Molecular Epidemiologic Investigation of Mycobacterium intracellulare Subspecies chimaera Lung Infections at an Adult Cystic Fibrosis Program

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

Abstract

Rationale: Outbreaks of nontuberculous mycobacteria (NTM) among people with cystic fibrosis (pwCF) have been reported at CF centers with conflicting conclusions. The occurrence of NTM at the UVMC (University of Vermont Medical Center) adult CF program was investigated. Objectives: Use the HALT NTM (Healthcare-associated Links in Transmission of NTM) toolkit to investigate the healthcare-associated transmission and/or acquisition of NTM among pwCF having genetically similar NTM isolates. Methods: Whole genome sequencing of NTM isolates from 23 pwCF was conducted to identify genetically similar NTM isolate clusters (30 or fewer single-nucleotide polymorphism differences). The epidemiological investigation, comparison of respiratory and healthcare environmental isolates, and home residence watershed mapping were analyzed. Results: Whole genome sequencing analysis revealed two clusters of NTM isolates (Mycobacterium avium and M. intracellulare ssp. chimaera) among pwCF. The epidemiologic investigation demonstrated opportunities for healthcare-associated transmission within both clusters. Healthcare environmental M. avium isolates revealed no genetic similarity to respiratory isolates. However, M. intracellulare ssp. chimaera respiratory isolates revealed greater genetic similarity to a hospital water biofilm isolate than to each other. Neither cluster had all subjects residing in the same watershed. Conclusions: This study suggests the healthcare-associated transmission of M. avium among pwCF is unlikely at UVMC but supports the healthcare-associated environmental acquisition of M. intracellulare ssp. chimaera. The presence of genetically similar isolates alone is insufficient to confirm healthcare-associated transmission and/or acquisition. The HALT NTM toolkit standardizes outbreak investigation with genetic analysis, epidemiologic investigation, healthcare environmental sampling, and home of residence watershed identification to test the frequency and nature of healthcare-associated NTM transmission among pwCF.

Keywords: CF; Mycobacterium avium; Mycobacterium chimaera; transmission; whole genome sequencing.

Figures

Figure 1.
Figure 1.
Phylogenetic trees comprising locally identified nontuberculous mycobacterial clusters among people with cystic fibrosis (CF) at the UVMC (University of Vermont Medical Center) adult CF program. Reference isolates, including type strains and previously published isolate genomes, are shown in gray circles with labels. Isolates from subjects receiving care at UVMC not identified in a cluster are represented in gray circles (unlabeled). (A and B) The two sets of clustered nontuberculous mycobacteria isolates are represented as colored circles, with each letter representing a cluster. The number in the cluster identifies the subject order on the basis of the first positive culture. The Mycobacterium intracellulare ssp. chimaera cluster (pink circles), M. avium cluster (blue circles), and one healthcare environmental isolate (green circle) are shown. SNP = single nucleotide polymorphism.
Figure 2.
Figure 2.
Nontuberculous mycobacteria (NTM) cluster network analysis. NTM species are identified by color, and the letter identifies the cluster: Mycobacterium intracellulare ssp. chimaera are shown in pink, M. avium are shown in blue, and the hospital water biofilm environmental isolate is shown in green. Nodes represent each subject infected by a clustered NTM isolate. The number in the node identifies the subject order on the basis of the first positive culture. Core genome single nucleotide polymorphism distances are shown as solid lines connecting patient-to-patient isolates and dashed lines connecting patient-to-healthcare environment isolates.
Figure 3.
Figure 3.
Timeline overlap analysis of people with cystic fibrosis infected by clustered nontuberculous mycobacteria (NTM) isolates demonstrating clinic visits (open circles), hospitalization days (solid circles), same-day clinic overlap (vertical solid lines), and hospitalization overlap (vertical purple bars). Subject NTM status is represented as smear negative and culture positive Mycobacterium avium complex (MAC; green plus), smear negative, culture positive whole genome sequenced and subspeciated (yellow plus), smear and culture negative (blue dash), and NTM positive for MAC prior to 2015. No subjects were identified as smear positive. The letter identifies the NTM cluster, and the number identifies the subject order on the basis of the first positive culture date. MAC = Mycobacterium avium complex; WGS = whole genome sequencing.
Figure 4.
Figure 4.
(A) Healthcare environmental sample collection of the clinic and hospital settings demonstrating nontuberculous mycobacterial (NTM) diversity and comparison with respiratory isolates from people with cystic fibrosis (pwCF) is shown. (B) A map of the inpatient cystic fibrosis hospital floor is shown. Rooms highlighted in green are where biofilms were sampled. Red room numbers are rooms in which pwCF in the Mycobacterium intracellulare ssp. chimaera cluster resided during one or more hospital admissions. The hospital water fountain is where the M. chimaera environmental isolate was recovered. NTM = nontuberculous mycobacteria; pwCF = people with cystic fibrosis.
Figure 5.
Figure 5.
Integrated pan-genome analysis comparing single nucleotide polymorphism (SNP) differences between pairs of nontuberculous mycobacteria isolates within clusters (x-axis) versus percentage shared accessory genome (y-axis). Mycobacterium intracellulare ssp. chimaera patient-to-patient isolate comparisons are represented by pink hexagons, and patient-to-healthcare environment isolate comparisons are represented by black squares. The M. avium patient-to-patient isolate comparison is represented by a blue triangle. Cutoff points of 30 or fewer SNPs and at least 95% shared accessory genome are noted in the dashed line box, representing a high degree of isolate similarity. SNP = single nucleotide polymorphism.
Figure 6.
Figure 6.
Healthcare-associated transmission of nontuberculous mycobacteria (NTM) investigation results at the University of Vermont Medical Center Adult Cystic Fibrosis Center. WGS criteria are defined as one or more NTM cultures available for research purposes. pwCF = people with cystic fibrosis; WGS = whole genome sequencing.

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