Novel urine-based biomarkers for diagnosis of pulmonary tuberculosis in people co-infected with HIV
TB/HIV co-infection remains an underestimated epidemic, spreading faster than our ability to detect and manage it, and tuberculosis (TB) remains the leading cause of death in people living with HIV/AIDS (PLWHA) 1,2. Yet approximately half of TB cases in this population remain undiagnosed. The challenges to diagnosing TB in PLWHA are many, including atypical pulmonary presentations, higher incidence rates of extra-pulmonary TB, and higher rates of sputum smear negativity by microscopy and culture due to the immunosuppression caused by HIV. We propose to remedy this situation by applying an innovative metabolomic approach using high- performance liquid chromatography coupled with mass spectrometry (LC-MS) to discover urinary metabolites specifically diagnostic of active TB infection in this population. Urine-based biomarkers have recently begun to emerge as clinically useful diagnostic markers of infectious disease and prognostic markers of treatment efficacy. Yet, there are a surprisingly small number of metabolomic studies of TB biomarkers and an even smaller number that utilize urine, which is an ideal biofluid for point-of-care tests due to its generally abundant and non-invasive nature. We propose to analyze an already existing biobank of urine samples prospectively collected from patients included in the SDART-TB trial ("A Trial of Same-Day Testing and Treatment to Improve Outcomes Among Symptomatic Patients Newly Diagnosed With HIV", NCT03154320). This study was conducted by Serena Patricia Koenig, Brigham and Women's Hospital, in partnership with the Center for Global Health, WCM, and other collaborators in Haiti. It included 500 newly diagnosed patients with HIV and symptoms of TB recruited between 2017 and 2019, of which 460 had urine collected at the time of enrollment and were shipped to the Belfer Research Building, WCM, where they are currently stored at -80°C. We propose to work with 2/3 (304) of the original cohort, of which approximately 1⁄4 (76) were diagnosed with pulmonary TB, to achieve a 3:1 ratio of age- and gendered-matched controls for every case. Previous work from our group identified and validated biomarkers that are increased in pulmonary drug-susceptible TB cases in HIV-negative patients and decreased with effective anti-TB treatment3,4. We now propose to build on these results by validating these previously identified biomarkers in PLHWA co-infected with pulmonary TB or potentially discovering additional biomarkers specific to the HIV+ population. Moreover, we believe we will be able to identify biomarkers that distinguish patients with TB in PLWHA from patients with non-TB pulmonary illness in PLWHA. PLWHA are disproportionally affected by TB and thus urgently need new diagnostic tools.