A highly sensitive molecular test for tuberculosis (TB) detected Mycobacterium tuberculosis DNA in a surprising proportion of hospitalized patients, raising questions about undetected forms of the disease, according to a study published yesterday in Nature Communications.
Using an ultrasensitive assay that can detect TB at levels below the limits of standard diagnostic tools, a team led by Boston University (BU) researchers tested a set of 146 anonymized respiratory samples collected at two Boston hospitals from May to September 2013 and 50 control samples collected from May to July 2014.
To determine clinical associations and outcomes, they also conducted a longitudinal clinical study with 101 samples collected from February to June 2014; all patients but one were hospitalized.
The Totally Optimized PCR [polymerase chain reaction] TB assay found TB DNA in a notable number of patients; in an initial set of samples collected at the hospitals, 12.3% tested positive for TB DNA, compared with 2% of control samples. In the follow-up cohort, 15.8% of samples were positive, although one sample couldn’t be sequenced. An incidence rate of 12% to 16% is far higher than expected, given Boston’s low rate of TB cases.
Findings mirror known TB patterns in US
While the findings were unexpected, they line up with what researchers currently know about TB. For example, 75% of patients who tested positive for TB DNA were age 50 or older. That fits with US patterns, in which TB is more common in older adults. Most new TB cases in the United States, roughly 85%, come from infections that were picked up years earlier and then reactivated later in life.
Four young patients in the study tested positive for TB DNA, three of whom shared a diagnosis of acute chest syndrome, which is “a striking and potentially consequential clinical association,” write the researchers. Acute chest syndrome is a life-threatening complication of sickle cell disease.
The clinical meaning of these findings remains unclear. The researchers hypothesize that the results may point to a previously unrecognized form of TB, referred to as paucibacillary TB disease, in which bacterial levels are too low to be detected by conventional TB tests.
“We began this research with the intent of sourcing respiratory samples to support the ongoing development of a new molecular assay for TB,” senior author Guillermo Madico, MD, PhD, of BU School of Medicine, said in a BU news release. “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,” he added. “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.”
Diagnosed cases might be ‘tip of the iceberg’
The findings may be evidence of the “iceberg principle,” in which US TB cases that are diagnosed using standard TB tests represent the visible tip of the iceberg, while many more cases are hidden below the surface, write the researchers.
“These findings suggest we may be missing a significant burden of TB disease, particularly in older Americans and in patients with certain underlying conditions,” lead author Edward C. Jones-Lopez, MD, said in the news release. “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.”
While the findings warrant dissemination “given the potential implications for medical care and public health in the US, and elsewhere,” write the authors, more research is needed. “These results will require confirmation in larger prospective studies that include clinical, radiological, immunological, and microbiological correlation,” they add.
