Visceral leishmaniasis (kala-azar)--the Bihar (India) perspective

From a hospital-based surveillance carried out in Rajendra Memorial Research Institute of Medical Sciences, Patna, Bihar, India, the socio-economic, demographic and treatment response information of 737 patients admitted with visceral leishmaniasis (VL) during January 2001-December 2003, were analysed. The disease was two times higher in males than in females because of several factors including clothing pattern, sleeping habits and occupation. In Bihar, the second poorest state in India, poverty plays a major role in perpetuation of the disease, contributing to malnutrition, illiteracy (60%), and poor housing (82%). Further, presences of peri-domestic animal shelters around houses (63%) and vegetations (77%) facilitate breeding of sand fly vector. Clinical and laboratory characteristics were similar in the age groups <12 years and >12 years. The increasing unresponsiveness of VL patients to conventional anti-leishmanial drugs, e.g. sodium antimony gluconate (SAG) and pentamidine, has definitely posed a major therapeutic challenge in combating the disease. Amphotericin B, though costly, is highly effective. Miltefosine is a highly promising new oral drug for VL.     

Visceral leishmaniasis (kala-azar) in solid organ transplantation: report of five cases and review.

Visceral leishmaniasis is an infectious disease that occurs only rarely in recipients of solid organ grafts but is associated with an elevated mortality rate despite proper treatment. We report five cases diagnosed in our hospital. All the patients were men aged 30 to 60 years who had undergone kidney transplantation (3 patients), heart transplantation (1), or liver transplantation (1). Three of the patients died, one had multiple recurrences, and one developed post-kala-azar cutaneous leishmaniasis. We review the clinical features, treatments, and outcomes of 26 previously reported cases, pointing out the lower cure rate associated with human immunodeficiency virus infection.     

Visceral leishmaniasis (kala-azar) as an opportunistic infection in patients infected with the human immunodeficiency virus in Spain

In an area endemic for visceral leishmaniasis, 16 patients with human immunodeficiency virus (HIV) infection developed the disease. All belonged to populations at risk for AIDS (15 were intravenous drug abusers). Five patients fulfilled the criteria for full-blown AIDS, and two more fulfilled them after diagnosis of leishmaniasis. All presented with the classic manifestations of visceral leishmaniasis, but leishmania serology was negative in 15 patients (93%). Leishmania donovani amastigotes were identified in the bone marrow in all cases. Most patients responded initially to treatment with pentavalent antimonial drugs, but seven (43%) followed a chronic course, with multiple relapses in five, despite alternative treatments. Visceral leishmaniasis occurred in patients with different levels of depression of the CD4 to CD8 lymphocyte ratio. Mortality was 37% (six patients) and was independent of the chronic-relapsing course of the disease. In no case was leishmaniasis the primary cause of death. Our data establish that visceral leishmaniasis is an opportunistic infection in HIV-infected patients, and we suggest that in endemic areas it should be considered an indicator disease for the diagnosis of AIDS.     

Estimation of Under-Reporting of Visceral Leishmaniasis Cases in Bihar, India

We report a 40-year old man in Uganda with ulcerated skins lesions, hypotension, and anaphylaxis caused by bites of safari ants. Treatment was successful. Physicians should be aware of anaphylaxis caused by ant bites.A 40-year old man came to the emergency department at St. Mary''s Hospital-Lacor in Gulu, Uganda. This is a rural hospital with limited resources. He had a history of alcohol abuse and had spent the preceding night sleeping in the bush. While asleep, he had been attacked by safari ants. He was unrousable and could not provide a medical history. Ants were still visible on his skin (Figure 1A). On examination, there were multiple erosions all over his body (Figure 1A). The patient had a Glasgow Coma Score of 6. His blood glucose level was 13 mg/dL (reference range = 70–100 mg/dL). A complete blood count was normal except for a leukocyte count of 12.4 × 10⁹/L (reference range = 4 × 10⁹/L–11 × 10⁹/L). Biochemical tests were not available.Open in a separate windowFigure 1.A, Multiple ulcers on the abdomen, shoulders, arms, neck, and head of the patient. Safari ant crawling on the hand and thumb (arrow) of the patient. B, Safari ant crawling on the bed sheet. This figure appears in color at www.ajtmh.org.He was resuscitated with two liters of Ringer''s lactate solution, followed by 2.5 liters/24 hours. His hypoglycemia was managed with 20 mL of 50% dextrose. Because the cause of the hypotension was not known, he was given 200 mg of hydrocortisone intravenously. Dopamine (5 μg/kg/minute) was given as an inotropic support agent. After blood cultures were obtained, he was treated with ampicillin and gentamicin. After five days, he improved sufficiently and was discharged. Blood cultures were negative, and we made a diagnosis of anaphylaxis secondary to ant bites with a possible secondary infection.Safari ants (Figure 1B) (order Hymenoptera, family Formicidae, genus Dorylus) (also known as driver ants, army ants, and Siafu) are found in central and eastern Africa and parts of Asia. Each anthill can contain up to 20 million ants. The venom of the ant has a protein component and an alkaloid component. The protein component causes anaphylaxis and the alkaloid component causes painful effects of the ant bite. Systemic (including anaphylaxis) symptoms are more common after multiple bites.¹ Anaphylactic reactions under these circumstances can be fatal.²     

Costs of patient management of visceral leishmaniasis in Muzaffarpur, Bihar, India

OBJECTIVES: To identify and quantify the direct and indirect economic cost of treatment for visceral leishmaniasis (VL) with conventional Amphotericin B deoxycholate, currently the first-line treatment in Muzaffarpur. METHODS: Costs of patient management for VL were estimated from a societal and household perspective by means of a questionnaire designed for this study, interviews and financial reports. RESULTS: The total cost of care per episode of VL from the societal perspective was estimated at US$355, equivalent to 58% of annual household income. The largest cost category was medical costs (55%), followed by indirect costs (36%) and non-medical costs (9%). The cost from the household perspective was equivalent to US$217. The largest cost category was indirect costs (59%), followed by medical costs (27%) and non-medical costs (15%). Loss of income because of illness and hospitalization and expenses for drugs were the largest cost components. CONCLUSIONS: The economic costs related to VL are substantial, both to society and the patient. Public health authorities in Bihar should focus on policies that detect VL in the early stage and implement interventions that minimize the burden to households affected by VL.     

Serious underreporting of visceral leishmaniasis through passive case reporting in Bihar, India

OBJECTIVES: Visceral leishmaniasis (VL) is a major public health problem in Bihar, India. Unfortunately, accurate data on the incidence or prevalence of the disease are not available. This longitudinal study was undertaken to determine the incidence of VL in a Community Development Block area of the state of Bihar. Survey results were compared with official reports of the disease to assess the extent of underreporting by the Government health system. METHODS: Three health subcentre areas in Kanti Block, consisting of 14 villages with a total population of 26 444, were selected. Active surveillance was performed every month from January 2001 to December 2003 by house to house survey to detect cases of fever for more than 15 days. Patients clinically suspected of suffering from VL were subjected to parasitological examination for confirmation. Analysis of records of the reporting agencies in the district was undertaken to compare and assess the extent of underreporting. RESULTS: A total of 202 cases of VL were identified in 3 years giving an average annual incidence rate of 2.49/1000 population (95% CI = 2.15-2.83). As identification data of patients was not available with the official reporting agencies for 2001 and 2002, extent of underreporting could be assessed for 2003 only. In the study population, 65 cases of VL were detected during 2003 providing an annual incidence rate of 2.36/1000 population. Only eight (12.30%) cases were reported officially, resulting in underreporting by a factor of 8.13. In 2003, the official incidence rate of VL for Kanti Block was 0.31/1000 against the actual rate of 2.36/1000. As the constraints for official reporting at the block and the district levels are similar, the underreporting at district level was also assumed to be similar. This finding has significance in the preparation for elimination programme.     

Identification of risk areas for visceral leishmaniasis in Teresina, Piaui State, Brazil

This study used spatial analysis to identify areas at greatest risk of visceral leishmaniasis (VL) in the urban area of Teresina, Brazil during 2001-2006. The results from kernel ratios showed that peripheral census tracts were the most heavily affected. Local spatial analysis showed that in the beginning of the study period local clusters of high incidence of VL were mostly located in the southern and northeastern parts of the city, but in subsequent years those clusters also appeared in the northern region of the city, suggesting that the pattern of VL is not static, and the disease may occasionally spread to other areas of the municipality. We also observed a spatial correlation between VL rates and all socioeconomic and demographic indicators evaluated (P < 0.01). The concentration of interventions in high-risk areas could be an effective strategy to control the disease in the urban setting.     

The economic value of a visceral leishmaniasis vaccine in Bihar state, India

Visceral leishmaniasis (VL) is responsible for substantial morbidity and mortality and current available treatments have many limitations. The ability of VL infection to generate life-long immunity offers promise for the development of a VL vaccine. A VL vaccine candidate has recently completed phase I clinical trials. We constructed a computer simulation model to determine the potential economic value of a VL vaccine in the endemic region of Bihar state, India. Results found a potential vaccine to be cost-effective (and in many cases economically dominant, i.e., saving costs and providing health benefits) throughout a wide range of vaccination costs and vaccine efficacies, and VL risks. Overall, our study strongly supports the continued development of a VL vaccine.     

Cost-effectiveness projections of single and combination therapies for visceral leishmaniasis in Bihar, India

Objectives  To assess the cost-effectiveness of current monotherapies and prospective combinations for treating visceral leishmaniasis (VL) in Bihar, India in terms of years of life lost (YLL) averted as well as deaths averted.
Methods  We employed two methods to estimate the number of avertable deaths in our analysis: one using estimated mortality, the other using direct incidence estimates for VL. Costs of care are based on an average private hospital in Bihar, and data on drug costs were obtained both locally and from the World Health Organization.
Results  The cost of monotherapies per averted YLL ranged from US$2 for paromomycin in an outpatient setting to US$20–22 for AmBisome^® at 20 mg/kg. The corresponding costs per death averted ranged from US$53–54 to US$523–527. Combinations ranged US$5–8 per YLL averted and US$124–213 per death averted.
Conclusion  The available treatments for VL are cost-effective, and our mortality and incidence-based methods produce consistent estimates. The combinations considered here were more cost-effective than most monotherapies. Having multiple treatment options and combining drugs are also likely to reduce drug pressure and prolong the drugs' life-span of effective use.     

Anthropometrically derived dosing and drug costing calculations for treating visceral leishmaniasis in Bihar, India

Objective and method  To estimate drug costs of treating visceral leishmaniasis (VL) based on data on the VL population structure from the high-burden, antimony-resistant area of Northern Bihar, India.
Results  Paromomycin is the cheapest option ($7450 to treat 1000 patients). Treating 1000 patients with oral miltefosine would cost $119 250 at the current private market price or $64 383–$75 129 at preferential public sector price depending on the size of the order. With AmBisome^® it would be $163 600 or $229 500 depending on the dose (10 or 15 mg/kg total). These costs are without considering other direct costs (daily intramuscular injections for 3 weeks for paromomycin; intravenous devices and hospitalization for AmBisome^®; directly observed treatment if applied for miltefosine) and indirect costs.
Conclusion  These calculations provide useful basic information for projections.     

Clinical epidemiologic profile of a cohort of post-kala-azar dermal leishmaniasis patients in Bihar, India

Post-kala-azar dermal leishmaniasis (PKDL) has important public health implications for transmission of visceral leishmaniasis (VL). Clinical and epidemiologic profiles of 102 PKDL patients showed that median age of males and females at the time of diagnosis was significantly different (P = 0.013). A significant association was observed between family history of VL and sex of PKDL patients (χ(2) = 5.72, P < 0.01). Nearly 33% of the patients showed development of PKDL within one year of VL treatment. The observed time (median = 12 months) between appearance of lesions and diagnosis is an important factor in VL transmission. A significant association was observed between type of lesions and duration of appearance after VL treatment (χ(2) = 6.59, P = 0.001). Because PKDL was observed during treatment with all currently used anti-leishmanial drugs, new drug regimens having high cure rates and potential to lower the PKDL incidence need to be investigated.     

Improved treatment of visceral leishmaniasis (kala-azar) by using combination of ketoconazole, miltefosine with an immunomodulator-Picroliv

Visceral leishmaniasis (VL) caused by the parasite Leishmania donovani, is a potentially fatal disease. It is characterized by prolonged fever, enlarged spleen and liver, substantial weight loss and progressive anemia. Available drugs are toxic, costly and require prolonged treatment duration viz; 28 days of oral treatment with miltefosine, 30 days infusion with Amphotericin B and 21 days intramascular with paromomycin sulfate. Drug combination for VL clinically proved to shorten the duration of treatment. The efficacy of drugs is also compromised due to suppression of immune function during the course of infection. To combat this situation leishmanicidal efficacy of already marketed standard antifungal drug, ketoconazole under the approach of 'therapeutic switching' in combination with standard antileishmanial drug, miltefosine and a potent immunomodulator agent, picroliv were evaluated in L. donovani/hamsters model. Animals treated with combination of ketoconazole (50 mg/kg, 5 days, po)+miltefosine (5 mg/kg, 5 days, po) showed augmentation in efficacy against leishmania parasite (72%) in comparison to those treated with ketoconazole (54.67%) and miltefosine (54.77%) separately. Co-administration of picroliv (10 mg/kg, 12 days, po) has further enhanced antileishmanial efficacy from 72% to 82%. Significant generation of ROS, RNS and H(2)O(2) and increased phagocytosis was observed in animals treated with ketoconazole+miltefosine; however, addition of picroliv to this combination did not alter the level of metabolites and phagocytosis due to its antioxidative and nonleishmanicidal characteristics, respectively. Significant rise in cell mediated immunity witnessed in this group reveals the role played by the immunomodulator, picroliv and justifies the significance of enhanced cell mediated immunity in the therapy. These findings suggest a new strategy for leishmanial chemotherapy at reduced cost and toxicity.     

Effectiveness and Safety of Liposomal Amphotericin B for Visceral Leishmaniasis under Routine Program Conditions in Bihar,India

We evaluated, through the prospective monitoring of 251 patients at Sadar Hospital in Bihar, India, the effectiveness and safety of 20 mg/kg body weight of liposomal amphotericin B for the treatment of visceral leishmaniasis. The treatment success rates for the intention-to-treat, per protocol, and intention-to-treat worse-case scenario analyses were 98.8%, 99.6%, and 81.3%, respectively. Nearly one-half of patients experienced mild adverse events, but only 1% developed serious but non–life-threatening lips swelling. The lost to follow-up rate was 17.5%. Our findings indicate that the 20 mg/kg body weight treatment dosage is effective and safe under routine program conditions. Given that the exorbitant cost of liposomal amphotericin B is a barrier to its widespread use, we recommend further study to monitor and evaluate a lowered dosage and a shorter treatment course.     

Optimizing Insecticide Allocation Strategies Based on Houses and Livestock Shelters for Visceral Leishmaniasis Control in Bihar,India

Visceral leishmaniasis (VL) is the most deadly form of the leishmaniasis family of diseases, which affects numerous developing countries. The Indian state of Bihar has the highest prevalence and mortality rate of VL in the world. Insecticide spraying is believed to be an effective vector control program for controlling the spread of VL in Bihar; however, it is expensive and less effective if not implemented systematically. This study develops and analyzes a novel optimization model for VL control in Bihar that identifies an optimal (best possible) allocation of chosen insecticide (dichlorodiphenyltrichloroethane [DDT] or deltamethrin) based on the sizes of human and cattle populations in the region. The model maximizes the insecticide-induced sandfly death rate in human and cattle dwellings while staying within the current state budget for VL vector control efforts. The model results suggest that deltamethrin might not be a good replacement for DDT because the insecticide-induced sandfly deaths are 3.72 times more in case of DDT even after 90 days post spray. Different insecticide allocation strategies between the two types of sites (houses and cattle sheds) are suggested based on the state VL-control budget and have a direct implication on VL elimination efforts in a resource-limited region.     

The poorest of the poor: a poverty appraisal of households affected by visceral leishmaniasis in Bihar, India

Objective  To provide data about wealth distribution in visceral leishmanisis (VL)-affected communities compared to that of the general population of Bihar State, India.
Methods  After extensive disease risk mapping, 16 clusters with high VL transmission were selected in Bihar. An exhaustive census of all households in the clusters was conducted and socio-economic household characteristics were documented by questionnaire. Data on the general Bihar population taken from the National Family Health Survey of India were used for comparison. An asset index was developed based on Principal Components Analysis and the distribution of this asset index for the VL communities was compared with that of the general population of Bihar.
Results  83% of households in communities with high VL attack rates belonged to the two lowest quintiles of the Bihar wealth distribution. All socio-economic indicators showed significantly lower wealth for those households.
Conclusion  Visceral leishmanisis clearly affects the poorest of the poor in India. They are most vulnerable, as this vector-born disease is linked to poor housing and unhealthy habitats. The disease leads the affected households to more destitution because of its impact on household income and wealth. Support for the present VL elimination initiative is important in the fight against poverty.     

Knowledge about sandflies in relation to public and domestic control activities of kala-azar in rural endemic areas of Bihar

Visceral Leishmaniasis (VL) control is a global cause of concern. To identify the gaps in People's knowledge/awareness about sand flies and control activities of kala-azar in rural endemic areas of Bihar, this study consisting of 450 respondents with 288 male and 162 female was carried out. The result showed that 95% respondents had heard about the disease up to some extent, but majority respondents were neither aware about the vector of kala-azar, nor they had any idea about transmission of the disease. About 61% had wrong impression that mosquitoes were causing kala-azar. Regarding knowledge about breeding and resting sites of vectors, 20% reported cattle shed, 16% crevices in the household followed by 15% damp dark places. The attitude of respondents towards vector control programme was poor, as 99% lost faith in the DDT spraying because of ineffectiveness, like no reduction in mosquito nuisance. Bed net was considered the best protection method against sand fly or mosquito nuisance but the cost was considered the major constraint in its use. Proper health education programme in Simple and local language along with visual demonstration should be promoted to enhance the awareness and co-operation at community level.     

Monitoring drug effectiveness in kala-azar in Bihar, India: cost and feasibility of periodic random surveys vs. a health service-based reporting system

Objective In 2009, a random survey was conducted in Muzaffarpur district to document the clinical outcomes of visceral leishmaniasis patients (VL) treated by the public health care system in 2008, to assess the effectiveness of miltefosine against VL. We analysed the operational feasibility and cost of such periodic random surveys as compared with health facility‐based routine monitoring. Methods A random sample of 150 patients was drawn from registers kept at Primary Health Care centres. Patient records were examined, and the patients were located at their residence. Patients and physicians were interviewed with the help of two specifically designed questionnaires by a team of one supervisor, one physician and one field worker. Costs incurred during this survey were properly documented, and vehicle log books maintained for analysis. Results Hundred and 39 (76.7%) of the patients could be located. Eleven patients were not traceable. Per patient, follow‐up cost was US$ 15.51 and on average 2.27 patients could be visited per team‐day. Human resource involvement constituted 75% of the total cost whereas involvement of physician costs 51% of the total cost. Conclusion A random survey to document clinical outcomes is costly and labour intensive but gives probably the most accurate information on drug effectiveness. A health service‐based retrospective cohort reporting system modelled on the monitoring system developed by tuberculosis programmes could be a better alternative. Involvement of community health workers in such monitoring would offer the additional advantage of treatment supervision and support.