Visceral leishmaniasis (VL) is common in South America and 90% of cases occur in Brazil. The main vector is Lutzomyia longipalpis and canines function as the main reservoir1. In recent years, the disease has spread to all regions and emerged in urban areas2. In Latin America, cutaneous manifestations in leishmaniasis are related to Leishmania from the subgenus Viannia3; however, there are reports of cutaneous lesions similar to those observed in post-kala-azar dermal leishmaniasis (PKDL), caused by Leishmania infantum, mainly in human immunodeficiency virus (HIV)-infected patients4,5. In addition, L. infantum can cause atypical cutaneous leishmaniasis in Central America unrelated to VL6. Here, we describe an HIV-negative patient with VL with an unusual clinical course and outcome, in which a relapse of VL was accompanied by a PKDL-like skin rash.
A 36-year-old farmer presented at the Public General Hospital in Santos City because of fever. He was born in the city of Sao Vicente in South-East Brazil. He reported that he had worked in Joao Pessoa, Paraíba, North-East Brazil, an endemic area for VL, from 2000 to 2006. During that time, his dog became ill and died. He first presented in November 2006 with a long history of daily fever, headache, general weakness, and dizziness, and he reported to have lost weight (18kg in the last 3 months). His weight at the time of admission was 53kg. Hepatosplenomegaly was noted on physical examination. VL was suspected and confirmed by a bone marrow aspirate that showed Leishmania amastigotes. HIV test results were negative. He was treated with meglumine antimoniate (Glucantime) intramuscular (IM) in a dose of 20mg/kg/day for 28 days with positive clinical response.
He did not return for follow-up but presented in January 2008 with a (clinically diagnosed) relapse and was treated with two cycles of Abelcet (amphotericin B lipid complex) daily (1mg/kg/day) for 20 days followed by two cycles of glucantime (20mg/kg/day for 28 days) combined with Abelcet (1mg/kg/day). In March 2008, he was admitted to the Institute of Infectology Emilio Ribas at São Paulo with fever and hepatosplenomegaly; a second relapse of VL was suspected. Anti-leishmania antibodies were demonstrated in the immunofluorescence test (immunoglobulin (Ig)G 1:160) and enzyme-linked immunosorbent assay (ELISA) (IgG 1: 1280); the Montenegro test results were negative. He was treated according to the National Guidelines for treatment of VL with liposomal amphotericin B (LAmb) (3 mg/kg once daily for 7 days) and exhibited a positive clinical response.
Five months later, he developed diarrhea and vomiting and he had lost 5 kg of weight. On physical examination, he was dehydrated, and his weight was 48 kg. In addition, on the skin of the chest and abdomen, erythematous macules and papules (diameter 0.5-1.0cm) were noted (Figure 1A and Figure 1B). He was re-admitted to the hospital and received intravenous (IV) fluid replacement. A bone marrow aspirate showed numerous Leishmaniaamastigotes; in addition, a skin biopsy demonstrated an inflammatory process characterized by numerous small, oval, plasmacytoid structures indicative of infection by Leishmania sp. Additionally, on the surface, the epidermis was thin, with fibrosis of the papillary dermis.
The immunofluorescence test for Leishmania showed an IgG titer of 1:64, whereas in the ELISA, the IgG titer was 1:320. Treatment was initiated with amphotericin B deoxycholate (50 mg/day for 4 days), followed by LAmb (3 mg/kg for 10 days), with positive response.
Laboratory investigations showed negative results for antibodies against HIV, human T-cell lymphotropic virus (HTLV)-1 and -2, T. cruzi, and hepatitis A. IgG antibodies were found against cytomegalovirus (CMV) and toxoplasma. The IgM ELISA results for schistosomiasis were positive. Immunological assessment revealed the following: cluster of differentiation CD4+count , 777 cells/mm3; CD8+count, 633 cells/mm3; and CD4/CD8 ratio: 1.23. Lymphocyte proliferation tests showed proliferation on stimulation with Leishmania and Toxoplasmaantigen. Proliferative responses against mitogens were normal.
Secondary prophylaxis was suggested, but he did not return for follow-up. Ten months later, he presented with fever and cervical lymphadenopathy that initiated 20 days earlier; a cervical lymph node biopsy showed its architecture replaced by hard granulomas without central necrosis and rare giant cells. In addition, in the macrophages, a large amount of Leishmania sp. was observed.
There was no evidence for hepatosplenomegaly. He was treated with LAmb 4 mg/kg/day for 7 days and secondary prophylaxis was initiated with pentavalent antimonial (IV or IM) (850 mg every 28 days), after which he remained well during 9 months of follow-up. To better characterize treatment response observed after treatment and secondary prophylaxis, we measured anti-Leishmania antibody titers using ELISA and indirect immunofluorescence (IFI), using Leishmania major-like total antigen; decreases in titers were observed 6 and 16 months post-treatment (Figure 2).
In this patient, inflammatory processes associated with fibrosis from papillary dermis with the presence of Leishmania was observed in cutaneous lesions. In macular lesions of PKDL, chronic inflammation is characterized by infiltrates of histiocytes, lymphocytes, and a few plasma cells, and Leishmania is also observed10. However, there are no consistent of infiltrates in PKDL lesions. The clinical manifestations of PKDL are immunologically mediated with features of a Th2 response in the skin and a systemic Th1 response, resulting in skin abnormalities in patients who are otherwise well without features of systemic leishmanial infection5–10,11. In this patient, the clinical progression from visceral disease with subsequent relapses to para-kala-azar dermal leishmaniasis and later isolated (post-kala-azar) lymphadenopathy without obvious clinical evidence of visceral disease suggests a similarly developing, but abnormal and inadequate systemic immune response11–13. In immunosuppressed patients, in particular those who are HIVinfected, relapses are common, as some degree of developing antileishmanial immunity is needed to prevent a relapse of VL. With each relapse, the treatment becomes more difficult5. This patient had a similar clinical syndrome, which justified the decision for maintenance treatment that to date seemed to be successful. There is no consensus regarding the preferred regimen; single-dose administration of pentavalent antimonial, Lamb (AmBisome ©) or pentamidine has been used, often in cycles of 3-4 weeks.
This case illustrates the need for follow-up of patients with VL, in particular to monitor for PKDL or para-kala-azar dermal leishmaniasis as experience elsewhere indicates that as the rash often remains unnoticed and self-cures, these patients often do not report to the clinic and may play a role in transmission.