Mycobacterium avium complex (MAC) genomics and transmission in a London hospital

Non-tuberculous mycobacteria (NTM) are ubiquitous environmental microorganisms and opportunistic pathogens in individuals with pre-existing lung conditions such as cystic fibrosis (CF) and non-CF bronchiectasis (BX). Whilst recent studies of Mycobacterium abscessus have identified transmission within single CF centres as well as nationally and globally, transmission of other NTM species is less well studied. We sequenced 996 Mycobacterium avium complex (MAC) isolates from CF and non-CF patients at the Royal Brompton Hospital (RBH), London. Genomic analysis was used to analyse local transmission. Epidemiological links were identified from patient records. These and previously published genomes were used to characterise global population structures. Analysis of the three predominant MAC species identified putative transmission clusters that contained patients with CF, BX and other lung conditions, although few epidemiological links could be identified. For M. avium, lineages were largely limited to single countries, whilst for M. chimaera, global transmission clusters previously associated with heater cooler units (HCUs) were found. However, the immediate ancestor of the lineage causing the major HCU-associated outbreak was a lineage already circulating in patients with pre-existing lung conditions. CF and non-CF patients shared transmission chains even in the presence of CF patient-focussed hospital control measures, although the lack of epidemiological links suggested that most transmission is indirect and may involve environmental intermediates or else asymptomatic carriage in the wider population. The major HCU-associated M. chimaera lineage being derived from an already circulating lineage, suggests that HCUs, while being responsible for a major global transmission event, are not the sole vector nor the ultimate source of this wider patient-infecting lineage. Future studies should include sampling of environmental reservoirs and potential asymptomatic carriers. Author summaryWhilst recent studies in Mycobacterium abscessus have identified transmission within single CF centres as well as nationally and globally, the transmission dynamics between CF and non-CF patients has not yet been comprehensively examined in the Mycobacterium avium complex (MAC). We believe this is the first study to use a well-sampled longitudinal isolate dataset, that includes both CF and non-CF patients from a single hospital setting, to investigate transmission of MAC species. We identified transmission clusters in the three predominant MAC species circulating in the hospital and showed that these included both CF and non-CF patients. We then incorporated isolates from previous studies to examine the global population structure of MAC species and showed that for M. avium there were UK-specific lineages circulating amongst patients, whilst for M. chimaera we could identify global lineages associated with HCUs. For the first time, we also show that the predominant HCU-associate lineage is likely derived from already circulating lineages associated with patients with respiratory diseases. Our study shows the value of integrating whole genome sequencing with epidemiological data to perform high-resolution molecular analyses to characterise MAC populations and identify transmission clusters. Knowledge of putative transmission networks can improve responses to outbreaks and inform targeted infection control and clinical practice.