Bacterial and host determinants of cough aerosol culture positivity in patients with drug-resistant versus drug-susceptible tuberculosis

A burgeoning epidemic of drug-resistant tuberculosis threatens to derail global control efforts. Although the mechanisms remain poorly clarified, drug-resistant strains are widely believed to be less infectious than drug-susceptible strains. Consequently, we hypothesised that lower proportions of drug-resistant TB patients would have culturable Mycobacterium tuberculosis from respirable cough-generated aerosols compared to drug-susceptible TB patients, and that multiple factors, including mycobacterial genomic variation, would predict culturable cough aerosol production. We enumerated colony forming units (CFU) in aerosols (≤10μm) from 500 tuberculosis patients (227 with drug-resistance), compared clinical characteristics, and performed mycobacterial whole genome sequencing, dormancy phenotyping, and drug susceptibility analyses on M. tuberculosis from sputum. After considering treatment duration, we found that almost half of drug-resistant tuberculosis patients were cough aerosol culture-positive. Surprisingly, neither mycobacterial genomic variants, lineage, nor dormancy status predicted cough aerosol culture-positivity. However, mycobacterial sputum bacillary load and clinical characteristics, including a lower symptom score and stronger cough, were strongly predictive; thereby supporting targeted transmission-limiting interventions. Effective treatment largely abrogated cough aerosol culture-positivity, however, this was not always rapid. These data question current paradigms, inform public health strategies, and suggest the need to redirect tuberculosis transmission-associated research efforts towards host-pathogen interactions