Candidate: My goal is to become an independent investigator in the field of pediatric infectious diseases, with a focus on research on internationl health and pediatric tuberculosis. I have a particular interest in improving TB diagnosis and intensified TB case-finding among children with and without HIV in resource-limited settings. Under the guidance of my mentors, Dr. Robert Husson, Dr. Kevin Cain, Dr. Kenneth McIntosh and Dr. Niaz Banaei, I have developed a comprehensive career development plan which will allow me to implement two research studies in Kenya, and complete a Master of Public Health degree and pursue additional educational training in advanced biostatistics and epidemiology at the Harvard School of Public Health. I will have the opportunity to conduct two prospective cohort studies in collaboration with the Kenya Medical Research Institute/Center for Diseases Control and Prevention Research and Public Health Collaboration (KEMRI/CDC) in Kenya. I developed the concept proposal for the studies and will be developing the protocols for the proposed studies. As the lead investigator, working with Dr. Cain, I will supervise the planning and the implementation of study activities. I will be responsible for the oversight of the data management, conduct the data analysis and disseminate findings through manuscripts and presentations. Environment: Children's Hospital Boston and Harvard School of Public Health are known for their world renowned faculty, several of whom will serve as mentors and advisors for me and my project. Children's also has an established Clinical Research Program which provides support for clinical investigators in all aspects of grant and protocol development and implementation, the NIH-funded Harvard Catalyst Program, a Clinical and Translational Science Center, and an outstanding didactic curriculum at the Harvard School of Public Health. KEMRI/CDC is one of the largest collaborations in sub-Saharan Africa carrying out public health and clinical research. KEMRI/CDC is conducting multiple clinical research studies on TB, including vaccine trials among infants, an adolescent cohort study and a study on intensified TB case-finding among adults with HIV and has a dedicated BSL-3 TB laboratory. Research: My research proposal addresses the greatest challenge to global pediatric TB control, the difficulty in diagnosing TB among young children with and without HIV. Despite the substantial global burden of pediatric TB and the higher risk of severe disease and death among young children than adults, childhood TB has been relatively neglected. Diagnosis of TB among children is challenging as symptoms are non-specific and definite microbiological diagnosis can be achieved in only a small proportion of infected children. Pediatric TB has no sensitive and specific "gold standard" diagnostic method. A positive culture of sputum, induced sputum, or gastric aspirate is probably grossly insensitive, albeit specific. Adding culture of lymph node aspirates to this improves sensitivity but still omits many cases with consistent radiology and response to treatment. In practice, diagnosis is often based on clinical judgment or insufficiently validated diagnostic algorithms. Moreover, pediatric data on the diagnostic utility of promising emerging diagnostic tools for TB, including the Xpert MTB/RIF using real-time PCR, the electronic nose, a non-invasive technology based on detection of volatile compounds, and a modified cytokine-based serological assay, are either limited or lacking. WHO and NIH identified research on improved diagnostic approaches for TB among children with and without HIV as a high priority. These research needs include the development of evidence-based clinical TB screening and diagnostic algorithms for TB among children with and without HIV that can be utilized in resource-limited settings. The implementation of sensitive TB screening and diagnostic algorithms has the potential to substantially reduce preventable illness and death among this vulnerable population by provision of preventive therapy if indicated, earlier treatment initiation and by avoidance of unnecessary treatment.
Our aims are to determine a sensitive and feasible approach for TB diagnosis among children with and without HIV, using an intensified work-up with multiple specimen types and the Xpert MTB/RIF, and to evaluate the diagnostic utility of both the electronic nose and modified cytokine-based serological assay for TB infection and TB disease in the same cohort. To achieve these aims, we will conduct a prospective cohort study in Kenya enrolling children with a high pretest probability of having microbiologic confirmed TB.
Our first aim i s to determine which combination of tests from which sources have the highest yield for TB diagnosis. Once this is determined, our second aim is to derive clinical algorithms for screening and diagnosis of TB among children with and without HIV in Kenya. To do this, we will conduct a prospective cohort study and enroll children who are at high risk of TB, including household contacts and children with HIV, and apply a standardized diagnostic work-up to all enrolled children by using the best and most feasible diagnostic approach, derived from the first study. We will then compare signs, symptoms, and results of simple, widely available tests to the result of the TB diagnostic testing to derive clinical algorithms.

Public Health Relevance

Tuberculosis is a leading cause of childhood morbidity and mortality worldwide. Diagnostic difficulties remain the greatest challenge to global pediatric tuberculosis control, particularly among young children and children with HIV. This proposal seeks to improve TB diagnosis among children with and without HIV, by using improved application of existing diagnostic methods, evaluating promising novel technologies and by deriving readily implementable clinical algorithms.

National Institute of Health (NIH)
Mentored Patient-Oriented Research Career Development Award (K23)
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AIDS Clinical Studies and Epidemiology Study Section (ACE)
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Worrell, Carol
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Children's Hospital Boston
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