Summary
Background
Systematic screening for tuberculosis using Xpert Ultra generates “trace” results of uncertain significance. Additional microbiological testing in this context is often negative, but individuals with trace results might have early disease or elevated risk of tuberculosis.
Methods
We screened for tuberculosis with Xpert Ultra in Uganda, enrolling individuals with trace-positive results and Ultra-negative controls. Participants without tuberculosis on extensive initial evaluation were followed, with repeat testing at 1, 3, and 6 months after trace results, and at 12 and 24 months for all participants. We estimated cumulative cause-specific hazards of incident tuberculosis, considering a definition of tuberculosis that included clinician judgment and one based strictly on microbiological results. We compared participants with Ultra-trace versus Ultra-negative sputum, and subgroups of participants with Ultra-trace sputum.
Findings
Of 129 participants with trace-positive screening results, 45 (35%) were recommended for treatment upon enrollment, and eight were lost to follow-up within three months. Of 76 remaining participants followed for median 697 (interquartile range 179-714) days, 20 (26%) were recommended for tuberculosis treatment. The cumulative hazard of clinician-defined incident tuberculosis was 26% (95% confidence interval: 14-38%) at one year and 35% (19-52%) at two years, versus 2% (0-5%) at two years for controls. Hazards were similar for microbiologically defined incident tuberculosis. Incident tuberculosis was strongly associated with abnormal baseline chest X-ray (hazard ratio 15.0 [3.4-65.1]) but not with baseline symptoms.
Interpretation
Individuals with trace-positive sputum during screening, particularly those with abnormal chest imaging, are at substantial risk of incident tuberculosis over the subsequent two years.
Funding
National Institutes of Health
Research in context
Evidence before this study
Recent advances in tuberculosis research have shifted the disease framework from a binary classification of latent versus active tuberculosis to a continuum of disease states. They have also led to a better understanding of the dynamic disease course of early tuberculosis, which can either progress to culture-positive disease or regress spontaneously over time. “Trace” results from Xpert MTB/RIF Ultra (“Ultra”) are sometimes perceived as false positives in individuals who subsequently test negative on additional diagnostic assays. However, some of these individuals may have early tuberculosis that falls below the detection threshold of existing diagnostic tests and could progress to microbiologically detectable disease over time. To investigate this, we searched PubMed for studies published up to February 7, 2025, using the terms “tuberculosis” AND (“Xpert OR “Xpert Ultra” OR “Ultra”) AND “Trace” and also reviewed the reference lists of relevant search results. Two prevalence surveys that used Xpert Ultra as a confirmatory test for individuals with symptoms or an abnormal chest X-ray found that 20% and 46% of those with trace-positive sputum had positive cultures. In a study conducted in Uganda where Ultra was used as an initial screening test, only 14% of individuals with a trace-positive result had positive sputum cultures. However, no prior studies have prospectively examined the incidence of tuberculosis among individuals with a trace-positive Ultra result during systematic screening who are otherwise microbiologically negative and not started on treatment.
Added value of this study
In this study, individuals with Ultra trace-positive screening results who were not started on treatment after extensive diagnostic testing were followed for up to two years with repeated testing. About 25% developed tuberculosis during follow-up, and the 2-year cumulative hazard of incident tuberculosis was substantial at 35% (95% confidence interval 19-52%). Those who had a normal chest X-ray at enrollment were at significantly lower risk of developing tuberculosis. Incident tuberculosis risk was similar between those who reported symptoms at the time of enrollment and those who did not.
Implications of all the available evidence
The high incidence of tuberculosis observed among people with trace results in this study support provision of treatment to most individuals who receive trace results during tuberculosis screening. These results also demonstrate that X-ray could be a useful tool to guide treatment decision-making for individuals with trace-positive sputum.
