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Extracorporeal life support (ECLS) is a means to support patients with acute respiratory failure. Initially, recommendations to treat severe cases of pandemic coronavirus disease 2019 (COVID‐19) with ECLS have been restrained. In the meantime, ECLS has been shown to produce similar outcomes in patients with severe COVID‐19 compared to existing data on ARDS mortality. We performed an international email survey to assess how ECLS providers worldwide have previously used ECLS during the treatment of critically ill patients with COVID‐19. A questionnaire with 45 questions (covering, e.g., indication, technical aspects, benefit, and reasons for treatment discontinuation), mostly multiple choice, was distributed by email to ECLS centers. The survey was approved by the European branch of the Extracorporeal Life Support Organization (ELSO); 276 ECMO professionals from 98 centers in 30 different countries on four continents reported that they employed ECMO for very severe COVID‐19 cases, mostly in veno‐venous configuration (87%). The most common reason to establish ECLS was isolated hypoxemic respiratory failure (50%), followed by a combination of hypoxemia and hypercapnia (39%). Only a small fraction of patients required veno‐arterial cannulation due to heart failure (3%). Time on ECLS varied between less than 2 and more than 4 weeks. The main reason to discontinue ECLS treatment prior to patient’s recovery was lack of clinical improvement (53%), followed by major bleeding, mostly intracranially (13%). Only 4% of respondents reported that triage situations, lack of staff or lack of oxygenators, were responsible for discontinuation of ECLS support. Most ECLS physicians (51%, IQR 30%) agreed that patients with COVID‐19‐induced ARDS (CARDS) benefitted from ECLS. Overall mortality of COVID‐19 patients on ECLS was estimated to be about 55%. ECLS has been utilized successfully during the COVID‐19 pandemic to stabilize CARDS patients in hypoxemic or hypercapnic lung failure. Age and multimorbidity limited the use of ECLS. Triage situations were rarely a concern. ECLS providers stated that patients with severe COVID‐19 benefitted from ECLS.

Background Severe COVID-19 induced acute respiratory distress syndrome (ARDS) often requires extracorporeal membrane oxygenation (ECMO). Recent German health insurance data revealed low ICU survival rates. Patient characteristics and experience of the ECMO center may determine intensive care unit (ICU) survival. The current study aimed to identify factors affecting ICU survival of COVID-19 ECMO patients. Methods 673 COVID-19 ARDS ECMO patients treated in 26 centers between January 1st 2020 and March 22nd 2021 were included. Data on clinical characteristics, adjunct therapies, complications, and outcome were documented. Block wise logistic regression analysis was applied to identify variables associated with ICU-survival. Results Most patients were between 50 and 70 years of age. PaO2/FiO2 ratio prior to ECMO was 72 mmHg (IQR: 58–99). ICU survival was 31.4%. Survival was significantly lower during the 2nd wave of the COVID-19 pandemic. A subgroup of 284 (42%) patients fulfilling modified EOLIA criteria had a higher survival (38%) (p = 0.0014, OR 0.64 (CI 0.41–0.99)). Survival differed between low, intermediate, and high-volume centers with 20%, 30%, and 38%, respectively (p = 0.0024). Treatment in high volume centers resulted in an odds ratio of 0.55 (CI 0.28–1.02) compared to low volume centers. Additional factors associated with survival were younger age, shorter time between intubation and ECMO initiation, BMI > 35 (compared to < 25), absence of renal replacement therapy or major bleeding/thromboembolic events. Conclusions Structural and patient-related factors, including age, comorbidities and ECMO case volume, determined the survival of COVID-19 ECMO. These factors combined with a more liberal ECMO indication during the 2nd wave may explain the reasonably overall low survival rate. Careful selection of patients and treatment in high volume ECMO centers was associated with higher odds of ICU survival. Trial registration Registered in the German Clinical Trials Register (study ID: DRKS00022964, retrospectively registered, September 7th 2020, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00022964. Graphical abstract

STRUCTURED ABSTRACTINTRODUCTIONHyperinflammation is frequently observed in patients with severe COVID-19. Inadequate and defective IFN type I responses against SARS-CoV-2, caused by autoantibodies in a proportion of patients, lead to severe courses. In addition, hyperactive responses of the humoral immune system have been described so far.RATIONALEIn the current study we investigated a possible role of neutralizing autoantibodies against anti-inflammatory mediators. Plasma from patients with severe and critical COVID-19 was screened by ELISA for antibodies against PGRN, IL-10, IL-18BP, IL-22BP and IL-1-RA. Autoantibodies were characterized and the antigens were analyzed for immunogenic alterations.RESULTSPGRN-autoantibodies were detected with high titers in 11 of 30 (36.7%), and IL-1-RA-autoantibodies in 14 of 30 (46.7%) patients of a discovery cohort with severe to critical COVID-19. In a validation cohort of 41 patients with critical COVID-19 high-titered PGRN-Abs were detected in 12 (29.3%) and IL-1-RA-Abs in 19 of 41 patients (46.2%). PGRN-Abs and IL-1-RA-Abs belonged to IgM and several IgG subclasses. In separate cohorts with non-critical COVID-19, PGRN-Abs and IL-1-RA-Abs were detected significantly less frequently and at low titers. Neither PGRN-nor IL-1-RA-Abs were found in 40 healthy controls vaccinated against SARS-CoV-2. PGRN-Abs were not cross-reactive against SARS-CoV-2 structural proteins or against IL-1-RA. Plasma levels of both free PGRN and IL-1-RA were significantly decreased in autoantibody-positive patients compared to Ab-negative and non-COVID controls. Functionally, PGRN-Abs from patients reduced PGRN-dependent inhibition of TNF-α signaling in vitro. The pSer81 hyperphosphorylated PGRN isoform was exclusively detected in patients with high-titer PGRN-Abs; likewise, a yet unidentified hyperphosphorylated IL-1-RA isoform was only found in patients with high-titer IL-1-RA-Abs. No autoantibodies against IL-10, IL-18BP or IL-22BP were found.CONCLUSIONTo conclude, neutralizing autoantibodies to IL-1-RA and PGRN occur in a significant proportion of patients with critical COVID-19, with a concomitant decrease in circulating PGRN and IL-1-RA, which is indicative of a misdirected, proinflammatory autoimmune response. The break of self-tolerance is likely caused by atypical isoforms of both antigens due to hyperphosphorylation. It remains to be determined whether these secondary modifications are induced by the SARS-CoV-2-infection itself, or are preexisting and predispose for a critical course.

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