Durations of asymptomatic, symptomatic, and care-seeking phases of tuberculosis disease with a Bayesian analysis of prevalence survey and notification data

Abstract

Background: Ratios of bacteriologically positive tuberculosis (TB) prevalence to notification rates are used to characterise typical durations of TB disease. However, this ignores the clinical spectrum of tuberculosis disease and potentially long infectious periods with minimal or no symptoms prior to care-seeking.

Methods: We developed novel statistical models to estimate progression from initial bacteriological positivity including smear conversion, symptom onset and initial care-seeking. Case-detection ratios, TB incidence, durations, and other parameters were estimated by fitting the model to tuberculosis prevalence survey and notification data (one subnational and 11 national datasets) within a Bayesian framework using Markov chain Monte Carlo methods.

Results: Analysis across 11 national datasets found asymptomatic tuberculosis durations in the range 4-8 months for African countries; three countries in Asia (Cambodia, Lao PDR, and Philippines) showed longer durations of > 1 year. For the six countries with relevant data, care-seeking typically began half-way between symptom onset and notification. For Kenya and Blantyre, Malawi, individual-level data were available. The sex-specific durations of asymptomatic bacteriologically-positive tuberculosis were 9.0 months (95% credible interval [CrI]: 7.2-11.2) for men and 8.1 months (95% CrI: 6.2-10.3) for women in Kenya, and 4.9 months (95% CrI: 2.6-7.9) for men and 3.5 months (95% CrI: 1.3-6.2) for women in Blantyre. Age-stratified analysis of data for Kenya showed no strong age-dependence in durations. For Blantyre, HIV-stratified analysis estimated an asymptomatic duration of 1.3 months (95% CrI: 0.3-3.0) for HIV-positive people, shorter than the 8.5 months (95% CrI: 5.0-12.7) for HIV-negative people. Additionally, case-detection ratios were higher for people living with HIV than HIV-negative people (93% vs 71%).

Conclusion: Asymptomatic TB disease typically lasts around 6 months. We found no evidence of age-dependence, but much shorter durations among people living with HIV, and longer durations in some Asian settings. To eradicate TB transmission, greater gains may be achieved by proactively screening people without symptoms through active case finding interventions.

Keywords: Bayesian statistics; Care-seeking; Epidemiology; Sub-clinical tuberculosis; Tuberculosis.

Fig. 1

Diagrams of model structure. White boxes are states representing all bacteriologically-positive TB accessible to prevalence surveys, with structure matched to available data. Dashed arrows represent transitions out of active disease, either through self-cure or death. Models are additionally stratified by sex, and for Kenya and Blantyre, Malawi by age and HIV in addition

Fig. 2

Total time in months spent in each state during bacteriologically-positive TB disease. ‘Not diagnosed’ includes all states (white boxes) in Fig. 1. Median and 95% quantiles are shown as points and error bars, respectively. Posterior distributions are shown by coloured kernel density estimates

Fig. 3

Smear-conversion rate and initial proportion smear-positive in symptomatic bacteriologically-positive TB disease. A joint posterior probability densities of initial proportion smear-positive (y-axis) and hazard of converting from smear-negative to smear-positive (x-axis) in symptomatic bacteriologically-positive TB by country, based on Model 3. B the correlation of percentage smear-positive at symptom onset and smear-type conversion rate. X-axis indicates the slopes of A estimated by linear regression (KHM = Cambodia, ETH = Ethiopia, KEN = Kenya, LAO = Lao People’s Democratic Republic, MWI = Malawi, PAK = Pakistan, PHL = Philippines, TZA = United Republic of Tanzania, UGA = Uganda, VNM = Viet Nam, ZMB = Zambia) (C) joint probability density of initial proportion smear-positive (y-axis) and hazard of converting from smear-negative to smear-positive (x-axis) pooled by weights of notified cases in 2019 (excluding Malawi and Vietnam as outliers)

Fig. 4

Healthcare cascade. The values are the fraction of the incident cohort reaching each stage. The second bars may be missing if the TB prevalence survey did not report results on care-seeking behaviour