Background The COVID-19 pandemic has led highly developed healthcare systems to the brink of collapse due to the large numbers of patients being admitted into hospitals. One of the potential prognostic indicators in patients with COVID-19 is frailty. The degree of frailty could be used to assist both the triage into intensive care, and decisions regarding treatment limitations. Our study sought to determine the interaction of frailty and age in elderly COVID-19 ICU patients. Methods A prospective multicentre study of COVID-19 patients ≥ 70 years admitted to intensive care in 138 ICUs from 28 countries was conducted. The primary endpoint was 30-day mortality. Frailty was assessed using the clinical frailty scale. Additionally, comorbidities, management strategies and treatment limitations were recorded. Results The study included 1346 patients (28% female) with a median age of 75 years (IQR 72–78, range 70–96), 16.3% were older than 80 years, and 21% of the patients were frail. The overall survival at 30 days was 59% (95% CI 56–62), with 66% (63–69) in fit, 53% (47–61) in vulnerable and 41% (35–47) in frail patients (p < 0.001). In frail patients, there was no difference in 30-day survival between different age categories. Frailty was linked to an increased use of treatment limitations and less use of mechanical ventilation. In a model controlling for age, disease severity, sex, treatment limitations and comorbidities, frailty was independently associated with lower survival. Conclusion Frailty provides relevant prognostic information in elderly COVID-19 patients in addition to age and comorbidities. Trial registration Clinicaltrials.gov: NCT04321265, registered 19 March 2020.
Significance There is growing evidence that preexisting autoantibodies neutralizing type I interferons (IFNs) are strong determinants of life-threatening COVID-19 pneumonia. It is important to estimate their quantitative impact on COVID-19 mortality upon SARS-CoV-2 infection, by age and sex, as both the prevalence of these autoantibodies and the risk of COVID-19 death increase with age and are higher in men. Using an unvaccinated sample of 1,261 deceased patients and 34,159 individuals from the general population, we found that autoantibodies against type I IFNs strongly increased the SARS-CoV-2 infection fatality rate at all ages, in both men and women. Autoantibodies against type I IFNs are strong and common predictors of life-threatening COVID-19. Testing for these autoantibodies should be considered in the general population.
A central paradigm of immunity is that interferon (IFN) mediated antiviral responses precede the pro-inflammatory ones, optimizing host protection and minimizing collateral damage. Here, we report that for COVID-19 this does not apply. By investigating temporal IFN and inflammatory cytokine patterns in 32 COVID-19 patients hospitalized for pneumonia and longitudinally followed for the development of respiratory failure and death, we reveal that IFN-λ and type I IFN production is both diminished and delayed, induced only in a fraction of patients as they become critically ill. On the contrary, pro-inflammatory cytokines such as TNF, IL-6 and IL-8 are produced before IFNs, in all patients, and persist for a prolonged time. By comparison, in 16 flu patients hospitalized for pneumonia with similar clinicopathological characteristics to COVID-19 and 24 milder non-hospitalized flu patients IFN-λ and type I IFN are robustly induced, earlier, at higher levels and independently of disease severity, while pro-inflammatory cytokines are only acutely and transiently produced. Notably, higher IFN-λ levels in COVID-19 patients correlate with lower viral load in bronchial aspirates and faster viral clearance, and a higher IFN-λ:type I IFN ratio with improved outcome of critically ill patients. Moreover, altered cytokine patterns in COVID-19 patients correlate with longer hospitalization time and higher incidence of critical disease and mortality compared to flu. These data point to an untuned antiviral response in COVID-19 contributing to persistent viral presence, hyperinflammation and respiratory failure.
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