Pro- and Anti-Inflammatory Responses in Severe COVID-19-Induced Acute Respiratory Distress Syndrome—An Observational Pilot Study

Abstract

Objectives The severity of Coronavirus Disease 2019 (COVID-19) is largely determined by the immune response. First studies indicate altered lymphocyte counts and function. However, interactions of pro- and anti-inflammatory mechanisms remain elusive. In the current study we characterized the immune responses in patients suffering from severe COVID-19-induced acute respiratory distress syndrome (ARDS). Methods This was a single-center retrospective study in patients admitted to the intensive care unit (ICU) with confirmed COVID-19 between March 14 th and May 28 th 2020 (n = 39). Longitudinal data were collected within routine clinical care, including flow-cytometry of lymphocyte subsets, cytokine analysis and growth differentiation factor 15 (GDF-15). Antibody responses against the receptor binding domain (RBD) of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike protein were analyzed. Results All patients suffered from severe ARDS, 30.8% died. Interleukin (IL)-6 was massively elevated at every time-point. The anti-inflammatory cytokine IL-10 was concomitantly upregulated with IL-6. The cellular response was characterized by lymphocytopenia with low counts of CD8+ T cells, natural killer (NK) and naïve T helper cells. CD8+ T and NK cells recovered after 8 to 14 days. The B cell system was largely unimpeded. This coincided with a slight increase in anti-SARS-CoV-2-Spike-RBD immunoglobulin (Ig) G and a decrease in anti-SARS-CoV-2-Spike-RBD IgM. GDF-15 levels were elevated throughout ICU treatment. Conclusions Massively elevated levels of IL-6 and a delayed cytotoxic immune defense characterized severe COVID-19-induced ARDS. The B cell response and antibody production were largely unimpeded. No obvious imbalance of pro- and anti-inflammatory mechanisms was observed, with elevated GDF-15 levels suggesting increased tissue resilience.

Biodistribution and serologic response in SARS-CoV-2 induced ARDS: A cohort study

“…Cycle thresholds of positive samples differed between survivors and non-survivors: Median cycles of oropharyngeal swabs were 35 (30)(31)(32)(33)(34)(35)(36)(37) in survivors and 30 (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32) in non-survivors (p = 0.003). However, no significant difference was observed in tracheal swabs with 31 (25)(26)(27)(28)(29)(30)(31)(32)(33)(34) in survivors and 27 (24)(25)(26)(27)(28)(29)(30)(31)(32) in non-survivors (p = 0.11). Median cycles (IQR) in blood samples were equal in survivors and non-survivors (p = 0.613).…”

“…In all but two patients (in which samples were not available) anti-SARS-CoV-2 IgG, IgM and IgA antibodies were detectable during the course of therapy (Fig 4). Median overall-concentrations of IgG were similar in survivors and non-survivors (20 [17][18][19][20][21][22][23] vs. 20 [15][16][17][18][19][20][21][22][23][24]; p = 0.99), whereas overall-concentrations of IgM and IgA were lower in survivors than in non-survivors (12 [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] vs. 20 ; p = 0.026 and 5 [3][4][5][6][7] vs. 8 [5][6][7][8][9]; p = 0.009). No difference in antibody concentrations was found when breaking down disease severity into moderate vs. severe ARDS on ICU admission (Fig 5).…”

Performance of three SARS-CoV-2 immunoassays, three rapid lateral flow tests and a novel bead-based affinity surrogate test for the detection of SARS-CoV-2 antibodies in human serum

“…Dynabeads ® M-270 Epoxy (ThermoFisher, Waltham, USA) were coated according to the manufacturer's instructions with different concentrations of either commercially available fulllength SARS-CoV2 S1-Spike-Protein (His-tagged, Sino Biological, Beijing, China) expressed and purified from HEK cells or with SARS-CoV-2 RBD protein expressed and purified from Expi293F™ cells (22)(23)(24)(25)(26). Importantly, the receptor binding domain of the viral spike protein has been found to be an immunodominant and highly specific target of antibodies in SARS-CoV-2 patients (27).…”

Innate Receptor Activation Patterns Involving TLR and NLR Synergisms in COVID-19, ALI/ARDS and Sepsis Cytokine Storms: A Review and Model Making Novel Predictions and Therapeutic Suggestions

“…Some patients experiencing severe COVID-19, the disease caused by the SARS-CoV-2 beta coronavirus, develop what is sometimes described as a “cytokine storm” or “cytokine release syndrome” characterized by the overstimulation of macrophages, dendritic cells and monocytes producing the cytokines interleukin 1 (IL1), interleukin 6 (IL6), interleukin 10 (IL10), tumor necrosis factor alpha (TNF-α), tumor necrosis factor beta (TNF-β) and ferritin [ 1 , 2 , 3 , 4 , 5 , 6 ]. These cytokines produce eosinopenia and lymphocytopenia characterized by low counts of eosinophils, CD8+ T cells, natural killer (NK) and naïve T-helper cells, simultaneously inducing naive B-cell activation, increased T-helper cell 17 (Th17) lymphocyte differentiation and the stimulation of monocyte and neutrophil recruitment [ 1 , 2 , 3 , 4 , 5 , 6 ]. Oddly, however, the release of cytokines interferon alpha (IFNα) and interferon gamma (IFNγ) are severely impaired in severe COVID-19 [ 1 , 2 , 3 , 4 , 5 , 6 ].…”

“…These cytokines produce eosinopenia and lymphocytopenia characterized by low counts of eosinophils, CD8+ T cells, natural killer (NK) and naïve T-helper cells, simultaneously inducing naive B-cell activation, increased T-helper cell 17 (Th17) lymphocyte differentiation and the stimulation of monocyte and neutrophil recruitment [ 1 , 2 , 3 , 4 , 5 , 6 ]. Oddly, however, the release of cytokines interferon alpha (IFNα) and interferon gamma (IFNγ) are severely impaired in severe COVID-19 [ 1 , 2 , 3 , 4 , 5 , 6 ]. The result is a generalized, nonspecific hyperinflammatory response in the lungs resulting in acute respiratory distress syndrome (ARDS) with the concomitant activation of nonspecific inflammatory reactivity in the circulatory system and other organs, sometimes leading to multiorgan failure, leaky vasculature, coagulopathies and strokes [ 1 , 7 ].…”