A systems approach to inflammation identifies therapeutic targets in SARS-CoV-2 infection

Abstract

Background Infection with SARS-CoV-2 manifests itself as a mild respiratory tract infection in the majority of individuals, which progresses to a severe pneumonia and acute respiratory distress syndrome (ARDS) in 10-15% of patients. Inflammation plays a crucial role in the pathogenesis of ARDS, with immune dysregulation in severe COVID-19 leading to a hyperinflammatory response. A comprehensive understanding of the inflammatory process in COVID-19 is lacking. Methods In this prospective, multicenter observational study, patients with PCR-proven or clinically presumed COVID-19 admitted to the intensive care unit (ICU) or clinical wards were included. Demographic and clinical data were obtained and plasma was serially collected. Concentrations of IL-6, TNF-α, complement components C3a, C3c and the terminal complement complex (TCC) were determined in plasma by ELISA. Additionally, 269 circulating biomarkers were assessed using targeted proteomics. Results were compared between ICU and non ICU patients. Findings A total of 119 (38 ICU and 91 non ICU) patients were included. IL-6 plasma concentrations were elevated in COVID-19 (ICU vs. non ICU, median 174.5 pg/ml [IQR 94.5-376.3 vs. 40.0 pg/ml [16.5-81.0]), whereas TNF-α concentrations were relatively low and not different between ICU and non ICU patients (median 24.0 pg/ml [IQR 16.5-33.5] and 21.5 pg/ml [IQR 16.0-33.5], respectively). C3a and terminal complement complex (TCC) concentrations were significantly higher in ICU vs. non ICU patients (median 556.0 ng/ml [IQR 333.3-712.5]) vs. 266.5 ng/ml [IQR 191.5-384.0 for C3a and 4506 mAU/ml [IQR 3661-6595 vs. 3582 mAU/ml [IQR 2947-4300] for TCC) on the first day of blood sampling. Targeted proteomics demonstrated that IL-6 (logFC 2.2), several chemokines and hepatocyte growth factor (logFC 1.4) were significantly upregulated in ICU vs. non ICU patients. In contrast, stem cell factor was significantly downregulated (logFC -1.3) in ICU vs. non ICU patients, as were DPP4 (logFC -0.4) and protein C inhibitor (log FC -1.0), the latter two factors also being involved in the regulation of the kinin-kallikrein pathway. Unsupervised clustering pointed towards a homogeneous pathogenetic mechanism in the majority of patients infected with SARS-CoV-2, with patient clustering mainly based on disease severity. Interpretation We identified important pathways involved in dysregulation of inflammation in patients with severe COVID-19, including the IL-6, complement system and kinin-kallikrein pathways. Our findings may aid the development of new approaches to host-directed therapy.

A distinct innate immune signature marks progression from mild to severe COVID-19

“…The comparison of data from healthy controls and patients with severe COVID-19 showed a strong upregulation of proinflammatory cytokines and chemokines ( Figure 5A ). IL-6, TNF, IFNγ, and IL-18 were significantly upregulated (significance cut-off false discovery rate (FDR) 1%) in patients with severe disease as shown by the proteomics measurements ( Figure 5A) consistent with previous reports (Blanco-Melo et al , 2020; Veerdonk et al , 2020). The elevated levels of IL-18 and increased LDH we observed might indicate a contribution of inflammasome activation (Lee et al , 2020; Merad and Martin, 2020; Yap, Moriyama and Iwasaki, 2020), although we did not detect an elevation of IL-1β ( Figure S5A ).…”

“…Analyzing the inflammatory cytokine and chemokine response to SARS-CoV-2 we identified a TNF and IL-6-dominated inflammatory response in COVID-19 patients in agreement with a previous report (Veerdonk et al , 2020). The initial inflammatory response was dominated by IFNγ, MCP-2, M-CSF, and IL-6, which were coregulated with the CD169 + monocyte subsets, most prominently the M12 cluster, and the low-density granulocytes as evidenced by an unsupervised correlation matrix.…”

“…Early data from China indicated that patients with severe disease mount a strong inflammatory response as shown by increased levels of proinflammatory cytokines, such as tumor necrosis factor (TNF), monocyte chemoattractant protein 1 (MCP-1, also known as CCL2), and macrophage inflammatory protein 1α (MIP-1α, also known as CCL3) (Huang et al , 2020). These data have been confirmed in other studies, which also revealed a distinct cytokine response with activated IL-1 and IL-6 pathways and chemokine enriched signatures (Blanco-Melo et al , 2020; Veerdonk et al , 2020). The type I IFN response during SARS and SARS-CoV-2 infection has gained particular attention; a suppressed or delayed type I IFN response may be associated with a severe disease course, potentially through the recruitment of proinflammatory monocytes to lungs even though the data are currently not conclusive (Channappanavar et al , 2016; Hadjadj et al , 2020; Lee et al , 2020; Park and Iwasaki, 2020).…”

Blocking IL-1 to prevent respiratory failure in COVID-19

“…Many other patients show signs of a cytokine storm syndrome, but do not fulfill the criteria of MAS/HLH. We and others have identified an IL-1/IL-6-driven innate immune response [ 30 – 36 ]. Interestingly, TNF concentrations in plasma were not significantly elevated in the early stages of disease in critically ill patients compared to patients admitted to the ward: median 24.0 pg/ml [IQR 16.5–33.5] and 21.5 pg/ml [IQR 16.0–33.5], respectively [ 30 ].…”

“…We and others have identified an IL-1/IL-6-driven innate immune response [ 30 – 36 ]. Interestingly, TNF concentrations in plasma were not significantly elevated in the early stages of disease in critically ill patients compared to patients admitted to the ward: median 24.0 pg/ml [IQR 16.5–33.5] and 21.5 pg/ml [IQR 16.0–33.5], respectively [ 30 ]. This might explain that hemodynamic instability is not a classical presentation of COVID-19, since both TNF and IL-1 as cytokines are needed to cause hemodynamic problems [ 37 ], arguing that the hyperinflammatory innate immune response initially is mainly an overactive IL-1/IL-6 response.…”