Impact of intensified control on visceral leishmaniasis in a highly-endemic district of Bihar, India: an interrupted time series analysis.

Visceral leishmaniasis (VL) is declining in India and the World Health Organization's (WHO) 2020 'elimination as a public health problem' target has nearly been achieved. Intensified combined interventions might help reach elimination, but their impact has not been assessed. WHO's Neglected Tropical Diseases 2021-2030 roadmap provides an opportunity to revisit VL control strategies. We estimated the combined effect of a district-wide pilot of intensified interventions in the highly-endemic Vaishali district, where cases fell from 3,598 in 2012-2014 to 762 in 2015-2017. The intensified control approach comprised indoor residual spraying with improved supervision; VL-specific training for accredited social health activists to reduce onset-to-diagnosis time; and increased Information Education & Communication activities in the community. We compared the rate of incidence decrease in Vaishali to other districts in Bihar state via an interrupted time series analysis with a spatiotemporal model informed by previous VL epidemiological estimates. Changes in Vaishali's rank among Bihar's endemic districts in terms of monthly incidence showed a change pre-pilot (3rd highest out of 33 reporting districts) vs. during the pilot (9th) (p<1e-10). The rate of decline in Vaishali's incidence saw no change in rank at 11th highest, both pre-pilot & during the pilot. Counterfactual model simulations suggest an estimated median of 352 cases (IQR 234-477) were averted by the Vaishali pilot between January 2015 and December 2017, which was robust to modest changes in the onset-to-diagnosis distribution. Strengthening control strategies may have precipitated a substantial change in VL incidence in Vaishali and suggests this approach should be piloted in other highly-endemic districts.

Leishmania donovani: dynamics of L. donovani evasion of innate immune cell attack due to malnutrition in visceral leishmaniasis.

OBJECTIVE: Malnutrition may be significant in the modulation of immune responses in visceral leishmaniasis (VL). Data on the relationship between malnutrition and innate immune response in VL are limited. The aim of this study was to examine the effect of malnutrition on the profile of innate immune functions of polymorphonuclear neutrophil granulocytes (PMNs) and monocytes through comparison of well-nourished and malnourished Indian patients with VL. METHODS: Forty individuals were enrolled comprising 20 active and untreated cases of VL and 20 non-VL individuals from the endemic region of Bihar, India. The patients with VL were segregated into two groups of 10 well-nourished and 10 malnourished participants. Patients' blood samples were directed against a crude Leishmania donovani extract (soluble leishmanial antigen) and phorbol 12-myristate-13-acetate plus ionomycin. The transendothelial cell adherence migration abilities of the PMNs and monocytes directed against these antigens were determined in whole-blood assays by flow cytometry. The chemokine (interleukin [IL]-8, macrophage inflammatory protein [MIP]-1 α) and cytokine support (tumor necrosis factor -α, interferon [IFN]-γ, IL-10), which could be significant in transendothelial cell migration, and efficacies of antileishmanial phagocytic function and reactive oxygen species (ROS) generation were also determined. RESULTS: Severe hindrance in the adherence of innate immune cells to the endothelial wall due to Leishmania parasites, as revealed by decreased shedding of l-selectin (CD62 L) and down-regulation of CD11 b expression on the surface of the PMNs and monocytes, occurred in malnourished VL patients. The production of MIP-1 α and IL-8 in response to L. donovani antigen was reduced in malnourished patients. In contrast, malnutrition in VL patients significantly reduced the IFN-γ and TNF-α produced by these immune cells, whereas the levels of IL-10 were significantly elevated. Malnourished VL patients were observed with severely dysfunctional PMNs and monocytes in terms of ROS activity that could not be recovered by stimulation with L. donovani antigen. CONCLUSIONS: Malnutrition linked to VL can be a decisive factor in the dynamics of L. donovani evasion of innate immune cell function in VL patients.