Post-kala-azar dermal leishmaniasis: recent developments

A substantial number of patients who recover from kala-azar will develop dermatosis [commonly known as post-kala-azar dermal leishmaniasis (PKDL)]. It usually occurs in the Indian subcontinent and East Africa. As many as 10-20% of Indian cases and 50-60% of Sudanese cases develop PKDL after successful treatment of visceral leishmaniasis. Most cases occur after infection with Leishmania donovani and less commonly after Leishmania infantum. However, the PKDL is extremely rare in patients infected with Leishmania chagasi. Though exact pathology is not yet fully known, here we review various evidence, which suggest that the pathogenesis is largely immunologically mediated. Our group has been of the opinion that PKDL disease manifestation is a result of in-vivo generation of quasi-species either as in-vivo hybridization of various circulating and latent populations of the causative species within the host cells or due to external reinfection. We, and other scientists, have recently demonstrated that strains of Leishmania that cause visceral diseases differ genetically from those that cause PKDL. We feel that this review will incite interest in several parasitologists and molecular biologists in the pathogenesis of this important manifestation of the infection, often blamed as the source of outbreaks of leishmaniasis.     

Post-kala-azar dermal leishmaniasis as an immune reconstitution inflammatory syndrome in a patient with acquired immune deficiency syndrome

Post-kala-azar dermal leishmaniasis (PKDL) is a complication of visceral leishmaniasis (VL) observed mainly in Sudan and India where it follows treated VL in 50% and 10% of cases, respectively. We report a 46-year-old patient with acquired immune deficiency syndrome who, 7 months after diagnosis of VL, developed PKDL and uveal leishmaniasis following HAART-induced immune recovery. In southern Europe PKDL seems to be an emerging clinical presentation among human immunodeficiency virus (HIV)-infected patients experiencing HAART-induced immune recovery after a previous diagnosis of VL. The best treatment among HIV-infected patients remains to be determined.     

Post-kala-azar dermal leishmaniasis in Nepal

BACKGROUND: Post-kala-azar dermal leishmaniasis (PKDL) manifests as a skin eruption after healing of visceral leishmaniasis (VL), either spontaneously or as a result of treatment. This study was undertaken to describe the demographic, clinical, and histopathologic features of PKDL in Nepal. METHODS: Demographic, clinical, microbiologic, and histopathologic features and response to treatment were studied in 22 patients with PKDL from April 1998 to March 2000. RESULTS: PKDL accounted for 0.13% of all new dermatologic cases. There were 13 (59.1%) males and nine (40.9%) females. A past history of kala-azar was present in all but one patient. A family history of kala-azar was noted in eight (36.4%) patients. All patients presented with multiple types of lesion, except for two in whom only macular lesions were seen. Oral lesions in the form of nodules and plaques were seen in four patients. Generalized lymphadenopathy was present in five patients. Slit skin smears revealed Leishman-Donovan bodies (LDBs) in nine (40.9%) patients. In macular lesions, there was a sparse infiltrate of plasma cells, lymphocytes, or histiocytes in the upper dermis. There was a dense chronic inflammatory infiltrate comprising plasma cells, lymphocytes, histiocytes, and epithelioid cells in the entire dermis from papules, plaques, or nodules. Giemsa staining of biopsy specimens revealed LDBs in seven (38.9%) patients only. Fine needle aspiration from epitrochlear lymph nodes in two patients demonstrated LDBs. All patients responded well to treatment with minimal side-effects. CONCLUSIONS: This study emphasizes the need to be aware of the possibility of cases of PKDL in endemic regions of leprosy, as the conditions may be difficult to distinguish clinically and histopathologically.     

POST-KALA-AZAR DERMAL LEISHMANIASIS IN THE SUDAN: PERIPHERAL NEURAL INVOLVEMENT

Four patients developed post-kala-azar dermal leishmaniasis and neuritis (PKDL) 1 to 6 months following apparently successful treatment of kala-azar. The duration of the lesion varied between 1 month and nearly 5 years. The lesions were macules, papules, or nodules affecting the face, extremities, and trunk. The diagnosis was made by demonstration of the parasite in slit smear and biopsies and by a positive direct agglutination test (DAT). Histologically, the patients were found to have neuritis affecting the cutaneous nerves in the lesion only. The nerves showed a lymphohistiocytic infiltration and occasionally parasites. There was no impairment of sensation. Response to sodium stibogluconate was good. PKDL may simulate leprosy both clinically and pathologically.     

Post-kala-azar dermal leishmaniasis--an overview

Post-kala-azar dermal leishmaniasis (PKDL) is a dermal sequela of visceral leishmaniasis (VL), reported mainly from two regions - Sudan in eastern Africa and the Indian subcontinent, with incidences of 50-60% and 5-10%, respectively. Importantly, patients with PKDL are considered as reservoirs of VL, linking its eradication to effective control of PKDL. The etiopathogenesis of PKDL is presumably due to an immunological assault on latent dermal parasites. Immunological markers include IL-10, whose expression in skin and plasma of Sudanese patients with VL predicted onset of PKDL. Cell-mediated immune responses, notably restoration of IFN-γ production by antigen-stimulated lymphocytes are well documented in Sudanese PKDL, but remain ambiguous in the Indian form; recently, antigen-specific IL-10-producing CD8+ lymphocytes have been implicated in pathogenesis. In Indian PKDL, upregulation of intralesional IFN-γ and TNF-α is counterbalanced by IL-10 and TGF-β together with downregulated IFN-γ R1. Although IL-10 curtails excessive IFN-γ-mediated reactivity and ensures parasite survival, its cellular source remains to be confirmed, with infiltrating regulatory T cells (Tregs) being a likely candidate. Future functional investigations on Tregs and their interaction with lesional effector lymphocytes would be indispensable for development of immunomodulatory therapies against Leishmania infection.     

Post-kala-azar dermal leishmaniasis: A light and electron microscopic study of 18 cases

Post-kala-azar dermal leishmaniasis (PKDL) is caused by the protozoan parasite, Leishmania donovani , and is seen in patients with history of having been treated earlier for the visceral disease form, kala-azar, caused by the same organism. The findings from 18 patients with PKDL are described in this study. The skin manifestations ranged from hypopigmented macules to infiltrated plaques and nodules. Histopathologic examination revealed a cellular infiltrate of lymphocytes, plasma cells, and macrophages. The macrophages were scattered amidst the infiltrate without any localization. In hypopigmented lesions, the infiltrate was confined to the perivascular region in the superficial dermis and was composed mainly of lymphocytes and few plasma cells. In the nodular lesions, the infiltrate occupied the entire thickness of the dermis. Leishman-Donovan bodies were scarce and identified in 16 cases after a prolonged search of Weigert's iron hematoxylin-stained sections. In 2 cases, Leishman-Donovan bodies were not demonstrable. Electronmicroscopic study revealed parasitized macrophages which showed no structural evidence of activation despite the active cellular response around them. The fine structure of the parasites in the histiocytes was also well maintained. This unusual tropical dermatosis is a unique example of change in organotropism of a parasite associated with a change in the host response.     

Identification of parasite antigen, correlation of parasite density and inflammation in skin lesions of post kala-azar dermal leishmaniasis

BACKGROUND: Post kala-azar dermal leishmaniasis (PKDL) is an unusual dermatosis following kala-azar (KA). Demonstration of the amastigotes in lesions plays an important role in the diagnosis of PKDL. It was aimed to evaluate the utility of an antibody G2D10 in detecting leishmania parasite antigen, to correlate the parasite number/percentage of parasites with the inflammation, and to assess the epidemiological significance associated with the location of the parasites. MATERIAL AND METHODS: The study was conducted on 50 cases. Hematoxylin and eosin (H & E) stains and immunohistochemical (IHC) stains, using G2D10 antibody, was performed on the skin biopsies. The number of parasites and density of inflammation were semiquantitatively assessed. RESULTS: Leishmania donovan bodies (LDBs) were identified in 50% of cases with the H & E compared to 80% positivity with the IHC. All 50 cases showed inflammation in the superficial dermis (SD). About 44% showed dense inflammation compared to 16% sparse and 40% moderate inflammation. Parasite percentage was maximum in the SD (100%) compared to 75 and 42% in the mid and deep dermis, respectively. CONCLUSIONS: The IHC showed a higher percentage of LDB localization (80 vs. 50%). Density of inflammation was maximum in the SD. The parasite percentage was correlated with the inflammation. Location of parasites could have an epidemiological significance.     

Decreased presence of Langerhans cells is a critical determinant for Indian Post kala‐azar dermal leishmaniasis

Post kala‐azar dermal leishmaniasis (PKDL) is the dermal sequel of visceral leishmaniasis (VL) and occurs after apparent cure or alongside with VL. It is confined to South Asia (India, Nepal and Bangladesh) and East Africa (mainly Sudan), the incidence being 5‐10% and 50‐60% respectively. In South Asia, as the transmission of VL is anthroponotic, PKDL patients are the proposed disease reservoir, thus assuming epidemiological significance, its eradication being linked to the control of leishmaniasis. In the absence of an animal model and its low incidence, factors contributing towards the immunopathogenesis of PKDL remain an open‐ended, yet pertinent question. This study delineated the lesional immunopathology in terms of granuloma formation, Langerhans cells, tissue macrophages along with mRNA expression of IL‐12p40 and IL‐10. Our study in Indian PKDL for the first time identified that the number of CD1a⁺/CD207⁺ Langerhans cells are decreased and CD68⁺ macrophages are increased along with the absence of an epitheloid granuloma. Importantly, this decrease in Langerhans cells was associated with decreased mRNA expression of IL‐12p40 and increased IL‐10. This was reverted with treatment allowing for elimination of parasites and disease resolution along with an increase in Langerhans cells and decrease in macrophages. Thus, in Indian PKDL, absence of a granuloma formation along with a decrease in Langerhans cells collectively caused immune inactivation essential for parasite persistence and disease sustenance.     

Post-kala-azar Dermal Leishmaniasis Developing in Miltefosine-Treated Visceral Leishmaniasis

Post-kala-azar dermal leishmaniasis (PKDL) is an unusual dermatosis occurring following an attack of visceral leishmaniasis (VL). There are only few reports of PKDL after successful treatment with miltefosine. We report two cases of PKDL that developed after successful treatment of VL with miltefosine.     

Miltefosine as an effective choice in the treatment of post-kala-azar dermal leishmaniasis

Background Post‐kala‐azar dermal leishmaniasis (PKDL) constitutes a parasite reservoir important in the transmission of visceral leishmaniasis (VL). Unacceptable treatment regimens and increasing drug resistance blight control programmes. The success of oral miltefosine in VL prompted a clinical, histopathological and parasitological study of this drug in PKDL. Objectives To define the dose and duration of miltefosine for treatment of PKDL. Methods Twenty‐six patients confirmed by slit‐skin smear, histopathology and molecular tests were enrolled in the study. They received miltefosine capsules 50 mg thrice daily after food. Treatment was for 60 days with a provision to increase by 30 days if a responder had not attained a cure. Cure was ascertained by clinical and histopathological examination, and measuring parasite burden using real‐time polymerase chain reaction. Results Twenty‐four patients with a wide range of parasite burden completed the study. Twenty‐three achieved a cure giving an initial cure rate of 96% (95% confidence interval 79–99%). Sixteen patients were cured with 50 mg thrice daily, 13 in 60 days and three within 90 days. In seven cases, miltefosine had to be reduced, because of gastrointestinal intolerance, to 50 mg twice daily to a total of 180 capsules. Lesional parasites were undetectable at 1 month post‐treatment. Treatment was safe with no relapses at 1‐year follow‐up. Conclusion Oral miltefosine, 50 mg thrice daily for 60 days or twice daily for 90 days, could be an effective treatment for PKDL.