This study illustrated that in-hospital mortality of ILD patients receiving ECMO for ARF was approximately 75%. It also demonstrated that advanced age, non-use of macrolides, and use of antifungal drugs were significantly associated with in-hospital mortality among these patients.
A systematic review of ILD patients treated in intensive care units without ECMO showed that mortality was 65% in patients with idiopathic pulmonary fibrosis during the period 2005–2017 and 48% in mixed ILD patients between 2010 and 2017 (2). In our study, the rate of in-hospital mortality (74.4%) in mixed ILD patients treated with ECMO turned out to be higher than previously reported mortality rates among patients receiving conventional treatments without ECMO. Possible reasons for the higher mortality in ECMO cases are that more severe patients who were refractory to conventional IMV were included, and that they might also have had complications associated with ECMO.
The decision regarding the time of ECMO weaning in successful cases or ECMO withdrawal in refractory cases needs to be discussed carefully. In this study, survivors were successfully weaned from ECMO after a median period of 8 days (IQR, 4–14) whereas ECMO was withdrawn in non-survivors at a median of 14 days (IQR, 8–27). Indeed, Kaplan-Meier survival curve indicated that successful weaning from ECMO was more frequent in the early days after its initiation. On the other hand, 67.2% of non-survivors died on the day of withdrawal, which implies that they relied entirely on ECMO as a life-sustaining procedure at the end of their lives. Our results suggest that continuation of ECMO over 14 days is less likely to produce any favorable outcome.
Here, we found that advanced age was significantly associated with high in-hospital mortality. The Respiratory EMO Survival Prediction score (11) and Predicting Death for Severe ARDS on Veno-venous ECMO (PRESERVE) score (12) have described young age as one of the favorable factors for receiving ECMO, regardless of the type of respiratory failure. Besides, the Extracorporeal Life Support Organization Guidelines for Adult Respiratory Failure published in 2017 have suggested considering a higher risk of a poor prognosis with increasing age (13). Furthermore, the Extracorporeal Life Support Organization Coronavirus Disease 2019 Interim Guidelines have referred to age ≥ 65 years as a relative contraindication for ECMO (14). Our results in ILD patients are consistent with these guidelines. ECMO therapy consumes considerable medical resources, so the cost-benefit balance needs to be considered on a case-by-case basis, especially in elderly patients.
There was no significant difference in BMI between survivors and non-survivors, which is not in agreement with the PRESERVE scoring system stating that a BMI value > 30 kg/m2 is related to a favorable prognosis (12). This disparity in results could be attributed to the number of obese patients in our study (n = 9), which might have been too small to be meaningful for statistical analyses. Further research is needed to determine how obesity affects the prognosis of ILD patients undergoing ECMO.
In the present study, use of macrolides was found to significantly correlate with a favorable prognosis. It is known that macrolides have immunomodulatory effects (15–17) and their combinational administration is capable of diminishing mortality in critically ill patients with community-acquired pneumonia (18). In fact, an official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America has recommended macrolide-containing regimens for the treatment of hospitalized patients with severe pneumonia (19). Besides, the effectiveness of azithromycin for treatment of acute exacerbation of idiopathic pulmonary fibrosis has been reported that mortality in patients treated with azithromycin was significantly lower than in those treated with fluoroquinolones (20). Therefore, antibiotic therapy with macrolide-containing regimens might prove effective not only in patients with severe community-acquired pneumonia but also in ILD patients receiving ECMO.
Our study also demonstrated an association between using antifungal drugs and increased in-hospital mortality. Since observational studies are unable to determine causal relationships, it remains unclear whether antifungal drug use or fungal infections could have impacted the results. Antifungal drugs are generally administered when patients are thought to develop fungal infections during immunosuppressive therapy. Thus, a diagnosis of fungal infections, rather than antifungal drug use per se, might influence patients’ prognosis.
In the current study, use of anti-influenza virus drugs was significantly associated with survival to discharge in the univariate analysis but lost its statistical significance in the multivariate analysis. The efficacy of ECMO in H1N1-related ARDS has been reported (5). In this regard, while ECMO might be beneficial for influenza-related respiratory disorder itself, its efficacy could be limited when this disease is accompanied by ILD.
The strength of this study is that a large number of patients from a nationwide database were included to be analyzed. However, some limitations derived from the retrospective nature of the study. First, we were unable to evaluate ARF causes, because such detailed data were not available from the DPC database. Second, no standardized ECMO initiation and management protocol exists among hospitals, giving rise to selection and intervention bias. Finally, long-term outcomes could not be clarified owing to the lack of post-discharge information.