Strong Association between Serological Status and Probability of Progression to Clinical Visceral Leishmaniasis in Prospective Cohort Studies in India and Nepal

Abstract

IntroductionAsymptomatic persons infected with the parasites causing visceral leishmaniasis (VL) usually outnumber clinically apparent cases by a ratio of 4–10 to 1. We assessed the risk of progression from infection to disease as a function of DAT and rK39 serological titers.MethodsWe used available data on four cohorts from villages in India and Nepal that are highly endemic for Leishmania donovani. In each cohort two serosurveys had been conducted. Based on results of initial surveys, subjects were classified as seronegative, moderately seropositive or strongly seropositive using both DAT and rK39. Based on the combination of first and second survey results we identified seroconvertors for both markers. Seroconvertors were subdivided in high and low titer convertors. Subjects were followed up for at least one year following the second survey. Incident VL cases were recorded and verified.ResultsWe assessed a total of 32,529 enrolled subjects, for a total follow-up time of 72,169 person years. Altogether 235 incident VL cases were documented. The probability of progression to disease was strongly associated with initial serostatus and with seroconversion; this was particularly the case for those with high titers and most prominently among seroconvertors. For high titer DAT convertors the hazard ratio reached as high as 97.4 when compared to non-convertors. The strengths of the associations varied between cohorts and between markers but similar trends were observed between the four cohorts and the two markers.DiscussionThere is a strongly increased risk of progressing to disease among DAT and/or rK39 seropositives with high titers. The options for prophylactic treatment for this group merit further investigation, as it could be of clinical benefit if it prevents progression to disease. Prophylactic treatment might also have a public health benefit if it can be corroborated that these asymptomatically infected individuals are infectious for sand flies.

Progress in the Mathematical Modelling of Visceral Leishmaniasis

“…Well established risk factors influencing the probability of disease development include malnutrition, HIV co-infection, and poverty-related conditions Boelaert et al, 2009;Alvar et al, 2008). Seroconversion or high Leishmania antibody titres indicate likely disease development, though are not specific markers (Hailu et al, 2009;Hasker et al, 2014;Carneiro et al, 2011;Badaro et al, 1986a;Chapman et al, 2015). Additional challenges in defining asymptomatic status are discussed elsewhere Carneiro et al, 2011).…”

Health-seeking behaviour, diagnostics and transmission dynamics in the control of visceral leishmaniasis in the Indian subcontinent

“…The extended model includes an incidence of infection and a latent class to account for delays between infection and onset of symptoms. Most latently infected individuals recover directly to the dormant stage without progressing to symptoms leading to kala-azar 11 . The instantaneous rate of infection is calculated as the weighted sum of the force of infection from the various potentially infectious states: latent, fever, kala-azar and dormant.…”

Systematic Review of Biomarkers To Monitor Therapeutic Response in Leishmaniasis

“…Besides the drawback of the long half-lives of antibodies, antibody detection tests tend to be positive in a significant proportion of noninfected or otherwise asymptomatic individuals living in areas where VL is endemic (135,155,156). Due to these crucial limitations in the use of antibodies to monitor therapies, these markers are excluded from Table 3.…”