@article{3000193,
    title = "Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure",
    author = "Giamarellos-Bourboulis, E.J. and Netea, M.G. and Rovina, N. and Akinosoglou, K. and Antoniadou, A. and Antonakos, N. and Damoraki, G. and Gkavogianni, T. and Adami, M.-E. and Katsaounou, P. and Ntaganou, M. and Kyriakopoulou, M. and Dimopoulos, G. and Koutsodimitropoulos, I. and Velissaris, D. and Koufargyris, P. and Karageorgos, A. and Katrini, K. and Lekakis, V. and Lupse, M. and Kotsaki, A. and Renieris, G. and Theodoulou, D. and Panou, V. and Koukaki, E. and Koulouris, N. and Gogos, C. and Koutsoukou, A.",
    journal = "Cell Host and Microbe",
    year = "2020",
    volume = "27",
    number = "6",
    pages = "992-1000.e3",
    publisher = "Cell Press",
    doi = "10.1016/j.chom.2020.04.009",
    keywords = "CD19 antigen;  CD4 antigen;  HLA DR antigen;  interleukin 6;  tocilizumab;  tumor necrosis factor;  HLA DR antigen;  interleukin 6;  monoclonal antibody;  tocilizumab, aged;  antigen expression;  Article;  CD4+ T lymphocyte;  coronavirus disease 2019;  cytokine production;  cytopenia;  female;  human;  immune dysregulation;  immune response;  lymphocytopenia;  macrophage activation syndrome;  major clinical study;  male;  monocyte;  natural killer cell;  plasma;  priority journal;  respiratory failure;  Severe acute respiratory syndrome coronavirus 2;  T cell depletion;  Coronavirus infection;  immunology;  inflammation;  macrophage activation;  pandemic;  pathology;  respiratory failure;  virus pneumonia, Aged;  Antibodies, Monoclonal, Humanized;  Coronavirus Infections;  Female;  HLA-DR Antigens;  Humans;  Inflammation;  Interleukin-6;  Killer Cells, Natural;  Lymphopenia;  Macrophage Activation;  Male;  Monocytes;  Pandemics;  Pneumonia, Viral;  Respiratory Insufficiency",
    abstract = "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. © 2020 Elsevier Inc.
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. © 2020 Elsevier Inc."
}