Age-related changes in plasma biomarkers and their association with mortality in COVID-19
Authors: Michels Erik H.A. , Appelman Brent , de Brabander Justin , van Amstel Rombout B.E. , Chouchane Osoul , van Linge Christine C.A. , Schuurman Alex R. , Reijnders Tom D.Y. , Sulzer Titia A.L. , Klarenbeek Augustijn M. , Douma Renée A. ,   Amsterdam UMC COVID-19 Biobank Study Group, Bos Lieuwe D.J. , Wiersinga W. Joost , Peters-Sengers Hessel , van der Poll Tom ,   Amsterdam UMC COVID-19 Biobank Study Group, van Agtmael Michiel , Algera Anne Geke , Appelman Brent , van Baarle Floor , Beudel Martijn , Bogaard Harm Jan , Bomers Marije , Bonta Peter , Bos Lieuwe , Botta Michela , de Brabander Justin , de Bree Godelieve , de Bruin Sanne , Bugiani Marianna , Bulle Esther , Buis David T.P. , Chouchane Osoul , Cloherty Alex , Dijkstra Mirjam , Dongelmans Dave A. , Dujardin Romein W.G. , Elbers Paul , Fleuren Lucas , Geerlings Suzanne , Geijtenbeek Theo , Girbes Armand , Goorhuis Bram , Grobusch Martin P. , Hagens Laura , Hamann Jorg , Harris Vanessa , Hemke Robert , Hermans Sabine M. , Heunks Leo , Hollmann Markus , Horn Janneke , Hovius Joppe W. , de Jong Hanna K. , de Jong Menno D. , Koning Rutger , Lemkes Bregje , Lim Endry H.T. , van Mourik Niels , Nellen Jeaninne , Nossent Esther J. , Olie Sabine , Paulus Frederique , Peters Edgar , Pina-Fuentes Dan A.I. , van der Poll Tom , Preckel Bennedikt , Prins Jan M. , Raasveld Jorinde , Reijnders Tom , de Rotte Maurits C.F.J. , Schinkel Michiel , Schultz Marcus J. , Schrauwen Femke A.P. , Schuurman Alex , Schuurmans Jaap , Sigaloff Kim , Slim Marleen A. , Smeele Patrick , Smit Marry , Stijnis Cornelis S. , Stilma Willemke , Teunissen Charlotte , Thoral Patrick , Tsonas Anissa M. , Tuinman Pieter R. , van der Valk Marc , Veelo Denise P. , Volleman Carolien , de Vries Heder , Vught Lonneke A. , van Vugt Michèle , Wouters Dorien , Zwinderman A.H. (Koos) , Brouwer Matthijs C. , Wiersinga W. Joost , Vlaar Alexander P.J. , van de Beek Diederik 
Published: April 2023

Background

Coronavirus disease 2019 (COVID-19)-induced mortality occurs predominantly in older patients. Several immunomodulating therapies seem less beneficial in these patients. The biological substrate behind these observations is unknown. The aim of this study was to obtain insight into the association between ageing, the host response and mortality in patients with COVID-19.

Methods

We determined 43 biomarkers reflective of alterations in four pathophysiological domains: endothelial cell and coagulation activation, inflammation and organ damage, and cytokine and chemokine release. We used mediation analysis to associate ageing-driven alterations in the host response with 30-day mortality. Biomarkers associated with both ageing and mortality were validated in an intensive care unit and external cohort.

Results

464 general ward patients with COVID-19 were stratified according to age decades. Increasing age was an independent risk factor for 30-day mortality. Ageing was associated with alterations in each of the host response domains, characterised by greater activation of the endothelium and coagulation system and stronger elevation of inflammation and organ damage markers, which was independent of an increase in age-related comorbidities. Soluble tumour necrosis factor receptor 1, soluble triggering receptor expressed on myeloid cells 1 and soluble thrombomodulin showed the strongest correlation with ageing and explained part of the ageing-driven increase in 30-day mortality (proportion mediated: 13.0%, 12.9% and 12.6%, respectively).

Conclusions

Ageing is associated with a strong and broad modification of the host response to COVID-19, and specific immune changes likely contribute to increased mortality in older patients. These results may provide insight into potential age-specific immunomodulatory targets in COVID-19.