Age is the main determinant of COVID-19 related in-hospital mortality with minimal impact of pre-existing comorbidities, a retrospective cohort study
Authors: Henkens M. T. H. M. , Raafs A. G. , Verdonschot J. A. J. , Linschoten M. , van Smeden M. , Wang P. , van der Hooft B. H. M. , Tieleman R. , Janssen M. L. F. , ter Bekke R. M. A. , Hazebroek M. R. , van der Horst I. C. C. , Asselbergs F. W. , Magdelijns F. J. H. , Heymans S. R. B. ,   on behalf of the CAPACITY-COVID collaborative consortium, Al-Ali A. K. , Al-Muhanna F. A. , Al-Windy N. Y. Y. , Almubarak Y. A. , Alnafie A. N. , Alshahrani M. , Alshehri A. M. , Anthonio R. L. , Asselbergs F. W. , Aujayeb A. , ten Berg J. M. , van Boxem A. J. M. , Captur G. , Caputo M. , Charlotte N. , Dark P. , De Sutter J. , Delsing C. E. , Dorman H. G. R. , Drost J. T. , Emans M. E. , Ferreira J. B. , Gabriel L. , van Gilst W. H. , Groenemeijer B. E. , Haerkens-Arends H. E. , van der Harst P. , Hedayat B. , van der Heijden D. J. , Hellou E. , Hermanides R. S. , Hermans-van Ast J. F. , van Hessen M. W. J. , Heymans S. R. B. , van der Horst I. C. C. , van Ierssel S. H. , Jewbali L. S. , Kearney M. T. , van Kesteren H. A. M. , Kietselaer B. L. J. H. , Koning A. M. H. , Kopylov P. Y. , Kuijper A. F. M. , Kwakkel-van Erp J. M. , van der Linden M. M. J. M. , Linschoten M. , Linssen G. C. M. , Macias Ruiz R. , Magdelijns F. J. H. , Martens F. M. A. C. , McCann G. P. , van der Meer P. , Meijs M. F. L. , Messiaen P. , Monraats P. S. , Montagna L. , Moriarty A. , Mosterd A. , Nierop P. R. , van Ofwegen-Hanekamp C. E. E. , Pinto Y. M. , Poorhosseini H. , Prasad S. , Redón J. , Reidinga A. C. , Ribeiro M. I. A. , Ripley D. P. , Salah R. , Saneei E. , Saxena M. , Schaap J. , Schellings D. A. A. M. , Schut A. , Shafiee A. , Shore A. C. , Siebelink H. J. , van Smeden M. , Smits P. C. , Pisters R. , Tessitore E. , Tieleman R. G. , Timmermans P. , Tio R. A. , Tjong F. V. Y. , den Uil C. A. , Van Craenenbroeck E. M. , van Veen H. P. A. A. , Veneman T. , Verschure D. O. , de Vries J. K. , van de Wal R. M. A. , van de Watering D. J. , Westendorp I. C. D. , Westendorp P. H. M. , Weytjens C. , Wierda E. , Williams B. , Woudstra P. , Wu K. W. , Zaal R. , Zaman A. G. , van der Zee P. M. 
Published: March 2022

Abstract
Background
Age and comorbidities increase COVID-19 related in-hospital mortality risk, but the extent by which comorbidities mediate the impact of age remains unknown.

Methods
In this multicenter retrospective cohort study with data from 45 Dutch hospitals, 4806 proven COVID-19 patients hospitalized in Dutch hospitals (between February and July 2020) from the CAPACITY-COVID registry were included (age 69[58–77]years, 64% men). The primary outcome was defined as a combination of in-hospital mortality or discharge with palliative care. Logistic regression analysis was performed to analyze the associations between sex, age, and comorbidities with the primary outcome. The effect of comorbidities on the relation of age with the primary outcome was evaluated using mediation analysis.

Results
In-hospital COVID-19 related mortality occurred in 1108 (23%) patients, 836 (76%) were aged ≥70 years (70+). Both age 70+ and female sex were univariably associated with outcome (odds ratio [OR]4.68, 95%confidence interval [4.02–5.45], OR0.68[0.59–0.79], respectively;both p<  0.001). All comorbidities were univariably associated with outcome (p<0.001), and all but dyslipidemia remained significant after adjustment for age70+ and sex. The impact of comorbidities was attenuated after age-spline adjustment, only leaving female sex, diabetes mellitus (DM), chronic kidney disease (CKD), and chronic pulmonary obstructive disease (COPD) significantly associated (female OR0.65[0.55–0.75], DM OR1.47[1.26–1.72], CKD OR1.61[1.32–1.97], COPD OR1.30[1.07–1.59]). Pre-existing comorbidities in older patients negligibly (<6% in all comorbidities) mediated the association between higher age and outcome.

Conclusions
Age is the main determinant of COVID-19 related in-hospital mortality, with negligible mediation effect of pre-existing comorbidities.

Trial registration
CAPACITY-COVID (NCT04325412)