Cutaneous leishmaniasis in three Sudanese patients

370 Erysipeloid infiltrative lesion of the nose and cheeks.

371 Note swelling, crusts and scales.

372 Facial lesion with cheilitis. Other forms of leishmaniasis that resemble PKDL or that may be found in the same endemic area be found may PKDL or that resemble leishmaniasis that of Other forms 6.

191 192 The PKDL Atlas. A Manual for Health Workers 373 Note thefaceisfree of lesions, Other forms which isunusualinPKDL. Multiple disseminated micro-nodular lesions. the pinnaof theear, showing crusting. leishmaniasis on Cutaneous leishmaniasis Cutaneous 374

(L. major) (L. from Sudan Cutaneous leishmaniasis (L. tropica) from Afghanistan

375

Clinical manifestations of CL showing various degrees of ulceration. Other forms of leishmaniasis that resemble PKDL or that may be found in the same endemic area be found may PKDL or that resemble leishmaniasis that of Other forms 6. 376 377 193 194 The PKDL Atlas. A Manual for Health Workers 380 Other forms Cutaneous leishmaniasis 378 (L. tropica) (L. Various degrees of ulceration (L. tropica) (L. in cutaneousleishmaniasis from Afghanistan from Afghanistan. Lupoid form. 379 381

Cutaneous leishmaniasis (L. aethiopica) from Ethiopia

382

CL due to L. aethiopica: diffuse infiltration of the skin

383 384 Other forms of leishmaniasis that resemble PKDL or that may be found in the same endemic area be found may PKDL or that resemble leishmaniasis that of Other forms 6. 385 195 196 The PKDL Atlas. A Manual for Health Workers 386 387 Other forms Leishmaniasis recidivans dueto Leishmaniasis recidivans L. aethiopica L. inEthiopianpatients. Leishmaniasis recidivans

388 Leishmaniasis recidivans due to (L. tropica) from Morocco. Note the healed scar from which new lesions develop. Other forms of leishmaniasis that resemble PKDL or that may be found in the same endemic area be found may PKDL or that resemble leishmaniasis that of Other forms 6.

197 198 The PKDL Atlas. A Manual for Health Workers 389 Other forms Leishmaniasis recidivans Leishmaniasis recidivans dueto Note thehealedscarsfrom whichnew lesionsdevelop. (L. tropica) (L. from Afghanistan. Leishmaniasis recidivans

390

391 Leishmaniasis recidivans due to L. tropica from Morocco (390,) and Afghanistan (391, 392).

392 Other forms of leishmaniasis that resemble PKDL or that may be found in the same endemic area be found may PKDL or that resemble leishmaniasis that of Other forms 6.

199 200 The PKDL Atlas. A Manual for Health Workers 393 Other forms not VLisendemic;there is from Ethiopia.Thepatient Highlands where CLand Leishmaniasis (DCL) parasites were found Diffuse Cutaneous originating from the no previous history of VL. in askinscraping. Diffuse Cutaneous Leishmaniasis Leishmania

395 394 Diffuse Cutaneous Leishmaniasis

396 Diffuse Cutaneous Leishmaniasis (DCL); Venezuela. 397

398 399

400 Other forms of leishmaniasis that resemble PKDL or that may be found in the same endemic area be found may PKDL or that resemble leishmaniasis that of Other forms

Diffuse Cutaneous Leishmaniasis 6. (DCL); Venezuela. 201 202 The PKDL Atlas. A Manual for Health Workers (DCL) inVenezuela by L. amazonensis L. leishmaniasis cutaneous Other forms is normally Diffuse 401 403 .

Diffuse Cutaneous Leishmaniasis 402 Diffuse Cutaneous Leishmaniasis

404

Diffuse cutaneous leishmaniasis; 405 Venezuela (see also Figs 357, 358 an 361 for comparison) Other forms of leishmaniasis that resemble PKDL or that may be found in the same endemic area be found may PKDL or that resemble leishmaniasis that of Other forms 6.

203 204 The PKDL Atlas. A Manual for Health Workers 407 and thegumsshouldbelooked for. Chronic ulceration of thenasalmucosa; previous history of VL.Lesions onthepalate Clinical clues: mucosal Mucosal leishmaniasis(Sudan).Fungating ortumour-like form. May beprimarily Before andafter treatment Other forms (L. major) (L. leishmaniasis (Sudan). with Pentostam®. orpost-kala-azar mucosal leishmaniasis Mucosal leishmaniasis Mucosal

(L. donovani). (L. 406 408 Leishmaniasis in tattoos

409

Cutaneous leishmaniasis in a tattoo due to L. infantum from Spain in an HIV –infected patient who had no previous history of CL or VL. The predilection for previous lesions or damaged skin is also a feature of PKDL (see Köbner’s phenomenon, Figs 186-189).

410

205

7. Literature

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22. Ramesh V, Singh N. A clinical and histopathological study of macular type of post-kala-azar dermal 7. Literature leishmaniasis. Tropical Doctor 1999;29:205-7. 209 210 The PKDL Atlas. A Manual for Health Workers 39. 38. 37. 36. 35. 34. 33. 32. 31. 30. 29. 28. 27. 26. 25. 24. 23. ICDDR,B HealthandScienceBulletin Vol. 5No.4December2007 (Formosa). Journalof theFormosan MedicalAssociation 1962;61:282-291. Morgan FM,Watten RH,Kuntz RE.Post-kala-azar dermalleishmaniasis.Acasereport from Taiwan and Leprology 2011;77:251. leishmaniasis andHIVco-infection: Report of three cases.IndianJournalof Dermatology, Venereology Soni P, Prasad N,Khandelwal K, Ghiya BC, Mehta RD,BumbRA,Salotra P. Unresponsive cutaneous Online Journal2009;15:9. Mehta V, Balachandran C, Rao R, Dil SK, Indusri L. Diffuse cutaneous leishmaniasis inHIV. Dermatology Bolivia. AmericanJournalof Tropical MedicineandHygiene 2009;81:555-8. Leishmania (Viannia) braziliensis and HIV: report of a case of mucosal leishmaniasis in Cochabamba, Torrico F, Parrado R,Castro R,Marquez CJ,Torrico MC,Solano M,Reithinger R,García AL. Co Infection of 2008;74:641-3. human immunodeficiency virus(HIV).IndianJournal of Dermatology, Venereology and Leprology Chaudhary RG, BilimoriaFE,Katare SK.Diffusecutaneousleishmaniasis: Co-infection with species. AmericanJournalof Tropical MedicineandHygiene 2011;85:55-9. immunodeficiency virus-positive patient simultaneouslyinfected bytwo viscerotropic Leishmania MP. Atypical lesions as asignof cutaneousdissemination of visceral leishmaniasisinahuman Santos-Oliveira JR,Da-CruzAM,Pires LH,CupolilloE,Kuhls K,Giacoia-Gripp CB,Oliveira-Neto 1996;35:316-9. as adermatomyositis-like eruption inAIDS.Journalof theAmericanAcademy of Dermatology Daudén E, Peñas PF, Rios L, Jimenez M, Fraga J, Alvar J, García-Diez A. Leishmaniasis presenting 2007;157:1032-6. Epub2007Sep13.Review. syndrome inapatient withacquired immunedeficiency syndrome. BritishJournal of Dermatology M, Meroni L.Post-kala-azar dermalleishmaniasisasanimmune reconstitution inflammatory Antinori S, Longhi E, Bestetti G, Piolini R, Acquaviva V, Foschi A, Trovati S, Parravicini C, Corbellino and uveitis inanHIV-positive patient. Infection 2008;36:184-6.Epub2008Mar10. Ramos A,CruzI,MuñezE,SalasC,FernándezAlvarez-Espejo T. Post-kala-azar dermalLeishmaniasis leishmaniasis (kala-azar) co-infection. Revistas Instituto Medico Tropical SaoPaulo. 2008;50:251-4. Roselino AM,Chociay MF, Costa RS,MachadoAA,Figueiredo JF. L.(L.)chagasiinAIDSandvisceral failure of oral miltefosine. AmericanJournalof Tropical MedicineandHygiene 2008;79:715-8. Kala-Azar dermalleishmaniasisinanHIV-1-infected woman: recovery after amphotericin Bfollowing Guffanti M,Gaiera G,Bossolasco S,Ceserani N,Ratti D,Cinque P, Salmaso F, Gianotti N,LazzarinA. Post- 2009;e504-7. Epub2009May 17. Leishmania (Leishmania) infantum chagasi:acasereport. International Journalof Infectious Diseases leishmaniasis similarto post-kala-azar dermalleishmaniasisinaBrazilian AIDSpatient infected with Carnaúba D Jr, Konishi CT, Petri V, Martinez IC,ShimizuL,Pereira-Chioccola VL.Atypical disseminated Series 2010;(949):xii-xiii,1-186. World HealthOrganization. Control of theleishmaniases.World HealthOrganization Technical Report A study of two cases.IndianJournalof Sexually Transmitted Diseases2010;31:42-4. Shah S,A,Prajapati S,BilimoriaF. Post-kala-azar dermalleishmaniasis inHIV-positive patients: of Dermatology 2010Oct;163(4):870-4.doi:10.1111/j.1365-2133.2010.09768.x. human immunodeficiency virus-positive patient onhighlyactive antiretroviral therapy. BritishJournal with ITS1sequencepolymorphismasacauseof para-kala-azar dermalleishmaniasisinanEthiopian Gelanew T, AmogneW,AbebeT, Kuhls K,HailuA,SchönianG.Aclinicalisolate of Leishmania donovani 2011;84:906-12. immunodeficiency syndrome inEthiopia.AmericanJournal of Tropical MedicineandHygiene three patients co-infected withvisceral leishmaniasisandhumanimmunodeficiency virus/acquired leishmaniasis resembling post-kala-azar dermalleishmaniasiscausedbyLeishmania donovani in Gelanew T, HurissaZ,Diro E,KassahunA,Kuhls K,SchönianG,HailuA.Disseminated cutaneous Literature 8. Acknowledgements/ List of contributors

Acknowledgements We are most grateful to all who generously contributed to this atlas. The Figures from Sudan were collected by the Leishmaniasis Research Group of the Institute of Endemic Diseases, Khartoum, under the leadership of Professor Ahmed Mohamed El-Hassan. We would like to express our sincere gratitude to all the patients who kindly consented to be photographed.

List of Contributors

Aditya P Dash José Angelo Lauletta Lindoso Vector-Borne and Neglected Rosimeire Silva Diseases, Tropical Diseases Control, Laboratório de Soroepidemiologia e WHO/SEARO, India Imunobiologia, Instituto de Medicina Figs 204, 205. Tropical de São Paulo - USP. São Paulo, Brazil Academic Medical Centre Figs 329-30. Department of Dermatology, Amsterdam, The Netherlands Rogelio López-Vélez Fig 149. Tropical Medicine & Clinical Parasitology. Infectious Diseases Philippe Desjeux Department. Ramon y Cajal Hospital, Formerly Senior program Officer, Madrid, Spain. PATH / OWH, Divonne, France Fig 331. Figs 227-31, 238, 248, 375-80, 386-9, 390-2. Médecins Sans Frontières-Holland Ermias Diro Amsterdam, the Netherlands Department of Internal Medicine, Figs 270-2, 277-85, 288-318. University of Gondar, Gondar, Ethiopia Wim van der Meijden Figs 220, 225-6, 235-6, 393-395. Dept of Dermatology, Erasmus MC Rotterdam, the Netherlands Abul Faiz Figs 152, 168, 171. Formerly of SSMC, Dhaka & Chittagong Medical College, Dhaka Damas Obvala Medical College, Dhaka University, Ministère de la Santé Publique, Ministry of Health. Dhaka, Brazzaville, Democratic Republic of Bangladesh Congo Figs 273, 275, 276, 319, 324-5. Figs 169, 170.

Tesfaye Gelanew Lluís Puig Institut fur Mikrobiologie Dept of Dermatology, Hospital de und Hygiene, Charité la Santa Creu i Sant Pau, Barcelona. Universitätsmedizin, Berlin, Germany; Spain CDC, Puerto Rico Fig 332. Figs 232, 343-349. contributors of /List 8. Acknowledgements

213 Acknowledgements/List of contributors 214 The PKDL Atlas. A Manual for Health Workers Figs 240-7,249-7,261-9. India Safdarjung Hospital.New Delhi, Department of Dermatology, V Ramesh Figs 320-3. Bangladesh Dhaka ShishuHospital,Dhaka, Child HealthResearch Foundation. Iftekhar Quasem The following figures were reproduced withpermissionfrom: Política Socialfor support. Recognition Isgiven to theFundación para laCooperación Internacional, Saludy – – Dermatology OnlineJournal2009;15:9.Figs357-60. 361-5. – IndianJournalof Dermatology, Venereology andLeprology 2011;77:251.Figs 355-6. – IndianJournalof Dermatology, Venereology andLeprology 2011;77:251.Figs – AmericanJournalof Tropical MedicineandHygiene 2009;81:555-8.Figs351-4. 50. – American Journal of Tropical Medicine and Hygiene 2011;84:906-12. Figs 344- – Journalof theAmericanAcademy of Dermatology 1996;35:316-9. Figs341-3. – AmericanJournalof Tropical MedicineandHygiene 2011;85:55-9.Fig337-40. – AmericanJournalof Tropical MedicineandHygiene 2008;79:715-8.Fig334-6. – Journalof theFormosan MedicalAssociation 1962;61:282-291.Fig328. – Tropical Doctor 2007;37:172-3.Figs250,251. – IndianJournalof Sexually Transmitted Diseases2010;31:42-4.Figs233 – – BritishJournalof Dermatology 2000;142:1-9.:Fig189. – Lancet Infectious Diseases2003;3:87-98:Figs51,63,66,190 – 52. Fig405. Transactions of theRoyal Society of Tropical MedicineandHygiene 1995;89:647- 1998;92:177-9. Fig202. Transactions of theRoyal Society of Tropical Medicine andHygiene, 193, 194,207,216,217,218,366,371-5,406,407. supplement 1:S59-S76.Figs:7,11,67,73,88,113,130,153,154,163,164, Transactions of theRoyal Society of Tropical Medicineand Hygiene 2001;95; Figs 174-5,396-405. MPPS. Caracas, Venezuela Instituto deBiomedicina,UCV. Olga Zerpa Figs 203,233-4. St Albans,UK TALC