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).