Immune Response Profile of SARS-CoV-2 Associated AARDS Patients During Extracorporeal Membrane Oxygenation

Abstract

Background: Extracorporeal membrane oxygenation (ECMO) is a life-saving rescue therapy in COVID-19 patients with ARDS. Extracorporeal support has been associated with development of lymphocytopenia that is common finding in COVID-19 outbreak. Cytokines storm complicates early stage of SARS-CoV-2 pneumonia, prompting therapy with steroids and immunomodulatory drugs. There is a paucity of data detailing the host immune response status of COVID-19 patients that require ECMO. We aimed to assess time course of leukocytes, lymphocyte and subpopulation count and of inflammatory and fibrinolysis markers during ECMO and how it might be affected by immunomodulatory therapies such as steroids and tocilizumab, an IL6 receptor blockade. Methods: All consecutive patients with confirmed COVID-19 associated ARDS who required veno-venous ECMO were enrolled. Data collected included patients’ demographic information, comorbidities, severity disease at ICU entry, new diagnoses of bloodstream infection (BSI) and ventilator associated pneumonia (VAP) and aetiologic pathogens. Time course of leukocytes, lymphocyte, subpopulation count, inflammatory and fibrinolysis biomarkers levels (such as c-reactive protein, procalcitonin, ferritin and DDdimer) was analyzed within 24, 72 hours, one week and three weeks from the beginning of ECMO support. Lymphocytes and subpopulation count and inflammatory and fibrinolysis markers concentration were compared in absence of treatment with both steroids and tocilizumab (No Treatment), in presence of treatment with steroids (Steroids), with tocilizumab (Tocilizumab) and with both drugs (Steroids + Tocilizumab). Results: Seventy-nine leukocyte, lymphocyte and thirty-eight subpopulation counts were obtained during 3 weeks of ECMO support from thirteen patients with COVID-19 associated ARDS. Among all lymphoid cells, CD3+ CD4+ and NK cells (CD16+ CD56+) displayed a trend of reduction, while CD3+ CD+ and CD19+ did not change. C-reactive protein, procalcitonin and ferritin significantly decreased over time, reaching the lowest value by 3 weeks. On the contrary, DDimer did not change over time. In presence of steroids and tocilizumab, total lymphocytes and all subpopulations were significantly lower compared to those obtained without treatment. Inflammatory and fibrinolysis markers were significantly reduced by steroids and tocilizumab alone or in combination. In a multivariable linear regression model, therapy with steroids, tocilizumab alone or in combination was significantly associated with reduction of lymphocytes count; instead time spent on ECMO was not associated with changes in lymphocytes count. Eleven over thirteen patients had bacterial superinfections, such as VAP and BSI. Multi-drug resistant Gram-negative bacilli were identified in seven over thirteen patients. Conclusions: In severe COVID-19 critically ill patients requiring ECMO, concomitant immunomodulatory therapies such as steroids and tocilizumab, along with mitigation of inflammation and fibrinolysis, had significant impact on the reduction of B and CD4+ T lymphocytes and natural killer cell count. Funding: None. Conflict of Interest: None. Ethical Approval: The hospital institutional review board approved the study using data collected for routine clinical practice and waived the requirement for informed consent (approval number 0028437).