Atypical disseminated leishmaniasis similar to post-kala-azar dermal leishmaniasis in a Brazilian AIDS patient infected with Leishmania (Leishmania) infantum chagasi: a case report

CASE REPORT

Atypical disseminated leishmaniasis similar to

post-kala-azar dermal leishmaniasis in a Brazilian AIDS

patient infected with

Leishmania (Leishmania)

infantum chagasi

: a case report

Dimas Carnau

´ba Jr

, Cassiana Tami Konishi

, Vale

´ria Petri

,

Isabel Cristina Pedro Martinez

, Laura Shimizu

,

Vera Lucia Pereira-Chioccola

*

a_{Centro de Refereˆncia em DST/AIDS de Santo Amaro, Sa˜o Paulo, SP, Brazil} b_{Universidade Federal de Sa˜o Paulo, Sa˜o Paulo, SP, Brazil}

c_{Hospital Ipiranga, Sa˜o Paulo, SP, Brazil}

d_{Laboratorio de Parasitologia, Instituto Adolfo Lutz, Av. Dr Arnaldo, 351, 8 andar, CEP 01246-000, Sa˜o Paulo, SP, Brazil}

Received 5 August 2008; received in revised form 14 January 2009; accepted 19 January 2009

Corresponding Editor:William Cameron, Ottawa, Canada

Introduction

Leishmaniases are endemic in 88 countries, 72 of which are developing countries. The worldwide prevalence of the dis-ease is estimated at 12 million cases, with 400 000—600 000 new cases per year for visceral forms.1,2_{In Brazil,}

approxi-mately 2500—5000 cases are reported each year.3

The genusLeishmaniacauses a wide spectrum of human diseases, ranging from self-limited cutaneous to the more severe diffuse cutaneous and visceral forms, as a conse-quence of the complex host immunological response.4,5

The causative agent of the American viscerotropic leishma-niasis in Latin-America isLeishmania (Leishmania) infantum chagasiincluded in the subgenusLeishmania.4,5

Despite some differences in cost of treatment, toxicity, drug resistance, and endemic region, treatment is usually based on the use of leishmanicidal drugs, principally injec-tions of pentavalent antimony compounds.1,2,4,6However, a significant proportion of the apparently cured

International Journal of Infectious Diseases (2009)13, e504—e507

http://intl.elsevierhealth.com/journals/ijid

KEYWORDS

Leishmania (Leishmania) infantum chagasi; AIDS;

Disseminated leishmaniasis

Summary We report the case of an atypical disseminated leishmaniasis with similar clinical characteristics to post-kala-azar dermal leishmaniasis, an uncommon disease in South America. This occurred in a Brazilian patient with AIDS, 3 years after the first episode of American visceral leishmaniasis.

#2009 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

* Corresponding author. Tel.: +55 11 3068 2991; fax: +55 11 3068 2890.

E-mail address:pchioccola@ial.sp.gov.br

(V.L. Pereira-Chioccola).

patients infected with Leishmania (Leishmania) donovani

in India, Nepal, Bangladesh, and East African countries develop post-kala-azar dermal leishmaniasis (PKDL).7_This

manifestation is a form of cutaneous leishmaniasis char-acterized by maculopapular or nodular lesions on the face, limbs or trunk, which appear after a symptom-free period following the end of visceral leishmaniasis treatment. The interval between kala-azar and PKDL is estimated as being months to years in India, but is considerably shorter in Africa (0—6 months).7—10 _{The association of Leishmania}

(Leishmania) infantum with PKDL is highly unusual in patients living in Europe11 _{and rarely present in}

patients infected with L. (L.) infantum chagasi in South America.12,13

Since the onset of the AIDS era, co-infection with HIV and leishmaniasis has become a high-priority emergent disease appearing throughout the world.2_{In Brazil, both infections}

are highly prevalent. In the past, both target populations were geographically separated. Currently, overlap appears because of the expansion of leishmaniasis into urban areas and of HIV infection into rural ones. Despite antiretroviral therapy, approximately 100 cases of this co-infection are reported per year in Brazil.14,15

Here, we report an AIDS patient with visceral leishma-niasis caused byL. (L.) infantum chagasi. After recurrence and the development of an atypical disseminated leishma-niasis with PKDL-like appearance of skin lesions, the patient died.

Case report

The case is that of a 42-year-old male who had migrated to Sao Paulo City, Brazil from Sa˜o Jose´ do Egito, Pernambuco, an area of Brazil endemic for visceral leishmaniasis, 27 years previously. He was found positive for HIV in1993 and had since undergone several different schedules of antiretroviral ther-apy. The overall clinical events, including CD4+ T cell counts, plasma viral load values, and treatments at each time period are shown inTable 1. Each event of antiretroviral therapy was made according to the guidelines of the previously estab-lished National Program of Sexual Diseases and AIDS of the Health Ministry of Brazil.16

Even on antiretroviral therapy, his CD4+ levels were found to have decreased and plasma viral load to have increased in May 2000. As a result, he had cerebral toxoplasmosis (July 2001) and hepatitis C (December 2002). In January 2004, his medication was again changed to stavudine, lamivudine and efavirenz because his CD4+ T cell count was decreased (144 cells/mm3_{) and his plasma viral load was 812 copies/ml. In}

November 2004 he was hospitalized after presenting with fever, weight loss, diarrhea, epistaxis, and hepatosplenome-galy (Figure 1A). The diagnosis of visceral leishmaniasis was confirmed due to the presence of amastigotes in the bone marrow aspirate. The specific leishmaniasis was treated with

N-methylglucamine antimonate (glucantime, 20 mg/kg/day) for 13 days, when he developed acute pancreatitis. At this time, the glucantime was replaced with liposomal

ampho-Table 1 Main clinical events

Period (month/year) Clinical event CD4+ T cell

count (cells/mm3₎

Plasma viral load (copies/ml)

Treatmenta

02/93 Positive for HIV/oral moniliasis 385 NA AZT

07/96 612 NA AZT/ddI

01/97 ddI intolerance 697 NA AZT/3TC

04/97 388 45 000 AZT/3TC

05/00 104 290 000 d4T/NVP/SQV

07/01 Cerebral toxoplasmosis 352 200 d4T/3TC/IDV/RTV

12/02 Hepatitis C 168 6860 d4T/3TC/SQV/RTV

01/04 144 812 d4T/3TC/EFV

11/04 Visceral leishmaniasisb

(hepatosplenomegaly/cachexia/ diarrhea/fever)

181 <400 d4T/3TC/EFV—glucantime,c amphotericin Bd

01/05 Ambulatory follow-up NA NA d4T/3TC/EFV—glucantime

05/05 Visceral leishmaniasis (second episode) (hepatosplenomegaly/cachexia/diarrhea/fever)

72 <400 d4T/3TC/EFV—glucantime

12/05 Visceral leishmaniasis (third episode)

(severe anemia/ epistaxis/hepatosplenomegaly)

NA NA d4T/3TC/EFV—liposomal

amphotericin

10/06 Visceral leishmaniasis (fourth episode) 78 831 d4T/3TC/ATV/RTV—

liposomal amphotericin

06/07 Multiple cutaneous lesions on face/thorax 66 <50 d4T/3TC/ATV/RTV

02/08 Death (visceral leishmaniasis) 09 <50 d4T/3TC/ATV/RTV

NA, not available; ATV, atazanavir; ddI, didanosine; EFV, efavirenz; IDV, indinavir; 3TC, lamivudine; NVP, nevirapine, RTV, ritonavir; SQV, saquinavir; d4T, stavudine; AZT, zidovudine.

a

Antiretroviral treatment was conducted as per the instructions established by the National Program of Sexual Diseases and AIDS of the Health Ministry of Brazil.

b_{Confirmed by bone marrow aspirate examination.} c_{For 13 days; developed acute pancreatitis.} d_{Treatment replaced.}

tericin B (50 mg/day for 3.2 weeks). After hospital discharge, in ambulatory follow-up, he took glucantime (81 mg) weekly. Over the course of two years he had three other recurrent episodes of visceral leishmaniasis (May 2005, December 2005, and October 2006) and was again treated with glucantime and liposomal amphotericin B. In October 2006, his antire-troviral therapy consisted of stavudine, lamivudine, ataza-navir and ritoataza-navir. His plasma viral load was becoming undetectable, but his CD4+ T cell count was still gradually decreasing (78 cells/mm3_{). In June 2007, his CD4+ T cell}

count was 66 cells/mm3_{when he developed multiple}

cuta-neous lesions on the face and thorax (Figure 1, C and D). Leishmania infection was also determined by the presence of amastigotes in histopathological examinations prepared from liver biopsies (Figure 1B) and skin lesions. The confirmation of American visceral leishmaniasis and species identification as

L. (L.) infantum chagasi were made by PCR as previously described.17 _{The RV1—RV2 marker amplified a 145-bp}

sequence from the LT1 fragment ofL. (L.) donovanicomplex kDNA minicircles18,19 _{(Figure 1E). He died of disseminated}

leishmaniasis in February 2008.

Discussion

Cutaneous manifestations ofLeishmaniaand HIV co-infection have been described in some patients having visceral leish-maniasis or as the only clinical manifestation of the disease. Cutaneous dissemination is generally observed among severely immunocompromised patients, and lesions tend to localize symmetrically.11,20_{In the present case, the patient}

developed visceral recurrent leishmaniasis, despite antire-troviral, liposomal amphotericin B, and glucantime

thera-pies. As a result, he developed an atypical disseminated leishmaniasis with PKDL-like appearance of skin lesions (non-itchy maculopapular erythematous lesions on the face and thorax).

The fact that the patient had a controlled viral load during the last five years, as determined in plasma, lead us to suppose that the antiretroviral therapy was efficient in accordance with the established guidelines.16 _However,

the low CD4+ T cell production was constant, suggesting a lack of immune function, and finally the patient died of disseminated visceral leishmaniasis.

As the incidence of HIV increases in areas in which Leish-mania species are endemic, visceral leishmaniasis is being recognized more frequently as an opportunistic infection in patients with AIDS. This case also emphasizes the potential use of PCR to confirm the diagnosis, forLeishmaniaspecies genotyping, and for clinical evaluation and follow-up of HIV patients undergoing antiretroviral therapy who have pre-viously had leishmaniasis or patients living in leishmaniasis endemic areas. In addition, atypical disseminated leishma-niasis with cutaneous lesions, similar to PKDL, should be considered in AIDS patients undergoing both antimony com-pound and antiretroviral treatment.

Conflict of interest:No conflict of interest to declare.

References

1. Desjeux P. Leishmaniasis: current situation and new perspec-tives.Comp Immunol Microbiol Infect Dis2004;27:305—18. 2. World Health Organization. Leishmaniasis; 2008. Available at:

http://www.who.int/tdr/diseases/leish/diseaseinfo.htm

(accessed March 2008).

Figure 1 Visceral leishmaniasis: clinical and histopathological diagnosis, and species genotyping by PCR. (A) Hepatosplenomegaly. (B) Histopathological examination of the liver biopsy revealing amastigotes and chronic inflammation (hematoxylin—eosin staining). Non-pruritic, erythematous maculopapular lesions on (C) face and (D) thorax. (E) Species genotyping by PCR; the RV1—RV2 marker amplified a 145-bp product from the LT1 fragment ofLeishmania donovanicomplex kDNA minicircles. The amplified PCR product was analyzed by electrophoresis on 2% agarose gel; lane 1, 100-bp ladder (the lowest band shown is 100 bp); lane 2, patient sample; lane 3, negative control.

3. Ministe´rio da Sau´de do Brasil (Health Ministry of Brazil). Manual de controle da leishmaniose visceral americana [American visc-eral leishmaniasis: surveillance and control. Technical manual]. Available at: http://portal.saude.gov.br/portal/arquivos/pdf/ manual_leish_visceral2006.pdf(accessed March 2008). 4. Grimaldi G, Tesh RB. Leishmaniasis of the New Word: current

concepts and implications for the future research.Clin Microbiol Rev1993;6_:230—50.

5. Lainson R, Shaw JJ. New world leishmaniasis. The neotropical

Leishmaniaspecies. In: Collier L, Balows A, Sussman M, editors. Topley and Wilson’s microbiology and microbial infectious dis-eases. 9th ed. Vol. 5. London: Arnold; 1998, p. 241—66. 6. Guerin PJ, Olliaro P, Sundar S, Boelaert M, Croft SL, Desjeux P,

et al.Visceral leishmaniasis: current status of control, diagnosis, and treatment, and a proposed research and development agenda.Lancet Infect Dis2002;2:494—501.

7. El Hassan AM, Ghalib HW, Zijlstra EE, Eltoum IA, Satti M, Ali MS,

et al.Post kala-azar dermal leishmaniasis in the Sudan: clinical features, pathology and treatment.Trans R Soc Trop Med Hyg 1992;86:245—8.

8. El Hassan AM, Khalil EA, El Sheikh EA, Zijlstra EE, Osman A, Ibrahim ME. Post kala-azar ocular leishmaniasis.Trans R Soc Trop Med Hyg1998;92:77—9.

9. Sundar S. Drug resistance in Indian visceral leishmaniasis.Trop Med Int Health2001;6:849—54.

10. Zijlstra EE, Musa AM, Khalil EA, EI-Hassan IM, EI-Hassan AM. Post kala-azar dermal leishmaniasis. Lancet Infect Dis 2003;3_: 87—98.

11. Antinori S, Longhi E, Bestetti G, Piolini R, Acquaviva V, Foschi A,

et al.Post-kala-azar dermal leishmaniasis as an immune recon-stitution inflammatory syndrome in a patient with acquired immune deficiency syndrome.Br J Dermatol2007;157:1032—6.

12. Bittencourt A, Silva N, Straatmann A, Nunes VL, Follador I, Badaro´ R. Post-kala-azar dermal leishmaniasis associated with AIDS.Braz J Infect Dis2003;7:229—33.

13. Moral L. Post-kala-azar dermal leishmaniasis and Leishmania infantum.Br J Dermatol1999;140:760.

14. Posada-Vergara MP, Lindoso JA, Tolezano JE, Pereira-Chioccola VL, Silva MV, Goto H. Tegumentary leishmaniasis as a manifesta-tion of immune reconstitumanifesta-tion inflammatory syndrome in 2 patients with AIDS.J Infect Dis2005;192_:1819—22.

15. Rabello A, Orsini M, Disch J. Leishmania/HIV co-infection in Brazil: an appraisal.Ann Trop Med Parasitol2003;97(Suppl 1):17—28. 16. Programa Nacional de DST/AIDS do Ministe´rio da Sau´de do Brasil.

Recomendac¸o˜es para terapia anti-retroviral em adultos infecta-dos pelo HIV, 2008 [National Program of Sexual Diseases and AIDS of the Health Ministry of Brazil; instructions for anti-retroviral therapy in infected adults, 2008. Technical manual]. Available at:http://www.aids.gov.br(accessed April 2009).

17. Gomes AH, Ferreira IM, Lima ML, Cunha EA, Garcia AS, Araujo MF,

et al.PCR identification of Leishmania in diagnosis and control of canine leishmaniasis.Vet Parasitol2007;144:234—41. 18. Lachaud L, Marchergui-Hammami S, Chabbert E, Dereure J,

Dedet JP, Bastien P. Comparison of six PCR methods using per-ipheral blood for detection of canine visceral leishmaniasis. J Clin Microbiol2002;40:210—5.

19. Ravel S, Cuny G, Reynes J, Veas F. A highly sensitive and rapid procedure for direct PCR detection ofLeishmania infantumwithin human peripheral blood mononuclear cells.Acta Trop1995;59_: 187—96.

20. Ridolfo AL, Gervasoni C, Antinori S, Pizzuto M, Santambrogio S, Trabattoni D,et al.Post-kala-azar dermal leishmaniasis during highly active antiretroviral therapy in an AIDS patient infected withLeishmania infantum.J Infect2000;40:199—202.