Investigating Nontuberculous Mycobacteria Transmission at the Colorado Adult Cystic Fibrosis Program

Jane E Gross, Silvia Caceres, Katie Poch, Nabeeh A Hasan, Fan Jia, L Elaine Epperson, Ettie Lipner, Charmie Vang, Jennifer R Honda, Matthew Strand, Vinicius Calado Nogueira de Moura, Charles L Daley, Michael Strong, Rebecca M Davidson, Jerry A Nick, Jane E Gross, Silvia Caceres, Katie Poch, Nabeeh A Hasan, Fan Jia, L Elaine Epperson, Ettie Lipner, Charmie Vang, Jennifer R Honda, Matthew Strand, Vinicius Calado Nogueira de Moura, Charles L Daley, Michael Strong, Rebecca M Davidson, Jerry A Nick

Abstract

Rationale: Healthcare-associated transmission of nontuberculous mycobacteria (NTM) among people with cystic fibrosis (pwCF) has been investigated at CF centers worldwide, with conflicting conclusions. We investigated transmission at the Colorado Adult CF Program. Objectives: To systematically investigate healthcare-associated transmission and/or acquisition of NTM to determine similarity among respiratory and environmental isolates, and to compare home residence watershed mapping among pwCF having genetically similar NTM isolates. Methods: Whole-genome sequencing of NTM isolates from 80 pwCF was conducted to identify genetically similar isolate clusters (⩽30 SNP differences). Epidemiology, comparison of respiratory and environmental isolates, and home residence watershed mapping were analyzed. Measurements and Main Results: Whole-genome sequencing analysis revealed 11 clusters of NTM [6 Mycobacterium abscessus subspecies (ssp.) abscessus, 1 M. abscessus ssp. massiliense, 2 Mycobacterium avium, and 2 Mycobacterium intracellulare] among pwCF. Epidemiologic investigation demonstrated opportunities for healthcare-associated transmission in two M. abscessus and two M. avium clusters. Respiratory and healthcare environmental isolate comparisons revealed no genetic similarity. Individuals comprising one M. abscessus cluster, with no plausible healthcare-associated transmission, resided in the same watershed. Conclusions: This study suggests healthcare-associated transmission of M. abscessus is rare and includes a report of potential healthcare-associated transmission of M. avium among pwCF. One M. abscessus cluster possibly had common acquisition arising from residing in the same watershed. The presence of genetically similar isolates is insufficient to demonstrate healthcare-associated NTM transmission. Standardizing epidemiologic investigation, combined with environmental sampling and watershed analysis, will improve understanding of the frequency and nature of healthcare-associated NTM transmission among pwCF.

Keywords: cystic fibrosis; epidemiology; nontuberculous mycobacteria; transmission; whole-genome sequencing.

Figures

Figure 1.
Figure 1.
Healthcare-associated transmission of nontuberculous mycobacteria (NTM) investigation. The flow diagram (A) overview and (B) Colorado Adult CF Center investigation results. *WGS criteria defined as more than three positive NTM cultures in 7 years. CF = cystic fibrosis; pwCF = people with cystic fibrosis; WGS = whole-genome sequencing.
Figure 2.
Figure 2.
Phylogenetic trees comprising all locally identified clusters among people with cystic fibrosis at the Colorado Adult CF Program are shown. Reference isolates, including type strains and previously published isolate genomes, are shown as gray circles with labels. Epidemiologically excluded subjects are identified by black squares. The 11 sets of clustered nontuberculous mycobacteria isolates are represented as colored circles, with each letter representing a cluster (A–K). The number in the cluster identifies the subject order based on the first positive culture. The six Mycobacterium abscessus subspecies (ssp.) abscessus clusters are shown with four clusters in the dominant circulating clone 1 (DCC1), (A) enlarged for detail. (B) Two Mycobacterium avium clusters, (C) one Mycobacterium abscessus ssp. massiliense cluster, and (D) two Mycobacterium intracellulare clusters are shown. CF = cystic fibrosis.
Figure 3.
Figure 3.
Cluster network analysis. Nontuberculous mycobacteria species are identified by color, and the letter identifies the cluster: Mycobacterium abscessus subspecies (ssp.) abscessus shown in yellow, Mycobacterium intracellulare shown in orange, Mycobacterium abscessus ssp. massiliense shown in blue, and Mycobacterium avium shown in green. Nodes represent each subject within a cluster. The number in the node identifies the subject order based on first positive culture. Core genome SNP distance is shown with the line connecting nodes.
Figure 4.
Figure 4.
Timeline overlap analysis of people with cystic fibrosis identified in nontuberculous mycobacteria (NTM) clusters demonstrating clinic visits (open circles), hospitalization days (closed circles), within–24-hour clinic overlap (vertical dashed lines), within–12-hour clinic overlap (vertical solid lines), and hospitalization overlap (vertical purple bars). Subject NTM status is represented as smear and culture positive (red plus), smear negative and culture positive (yellow plus), and smear and culture negative (blue dash). The letter identifies the cluster, and the number identifies the subject order based on first positive culture date. Clusters that did not have overlaps or had overlaps occurring >2 years before the second subject becoming NTM positive are not shown. DCC = dominant circulating clone. M. = Mycobacterium.
Figure 5.
Figure 5.
(A) Healthcare environmental sample collection of the clinic and hospital settings demonstrating nontuberculous mycobacteria (NTM) diversity and comparison with respiratory isolates from people with cystic fibrosis (pwCF) is shown. (B) Within the state of Colorado, (B.1) cities and county lines are shown. (B.2) Watershed boundaries are shown, and (B.3) home of residence mapping of pwCF in Mycobacterium abscessus subspecies (ssp.) abscessus clusters demonstrates M. abscessus cluster E shared the same home residence watershed in the absence of any evidence of healthcare-associated overlaps. Mycobacterium intracellulare, Mycobacterium abscessus ssp. massiliense, and Mycobacterium avium clusters (not shown) did not demonstrate shared home of residence watershed.
Figure 6.
Figure 6.
Integrated pan-genome analysis comparing SNP differences between pairs of nontuberculous mycobacteria isolates within clusters (x-axis) versus percentage shared accessory genome (y-axis). Mycobacterium abscessus (ssp.) abscessus clusters are represented by circles, Mycobacterium avium clusters are represented by triangles, the Mycobacterium intracellulare cluster is represented by a diamond, and the Mycobacterium abscessus ssp. massiliense cluster is represented by an upside-down triangle. Clusters A (blue circles) and J (scarlet circles), as well as M. avium clusters D (caramel triangles) and I (chartreuse triangles), demonstrated episodes of healthcare-associated opportunities for transmission. Cutoff points of ⩽10 SNPs and ⩾95% shared accessory genome are noted in the dashed line box, representing the most stringent degree of clustered isolate similarity. M. avium cluster D, with sequential healthcare-associated opportunity for transmission from D1 to D2 and D2 to D3, M. abscessus cluster K with no evidence of healthcare-associated opportunity for transmission, and M. abscessus cluster E, with no evidence of healthcare-associated opportunity for transmission but residing in the same watershed, fall within the stringent genetic similarity cutoffs.

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