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

Cell Host Microbe. 2020 Jun 10;27(6):992-1000.e3. doi: 10.1016/j.chom.2020.04.009. Epub 2020 Apr 21.


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.

Keywords: COVID-19; HLA-DR; SARS-CoV-2; dysregulation; ferritin; interleukin-6; lymphopenia; macrophage activation; monocytes; respiratory failure.

MeSH terms

  • Aged
  • Antibodies, Monoclonal, Humanized / administration & dosage
  • COVID-19
  • Coronavirus Infections / immunology*
  • Coronavirus Infections / pathology*
  • Female
  • HLA-DR Antigens / immunology
  • Humans
  • Inflammation / pathology
  • Interleukin-6 / immunology
  • Killer Cells, Natural / pathology
  • Lymphopenia / pathology
  • Macrophage Activation
  • Male
  • Monocytes / pathology
  • Pandemics
  • Pneumonia, Viral / immunology*
  • Pneumonia, Viral / pathology*
  • Respiratory Insufficiency / immunology*


  • Antibodies, Monoclonal, Humanized
  • HLA-DR Antigens
  • Interleukin-6
  • tocilizumab