Work

Diagnostic information from a negative QuantiFERON-TB Gold Plus result in adults evaluated for tuberculosis in Brazil and South Africa

Year: 2026

Type: preprint

Abstract: ABSTRACT Interferon-gamma release assays detect Mycobacterium tuberculosis infection but cannot distinguish infection from active tuberculosis (TB). We evaluated the diagnostic information provided by QuantiFERON-TB Gold Plus (QFT-Plus) among adults investigated for active TB in Brazil and South Africa. Adults with presumptive TB were prospectively enrolled by convenience sampling. QFT-Plus was the index test, and diagnostic classification required microbiological confirmation of TB or an established alternative diagnosis. QFT-Plus results did not inform diagnostic classification. Accuracy was assessed among participants with determinate results, primarily using likelihood ratios. Of 723 participants tested, 48 (6.6%) had indeterminate results, all due to low mitogen responses. Among 675 participants with determinate results, 147 (21.8%) had confirmed TB. Sensitivity was 68.0% (95% CI, 60.1–75.0), specificity was 59.3% (95% CI, 55.0–63.4), and the negative likelihood ratio was 0.54 (95% CI, 0.42– 0.69). At the observed prevalence, a negative result left a 13.1% probability of active TB. Negative likelihood ratio confidence intervals included 1 in both South African HIV strata. Specificity was higher among participants with HIV in both countries. Adding TB2 to TB1 alone identified 15 additional TB cases and generated 18 additional positive results among participants without active TB. HIV and active TB were independently associated with indeterminate results in exploratory regression. A negative QFT-Plus result provided insufficient information to exclude active TB. Higher negative predictive values among participants with HIV reflected lower disease prevalence and higher specificity rather than greater sensitivity. Negative or indeterminate results should not terminate diagnostic evaluation. IMPORTANCE Blood tests that detect immune responses to Mycobacterium tuberculosis can yield negative results in people with active tuberculosis. Understanding how much reassurance a negative result provides is therefore important when these tests are encountered during diagnostic investigation. Among symptomatic adults in Brazil and South Africa, a negative QuantiFERON-TB Gold Plus result left a substantial probability of active disease. Differences between populations showed why apparently reassuring negative predictive values can be misleading. The additional antigen tube detected more cases but did not overcome the test’s limited ability to exclude disease. Indeterminate results were associated with human immunodeficiency virus infection and active tuberculosis. These findings support laboratory reporting and clinical interpretation that clearly communicate the limitations of negative and indeterminate results and the need for continued investigation when active tuberculosis remains suspected.

Source: medRxiv

DOI: 10.64898/2026.09.25.26363952