Clinical frailty, and not features of acute infection, is associated with late mortality in COVID-19: a retrospective cohort study

Abstract

Background: Coronavirus disease 2019 (COVID-19) is associated with excess mortality after hospital discharge. Identification of patients at increased risk of death following hospital discharge is needed to guide clinical monitoring and early intervention. Herein, we aimed to identify predictors of early vs. late mortality in COVID-19 patients.

Methods: A total of 471 patients with polymerase chain reaction-confirmed COVID-19 were followed up for 9 months [median (inter-quartile range) of follow-up time: 271 (14) days] after hospital admission. COVID-19-related signs and symptoms, laboratory features, co-morbidities, Coronavirus Clinical Characterisation Consortium (4C) mortality and Clinical Frailty Scale (CFS) scores were analysed by logistic regression for association with early (28 day) vs. late mortality. Receiver operating characteristic (ROC) analysis was used to determine the discriminative value of 4C and CFS scores for early vs. late mortality.

Results: A total of 120 patients died within 28 days from hospital admission. Of the remaining 351 patients, 41 died within the next 8 months. Respiratory failure, systemic inflammation, and renal impairment were associated with early mortality, while active cancer and dementia were associated with late mortality, after adjustment for age and sex. 4C mortality score and CFS were associated with both early [odds ratio (OR) (95% confidence interval-CI): 4C: 1.34 (1.25-1.45); CFS: 1.49 (1.33-1.66)] and late [OR (95% CI): 4C: 1.23 (1.12-1.36); CFS: 2.04 (1.62-2.56)] mortality. After adjustment for CFS, the association between 4C and late mortality was lost. By ROC analysis, 4C mortality score was superior to CFS for 28 day mortality [area under the curve (AUC) (95% CI): 0.779 (0.732-0.825) vs. 0.723 (0.673-0.773), respectively; P = 0.039]. In contrast, CFS had higher predictive value for late mortality compared with 4C mortality score [AUC (95% CI): 0.830 (0.776-0.883) vs. 0.724 (0.650-0.798), respectively; P = 0.007].

Conclusions: In our cohort, late mortality in COVID-19 patients is more strongly associated with premorbid clinical frailty than with severity of the acute infection phase.

Keywords: 4C mortality score; COVID-19; Frailty; Late mortality; Prognosis.

Figure 1

Forest plots showing odds ratios and 95% confidence intervals of independent predictors for early (28 day) and late mortality after adjustment for age and sex. Odds ratios correspond to 1‐unit increase in Clinical Frailty Scale (CFS) score, 10 breaths per minute increase in respiratory rate (RR), 10 g/L increase in haemoglobin levels, 10 × 10⁹/L increase in number of neutrophils, 100 mg/L increase in C‐reactive protein (CRP), 10 g/L increase in albumin, 10 mmol/L increase in urea levels, 10 mL/min/1.73 m² increase in estimated glomerular filtration rate (eGFR), 10 mmol/L increase in sodium levels, and 10‐unit increase in 4C mortality score. OR for white blood cells (WBCs) corresponds to the presence of leukocytosis (>12 × 10⁹/L WBCs) or leukopenia (<4 × 10⁹/L WBCs). X‐axis is log₂‐transformed for visual clarity. ALP, alkaline phosphatase; CHF, congestive heart failure; SOB, shortness of breath.

Figure 2

(A, B) Mortality rate in COVID‐19 patients according to 4C mortality score and Clinical Frailty Scale (CFS) risk groups. (A) Patients were classified according to 4C mortality score in four groups: low risk (4C: 0–3; n = 31), intermediate risk (4C: 4–8; n = 97), high risk (4C: 9–14; n = 232), and very high risk (4C: ≥15; n = 75). Bars represent mortality rate at 28 days after admission (early mortality) and between 29 days and 8 months (late mortality). (B) Early and late mortality according to CFS in five groups: very fit to managing well (CFS 1–3; n = 195), vulnerable (CFS 4; n = 44), mildly frail (CFS 5; n = 58), moderately frail (CFS 6; n = 71), and severely frail/terminally ill (CFS 7–9; n = 93). Receiver operating characteristic (ROC) curves and corresponding area(s) under the curve (AUC) for (C) early (28 day) and (D) late mortality in patients hospitalized with COVID‐19. The discriminatory performance of the 4C mortality and CFS scores for the occurrence of death is graphically assessed by corresponding ROC curves, and AUCs are compared with derive P‐values using the χ ² distribution with one degree of freedom.

Figure 3

Forest plots showing odds ratios and 95% confidence intervals of independent predictors for early (28 day) and late mortality after adjustment for Clinical Frailty Scale. Odds ratios correspond to 10 year increase in age, 10 breaths per minute increase in respiratory rate (RR), 10 g/L increase in haemoglobin levels, 10 × 10⁹/L increase in number of neutrophils, 100 mg/L increase in reactive protein (CRP), 10 g/L increase in albumin, 10 mmol/L increase in urea levels, 10 mL/min/1.73 m² increase in estimated glomerular filtration rate (eGFR), 10 mmol/L increase in sodium levels, and 10‐unit increase in 4C mortality score. OR for white blood cells (WBCs) corresponds to the presence of leukocytosis (>12 × 10⁹/L WBCs) or leukopenia (<4 × 10⁹/L WBCs). X‐axis is log₂‐transformed for visual clarity. CHF, congestive heart failure; SOB, shortness of breath.