In this retrospective cohort study, we found that ECMO rescue therapy was associated with lower in-hospital mortality, better oxygenation, and fewer organ failures compared to historical control (usual care) in patients with severe MERS-CoV. However, the length of hospital stay was the same and a possible explanation is that during the crisis phase, patients were mechanically ventilated in the ward when ICU beds are full, and it is possible that this could have contributed to similar stay in hospital in both groups.
Although ELSO issued guidelines on the use of ECMO in patients with ARDS, these guidelines do not address specific disease context, and are difficult to generalize to the heterogeneous ARDS population. Therefore, we conducted this observational study to report on the efficacy and safety of ECMO in patients with severe MERS-CoV infection.
There is a single case report in the literature looking at ECMO in MERS-CoV patients. Guery et al. described the use of ECMO in two patients with acute respiratory failure secondary to MERS-CoV infection in France, where both patients developed severe hypoxia and increasing oxygen requirements, leading to mechanical ventilation and ECMO use. One patient died, and the other survived after approximately 2 months in hospital .
ECMO use in respiratory failure has been reported with variable survival rates. The first 2 randomized clinical trials (RCTs) failed to prove superiority of ECMO over conventional management [11, 12]. However, the severe adult respiratory failure (CESAR) trial showed improved 6-month survival in patients who were referred early to an ECMO center . This was the largest clinical trial to investigate the efficacy of early use ECMO in patients with ARDS. Despite concerns about the trial design and possible differences in steroid use and ventilator strategies, these results contributed to the increasing use of ECMO worldwide.
In this study, we observed no significant differences in the use of adjunctive therapies except for ribavirin use in the ECMO group. The benefit of antiviral therapy in MERS-CoV infection remains unclear. Recent Korean guidelines published during the 2015 MERS-CoV outbreak in South Korea suggested the use of antiviral therapy in patients with severe MERS-CoV .
In patients with respiratory failure from H1N1 infection who required the use of ECMO, the survival rate varied considerably between studies ranging from 35 to 90% [15,16,17,18,19,20,21,22,23,24,25,26,27,28]. There was a large variation in survival rates, which could be explained by differences in patients’ baseline characteristics and severity of illness. In one study, older, obese, diabetic, or immunocompromised patients were found to be at a higher risk of developing severe MERS-CoV infection [28,29,30,31]. In this study, the two groups were comparable at baseline, and there were no significant differences between groups in any of these variables. Another large observational study examined the predictors of death in H1N1 patients who underwent V–V ECMO and found that creatinine and bilirubin levels, systemic arterial pressure, hematocrit, and pre-ECMO hospital length of stay were associated with higher mortality .
Another important factor is the center experience and volume of cases; this could have contributed to the variability in survival rates with ECMO use. A recent study by Barbaro et al.  demonstrated that centers with > 30 ECMO cases/year had better survival rates than centers with less than 6 cases per year. In Saudi Arabia, ECMO was not available except in one center until the MERS-CoV crisis; thereafter, the ECMO program was implemented as a therapeutic option for patients with refractory hypoxemia. ECMO interventions were run in tertiary centers with equipped ICUs by most experienced intensivists and perfusionists who received training in ECMO prior to the start of the program.
Although more ECMO patients received ribavirin and interferon therapy, we do not believe that this difference has an impact to our findings. Published reports on this therapy are limited, but none showed significant improvement with this combination [34,35,36]. The largest study to date published in abstract format  showed no reduction in mortality. Therefore, we believe that the imbalance of co-interventions between the two groups is unlikely to affect the estimation of treatment effect.
In regard to infection control issues, caregivers safety of ECMO patients was organized and maintained by aggressive measures which were applied strictly and monitored closely with all admissions were taken to airborne isolated rooms which impacted the containment of the virus plus applying the universal protective personal measures all the time during the patients encounter. Because of these stringent measures, there were no reports by or about any caregiver of any ECMO patient being affected.
To our knowledge, this is the largest study to describe outcomes in patients with MERS-CoV who received ECMO. There are several strengths to our study: the “before and after” design allowed us to compare ECMO cases to a control group with similar demographics and within the same institutions. We also collected data on important variables and confounders, and conducted adjusted analyses to assess the impact on the results. We adhered to the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) guidelines .
Despite the strengths of our study, it has several important limitations. First, the retrospective nature of this study renders it at risk of bias. All patients in the control group died, which may be explained by the severity of illness, as these were patients who had ARDS and were eligible otherwise. We cannot rule out the possibility of selection bias, as we were unable to track all transfer requests due to the outbreak and crisis at the time, leaving us with limited information. In addition, some patients were transferred from non-participating ECMO centers; therefore, baseline pre-ECMO data such as blood gases and ventilator settings could not be obtained. Furthermore, due to insufficient documentation during the outbreak and crisis circumstances, we were not able to track the ECMO requests to the referral call center.
There were differences in some co-interventions (e.g., antiviral therapy), and the influence of unmeasured confounders cannot be excluded. Such concerns can only be addressed in RCTs; however, conducting RCT is likely to be challenging in the context of epidemics. This study was not designed to compare the cost of 2 interventions; although it is an important outcome that could help the clinicians and stakeholders to make decisions. Lastly, the small sample size limited our ability to perform an adequate multivariate analysis. Similar to other ECMO studies, it is difficult to determine if the mortality was the result of refractory respiratory failure or other causes like septic shock or other organs failure.
In summary, the use of ECMO was associated with lower mortality in patients with severe MERS-CoV infection and refractory hypoxia. Future randomized trials, although challenging to conduct, are highly needed to confirm or dispute these observations. Until more data are available, ECMO could be considered as a rescue therapy in selected MERS-CoV patients with refractory hypoxemia.