Systematic assessment of clinical and bacteriological markers for tuberculosis reveals discordance and inaccuracy of symptom-based diagnosis for treatment response monitoring

Abstract

Background: Clinical symptoms are the benchmark of tuberculosis (TB) diagnosis and monitoring of treatment response but are not clear how they relate to TB bacteriology, particularly the novel tuberculosis-molecular bacterial load assay (TB-MBLA).

Methods: Presumptive cases were bacteriologically confirmed for TB and assessed for symptoms and bacteriological resolution using smear microscopy (SM), culture, and TB-MBLA over 6-month treatment course. Kaplan-Meier and Kappa statistics were used to test the relationship between symptoms and bacteriological positivity.

Results: A cohort of 46 bacteriologically confirmed TB cases were analyzed for treatment response over a 6-month treatment course. Pre-treatment symptoms and bacteriological positivity concurred in over 70% of the cases. This agreement was lost in over 50% of cases whose chest pain, night sweat, and loss of appetite had resolved by week 2 of treatment. Cough resolved at a 3.2% rate weekly and was 0.3% slower than the combined bacteriological (average of MGIT and TB-MBLA positivity) resolution rate, 3.5% per week. A decrease in TB-MBLA positivity reflected a fall in bacillary load, 5.7 ± 1.3- at baseline to 0.30 ± 1.0- log₁₀ eCFU/ml at month 6, and closer to cough resolution than other bacteriological measures, accounting for the only one bacteriologically positive case out of seven still coughing at month 6. Low baseline bacillary load patients were more likely to be bacteriologically negative, HR 5.6, p = 0.003 and HR 3.2, p = 0.014 by months 2 and 6 of treatment, respectively.

Conclusion: The probability of clinical symptoms reflecting bacteriological positivity weakens as the patient progresses on anti-TB therapy, making the symptom-based diagnosis a less reliable marker of treatment response.

Keywords: TB symptoms; TB-MBLA; bacteriological tests; diagnosis; monitoring.

FIGURE 1

Screening workflow, enrollment, follow-up, and final outcomes. Three hundred and three patients were screened out because they were bacteriological test negative at diagnosis and were treated clinically. Of the 59 enrolled patients, seven patients withdrew from the study (two died, three transferred out of the area, and three were lost to follow-up). Six patients were excluded from the final analysis (four due to inconsistent Xpert MTB/RIF results at the health facility and confirmatory Xpert MTB/RIF test at the NIMR-MMRC testing laboratory and two patients had low sputum volume for TB-MBLA at baseline). Three patients were lost to follow-up and two patients who were HIV positive died.

FIGURE 2

Relationship of TB clinical symptoms clearance with bacteriological tests. Clinical symptoms resolved rapidly during TB therapy with the exception of cough and sputum production which resolved slowly than culture, microscopy, and TB-MBLA. Data are presented as the percentage (%) of patients with clinical symptoms and bacteriological positivity over the time in treatments (weeks).

FIGURE 3

Average bacteriological positivity compared to clinical symptoms clearance. Relationship of clinical symptoms clearance compared to average bacteriological positivity of TB-MBLA and culture. Clinical symptoms (sweats, loss of appetite, and chest pain) resolved more rapidly than the average bacteriological positivity. Resolution of cough was slow matching the resolution of average bacteriological positivity, while sputum production resolved more slowly than average bacteriological positivity. Data are presented as the percentage (%) of patients with clinical symptoms and average bacteriological positivity over the time in treatments (weeks). The average bacteriological positivity (±SD) was 96.7 ± 4.6, 82.6 ± 9.2, 44.6 ± 23.1, 4.3 ± 0, and 6.5 ± 3.04 at baseline (week 0), weeks 2, 8, 22, and 26, respectively.

FIGURE 4

Bacillary load clearance during treatment in relation to baseline bacterial loads. Kaplan–Meier curves show TB-MBLA bacillary load clearance by week 8 of treatment (A) and by the end of treatment week 26 (B) among patients with high and low baseline bacterial load. Low baseline bacterial load patients were more likely to clear bacillary load at week 8, HR 5.6, p = 0.003 and at week 26 of treatment, HR 3.2, p = 0.014 than high baseline bacterial load patients.