Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure

• Published in: Cell host & microbe Vol. 27; no. 6; pp. 992 - 1000.e3
• Main Authors: Giamarellos-Bourboulis, Evangelos J., Netea, Mihai G., Rovina, Nikoletta, Akinosoglou, Karolina, Antoniadou, Anastasia, Antonakos, Nikolaos, Damoraki, Georgia, Gkavogianni, Theologia, Adami, Maria-Evangelia, Katsaounou, Paraskevi, Ntaganou, Maria, Kyriakopoulou, Magdalini, Dimopoulos, George, Koutsodimitropoulos, Ioannis, Velissaris, Dimitrios, Koufargyris, Panagiotis, Karageorgos, Athanassios, Katrini, Konstantina, Lekakis, Vasileios, Lupse, Mihaela, Kotsaki, Antigone, Renieris, George, Theodoulou, Danai, Panou, Vassiliki, Koukaki, Evangelia, Koulouris, Nikolaos, Gogos, Charalambos, Koutsoukou, Antonia
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.06.2020
• Subjects: Aged; Antibodies, Monoclonal, Humanized - administration & dosage; Coronavirus Infections - immunology; Coronavirus Infections - pathology; COVID-19; dysregulation; Female; ferritin; HLA-DR; HLA-DR Antigens - immunology; Humans; Inflammation - pathology; interleukin-6; Interleukin-6 - immunology; Killer Cells, Natural - pathology; lymphopenia; Lymphopenia - pathology; Macrophage Activation; Male; monocytes; Monocytes - pathology; Pandemics; Pneumonia, Viral - immunology; Pneumonia, Viral - pathology; respiratory failure; Respiratory Insufficiency - immunology; SARS-CoV-2; COVID-19; monocytes; ferritin; SARS-CoV-2; HLA-DR; dysregulation; respiratory failure; macrophage activation; interleukin-6; lymphopenia
• ISSN: 1931-3128; 1934-6069; 1934-6069
• DOI: 10.1016/j.chom.2020.04.009

Proper management of COVID-19 mandates better understanding of disease pathogenesis. The sudden clinical deterioration 7–8 days after initial symptom onset suggests that severe respiratory failure (SRF) in COVID-19 is driven by a unique pattern of immune dysfunction. We studied immune responses of 54 COVID-19 patients, 28 of whom had SRF. All patients with SRF displayed either macrophage activation syndrome (MAS) or very low human leukocyte antigen D related (HLA-DR) expression accompanied by profound depletion of CD4 lymphocytes, CD19 lymphocytes, and natural killer (NK) cells. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production by circulating monocytes was sustained, a pattern distinct from bacterial sepsis or influenza. SARS-CoV-2 patient plasma inhibited HLA-DR expression, and this was partially restored by the IL-6 blocker Tocilizumab; off-label Tocilizumab treatment of patients was accompanied by increase in circulating lymphocytes. Thus, the unique pattern of immune dysregulation in severe COVID-19 is characterized by IL-6-mediated low HLA-DR expression and lymphopenia, associated with sustained cytokine production and hyper-inflammation. [Display omitted] •Severe COVID-19 patients display immune dysregulation or macrophage activation syndrome•Severe respiratory failure is associated with a major decrease of HLA-DR on CD14 monocytes•CD4 cell and NK cell cytopenias are characteristics of severe COVID-19•IL-6 blocker Tocilizumab partially rescues SARS-CoV-2-associated immune dysregulation Proper management of COVID-19 mandates better understanding of disease pathogenesis. Giamarellos-Bourboulis et al. describe two main features preceding severe respiratory failure associated with COVID-19: the first is macrophage activation syndrome; the second is defective antigen-presentation driven by interleukin-6. An IL-6 blocker partially rescues immune dysregulation in vitro and in patients.