DESCRIPTION (provided by applicant): The objective of 'Investigating febrile Deaths In Tanzania (INDITe)' is to identify actionable patient management and health system interventions that could avert fatal outcomes among patients with severe febrile illness in low-resource areas. Fever is among the most common reasons for seeking health care in less developed countries and hospitalized patients with fever have high case fatality ratios. However, there is an incomplete picture of the causes of severe fever illness, especially among patients with fatal outcomes. Gaining a more complete picture of why persons with fever die is essential to design patient management strategies and health systems that improve survival. Doing so is consistent with the US National Institutes of Health's mission to enhance health, lengthen life, and reduce illness and disability. The specific aims of the INDITe study are to: 1). Determine the microbiologic etiologies of fatal febrile illness among children and adults in northern Tanzania using full and minimally invasive autopsy combined with innovative pathogen discovery approaches; 2). Assess the performance of clinical diagnosis and verbal autopsy against diagnostic autopsy for determining cause of death among febrile patients; and 3). Determine the contribution of non-biologic factors to in-hospital mortality of febrile illness among children and adults in northern Tanzania. Aim 1 will be achieved using a prospective febrile illness cohort study in children and adults that employs an expanded pre-mortem clinical diagnostic evaluation for all participants enrolled, and in the case of fatal outcomes, a pre-specified infectious diseases pathology evaluation algorithm with innovative pathogen discovery approaches to identify neglected, non-neglected, and novel pathogens in tissues obtained via minimally-invasive autopsy. Aim 2 will be achieved by collecting diagnoses in life assigned by World Health Organization (WHO) Integrated Management of Childhood Illnesses (IMCI) and Integrated Management of Adolescent and Adult Illness (IMAI) district hospital syndromic management algorithms; MD-level clinician diagnoses; and cause of death assigned by WHO verbal autopsy instruments and comparing these with the findings of diagnostic autopsy. Aim 3 will be achieved by adapting retrospective, community-based social autopsy surveys to the prospective, hospital- based, pre-mortem setting in order to assess potential risk factors such as failure by patients or families to recognize severe signs of illness, delays in care-seeking, lack f appropriate healthcare resources, and inadequate case management by healthcare providers.

PUBLIC HEALTH RELEVANCE: Fever is one of the most common causes of hospitalization and death in sub-Saharan Africa, but the infections causing these deaths and the contribution of lack of access to healthcare and problems in the health system are poorly understood. We will use extended diagnostic evaluations including autopsy and new approaches to understanding challenges with health access and the health system to understand causes of death among persons with fever. These studies will enable the development of targeted treatment and prevention interventions to reduce deaths due to infectious diseases in low-resource settings.