THE EPIDEMIOLOGY OF SCRUB TYPHUS AND RICKETTISIAL INFECTIONS IN A HIGHLY ENDEMIC RURAL SETTING IN SOUTH INDIA: POPULATION-BASED COHORT STUDY

Scrub typhus is a bacterial infection causing febrile illness in many tropical and subtropical countries in East, South East and South Asia. Countries where scrub typhus occurs include India, China, Bangladesh, Pakistan, Indonesia, Vietnam, Thailand, Japan and Australia. The bacterium (Orienta tsutsugamushi) is transmitted by the larvae of mites during blood-feeding. Scrub typhus can lead to severe complications including lung failure, kidney failure and brain infection. Scrub typhus appears to be very common in affected regions, accounting for up to a third of all fever cases in some settings. Nevertheless, little is known with respect to the transmission of scrub typhus. Scrub typhus is one of the most neglected tropical infections in terms of research, clinical management and prevention. We do not know how many cases develop fever after infection and how many cases with fever develop complications. We further do not know how scrub typhus infection is transmitted in the community and what role rodents play in attracting mite larvae. This study is the first large scale cohort study specifically designed to gain a fundamental understanding of scrub typhus epidemiology in a region that is highly affected by the disease. While the main emphasis of this study is on scrub typhus as the most important infection, we will study two less common infections caused by very similar bacteria called Rickettsia: flea-borne murine typhus and tick-borne spotted fever. The study will be conducted in South India (Tamil Nadu) and follows up 40,000 people living in affected villages. Participants will be followed up at 2 monthly intervals to ask for the occurrence of fever in the past 2 months. We will take blood samples of all identified fever cases and test for the three infections (scrub typhus, murine typhus and spotted fever). They will be asked to proactively come to study clinics in the case of any fever or subfebrile temperature. In these ongoing fever cases we will do additional blood tests including polymerase chain reaction to understand the genetic variety of Orienta tsutsugamushi. Participants will be asked questionnaires regarding living conditions, socio-economic data and occupational factors. We will use satellite images and GPS data to study the geographical risk factors for scrub typhus and Rickettsia infections. We will catch rodents (the main carriers of infected mite larvae) at different locations in the study area and explore whether there is a relationship between the number of infected mite larvae on rodents and the occurrence of human cases in the neighbourhood.
The data collected in this study will be used to estimate the incidence of scrub typhus and severe scrub typhus in the community. We will calculate household and spatial risk factors for scrub typhus and the economic impact of scrub typhus in the community. While expected case numbers for murine typhus and spotted fever may be lower, we aim at estimating most of these same parameters for these two infections as well alongside scrub typhus.
The data from this study will help doctors to decide on treatment approaches and public health services to decide on intervention efforts. The immunological data will help vaccine developers to understand better how scrub typhus infection confers immunity. Data on rodents and mites will help inform disease control policies. Data on murine typhus and spotted fever will provide a basic understanding of the epidemiology of these rarely studied infections.

Scrub typhus is febrile illness caused by Orientia tsutsugamushi, bacteria related to the genus Rickettsia. The infection is transmitted by the larvae (chiggers) of trombiculid mites which infect mammals as incidental hosts. Scrub typhus occurs over much of tropical and subtropical East Asia, South Asia and South-east Asia. Scrub typhus is one of the main causes of febrile illness in endemic areas and if untreated has a high mortality. Despite being a major cause of complicated undifferentiated fever in Asia, little is known about the incidence and immunogenicity of scrub typhus infection. Basic epidemiological parameters to inform control efforts and vaccine development are not available. This is a population based cohort study in a highly endemic rural setting in south India aiming at estimating the incidence of serological, symptomatic and severe scrub typhus infection. In addition we will study two rickettsial infections occuring in the study area: flea-borne murine typhus and tick-borne spotted fever. Enrolled will be 40,000 individuals who will be followed up for the development of fever using active and passive surveillance. Active surveillance will include household screening every two months. Fever cases occuring in the past two months will be tested for Scrub typhus, murine typhus and spotted fever IgM. 1200 individuals will be followed up by annual serological testing to identify asymptomatic infections. The research includes spatial and socio-economic risk factor analysis. In an entomological study rodents carrying mite larvae will be trapped to compare the intensity of mite infestation between areas of high and low risk for human scrub typhus. The results from this study will help clinicians to elucidate the natural course of scrub typhus infection, health policy makers to estimate the global burden of disease and the scope for community-based interventions and immunologists to better understand the immunogenicity of single and repeat infections.

This large cohort study aims at providing fundamental epidemiological data on the transmission of scrub typhus, a common febrile illness in Asia and other parts of the world. Scrub typhus is a highly neglected tropical infection with a potentially high burden of disease in terms of morbidity and mortality. Large cohort studies conducted in the community estimating incidence of scrub typhus and immune response to infection are not available.
The research will benefit the populations of regions affected by scrub typhus by impacting on case management of scrub typhus and raise awareness with respect to the occurrence of this potentially fatal disease which is currently underdiagnosed. The research will contribute to our knowledge of the immunology of scrub typhus and thus may contribute to vaccine development. It will contribute to the question of whether environmental management or rodent control may reduce scrub typhus risk.
The research will help doctors understand the risk of progression from mild to complicated scrub typhus infection and initiate or withhold empirical treatment as required. Having data on murine typhus and spotted fever will help in this regard as these infections are managed with the same antibiotic regimen and may therefore widen the scope for empirical treatment.
Immunologists and vaccine developers will be able to use the data from this study to better understand immunogenicity of infection and the role of previous exposure to scrub typhus on the risk of subsequent infection.
Calculating the association between seroprevalence and incidence of scrub typhus will allow extrapolating the findings to other settings with known seroprevalence but unknown incidence. Health economists and public health practitioners will make use of these data by calculating the regional and global burden of disease for scrub typhus infection and allocate clinical and public health resources accordingly.
The research will encourage and inform future studies on scrub typhus, murine typhus and spotted fever in different settings such as entomological, serological/immunological and spatial studies. The research will provide preliminary data to inform future studies on scrub typhus in pregnancy which is thought to cause frequent miscarriages and low birth weight.