Estimating the contribution of subclinical tuberculosis disease to transmission – an individual patient data analysis from prevalence surveys

Abstract

Background Individuals with bacteriologically confirmed pulmonary tuberculosis disease (TB) that do not report symptoms (subclinical TB) represent around half of all prevalent cases of TB, yet their contribution to Mycobacterium tuberculosis (Mtb) transmission is unknown, especially compared to individuals who report symptoms at time of diagnosis (clinical TB). Relative infectiousness can be approximated by cumulative infections in household contacts, but such data are rare. Methods and Findings We reviewed the literature to identify studies where surveys of Mtb infection were linked to population surveys of TB disease. We collated individual population data for analysis and used literature on the relative durations of subclinical and clinical TB to estimate relative infectiousness through a cumulative hazard model, accounting for sputum-smear status. Relative prevalence of subclinical and clinical disease in high burden settings was used to estimate the contribution of subclinical TB to global Mtb transmission. We collated data on 414 index cases and 789 household contacts from three prevalence surveys (Bangladesh, Philippines, Viet Nam) and one case-finding trial in Viet Nam. The odds ratio of household infection prevalence was 1.2 (0.6-2.3, 95% Confidence Interval). Adjusting for duration of disease, we found a per-unit-time infectiousness of subclinical TB relative to clinical TB of 1.93 (0.62-6.18, 95% Prediction Interval (PrI)). 14 countries across Asia and Africa provided data on relative prevalence of subclinical and clinical TB, suggesting an estimated 68% (27-92%, 95% PrI) of global transmission is from subclinical TB. Conclusions Our results suggest that subclinical TB contributes substantially to transmission and needs to be diagnosed and treated for effective progress towards TB elimination.

The impact of alternative delivery strategies for novel tuberculosis vaccines in low-income and middle-income countries: a modelling study

“… 8 , 9 We represented tuberculosis natural history with eight compartments, allowing for M tuberculosis infection along a spectrum from uninfected to active clinical disease. 10 , 11 A detailed description is provided in appendix 5 (pp 3–14) .…”

Disease Transmission by Patients With Subclinical Tuberculosis

“…This evidence, combined with the findings in our study, suggests that classic TB symptoms, especially cough, are not required for TB transmission and subclinical TB is likely to contribute a substantial part of TB transmission on a population scale. This was suggested by a recent analysis of multiple datasets to which our data contributed [ 32 ]. While this analysis took a somewhat different approach in analyzing background transmission, the results were in line with ours.…”

Re-evaluating progression and pathways followingMycobacteria tuberculosisinfection within the spectrum of tuberculosis disease

“…A lower threshold acknowledging any infectious disease, regardless of reported symptoms, recognised another third of the cohort in addition to those with infectious, symptomatic disease. This encompassed all those who contribute to Mtb transmission (15,63). As nearly half of individuals who developed subclinical TB went on to develop clinical TB, a threshold of infectious disease has potential individual benefit through the opportunity to avert further morbidity and possible mortality, as well as population benefit from the interruption of further transmission.…”

“…Intermediate disease states between Mtb infection and infectious symptomatic TB disease merit further attention. Infectious subclinical TB is as prevalent as infectious symptomatic disease globally (14) and likely contributes substantially to onward transmission (15)(16)(17). Pathological disease is also highly prevalent (18), and, even when non-infectious, can be severe.…”