key: cord-0710866-07libmtg
authors: Takeuchi, Taro; Zha, Ling; Tanaka, Kenta; Katayama, Yusuke; Sobue, Tomotaka; Hirayama, Atsushi; Komukai, Sho; Shimazu, Takeshi; Kitamura, Tetsuhisa
title: Clinical epidemiology and outcomes of COVID-19 patients with extracorporeal membrane oxygenation (ECMO) support in Japan: a retrospective study
date: 2022-04-08
journal: IJID Regions
DOI: 10.1016/j.ijregi.2022.04.001
sha: bbe840ccb51027fdcecb32e40139a69c69822f72
doc_id: 710866
cord_uid: 07libmtg

Objective : To elucidate the clinical epidemiology and outcomes of patients with coronavirus disease (COVID-19) in the Osaka Prefecture, Japan who received extracorporeal membrane oxygenation (ECMO). Methods : This was a retrospective study of COVID-19 patients who received ECMO. Among patients diagnosed with COVID-19 between January 29, 2020 and November 9, 2020, we targeted patients who received ECMO. The outcome was all-cause mortality. The baseline characteristics of the COVID-19 patients who received ECMO were summarized according to the outcome. The univariable logistic regression model was applied to evaluate the association of each factor (sex, age group, city of residence, presence of comorbidities, presence of close contact, use of dialysis, and surge) with all-cause mortality. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Results : Among the 14,864 patients diagnosed with COVID-19 during the study period, 39 patients received ECMO. Fourteen patients (35.9%) died. All patients aged 30–39 years survived, whereas all patients aged ≥80 years died. The univariable logistic regression model showed that the presence of comorbidities was significantly associated with higher mortality (OR: 3.67, 95% CI: 1.19–11.35). Conclusions : Of the 14,864 COVID-19 patients in Osaka Prefecture until November 2020, 39 underwent ECMO. Of these, 14 died.

The coronavirus disease has spread to almost every country worldwide. In Japan, a total of 419,015 COVID-19 cases were confirmed as of February 17, 2021 (Ministry of Health Labour and Welfare of Japan, 2021) . The Osaka Prefecture, which is the largest metropolitan area in western Japan, has the second highest number of COVID-19 patients in Japan , Takeuchi et al., 2020a , Takeuchi et al., 2020b . The cumulative number of confirmed COVID-19 cases in the Osaka Prefecture was 46,247 as of February 17, 2021 (Government, 2021) .

Some COVID-19 patients develop severe diseases, including severe acute respiratory distress syndrome (ARDS) (Barbaro et al., 2020 , Schmidt et al., 2020 . Extracorporeal membrane oxygenation (ECMO) support is used to treat lung injury in these severe ARDS patients (Barbaro et al., 2020 , Combes et al., 2018 , Schmidt et al., 2020 . Previous studies in foreign countries have reported the characteristics and outcomes of COVID-19 patients who received ECMO (Barbaro et al., 2020 , Bartlett et al., 2020 , Biancari et al., 2021 , Haiduc et al., 2020 , Ma et al., 2020 , Ramanathan et al., 2020 , Schmidt et al., 2020 , Shaefi et al., 2021 , Zhu et al., 2021 .

In Japan, although a previous study by the "Japan ECMOnet for COVID-19," a nationwide registry of COVID-19 patients with ECMO use in Japan, reported the characteristics of the first 14 COVID-19 cases that involved ECMO use (Takeda, 2020) , details on the clinical epidemiology and outcomes of COVID-19 patients treated using ECMO are not fully understood.

In this study, we aimed to elucidate the clinical epidemiology and outcomes of COVID-19 patients who received ECMO by conducting a retrospective study in the Osaka Prefecture, Japan.

This was a retrospective study of COVID-19 patients who received ECMO in the Osaka Prefecture, Japan. Details of the data collection are described elsewhere . In the Osaka Prefecture, in accordance with the Infectious Diseases Control Law (Government, 2020c , an active epidemiological investigation into COVID-19 was conducted to collect epidemiological information on COVID-19 patients (Government, 2020c .

The requirement for informed consent was waived. Among COVID-19 patients who were registered in the system by the end of November 2020 and whose follow-up was completed, we targeted patients who received ECMO. Of the COVID-19 cases enrolled by the data collection system from January 2020 to November 2020, we received cases only with complete follow-up history from Osaka Prefecture. In accordance with the definitions outlined by Osaka Prefecture, we defined the surge according to the onset date as follows: the first surge (until 13 June 2020), the second surge (from 14 June 2020 to 9 October 2020), and the third surge (after 10 October 2020) (Government, 2020b) . High-risk comorbidities, such as diabetes; heart failure; respiratory diseases, including chronic obstructive pulmonary disease (COPD); chronic kidney diseases requiring dialysis; and the use of immunosuppressants and anticancer drugs, were summarized in this database (Government, 2020b) . A cluster was a group of five or more COVID-19 positive cases with an epidemiological link to the primary identified COVID-19 cases identified from various facilities, such as nursing homes, medical institutions, and restaurants (Diseases, 2021) . Close contacts were identified by local public health centers as those who lived with the confirmed cases or had prolonged contact with the patients; those who examined, nursed, or cared for the confirmed cases without personal protection equipment; those who were likely to have had direct contact with contaminated materials; or those who had contact with confirmed cases for >15 min at a short distance (approximately 1 m) without personal protection equipment (Diseases, 2021) . Symptoms at diagnosis were defined as follows: asymptomatic, mild (only cough without breathlessness or respiratory symptoms), moderate (breathlessness, pneumonia, or necessity of oxygen therapy), and severe (necessity of stay in the ICU or the u se of MV) . Cluster in this study was categorized as follows: no, medical institution, and others. The onset date was defined as the date when symptoms were estimated to have appeared (Takeuchi et al., 2020a) . If the onset date was missing, we substituted the onset date for the date of medical treatment, the date of hospital admission, or the date when a change in symptoms was noted, whichever occurred first. Hospitalized patients had any of the following items: date of hospitalization and/or discharge or reason of discharge (alive or death).

The outcome was all-cause mortality. Follow-up was started on the day of ECMO initiation.

Follow-up ended on the day of ECMO termination or the day the patient died, whichever occurred first. To deal with the situation where the day of ECMO initiation was equal to the day of ECMO termination, we added one day to the observation period for all the patients.

The baseline characteristics of the COVID-19 patients who received ECMO in the Osaka Prefecture, Japan, were summarized according to the outcome (survivors/non-survivors).

Information on sex, age group (ages: 30-39, 40-49, 50-59, 60-69, 70-79, ≥80 years), city of residence (Osaka City, other cities), presence of comorbidities (with/without), presence of close contact (with/without), use of dialysis (with/without), surge (first surge/second surge), days from the onset date to ECMO initiation, and days from ECMO initiation to ECMO termination was collected. In this database, summarized data on comorbidities such as diabetes, heart failure, respiratory diseases including chronic obstructive pulmonary disease, chronic kidney diseases requiring dialysis, conditions that compromise the immune system, and cancer were available (Government, 2020a) . We defined the surge according to the onset date for each patient: January 29, 2020 to June 13, 2020 and June 14, 2020 to November 9, 2020 for the first and second surges, respectively (Government, 2020a) . Categorical variables are summarized by count and proportion, and continuous variables are summarized as median and interquartile range (IQR).

The distribution of follow-up status (survivor with follow-up, survivor with the end of follow-up, death) of the study population was summarized at each point from the ECMO initiation (10 days, 20 days, 30 days, 40 days, 45 days). In this analysis, patients with missing information on the date of ECMO initiation were excluded. The univariable logistic regression model was used to evaluate the association of each factor (sex, age group, city of residence, presence of comorbidities, presence of close contact, use of dialysis, and surge) with all-cause mortality. The reference category was as follows: sex, male; age group, 60-69 years; city of residence, Osaka City; presence of comorbidities, without; presence of having close contact, without; use of dialysis, without; and surge, first surge. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated.

All P values were two-tailed, and P < 0.05 was considered statistically significant. All statistical analyses were conducted using STATA version 14.0 MP software (StataCorp LP).

In the Osaka Prefecture, Japan, a total of 14,864 patients were diagnosed with COVID-19 between January 29, 2020 and November 9, 2020. Among them, 39 patients received ECMO support (Figure 1 ). than among those who survived (14 days). The median days from ECMO initiation to ECMO termination were also shorter among patients who died (10 days) than among those who survived (15 days). Table 2 shows the distribution of the follow-up status at each point (10 days, 20 days, 30 days, 40 days, 45 days) from the ECMO initiation. In this analysis, two patients with missing information on the date of ECMO initiation were excluded. Table 3 shows the results of the univariable logistic regression analysis. The presence of comorbidities was significantly associated with higher mortality (OR: 3.67, 95% CI: 1.19-11.35). Higher mortality was observed among patients in the higher age group, and the P value for trend was significant (P value for trend: 0.04). Other factors were not significantly associated with mortality.

This retrospective analysis of 39 COVID-19 patients who received ECMO in the Osaka Prefecture, Japan, revealed that 14 out of 39 patients (35.9%) died. All patients aged 30-39 years survived, whereas all patients aged ≥80 years died. To the best of our knowledge, the present study is the first in Japan to elucidate the clinical epidemiology and outcomes of COVID-19 patients treated using ECMO in detail.

In this study, all patients aged 30-39 years survived, whereas all patients aged ≥80 years died. The most noteworthy result of our findings is that 65% (13/20) of patients aged 60 -79 years survived, in spite of the relatively small sample size. Previous studies conducted in foreign countries also reported the mortality of COVID-19 patients who received ECMO (Barbaro et al., 2020 , Bartlett et al., 2020 , Biancari et al., 2021 , Haiduc et al., 2020 , Ma et al., 2020 , Ramanathan et al., 2020 , Schmidt et al., 2020 , Shaefi et al., 2021 , Zhu et al., 2021 . In the Extracorporeal Life Support Organization (ELSO) registry, the in-hospital mortality 30, 60, and 90 days after the initiation of ECMO support was estimated to be approximately 30%, 37%, and 37%, respectively, taken from a previous report (Barbaro et al., 2020) . Another study using data from the Study of the Treatment and Outcomes in Critically Ill Patients with COVID -19 (STOP-COVID) reported that 34.6% of COVID-patients who received ECMO died within 60 days from the initiation of ECMO (Shaefi et al., 2021) . Although the mortality observed in the present study was similar to that of previous studies, a longer follow-up period is needed to determine the mortality of COVID-19 patients who received ECMO in Japan.

In this study, all patients aged 30-39 years survived, whereas all patients aged ≥80 years died. Previous studies in foreign countries reported that higher age was associated with higher mortality among COVID-19 patients who received ECMO. In a report from the ELSO registry (Barbaro et al., 2020) , a significantly higher mortality was observed among patients aged ≥60 years compared to patients aged 16-39 years. Another study from five European countries reported that the proportion of patients aged >60 years was higher among six-month non-survivors than among six-month survivors (Biancari et al., 2021) . Higher age was one of the adverse prognostic factors among COVID-19 patients who received ECMO (Shared Research Group in Ministry of Health, 2020). ECMO support may not be recommended for super-elderly COVID-19 patients because of the higher mortality among these patients.

Due to lack of knowledge of the virus and adequate clinical treatment experience at the beginning of the COVID-19 epidemic, the criteria to procced to ECMO support in Japan were based on the respiratory status of progressive deterioration, with PEEP10 cmH 2 O and P/F < 100, and were final judged comprehensively by clinicians at each institution (Ministry of Health Labour and Welfare, 2021) (ECMOnet, 2020, Shared Research Group in Ministry of Health, 2020) (Shared Research Group in Ministry of Health, 2020). Therefore, there is no definite age cutoff in relation to decisions mad to proceed with ECMO support in Japan. In Asai et al.

Gerontology 2022, there was data on elderly patients with COVID-19 from Japan, but they described ECMO introduction up to the 80s (Asai et al., 2022) . Also, In a previous study from overseas, the age cutoff does not seem to be specified (Badulak et al., 2021) . In the ELSO registry analysis, some cases appear to be older than 70 years, and the results are similar to those of our study, indicating that proceeding to ECMO support to the patient who beyond the recommended age, such as older than 75 years old, did not effectively improve the prognosis of severe and critical patients with COVID-19 (Bartlett et al., 2020 , Broman et al., 2021 .

In this study, there were the small number of females (8% [3/39]) receiving ECMO support.

Gender difference was observed in the present study, which was also found in the ELSO registry (Barbaro et al., 2020) . Although the explanation for the variation in mortality between genders is unclear, it may be associated with alterations in immunological response to COVID-19 between the genders. However, this study lacked information on smoking status, which may have obscured confounding factors in the gender difference . According to a recent study regarding smoking status and severe illness in hospitalized COVID -19 patients in Japan (Matsushita et al., 2021) , smokers are more probable to develop smoking-related diseases such as cardiovascular disease, cancer, and lung disease. The patients who have these comorbidities are more likely to contribute to the risk of being severe and critical, resulting to an increasing mortality. Moreover, a systematic review and meta-analysis reported that females were less likely received MV or renal replacement therapy than males and had shorter ICU stays. This is the result of a complex interaction between physiological and societal factors (Asai et al., 2022) . Additional researchers on gender difference in COVID-19 patients are also needed in Japan as well as world.

This study had several limitations. First, as we have already mentioned, we did not provide detailed information on the types of comorbidities. Second, the epidemiological data, following active epidemiological investigation, did not include detailed information on the clinical characteristics of COVID-19 patients who received ECMO, such as Sequential Organ Failure Assessment score, Respiratory Extracorporeal Membrane Oxygenation Survival Prediction score, types of ECMO support, ventilation parameters, laboratory parameters, and blood gases.

Furthermore, there are no studies reporting the percentage of Veno-venous (VV) and

Veno-arterial (VA) ECMO in Japan. According to the previous literatures from other countries, 99% of ECMO is VV ECMO. Therefore, further large-scale observational studies to improve the prognosis of COVID-19 patients receiving ECMO support in Japan are needed. Third, we could not conduct multivariable analyses because of the limited sample size. While the sample size is limited, to our knowledge, the majority of papers focusing on ECMO support in Japan are case reports, and no investigations from population-based epidemiological data have been published.

Given the scarcity of evidence from Japan, our study is essential and is likely to be used as fundamental data which will connect to the next step of research on ECMO support in severe and critical patients with COVID-19, regardless of the limited cases. Finally, unmeasured confounding factors might have affected the results of the present study.

Among COVID-19 patients who received ECMO support in the Osaka Prefecture, Japan, 14 of 39 patients (35.9%) died.

TT, LZ and TK conceive the study design. TT drafted the manuscript and TT, LZ and KT performed statistical analyses. YK, TSo, AH, SK, TSh and TK input their clinical expertise and critically revised the manuscript. All authors approved the version for publication. TK supervised the whole manuscript.

None.

All authors declare no conflict of interest

We thank all of the stuff members of Osaka Prefectural Government and public health centers in Osaka for their efforts in collecting the data used in the study. We also thank all medical staff who treat patients with COVID-19 in Osaka prefecture. Furthermore, we also thank our colleagues from Osaka University Center of Medical Data Science and Advanced Clinical Epidemiology Investigator's Research Project for providing their insight and expert advice to help improve our research. We also thank Editage (www.editage.com) for English language editing. Taro Takeuchi was supported by the Osaka University Medical Doctor Scientist Training Program.

We express our sincere thanks to Dr. Aiko Tanaka for helpful comments and suggestions on Discussions.

The present study was approved by the Osaka University Hospital Ethical Review Committee (reference no. 20397). *Two patients with missing information on the date of ECMO initiation were excluded. 

Comorbidities as Risk Factors for Severe Disease in Hospitalized Elderly COVID-19 Patients by Different Age-Groups in Japan

Extracorporeal Membrane Oxygenation for COVID-19: Updated 2021 Guidelines from the Extracorporeal Life Support Organization

Extracorporeal membrane oxygenation support in COVID-19: an international cohort study of the Extracorporeal Life Support Organization registry

Initial ELSO guidance document: ECMO for COVID-19 patients with severe cardiopulmonary failure

Six -month survival after extracorporeal membrane oxygenation for severe COVID-19

Extracorporeal membrane oxygenation for COVID-19 during first and second waves

Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome

Guidelines for Conducting Active Epidemiological Surveillance of Patients with Novel Coronavirus Infections

Introduction to Respiratory ECMO. 2020. Government OP. 27th Novel Coronavirus Response Headquarters.; 2020a

The press release on providing COVID-19 patients data for academic research institutes

The Press Releases and Documents about COVID-19 Patients

Role of extracorporeal membrane oxygenation in COVID-19: a systematic review

The characteristics and clinical course of patients with COVID-19 who received invasive mechanical ventilation in Osaka

Characteristics and Outcomes of Pediatric COVID-19 Patients in Osaka

Extracorporeal membrane oxygenation (ECMO) in critically ill patients with coronavirus disease 2019 (COVID -19) pneumonia and acute respiratory distress syndrome (ARDS)

Ministry of Health LaW. COVID-19 Guide to Medical Treatment Version 5.3. 2021. Ministry of Health LaWoJ. The Statistics of Patients with COVID-19

Planning and provision of ECMO services for severe ARDS during the COVID-19 pandemic and other outbreaks of emerging infectious diseases

Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome associated with COVID-19: a retrospective cohort study

Extracorporeal membrane oxygenation in patients with severe respiratory failure from COVID-19

Shared Research Group in Ministry of Health LaWSRGfaRfRAoEaR-eIDaIoRM. Mechanical ventilation and extracorporeal membrane oxygenation for acute respiratory failure owing to COVID-19: basic concept

Nationwide system to centralize decisions around extracorporeal membranous oxygenation use for severe COVID-19 pneumonia in Japan

Profile of patients with novel coronavirus disease 2019 (COVID-19) in Osaka Prefecture, Japan: a population-based descriptive study

Characteristics of patients with novel coronavirus disease (COVID-19) during the first surge versus the second surge of infections in Osaka Prefecture

Characteristics and outcomes of older patients with coronavirus disease 2019 in Japan

Characteristics and Survival of Intensive Care Unit Patients with Coronavirus Disease in Osaka, Japan: A Retrospective Observational Study

Extracorporeal membrane oxygenation versus mechanical ventilation alone in adults with severe acute respiratory distress syndrome: A systematic review and meta-analysis

Address: 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan Phone: +81-6-6879-3922; Fax: +81-6-6879-3929 E-mail: sarin@envi.med.osaka-u.ac.jp