Mycobacterium chimaera infections in post – operative patients exposed to heater – cooler devices : An overview

A multi-country outbreak of Mycobacterium chimaera infection associated with contaminated heater–cooler devices (HCDs) has been reported, with more than 70 cases in Europe and the United States and two cases in Canada to date. The epidemiological and microbiological characteristics of this outbreak provide evidence for common-source transmission of M. chimaera from the exhaust air of intrinsically contaminated HCDs to patients during cardiac surgery. To date, all reported cases have been associated with Stöckert 3T HCDs manufactured at one plant by LivaNova prior to September 2014. Implantation of prosthetic material increases the risk of infection. Infections usually present as prosthetic valve endocarditis, vascular graft infection or disseminated infection. Reported mortality rates have varied, but were often over 40%. Several measures are recommended to facilitate case-finding and mitigate risk of exposure. The feasibility of some risk mitigation measures and their effectiveness in reducing the risk of exposure are yet to be determined. Until HCDs are redesigned in a manner that prevents water contamination and aerosolization, separating the HCD exhaust air from the operating room air during surgery may be the most effective risk mitigation strategy. However, possible unintended consequences of this approach should be considered. This overview summarizes findings from peer-reviewed and other relevant national documents on key features of the outbreak, including the source, identified risk factors for infection, signs and symptoms of infection, burden of disease, risk mitigation measures, management challenges and knowledge


Introduction
Health care-associated infections related to medical device contamination and biofilm formation have been documented in the literature (1).Recently, heater-cooler devices (HCDs) used during cardiopulmonary bypass (CPB) for cardiac surgeries and during extracorporeal membrane oxygenation (ECMO) have come under scrutiny due to infections linked to contaminated devices (2,3).
Heater-cooler devices have water tanks that pump temperature-controlled water through closed circuits to external heat exchangers that regulate patient body temperature by convection (4).The device is equipped with a radiator and fan to facilitate constant dissipation of excess heat through grid openings and the stirring of water in the tank results in aerosolization via the exhaust air (4,5).HCDs are subject to biofilm formation.A biofilm is an aggregate of microorganisms embedded within an extracellular matrix that adhere to each other and to internal surfaces, such as the interior of HCDs.
Several types of microorganisms have been isolated from contaminated HCDs, including nontuberculous mycobacteria (NTM), which are ubiquitous in soil and water and have been linked to health care-associated infections (6)(7)(8)(9).Investigations of NTM infection clusters following cardiac surgery detected Mycobacterium chimaera as the causative microorganism.M. chimaera is a slow-growing NTM included in the Mycobacterium avium complex (3,(9)(10)(11)(12).It is less susceptible to disinfection procedures due to its cell wall constituents and its ability to form biofilms. Isolation and identification of M. chimaera from clinical specimens requires specialized microbiological techniques (3).Transmission was associated with a single model of HCD manufactured by Sorin (now LivaNova) (3,13).Cultures from HCD water tanks, water circuits and air samples taken while HCDs were in use have grown M. chimaera (5,8,9,11).
Although M. chimaera contamination of ECMO devices has been reported, contamination did not spread to the air in the room while the devices were running and no ECMO-associated M. chimaera infections were reported (2,14).Nonetheless, the need to assess potential patient exposure from ECMO has been recognized since patients treated with ECMO, who are often critically ill and highly immunocompromised, may be exposed to the device for an extended period of time (2).National guidance documents and safety communications describing risk mitigation measures and testing recommendations in Canada, United Kingdom (UK), United States (US) and Australia have been published (13,(15)(16)(17)(18)(19)(20).
The objective of this overview is to summarize relevant literature on the current multi-country outbreak of M. chimaera infection.The source of exposure, risk factors for infection, signs and symptoms of infection, disease burden, risk mitigation measures, challenges and gaps are summarized.This overview may be a helpful resource for Canadian health care facilities and providers who use HCDs.It may also support informed decision-making by authorities responsible for implementing infection prevention and control measures.

Scope
A worldwide literature search was undertaken by the Health Library (Health Canada) using Ovid MEDLINE, EMBASE and Global Health databases for studies published from January 1, 2007 to March 8, 2017.The search strategy was developed using database-specific thesauri for "Mycobacterium chimaera", "heater-cooler devices", and "cardiac surgery".The search was limited to studies in English and French with no filters applied to limit retrieval by study design.A grey literature search was also conducted by the Health Library to identify relevant national guidance documents and safety communications.The reference lists of relevant guidance documents were hand searched for additional relevant studies.
Full texts of all relevant studies were screened to identify those reporting on HCD-associated M. chimaera infection in postoperative cardiac surgery patients and any risk mitigation measures described.A narrative synthesis of the relevant peer-reviewed publications, national guidance documents and/or safety communications was done.

Findings
A total of 95 articles were retrieved from peer-reviewed and grey literature searches, including a reference list search of identified documents.Information from 38 relevant documents was included in this overview.Fifty-seven articles were excluded for one of several reasons including studies that reported on case(s) already described in detail elsewhere; studies that focused on NTM in general (not specifically M. chimaera); studies that did not discuss patient exposure or transmission; and national guidance documents or safety communications that did not provide additional information to that obtained from similar documents from Canada, the US, Australia and Europe.

Source of exposure
To date, all cases of M. chimaera infection reported internationally have been associated with Stöckert 3T HCDs manufactured in Germany by LivaNova before September 2014 (3,9,13,15,(21)(22)(23). Phylogenetic analysis by whole genome sequencing and other means showed that isolates from infected patients and from water and exhaust air of used and new Stöckert 3T HCDs were closely related, suggesting global distribution of contaminated HCDs and a hospital-independent, common source for the current outbreak (5,9,12,22,(24)(25)(26). LivaNova implemented changes to their disinfection processes in an attempt to reduce the risk of M. chimaera contamination of 3T HCDs manufactured after September 2014 (13,15,27,28).Tests conducted on HCDs manufactured by a different company detected M. chimaera in the water but not in air samples, and the isolate obtained was genetically distinct from isolates obtained from Stöckert 3T HCDs (12,25,29).
During surgeries, the HCD is often positioned adjacent to the cardiopulmonary bypass machine and the patient.Recently, one of the considerations related to minimizing patient exposure to exhaust air from the HCD has to do with the feasibility of positioning the HCD immediately beside the floor-level exhaust in the operating room.

Risk factors for infection
Cases of M. chimaera infection following exposure to HCDs during cardiopulmonary bypass have been reported in patients who had undergone surgery in Europe (UK, France, Switzerland, Netherlands, Germany, Ireland and Spain) as well as in the US, Australia, Canada and Hong Kong Special Administrative Region (18).Patients undergoing cardiac surgery involving cardiopulmonary bypass where body temperature is regulated by HCDs are at risk of exposure and infection (8).Patients undergoing cardiopulmonary bypass for over two hours had higher odds of NTM infection (odds ratio: 16.5; 95% CI: 3.2-84) (8).In hospitals where at least one HCD-associated M. chimaera infection was identified, the risk of a patient getting an infection was approximately 0.1-1% (11,30,31).Of 115,664 surgical procedures in England involving repair or replacement of cardiac valves (between 2007 and 2014), the risk of NTM infections increased from less than 0.2/10,000 person-years before 2010 to 1.65/10,000 person-years in 2013 (29).
No case has occurred in operating room personnel exposed to aerosolization from HCDs.

Signs and symptoms of infection
Signs and/or symptoms of invasive M. chimaera infection following exposure to aerosols from an HCD may not occur for months or years after exposure, with a mean time between exposure and diagnosis of 1.6 years (range: 0.1-6.3years) (3,10,14,23,32).The infection usually presents as prosthetic valve endocarditis, vascular graft infection or disseminated infection although a variety of extracardiac sites may also be infected (Table 1) (9)(10)(11)13,18,29,33). Clinical manifestations of infection are diverse and symptoms may be nonspecific (12,23).In some cases, extracardiac manifestations preceded cardiovascular disease (11).A description of a compatible syndrome for NTM infection published by the Canadian Public Health Laboratory Network (CPHLN) is shown in Table 1 (16).

Disease burden
M. chimaera infection requires aggressive medical treatment with combination antimycobacterial therapy and sometimes repeat surgical intervention.The infection generally results in substantial morbidity with prolonged hospitalization, adverse effects of medical and surgical treatment, and/or treatment failure (3,11,18,29).In Europe, at least 52 cases have been reported as of January 2017 (12,18).Three cases have been identified in Australia, 24 in the US and two in Canada (20,23,32,34).Individual patient information was not always reported.From the data available, most cases were in older adults although patient age ranged from one to 81 years old, including two pediatric patients.Approximately 83% of the patients were male.Most studies reported a mortality rate over 40% (see Table 2) (3,11,12,29,32) and mortality was high when significant delays in diagnosis occurred and patients were severely ill when appropriate antimycobacterial treatment was implemented.It remains unclear whether increased awareness and earlier diagnosis will reduce the mortality associated with M. chimaera infection.

Risk mitigation measures
Key measures identified to facilitate case-finding and mitigate future exposure to M. chimaera are summarized in Table 3.   • The ECDC has published a protocol for case detection.

Ensure traceability of HCDs in use (12)
• Individual units used in each surgery should be recorded in the event of a later infection.
Remove potentially contaminated HCDs from service (12,15,27) • Where possible, all Stöckert 3T HCDs manufactured by LivaNova prior to September 2014 should be removed from service.• In some settings, risk of deferring surgery exceeds risk of surgery with use of proven or suspect contaminated HCD.

Replace contaminated
HCDs, plus accessories, tubing and connectors, to prevent recontamination (13,15,27,35) • LivaNova implemented a program to, in some circumstances, provide users with a loaner device to continue surgical procedures while their devices are undergoing deep disinfection.International demands for replacement of HCDs may result in a backlog in supply.Options include: • Place the HCD outside the operating room with tubing connected through an opening  1 Nine cases were confirmed and one was probable 2 An additional death was not linked to M. chimaera infection 3 All cases were probable 4 Number of deaths were not reported 5 Some of these cases have been reported in other publications 6 Cause of death not described or not all deaths attributed to the infection 7 Percent mortality not reported in the study, was calculated for inclusion in this table

Challenges and gaps
Table 4 summarizes the challenges and gaps in evidence informing the clinical management of M. chimaera infection.

Discussion
Findings from this overview indicate a low but increased risk of M. chimaera infection with use of common source-contaminated HCDs during CPB (29).Given the long latency period, additional cases are expected.The true magnitude of risk following exposure is uncertain; current estimates are based on very limited data.Nonetheless, the risk of delaying cardiac surgery is generally considered far greater than the risk posed by this infection, even when the infection risk has not been entirely mitigated (28).
Future patient exposure may be prevented by implementing risk mitigation measures, including the use of uncontaminated HCDs or replacement of contaminated HCDs as soon as possible.Case finding may be expedited by the development of polymerase chain reaction (PCR)-based assays for rapid and reliable detection of M. chimaera in clinical or environmental samples.
Improved HCD designs that facilitate reliable decontamination and prevent aerosols from reaching the operative field are urgently needed (5,11).These developments may require collaborative discussions between medical device manufacturers, engineers and infection prevention and control experts.
This overview is limited by insufficient data to estimate the true magnitude of risk of infection and absence of data on efficacy and feasibility of risk mitigation measures.

Conclusion
The epidemiological and microbiological characteristics of this outbreak provide evidence for transmission of M. chimaera from the exhaust air of contaminated Stöckert 3T HCDs to patients during CPB, resulting in endocarditis, surgical site infections and/ or disseminated infections.The true magnitude of risk following exposure is uncertain; it is currently estimated based on very limited data.
Strategies that separate the HCD exhaust air from the operating room air during surgery may be the most effective risk mitigation measures.The feasibility of implementing currently recommended risk mitigation measures is yet to be determined and studies are needed to determine if there are any unintended  • Construction of custom-built containers with HEPA filters to house HCDs that cannot be placed outside the operating room is underway, but their effectiveness is currently unknown.• HCD manufacturers are modifying HCD designs to limit aerosolization and prevent transmission.

Table 1 :
(16)ical symptoms of patients with Mycobacterium chimaera infectionReproduced with permission from the Canadian Public Health Laboratory Network(16)

Table 2 :
Reported mortality from Mycobacterium chimaera infection associated with heater-cooler devices

Table 3 :
Recommended measures to facilitate case-finding and mitigate future risk of Mycobacterium chimaera exposure

Table 4 :
Challenges and gaps in evidence informing the management of Mycobacterium chimaera infection If unable to reliably separate HCD exhaust air from operating room air, move the HCD as far as possible (preferably more than five metres) from the surgical field with the vent exhaust directed away from both the patient and the exposed instruments, and if possible, place the HCD close to the room air exhaust.Smoke dispersal experiments demonstrated that exhaust air from HCDs was propelled to merge with ultraclean airflow near the ceiling of the operating room.As a result, it is unclear whether this approach is useful in separating HCD exhaust air from operating room air (4).
Abbreviations: CPB, cardiopulmonary bypass; ECDC, European Centre for Disease Prevention and Control; HCD, heater-cooler device; NTM, nontuberculous mycobacteria; US FDA, United States Food and Drug Administration

Table 3 :
Recommended measures to facilitate case-finding and mitigate future risk of Mycobacterium chimaera exposure (continued)

Table 4 :
Challenges and gaps in evidence informing the management of Mycobacterium chimaera infection (continued) : HCD, heater-cooler device; HEPA, high-efficiency particulate air; UK, United Kingdom consequences from implementation of these measures.Development of HCDs with new designs that are airtight and/ or not susceptible to biofilm formation may help address this problem. Abbreviations