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Original Study| Volume 22, ISSUE 9, P1845-1852.e1, September 2021

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Frailty Assessment in the Emergency Department for Risk Stratification of COVID-19 Patients Aged ≥80 Years

      Abstract

      Objectives

      To evaluate, in a cohort of adults aged ≥80 years, the overlapping effect of clinical severity, comorbidities, cognitive impairment, and frailty, for the in-hospital death risk stratification of COVID-19 older patients since emergency department (ED) admission.

      Design

      Single-center prospective observational cohort study.

      Setting and Participants

      The study was conducted in the ED of a teaching hospital that is a referral center for COVID-19 in central Italy. We enrolled all patients with aged ≥80 years old consecutively admitted to the ED between April 2020 and March 2021.

      Methods

      Clinical variables assessed in the ED were evaluated for the association with all-cause in-hospital death. Evaluated parameters were severity of disease, frailty, comorbidities, cognitive impairment, delirium, and dependency in daily life activities. Cox regression analysis was used to identify independent risk factors for poor outcomes.

      Results

      A total of 729 patients aged ≥80 years were enrolled [median age 85 years (interquartile range 82-89); 346 were males (47.3%)]. According to the Clinical Frailty Scale, 61 (8.4%) were classified as fit, 417 (57.2%) as vulnerable, and 251 (34.4%) as frail. Severe disease [hazard ratio (HR) 1.87, 95% confidence interval (CI) 1.31-2.59], ≥3 comorbidities (HR 1.54, 95% CI 1.11-2.13), male sex (HR 1.46, 95% CI 1.14-1.87), and frailty (HR 6.93, 95% CI 1.69-28.27) for vulnerable and an overall HR of 12.55 (95% CI 2.96-53.21) for frail were independent risk factors for in-hospital death.

      Conclusions and Implications

      The ED approach to older patients with COVID-19 should take into account the functional and clinical characteristics of patients being admitted. A sole evaluation based on the clinical severity and the presence of comorbidities does not reflect the complexity of this population. A comprehensive evaluation based on clinical severity, multimorbidity, and frailty could effectively predict the clinical risk of in-hospital death for patients with COVID-19 aged ≥80 years at the time of ED presentation.

      Keywords

      Since December 2019, the novel coronavirus designated as SARS-CoV-2 has determined the tragic pandemic of the respiratory illness named COVID-19.
      • Guan W.J.
      • Ni Z.Y.
      • Hu Y.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      ,
      • Huang C.
      • Wang Y.
      • Li X.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      Vaccination campaigns had started in most countries of the world, however, the number of affected patients and the death toll is still increasing.
      World Health Organization
      WHO Coronavirus Disease (COVID-19) Dashboard.
      Italy faces one of the worst clusters of COVID-19, and the mortality rate and death toll are particularly high.
      Ministero della Salute
      COVID-19 Situazione in Italia.
      The clinical course of COVID-19 is various, ranging from possible asymptomatic patients to severe progressive pneumonia leading to death.
      • Weiss P.
      • Murdoch D.R.
      Clinical course and mortality risk of severe COVID-19.
      Overall, the prevalence of respiratory failure in patients hospitalized with COVID-19 was estimated to be about 19%, with up to 12% of patients requiring mechanical ventilation.
      • Guan W.J.
      • Ni Z.Y.
      • Hu Y.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      ,
      • Huang C.
      • Wang Y.
      • Li X.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      ,
      • Grasselli G.
      • Greco M.
      • Zanella A.
      • et al.
      COVID-19 Lombardy ICU network
      Risk factors associated with mortality among patients with COVID-19 in intensive care units in Lombardy, Italy.
      In this context of an overflow of critically ill patients, the emergency department (ED) physician must establish clear and objective criteria to stratify COVID-19 death risk.
      Patients ≥80 years old are the most at risk of death for COVID-19.
      • Hwang J.
      • Ryu H.S.
      • Kim H.A.
      • et al.
      Prognostic factors of COVID-19 infection in elderly patients: A multicenter study.
      • Becerra-Muñoz V.M.
      • Núñez-Gil I.J.
      • Eid C.M.
      • et al.
      Clinical profile and predictors of in-hospital mortality among older patients hospitalised for COVID-19.
      • Covino M.
      • De Matteis G.
      • Santoro M.
      • et al.
      Clinical characteristics and prognostic factors in COVID-19 patients aged ≥80 years.
      • Covino M.
      • De Matteis G.
      • Burzo M.L.
      • et al.
      Predicting in-hospital mortality in COVID-19 older patients with specifically developed scores.
      • Blagosklonny M.V.
      From causes of aging to death from COVID-19.
      • Zuccaro V.
      • Celsa C.
      • Sambo M.
      • et al.
      Competing-risk analysis of coronavirus disease 2019 in-hospital mortality in a Northern Italian centre from SMAtteo COvid19 REgistry (SMACORE).
      • Mueller A.L.
      • McNamara M.S.
      • Sinclair D.A.
      Why does COVID-19 disproportionately affect older people?.
      Most of the current research focuses on the presence of multiple comorbidities in these populations to explain for the disproportionate death rate that has characterized the clinical course of these patients.
      • Guan W.J.
      • Ni Z.Y.
      • Hu Y.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      ,
      • Huang C.
      • Wang Y.
      • Li X.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      ,
      • Weiss P.
      • Murdoch D.R.
      Clinical course and mortality risk of severe COVID-19.
      • Grasselli G.
      • Greco M.
      • Zanella A.
      • et al.
      COVID-19 Lombardy ICU network
      Risk factors associated with mortality among patients with COVID-19 in intensive care units in Lombardy, Italy.
      • Hwang J.
      • Ryu H.S.
      • Kim H.A.
      • et al.
      Prognostic factors of COVID-19 infection in elderly patients: A multicenter study.
      • Becerra-Muñoz V.M.
      • Núñez-Gil I.J.
      • Eid C.M.
      • et al.
      Clinical profile and predictors of in-hospital mortality among older patients hospitalised for COVID-19.
      • Covino M.
      • De Matteis G.
      • Santoro M.
      • et al.
      Clinical characteristics and prognostic factors in COVID-19 patients aged ≥80 years.
      • Covino M.
      • De Matteis G.
      • Burzo M.L.
      • et al.
      Predicting in-hospital mortality in COVID-19 older patients with specifically developed scores.
      • Blagosklonny M.V.
      From causes of aging to death from COVID-19.
      • Zuccaro V.
      • Celsa C.
      • Sambo M.
      • et al.
      Competing-risk analysis of coronavirus disease 2019 in-hospital mortality in a Northern Italian centre from SMAtteo COvid19 REgistry (SMACORE).
      • Mueller A.L.
      • McNamara M.S.
      • Sinclair D.A.
      Why does COVID-19 disproportionately affect older people?.
      However, it has been argued that these conditions cannot comprehensively predict the extremely poor outcomes observed in older patients with COVID-19.
      • Mueller A.L.
      • McNamara M.S.
      • Sinclair D.A.
      Why does COVID-19 disproportionately affect older people?.
      Older adults have heterogeneous baseline clinical conditions. Often, chronological age and comorbidities do not truly reflect the overall health status of older patients. To overcome these issues, the frailty syndrome was introduced to include several dimensions of physical fitness and autonomy. Frailty is defined as a condition characterized by a progressive declined physiologic function and diminished strength leading to vulnerability and reduced resilience to stressors that led to an increased risk of adverse outcomes.
      • Vermeiren S.
      • Vella-Azzopardi R.
      • Beckwée D.
      • et al.
      Gerontopole Brussels Study group
      Frailty and the prediction of negative health outcomes: A meta-analysis.
      Frailty was found to be an independent predictor for death in hospitalized patients with several clinical conditions as well as COVID-19.
      • Zhang X.M.
      • Jiao J.
      • Cao J.
      • et al.
      Frailty as a predictor of mortality among patients with COVID-19: A systematic review and meta-analysis.
      • Aliberti M.G.R.
      • Covinsky K.E.
      • Barreto Garcez F.
      • et al.
      A fuller picture of COVID-19 prognosis: The added value of vulnerability measures to predict mortality in hospitalised older adults Age.
      • Blomaard L.C.
      • van der Linden C.M.J.
      • van der Bol J.M.
      • et al.
      Frailty is associated with in- hospital mortality in older hospitalised COVID-19 patients in the Netherlands: The COVID-OLD study.
      • Pranata R.
      • Henrina J.
      • Lim M.A.
      • et al.
      Clinical frailty scale and mortality in COVID-19: A systematic review and dose-response meta-analysis.
      • Hägg S.
      • Jylhävä J.
      • Wang Y.
      • et al.
      Age, frailty, and comorbidity as prognostic factors for short-term outcomes in patients with coronavirus disease 2019 in geriatric care.
      • Laosa O.
      • Pedraza L.
      • Álvarez-Bustos A.
      • et al.
      Rapid assessment at hospital admission of mortality risk from COVID-19: The role of functional status.
      • De Smet R.
      • Mellaerts B.
      • Vandewinckele H.
      • et al.
      Frailty and mortality in hospitalized older adults with COVID-19: Retrospective observational study.
      Furthermore, several other conditions such as cognitive impairment
      • Covino M.
      • De Matteis G.
      • Santoro M.
      • et al.
      Clinical characteristics and prognostic factors in COVID-19 patients aged ≥80 years.
      ,
      • Foley N.C.
      • Affoo R.H.
      • Martin R.E.
      A systematic review and meta-analysis examining pneumonia-associated mortality in dementia.
      ,
      • Hariyanto T.I.
      • Putri C.
      • Arisa J.
      • et al.
      Dementia and outcomes from coronavirus disease 2019 (COVID-19) pneumonia: A systematic review and meta-analysis.
      and occurrence of delirium could play a significant prognostic role for hospitalized older adults, including those with COVID-19.
      • Zhang Z.
      • Pan L.
      • Ni H.
      Impact of delirium on clinical outcome in critically ill patients: A meta-analysis.
      ,
      • Garcez F.B.
      • Aliberti M.J.R.
      • Poco P.C.E.
      • et al.
      Delirium and adverse outcomes in hospitalized patients with COVID-19.
      This study aims to evaluate, in a cohort of adults aged ≥80 years, the overlapping effect of clinical severity, comorbidities, cognitive impairment, frailty, and occurrence of delirium for the risk stratification of COVID-19 older patients since ED admission.

      Methods

      Study Design

      This is a single-center, prospective observational cohort study, conducted in the ED of an urban teaching hospital, which is a referral center for COVID-19, in central Italy. The study enrolled all the patients aged ≥80 years consecutively admitted to our ED from April 2020 to March 2021. COVID-19 was diagnosed based on the WHO interim guidance. We included in the analysis only patients with a positive result of real-time reverse transcriptase–polymerase chain reaction assay of nasal and pharyngeal swab specimens.
      World Health Organization
      Clinical management of severe acute respiratory infection when novel coronavirus (2019-nCoV) infection is suspected: Interim guidance.
      Patients who did not receive a complete frailty assessment in the ED and patients who refused to participate in the study were excluded from the analysis.

      Study Variables

      All patients were assessed in the ED to retrieve the following clinical and demographic data:
      • Age, gender
      • Overall frailty: assessed using the Clinical Frailty Scale,
        • Rockwood K.
        • Song X.
        • MacKnight C.
        • et al.
        A global clinical measure of fitness and frailty in elderly people.
        patients were further categorized as fit, for scores 1 to 3 (corresponding to fit and mild vulnerability); vulnerable, for scores 4 to 6 (corresponding to vulnerable or mild frail); and frail, for scores 7 to 9 (corresponding to moderate to severe frailty)
      • Presence of cognitive impairment, based on an established dementia diagnosis before SARS-CoV-2 infection
      • Dependency in activities of daily living (ADL), based on the clinical status before SARS-CoV-2 infection
      • Delirium occurrence: established based on the Richmond Agitation-Sedation Scale
        • Sessler C.N.
        • Gosnell M.S.
        • Grap M.J.
        • et al.
        The Richmond Agitation-Sedation Scale: Validity and reliability in adult intensive care unit patients.
        at 24 hours since ED admission
      • Clinical presentation symptoms including fever, dyspnea, cough, diarrhea, abdominal pain, neurologic symptoms (including headache, ageusia/anosmia, and confusion), myalgia/asthenia, and syncope/presyncope
      • Physiological parameters, including body temperature, heart rate, respiratory rate, blood pressure, Glasgow Coma Scale, and peripheral oxygen saturation: based on these measures, the National Early Warning Score was calculated for each patient
        • Smith G.B.
        • Prytherch D.R.
        • Meredith P.
        • et al.
        The ability of the National Early Warning Score (NEWS) to discriminate patients at risk of early cardiac arrest, unanticipated intensive care unit admission, and death.
      • Classification according to WHO guidelines in severe or nonsevere presentations: defined as severe COVID-19 for respiratory distress, respiratory frequency ≥30 times/min, peripheral oxygen saturation at rest ≤92%, or oxygenation index (Pao2/Fio2) ≤300 mm Hg; a National Early Warning Score >5 at presentation was also considered a severe disease
      • Clinical history and comorbidities: hypertension, severe obesity (defined as body mass index >40), history of coronary artery disease, congestive heart failure, cerebrovascular disease, dementia, diabetes, chronic obstructive pulmonary disease, chronic kidney disease, and malignancy. The overall comorbidity presence was assessed by the Charlson Comorbidity index for each patient.
        • Charlson M.
        • Szatrowski T.P.
        • Peterson J.
        • Gold J.
        Validation of a combined comorbidity index.
      • Radiologic findings: based on chest radiographs, patients were categorized as either negative/interstitial involvement or positive for consolidative pneumonia
      • A comprehensive laboratory evaluation and a blood gas determination of all patients in the ED
      • Time of infection: patients admitted in the first wave of infections in Italy (from April 1 to August 31, 2020) were compared with those infected later (September 1, 2020, to March 30, 2021).

      Study Endpoint

      The primary study endpoint was all-cause in-hospital death.

      Statistical Analysis

      Continuous variables were reported as median [interquartile range (IQR)] and are compared at univariate analysis by Mann-Whitney U test or Kruskal-Wallis test in case of 3 or more groups. Categorical variables were reported as absolute number (percentage) and are compared by chi-square test (with Fisher test if appropriate).
      Receiver operating characteristic (ROC) curve analysis was used to evaluate the overall performance of the Clinical Frailty Scale in predicting in-hospital death. Follow-up and length of hospital stay were calculated from the time of ED admission to discharge or death. Survival curves were estimated by the Kaplan-Meier methods.
      The study variables were assessed for the association to all-cause in-hospital death by a univariate Cox regression analysis. Significant variables at univariate analysis were entered into a multivariate Cox regression model to identify independent risk factors for survival. For a better model fit and hazard estimation, we categorized the continuous variables (National Early Warning Score, Charlson Comorbidity index) into dichotomous parameters (ie, low/high). For each variable, we obtained the optimal dividing cutoff by the Youden index, performing an ROC curve analysis for the association with death. To avoid model redundancy or overfitting, single items composing derived variables (like Charlson Comorbidity index and National Early Warning Score) were excluded from multivariate analysis. Multivariate association of factors to the risk of in-hospital death was expressed as hazard ratios (HRs) and 95% confidence intervals (CIs).
      Further multivariate Cox regression models were performed to obtain the adjusted HR for death comparing the patients admitted in the first months of COVID-19 with the later waves of infection. Similarly, we estimated the age-adjusted survival rates for the patients divided into 5-year age groups (80-84, 85-89, 90-94, and ≥95 years old). A 2-sided P ≤.05 was considered significant. Data were analyzed by SPSS, version 25 (IBM, Armonk, NY, USA).

      Statement of Ethics

      The study was conducted according to the Declaration of Helsinki and its later amendments and was approved by the local institutional review board (IRB 001705520). Each patient gave informed consent to be included in the analysis.

      Results

      Study Cohort and Baseline Characteristics

      Overall, 7742 patients aged ≥80 years were evaluated in the ED in the study period. Among them, 843 had a positive swab for SARS-CoV-2. After excluding patients who did not complete the frailty assessment and those who refused to be enrolled, we included in the study cohort 729 patients.
      Enrolled patients had a median age of 85 years (IQR 82-89) and males were 346 (47.3%). According to the Clinical Frailty Scale scores, 61 (8.4%) aged 84 years (IQR 81-85) were classified as fit, 417 (57.2%) aged 84 years (IQR 81-87) were classified as vulnerable, and 251 (34.4%) aged 88 years (IQR 85-92) were classified as frail. Overall, 192 (26.3%) patients had an established cognitive impairment diagnosed, and 400 (54.9%) were dependent for ADL.

      Clinical Characteristics at Presentation According to Frailty Group

      Clinical presentation was similar across frailty groups. Fit patients reported more fever, cough, diarrhea, and neurologic symptoms. Frail and vulnerable patients were generally referred to the ED by their caregivers, mainly for dyspnea and fever (Table 1).
      Table 1Clinical Characteristics of Enrolled Patients According to Frailty Status
      All Cases (N = 729)Fit (n = 61)Vulnerable (n = 417)Frail (n = 251)P

      Value
      Age, y, median (IQR)85 (82-89)84 (81-85)84 (81-87)88 (85-92)<.001
      Sex: male345 (47.3)30 (49.2)204 (48.9)111 (44.2).48
      ED presentation symptoms
       Fever494 (67.8)54 (88.5)278 (66.7)162 (64.5).001
       Dyspnea461 (63.2)37 (60.7)279 (66.9)145 (57.8).06
       Cough63 (8.6)9 (14.8)39 (9.4)15 (6.0).07
       Diarrhea21 (2.9)6 (9.8)10 (2.4)5 (2.0).003
       Abdominal pain28 (3.8)0 (0)20 (4.8)8 (3.2).15
       Neurologic symptoms69 (9.5)10 (16.4)41 (9.8)18 (7.2).08
       Malaise49 (6.7)3 (4.9)31 (7.4)15 (6.0).65
       Syncope/presyncope27 (3.7)1 (1.6)18 (4.3)8 (3.2).51
      Clinical evaluation and physiological parameters
       Severe COVID-19
      Severe COVID-19 was defined as respiratory rate ≥30 times/min, Pao2 at rest ≤92%, Pao2/Fio2 ≤300 mm Hg, or NEWS >5.
      64 (8.8)1 (1.6)32 (7.7)31 (12.4).014
       SaO294 (90-96)94 (90-96)94 (91-96)93 (88-95).006
       Heart rate85 (75-95)88 (75-97)83 (73-91)86 (75-99).022
       Respiratory rate24 (20-28)22 (14-26)24 (20-28)25 (19-29).18
       Maximum BP129 (114-145)125 (116-144)130 (119-148)125 (109-140).004
       Minimum BP75 (65-83)75 (66-81)76 (67-85)71 (63-82).15
       Pao2/Fio2270 (212-319)311 (263-386)261 (214-321)271 (195-314).13
       NEWS6 (4-7)5 (4-6)5 (4-7)6 (4-7.25).17
       Consolidation at radiography454 (62.3)42 (68.9)267 (64.0)145 (57.8).15
       Delirium82 (11.2)0 (0)44 (10.6)38 (15.1).003
      Laboratory values
       Neutrophil, cells/mm37190 (4990-10,100)8300 (6237-10,605)7510 (5475-10,545)6335 (4820-9928).14
       Lymphocyte, cells/mm3940 (670-1280)990 (795-1417)950 (670-1286)915 (627-1270).52
       Creatinine, mg/dL0.98 (0.76-1.40)0.83 (0.63-1.07)1.13 (0.80-1.70)0.94 (0.71-1.38).06
       BUN, mg/dL25 (19-38)16 (12-20)24 (16-39)27 (20-40).001
       LDH, IU/L283 (219-377)238 (203-343)309 (233-431)263 (203-338).04
       C-reactive protein, mg/L65 (28-132)52 (26-86)59 (24-140)73 (31-132).50
      Clinical history—comorbidities
       Dependent in ADL400 (54.9)0 (0)149 (35.7)251 (100)<.001
       Hypertension318 (43.6)30 (49.2)194 (46.5)94 (37.5).048
       Severe obesity7 (1.0)0 (0)6 (1.4)1 (0.4).30
      Comorbidities in Charlson Comorbidity Index
       Dementia192 (26.3)0 (0)49 (11.8)143 (57.0)<.001
       History of CAD110 (15.1)5 (8.2)73 (17.5)32 (12.7).07
       Congestive heart failure116 (15.9)4 (6.6)65 (15.6)47 (18.7).06
       Cerebrovascular disease40 (5.5)1 (1.6)15 (3.6)24 (9.6).002
       COPD106 (14.5)3 (4.9)68 (16.3)35 (13.9).06
       Diabetes167 (22.9)11 (18.0)94 (22.5)62 (24.7).52
       Chronic kidney disease75 (10.3)1 (1.6)49 (11.8)25 (10.0).05
       Malignancy27 (3.7)1 (1.6)17 (4.1)9 (3.6).64
       Other in CCI24 (3.3)0 (0)17 (4.1)7 (2.8).21
       CCI5 (4-6)4 (4-5)5 (4-6)5 (4-6)<.001
       CCI comorbidities ≥372 (9.9)1 (1.6)36 (8.6)35 (13.9).007
      ADL, activities of daily living; BUN, blood urea nitrogen; CAD, coronary artery disease; CCI, Charlson Comorbidity Index; COPD, chronic obstructive pulmonary disease; LDH, lactate dehydrogenase; NEWS, National Early Warning Score.
      Values are median (IQR) or n (%). Frailty was defined as fit for Clinical Frailty Scale (CFS) scores 1 to 3, vulnerable for CFS scores 4 to 6, and frail for CFS scores 7 to 9.
      Severe COVID-19 was defined as respiratory rate ≥30 times/min, Pao2 at rest ≤92%, Pao2/Fio2 ≤300 mm Hg, or NEWS >5.
      Physiological parameters were slightly worse in frail patients, and as a result, both the National Early Warning Score and the rate of presentation with severe disease were higher in frailer patients. The rate of pulmonary involvement, reflected by consolidation at chest radiograph was similar among the 3 groups. Interestingly, but not unexpectedly, delirium occurred only in vulnerable and frail patients (Table 1).
      Most of the enrolled patients had comorbidities. Frail and vulnerable patients had more comorbidities, as shown by a higher rate of patients having 3 or more major comorbidities. As largely expected, the frailer patients were more dependent in ADL and had a higher rate of cognitive impairment (Table 1).

      Factors Associated With In-Hospital Death

      In line with several COVID-19 reports, the deceased patients in our cohort were significantly older and were more frequently male (Table 2). Although the main symptoms were similar for the deceased and survived groups, physiological parameters at admission were significantly out of range in the deceased group, particularly for lower peripheral oxygen saturation (Table 2). As a result, the National Early Warning Score was higher in the deceased, and the number of patients with severe disease was higher in the deceased group (Table 2).
      Table 2Study Variables in Survived vs Deceased Patients
      Survived (n = 442)Deceased (n = 287)P Value
      Age, y85 (82-88)86 (83-90).001
      Sex: male194 (43.9)151 (52.6).021
      ED presentation symptoms
       Fever320 (72.4)174 (60.6).001
       Dyspnea297 (67.2)164 (57.1).006
       Cough43 (9.7)20 (7.0).20
       Diarrhea16 (3.6)5 (1.7).14
       Abdominal pain18 (4.1)10 (3.5).69
       Neurologic symptoms47 (10.6)22 (7.7).18
       Malaise29 (6.6)20 (7.0).83
       Syncope/presyncope18 (4.1)9 (3.1).51
      Clinical evaluation
       Severe COVID-19
      Severe COVID-19 was defined as respiratory rate ≥30 times/min, Pao2 at rest ≤92%, Pao2/Fio2 ≤300 mm Hg, or NEWS >5.
      19 (4.3)45 (15.7)<.001
       Sao294 (91-97)92 (88-95)<.001
       Heart rate83 (74-92)85 (77-99).020
       Respiratory rate23 (19-28)25 (21-28).06
       Maximum BP130 (119-145)125 (110-144).004
       Minimum BP77 (68-85)70 (60-81).005
       Pao2/Fio2291 (228-347)238 (181-300)<.001
       NEWS5 (4-6)6 (5-7).030
       Consolidation at chest radiography281 (63.6)173 (60.3).37
       Delirium41 (9.3)41 (14.3).036
      Frailty assessment
       Fit (CFS scores 1-3)59 (96.7)2 (3.3)<.001
       Vulnerable (CFS scores 4-6)289 (69.3)128 (30.7)<.001
       Frail (CFS scores 7-9)94 (37.5)157 (62.5)<.001
      Laboratory values
       Neutrophil, cells/mm37220 (5020-9850)7030 (4897-10,115).78
       Lymphocyte, cells/mm31050 (770-1370)785 (585-1110).002
       Creatinine, mg/dL0.93 (0.69-1.30)1.10 (0.80-1.77).050
       BUN, mg/dL21 (16-30)29 (22-42)<.001
       LDH, IU/L284 (213-373)276 (220-429).41
       C-reactive protein, mg/L48 (24-93)98 (51-155)<.001
      Clinical history—comorbidities
       Dependent in ADL189 (42.8)211 (73.5)<.001
       Hypertension203 (45.9)115 (40.1).12
       Severe obesity4 (0.9)3 (1.0).85
      Comorbidities included in CCI
       Dementia89 (20.1)103 (35.9)<.001
       History of CAD64 (14.5)46 (16.0).57
       Congestive heart failure61 (13.8)55 (19.2).05
       Cerebrovascular disease17 (3.8)23 (8.0).016
       COPD68 (15.4)38 (13.2).42
       Diabetes102 (23.1)65 (22.6).89
       Chronic kidney disease37 (8.4)38 (13.2).034
       Malignancy14 (3.2)13 (4.5).31
       Other in CCI11 (2.5)13 (4.5).13
       Charlson Comorbidity Index5 (3-6)5 (4-7).010
       CCI comorbidities ≥326 (5.9)46 (16.0)<.001
      ADL, activities of daily living; BP, blood pressure; BUN, blood urea nitrogen; CAD, coronary artery disease; CCI, Charlson Comorbidity Index; CFS, Clinical Frailty Scale; COPD, chronic obstructive pulmonary disease; LDH, lactate dehydrogenase; NEWS, National Early Warning Score.
      Values are median (IQR) or n (%). All-cause in-hospital death was considered.
      Severe COVID-19 was defined as respiratory rate ≥30 times/min, Pao2 at rest ≤92%, Pao2/Fio2 ≤300 mm Hg, or NEWS >5.
      Survival was significantly different for different grades of frailty, with deceased patients mostly classified as vulnerable or frail according to the Clinical Frailty Scale (Table 2). Deceased patients had a higher rate of delirium occurrence, a higher rate of dependency in ADL, cognitive impairment, and had ≥3 comorbidities (Table 2). Overall, the Clinical Frailty Scale had a fair predicting ability for in-hospital poor outcome, with an area under the ROC curve for death of 0.743 (range 0.708-0.779).

      Multivariate Analysis for In-Hospital Death

      When entered into a multivariate Cox regression analysis, several factors emerged as independent predictors of poor outcomes in our cohort. Among these, frailty was a significant risk factor for death, with the HR for vulnerable patients being 7 times higher than fit ones and a further doubling of the risk for frail patients (Table 3). Interestingly, though predictably, once adjusted for baseline covariates and frailty, both dementia and dependency in ADL were not independent risk factors for death. Similarly, the occurrence of delirium was not associated with an increased adjusted HR for death in this cohort (Table 3).
      Table 3Multivariate Analysis (Cox Regression Model) of Significant Factor Associated With Survival at Univariate Analysis
      FactorWaldHazard Ratio (95% Confidence Interval)Multivariate

      P Value
      Frailty
       Fit (CFS scores 1-3)19.649Reference<.001
       Vulnerable (CFS scores 4-6)7.2776.93 (1.69-28.27).007
       Frail (CFS scores 7-9)11.77412.55 (2.96-53.21).001
      Sex: male8.8691.46 (1.14-1.87).003
      Age ≥85 y1.2911.16 (0.89-1.51).26
      Severe COVID-19 at ED admission13.9671.87 (1.34-2.59)<.001
      CCI comorbidities ≥36.6761.54 (1.11-2.13).010
      Dependent in ADL1.3331.24 (0.86-1.80).25
      Dementia0.0151.02 (0.77-1.35).90
      Delirium in ED1.6980.79 (0.56-1.12).19
      ADL, activities of daily living; CCI, Charlson Comorbidity Index; ED, emergency department; NEWS, National Early Warning Score.
      Cutoff values for continuous variables were chosen according to receiver operating characteristic (ROC) curve analysis Youden index J. Time was calculated from ED admission to discharge/death.
      As expected, the clinical severity at admission significantly increased the overall death risk as well as the presence of ≥3 comorbidities. The analysis also found an increased risk for male sex (Table 3). Overall, the death risk progressively increased for severe disease, comorbidity, and frailty, being almost 100% in patients combining all these factors (Figure 1).
      Figure thumbnail gr1
      Fig. 1Number of patients and mortality rate (%) according to the presence of a severe clinical presentation, Charlson comorbidities ≥3, and frailty assessed by the Clinical Frailty Scale (CFS). Frailty was defined as Fit for CFS scores 1 to 3, vulnerable for CFS scores 4 to 6, and frail for CFS scores 7 to 9. Green is for mortality 0% to 33%, yellow for mortality 33% to 66%, and red for mortality >66%.

      Age-Related Survival Analysis

      Dividing the patients into 5-year groups, we observed a progressive increase in the crude death rate for older ages. Overall, 111 of 331 patients (34.4%) died in the 80-84-year age group, 97 of 231 (42.0%) in the 85-89-year age group, 52 of 128 (40.6%) in the 90-94-year age group, and 24 of 39 (61.5%) in the ≥95-year age group (P = .007). However, when the age group was combined with frailty, comorbidity, sex, and disease severity in a Cox multivariate model, the adjusted hazard risk for death did not significantly differ among the groups. Compared with the 80-84-year age group, the hazard ratio for death was 0.99 (IQR 0.69-1.40) for 85-89 years, 1.19 (IQR 0.89-1.57) for 90-94 years, and 1.37 (0.86-2.19) for those aged ≥95 years (Supplementary Figure 1).

      Death Rate According to the Period of the Pandemic

      Considering the 203 patients admitted in the first phase of the pandemic (April to August 2020) and the 526 patients admitted from September 2020 to March 2021, we observed 89 deaths (43.8%) in the first period and 198 (37.6%) deaths in the successive months. Although the crude mortality was lower, the adjusted hazard risk for death was not significantly different [0.79 (IQR 0.61-1.02); P = .072) (Supplementary Figure 2).

      Discussion

      The main finding of the present study is that in patients aged ≥80 years, frailty assessment in the ED could accurately recognize patients at increased risk for in-hospital death for COVID-19. The frailty evaluation identifies patients at risk independently from other well-known risk factors for COVID-19, such as clinical severity of the disease, presence of comorbidities, and male sex.
      • Guan W.J.
      • Ni Z.Y.
      • Hu Y.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      ,
      • Huang C.
      • Wang Y.
      • Li X.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      ,
      • Grasselli G.
      • Greco M.
      • Zanella A.
      • et al.
      COVID-19 Lombardy ICU network
      Risk factors associated with mortality among patients with COVID-19 in intensive care units in Lombardy, Italy.
      • Hwang J.
      • Ryu H.S.
      • Kim H.A.
      • et al.
      Prognostic factors of COVID-19 infection in elderly patients: A multicenter study.
      • Becerra-Muñoz V.M.
      • Núñez-Gil I.J.
      • Eid C.M.
      • et al.
      Clinical profile and predictors of in-hospital mortality among older patients hospitalised for COVID-19.
      • Covino M.
      • De Matteis G.
      • Santoro M.
      • et al.
      Clinical characteristics and prognostic factors in COVID-19 patients aged ≥80 years.
      • Covino M.
      • De Matteis G.
      • Burzo M.L.
      • et al.
      Predicting in-hospital mortality in COVID-19 older patients with specifically developed scores.
      At the same time, the comprehensive frailty assessment includes by definition other known factors that have been associated with poor COVID-19 prognosis in older adults, including dementia, dependency in ADL, and delirium.
      • Zuccaro V.
      • Celsa C.
      • Sambo M.
      • et al.
      Competing-risk analysis of coronavirus disease 2019 in-hospital mortality in a Northern Italian centre from SMAtteo COvid19 REgistry (SMACORE).
      • Mueller A.L.
      • McNamara M.S.
      • Sinclair D.A.
      Why does COVID-19 disproportionately affect older people?.
      • Vermeiren S.
      • Vella-Azzopardi R.
      • Beckwée D.
      • et al.
      Gerontopole Brussels Study group
      Frailty and the prediction of negative health outcomes: A meta-analysis.
      • Zhang X.M.
      • Jiao J.
      • Cao J.
      • et al.
      Frailty as a predictor of mortality among patients with COVID-19: A systematic review and meta-analysis.
      • Aliberti M.G.R.
      • Covinsky K.E.
      • Barreto Garcez F.
      • et al.
      A fuller picture of COVID-19 prognosis: The added value of vulnerability measures to predict mortality in hospitalised older adults Age.
      • Blomaard L.C.
      • van der Linden C.M.J.
      • van der Bol J.M.
      • et al.
      Frailty is associated with in- hospital mortality in older hospitalised COVID-19 patients in the Netherlands: The COVID-OLD study.
      • Pranata R.
      • Henrina J.
      • Lim M.A.
      • et al.
      Clinical frailty scale and mortality in COVID-19: A systematic review and dose-response meta-analysis.
      • Hägg S.
      • Jylhävä J.
      • Wang Y.
      • et al.
      Age, frailty, and comorbidity as prognostic factors for short-term outcomes in patients with coronavirus disease 2019 in geriatric care.
      • Laosa O.
      • Pedraza L.
      • Álvarez-Bustos A.
      • et al.
      Rapid assessment at hospital admission of mortality risk from COVID-19: The role of functional status.
      • De Smet R.
      • Mellaerts B.
      • Vandewinckele H.
      • et al.
      Frailty and mortality in hospitalized older adults with COVID-19: Retrospective observational study.
      • Foley N.C.
      • Affoo R.H.
      • Martin R.E.
      A systematic review and meta-analysis examining pneumonia-associated mortality in dementia.
      • Hariyanto T.I.
      • Putri C.
      • Arisa J.
      • et al.
      Dementia and outcomes from coronavirus disease 2019 (COVID-19) pneumonia: A systematic review and meta-analysis.
      • Zhang Z.
      • Pan L.
      • Ni H.
      Impact of delirium on clinical outcome in critically ill patients: A meta-analysis.
      • Garcez F.B.
      • Aliberti M.J.R.
      • Poco P.C.E.
      • et al.
      Delirium and adverse outcomes in hospitalized patients with COVID-19.
      Hence, the adjusted HR for these latter factors did not reach statistical significance in our cohort.
      An optimal screening tool for frailty in the ED setting should be practical, simple, and accurate. Among the existing clinical score, we adopted the Clinical Frailty Scale, which is already widely used and is particularly efficient for the emergency setting because there are only 5 patient domains that need to be assessed.
      • Juma S.
      • Taabazuing M.M.
      • Montero-Odasso M.
      Clinical frailty scale in an acute medicine unit: A simple tool that predicts length of stay.
      The CSF was already found to be linearly correlated with death in a meta-analysis on a pooled sample of 3817 patients with COVID-19. However, the analysis included patients of different age groups, and the pooled analysis was not fully adjusted for disease severity or comorbidities.
      • Pranata R.
      • Henrina J.
      • Lim M.A.
      • et al.
      Clinical frailty scale and mortality in COVID-19: A systematic review and dose-response meta-analysis.
      The concept of frailty is often confused in clinical practice with multimorbidity. However, contrary to general perception, multimorbidity does not necessarily imply the onset of frailty.
      • Onder G.
      • Cesari M.
      • Maggio M.
      • Palmer K.
      Defining a care pathway for patients with multimorbidity or frailty.
      ,
      BritainThinks
      Frailty, language and perceptions: a report prepared by BritainThinks on behalf of Age UK and the British Geriatrics.
      Nevertheless, these conditions share several aspects, and chronic diseases are often a key component of the frailty status.
      • Fried L.P.
      • Tangen C.M.
      • Walston J.
      • et al.
      Frailty in older adults: Evidence for a phenotype.
      Indeed, both conditions are associated with an increased risk of poor outcomes in hospitalized patients.
      • Kojima G.
      Frailty defined by FRAIL scale as a predictor of mortality: A systematic review and meta-analysis.
      Since the first COVID-19 clinical reports, comorbidities have been identified as the crucial factors to define the risk of poor outcome in COVID-19.
      • Guan W.J.
      • Ni Z.Y.
      • Hu Y.
      • et al.
      Clinical characteristics of coronavirus disease 2019 in China.
      • Huang C.
      • Wang Y.
      • Li X.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      World Health Organization
      WHO Coronavirus Disease (COVID-19) Dashboard.
      Ministero della Salute
      COVID-19 Situazione in Italia.
      • Weiss P.
      • Murdoch D.R.
      Clinical course and mortality risk of severe COVID-19.
      • Grasselli G.
      • Greco M.
      • Zanella A.
      • et al.
      COVID-19 Lombardy ICU network
      Risk factors associated with mortality among patients with COVID-19 in intensive care units in Lombardy, Italy.
      • Hwang J.
      • Ryu H.S.
      • Kim H.A.
      • et al.
      Prognostic factors of COVID-19 infection in elderly patients: A multicenter study.
      • Becerra-Muñoz V.M.
      • Núñez-Gil I.J.
      • Eid C.M.
      • et al.
      Clinical profile and predictors of in-hospital mortality among older patients hospitalised for COVID-19.
      • Covino M.
      • De Matteis G.
      • Santoro M.
      • et al.
      Clinical characteristics and prognostic factors in COVID-19 patients aged ≥80 years.
      • Covino M.
      • De Matteis G.
      • Burzo M.L.
      • et al.
      Predicting in-hospital mortality in COVID-19 older patients with specifically developed scores.
      Several factors have been advocated as the main determinant of risk, including older age, cardiovascular comorbidities, obesity, diabetes, and chronic kidney disease.
      • Grasselli G.
      • Greco M.
      • Zanella A.
      • et al.
      COVID-19 Lombardy ICU network
      Risk factors associated with mortality among patients with COVID-19 in intensive care units in Lombardy, Italy.
      • Hwang J.
      • Ryu H.S.
      • Kim H.A.
      • et al.
      Prognostic factors of COVID-19 infection in elderly patients: A multicenter study.
      • Becerra-Muñoz V.M.
      • Núñez-Gil I.J.
      • Eid C.M.
      • et al.
      Clinical profile and predictors of in-hospital mortality among older patients hospitalised for COVID-19.
      • Covino M.
      • De Matteis G.
      • Santoro M.
      • et al.
      Clinical characteristics and prognostic factors in COVID-19 patients aged ≥80 years.
      • Covino M.
      • De Matteis G.
      • Burzo M.L.
      • et al.
      Predicting in-hospital mortality in COVID-19 older patients with specifically developed scores.
      ,
      • Hägg S.
      • Jylhävä J.
      • Wang Y.
      • et al.
      Age, frailty, and comorbidity as prognostic factors for short-term outcomes in patients with coronavirus disease 2019 in geriatric care.
      In the present analysis, the considered comorbidities were those included in the well-established Charlson Comorbidity index. Nevertheless, >95% of comorbidities reported in our cohort consisted of dementia, history of coronary artery disease, congestive heart failure, cerebrovascular disease, diabetes, chronic obstructive pulmonary disease, chronic kidney disease, and malignancy. This finding is consistent with current literature
      • Grasselli G.
      • Greco M.
      • Zanella A.
      • et al.
      COVID-19 Lombardy ICU network
      Risk factors associated with mortality among patients with COVID-19 in intensive care units in Lombardy, Italy.
      • Hwang J.
      • Ryu H.S.
      • Kim H.A.
      • et al.
      Prognostic factors of COVID-19 infection in elderly patients: A multicenter study.
      • Becerra-Muñoz V.M.
      • Núñez-Gil I.J.
      • Eid C.M.
      • et al.
      Clinical profile and predictors of in-hospital mortality among older patients hospitalised for COVID-19.
      • Covino M.
      • De Matteis G.
      • Santoro M.
      • et al.
      Clinical characteristics and prognostic factors in COVID-19 patients aged ≥80 years.
      • Covino M.
      • De Matteis G.
      • Burzo M.L.
      • et al.
      Predicting in-hospital mortality in COVID-19 older patients with specifically developed scores.
      ,
      • Hägg S.
      • Jylhävä J.
      • Wang Y.
      • et al.
      Age, frailty, and comorbidity as prognostic factors for short-term outcomes in patients with coronavirus disease 2019 in geriatric care.
      ,
      • Li Y.
      • Ashcroft T.
      • Chung A.
      • et al.
      Risk factors for poor outcomes in hospitalised COVID-19 patients: A systematic review and meta-analysis.
      ,
      • Cheng S.
      • Zhao Y.
      • Wang F.
      • et al.
      Comorbidities' potential impacts on severe and non-severe patients with COVID-19: A systematic review and meta-analysis.
      and suggests that a simplified comorbidity assessment including these 7 factors could be sufficient for the risk stratification of patients with COVID-19 aged ≥80 years.
      Apart from specific diseases and syndromes, neurologic comorbidities and dementia have been identified as specific risk factors for poor prognosis in older patients.
      • Covino M.
      • De Matteis G.
      • Santoro M.
      • et al.
      Clinical characteristics and prognostic factors in COVID-19 patients aged ≥80 years.
      • Covino M.
      • De Matteis G.
      • Burzo M.L.
      • et al.
      Predicting in-hospital mortality in COVID-19 older patients with specifically developed scores.
      • Blagosklonny M.V.
      From causes of aging to death from COVID-19.
      In the present study, dementia was confirmed to be significantly associated with poor outcomes; however, when the analysis was adjusted for frailty status, it did not emerge as an independent factor for death. This latter finding could help to clarify the role of cognitive impairment for COVID-19 prognosis. Based on a meta-analysis of available data, dementia seems to be associated with an enhanced risk of mortality from COVID-19 infection.
      • Hariyanto T.I.
      • Putri C.
      • Situmeang R.F.V.
      • Kurniawan A.
      Dementia is a predictor for mortality outcome from coronavirus disease 2019 (COVID-19) infection.
      Several explanations have been advocated to explain this result. First, it was suggested that most of the patients with dementia were old and had several comorbidities, and as such dementia was only a marker of these conditions.
      • Hariyanto T.I.
      • Putri C.
      • Situmeang R.F.V.
      • Kurniawan A.
      Dementia is a predictor for mortality outcome from coronavirus disease 2019 (COVID-19) infection.
      Furthermore, it has been speculated that older patients with dementia and COVID-19 infection may present with atypical symptoms, such as delirium or isolated functional decline, impeding the early recognition of the disease.
      • Numbers K.
      • Brodaty H.
      The effects of the COVID-19 pandemic on people with dementia.
      Other hypotheses included the association of ApoE e4 genotype with dementia and the modulation of pro- and anti-inflammatory phenotypes and the expression of ACE2 receptors.
      • Kuo C.L.
      • Pilling L.C.
      • Atkins J.L.
      • et al.
      APOE e4 genotype predicts severe COVID-19 in the UK Biobank Community Cohort.
      Our data suggest that cognitive impairment could be just a marker of increased frailty, and certainly it constitutes one of its major determinants. In this way, a comprehensive frailty assessment includes in the frail group those with cognitive impairment. Hence, it is frailty and not dementia in itself that justifies the increased mortality. This point of view could easily be extended to other medical conditions, and explain the association between dementia and mortality that could be seen even for non–COVID-19 pneumonia-associated mortality.
      • Manabe T.
      • Fujikura Y.
      • Mizukami K.
      Pneumonia-associated death in patients with dementia: A systematic review and meta-analysis.
      Similar to dementia, the dependency in ADL shares some aspects with overall frailty and constitutes one of its main manifestations. Although associated with poor outcomes in COVID-19 older patients,
      • Hwang J.
      • Ryu H.S.
      • Kim H.A.
      • et al.
      Prognostic factors of COVID-19 infection in elderly patients: A multicenter study.
      ,
      • Becerra-Muñoz V.M.
      • Núñez-Gil I.J.
      • Eid C.M.
      • et al.
      Clinical profile and predictors of in-hospital mortality among older patients hospitalised for COVID-19.
      ,
      • Zhang X.M.
      • Jiao J.
      • Cao J.
      • et al.
      Frailty as a predictor of mortality among patients with COVID-19: A systematic review and meta-analysis.
      • Aliberti M.G.R.
      • Covinsky K.E.
      • Barreto Garcez F.
      • et al.
      A fuller picture of COVID-19 prognosis: The added value of vulnerability measures to predict mortality in hospitalised older adults Age.
      • Blomaard L.C.
      • van der Linden C.M.J.
      • van der Bol J.M.
      • et al.
      Frailty is associated with in- hospital mortality in older hospitalised COVID-19 patients in the Netherlands: The COVID-OLD study.
      ,
      • Laosa O.
      • Pedraza L.
      • Álvarez-Bustos A.
      • et al.
      Rapid assessment at hospital admission of mortality risk from COVID-19: The role of functional status.
      ,
      • Heras E.
      • Garibaldi P.
      • Boix M.
      • et al.
      COVID-19 mortality risk factors in older people in a long-term care center.
      when the analysis was adjusted for frailty assessment, dependency in ADL alone did not result as an independent risk factor for death. Once again, it can be speculated that dependency of ADL constitutes a marker of frailty instead of a risk determinant by itself.
      The same explanation could be extended to delirium, which occurs most frequently in frailer patients.
      • Rebora P.
      • Rozzini R.
      • Bianchetti A.
      • et al.
      CoViD-19 Lombardia Team
      Delirium in patients with SARS-CoV-2 infection: a multicenter study.
      Disease severity at presentation is an obvious prognostic determinant for patients with COVID-19. Although several aspects could contribute to define the clinical severity of a given patient, the ED determination of physiological parameters could successfully resume the overall status by a single variable.
      • Kostakis I.
      • Smith G.B.
      • Prytherch D.
      • et al.
      Portsmouth Academic ConsortIum For Investigating COVID-19 (PACIFIC-19)
      The performance of the National Early Warning Score and National Early Warning Score 2 in hospitalised patients infected by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
      ,
      • Covino M.
      • Sandroni C.
      • Santoro M.
      • et al.
      Predicting intensive care unit admission and death for COVID-19 patients in the emergency department using early warning scores.
      Several tools have been proposed for this purpose.
      • Covino M.
      • De Matteis G.
      • Burzo M.L.
      • et al.
      Predicting in-hospital mortality in COVID-19 older patients with specifically developed scores.
      In this study, the clinical severity was defined according to WHO guidelines and the National Early Warning Score evaluation, which demonstrated effectiveness in predicting both death and intensive care unit admission in the general population with COVID-19 and in older adults.
      • Covino M.
      • De Matteis G.
      • Burzo M.L.
      • et al.
      Predicting in-hospital mortality in COVID-19 older patients with specifically developed scores.
      ,
      • Kostakis I.
      • Smith G.B.
      • Prytherch D.
      • et al.
      Portsmouth Academic ConsortIum For Investigating COVID-19 (PACIFIC-19)
      The performance of the National Early Warning Score and National Early Warning Score 2 in hospitalised patients infected by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
      ,
      • Covino M.
      • Sandroni C.
      • Santoro M.
      • et al.
      Predicting intensive care unit admission and death for COVID-19 patients in the emergency department using early warning scores.
      Indeed, because respiratory illness is the key determinant of COVID-19 morbidity, a rapid assessment of disease severity could be obtained just by evaluating the respiratory parameters (SaO2, respiratory rate, and Pao2/Fio2). The present analysis confirmed that patients defined as clinically severe had a worse prognosis and, not unexpectedly, this was independent of other conditions such as comorbidities and frailty.
      The correlation between older age and the risk of death for COVID-19 has been widely recognized. This often led to resources allocation strategies and guidelines that could directly or indirectly result in discrimination based on age.
      • Savulescu J.
      • Cameron J.
      • Wilkinson D.
      Equality or utility? Ethics and law of rationing ventilators.
      ,
      NICE Guidelines
      COVID-19 rapid guideline: Arranging planned care in hospitals and diagnostic services.
      However, most of the current data on the correlation between age and mortality for COVID-19 do not take into account the specific subset of patients aged ≥80 years, which are mostly considered as a single group.
      • Bonanad C.
      • García-Blas S.
      • Tarazona-Santabalbina F.
      • et al.
      The effect of age on mortality in patients with COVID-19: A meta-analysis with 611,583 subjects.
      The covariate-adjusted analysis in the present study demonstrates that the simple increase of chronological age is not an independent predictor of poor outcomes in patients aged ≥80 years. This was true both when stratifying patients by the 85-year cutoff chosen by ROC analysis and when dividing the patients into 5-year subgroups. In both the analyses, we observed a crude mortality rate higher for older cohorts; however, when the analysis was adjusted for disease severity and frailty, the difference was not statistically significant (Supplementary Figure 2). This already emerged in some studies on patients with COVID-19
      • Covino M.
      • De Matteis G.
      • Santoro M.
      • et al.
      Clinical characteristics and prognostic factors in COVID-19 patients aged ≥80 years.
      and was demonstrated also for the non-COVID hospitalized population ≥80 years old.
      • Landi F.
      • Liperoti R.
      • Russo A.
      • et al.
      Disability, more than multimorbidity, was predictive of mortality among older persons aged 80 years and older.
      The clinical complexity of the geriatric patients and the overlap between multimorbidity, cognitive impairment, dependency in ADL, and increasing age often make difficult the clinical assessment of older patients. This is particularly true in the ED where the already limited time for an effective clinical evaluation is made even more difficult by the wearing of personal protective equipment for COVID-19. The present research suggests that although in general patients with COVID-19 an effective and quick risk stratification could be obtained in the ED by evaluating the clinical severity and by assessing the presence of comorbidities, this could not be sufficient for patients aged ≥80 years. In these latter patients, a further component of clinical evaluation should include the assessment of frailty, which is different from the simple assessment of multimorbidity.
      • Aliberti M.J.R.
      • Szlejf C.
      • Avelino-Silva V.I.
      • et al.
      COVID HCFMUSP Study Group
      COVID-19 is not over and age is not enough: Using frailty for prognostication in hospitalized patients.
      As a final clue emerging from our investigation, we evaluated the changes in mortality rate between the first phase of the pandemic and the later “waves” of infection. Some authors reported a decreased mortality over time in the geriatric population, particularly during the first wave.
      • Xu H.
      • Garcia-Ptacek S.
      • Annetorp M.
      • et al.
      Decreased mortality over time during the first wave in patients with COVID-19 in geriatric care: Data from the Stockholm GeroCovid Study.
      Although not completely explained, this observation could be ascribed to a general increase in the awareness for the disease, associated with precocious diagnoses, and to a general improvement in the hospital care for COVID-19. However, available data were not corrected for frailty, and thus it could be also speculated that the high mortality rates at the very beginning of the pandemic could be just due to a “harvest” effect on the frailer part of the geriatric population. This latter hypothesis could be supported by the present study. Indeed, although the crude mortality rate was higher in the early phase of the pandemic, the adjusted survival rates were similar when corrected for disease severity, comorbidities, and frailty (Supplementary Figure 1).

      Study Limitations

      Our research presents some limitations. First, it is conducted in a single institution, which is also a referral center for COVID-19, and for this reason it could not be generalizable to all EDs. Moreover, our ED has a dedicated geriatric unit for the early identification of frail patients, and our comprehensive frailty assessment could be more accurate compared with those of general ED physicians.

      Conclusions and Implications

      The emergency physician approach to older patients with COVID-19 should take into account the peculiar clinical and functional characteristics of this population and should not be simply conditioned by the chronological age. The common evaluation based on the assessment of clinical severity and presence of comorbidities should be enriched by a further evaluation based on a frailty assessment. The comprehensive evaluation based on severity, multimorbidity, and frailty could effectively predict the clinical risk of in-hospital death for patients with COVID-19 aged ≥80 years after ED admission.

      Supplementary Data

      Figure thumbnail fx1
      Supplementary Fig. 1Adjusted age-related survival was obtained by dividing the patients into 5-year groups. Crude death rate was 111 of 331 (34.4%) in the 80-84-year group, 97 of 231 (42.0%) in the 85-89-year group, 52 of 128 (40.6%) for the 90-94-year group, and 24 of 39 (61.5%) in the ≥95-year group (P = .007). Compared with the 80-84-year group, the Hazard for death was 0.99 (0.69-1.40) for 85-89 years, 1.19 (0.89-1.57) for 90-94 years, and 1.37 (0.86-2.19) for those ≥95 years. The frailty, comorbidity, and severity-adjusted hazard risk for death did not significantly differ among the groups.
      Figure thumbnail fx2
      Supplementary Fig. 2Adjusted period-related survival was obtained for patients admitted from April to August 2020 and patients admitted from September 2020 and March 2021. Overall, 203 patients were admitted in the first phase with 89 deaths (43.8%), and 526 patients were admitted in the second phase with 198 deaths (37.6%). The adjusted hazard risk for death was not significantly different [second wave HR = 0.79 (0.61-1.02); P = .072].

      References

        • Guan W.J.
        • Ni Z.Y.
        • Hu Y.
        • et al.
        Clinical characteristics of coronavirus disease 2019 in China.
        N Engl J Med. 2020; 382: 1708-1720
        • Huang C.
        • Wang Y.
        • Li X.
        • et al.
        Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
        Lancet. 2020; 395: 497-506
        • World Health Organization
        WHO Coronavirus Disease (COVID-19) Dashboard.
        (Available at:)
        https://covid19.who.int/
        Date accessed: March 12, 2021
        • Ministero della Salute
        COVID-19 Situazione in Italia.
        (Available at:)
        • Weiss P.
        • Murdoch D.R.
        Clinical course and mortality risk of severe COVID-19.
        Lancet. 2020; 395: 1014-1015
        • Grasselli G.
        • Greco M.
        • Zanella A.
        • et al.
        • COVID-19 Lombardy ICU network
        Risk factors associated with mortality among patients with COVID-19 in intensive care units in Lombardy, Italy.
        JAMA Intern Med. 2020; 180: 1345-1355
        • Hwang J.
        • Ryu H.S.
        • Kim H.A.
        • et al.
        Prognostic factors of COVID-19 infection in elderly patients: A multicenter study.
        J Clin Med. 2020; 9: 3932
        • Becerra-Muñoz V.M.
        • Núñez-Gil I.J.
        • Eid C.M.
        • et al.
        Clinical profile and predictors of in-hospital mortality among older patients hospitalised for COVID-19.
        Age Ageing. 2021; 50: 326-334
        • Covino M.
        • De Matteis G.
        • Santoro M.
        • et al.
        Clinical characteristics and prognostic factors in COVID-19 patients aged ≥80 years.
        Geriatr Gerontol Int. 2020; 20: 704-708
        • Covino M.
        • De Matteis G.
        • Burzo M.L.
        • et al.
        Predicting in-hospital mortality in COVID-19 older patients with specifically developed scores.
        J Am Geriatr Soc. 2021; 69: 37-43
        • Blagosklonny M.V.
        From causes of aging to death from COVID-19.
        Aging (Albany NY). 2020; 12: 10004-10021
        • Zuccaro V.
        • Celsa C.
        • Sambo M.
        • 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: 1137
        • Mueller A.L.
        • McNamara M.S.
        • Sinclair D.A.
        Why does COVID-19 disproportionately affect older people?.
        Aging (Albany NY). 2020; 12: 9959-9981
        • Vermeiren S.
        • Vella-Azzopardi R.
        • Beckwée D.
        • et al.
        • Gerontopole Brussels Study group
        Frailty and the prediction of negative health outcomes: A meta-analysis.
        J Am Med Dir Assoc. 2016; 17: 1163.e1-1163.e17
        • Zhang X.M.
        • Jiao J.
        • Cao J.
        • et al.
        Frailty as a predictor of mortality among patients with COVID-19: A systematic review and meta-analysis.
        BMC Geriatr. 2021; 21: 186
        • Aliberti M.G.R.
        • Covinsky K.E.
        • Barreto Garcez F.
        • et al.
        A fuller picture of COVID-19 prognosis: The added value of vulnerability measures to predict mortality in hospitalised older adults Age.
        Ageing. 2021; 5: 32-39
        • Blomaard L.C.
        • van der Linden C.M.J.
        • van der Bol J.M.
        • et al.
        Frailty is associated with in- hospital mortality in older hospitalised COVID-19 patients in the Netherlands: The COVID-OLD study.
        Age Ageing. 2021; 50: 631-640
        • Pranata R.
        • Henrina J.
        • Lim M.A.
        • et al.
        Clinical frailty scale and mortality in COVID-19: A systematic review and dose-response meta-analysis.
        Arch Gerontol Geriatr. 2021; 93: 104324
        • Hägg S.
        • Jylhävä J.
        • Wang Y.
        • et al.
        Age, frailty, and comorbidity as prognostic factors for short-term outcomes in patients with coronavirus disease 2019 in geriatric care.
        J Am Med Dir Assoc. 2020; 21: 1555-1559.e2
        • Laosa O.
        • Pedraza L.
        • Álvarez-Bustos A.
        • et al.
        Rapid assessment at hospital admission of mortality risk from COVID-19: The role of functional status.
        J Am Med Dir Assoc. 2020; 21: 1798-1802.e2
        • De Smet R.
        • Mellaerts B.
        • Vandewinckele H.
        • et al.
        Frailty and mortality in hospitalized older adults with COVID-19: Retrospective observational study.
        J Am Med Dir Assoc. 2020; 21: 928-932.e1
        • Foley N.C.
        • Affoo R.H.
        • Martin R.E.
        A systematic review and meta-analysis examining pneumonia-associated mortality in dementia.
        Dement Geriatr Cogn Disord. 2015; 39: 52-67
        • Hariyanto T.I.
        • Putri C.
        • Arisa J.
        • et al.
        Dementia and outcomes from coronavirus disease 2019 (COVID-19) pneumonia: A systematic review and meta-analysis.
        Arch Gerontol Geriatr. 2021; 93: 104299
        • Zhang Z.
        • Pan L.
        • Ni H.
        Impact of delirium on clinical outcome in critically ill patients: A meta-analysis.
        Gen Hosp Psychiatry. 2013; 35: 105-111
        • Garcez F.B.
        • Aliberti M.J.R.
        • Poco P.C.E.
        • et al.
        Delirium and adverse outcomes in hospitalized patients with COVID-19.
        J Am Geriatr Soc. 2020; 68: 2440-2446
        • World Health Organization
        Clinical management of severe acute respiratory infection when novel coronavirus (2019-nCoV) infection is suspected: Interim guidance.
        (Available at:)
        • Rockwood K.
        • Song X.
        • MacKnight C.
        • et al.
        A global clinical measure of fitness and frailty in elderly people.
        CMAJ. 2005; 173: 489-495
        • Sessler C.N.
        • Gosnell M.S.
        • Grap M.J.
        • et al.
        The Richmond Agitation-Sedation Scale: Validity and reliability in adult intensive care unit patients.
        Am J Respir Crit Care Med. 2002; 166: 1338-1344
        • Smith G.B.
        • Prytherch D.R.
        • Meredith P.
        • et al.
        The ability of the National Early Warning Score (NEWS) to discriminate patients at risk of early cardiac arrest, unanticipated intensive care unit admission, and death.
        Resuscitation. 2013; 84: 465-470
        • Charlson M.
        • Szatrowski T.P.
        • Peterson J.
        • Gold J.
        Validation of a combined comorbidity index.
        J Clin Epidemiol. 1994; 47: 1245-1251
        • Juma S.
        • Taabazuing M.M.
        • Montero-Odasso M.
        Clinical frailty scale in an acute medicine unit: A simple tool that predicts length of stay.
        Can Geriatrics J. 2016; 19: 34-39
        • Onder G.
        • Cesari M.
        • Maggio M.
        • Palmer K.
        Defining a care pathway for patients with multimorbidity or frailty.
        Eur J Intern Med. 2017; 38: 1-2
        • BritainThinks
        Frailty, language and perceptions: a report prepared by BritainThinks on behalf of Age UK and the British Geriatrics.
        Society. 2015; (2015)
        • Fried L.P.
        • Tangen C.M.
        • Walston J.
        • et al.
        Frailty in older adults: Evidence for a phenotype.
        J Gerontol A Biol Sci Med Sci. 2001; 56: 146-156
        • Kojima G.
        Frailty defined by FRAIL scale as a predictor of mortality: A systematic review and meta-analysis.
        J Am Med Dir Assoc. 2018; 19: 480-483
        • Li Y.
        • Ashcroft T.
        • Chung A.
        • et al.
        Risk factors for poor outcomes in hospitalised COVID-19 patients: A systematic review and meta-analysis.
        J Glob Health. 2021; 11: 10001
        • Cheng S.
        • Zhao Y.
        • Wang F.
        • et al.
        Comorbidities' potential impacts on severe and non-severe patients with COVID-19: A systematic review and meta-analysis.
        Medicine (Baltimore). 2021; 100: e24971
        • Hariyanto T.I.
        • Putri C.
        • Situmeang R.F.V.
        • Kurniawan A.
        Dementia is a predictor for mortality outcome from coronavirus disease 2019 (COVID-19) infection.
        Eur Arch Psychiatry Clin Neurosci. 2021; 271: 393-395
        • Numbers K.
        • Brodaty H.
        The effects of the COVID-19 pandemic on people with dementia.
        Nat Rev Neurol. 2021; 6: 1-2
        • Kuo C.L.
        • Pilling L.C.
        • Atkins J.L.
        • et al.
        APOE e4 genotype predicts severe COVID-19 in the UK Biobank Community Cohort.
        J Gerontol A Biol Sci Med Sci. 2020; 75: 2231-2232
        • Manabe T.
        • Fujikura Y.
        • Mizukami K.
        Pneumonia-associated death in patients with dementia: A systematic review and meta-analysis.
        PLoS One. 2019; 14: e0213825
        • Heras E.
        • Garibaldi P.
        • Boix M.
        • et al.
        COVID-19 mortality risk factors in older people in a long-term care center.
        Eur Geriatr Med. 2020; 27: 1-7
        • Rebora P.
        • Rozzini R.
        • Bianchetti A.
        • et al.
        • CoViD-19 Lombardia Team
        Delirium in patients with SARS-CoV-2 infection: a multicenter study.
        J Am Geriatr Soc. 2021; 69: 293-299
        • Kostakis I.
        • Smith G.B.
        • Prytherch D.
        • et al.
        • Portsmouth Academic ConsortIum For Investigating COVID-19 (PACIFIC-19)
        The performance of the National Early Warning Score and National Early Warning Score 2 in hospitalised patients infected by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
        Resuscitation. 2021; 159: 150-157
        • Covino M.
        • Sandroni C.
        • Santoro M.
        • et al.
        Predicting intensive care unit admission and death for COVID-19 patients in the emergency department using early warning scores.
        Resuscitation. 2020; 156: 84-91
        • Savulescu J.
        • Cameron J.
        • Wilkinson D.
        Equality or utility? Ethics and law of rationing ventilators.
        Br J Anaesth. 2020; 125: 10-15
        • NICE Guidelines
        COVID-19 rapid guideline: Arranging planned care in hospitals and diagnostic services.
        National Institute for Health and Care Excellence (UK), London2020
        • Bonanad C.
        • García-Blas S.
        • Tarazona-Santabalbina F.
        • et al.
        The effect of age on mortality in patients with COVID-19: A meta-analysis with 611,583 subjects.
        J Am Med Dir Assoc. 2020; 21: 915-918
        • Landi F.
        • Liperoti R.
        • Russo A.
        • et al.
        Disability, more than multimorbidity, was predictive of mortality among older persons aged 80 years and older.
        J Clin Epidemiol. 2010; 63: 752-759
        • Aliberti M.J.R.
        • Szlejf C.
        • Avelino-Silva V.I.
        • et al.
        • COVID HCFMUSP Study Group
        COVID-19 is not over and age is not enough: Using frailty for prognostication in hospitalized patients.
        J Am Geriatr Soc. 2021; 69: 1116-1127
        • Xu H.
        • Garcia-Ptacek S.
        • Annetorp M.
        • et al.
        Decreased mortality over time during the first wave in patients with COVID-19 in geriatric care: Data from the Stockholm GeroCovid Study.
        J Am Med Dir Assoc. 2021; 22: 1565-1573.e4