Understanding the immunology and morbidity of adolescent tuberculosis (DEFIANT)

During adolescence, the predominant clinical phenotype of TB shifts from intrathoracic lymph node disease to adult-type pulmonary TB. It is increasingly recognized that adolescents contribute to substantial Mtb transmission and that disease in this age group leads to substantial post-TB lung disease (PTLD). The underlying mechanisms for these changes in biology remain poorly understood. We will enroll 100 adolescents with pulmonary TB disease and 200 healthy adolescent controls. We will assess pubertal development using Tanner staging and sex steroid profiling. We will evaluate associations between pubertal stage and inflammation in the blood – evaluated by SomaScan, RNA-seq and innate and T cell response to mycobacteria and modulatory cytokines. For individuals with TB disease, we will use chest radiography and 18F-FDG-PET/CT imaging to evaluate disease severity and will collect sputum samples to measure host immunology at the site of disease. We will follow adolescents with TB for 12 months to characterize different phenotypes of PTLD, before identifying clinical features, radiological parameters and biomarkers at baseline that predict progression to these phenotypes. Finally, we will determine immunological pathways leading to PTLD and then simulate in silico the impact of host-directed therapies to ameliorate these pathways.