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JCI Insight ; 5(17)2020 09 03.
Article in English | MEDLINE | ID: covidwho-676865


BACKGROUNDElevated levels of inflammatory cytokines have been associated with poor outcomes among COVID-19 patients. It is unknown, however, how these levels compare with those observed in critically ill patients with acute respiratory distress syndrome (ARDS) or sepsis due to other causes.METHODSWe used a Luminex assay to determine expression of 76 cytokines from plasma of hospitalized COVID-19 patients and banked plasma samples from ARDS and sepsis patients. Our analysis focused on detecting statistical differences in levels of 6 cytokines associated with cytokine storm (IL-1ß, IL-1RA, IL-6, IL-8, IL-18, and TNF-α) between patients with moderate COVID-19, severe COVID-19, and ARDS or sepsis.RESULTSFifteen hospitalized COVID-19 patients, 9 of whom were critically ill, were compared with critically ill patients with ARDS (n = 12) or sepsis (n = 16). There were no statistically significant differences in baseline levels of IL-1ß, IL-1RA, IL-6, IL-8, IL-18, and TNF-α between patients with COVID-19 and critically ill controls with ARDS or sepsis.CONCLUSIONLevels of inflammatory cytokines were not higher in severe COVID-19 patients than in moderate COVID-19 or critically ill patients with ARDS or sepsis in this small cohort. Broad use of immunosuppressive therapies in ARDS has failed in numerous Phase 3 studies; use of these therapies in unselected patients with COVID-19 may be unwarranted.FUNDINGFunding was received from NHLBI K23 HL125663 (AJR); The Bill and Melinda Gates Foundation OPP1113682 (AJR and CAB); Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Diseases #1016687 NIH/NIAID U19AI057229-16; Stanford Maternal Child Health Research Institute; and Chan Zuckerberg Biohub (CAB).

Coronavirus Infections/immunology , Cytokine Release Syndrome/immunology , Cytokines/immunology , Pneumonia, Viral/immunology , Respiratory Distress Syndrome/immunology , Sepsis/immunology , Adult , Aged , COVID-19 , Case-Control Studies , Coronavirus Infections/blood , Cytokine Release Syndrome/blood , Cytokines/blood , Female , Humans , Interleukin 1 Receptor Antagonist Protein/blood , Interleukin 1 Receptor Antagonist Protein/immunology , Interleukin-18/blood , Interleukin-18/immunology , Interleukin-1beta/blood , Interleukin-1beta/immunology , Interleukin-6/blood , Interleukin-6/immunology , Interleukin-8/blood , Interleukin-8/immunology , Male , Middle Aged , Pandemics , Pneumonia, Viral/blood , Respiratory Distress Syndrome/blood , Sepsis/blood , Severity of Illness Index , Tumor Necrosis Factor-alpha/blood , Tumor Necrosis Factor-alpha/immunology
Nat Med ; 26(7): 1070-1076, 2020 07.
Article in English | MEDLINE | ID: covidwho-591473


There is an urgent need to better understand the pathophysiology of Coronavirus disease 2019 (COVID-19), the global pandemic caused by SARS-CoV-2, which has infected more than three million people worldwide1. Approximately 20% of patients with COVID-19 develop severe disease and 5% of patients require intensive care2. Severe disease has been associated with changes in peripheral immune activity, including increased levels of pro-inflammatory cytokines3,4 that may be produced by a subset of inflammatory monocytes5,6, lymphopenia7,8 and T cell exhaustion9,10. To elucidate pathways in peripheral immune cells that might lead to immunopathology or protective immunity in severe COVID-19, we applied single-cell RNA sequencing (scRNA-seq) to profile peripheral blood mononuclear cells (PBMCs) from seven patients hospitalized for COVID-19, four of whom had acute respiratory distress syndrome, and six healthy controls. We identify reconfiguration of peripheral immune cell phenotype in COVID-19, including a heterogeneous interferon-stimulated gene signature, HLA class II downregulation and a developing neutrophil population that appears closely related to plasmablasts appearing in patients with acute respiratory failure requiring mechanical ventilation. Importantly, we found that peripheral monocytes and lymphocytes do not express substantial amounts of pro-inflammatory cytokines. Collectively, we provide a cell atlas of the peripheral immune response to severe COVID-19.

Betacoronavirus/immunology , Coronavirus Infections , Immunity, Cellular , Leukocytes, Mononuclear , Pandemics , Pneumonia, Viral , Sequence Analysis, RNA/methods , Single-Cell Analysis/methods , Adult , Aged , Aged, 80 and over , COVID-19 , Case-Control Studies , Coronavirus Infections/genetics , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Cytokines/genetics , Cytokines/metabolism , Female , Gene Expression Profiling/methods , Humans , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/metabolism , Leukocytes, Mononuclear/virology , Male , Middle Aged , Pneumonia, Viral/genetics , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , RNA-Seq/methods , SARS-CoV-2 , Severity of Illness Index , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Young Adult