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Genomic Analysis of Cardiac Surgery--Associated Mycobacterium chimaera Infections, United States.

Mycobacterium chimaera is a species in the Mycobacterium avium complex (MAC) (1). MAC is the most frequently reported cause of nontuberculous mycobacterium (NTM) infection in the United States, although disseminated M. chimaera infections are relatively rare (2). In 2012, investigators in Switzerland found that some patients with disseminated M. chimaera infections had undergone open-chest cardiac surgeries, during which they were exposed to heater-cooler units (HCUs) (3). These devices, Stockert 3T Heater-Cooler Units (LivaNova PLC, https:// www.livanova.com; formerly Sorin Group Deutschland GmbH), manufactured in Germany, were unknowingly contaminated with M. chimaera (4,5). In the same year, a Pennsylvania hospital identified a cluster of invasive M. chimaera infections among open-chest cardiac surgery patients exposed to LivaNova 3T HCUs contaminated with M. chimaera (6), which prompted notification of [approximately equal to]1,300 patients with exposure to these units (7). Additional cases of disseminated M. chimaera infection among cardiac surgery patients have emerged worldwide, with evidence implicating bioaerosols produced by contaminated LivaNova 3T HCUs as the source of post-cardiac surgery M. chimaera infections (8,9). We report the relationships among HCU-associated isolates from patients and LivaNova 3T HCUs in the United States and their context among the global outbreak.

The Study

During 2015-2016, we collected NTM isolates from 3T HCU water (n = 38 isolates) and suspected patient cases (n = 24 isolates) from 8 US locations. We identified isolates and conducted high-throughput whole-genome sequencing using the Illumina Miseq system (https://www. illumina.com). We selected Pennsylvania isolate 20152271 (USA_PA_PAT_9) for Pacific Biosciences (https:// www.pacb.com) single-molecule real-time sequencing (100). We downloaded publicly available M. chimaera genomes from isolates collected in Australia, Denmark, Italy, New Zealand, the United Kingdom, and Switzerland from the National Center for Biotechnology Information (NCBI) Sequence Read Archive (SRA). We included Zurich CHE_HCU_1 isolate as a representative of the genotype isolated from HCUs, patients, and manufacturing sites in Europe (9). For each isolate, we mapped the sequence reads to the M. chimaera strain CDC 2015-22-71 reference genome (GenBank accession no. NZ_CP019221.1) to detect single-nucleotide polymorphisms (SNPs) (Appendix, http:// wwwnc.cdc.gov/EID/article/25/3/18-1282-App1.pdf).

We reconstructed phylogenetic relationships among M. chimaera isolates collected from post-cardiac surgery patients and HCUs in 8 locations across the United States, as well as HCU-associated strains from Australia, New Zealand, and Europe (Table; Appendix Figure 1). We compared all HCU-associated isolates with 7 M. chimaera respiratory isolates obtained from US patients with no history of cardiac surgery. We identified 18,190 SNPs in the 3.82-Mb core genome (62.8% of the reference genome) among 126 M. chimaera isolates.

The NeighborNet splitstree (Appendix) of M. chimaera showed 3 groups (HCU1, HCU2, and non-HCU; Figure 1). Clade HCU1 (n = 112 isolates; Figure 2) is a discrete cluster composed entirely of HCU-associated isolates from case-patients and HCUs (mean pairwise distance 4 SNPs, range 0-23 SNPs; Appendix Figure 2) from Australia, Denmark, New Zealand, Switzerland, the United Kingdom, and the United States. Clade HCU2 was composed of 3 HCU-associated M. chimaera isolates from Switzerland (2) and Australia (AUS_HCU_30 and AUS_HCU_31). The mean difference among HCU2 isolates was 21.3 SNPs (range 19-25 SNPs; Appendix). Clade 3 was composed of US non-HCU-associated isolates (non-HCU). Two HCU-associated patient isolates from Australia (mean non-HCU-associated isolate pairwise SNPs 52, range 3-111 SNPs; Appendix) were unclustered. The mean distance between HCU1 and international HCU isolates was 13.58 SNPs (range 0-521 SNPs; Appendix Figure 3); the mean distance between HCU1 and non-HCU-associated isolates was 510.5 SNPs (range 506-610 SNPs; Appendix). In comparison, the mean distance between HCU2 and nonHCU isolates was 17,130.7 SNPs (range 17,057-17,221 SNPs). Of the 117 HCU-associated isolates we analyzed, 112 (95.7%) were HCU1 cluster, 3 (2.6%) were HCU2 cluster, and 2 isolates (1.7%) were not in a major clade.

Whole-genome sequencing of US HCU-associated M. chimaera isolates and their comparisons with global HCU-associated isolates provides further evidence for point-source contamination and worldwide dissemination of a M. chimaera strain (3-5). Twenty-two of 24 (92%) US patient isolates associated with HCU exposure during cardiac surgery phylogenetically clustered with international HCU-derived and post-cardiac surgery patient isolates, including those from Australia, Europe, and New Zealand (HCU1). None of the 8 US non-HCU-associated isolates were genetically similar to the HCU1 or HCU2 clusters. Isolates from US post-cardiac surgery patients were genetically more similar to isolates derived from international LivaNova 3T HCUs (mean pairwise distance 4 SNPs) than M. chimaera isolates from US patients without a history of cardiac surgery (mean pairwise distance 511 SNPs). This evidence supports the hypothesis that US post-cardiac surgery M. chimaera infections were acquired from exposure to factory-contaminated HCUs rather than local populations of waterborne M. chimaera in each hospital.

Our analyses revealed that all US M. chimaera isolates associated with LivaNova 3T HCU exposure genetically cluster with HCU1 genotype isolates implicated in the global outbreak of post-cardiac surgery M. chimaera infections. The HCU2 cluster was not observed in the United States but included 2 isolates from HCUs in Australia, as well as a representative genotype of M. chimaera found in HCUs in Europe and at the HCU production site. Consistent with previous findings, this finding suggests the international circulation of a second, less plentiful, strain in the manufacturing site water system (8).

These observations support the hypothesis that the LivaNova 3T HCU design provided suitable conditions for both NTM colonization and aerosolization, particularly by M. chimaera. Even though production site contamination with M. chimaera has been confirmed, the medical community needs to remain alert for HCU-associated NTM infections involving other species (4). HCUs are vulnerable to contamination from in-hospital water sources, use of improper water sources, and improper maintenance, each of which may increase the risk of infection by NTM (including M. abscessus, M. chelonae, and M. gordonae, in addition to M. chimaera) (6). Contaminated HCUs may contain NTM-contaminated biofilms. Furthermore, water from the LivaNova 3T HCUs can become aerosolized during normal function, leading to introduction of potentially infectious particles into the sterile field, onto graft materials, or into the open chest cavity during cardiac surgery. The death rate for HCU-associated M. chimaera infections has been reported to be 50%; the latent period to diagnosis can be up to 5 years postsurgery (4,6,7,9,10), further emphasizing necessary diligence on the part of physicians and cardiac surgery patients to monitor for symptoms of disseminated NTM infection.

Our study has some limitations in methodology. We did not obtain samples from every US hospital that reported LivaNova 3T HCU-associated M. chimaera cases; no submitting hospital collected all 3 types of samples (HCUs, non-HCU samples, and suspected case-patients); and HCU samples were not collected by a single person or according to a standardized collection protocol. Despite these limitations, this analysis of US HCU-associated M. chimaera isolates clearly shows the clustering of isolates from epidemiologically linked US cases to international LivaNova 3T HCU M. chimaera isolates and the HCU1 genotype found within the LivaNova manufacturing site.

In conclusion, the application of WGS has advanced our understanding of M. chimaera present in US LivaNova 3T HCUs and patient cases after the initial analysis of suspected cases in Pennsylvania and Iowa. Given the innate drug resistance and the high death rate of HCU-associated M. chimaera infections, it remains imperative for hospitals to follow Food and Drug Administration guidelines (9) and the manufacturer's instructions to minimize the risk of patient infection. In addition, clinicians should monitor patients who have had cardiac surgery using LivaNova 3T HCUs for signs and symptoms of NTM infection to enable early diagnosis and treatment.

N.A.H., L.E.E., C.L.D., and M.S. acknowledge the support of the National Jewish Health NTM Center for Excellence and the Colorado Cystic Fibrosis Foundation Research Development Program (grant no. NICK15R0); M.S., N.A.H., and L.E.E. acknowledge the support of the Boettcher Foundation; and A.L., A.L.H., M.B.C., J.F.P., H.M.M., K.M.P., and K.A.P. acknowledge the support of the US Centers for Disease Control and Prevention.

Dr. Hasan is a researcher at the Center for Genes, Environment and Health at National Jewish Health, Denver, Colorado, USA. His main research focuses on nontuberculous Mycobacteria comparative genomics to discover genetic markers associated with pathoadaptation and conduct outbreak surveillance.

References

(1.) van Ingen J, Turenne CY, Tortoli E, Wallace RJ Jr, Brown-Elliott BA. A definition of the Mycobacterium avium complex for taxonomical and clinical purposes, a review. Int J Syst Evol Microbiol. 2018;68:3666-77. http://dx.doi.org/ 10.1099/ijsem.0.003026

(2.) Tan N, Sampath R, Abu Saleh OM, Tweet MS, Jevremovic D, Alniemi S, et al. Disseminated Mycobacterium chimaera infection after cardiothoracic surgery. Open Forum Infect Dis. 2016;3:ofw131. http://dx.doi.org/10.1093/ofid/ofw131

(3.) Achermann Y, Rossle M, Hoffmann M, Deggim V, Kuster S, Zimmermann DR, et al. Prosthetic valve endocarditis and bloodstream infection due to Mycobacterium chimaera. J Clin Microbiol. 2013;51:1769-73. http://dx.doi.org/10.1128/ JCM.00435-13

(4.) Sax H, Bloemberg G, Hasse B, Sommerstein R, Kohler P, Achermann Y, et al. Prolonged outbreak of Mycobacterium chimaera infection after open-chest heart surgery. Clin Infect Dis. 2015;61:67-75. http://dx.doi.org/10.1093/cid/civ198

(5.) Kohler P, Kuster SP, Bloemberg G, Schulthess B, Frank M, Tanner FC, et al. Healthcare-associated prosthetic heart valve, aortic vascular graft, and disseminated Mycobacterium chimaera infections subsequent to open heart surgery. Eur Heart J. 2015;36:2745-53. http://dx.doi.org/10.1093/eurheartj/ehv342

(6.) Food and Drug Administration. Nontuberculous mycobacterium (NTM) infections associated with heater-cooler devices (HCD) during cardiothoracic surgery. 2016 Meeting Materials of the Circulatory System Devices Panel [cited 2018 Mar 29]. https://www.fda.gov/AdvisoryCommittees/CommitteesMeeting- Materials/MedicalDevices/MedicalDevicesAdvisoryCommittee/ CirculatorySystemDevicesPanel/ucm485091.htm

(7.) WellSpan Health System. WellSpan York Hospital notifies open-heart surgery patients of possible infection risk. 2015 [cited 2018 Mar 30]. https://www.wellspan.org/news/story/15810

(8.) Haller S, Holler C, Jacobshagen A, Hamouda O, Abu Sin M, Monnet D, et al. Contamination during production of heater-cooler units by Mycobacterium chimaera potential cause for invasive cardiovascular infections: results of an outbreak investigation in Germany, April 2015 to February 2016. Euro Surveill. 2016;21:30215. http://dx.doi.org/10.2807/1560-7917.ES.2016. 21.17.30215

(9.) van Ingen J, Kohl TA, Kranzer K, Hasse B, Keller PM, Katarzyna Szafranska A, et al. Global outbreak of severe Mycobacterium chimaera disease after cardiac surgery: a molecular epidemiological study. Lancet Infect Dis. 2017;17:1033-41. http://dx.doi.org/10.1016/S1473-3099(17)30324-9

(10.) Hasan NA, Lawsin A, Perry KA, Alyanak E, Toney NC, Malecha A, et al. Complete genome sequence of Mycobacterium chimaera strain CDC 2015-22-71. Genome Announc. 2017; 5:e00693-17. http://dx.doi.org/10.1128/genomeA.00693-17

(11.) Perkins KM, Lawsin A, Hasan NA, Strong M, Halpin AL, Rodger RR, et al. Notes from the field: Mycobacterium chimaera contamination of heater-cooler devices used in cardiac surgery-United States. MMWR Morb Mortal Wkly Rep. 2016;65:1117-8. http://dx.doi.org/10.15585/mmwr.mm6540a6

(12.) Williamson D, Howden B, Stinear T. Mycobacterium chimaera spread from heating and cooling units in heart surgery. N Engl J Med. 2017;376:600-2. http://dx.doi.org/10.1056/ NEJMc1612023

(13.) Chand M, Lamagni T, Kranzer K, Hedge J, Moore G, Parks S, et al. Insidious risk of severe Mycobacterium chimaera infection in cardiac surgery patients. Clin Infect Dis. 2017;64:335-42. http://dx.doi.org/10.1093/cid/ciw754

Address for correspondence: Nabeeh A. Hasan, National Jewish Health Center for Genes, Environment and Health, 1400 Jackson St A632, Denver, CO 80206, USA; email: hasann@NJHealth.org

Author affiliations: National Jewish Health, Denver, Colorado, USA (N.A. Hasan, L.E. Epperson, R.R. Rodger, M. Salfinger, C.L Daley, M. Strong); Centers for Disease Control and Prevention, Atlanta, Georgia, USA (A. Lawsin, K.M. Perkins, A.L. Halpin, K.A. Perry, H. Moulton-Meissner, M.B. Crist, J.F. Perz); University of Iowa, Iowa City, Iowa, USA (D.J. Diekema)

DOI: https://doi.org/10.3201/eid2503.181282

Caption: Figure 1. Neighbor Net splitstree of Mycobacterium chimaera isolates: relationships between M. chimaera isolates (n = 124) mapped against the M. chimaera strain CDC 2015-22-71 heater-cooler unit (HCU) reference genome (18,190 single-nucleotide polymorphisms [SNPs] in 3,815,639 core positions). Isolates were grouped with a threshold of <500 SNPs to the nearest cluster. Clustered HCU isolates, including the reference strain CDC 2015-22-71, comprise the HCU1 cluster (n = 112) and HCU2 (n = 3). Unclustered isolates include Australian (AUS) HCU isolates (n = 2), USA non-HCU isolates (n=8), and the type strain FI-01069. Scale bar indicates SNPs.

Caption: Figure 2. Maximum-likelihood phylogenetic relationships between HCU1 and US non-HCU-associated isolates (651 singlenucleotide polymorphisms [SNPs] in 4,024,718 core positions) as a circular phylogeny. From the center to the perimeter, colored circles indicate the country of origin, isolate source, and HCU genotype(s). Clinical isolate labels use country abbreviation: Australia (AUS), Denmark (DNK), Florence, Italy (FI), New Zealand (NZL), Switzerland (CHE), United Kingdom (GBR), United States (USA); HCU or PAT; isolate number. Non-HCU-associated isolates are from respiratory patients without a history of cardiac surgery. Suspected cases are isolates from blood or tissue samples collected from post-cardiac surgery patients; HCU are isolates collected from hospital HCUs (swabs, water, bioaerosols). Scale bar indicates SNPs. HCU, heater-cooler unit; PAT, suspected case-patient.
Table. Mycobacteria chimaera isolated from HCUs, suspected patient
case(s), and non-HCU-associated M. chimaera isolates in Australia,
Europe, New Zealand, and the United States *

                              No.        No.      No.
Location                    isolates   clinical   HCU   Status

Iowa 1                         9          3        6      HCU
Iowa 2                         3          0        3      HCU
Kentucky                       1          0        1      HCU
Massachusetts 1                4          0        4      HCU
Michigan                       17         8        9      HCU
Minnesota                      1          1        0      HCU
Pennsylvania 1 ([dagger])      25         10      15      HCU
Virginia                       2          2        0      HCU
Australia 1                    6          0        6      HCU
Australia 2                    13         1       12      HCU
Australia 3                    7          2        5      HCU
Australia 4                    10         2        8      HCU
Denmark                        4          0        4      HCU
New Zealand 1                  2          0        2      HCU
New Zealand 2                  3          0        3      HCU
New Zealand 3                  5          0        5      HCU
New Zealand 4                  2          0        2      HCU
United Kingdom                 3          0        3      HCU
Zurich                         2          0        2      HCU
Italy                          1          1        0    Non-HCU
Maryland                       1          1        0    Non-HCU
Massachusetts 2                1          1        0    Non-HCU
North Carolina                 1          1        0    Non-HCU
Pennsylvania 2                 1          1        0    Non-HCU
Tennessee                      2          2        0    Non-HCU
Texas                          2          2        0    Non-HCU
Total                                     38      90

                            Genotypes/       No. HCU1
Location                     location      genotypes (%)

Iowa 1                          1             9 (100)
Iowa 2                          1             3 (100)
Kentucky                        1             1 (100)
Massachusetts 1                 1             4 (100)
Michigan                        1            17 (100)
Minnesota                       1             1 (100)
Pennsylvania 1 ([dagger])       2             23 (92)
Virginia                        1             2 (100)
Australia 1                     1             6 (100)
Australia 2                     3            11 (84.6)
Australia 3                     3            5 (71.4)
Australia 4                     2             9 (90)
Denmark                         1             4 (100)
New Zealand 1                   1             2 (100)
New Zealand 2                   1             3 (100)
New Zealand 3                   1             5 (100)
New Zealand 4                   1             2 (100)
United Kingdom                  1             3 (100)
Zurich                          2             1 (50)
Italy                           1                0
Maryland                        1                0
Massachusetts 2                 1                0
North Carolina                  1                0
Pennsylvania 2                  1                0
Tennessee                       1                0
Texas                           1                0
Total                                        112 (95)
                                         ([double dagger])

Location                    NCBI BioProject no.       Reference

Iowa 1                          PRJNA345021       (11); this study
Iowa 2                          PRJNA345021          This study
Kentucky                        PRJNA345021          This study
Massachusetts 1                 PRJNA345021          This study
Michigan                        PRJNA345021          This study
Minnesota                       PRJNA345021          This study
Pennsylvania 1 ([dagger])       PRJNA344472       (11); this study
Virginia                        PRJNA345021          This study
Australia 1                     PRJEB15375              (12)
Australia 2                     PRJEB15375              (12)
Australia 3                     PRJEB15375              (12)
Australia 4                     PRJEB15375              (12)
Denmark                         PRJEB18427              (13)
New Zealand 1                   PRJEB15375              (12)
New Zealand 2                   PRJEB15375              (12)
New Zealand 3                   PRJEB15375              (12)
New Zealand 4                   PRJEB15375              (12)
United Kingdom                  PRJNA324238             (13)
Zurich                         PRJNA313770,              (9)
                                PRJNA314007
Italy                           PRJEB18427               (9)
Maryland                        PRJNA345021          This study
Massachusetts 2                 PRJNA319839          This study
North Carolina                  PRJNA345021          This study
Pennsylvania 2                  PRJNA345021          This study
Tennessee                       PRJNA319839          This study
Texas                           PRJNA345021          This study
Total

* US isolates were collected during 2015-2016.Status refers to
HCU-associated isolates (HCU) collected directly from Stockert 3T
Heater-Cooler Units (LivaNova PLC, https://www.livanova.com; formerly
Sorin Group Deutschland GmbH) or from patients with suspected
HCU-derived M.chimaera, and isolates from pulmonary NTM patients
without history of HCU exposure (non-HCU).HCU, heater-cooler unit;
NCBI, National Center for Biotechnology Information.

([dagger]) Denotes the location from which the 2 samples
(USA_PA_HCU_0, 2015-06-01; and USA_PA_PAT_10, 2015-22-65) did not pass
the genomics quality control assessment and were excluded from the
analyses.

([double dagger]) Percentage was derived from the number of HCU1
genotype isolates in the number of isolates collected directly from
LivaNova 3T HCU or suspected patient cases.
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Article Details
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Title Annotation:DISPATCHES
Author:Hasan, Nabeeh A.; Epperson, L. Elaine; Lawsin, Adrian; Rodger, Rachael R.; Perkins, Kiran M.; Halpin
Publication:Emerging Infectious Diseases
Geographic Code:8AUST
Date:Mar 1, 2019
Words:2805
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