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. 2024 Jul 9;16(1):86.
doi: 10.1186/s13073-024-01359-8.

Clinical and genomic features of Mycobacterium avium complex: a multi-national European study

Nils Wetzstein #  1   2   3 , Margo Diricks #  4   5 , Thomas B Anton  6 , Sönke Andres  5   7 , Martin Kuhns  5   7 , Thomas A Kohl  4   5 , Carsten Schwarz  8 , Astrid Lewin  9 , Jan Kehrmann  10 , Barbara C Kahl  11 , Annika Schmidt  12 , Stefan Zimmermann  13 , Moritz K Jansson  14 , Sophie A Baron  15 , Bettina Schulthess  16 , Michael Hogardt  17   18 , Inna Friesen  5   7 , Stefan Niemann #  4   5   7 , Thomas A Wichelhaus #  17
Affiliations

Clinical and genomic features of Mycobacterium avium complex: a multi-national European study

Nils Wetzstein et al. Genome Med. .

Abstract

Background: The Mycobacterium avium complex (MAC) comprises the most frequent non-tuberculous mycobacteria (NTM) in Central Europe and currently includes twelve species. M. avium (MAV), M. intracellulare subsp. intracellulare (MINT), and M. intracellulare subsp. chimaera (MCH) are clinically most relevant. However, the population structure and genomic landscape of MAC linked with potential pathobiological differences remain little investigated.

Methods: Whole genome sequencing (WGS) was performed on a multi-national set of MAC isolates from Germany, France, and Switzerland. Phylogenetic analysis was conducted, as well as plasmids, resistance, and virulence genes predicted from WGS data. Data was set into a global context with publicly available sequences. Finally, detailed clinical characteristics were associated with genomic data in a subset of the cohort.

Results: Overall, 610 isolates from 465 patients were included. The majority could be assigned to MAV (n = 386), MCH (n = 111), and MINT (n = 77). We demonstrate clustering with less than 12 SNPs distance of isolates obtained from different patients in all major MAC species and the identification of trans-European or even trans-continental clusters when set into relation with 1307 public sequences. However, none of our MCH isolates clustered closely with the heater-cooler unit outbreak strain Zuerich-1. Known plasmids were detected in MAV (325/1076, 30.2%), MINT (62/327, 19.0%), and almost all MCH-isolates (457/463, 98.7%). Predicted resistance to aminoglycosides or macrolides was rare. Overall, there was no direct link between phylogenomic grouping and clinical manifestations, but MCH and MINT were rarely found in patients with extra-pulmonary disease (OR 0.12 95% CI 0.04-0.28, p < 0.001 and OR 0.11 95% CI 0.02-0.4, p = 0.004, respectively) and MCH was negatively associated with fulfillment of the ATS criteria when isolated from respiratory samples (OR 0.28 95% CI 0.09-0.7, p = 0.011). With 14 out of 43 patients with available serial isolates, co-infections or co-colonizations with different strains or even species of the MAC were frequent (32.6%).

Conclusions: This study demonstrates clustering and the presence of plasmids in a large proportion of MAC isolates in Europe and in a global context. Future studies need to urgently define potential ways of transmission of MAC isolates and the potential involvement of plasmids in virulence.

Keywords: Mycobacterium avium; Mycobacterium avium complex; Mycobacterium chimaera; Mycobacterium intracellulare; Genome; Genomics; MAC; NTM; Non-tuberculous mycobacteria; Whole genome sequencing.

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Conflict of interest statement

Nils Wetzstein, Margo Diricks, Thomas B. Anton, Sönke Andres, Thomas A. Kohl, Carsten Schwarz, Astrid Lewin, Barbara C. Kahl, Annika Schmidt, Stefan Zimmermann, Moritz K. Jansson, Sophie Baron, Bettina Schulthess, Inna Friesen, and Stefan Niemann have nothing to disclose.

Martin Kuhns received institutional funding as National Reference Laboratory from the German Ministry of Health, institutional contracts with Bruker/Hain Liefescience, and INSTAND, and support for attending meetings from the German Ministry of Health. Jan Kehrmann received honoraria for lectures and support for travel from INSMED outside the submitted work. Michael Hogardt reports grants from Mukoviszidose Institut gGmbH and the German Federal Ministry of Health, honoraria for lectures from the Landesärztekammer Hessen and bioMérieux, and funding from Merck AG outside the submitted work. Thomas A. Wichelhaus reports research grants from BMBF, JPIAMR, Deutsche Krebshilfe, MSD as well as speaker fees and consulting honoraria from Insmed, Osartis, all outside the submitted work.

Figures

Fig. 1
Fig. 1
Map of geographical origin of included isolates (A), timeline of included isolates (B), and sample types of included isolates (C). n.f.s.—not further specified
Fig. 2
Fig. 2
Mash distance tree of included isolates in this study (n = 610) and 17 reference strains (red points). Inner ring— species, 2nd ring—site of sampling, 3rd ring— pulmonary or extrapulmonary sample, fourth ring—clustering of isolate (overall—clusters with less than 12 SNPs in species-specific SNP analysis, specific—clusters with species specific threshold in cluster-specific analysis), fifth ring—presence of known plasmids. MAVa—M. avium subsp. avium, MCH—M. intracellulare subsp. chimaera, MINT—M. intracellulare subsp. intracellulare, NA—not available, n—no, y—yes
Fig. 3
Fig. 3
Age density plot (A), maximum-likelihood phylogenetic tree of first isolates from single patients (n = 184), based on 30,345 distinct alignment patterns, (B), and overall clinical characteristics (C) of patients from Frankfurt University Hospital. IP—isolated pulmonary manifestation, IE—isolated extra-pulmonary manifestation, diss.—disseminated disease, NA—not applicable, n—no, y—yes
Fig. 4
Fig. 4
Timeline of serial isolates in 43 patients treated at Frankfurt University hospital (left panel) and associated clinical characteristics (right panel). Clonal—same strain during the whole observation period, multiple strains—different strains of the same species or different species within the MAC, different species—different species within the MAC. CF—cystic fibrosis, HIV—human immunodeficiency virus, n—no, y—yes
See this image and copyright information in PMC

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