Diagnostic biomarker for early detection of active tuberculosis in HIV-infected individuals
Analysis of blood samples for the African Cohort Study (AFRICOS).
Specific biomarkers in the blood can indicate the onset of tuberculosis (TB) in HIV-infected individuals six to twelve months earlier than TB diagnosis by sputum. This is the finding of researchers from the German Center for Infection Research (DZIF), the LMU University Hospital Munich and the U.S. Military HIV Research Program in collaboration with the African Cohort Study (AFRICOS) group. Early diagnosis via blood-based biomarkers followed by medical treatment could thus prevent progression and transmission of the disease. The results of the longitudinal study were published in the journal eClinicalMedicine/The Lancet.
According to the World Health Organisation, one quarter of the world’s population is estimated to be infected with Mycobacterium tuberculosis (MTB), which can cause Tuberculosis (TB). Although it is preventable and curable, 1.5 million people die from the infectious lung disease each year. TB is also a leading cause of death for people living with HIV. Most people infected with M. tuberculosis remain in a stage of latent TB and never develop TB disease. However, about five to 15 percent of people with latent TB develop active, transmissible TB disease during their lifetime. To date, however, X-ray and computed tomography diagnostics have been too nonspecific to detect such subclinical TB disease early and accurately. Therefore, there have been no diagnostic tools to detect TB activity early in patients with clinically latent TB or HIV/TB co-infection.
An international research team in collaboration with the AFRICOS Study Group has now taken a closer look at the dynamics of TB disease activity in the body. Led by DZIF scientists Prof Michael Hoelscher, Dr Christof Geldmacher and Dr Inge Kroidl, and Colonel Julie Ake from the U.S. Military HIV Research Program (MHRP) at the Walter Reed Army Institute of Research, the researchers studied TB disease activity in HIV/TB-coinfected patients of the AFRICOS study cohort over a five-year period. The team analysed a blood-based biomarker during a multi-year follow-up, combined with an annual survey for the presence of TB bacteria in sputum (coughed-up bronchial secretions).
AFRICOS—a systematic longitudinal cohort study
Established by MHRP in 2013, AFRICOS is a systematic 15-year longitudinal cohort study of people living with HIV and of HIV-negative adults. The study is being conducted in 11 clinics in five geographically distinct HIV treatment and care programmes supported by the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) in Kenya, Tanzania, Uganda, and Nigeria.
"AFRICOS helps us get a more comprehensive picture of the overall health of our HIV-infected patients, including outcome data on co-infections such as TB," says Col. Julie Ake, M.D., director of MHRP and lead investigator of the AFRICOS study. "Progression of latent TB to active disease can be life-threatening for people with HIV infection, so an early biomarker for active TB disease could be a critical tool to fundamentally improve clinical outcomes for patients with this co-infection."
Between January 2013 and August 2018, participating African clinics tested blood samples from 2,014 HIV-infected individuals annually for active TB using the biomarker-based Xpert MTB/RIF diagnostic assay. In addition, the scientific team examined blood samples from HIV-infected participants before, during, and after microbiologically confirmed diagnosis of active TB and TB relapse, as well as from patients with clinically latent TB infection for up to five years.
Using these samples, the researchers analysed the activation status of M. tuberculosis-specific CD4+ T cells (T lymphocytes that carry the surface antigen CD4 and are involved in the immune response after activation) as a biomarker for the diagnosis of TB disease in HIV-positive patients.
"Activated M. tuberculosis-specific CD4+ T cells in blood are a sputum-independent surrogate biomarker, which has been shown to discriminate between latent and active TB disease with high accuracy, reflecting TB disease activity in vivo," Dr. Geldmacher explains.
Blood-based biomarker as a promising diagnostic tool
Lab analysis indicated that M. tuberculosis-specific CD4+ T-cell activation could distinguish active TB from latent TB in HIV-positive patients with a sensitivity and specificity of 86 percent. In many cases, active TB disease began six to 12 months before TB was diagnosed based on clinical symptoms and the detection of bacteria in sputum. The results suggest that determining the activation status of M. tuberculosis-specific CD4+ T-cells in blood could facilitate early detection of incipient TB. Diagnostics developed on the basis of this biomarker could therefore help to reduce M. tuberculosis transmission, improve therapeutic outcomes and potentially save lives in the future.
Source: Press release of the LMU University Hospital Munich.
