A systems approach to inflammation identifies therapeutic targets in SARS-CoV-2 infection
Authors: van de Veerdonk Frank L. , Janssen Nico A.F. , Grondman Inge , de Nooijer Aline H. , Koeken Valerie A.C.M. , Matzaraki Vasiliki , Boahen Collins K. , Kumar Vinod , Kox Matthijs , Koenen Hans J.P.M. , Smeets Ruben L. , Joosten Irma , Brüggemann Roger J.M. , Kouijzer Ilse J.E. , van der Hoeven Hans G. , Schouten Jeroen A. , Frenzel Tim , Reijers Monique , Hoefsloot Wouter , Dofferhoff Anton S.M. , Kerckhoffs Angèle P.M. , Blaauw Marc J.T. , Veerman Karin , Maas Coen , Schoneveld Arjan H. , Hoefer Imo E. , Derde Lennie P.G. , Willems Loek , Toonen Erik , van Deuren Marcel , van der Meer Emeritus Jos W.M. , van Crevel Reinout , Giamarellos-Bourboulis Evangelos J. , Joosten Leo A.B. , van den Heuvel Michel M. , Hoogerwerf Jacobien , de Mast Quirijn , Pickkers Peter , Netea Mihai G. 
Published: May 2020

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.).