Visceral Leishmaniasis In Bihar Research Articles

Spatial Variation in Delayed Diagnosis of Visceral Leishmaniasis in Bihar, India

Spatial Variation in Delayed Diagnosis of Visceral Leishmaniasis in Bihar, India

Mathematical modelling of the use of insecticide-treated nets for elimination of visceral leishmaniasis in Bihar, India.

Visceral leishmaniasis (VL) is a deadly neglected tropical disease caused by a parasite Leishmania donovani and spread by female sand flies Phlebotomus argentipes. There is conflicting evidence regarding the role of insecticide-treated nets (ITNs) on the prevention of VL. Numerous studies demonstrated the effectiveness of ITNs. However, KalaNet, a large trial in Nepal and India did not support those findings. The purpose of this paper is to gain insight into the situation by mathematical modelling. We expand a mathematical model of VL transmission based on the KalaNet trial and incorporate the use of ITNs explicitly into the model. One of the major contributions of this work is that we calibrate the model based on the available epidemiological data, generally independent of the KalaNet trial. We validate the model on data collected during the KalaNet trial. We conclude that in order to eliminate VL, the ITN usage would have to stay above 96%. This is higher than the 91% ITNs use at the end of the trial which may explain why the trial did not show a positive effect from ITNs. At the same time, our model indicates that asymptomatic individuals play a crucial role in VL transmission.

Xenodiagnosis to evaluate the infectiousness of humans to sandflies in an area endemic for visceral leishmaniasis in Bihar, India: a transmission-dynamics study

SummaryBackgroundVisceral leishmaniasis, also known on the Indian subcontinent as kala-azar, is a fatal form of leishmaniasis caused by the protozoan parasite Leishmania donovani and transmitted by the bites of the vector sandfly Phlebotomus argentipes. To achieve and sustain elimination of visceral leishmaniasis, the transmission potential of individuals exposed to L donovani from across the infection spectrum needs to be elucidated. The aim of this study was to evaluate the relative infectiousness to the sandfly vector of patients with visceral leishmaniasis or post-kala-azar dermal leishmaniasis, before and after treatment, and individuals with asymptomatic infection.MethodsIn this prospective xenodiagnosis study done in Muzaffarpur district of Bihar, India, we included patients with clinically confirmed active visceral leishmaniasis or post-kala-azar dermal leishmaniasis who presented to the Kala-Azar Medical Research Center. These participants received treatment for L donovani infection. We also included asymptomatic individuals identified through a serosurvey of 17 254 people living in 26 high-transmission clusters. Eligible participants were aged 12–64 years, were HIV negative, and had clinically or serologically confirmed L donovani infection. During xenodiagnosis, the forearms or lower legs of participants were exposed to 30–35 female P argentipes sandflies for 30 min. Blood-engorged flies were held in an environmental cabinet at 28°C and 85% humidity for 60–72 h, after which flies were dissected and evaluated for L donovani infection by microscopy and quantitative PCR (qPCR). The primary endpoint was the proportion of participants with visceral leishmaniasis or post-kala-azar dermal leishmaniasis, before and after treatment, as well as asymptomatic individuals, who were infectious to sandflies, with a participant considered infectious if promastigotes were observed in one or more individual flies by microscopy, or if one or more of the pools of flies tested positive by qPCR.FindingsBetween July 12, 2016, and March 19, 2019, we recruited 287 individuals, including 77 with active visceral leishmaniasis, 26 with post-kala-azar dermal leishmaniasis, and 184 with asymptomatic infection. Of the patients with active visceral leishmaniasis, 42 (55%) were deemed infectious to sandflies by microscopy and 60 (78%) by qPCR before treatment. No patient with visceral leishmaniasis was found to be infectious by microscopy at 30 days after treatment, although six (8%) were still positive by qPCR. Before treatment, 11 (42%) of 26 patients with post-kala-azar dermal leishmaniasis were deemed infectious to sandflies by microscopy and 23 (88%) by qPCR. Of 23 patients who were available for xenodiagnosis after treatment, one remained infectious to flies by qPCR on the pooled flies, but none remained positive by microscopy. None of the 184 asymptomatic participants were infectious to sandflies.InterpretationThese findings confirm that patients with active visceral leishmaniasis and patients with post-kala-azar dermal leishmaniasis can transmit L donovani to the sandfly vector and suggest that early diagnosis and treatment could effectively remove these individuals as infection reservoirs. An important role for asymptomatic individuals in the maintenance of the transmission cycle is not supported by these data.FundingBill & Melinda Gates Foundation.

Post Kala-Azar Dermal Leishmaniasis Following Treatment with 10 mg/kg of Single Dose AmBisome for Visceral Leishmaniasis in Bihar, India

In view of the significant role of Post kala-azar dermal Leishmaniasis (PKDL) patients in the transmission/recurrence of visceral leishmaniasis (VL) outbreaks, control of PKDL is among the priorities. As the Single Dose AmBisome 10 mg/kg (SDA) became the obvious choice for the treatment of VL, therefore, in this study, 896 patients were included to explore the probability of developing PKDL. Among the treated patients, 30 (3.35%) of them found confirmed as PKDL with clinical symptoms. Out of the 30 patients, 53.33% male and 46.67% female patients had macular lesions respectively, with a median time (Interquartile range [IQR]) to development of 13.5 (9–23.5) and 23 (9-17) months following treatment. No, significant associations were established concerning any patient's demographics and clinical characteristics. However, with the patients presenting with confirmed PKDL, females were significantly younger than males. This study suggests the rate of PKDL appearance is directly associated with 10 mg/kg of SDA and therefore there is a need for more concerns regarding doses during treatment.

Seasonal dynamics of egg-laying and adult emergence of Kalaazar vector P. argentipes in Bihar, India

The dynamics of egg laying, larval hatching, pupation, adult emergence and sex ratio were studied in laboratory condition of natural population collected from an endemic pocket of visceral leishmaniasis in Bihar (India). The mean number of eggs laid/female was highest during summer season (49.7eggs/female), followed by winter (43.3 egg/female) and rainy (23.3). The larval hatching rate was highest in the winter (87%) and lowest in the summer (74%). Maximum sterility was also observed during summer Pupation rate is highest in winter and lowest in summer Season. Similarly the adult emergence rate was highest in winter and lowest in rainy Season. The secondary sex ratio, i.e., no. of female/100 males was highest in rainy (157) & lowest in winter (103). The probable effect of genetic and epigenetic factors, on the seasonal variations in these parameters have been suggested. A comparison of the present data with these from other parts of the world hints that the present population of P. argentipes is comparatively more dangerous and

Understanding the transmission dynamics of Leishmania donovani to provide robust evidence for interventions to eliminate visceral leishmaniasis in Bihar, India.

Visceral Leishmaniasis (VL) is a neglected vector-borne disease. In India, it is transmitted to humans by Leishmania donovani-infected Phlebotomus argentipes sand flies. In 2005, VL was targeted for elimination by the governments of India, Nepal and Bangladesh by 2015. The elimination strategy consists of rapid case detection, treatment of VL cases and vector control using indoor residual spraying (IRS). However, to achieve sustained elimination of VL, an appropriate post elimination surveillance programme should be designed, and crucial knowledge gaps in vector bionomics, human infection and transmission need to be addressed. This review examines the outstanding knowledge gaps, specifically in the context of Bihar State, India.The knowledge gaps in vector bionomics that will be of immediate benefit to current control operations include better estimates of human biting rates and natural infection rates of P. argentipes, with L. donovani, and how these vary spatially, temporally and in response to IRS. The relative importance of indoor and outdoor transmission, and how P. argentipes disperse, are also unknown. With respect to human transmission it is important to use a range of diagnostic tools to distinguish individuals in endemic communities into those who: 1) are to going to progress to clinical VL, 2) are immune/refractory to infection and 3) have had past exposure to sand flies.It is crucial to keep in mind that close to elimination, and post-elimination, VL cases will become infrequent, so it is vital to define what the surveillance programme should target and how it should be designed to prevent resurgence. Therefore, a better understanding of the transmission dynamics of VL, in particular of how rates of infection in humans and sand flies vary as functions of each other, is required to guide VL elimination efforts and ensure sustained elimination in the Indian subcontinent. By collecting contemporary entomological and human data in the same geographical locations, more precise epidemiological models can be produced. The suite of data collected can also be used to inform the national programme if supplementary vector control tools, in addition to IRS, are required to address the issues of people sleeping outside.

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.

Susceptibility of the sandfly Phlebotomus argentipes Annandale and Brunetti (Diptera: Psychodidae) to insecticides in endemic areas of visceral leishmaniasis in Bihar, India.

We present the results of susceptibility tests conducted on the sandfly Phlebotomus argentipes, the vector of visceral leishmaniasis in India. Adult P. argentipes insects were collected from 42 villages in 6 districts of the state of Bihar, India, as follows: Patna, Vaishali, Muzaffarpur, Samastipur, Sheohar, and Sitamarhi. These adult insects were exposed to 4% DDT-, 5% malathion-, and 0.05% deltamethrin-impregnated papers using a WHO test kit by following the standard procedures. In 16 (38.1%) of 42 villages surveyed, the P. argentipes populations developed resistance to DDT. Susceptibility tests using the organophosphate malathion in 22 villages revealed that in 1 (4.5%) village, the species developed resistance to this insecticide. P. argentipes was, however, highly susceptible to the synthetic pyrethroid deltamethrin. For long-term vector control of P. argentipes, it will be necessary to overcome the threat of insecticide resistance in this species.

Health & Demographic Surveillance System profile: the Muzaffarpur-TMRC Health and Demographic Surveillance System.

The Muzaffarpur-TMRC Health and Demographic Surveillance System (HDSS), established in 2007, was developed as an enlargement of the scope of a research collaboration on the project Visceral Leishmaniasis in Bihar, which had been ongoing since 2005. The HDSS is located in a visceral leishmaniasis (VL)-endemic area in the Muzaffarpur district of Bihar state in India. It is the only HDSS conducting research on VL, which is a vector-borne infectious disease transmitted by female phlebotomine sandflies and is fatal if left untreated. Currently the HDSS serves a population of over 105,000 in 66 villages. The HDSS collects data on vital events including pregnancies, births, deaths, migration and marriages, as well as other socio-economic indicators, at regular intervals. Incident VL cases are identified. The HDSS team is experienced in conducting both qualitative and quantitative studies, sample collection and rapid diagnostic tests in the field. In each village, volunteers connect the HDSS team with the community members. The Muzaffarpur-TMRC HDSS provides opportunities for studies on VL and other neglected tropical diseases (NTDs) and their interaction with demographic events such as migration. Queries related to research collaborations and data sharing can be sent to Dr Shyam Sundar at [drshyamsundar@hotmail.com].

Impact of ASHA training on active case detection of visceral leishmaniasis in Bihar, India.

BackgroundOne of the major challenges for management of visceral leishmaniasis (VL) is early diagnosis of cases to improve treatment outcome and reduce transmission. We have therefore investigated active case detection of VL with the help of accredited social health activists (ASHA). ASHAs are women who live in the community and receive performance-based incentives for overseeing maternal and other health-related issues in their village.Methods and Principal FindingThrough conducting interviews with 400 randomly selected ASHAs from four primary health care centers (PHCs), it was observed that their level of knowledge about visceral leishmaniasis (VL) regarding transmission, diagnosis, and treatment was limited. The baseline data indicated that less than 10% of VL cases seeking treatment at the PHCs were referred by ASHAs. To increase the knowledge and the referral rate of VL cases by ASHAs, training sessions were carried out during the monthly ASHA meetings at their respective PHCs. Following a single training session, the referral rate increased from less than 10% to over 27% and the overall knowledge about VL substantially improved. It was not possible, however, to demonstrate that ASHA training reduced the time that individuals had fever before treatment at the PHC.ConclusionsTraining ASHAs to identify VL cases in villages for early diagnosis and treatment at the local PHC is feasible and should be undertaken routinely to improve knowledge about VL.

HIV and visceral leishmaniasis coinfection in Bihar, India: an underrecognized and underdiagnosed threat against elimination.

Although human immunodeficiency virus (HIV) and visceral leishmaniasis coinfection is recognized as a major public health challenge in Africa, data regarding the prevalence in India are very limited. Consecutive HIV screening of 2077 patients aged ≥14 years with confirmed visceral leishmaniasis in Bihar, eastern India, found that 5.6% were HIV positive, including 2.4% with newly diagnosed HIV infection.

Post Kala-Azar Dermal Leishmaniasis following Treatment with 20 mg/kg Liposomal Amphotericin B (Ambisome) for Primary Visceral Leishmaniasis in Bihar, India

BackgroundThe 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.Methods and Principal FindingsOver 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.ConclusionsIn 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.

One-Year Follow-up of Immunocompetent Male Patients Treated With Miltefosine For Primary Visceral Leishmaniasis in Bihar, India

One-Year Follow-up of Immunocompetent Male Patients Treated With Miltefosine For Primary Visceral Leishmaniasis in Bihar, India

Impact of socio-economic conditions on the incidence of visceral leishmaniasis in Bihar, India

Visceral leishmaniasis (VL) is one of the world's worst parasitic killers, second only to Malaria, claiming thousands of lives every year. More than three fifths of the world's VL cases occur in the Indian state of Bihar alone. While some research has been conducted with emphasis on the effects of climatic variables on the VL incidence rate, rigorous analysis of the effects of socio-economic variables is still lacking. In this paper a regression model is developed that describes the relationship between VL incidence rate and a variety of socio-economic factors. It uses data from 2005 and explains 92% of the observed variance. In addition, a stepwise regression model is also used to identify the most important factors that facilitate the prevalence of the VL disease. A discussion on how to most effectively distribute Bihar's limited resources on various control measures to decrease the incidence of VL is also presented.

Risk factors for visceral leishmaniasis in India: further evidence on the role of domestic animals

Studies investigating risk factors for visceral leishmaniasis (VL) on the Indian Subcontinent have shown contradictory results related to the role of domestic animals. In some studies having animals in or around the house was a risk factor, in others it was protective. We investigated the specific hypothesis that keeping domestic animals inside the house at night is a risk factor for VL. Individually matched case-control study. All patients with VL diagnosed in the study area in Bihar, India between March 1st, 2007 and December 1st, 2008 were eligible. For each case, we selected two random controls, with no history of previous VL; matched on sex, age group and neighbourhood. Patients and controls were subjected to a structured interview on the main exposure of interest and potential confounders; a conditional logistic regression model was used to analyse the data. We enrolled 141 patients and 282 controls. We found no significant associations between VL and keeping domestic animals inside the house (OR of 0.88 for bovines and 1.00 for 'any animal') or ownership of domestic animals (OR of 0.97 for bovines and 1.02 for 'any animal'). VL was associated with housing conditions. Living in a thatched house (OR 2.60, 95% CI 1.50-4.48) or in a house with damp floors (OR 2.60, 95% CI 1.25-5.41) were risk factors, independently from socio economic status. Keeping animals inside the house is not a risk factor for VL in Bihar, India. Improving housing conditions for the poor has the potential to reduce VL incidence.

Household cost‐of‐illness of visceral leishmaniasis in Bihar, India

To determine the cost of kala-azar (KA) to patients in Bihar, India. A semi-structured questionnaire was used to collect costs of illness--direct (medical; non-medical) and indirect costs (work days lost). After screening the community known to be endemic for visceral leishmaniasis (VL), households (HHs) with VL were recruited which reported a case of KA who received treatment between September 2005 and September 2006. The total costs were calculated as a summation of individual costs category. Medians were estimated for the total and for each of the cost categories. Data from 171 HHs and 183 patients revealed that median age of patients with KA was 18; 59% were men; 33% were employed; household size was 7; household median monthly income was $38. The median total costs per patient were $127, equal to >3 months of income, of which medical care comprised $83 (provider fees $13, medicines $50, diagnostics $9, hospital stay $30); and food and transport comprised $33. Patients also lost almost 2 weeks of work time during illness and even after recovery. Despite provision of free/subsidized medicines, diagnostics, and hospital stay at public and Non-Governmental Organization facilities, the impoverished HHs of Bihar with a case of KA incur high expenditures. Easier access to, and more use of free public health services, plus innovative health financing schemes, are urgently required.

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

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. 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. 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. 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.

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

To provide data about wealth distribution in visceral leishmaniasis (VL)-affected communities compared to that of the general population of Bihar State, India. 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. 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. Visceral leishmaniasis 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.

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

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. 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. These calculations provide useful basic information for projections.

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

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. 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. 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. 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.