The association between symptoms and microbiologically defined response to tuberculosis treatment

Abstract

Rationale: The lack of consistent associations between clinical outcomes and microbiological responses to therapy for some infectious diseases has raised questions about the adequacy of microbiological endpoints for tuberculosis treatment trials.

Objectives: To evaluate the association between symptoms and microbiological response to tuberculosis treatment.

Methods: We performed a retrospective analysis of four clinical trials in which participants had culture-positive tuberculosis, standardized symptom assessment, and follow-up mycobacterial cultures. Two trials (studies 22 and 23) followed participants to identify recurrent tuberculosis; participants in studies 27 and 28 were only followed to treatment completion.

Measurements and main results: This analysis included 1,978 participants; 39 (2.0%) had culture-confirmed treatment failure, and 75 (3.9%) had culture-confirmed recurrence. Productive cough was associated with indices of increased mycobacterial burden at diagnosis (acid-fast smear grade, severity of radiographic abnormalities). Fever and sweats improved rapidly with treatment, whereas productive cough decreased more slowly and was present in 20% of visits after treatment completion. During treatment, study participants with productive cough more often had concurrent culture positivity compared with those without productive cough (studies 22 and 23: adjusted odds ratio, 1.80; 95% confidence interval [CI], 1.33-2.44). Finally, symptoms during the latter part of treatment and follow-up were associated with culture-confirmed treatment failure and recurrence in studies 22 and 23 (for cough: adjusted hazard ratio, 2.07; 95% CI, 1.23-3.49; for fever: adjusted hazard ratio, 5.05; 95% CI, 2.76-9.19).

Conclusions: There are consistent relationships between symptoms and microbiological indices of tuberculosis, including measures of mycobacterial burden at baseline, culture positivity during treatment, and time to culture-confirmed treatment failure and recurrence.

Figure 1.

Frequency of fever (A), sweats (B), productive cough (C), and culture positivity (by solid or liquid culture) (D) during Weeks 0 to 24 after initiation of tuberculosis treatment among patients in Tuberculosis Trials Consortium (TBTC) Studies 22, 23, 27, and 28. Study 23 data are not included for Week 0 because enrollment occurred after the beginning of treatment.