Dysregulated Host Response in Severe Acute Respiratory Syndrome Coronavirus 2-Induced Critical Illness

Abstract

Background: Impaired immune response has been reported to be the cause of the development of coronavirus disease 2019 (COVID-19)-related respiratory failure. Further studies are needed to understand the immunopathogenesis and to enable an improved stratification of patients who are at risk for critical illness.

Methods: Thirty-two severely ill patients hospitalized with COVID-19 were recruited in our center at the University Hospital Heidelberg. We performed a comprehensive analysis of immune phenotype, cytokine, and chemokine profiling and leukocyte transcripts in patients with severe COVID-19 and compared critically ill patients who required mechanical ventilation and high-flow oxygen therapy and noncritically ill patient who received low-flow oxygen therapy.

Results: Critically ill patients exhibited low levels of CD8 T cells and myeloid dendritic cells. We noted a pronounced CCR6⁺ TH17 phenotype in CD4 central memory cells and elevated circulating levels of interleukin-17 in the critical group. Gene expression of leukocytes derived from critically ill patients was characterized by an upregulation of proinflammatory cytokines and reduction of interferon (IFN)-responsive genes upon stimulation with Toll-like receptor 7/8 agonist. When correlating clinical improvement and immune kinetics, we found that CD8 T-cell subsets and myeloid dendritic cells significantly increased after disconnection from the ventilator.

Conclusion: Critical illness was characterized by a TH17-mediated response and dysfunctional IFN-associated response, indicating an impaired capacity to mount antiviral responses during severe acute respiratory syndrome coronavirus 2 severe infection.

Keywords: COVID-19; IFN-responsive genes; TH17 immunity; critical illness; inflammation.

Figure 1.

Clinical diagnosis of severe respiratory failure correlates with decreased CD4 and CD8 counts, but not with viral ribonucleic acid load. (A) Absolute counts of peripheral blood-derived CD8 and CD4 T cells in critically ill (N = 14) and noncritically ill (N = 10) patients at day 0–2 after admission. (B) Absolute counts of circulating dendritic cells (DCs) in peripheral blood of critically ill and noncritically ill patients. Frequency of CD11c and CD123 in the DC population, identifying myeloid and plasmacytoid DC, respectively. All bar figures represent mean ± standard error of the mean. P value calculated by Mann-Whitney U test.

Figure 2.

Coronavirus disease 2019 (COVID-19)-related acute respiratory distress syndrome is correlated with an enhanced TH17 phenotype in the CD4 T central memory cell (TCM) subset. (A) Cell counts of CD4 T central memory (TCM) and CD4 T effector memory (TEM) in critical (N = 14) and non-critical groups (N = 10). Frequency of CCR6+CXCR3- cells, identifying the TH17 cell subset, within the CD4 TCM population of critically ill and non-critically ill COVID19 cases. (B) Serum concentration of circulating IL-17 and IL-6 levels in the critical and non-critical group (n = 9 in each group). All bar figures represent mean ± standard error of the mean. P value calculated by Mann-Whitney U test.

Figure 3.

Dysfunctional interferon (IFN)-mediated response in severe coronavirus disease 2019 patients upon stimulation with TLR7/8 agonist R848. Human leukocytes derived from 8 individuals per group at day 0–2 after admission were used in the assay. (A) Relative messenger ribonucleic acid expression of IL1B and IL18 in response to TLR7/8 agonist R848. (B) Response to R848, assessed by change in expression of the IFN-responsive genes, MX1, IFIT1, and IF44L, is shown. All bar figures represent mean ± SEM. Mann-Whitney U test was used to calculate P values.

Figure 4.

Increase in CD8 effector memory T cells (TEM), activated CD8 T cells, and dendritic cells marks clinical improvement. (A) Time course of oxygen support is depicted for each of the 7 critically ill patients. Comparisons are conducted between day of admission (T1) and day 0/1 after disconnection (T2) from the ventilator for each subject. (B) Changes in absolute counts of CD8 T cells and myeloid dendritic cells at T1 and T2. (C) Changes in the frequency of CCR6+CXCR3- cells, indicative of TH17 phenotype, within the CD4 T cell subset at the two time points. (D) Absolute counts of CD45-RA-CCR7- CD8 T cells and frequency of CD45-RA-CCR7- cells, indicative of effector memory cell function, within the CD8 T cell subset at the two time points. (E) Changes in the absolute counts of CD38+ HLA-DR+ CD8 T cells and frequency of CD38+ HLA-DR+ cells within the CD8 T cell subset before and after disconnection from the ventilator. P values are generated by using Wilcoxon signed rank test.