Nature Commun
Hidden TB signal? DNA test flags unexpected U.S. cases
Clinical takeaway: An ultrasensitive assay detected TB DNA in about 12% to 16% of hospitalized patients with low clinical suspicion and negative standard TB tests. Clinical significance remains unclear, but researchers argue the signal may have public health implications.
Tuberculosis is uncommon in most U.S. hospital settings, and current diagnostics rely on culture or standard molecular tests. This study explored whether a more sensitive approach could identify cases that are otherwise missed.
Across three separate studies over six years, researchers tested 297 respiratory samples from hospitalized patients in Boston. The assay detected Mycobacterium tuberculosis DNA in 12% to 16% of samples, despite negative results on conventional testing.
Most TB DNA–positive patients were older, consistent with reactivation patterns in the U.S. population. Many also tested negative on standard TB infection tests, a pattern seen in older or immunologically impaired patients.
A notable signal emerged in patients with sickle cell disease. All three patients diagnosed with acute chest syndrome during the study period were TB DNA–positive, despite negative standard microbiologic workups. This small but striking cluster raises the possibility of an unrecognized infectious contribution.
TB DNA–positive patients were more likely to present with sickle cell pain crisis or chest pain and showed signs of more severe illness—including anemia, elevated bilirubin, and leukocytosis—with all cases of acute chest syndrome occurring in this group.
"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. Edward 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.”
Despite the high rate of TB DNA detection, none of the positive patients developed clinically diagnosed or culture-confirmed TB during follow-up. This leaves the central question unresolved: whether the assay is detecting early disease, low-level infection, or biologically irrelevant signal.
The results challenge the assumption that culture-negative patients are free of disease and suggest there may be a spectrum of TB that current diagnostics don't capture. Next steps include prospective, multicenter studies to clarify clinical significance and outcomes, alongside further validation and regulatory development of the assay to determine whether it can be integrated into routine TB screening or diagnosis.
Source: Jones-López EC. Nature Commun. 2026 Apr 14. Unexpected detection of Mycobacterium tuberculosis DNA in US-born patients in putative association with clinical syndromes