Systemic hyperinflammation in COVID-MDR but not MDR
The absence of viral RNA in the skin suggested that a massive systemic
inflammatory response rather than SARS-CoV-2 in the skin favored the
development of COVID-MDR in severely ill COVID-19 patients. We measured
a panel of 92 inflammation-related proteins in the serum of COVID-MDR,
MDR, and DRESS patients in comparison to HC using the proximity
extension assay high-throughput proteomic platform (Table S4). Principal
component analysis (PCA) of the transcriptome shows that serum samples
from patients with COVID-MDR, MDR, and HC clusters were separated from
each other, while DRESS had overlaps with MDR and COVID-MDR samples
(Figure 5A).
Protein expression patterns of three different groups are shown in
Figure 5B and 5C. There were striking differences between COVID-MDR,
MDR, DRESS and HC. Increased expression of eight proinflammatory
proteins overlapped in all three diseases, namely CXCL9, CXCL10, CXCL11,
4E-BP1, CDCP1, CCL20, IL-10 and IL-6. In COVID-MDR, a total of 49
proteins were significantly upregulated and 1 protein was significantly
downregulated compared to HC. 24 proteins were significantly
differentially expressed only in COVID-MDR (Figure 5B-C). The proteomic
serum signature in COVID-MDR showed a cytokine storm. This was evidenced
by a strong upregulation of inflammatory cytokines such as IL-6,
tumor-necrosis factor and IL-8, type I cytokines and chemokines
(interferon-γ, CXCL9, CXCL10, CXCL11), but also of mediators of a type 2
response (IL-4, IL-5, IL-13), eosinophil chemotaxis and a suppressive
immune response (Figure 5D). Strikingly, DRESS shared the cytokine
storm-related inflammatory cytokines and chemokines. These results are
clearly indicative of systemic hyperinflammation and immune dysfunction
in COVID-MDR patients, and, to a lesser extent, in DRESS (Figure S5).