Researchers at Boston University have discovered an unexpectedly high prevalence of Mycobacterium tuberculosis DNA (TB DNA) in patients hospitalized in Boston, suggesting that tuberculosis disease may be significantly underdiagnosed in the United States. The findings, published today in Nature Communications, could reshape how clinicians approach tuberculosis (TB) detection and help accelerate progress toward elimination goals.
Using an ultrasensitive molecular assay developed at Boston University called the Totally Optimized PCR (TOP) TB assay, researchers detected TB DNA in 12-16 percent of respiratory samples from predominantly U.S.-born patients at Boston Medical Center – far higher than expected given Boston's low TB incidence rate. Most striking was the finding that all three patients diagnosed during the study period with acute chest syndrome, a life-threatening complication of sickle cell disease, tested positive for TB DNA.
"We began this research with the intent of sourcing respiratory samples to support the ongoing development of a new molecular assay for TB," said Dr. Guillermo Madico, scientist at Boston University's National Emerging Infectious Diseases Laboratories (NEIDL) and co-inventor of the TOP TB assay. "What we found was completely unexpected. Our ultrasensitive test is detecting Mycobacterium tuberculosis DNA in patients who are unlikely to be diagnosed with TB using current methods. This opens the possibility that there could be thousands of Americans infected with forms of tuberculosis disease that remain hidden from our current diagnostic tools – putting them at risk of developing more serious complications or potentially transmitting the disease to others."
Tuberculosis remains the leading cause of death from an infectious disease globally. In the United States, TB killed nearly 600 people and sickened more than 9,600 in 2023, with an estimated 13 million people carrying latent TB infection. Despite decades of progress, the U.S. elimination campaign has stalled, with the number of new infections increasing between 2021-2024.
The Boston University team, led by Dr. Madico and Dr. Edward C. Jones-López, conducted three separate studies over six years, testing 297 respiratory samples from patients hospitalized at Boston Medical Center and St. Elizabeth's Medical Center. The TOP TB assay proved far more sensitive than standard mycobacterial cultures and other molecular tests, detecting TB DNA in samples that tested negative by conventional methods.
The study found that 75 percent of TB DNA-positive patients were age 50 or older, consistent with U.S. TB epidemiology where most cases result from reactivation of latent infections. Interestingly, most TB DNA-positive patients tested negative on standard TB infection tests (tuberculin skin tests or interferon-gamma release assays), a poorly understood phenomenon associated with advanced age and poor outcomes.
"These findings suggest we may be missing a significant burden of TB disease, particularly in older Americans and in patients with certain underlying conditions," said Dr. Jones-López, who conducted the research while at Boston Medical Center and Boston University Chobanian & Avedisian School of Medicine. "Most concerning is the potential association with acute chest syndrome in sickle cell patients. If confirmed and expanded upon in larger studies, this finding could lead to better health outcomes for patients with this potentially life-threatening condition."
The researchers emphasize that these preliminary findings require confirmation in larger, prospective multicenter studies that include comprehensive clinical, radiological, immunological, and microbiological correlation. However, they argue the evidence warrants immediate dissemination given potential implications for medical care and public health.
The TOP TB assay, which targets a gene involved in M. tuberculosis cell wall assembly, has been validated in over 400 patients with suspected TB in Uganda, Brazil, and the United States. While currently a research-use-only tool pending regulatory clearance, the technology demonstrates how molecular diagnostics with sensitivity superior to culture are transforming infectious disease detection.
The research team notes that current TB diagnostic strategies may be hampered by over-reliance on mycobacterial cultures, which require viable, actively growing bacteria. The TOP assay's ability to detect very low levels of TB DNA may identify earlier disease stages or variants that don't fit traditional definitions – challenging clinicians and researchers to reconsider how TB disease is classified and diagnosed.
About the National Emerging Infectious Diseases Laboratories (NEIDL) Boston University's National Emerging Infectious Diseases Laboratories (NEIDL) is a specialized research facility equipped with Biosafety Level 3 (BSL-3) and Biosafety Level 4 (BSL-4) laboratories, enabling scientists to safely study emerging and re-emerging infectious diseases. Our research focuses on understanding how pathogens cause disease and translating these findings into diagnostics, vaccines, and therapeutics that protect human health. Through strategic partnerships with government agencies, industry, and academic institutions, NEIDL accelerates the development of life-saving solutions for emerging infectious threats. To learn more, visit www.bu.edu/neidl/ .
Technical Note for Journalists: The study detected Mycobacterium tuberculosis DNA, not viable bacteria, in patient samples. The clinical significance and transmissibility of these findings require further investigation. High-resolution images and additional technical details are available upon request.
