A systems approach to inflammation identifies therapeutic targets in SARS-CoV-2 infection
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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.
Funding
Vidi grant (F.L.v.d.V.) and Spinoza grant (M.G.N.) from the Netherlands Organization for Scientific Research, and ERC Advanced Grant (#833247 to M.G.N.).
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SciScore for 10.1101/2020.05.23.20110916: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IACUC: The local independent ethical committee approved the study protocol (CMO 2020-6344 and CMO 2016-2923).
Consent: All patients (or their representatives) admitted to the Radboud University Medical Center (Radboudumc), a tertiary care university medical care facility, with a PCR-proven SARS-CoV-2 infection or presumed infection (based on signs and symptoms and findings on computed tomography (CT) scans) were asked for informed consent for participation in this study.Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources For complement data … SciScore for 10.1101/2020.05.23.20110916: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IACUC: The local independent ethical committee approved the study protocol (CMO 2020-6344 and CMO 2016-2923).
Consent: All patients (or their representatives) admitted to the Radboud University Medical Center (Radboudumc), a tertiary care university medical care facility, with a PCR-proven SARS-CoV-2 infection or presumed infection (based on signs and symptoms and findings on computed tomography (CT) scans) were asked for informed consent for participation in this study.Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources For complement data analysis, data from healthy controls (from the 200FG cohort; www.humanfunctionalgenomics.org) and bacterial septic shock patients early in their course of disease (classified according to the Sepsis 3 criteria) (from the PROVIDE Study cohort; ClinicalTrials.gov NCT03332225) were used as comparisons for COVID-19 patients. PROVIDEsuggested: (ProViDE, RRID:SCR_004709)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT03332225 Completed A Trial of Validation and Restoration of Immune Dysfunction … Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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