Is frailty incremental to the 4C Mortality model for mortality risk prediction in hospitalized older individuals with COVID-19 disease?

Anum Zahra; Bas F M van Raaij; Maarten van Smeden; Rishi K Gupta; Jacobijn Gussekloo; Kim Luijken; Karel G M Moons; Simon P Mooijaart; Raymond Noordam; Anne A H de Hond; COOP consortium; COVID-OLD study group

doi:10.1016/j.jclinepi.2025.111873

Is frailty incremental to the 4C Mortality model for mortality risk prediction in hospitalized older individuals with COVID-19 disease?

J Clin Epidemiol. 2025 Jun 23:111873. doi: 10.1016/j.jclinepi.2025.111873. Online ahead of print.

Collaborators Collaborators

COOP consortium:
Simon P Mooijaart⁷, Jacobijn Gussekloo⁸, Harmke A Polinder-Bos⁹, Karel G M Moons¹⁰, Maarten van Smeden¹⁰, Geeske Peeters¹¹, René J F Melis¹¹, Petra J M Elders¹², Jan Festen¹³
COVID-OLD study group:
Simon P Mooijaart⁷, Harmke A Polinder-Bos⁹, Carolien M J van der Linden¹⁴, Steffy W M Jansen¹⁴, Hanna C Willems¹⁵, Jessica M van der Bol¹⁶

Affiliations

¹ Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht University, Utrecht, the Netherlands. Electronic address: a.zahra@umcutrecht.nl.
² Department of Internal Medicine, Section of Geriatrics and Gerontology, Leiden University Medical Center, Leiden, The Netherlands; LUMC Center for Medicine for Older People, Leiden University Medical Center, Leiden, The Netherlands.
³ Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht University, Utrecht, the Netherlands.
⁴ UCL Respiratory, Division of Medicine, Institute for Global Health University College London, London, UK.
⁵ Department of Internal Medicine, Section of Geriatrics and Gerontology, Leiden University Medical Center, Leiden, The Netherlands; LUMC Center for Medicine for Older People, Leiden University Medical Center, Leiden, The Netherlands; Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands.
⁶ Department of Internal Medicine, Section of Geriatrics and Gerontology, Leiden University Medical Center, Leiden, The Netherlands; Health Campus The Hague, department of Public Health and Primary Care, Leiden University Medical Center, the Hague, The Netherlands.
⁷ Department of Internal Medicine, Section of Geriatrics and Gerontology, Leiden University Medical Center, Leiden, The Netherlands; LUMC Center of Medicine for Older People, Leiden University Medical Center, Leiden, The Netherlands.
⁸ Department of Internal Medicine, Section of Geriatrics and Gerontology, Leiden University Medical Center, Leiden, The Netherlands; LUMC Center of Medicine for Older People, Leiden University Medical Center, Leiden, The Netherlands; Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands.
⁹ Division of Geriatric Medicine, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
¹⁰ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
¹¹ Department of Geriatric Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
¹² Department of General Practice & Elderly Care Medicine, Amsterdam Public Health Research Institute, VU University Medical Centre, Amsterdam, The Netherlands.
¹³ KBO-PCOB, Etten-Leur, The Netherlands.
¹⁴ Department of Geriatric Medicine, Catharina Hospital, Eindhoven, The Netherlands.
¹⁵ Department of Internal Medicine and Geriatrics, Amsterdam University Medical Center, Amsterdam, The Netherlands.
¹⁶ Department of Geriatric Medicine, Reinier de Graaf Hospital, Delft, The Netherlands.

PMID: 40562252
DOI: 10.1016/j.jclinepi.2025.111873

Abstract

Background: External validation of COVID-19 prognostic models showed that most performed poorly in older populations, except the 4C Mortality model. Frailty status, measured as Clinical Frailty Scale (CFS), can improve prognostication in older adults.

Objective: This study evaluated incremental value of frailty in addition to 4C Mortality model in predicting in-hospital mortality in older hospitalized COVID-19 patients.

Methods: We included individuals aged ≥70 years from the COVID-OLD cohort, hospitalized with COVID-19 in the Netherlands (February 2020 - April 2022). CFS was added to three versions of the 4C Mortality model: original, recalibrated, and revised. Predictive performance was calculated by scaled brier score, discrimination, calibration and visual distribution of predicted risks.

Results: 3,067 participants were included in the study with an in-hospital mortality fraction of 31%. External validation of the 4C Mortality model demonstrated a scaled brier score of 0.03 [-0.01 to 0.06], discrimination of 0.70 [0.68 to 0.72] and a calibration slope of 0.88 [0.77 to 0.98]. Adding CFS to original 4C Mortality model marginally improved predictive performance, with scaled brier score of 0.04 [0.01 to 0.07], discrimination to 0.71 [0.69 to 0.73], and a calibration slope of 0.89 [0.79 to 1.00]. Addition of CFS to the recalibrated 4C Mortality model also marginally improved the predictive performance scaled brier score from 0.09 to 0.11, and discrimination from 0.70 to 0.71. Model revision, with and without addition of CFS, displayed limited incremental value of CFS on top of existing predictors in 4C Mortality model with a change in scaled brier score from 0.21 [0.19 to 0.25] to 0.24 [0.22 to 0.28], and discrimination from 0.79 [0.77 to 0.81] to 0.80 [0.78 to 0.81].

Conclusion: Frailty reflected by CFS demonstrated limited incremental value for in-hospital mortality prediction in addition to validated 4C Mortality model. Future research should explore other predictors that capture heterogeneity in older population.

Keywords: COVID‐19; Clinical frailty scale; Frailty; Older people; Prognostic research; Vulnerability.