Revisiting the Natural History of Pulmonary Tuberculosis: A Bayesian Estimation of Natural Recovery and Mortality Rates.

BACKGROUND: Tuberculosis (TB) natural history remains poorly characterized, and new investigations are impossible as it would be unethical to follow up TB patients without treatment. METHODS: We considered the reports identified in a previous systematic review of studies from the prechemotherapy era, and extracted detailed data on mortality over time. We used a Bayesian framework to estimate the rates of TB-induced mortality and self-cure. A hierarchical model was employed to allow estimates to vary by cohort. Inference was performed separately for smear-positive TB (SP-TB) and smear-negative TB (SN-TB). RESULTS: We included 41 cohorts of SP-TB patients and 19 cohorts of pulmonary SN-TB patients in the analysis. The median estimates of the TB-specific mortality rates were 0.389 year-1 (95% credible interval [CrI], .335-.449) and 0.025 year-1 (95% CrI, .017-.035) for SP-TB and SN-TB patients, respectively. The estimates for self-recovery rates were 0.231 year-1 (95% CrI, .177-.288) and 0.130 year-1 (95% CrI, .073-.209) for SP-TB and SN-TB patients, respectively. These rates correspond to average durations of untreated TB of 1.57 years (95% CrI, 1.37-1.81) and 5.35 years (95% CrI, 3.42-8.23) for SP-TB and SN-TB, respectively, when assuming a non-TB-related mortality rate of 0.014 year-1 (ie, a 70-year life expectancy). CONCLUSIONS: TB-specific mortality rates are around 15 times higher for SP-TB than for SN-TB patients. This difference was underestimated dramatically in previous TB modeling studies, raising concerns about the accuracy of the associated predictions. Despite being less infectious, SN-TB may be responsible for equivalent numbers of secondary infections as SP-TB due to its much longer duration.

The Importance of Heterogeneity to the Epidemiology of Tuberculosis.

Although less well-recognized than for other infectious diseases, heterogeneity is a defining feature of tuberculosis (TB) epidemiology. To advance toward TB elimination, this heterogeneity must be better understood and addressed. Drivers of heterogeneity in TB epidemiology act at the level of the infectious host, organism, susceptible host, environment, and distal determinants. These effects may be amplified by social mixing patterns, while the variable latent period between infection and disease may mask heterogeneity in transmission. Reliance on notified cases may lead to misidentification of the most affected groups, as case detection is often poorest where prevalence is highest. Assuming that average rates apply across diverse groups and ignoring the effects of cohort selection may result in misunderstanding of the epidemic and the anticipated effects of control measures. Given this substantial heterogeneity, interventions targeting high-risk groups based on location, social determinants, or comorbidities could improve efficiency, but raise ethical and equity considerations.

The role of super-spreading events in Mycobacterium tuberculosis transmission: evidence from contact tracing.

BACKGROUND: In current epidemiology of tuberculosis (TB), heterogeneity in infectiousness among TB patients is a challenge, which is not well studied. We aimed to quantify this heterogeneity and the presence of "super-spreading" events that can assist in designing optimal public health interventions. METHODS: TB epidemiologic investigation data notified between 1 January 2005 and 31 December 2015 from Victoria, Australia were used to quantify TB patients' heterogeneity in infectiousness and super-spreading events. We fitted a negative binomial offspring distribution (NBD) for the number of secondary infections and secondary active TB disease each TB patient produced. The dispersion parameter, k, of the NBD measures the level of heterogeneity, where low values of k (e.g. k < 1) indicate over-dispersion. Super-spreading was defined as patients causing as many or more secondary infections as the 99th centile of an equivalent homogeneous distribution. Contact infection was determined based on a tuberculin skin test (TST) result of ≥10 mm. A NBD model was fitted to identify index characteristics that were associated with the number of contacts infected and risk ratios (RRs) were used to quantify the strength of this association. RESULTS: There were 4190 (2312 pulmonary and 1878 extrapulmonary) index TB patients and 18,030 contacts. A total of 15,522 contacts were tested with TST, of whom 3213 had a result of ≥10 mm. The dispersion parameter, k for secondary infections was estimated at 0.16 (95%CI 0.14-0.17) and there were 414 (9.9%) super-spreading events. From the 3213 secondary infections, 2415 (75.2%) were due to super-spreading events. There were 226 contacts who developed active TB disease and a higher level of heterogeneity was found for this outcome than for secondary infection, with k estimated at 0.036 (95%CI 0.025-0.046). In regression analyses, we found that infectiousness was greater among index patients found by clinical presentation and those with bacteriological confirmation. CONCLUSION: TB transmission is highly over dispersed and super-spreading events are responsible for a substantial majority of secondary infections. Heterogeneity of transmission and super-spreading are critical issues to consider in the design of interventions and models of TB transmission dynamics.

Heterogeneous infectiousness in mathematical models of tuberculosis: A systematic review.

TB mathematical models employ various assumptions and approaches in dealing with the heterogeneous infectiousness of persons with active TB. We reviewed existing approaches and considered the relationship between them and existing epidemiological evidence. We searched the following electronic bibliographic databases from inception to 9 October 2018: MEDLINE, EMBASE, Biosis, Global Health and Scopus. Two investigators extracted data using a standardised data extraction tool. We included in the review any transmission dynamic model of M. tuberculosis transmission explicitly simulating heterogeneous infectiousness of person with active TB. We extracted information including: study objective, model structure, number of active TB compartments, factors used to stratify the active TB compartment, relative infectiousness of each active TB compartment and any intervention evaluated in the model. Our search returned 1899 unique references, of which the full text of 454 records were assessed for eligibility, and 99 studies met the inclusion criteria. Of these, 89 used compartmental models implemented with ordinary differential equations, while the most common approach to stratification of the active TB compartment was to incorporate two levels of infectiousness. However, various clinical characteristics were used to stratify the active TB compartments, and models differed as to whether they permitted transition between these states. Thirty-four models stratified the infectious compartment according to sputum smear status or pulmonary involvement, while 18 models stratified based on health care-related factors. Variation in infectiousness associated with drug-resistant M. tuberculosis was the rationale for stratifying active TB in 33 models, with these models consistently assuming that drug-resistant active TB cases were less infectious. Given the evidence of extensive heterogeneity in infectiousness of individuals with active TB, an argument exists for incorporating heterogeneous infectiousness, although this should be considered in light of the objectives of the study and the research question. PROSPERO Registration: CRD42019111936.