Sputum scarcity and associated factors in people undergoing tuberculosis testing in South Africa, Uganda, India, and the Philippines: an analysis of cross-sectional observational data

Background
Tuberculosis (TB) testing often excludes people who cannot expectorate sputum. Non-sputum tests are a priority; however, there are limited data on the frequency and characteristics of sputum scarcity, which will influence the impact of non-sputum tests.
Methods
We analysed adults with presumptive pulmonary TB recruited between February 2018 and February 2024 from a multi-country study (South Africa, Uganda, India, The Philippines; Cohort A, n = 2224), a South African cohort (Cohort B, n = 2179), and a South African cohort of people living with HIV (PLHIV) initiating antiretroviral therapy (ART) without syndromic selection (Cohort C, n = 297). Participants provided sputum for Xpert MTB/RIF Ultra (Ultra) and MGIT960 culture. Individuals unable to spontaneously produce sputum (non-salivary, >= 1 ml) underwent induction. We performed multivariable regression analysis and present adjusted ORs from LASSO to describe the relationship of variables with sputum scarcity. Separate sub-analysis was conducted for variables with >10% missing data.
Findings
Overall, 13% (618/4700) people had sputum scarcity. Female sex [adjusted odds ratio [(aOR) 1.58 (95% confidence interval (CI) 1.31, 1.91)], and culture-negativity [1.45 (1.02, 2.08)] were positively associated with sputum scarcity. In Cohort A and B, country was also positively associated with sputum scarcity: India [1.43 (1.07, 1.91) and The Philippines [7.16 (5.34, 9.61] relative to South Africa. Smoking [0.61 (0.43, 0.88)], TB symptoms: cough [0.17 (0.13, 025)] and night sweats [0.71 (0.58, 0.86)] were negatively associated with sputum scarcity as well as previous TB [0.63 (0.47, 0.85)]. In people with TB, the only additional factor associated with sputum scarcity was, among PLHIV, being on ART [3.70 (1.19, 11.46)] were positively associated with sputum scarcity. Ultra sensitivity did not differ between induced and expectorated sputum [84% (64, 95) vs. 89% (84, 93); p = 0.218].
Interpretation
People with sputum scarcity are more likely to be female, do not smoke, have few symptoms and test culture-negative. Sputum scarcity also shows geographic variation. Among people with TB, those on ART are more likely to be sputum-scare. Sputum induction did not compromise Ultra sensitivity compared to expectorated sputum. These findings highlight people who may benefit most from non-sputum tests and the importance of such tests in people with milder disease.