A multistate model of frailty progression after severe infections in adults ≥65 years in England: a matched-cohort study
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Background
Evidence on frailty progression following severe infections is limited. We compared rates of transition to greater frailty or death between adults with and without severe infection in England.
Methods
We conducted a matched-cohort study among adults aged ≥65 years (1,452,117: median age 76 years, 45% male) in Clinical Practice Research Datalink Aurum (2006-2019). Adults with severe infection (hospitalised primarily due to infection) were matched on calendar time to individuals without severe infection on age, sex, and primary care practice. The admission date was used as index date and same was assigned to matched unexposed adults. We measured frailty using Electronic Frailty Index, a proportion of 36 health deficits in validated categories (Fit 0-0.12, Mild >0.12-0.24, Moderate >0.24-0.36, Severe >0.36).
In a time-varying Markov multistate model, we focused on forward transitions from baseline or intermediate frailty states to higher states or death. For each transition, we used Cox regression to estimate cause-specific transition hazard ratios (HR) with 95% confidence intervals (CIs), comparing adults with and without severe infection. We adjusted for baseline frailty score, age, sex, deprivation, harmful alcohol use, smoking, and primary care infection history 5 years before index date. We estimated state occupancy probabilities, and expected length of stay (ELOS) in each state at year five among adults with and without severe infection. We explored effect modification by infection type.
Results
Across all transitions, severe infection was associated with higher adjusted hazards of transitioning to worsening frailty or death, HR, 95% CI: ( fit to : mild[1.56, 1.54-1.58], moderate[2.51, 1.79-3.51], death[4.57, 4.50-4.65]; mild to : moderate[1.52, 1.50-1.53], severe[1.90, 1.43-2.52], death[2.67, 2.64-2.70]; moderate to : severe[1.40, 1.38-1.42], death[1.87, 1.85-1.90]; severe to death[1.48, 1.46-1.50]). Transition hazard ratios were strongest for lower respiratory tract infections, followed by sepsis, urinary tract infections, meningitis/encephalitis, gastroenteritis, and skin and soft tissue infections. At five years, adults with severe infection had higher probabilities of transitioning to greater frailty or death across all transitions and lower ELOS in each frailty state than those without severe infection.
Interpretation
Severe infections may accelerate frailty deterioration in older age. Prevention through vaccination, early detection, and prompt management may help mitigate this decline.
Research in context
Evidence before this study
We searched PubMed (inception to May 08, 2026), for published articles evaluating the association between infections and frailty progression with multistate modelling including studies that focused on one transition only with no language restrictions. We used the search terms [(infection OR infectious) AND (frailty OR frail) AND optional (progression OR multistate OR multi-state OR transition)].
We identified five longitudinal studies that compared transition hazard rates from a baseline fit state to pre-frailty or frailty during follow-up between individuals with specific infections (SARS-CoV-2, HIV, history of 20 infections based on International Classification of Diseases [ICD] codes and prescribed medications, cytomegalovirus antibody concentration quartiles, and seropositivity of herpes viruses [HSV 1 and 2, varicella-zoster, and Epstein-Barr]) versus those without infection. The studies found that infection or infection history increased the hazards of transition from a fit/pre-frail state to frailty after adjusting for confounders. The hazards of frailty recovery from frail to fit state was higher among individuals with HIV infection than those without.
None of the studies accounted for the competing risk of death, and all modelled transitions along a single pathway between fit/pre-frail and frail states. Furthermore, frailty was conceptualised as a binary outcome, whereas validated frailty risk prediction models typically define frailty in progressive categories of deterioration, commonly classified as fit, mild, moderate, and severe. There is limited evidence on the risk of transition from baseline and intermediate frailty states to more advanced states following infection, while accounting for competing risk of death.
To identify subgroups for targeted care, it is important to determine whether frailty deterioration after severe infection varies by infection type (sepsis, urinary tract infection, skin and soft tissue infection, meningitis/encephalitis, lower respiratory tract infection, and gastroenteritis), age, sex, social deprivation, diabetes, and dementia.
Added value of this study
Our study compared rates of transition to greater frailty or death between older adults with and without severe infection (hospitalisation primarily for infection). We found that severe infection increased the hazards of transition from baseline and intermediate frailty states to more advanced frailty states or death. From each same starting frailty state, outgoing transition hazards increased progressively towards more advanced frailty states or death. The hazards of progression to greater frailty or death also varied by infection type, with the strongest associations observed for LRTI, followed by sepsis, UTI, meningitis/encephalitis, gastroenteritis, and skin and soft tissue infections.
Implications of all the available evidence
Our findings underscore the importance of infection prevention in reducing the risk of frailty progression in older age. Additional studies are required to explore other wider life-course influences on frailty, to guide the development of comprehensive preventive strategies.
