COVID-19 ARDS is characterized by a dysregulated host response that differs from cytokine storm and is modified by dexamethasone

Abstract

We performed comparative lower respiratory tract transcriptional profiling of 52 critically ill patients with the acute respiratory distress syndrome (ARDS) from COVID-19 or from other etiologies, as well as controls without ARDS. In contrast to a cytokine storm, we observed reduced proinflammatory gene expression in COVID-19 ARDS when compared to ARDS due to other causes. COVID-19 ARDS was characterized by a dysregulated host response with increased PTEN signaling and elevated expression of genes with non-canonical roles in inflammation and immunity that were predicted to be modulated by dexamethasone and granulocyte colony stimulating factor. Compared to ARDS due to other types of viral pneumonia, COVID-19 was characterized by impaired interferon-stimulated gene expression (ISG). We found that the relationship between SARS-CoV-2 viral load and expression of ISGs was decoupled in patients with COVID-19 ARDS when compared to patients with mild COVID-19. In summary, assessment of host gene expression in the lower airways of patients with COVID-19 ARDS did not demonstrate cytokine storm but instead revealed a unique and dysregulated host response predicted to be modified by dexamethasone.

Impaired immune signaling and changes in the lung microbiome precede secondary bacterial pneumonia in COVID-19

“…In contrast, we found that T cells from patients who later developed VAP expressed lower levels of IFNγ at the time of intubation. This difference may relate to species-specific variations in immune signaling or intrinsic differences in the host response to influenza virus versus SARS-CoV-2 (14, 18) .…”

“…SARS-CoV-2 viral load correlates with interferon stimulated gene expression (14, 18) and thus we initially hypothesized that differences in viral load between groups might relate to individual VAP susceptibility. However, we found no difference between groups at the “early” timepoint.…”

“…All other patients were excluded, including patients with clinically-suspected bacterial pneumonia who did not meet CDC VAP criteria. Eight intubated patients from a recent study (18) (Cohort 2) were included as controls and were selected because they had previously been adjudicated as having no evidence of lower respiratory tract infection. This group included four patients with non-infectious ARDS and four patients with no ARDS who were intubated for other reasons (subdural hematoma (N=1), retroperitoneal hemorrhage (N=1), or neurosurgical procedure (N=2)).…”

Molecular relationships between SARS-CoV-2 Spike protein and LIFR, a pneumonia protective IL-6 family cytokine receptor

“…Previous studies indicate that LIFR is required for lung protection during pneumonia, for example, in respiratory syncytial virus infections (RSV) [31][32][33][34] . Furthermore, its ligand, LIF, is one of the cytokines in the IL-6 family and is increased in the lungs of patients with ARDS 35,36 , which has been observed in COVID-19 patients 2,37,38 . Notably, because the D614G variant is located within the SARS-CoV-2 ITIM, the mutational distance between the LIFR ITIM and the corresponding ITIM sequence in D614G viruses increases from 2 to 3 which could reduce the potential molecular mimicry or subversion of LIFR by the D614G associated ITIM.…”

“…Coronavirus disease 19 (COVID-19) patients exhibit varying degrees of immune system dysfunction including potential cytokine storms 1 , acute respiratory distress syndrome (ARDS) 2 and the production of autoantibodies against several self-antigens [3][4][5] . This implicates dysregulation of immune homeostasis and self-tolerance in the pathology of the disease, an area that remains understudied.…”