article: The skin disorder Post Kala-Azar Dermal Leishmaniasis (PKDL) occurs in up to 10% of patients treated for visceral leishmaniasis (VL) in India. The pathogenesis of PKDL is not yet fully understood. Cases have been reported in India following therapy with most available treatments, but rarely in those treated with liposomal amphotericin B (Ambisome). Between July 2007 and August 2012 with the support of the Rajendra Memorial Research Institute (RMRI), Médecins Sans Frontières (MSF) supported a VL treatment programme in Bihar, India—an area highly endemic for Leishmania donovani—in which 8749 patients received 20 mg/kg intravenous Ambisome as first-line treatment. This study describes the characteristics of patients who returned to the MSF supported treatment programme with PKDL. Over a 5-year period, Ambisome was administered to 8749 patients with laboratory-confirmed VL (clinical signs, rK39 positive, with/without parasite confirmation) in four intravenous doses of 5 mg/kg to a total of 20 mg/kg, with a high initial-cure rate (99. 3%) and low default rate (0. 3%). All patients received health education highlighting the possibility and symptoms of developing PKDL, and advice to return to the MSF programme if these symptoms developed. This is an observational retrospective cohort study of the programme outcomes. Of the 8311 patients completing treatment for their first episode of VL, 24 (0. 3%) returned passively to the programme complaining of symptoms subsequently confirmed as PKDL, diagnosed from clinical history, appearance consistent with PKDL, and slit-skin smear examination. Of the 24 patients, 89% had macular lesions, with a median time (interquartile range) to development of 1. 2 (0. 8–2. 2) years following treatment. Comparison of the demographic and clinical characteristics of the VL patients treated with Ambisome who later developed PKDL, with those of the remaining cohort did not identify any significant risk factors for PKDL. However, the time to developing PKDL was significantly shorter with Ambisome than in a subset of patients presenting to the programme with PKDL following previous sodium stibogluconate treatment for VL. In this large cohort of patients with VL in Bihar who were treated with 20 mg/kg Ambisome, PKDL following treatment appears to be infrequent with no predictive risk factors. The shorter median time to developing symptoms of PKDL compared with that after conventional VL treatments should be taken into account when counseling patients treated with regimens including Ambisome.
  The skin condition post Kala-azar dermal leishmaniasis (PKDL) usually develops following treatment for visceral leishmaniasis (VL), which is caused by the protozoa Leishmania donovani. Although cases of PKDL have been described in patients not previously diagnosed with or treated for VL, up to 10% of patients with VL in the Indian subcontinent go onto develop PKDL following treatment for symptomatic VL [1]. This proportion has been shown to be as high as 60% in Sudan [2] where, although the same species is responsible, the presentation of PKDL and its disease characteristics are different to that seen in the Indian subcontinent. Little is known about the cause, risk factors, and pathogenesis of PKDL although host factors [3], in vivo hybridization of parasites [4], and the possibility that PKDL is a drug-related phenomenon [5] have all been considered. In the Indian context particularly, the low incidence of PKDL makes prospective studies challenging. Traditionally, PKDL has been thought of as an important reservoir of L. donovani during intra-epidemic periods of VL, and may have been responsible for an epidemic of VL in an area of West Bengal [6]. Clarification of the potential transmissibility of different morphologies of PKDL remains an area of research priority [7]. Between July 2007 and August 2012, Médecins Sans Frontières (MSF), in coordination with the Rajendra Memorial Research Institute of Medical Sciences (RMRIMS; Patna, Bihar), the Bihar State Health Society, and the National Vector Borne Disease Control Programme of India treated 8311 patients diagnosed with a first episode of VL with 20 mg/kg intravenous liposomal amphotericin B (Ambisome; Gilead Pharmaceuticals, Foster City, CA, USA) as first-line treatment. Ambisome is a brand name for Liposomal Amphotericin B. There are a number of preparations of Liposomal Amphotericin B available on the market; however due to the lack of standard and widely applicable regulations or guidance for liposomal technology, it is important that this specific preparation be named. At time of publication, none of the rival preparations have undergone peer reviewed non-inferiority studies against Ambisome nor received stringent regulatory approval for use in VL. It is for this reason that MSF and the WHO currently only use Ambisome rather than other preparations. However it is urgent that clear regulatory guidelines for endemic countries be established by a normative setting organisation like the WHO and other existing formulations be formally evaluated [8]. This is the largest cohort of VL patients treated with Ambisome worldwide. Here, we describe the characteristics of patients who re-attended the programme with confirmed PKDL. As far as the authors are aware, to date PKDL has been described following all VL treatments, but so far in only 2 patients treated with Ambisome in the Indian context [9].
  This analysis met the Médecins Sans Frontières Institutional Ethics Review Committee' s criteria for a study involving the analysis of routinely collected programme data. Although a new treatment in the Indian setting, the programme utilised a recognised treatment for VL and was run in coordination with the State Health Society through a memorandum of understanding, which is the usual procedure for NGOs operating in this context. All electronic data were analysed anonymously.
  Over the 5-year period of analysis, 41 patients presented to the MSF programme with confirmed PKDL and a history of treatment with SSG for their original episode of VL (Table 2). The main differences between the post-Ambisome and post-SSG cohorts were time to onset/diagnosis of symptoms and lesion morphology. In patients with a history of SSG treatment, maculo-papular lesions were much more prevalent than in those treated with Ambisome, and the median time from treatment to onset of symptoms was significantly higher (2. 9 years for SSG vs 1. 2 years for Ambisome; p = 0. 002).
  PKDL remains a challenging condition from all perspectives. The causes of PKDL are likely to be multifactorial [10], but there is no detailed understanding of its pathogenesis. Until recently it was assumed that PKDL occurred only after treatment for VL, but there is increasing evidence that PKDL can occur during VL or even before any clinical manifestation [9], [11]. The lack of simple and accurate diagnostic tools exacerbates the situation, particularly in resource-challenged areas. Currently in Bihar the only feasible method of confirming the diagnosis of PKDL is microscopic demonstration of L. donovani amastigotes from skin tissue aspirates. A study carried out in India found that 7–33% of macular PKDL lesions show amastigotes compared with 67–100% of nodular lesions [12]. This is of particular concern because a substantial proportion of cases of PKDL in the Indian subcontinent appear to be of macular morphology [9], [13], [14]. Moreover, the frequency of macular lesions may be underestimated as they are probably less likely to cause patients to seek treatment than the more disfiguring nodular and polymorphic lesions. Assays based on polymerase chain reaction have shown promising results and are more widely available in Nepal and Bangladesh [13], but this useful diagnostic tool is not routinely accessible in Bihar. Recent studies have suggested that serum immunoglobulin G levels could prove to be a useful tool in monitoring polymorphic PKDL incidence [15]. However, it is also important to reflect that the exclusion of parasite negative patients may bias this and other epidemiological analysis, which focus mainly on parasitologically confirmed PKDL. The recent WHO manual on PKDL management and control accepts a clinical case definition for initiation of treatment, and only recommends parasitological or molecular conformation in case of unresponsiveness to treatment [7]. Considering the lack of field diagnostic confirmatory tools and the high proportion of macular morphology patients, the practice of excluding parasite negative ‘suspected’ PKDL cases may inadvertently undermine the validity of current research into PKDL. Several studies have described the characteristics of PKDL in the Indian subcontinent, but most are limited by small sample sizes and all describe patients mainly treated with SSG. Few studies have been able to identify any risk factors for developing PKDL. One retrospective cohort study in Nepal attempted to trace all patients who had received VL treatment in five endemic areas over a 10-year period to screen for PKDL. The study identified 2. 4% of patients (16 of 680) with probable or confirmed PKDL and suggested that unsupervised treatment and inadequate SSG treatment in the past were significantly associated with PKDL; however clinical markers were not examined [14]. In the present study, all patients completed treatment with Ambisome and after examining clinical and demographic features no significant risk factors were identified. The cohort of patients with VL described in the present study is the largest worldwide to date to have been treated with Ambisome, and comprises an estimated 5. 8% of all reported VL cases in India between 2008 and 2011 [16]. Although clearly limited by passive re-attendance of patients with PKDL to the MSF programme, the regular arrival of patients with no history of contact with the programme suggests that the active community IEC strategy had some success in raising awareness and identifying PKDL cases in the wider community. A particular strength of this study is the robust database that has been maintained throughout the programme and has minimal missing data. However, there are several limitations, which mean caution must be taking in interpreting the data. Despite comprehensive patient education during treatment, reliance on passive re-attendance by patients means that the recorded incidence of PKDL following treatment is very likely to be an underestimate. Additionally, the variability in time from VL treatment to presentation with PKDL makes the interpretation of incidence more difficult. For example, most SSG-treated patients present with PKDL >3 years following treatment, and as this period post-treatment has yet to elapse for most of the cohort treated with Ambisome, there remains the possibility of a biphasic incidence curve which could show a further peak after an increased period of follow-up. Also, the lack of sensitive diagnostic tools meant that the primary analysis was only determined for those patients with confirmed PKDL, excluding probable cases of PKDL. Finally, for the patients with PKDL who presented following treatment with SSG, it was not possible to confirm the accuracy of patient-reported timing of treatment and onset of symptoms. It is worth emphasizing that the present analysis reflects a minimum estimate of PKDL incidence following treatment with 20 mg/kg Ambisome in Bihar. The incidence (0. 3%) of confirmed PKDL cases found in the present study of primary VL patients is lower than that reported following treatment with mostly SSG in India [1] and Nepal [14], and much lower than what has been reported in Bangladesh [11]. The difference in incidence of PKDL within the subcontinent countries, despite the same pathogen and treatment histories, is of interest and worthy of further research. Indeed, the experience of MSF in Bangladesh has suggested that an estimated 10% of patients with VL proceed to develop PKDL after treatment with intravenous Ambisome 15 mg/kg, although this estimate includes probable cases and was based on active case detection (K. Ritmeijer, personal communication). Most (>85%) patients with confirmed or suspected PKDL in the present study showed exclusively macular morphology, whereas in previous reports from India the proportion of patients with macular PKDL lesions following treatment with more established drugs has been estimated as 23% [17] and 48% [9]. This could be as a consequence of treatment with Ambisome, however the pattern is similar to that described in Bangladesh and Nepal [13], [14]. This might be explained by increased identification of ‘milder’ cases of PKDL through IEC at the community level - cases that may not have otherwise presented to health providers. Alternatively, it is possible that the development of PKDL following treatment with Ambisome is more likely to be of macular morphology, which could in turn be associated with a lower risk of transmission. If true, Ambisome could be considered a better therapeutic option considering the ultimate aim of disease elimination. A particular area of difference between treatment with Ambisome and treatment with SSG was the median post-treatment time-to-onset of PKDL. At 1. 2 years with Ambisome, this period appears much shorter than seen both in our comparison analysis with SSG-treated patients and than that reported from other studies. SSG and conventional amphotericin B are strong immunomodulators [18], [19], whilst Ambisome is thought to have additional capacity in down-regulating disease promoting suppressive cytokines [20]. Considering these results, immunoprofiling of patients following treatment with Ambisome may be helpful in identifying other risk factors of potential importance in the development of PKDL. Meanwhile, the WHO recommendation of a 10 mg single-dose liposomal amphotericin B dose and lower-dose combination therapies for the treatment of patients with VL in the Indian subcontinent [21] increases the importance of educating patients and monitoring outcomes with regards to PKDL. In conclusion, this study demonstrates that in the Indian context, the development of PKDL following treatment for VL with 20 mg/kg liposomal amphotericin B (Ambisome) is a possibility. We suggest that it occurs after shorter time periods than might have been expected, although no risk factors for its development were identified.
summary: Visceral leishmaniasis (VL), also known as Kala-azar, is caused by the parasite L. donovani. Half of cases worldwide occur in India, with up to 90% of these in Bihar state. Post Kala-azar dermal leishmaniasis (PKDL) is a difficult to treat skin condition that develops in up to 10% of VL cases following treatment in the Indian subcontinent. Although often mild, PKDL can be severe and disfiguring. Patients are otherwise healthy. PKDL is considered a reservoir of L. donovani and requires treating to support disease elimination. Between 2007–2012,8311 patients diagnosed with a first episode of VL completed treatment with 20 mg/kg intravenous liposomal amphotericin B (Ambisome) in a Médecins Sans Frontières (MSF) programme supported by the Rajendra Memorial Research Institute (RMRI) in Bihar. Ambisome is a safe and effective treatment that is recommended by the WHO for first-line use in the Indian subcontinent; although not yet included in the Indian guidelines. PKDL has been described following all VL treatments, but so far in only two patients treated with Ambisome. Here, we describe 24 patients treated with Ambisome who returned to the MSF treatment programme with confirmed PKDL. We found no risk factors for PKDL following treatment; however, the average time to development of PKDL was much shorter than that seen following older treatments.
keywords: medicine
  dermatology
  infectious diseases
  leishmaniasis
  neglected tropical diseases
  parasitic diseases
title: Post Kala-Azar Dermal Leishmaniasis following Treatment with 20 mg/kg Liposomal Amphotericin B (Ambisome) for Primary Visceral Leishmaniasis in Bihar, India