Clinical factors associated with negative GeneXpert Ultra results among adults with pulmonary TB disease

Abstract

Abstract Background: Xpert MTB/RIF Ultra is a sputum diagnostic test for pulmonary tuberculosis (TB) disease, but false negative results may occur. Understanding the characteristics associated with Ultra-negative pulmonary TB disease (UN-PTB) can minimize risks of missed or delayed diagnosis in TB endemic regions. Methods: We conducted a secondary analysis of the PROVE TB 1 and 2 studies, which were prospective cohorts of adults being evaluated at several clinics or a hospital for pulmonary TB disease in KwaZulu-Natal, South Africa. For both studies, participants at risk of pulmonary TB disease were enrolled and followed for at least two months. At time of initiation of anti-TB therapy, TB nurses collected sputum specimens for Xpert Ultra, as well as solid and liquid Mycobacterium tuberculosis (Mtb) culture. Participants could have been either microbiologically or clinically diagnosed with pulmonary TB, and those Ultra-negative were considered to have UN-PTB. Logistic regression was used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for factors associated with UN-PTB. Results: Among 424 adults with pulmonary TB disease, with a median age of 37 years, 44% female, and 77% were living with HIV. 199 (47%) people had UN-PTB at baseline, including 5 participants with positive Mtb cultures. Among those with UN-PTB, 100 (50%) were diagnosed empirically at baseline and 99 (50%) were diagnosed during follow-up. Compared to participants with Ultra-positive PTB, those with UN-PTB were more likely to be female, living with HIV, and hospitalized at enrollment. In multivariable analyses, UN-PTB was associated with hospitalization at enrollment (aOR 2.66, 95% CI 1.72–4.15), chest X-ray findings not indicative of TB (aOR 2.09, 95% CI 1.14–3.88), living with HIV (aOR 1.85, 95% CI 1.10–3.15), and female sex (aOR 1.73, 95% CI 1.14–2.64. Cough was associated with a significantly lower odds of UN-PTB (aOR 0.47, 95% CI 0.23–0.89). Conclusions: In this South African cohort, roughly half of people diagnosed with pulmonary TB disease had UN-PTB. UN-PTB was more common among patients who were hospitalized, living with HIV, female, or had chest X-ray findings not suggestive of TB. These findings identify clinical and diagnostic gaps that could be addressed to reduce the risk of missed or delayed TB diagnosis.