Age is the main determinant of COVID-19 related in-hospital mortality with minimal impact of pre-existing comorbidities, a retrospective cohort study

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

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 ).

Keywords: COVID-19; Hospitalization; Mediation analysis; Mortality; Netherlands.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Predicted and observed in-hospital mortality (univariable age-restricted cubic spline adjusted). % Mortality predicted: The white line represents the predicted mortality rates at different ages, accompanied by 95% confidence intervals in blue. # Observed patients: The grey bars represent the number of patients observed within the different age categories. The light grey bars are the patients that were discharged without palliative care. The dark grey bars are the patients in which in-hospital mortality (or palliative discharge) occurred
Fig. 2
Fig. 2
Associations of age and comorbidities with in-hospital mortality. A) Univariable association of age 70+, sex, and comorbidities with in-hospital mortality; B) Association of all comorbidities after adjustment for age 70+ and sex; C) Association of sex and all comorbidities after age spline adjustment. COPD = chronic obstructive pulmonary disease
Fig. 3
Fig. 3
Mediation analysis with age ≥ 70 years as independent predictor, the individual comorbidities as mediator and in-hospital mortality as outcome. All comorbidities partly mediated the effect of age on in-hospital mortality (all p-values < 0.001). The mediation effect was 5% (95% CI 2–9%) for hypertension, 3% (95% CI 2–4%) for diabetes mellitus, 3% (95% CI 0.4–6%) for dyslipidemia, 5% (95% CI 3–7%) for chronic kidney disease, 2% (95% CI 1–3%) for COPD, and 5% (95% CI 2–9%) for history of cardiac disease. COPD = chronic obstructive pulmonary disease

References

    1. WHO COVID-19 Dashboard. Geneva: World Health Organization, 2020. Available online: (last cited: 16-07-2021).
    1. Sun P, Lu X, Xu C, Sun W, Pan B. Understanding of COVID-19 based on current evidence. J Med Virol. 2020;92(6):548–551. doi: 10.1002/jmv.25722.
    1. Wu C, Chen X, Cai Y, Ja X, Zhou X, Xu S, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA. Intern Med. 2020;180(7):934–943.
    1. Grasselli G, Greco M, Zanella A, Albano G, Antonelli M, Bellani G, et al. Risk factors associated with mortality among patients with COVID-19 in intensive care units in Lombardy, Italy. JAMA Intern Med. 2020;180(10):1345–1355. doi: 10.1001/jamainternmed.2020.3539.
    1. NHS Digital . Coronavirus (COVID-19): shielded patients list. 2020.
    1. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054–1062. doi: 10.1016/S0140-6736(20)30566-3.
    1. Rijksinstituut voor volksgezondheid (RIVM): Mortality rates, Coronadashboard, (last cited: 16-7-2021). 2021.
    1. Ariës MJH, van den Bergh JP, Beudel M, Boersma W, Dormans T, Douma RA, et al. Clinical course of COVID-19 in the Netherlands: an overview of 2607 patients in hospital during the first wave. Ned Tijdschr Geneeskd. 2021;165:1-5.
    1. Posso M, Comas M, Román M, Domingo L, Louro J, González C, et al. Comorbidities and mortality in patients with COVID-19 aged 60 years and older in a University Hospital in Spain. Arch Bronconeumol. 2020;56(11):756–758. doi: 10.1016/j.arbres.2020.06.012.
    1. Zuccaro V, Celsa C, Sambo M, Battaglia S, Sacchi P, Biscarini S, et al. Competing-risk analysis of coronavirus disease 2019 in-hospital mortality in a northern Italian Centre from SMAtteo COvid19 REgistry (SMACORE) Sci Rep. 2021;11(1):1137. doi: 10.1038/s41598-020-80679-2.
    1. Docherty AB, Harrison EM, Green CA, Hardwick HE, Pius R, Norman L, et al. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO clinical characterisation protocol: prospective observational cohort study. Bmj. 2020;369:m1985. doi: 10.1136/bmj.m1985.
    1. Williamson EJ, Walker AJ, Bhaskaran K, Bacon S, Bates C, Morton CE, et al. Factors associated with COVID-19-related death using OpenSAFELY. Nature. 2020;584(7821):430–436. doi: 10.1038/s41586-020-2521-4.
    1. Atkins JL, Masoli JAH, Delgado J, Pilling LC, Kuo C-L, Kuchel GA, et al. Preexisting comorbidities predicting COVID-19 and mortality in the UK biobank community cohort. J Gerontol Ser A. 2020;75(11):2224–2230. doi: 10.1093/gerona/glaa183.
    1. Linschoten M, Asselbergs FW. CAPACITY-COVID: a European registry to determine the role of cardiovascular disease in the COVID-19 pandemic. Eur Heart J. 2020;41(19):1795–1796. doi: 10.1093/eurheartj/ehaa280.
    1. CAPACITY-COVID Collaborative Consortium and LEOSS Study Group. Clinical presentation, disease course, and outcome of COVID-19 in hospitalized patients with and without pre-existing cardiac disease: a cohort study across 18 countries. Eur Heart J. 2021:ehab656. 10.1093/eurheartj/ehab656. Epub ahead of print. PMID: 34734634.
    1. Wang Y, Kang H, Liu X, Tong Z. Combination of RT-qPCR testing and clinical features for diagnosis of COVID-19 facilitates management of SARS-CoV-2 outbreak. J Med Virol. 2020;92(6):538–539. doi: 10.1002/jmv.25721.
    1. Harrell FE., Jr . Rms: regression modeling strategies. R package version 6.2-0. 2021.
    1. Tingley D, Yamamoto T, Hirose K, Keele L, Imai K. Mediation: R package for causal mediation analysis. J Stat Softw. 2014;59(5):1–38. doi: 10.18637/jss.v059.i05.
    1. R Core Team . R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2021.
    1. Max Gordon and Thomas Lumley . Forestplot: advanced Forest plot using 'grid' graphics. R package version 1.10.1. 2020.
    1. Wickham H. ggplot2: elegant graphics for data analysis. New York: Springer-Verlag; 2016.
    1. Zheng Z, Peng F, Xu B, Zhao J, Liu H, Peng J, et al. Risk factors of critical & mortal COVID-19 cases: a systematic literature review and meta-analysis. J Inf Secur. 2020;81(2):e16–e25.
    1. Mendes A, Serratrice C, Herrmann FR, Genton L, Périvier S, Scheffler M, et al. Predictors of in-hospital mortality in older patients with COVID-19: the COVIDAge study. J Am Med Dir Assoc. 2020;21(11):1546–54.e3. doi: 10.1016/j.jamda.2020.09.014.
    1. Gebhard C, Regitz-Zagrosek V, Neuhauser HK, Morgan R, Klein SL. Impact of sex and gender on COVID-19 outcomes in Europe. Biol Sex Differ. 2020;11(1):29. doi: 10.1186/s13293-020-00304-9.
    1. Mohamed MO, Gale CP, Kontopantelis E, Doran T, de Belder M, Asaria M, et al. Sex differences in mortality rates and underlying conditions for COVID-19 deaths in England and Wales. Mayo Clin Proc. 2020;95(10):2110–2124. doi: 10.1016/j.mayocp.2020.07.009.
    1. Ottenhoff MC, Ramos LA, Potters W, Janssen MLF, Hubers D, Hu S, et al. Predicting mortality of individual patients with COVID-19: a multicentre Dutch cohort. BMJ Open. 2021;11(7):e047347. doi: 10.1136/bmjopen-2020-047347.
    1. Peckham H, de Gruijter NM, Raine C, Radziszewska A, Ciurtin C, Wedderburn LR, et al. Male sex identified by global COVID-19 meta-analysis as a risk factor for death and ITU admission. Nat Commun. 2020;11(1):6317. doi: 10.1038/s41467-020-19741-6.
    1. Schiffer VMMM, Janssen EBNJ, van Bussel BCT, Jorissen LLM, Tas J, Sels J-WEM, et al. The "sex gap" in COVID-19 trials: a scoping review. EClinicalMedicine. 2020;29:100652.
    1. Linschoten M, Peters S, van Smeden M, Jewbali LS, Schaap J, Siebelink HM, et al. Cardiac complications in patients hospitalised with COVID-19. Eur Heart J Acute Cardiovasc Care. 2020;9(8):817–823. doi: 10.1177/2048872620974605.
    1. Linschoten M, Nab L, van der Horst ICC, Tieleman R, Asselbergs FW. Response to "early hydroxychloroquine but not chloroquine use reduces ICU admission in COVID-19 patients". Int J Infect Dis. 2021;103:560–561. doi: 10.1016/j.ijid.2020.12.006.
    1. Rijksinstituut voor volksgezondheid (RIVM): Mortality rates, Coronadashboard. . 2021.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner