Multiple house occupancy is associated with mortality in hospitalized patients with COVID-19.

BACKGROUND: In response to the COVID-19 pandemic, many countries mandated staying at home to reduce transmission. This study examined the association between living arrangements (house occupancy numbers) and outcomes in COVID-19. METHODS: Study population was drawn from the COPE study, a multicentre cohort study. House occupancy was defined as: living alone; living with one other person; living with multiple other people; or living in a nursing/residential home. Outcomes were time from admission to mortality and discharge (Cox regression), and Day 28 mortality (logistic regression) analyses were adjusted for key comorbidities and covariates including admission: age, sex, smoking, heart failure, admission C-reactive protein (CRP), chronic obstructive pulmonary disease, estimated glomerular filtration rate, frailty and others. RESULTS: A total of 1584 patients were included from 13 hospitals across UK and Italy: 676 (42.7%) were female, 907 (57.3%) were male, median age was 74 years (range: 19-101). At 28 days, 502 (31.7%) had died. Median admission CRP was 67, 82, 79.5 and 83 mg/l for those living alone, with someone else, in a house of multiple occupancy and in a nursing/residential home, respectively. Compared to living alone, living with anyone was associated with increased mortality: within a couple [adjusted hazard ratios (aHR) = 1.39, 95% confidence intervals (CI) 1.09-1.77, P = 0.007]; living in a house of multiple occupancy (aHR = 1.67, 95% CI 1.17-2.38, P = 0.005); and living in a residential home (aHR = 1.36, 95% CI 1.03-1.80, P = 0.031). CONCLUSION: For patients hospitalized with COVID-19, those living with one or more people had an increased association with mortality, they also exhibited higher CRP indicating increased disease severity suggesting they delayed seeking care.

Comparison between first and second wave of COVID-19 outbreak in older people: the COPE multicentre European observational cohort study.

BACKGROUND: Effective shielding measures and virus mutations have progressively modified the disease between the waves, likewise healthcare systems have adapted to the outbreak. Our aim was to compare clinical outcomes for older people with COVID-19 in Wave 1 (W1) and Wave 2 (W2). METHODS: All data, including the Clinical Frailty Scale (CFS), were collected for COVID-19 consecutive patients, aged ≥65, from 13 hospitals, in W1 (February-June 2020) and W2 (October 2020-March 2021). The primary outcome was mortality (time to mortality and 28-day mortality). Data were analysed with multilevel Cox proportional hazards, linear and logistic regression models, adjusted for wave baseline demographic and clinical characteristics. RESULTS: Data from 611 people admitted in W2 were added to and compared with data collected during W1 (N = 1340). Patients admitted in W2 were of similar age, median (interquartile range), W2 = 79 (73-84); W1 = 80 (74-86); had a greater proportion of men (59.4% vs. 53.0%); had lower 28-day mortality (29.1% vs. 40.0%), compared to W1. For combined W1-W2 sample, W2 was independently associated with improved survival: time-to-mortality adjusted hazard ratio (aHR) = 0.78 [95% confidence interval (CI) 0.65-0.93], 28-day mortality adjusted odds ratio = 0.80 (95% CI 0.62-1.03). W2 was associated with increased length of hospital stay aHR = 0.69 (95% CI 0.59-0.81). Patients in W2 were less frail, CFS [adjusted mean difference (aMD) = -0.50, 95% CI -0.81, -0.18], as well as presented with lower C-reactive protein (aMD = -22.52, 95% CI -32.00, -13.04). CONCLUSIONS: COVID-19 older adults in W2 were less likely to die than during W1. Patients presented to hospital during W2 were less frail and with lower disease severity and less likely to have renal decline.

Duration of antibiotic treatment using procalcitonin-guided treatment algorithms in older patients: a patient-level meta-analysis from randomized controlled trials.

BACKGROUND: Older patients have a less pronounced immune response to infection, which may also influence infection biomarkers. There is currently insufficient data regarding clinical effects of procalcitonin (PCT) to guide antibiotic treatment in older patients. OBJECTIVE AND DESIGN: We performed an individual patient data meta-analysis to investigate the association of age on effects of PCT-guided antibiotic stewardship regarding antibiotic use and outcome. SUBJECTS AND METHODS: We had access to 9,421 individual infection patients from 28 randomized controlled trials comparing PCT-guided antibiotic therapy (intervention group) or standard care. We stratified patients according to age in four groups (<75 years [n = 7,079], 75-80 years [n = 1,034], 81-85 years [n = 803] and >85 years [n = 505]). The primary endpoint was the duration of antibiotic treatment and the secondary endpoints were 30-day mortality and length of stay. RESULTS: Compared to control patients, mean duration of antibiotic therapy in PCT-guided patients was significantly reduced by 24, 22, 26 and 24% in the four age groups corresponding to adjusted differences in antibiotic days of -1.99 (95% confidence interval [CI] -2.36 to -1.62), -1.98 (95% CI -2.94 to -1.02), -2.20 (95% CI -3.15 to -1.25) and - 2.10 (95% CI -3.29 to -0.91) with no differences among age groups. There was no increase in the risk for mortality in any of the age groups. Effects were similar in subgroups by infection type, blood culture result and clinical setting (P interaction >0.05). CONCLUSIONS: This large individual patient data meta-analysis confirms that, similar to younger patients, PCT-guided antibiotic treatment in older patients is associated with significantly reduced antibiotic exposures and no increase in mortality.

Association of kidney function with effectiveness of procalcitonin-guided antibiotic treatment: a patient-level meta-analysis from randomized controlled trials.

Objectives: Patients with impaired kidney function have a significantly slower decrease of procalcitonin (PCT) levels during infection. Our aim was to study PCT-guided antibiotic stewardship and clinical outcomes in patients with impairments of kidney function as assessed by creatinine levels measured upon hospital admission. Methods: We pooled and analyzed individual data from 15 randomized controlled trials who were randomly assigned to receive antibiotic therapy based on a PCT-algorithms or based on standard of care. We stratified patients on the initial glomerular filtration rate (GFR, ml/min/1.73 m2) in three groups (GFR >90 [chronic kidney disease; CKD 1], GFR 15-89 [CKD 2-4] and GFR<15 [CKD 5]). The main efficacy and safety endpoints were duration of antibiotic treatment and 30-day mortality. Results: Mean duration of antibiotic treatment was significantly shorter in PCT-guided (n=2,492) compared to control patients (n=2,510) (9.5-7.6 days; adjusted difference in days -2.01 [95% CI, -2.45 to -1.58]). CKD 5 patients had overall longer treatment durations, but a 2.5-day reduction in treatment duration was still found in patients receiving in PCT-guided care (11.3 vs. 8.6 days [95% CI -3.59 to -1.40]). There were 397 deaths in 2,492 PCT-group patients (15.9%) compared to 460 deaths in 2,510 control patients (18.3%) (adjusted odds ratio, 0.88 [95% CI 0.78 to 0.98)]. Effects of PCT-guidance on antibiotic treatment duration and mortality were similar in subgroups stratified by infection type and clinical setting (p interaction >0.05). Conclusions: This individual patient data meta-analysis confirms that the use of PCT in patients with impaired kidney function, as assessed by admission creatinine levels, is associated with shorter antibiotic courses and lower mortality rates.

Three-Year Hospitalization and Mortality in Elderly Smokers with Chronic Obstructive Pulmonary Disease or Chronic Heart Failure.

BACKGROUND: In elderly smokers, chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF) usually present with dyspnoea. COPD and CHF are associated -almost invariably with concomitant chronic diseases, which contribute to severity and prognosis. OBJECTIVES: We investigated similarities and differences in the clinical presentation, concomitant chronic diseases and risk factors for -mortality and hospitalization at 3-year follow-up in elderly smokers/ex-smokers with a primary diagnosis of COPD or CHF recruited and followed in specialized centers. METHODS: We examined 144 patients with COPD and 96 with CHF, ≥65 years, ≥20 pack/years, and measured COPD Assessment Test (CAT) score, modified Medical Research Council, NYHA, and Charlson Index, routine blood test, estimated glomerular filtration rate, HRCT scan, 6-min walk test. In addition, in each patient we actively searched for CHF, COPD, peripheral vascular disease, and metabolic syndrome. RESULTS: COPD and CHF patients had mild to moderate disease, but the majority was symptomatic. Comorbidities were highly prevalent and often unrecognized in both groups. COPD and CHF patients had a similar risk of hospitalization and death at 3 years. Lower glomerular filtration rate, shorter 6MWT, and ascending aorta calcification score ≥2 were independent predictors of mortality in COPD, whereas previous 12 months hospitalizations, renal disease, and heart diameter were in CHF patients. Lower glomerular filtration rate value, higher CAT score, and lower FEV1/FVC ratio were associated with hospitalization in COPD, while age, lower FEV1% predicted, and peripheral vascular disease were in CHF. CONCLUSIONS: There are relevant similarities and differences between patients with COPD and CHF even when admitted to specialized outpatient centers, suggesting that these patients should be manage in multidisciplinary units.

Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections.

BACKGROUND: Acute respiratory infections (ARIs) comprise of a large and heterogeneous group of infections including bacterial, viral, and other aetiologies. In recent years, procalcitonin (PCT), a blood marker for bacterial infections, has emerged as a promising tool to improve decisions about antibiotic therapy (PCT-guided antibiotic therapy). Several randomised controlled trials (RCTs) have demonstrated the feasibility of using procalcitonin for starting and stopping antibiotics in different patient populations with ARIs and different settings ranging from primary care settings to emergency departments, hospital wards, and intensive care units. However, the effect of using procalcitonin on clinical outcomes is unclear. This is an update of a Cochrane review and individual participant data meta-analysis first published in 2012 designed to look at the safety of PCT-guided antibiotic stewardship. OBJECTIVES: The aim of this systematic review based on individual participant data was to assess the safety and efficacy of using procalcitonin for starting or stopping antibiotics over a large range of patients with varying severity of ARIs and from different clinical settings. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE, and Embase, in February 2017, to identify suitable trials. We also searched ClinicalTrials.gov to identify ongoing trials in April 2017. SELECTION CRITERIA: We included RCTs of adult participants with ARIs who received an antibiotic treatment either based on a procalcitonin algorithm (PCT-guided antibiotic stewardship algorithm) or usual care. We excluded trials if they focused exclusively on children or used procalcitonin for a purpose other than to guide initiation and duration of antibiotic treatment. DATA COLLECTION AND ANALYSIS: Two teams of review authors independently evaluated the methodology and extracted data from primary studies. The primary endpoints were all-cause mortality and treatment failure at 30 days, for which definitions were harmonised among trials. Secondary endpoints were antibiotic use, antibiotic-related side effects, and length of hospital stay. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable hierarchical logistic regression adjusted for age, gender, and clinical diagnosis using a fixed-effect model. The different trials were added as random-effects into the model. We conducted sensitivity analyses stratified by clinical setting and type of ARI. We also performed an aggregate data meta-analysis. MAIN RESULTS: From 32 eligible RCTs including 18 new trials for this 2017 update, we obtained individual participant data from 26 trials including 6708 participants, which we included in the main individual participant data meta-analysis. We did not obtain individual participant data for four trials, and two trials did not include people with confirmed ARIs. According to GRADE, the quality of the evidence was high for the outcomes mortality and antibiotic exposure, and quality was moderate for the outcomes treatment failure and antibiotic-related side effects.Primary endpoints: there were 286 deaths in 3336 procalcitonin-guided participants (8.6%) compared to 336 in 3372 controls (10.0%), resulting in a significantly lower mortality associated with procalcitonin-guided therapy (adjusted OR 0.83, 95% CI 0.70 to 0.99, P = 0.037). We could not estimate mortality in primary care trials because only one death was reported in a control group participant. Treatment failure was not significantly lower in procalcitonin-guided participants (23.0% versus 24.9% in the control group, adjusted OR 0.90, 95% CI 0.80 to 1.01, P = 0.068). Results were similar among subgroups by clinical setting and type of respiratory infection, with no evidence for effect modification (P for interaction > 0.05). Secondary endpoints: procalcitonin guidance was associated with a 2.4-day reduction in antibiotic exposure (5.7 versus 8.1 days, 95% CI -2.71 to -2.15, P < 0.001) and lower risk of antibiotic-related side effects (16.3% versus 22.1%, adjusted OR 0.68, 95% CI 0.57 to 0.82, P < 0.001). Length of hospital stay and intensive care unit stay were similar in both groups. A sensitivity aggregate-data analysis based on all 32 eligible trials showed similar results. AUTHORS' CONCLUSIONS: This updated meta-analysis of individual participant data from 12 countries shows that the use of procalcitonin to guide initiation and duration of antibiotic treatment results in lower risks of mortality, lower antibiotic consumption, and lower risk for antibiotic-related side effects. Results were similar for different clinical settings and types of ARIs, thus supporting the use of procalcitonin in the context of antibiotic stewardship in people with ARIs. Future high-quality research is needed to confirm the results in immunosuppressed patients and patients with non-respiratory infections.

Influence of frailty on cardiovascular events and mortality in patients with Chronic Obstructive Pulmonary Disease (COPD): Study protocol for a multicentre European observational study.

BACKGROUND: Frailty is a clinical state that increases susceptibility to minor stressor events. The risk of frailty is higher in chronic conditions, such as Chronic Obstructive Pulmonary Disease (COPD). Recent studies on COPD have shown that patients living with frailty have an increased risk of mortality. The presence of cardiovascular diseases or conditions are common in COPD and may increase the risk of death. METHODS: This protocol describes a European prospective cohort study of community-based people, in a stable condition with diagnosis of COPD (as defined by GOLD guidelines) across hospitals in Italy and UK. Frailty prevalence will be assessed using the Clinical Frailty Scale. At 1- and 2-year follow up, primary outcome will be the impact of frailty on the number of cardiovascular events; secondary outcomes: the influence of frailty on cardiovascular mortality, all-cause mortality, and deaths due to COPD. For the primary outcome a zero-inflated Poisson regression will compare the number of cardiovascular events at 1 year. Secondary outcomes will be analysed using the time to mortality. DISCUSSION: This multicentre study will assess the association between frailty and cardiovascular events and mortality in population with COPD. Data collection is prospective and includes routine clinical data. This research will have important implications for the management of patients with COPD to improve their quality of care, and potentially prognosis. TRIAL REGISTRATION NUMBER: NCT05922202 (www.clinicaltrials.gov).

Impact of Frailty on Symptom Burden in Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD), the sixth leading cause of death in the United States in 2022 and the third leading cause of death in England and Wales in 2022, is associated with high symptom burden, particularly dyspnoea. Frailty is a complex clinical syndrome associated with an increased vulnerability to adverse health outcomes. The aim of this review was to explore the current evidence of the influence of frailty on symptoms in patients with a confirmed diagnosis of COPD according to GOLD guidelines. Fourteen studies report a positive association between frailty and symptoms, including dyspnoea, assessed with the COPD Assessment Test (CAT) and the modified Medical Research Council (mMRC) scale. Data were analysed in a pooled a random-effects meta-analysis of mean differences (MDs). There was an association between COPD patients living with frailty and increased CAT score versus COPD patients without frailty [pooled SMD, 1.79 (95% CI 0.72-2.87); I2 = 99%]. A lower association was found between frailty and dyspnoea measured by the mMRC scale versus COPD patients without frailty [pooled SMD, 1.91 (95% CI 1.15-2.66); I2 = 98%]. The prevalence of frailty ranged from 8.8% to 82% and that of pre-frailty from 30.4% to 73.7% in people living with COPD. The available evidence supports the role of frailty in worsening symptom burden in COPD patients living with frailty. The review shows that frailty is common in patients with COPD. Future research is needed to have further details related to the data from CAT to improve our knowledge of the frailty impact in this population.

Mechanisms of acute exacerbation of respiratory symptoms in chronic obstructive pulmonary disease.

Exacerbations of chronic obstructive respiratory disease (ECOPD) are acute events characterized by worsening of the patient's respiratory symptoms, particularly dyspnoea, leading to change in medical treatment and/or hospitalisation. AECOP are considered respiratory diseases, with reference to the respiratory nature of symptoms and to the involvement of airways and lung. Indeed respiratory infections and/or air pollution are the main causes of ECOPD. They cause an acute inflammation of the airways and the lung on top of the chronic inflammation that is associated with COPD. This acute inflammation is responsible of the development of acute respiratory symptoms (in these cases the term ECOPD is appropriate). However, the acute inflammation caused by infections/pollutants is almost associated with systemic inflammation, that may cause acute respiratory symptoms through decompensation of concomitant chronic diseases (eg acute heart failure, thromboembolism, etc) almost invariably associated with COPD. Most concomitant chronic diseases share with COPD not only the underlying chronic inflammation of the target organs (i.e. lungs, myocardium, vessels, adipose tissue), but also clinical manifestations like fatigue and dyspnoea. For this reason, in patients with multi-morbidity (eg COPD with chronic heart failure and hypertension, etc), the exacerbation of respiratory symptoms may be particularly difficult to investigate, as it may be caused by exacerbation of COPD and/or ≥ comorbidity, (e.g. decompensated heart failure, arrhythmias, thromboembolisms) without necessarily involving the airways and lung. In these cases the term ECOPD is inappropriate and misleading.

Frailty and its influence on mortality and morbidity in COPD: A Systematic Review and Meta-Analysis.

Frailty increases vulnerability to adverse outcomes. Long-term conditions increase the risk of frailty. We searched PubMed, Web of Science, The Cochrane Library, EMBASE from inception to March 2022. Quality assessment was conducted using the NOS. Data was analysed in a pooled a random-effects meta-analysis. Our primary outcome was the impact of frailty on mortality in adults with Chronic Obstructive Pulmonary Disease (COPD) diagnosis according to the guidelines. Secondary outcomes were: frailty and association with readmissions, hospitalisations, exacerbation rates, and prevalence of frailty in COPD. We identified 25 studies, with 5882 participants. The median prevalence of frailty was 47% (IQR, 39.3-66.3%, range 6.4-72%). There was an association between COPD patients living with frailty and increased risk of mortality versus COPD patients without frailty (pooled OR, 4.21 (95% CI 2.99-5.93, I2 55%). A descriptive analysis of relationship between frailty and hospital readmission and all cause hospitalization showed positive associations. The relationship between frailty and the risk of exacerbation showed a pooled OR, 1.45 (95% CI 0.37-5.70, I2 80%). Frailty is significantly associated with higher mortality risk in COPD. Frailty is common in patients with COPD and its measurement should be considered in clinical practice to better characterise COPD.

Frailty Prevalence and Association with Clinical Outcomes in Interstitial Lung Disease, Asthma, and Pleural Disease.

BACKGROUND: Frailty is a syndrome characterised by increased vulnerability to negative outcomes. Interstitial lung disease (ILD), asthma, and pleural disease are leading causes of morbidity and mortality. We aimed to investigate the prevalence and impact of frailty in adult patients with these diseases. METHODS: We conducted a systematic review and meta-analysis, searching PubMed, Web of Science, The Cochrane Library, and EMBASE for studies reporting on frailty in ILD, asthma, and pleural disease. MeSH terms including interstitial lung disease, Idiopathic Pulmonary Fibrosis, Non-specific Interstitial Pneumonia, Chronic Hypersensitivity Pneumonitis, systemic sclerosis-associated ILD, connective tissue disease-associated ILD, and frailty were used as key words. The primary outcome was prevalence of frailty. Where enough contextually homogeneous studies were included, a pooled random-effects meta-analysis was performed with mortality and hospitalisation as the outcomes. RESULTS: The review found three studies relating to frailty in asthma. No studies relating to pleural disease and frailty were identified. The median prevalence in asthma was 9.5% (IQR, 7.8-11.3). Six relevant studies incorporating 1471 ILD patients (age 68.3 ± SD2.38; 50% male) were identified, which were either cohort or cross-sectional design rated either good or fair. The median prevalence of frailty was 48% (IQR, 25-50). There was a positive association between frail ILD patients and increased risk of long-term mortality (pooled OR, 2.33 95%CI 1.31-4.15, I2 9%). One study reported a hospitalization rate of HR = 1.97(1.32-3.06) within 6 months in frail ILD patients. CONCLUSIONS: Frailty is very common and associated with increased mortality in patients with ILD. There are still minimal data regarding the prevalence of frailty and its influence on the risk in this population.

Quality of life and intrinsic capacity in patients with post-acute COVID-19 syndrome is in relation to frailty and resilience phenotypes.

The objective of this study was to characterize frailty and resilience in people evaluated for Post-Acute COVID-19 Syndrome (PACS), in relation to quality of life (QoL) and Intrinsic Capacity (IC). This cross-sectional, observational, study included consecutive people previously hospitalized for severe COVID-19 pneumonia attending Modena (Italy) PACS Clinic from July 2020 to April 2021. Four frailty-resilience phenotypes were built: "fit/resilient", "fit/non-resilient", "frail/resilient" and "frail/non-resilient". Frailty and resilience were defined according to frailty phenotype and Connor Davidson resilience scale (CD-RISC-25) respectively. Study outcomes were: QoL assessed by means of Symptoms Short form health survey (SF-36) and health-related quality of life (EQ-5D-5L) and IC by means of a dedicated questionnaire. Their predictors including frailty-resilience phenotypes were explored in logistic regressions. 232 patients were evaluated, median age was 58.0 years. PACS was diagnosed in 173 (74.6%) patients. Scarce resilience was documented in 114 (49.1%) and frailty in 72 (31.0%) individuals. Predictors for SF-36 score < 61.60 were the phenotypes "frail/non-resilient" (OR = 4.69, CI 2.08-10.55), "fit/non-resilient" (OR = 2.79, CI 1.00-7.73). Predictors for EQ-5D-5L < 89.7% were the phenotypes "frail/non-resilient" (OR = 5.93, CI 2.64-13.33) and "frail/resilient" (OR = 5.66, CI 1.93-16.54). Predictors of impaired IC (below the mean score value) were "frail/non-resilient" (OR = 7.39, CI 3.20-17.07), and "fit/non-resilient" (OR = 4.34, CI 2.16-8.71) phenotypes. Resilience and frailty phenotypes may have a different impact on wellness and QoL and may be evaluated in people with PACS to identify vulnerable individuals that require suitable interventions.

Frailty is associated with poor mental health 1 year after hospitalisation with COVID-19.

BACKGROUND: Frailty is associated with long-term physical deterioration after COVID-19. Mental health recovery has been less well investigated. Early studies have shown minimal effect from the virus, although studies have not focused on whether people living with frailty may have different psychiatric outcomes. We aimed to examine the effect of living with frailty on mental health outcomes one year after hospital with COVID-19. METHODS: We undertook a multicentre cross-sectional study of people admitted with COVID-19. We assessed quality of life (ICECAP-O and MRC), psychiatric symptoms including: generalised anxiety (GAD-7), depression (Patient Health Questionnaire-9), and trauma (Trauma Screening Questionnaire). Frailty was measured using the Clinical Frailty Scale (CFS). We used a multivariable mixed-effects logistic and linear regression to examine the adjusted odds ratio (aOR) and adjusted mean difference (aMD). RESULTS: From eight hospitals 224 participants consented. Median follow-up time from admission 358 days (IQR 153-418), mean age 63.8 (SD = 13.7), 34.8% female (n = 78), and 43.7% living with frailty (n = 98 CFS 4-8). People living with frailty were significantly more likely to have symptoms of anxiety aOR = 5.72 (95% CI 1.71-19.13), depression aOR = 2.52 (95% CI 1.59-14.91), post-traumatic stress disorder aMD = 1.16 (95% CI 0.47, 1.85), and worse quality of life aMD = 1.06 (95% CI 0.76-1.36). LIMITATIONS: Patient-rated symptoms were captured rather than formal mental health diagnoses. CFS has not been validated in under 65-year-olds. CONCLUSIONS: Living with frailty is associated with significant psychiatric morbidity and reduced wellbeing one year after COVID-19 hospital admission. We recommend clinical follow-up after COVID-19 for people living with frailty should include a psychiatric assessment.

Metabolic-Associated Fatty Liver Disease Is Highly Prevalent in the Postacute COVID Syndrome.

BACKGROUND: A proposal has recently been advanced to change the traditional definition of nonalcoholic fatty liver disease to metabolic-associated fatty liver disease (MAFLD), to reflect the cluster of metabolic abnormalities that may be more closely associated with cardiovascular risk. Long coronavirus disease 2019 (COVID-19) is a smoldering inflammatory condition, characterized by several symptom clusters. This study aims to determine the prevalence of MAFLD in patients with postacute COVID syndrome (PACS) and its association with other PACS-cluster phenotypes. METHODS: We included 235 patients observed at a single university outpatient clinic. The diagnosis of PACS was based on ≥1 cluster of symptoms: respiratory, neurocognitive, musculoskeletal, psychological, sensory, and dermatological. The outcome was prevalence of MAFLD detected by transient elastography during the first postdischarge follow-up outpatient visit. The prevalence of MAFLD at the time of hospital admission was calculated retrospectively using the hepatic steatosis index. RESULTS: Of 235 patients, 162 (69%) were men (median age 61). The prevalence of MAFLD was 55.3% at follow-up and 37.3% on admission (P < .001). Insulin resistance (odds ratio [OR] = 1.5; 95% confidence interval [CI], 1.14-1.96), body mass index (OR = 1.14; 95% CI, 1.04-1.24), and the metabolic syndrome (OR = 2.54; 95% CI, 1.13-5.68) were independent predictors of MAFLD. The number of PACS clusters was inversely associated with MAFLD (OR = 0.86; 95% CI, .76-0.97). Thirty-one patients (13.2%) had MAFLD with no other associated PACS clusters. All correlations between MAFLD and other PACS clusters were weak. CONCLUSIONS: Metabolic-associated fatty liver disease was highly prevalent after hospital discharge and may represent a specific PACS-cluster phenotype, with potential long-term metabolic and cardiovascular health implications.

The role of C-reactive protein as a prognostic marker in COVID-19.

BACKGROUND: C-reactive protein (CRP) is a non-specific acute phase reactant elevated in infection or inflammation. Higher levels indicate more severe infection and have been used as an indicator of COVID-19 disease severity. However, the evidence for CRP as a prognostic marker is yet to be determined. The aim of this study is to examine the CRP response in patients hospitalized with COVID-19 and to determine the utility of CRP on admission for predicting inpatient mortality. METHODS: Data were collected between 27 February and 10 June 2020, incorporating two cohorts: the COPE (COVID-19 in Older People) study of 1564 adult patients with a diagnosis of COVID-19 admitted to 11 hospital sites (test cohort) and a later validation cohort of 271 patients. Admission CRP was investigated, and finite mixture models were fit to assess the likely underlying distribution. Further, different prognostic thresholds of CRP were analysed in a time-to-mortality Cox regression to determine a cut-off. Bootstrapping was used to compare model performance [Harrell's C statistic and Akaike information criterion (AIC)]. RESULTS: The test and validation cohort distribution of CRP was not affected by age, and mixture models indicated a bimodal distribution. A threshold cut-off of CRP ≥40 mg/L performed well to predict mortality (and performed similarly to treating CRP as a linear variable). CONCLUSIONS: The distributional characteristics of CRP indicated an optimal cut-off of ≥40 mg/L was associated with mortality. This threshold may assist clinicians in using CRP as an early trigger for enhanced observation, treatment decisions and advanced care planning.

Routine use of immunosuppressants is associated with mortality in hospitalised patients with COVID-19.

BACKGROUND: Whilst there is literature on the impact of SARS viruses in the severely immunosuppressed, less is known about the link between routine immunosuppressant use and outcome in COVID-19. Consequently, guidelines on their use vary depending on specific patient populations. METHODS: The study population was drawn from the COPE Study (COVID-19 in Older People), a multicentre observational cohort study, across the UK and Italy. Data were collected between 27 February and 28 April 2020 by trained data-collectors and included all unselected consecutive admissions with COVID-19. Load (name/number of medications) and dosage of immunosuppressant were collected along with other covariate data. Primary outcome was time-to-mortality from the date of admission (or) date of diagnosis, if diagnosis was five or more days after admission. Secondary outcomes were Day-14 mortality and time-to-discharge. Data were analysed with mixed-effects, Cox proportional hazards and logistic regression models using non-users of immunosuppressants as the reference group. RESULTS: In total 1184 patients were eligible for inclusion. The median (IQR) age was 74 (62-83), 676 (57%) were male, and 299 (25.3%) died in hospital (total person follow-up 15,540 days). Most patients exhibited at least one comorbidity, and 113 (~10%) were on immunosuppressants. Any immunosuppressant use was associated with increased mortality: aHR 1.87, 95% CI: 1.30, 2.69 (time to mortality) and aOR 1.71, 95% CI: 1.01-2.88 (14-day mortality). There also appeared to be a dose-response relationship. CONCLUSION: Despite possible indication bias, until further evidence emerges we recommend adhering to public health measures, a low threshold to seek medical advice and close monitoring of symptoms in those who take immunosuppressants routinely regardless of their indication. However, it should be noted that the inability to control for the underlying condition requiring immunosuppressants is a major limitation, and hence caution should be exercised in interpretation of the results. PLAIN LANGUAGE SUMMARY: Regular Use of Immune Suppressing Drugs is Associated with Increased Risk of Death in Hospitalised Patients with COVID-19 Background: We do not have much information on how the COVID-19 virus affects patients who use immunosuppressants, drugs which inhibit or reduce the activity of the immune system. There are various conflicting views on whether immune-suppressing drugs are beneficial or detrimental in patients with the disease. Methods: This study collected data from 10 hospitals in the UK and one in Italy between February and April 2020 in order to identify any association between the regular use of immunosuppressant medicines and survival in patients who were admitted to hospital with COVID-19. Results: 1184 patients were included in the study, and 10% of them were using immunosuppressants. Any immunosuppressant use was associated with increased risk of death, and the risk appeared to increase if the dose of the medicine was higher. Conclusion: We therefore recommend that patients who take immunosuppressant medicines routinely should carefully adhere to social distancing measures, and seek medical attention early during the COVID-19 pandemic.

Study protocol for the COPE study: COVID-19 in Older PEople: the influence of frailty and multimorbidity on survival. A multicentre, European observational study.

INTRODUCTION: This protocol describes an observational study which set out to assess whether frailty and/or multimorbidity correlates with short-term and medium-term outcomes in patients diagnosed with COVID-19 in a European, multicentre setting. METHODS AND ANALYSIS: Over a 3-month period we aim to recruit a minimum of 500 patients across 10 hospital sites, collecting baseline data including: patient demographics; presence of comorbidities; relevant blood tests on admission; prescription of ACE inhibitors/angiotensin receptor blockers/non-steroidal anti-inflammatory drugs/immunosuppressants; smoking status; Clinical Frailty Score (CFS); length of hospital stay; mortality and readmission. All patients receiving inpatient hospital care >18 years who receive a diagnosis of COVID-19 are eligible for inclusion. Long-term follow-up at 6 and 12 months is planned. This will assess frailty, quality of life and medical complications.Our primary analysis will be short-term and long-term mortality by CFS, adjusted for age (18-64, 65-80 and >80) and gender. We will carry out a secondary analysis of the primary outcome by including additional clinical mediators which are determined statistically important using a likelihood ratio test. All analyses will be presented as crude and adjusted HR and OR with associated 95% CIs and p values. ETHICS AND DISSEMINATION: This study has been registered, reviewed and approved by the following: Health Research Authority (20/HRA1898); Ethics Committee of Hospital Policlinico Modena, Italy (369/2020/OSS/AOUMO); Health and Care Research Permissions Service, Wales; and NHS Research Scotland Permissions Co-ordinating Centre, Scotland. All participating units obtained approval from their local Research and Development department consistent with the guidance from their relevant national organisation.Data will be reported as a whole cohort. This project will be submitted for presentation at a national or international surgical and geriatric conference. Manuscript(s) will be prepared following the close of the project.

The Clinical Frailty Scale: Estimating the Prevalence of Frailty in Older Patients Hospitalised with COVID-19. The COPE Study.

Frailty assessed using Clinical Frailty Scale (CFS) is a good predictor of adverse clinical events including mortality in older people. CFS is also an essential criterion for determining ceilings of care in people with COVID-19. Our aims were to assess the prevalence of frailty in older patients hospitalised with COVID-19, their sex and age distribution, and the completion rate of the CFS tool in evaluating frailty. Methods: Data were collected from thirteen sites. CFS was assessed routinely at the time of admission to hospital and ranged from 1 (very fit) to 9 (terminally ill). The completion rate of the CFS was assessed. The presence of major comorbidities such as diabetes and cardiovascular disease was noted. Results: A total of 1277 older patients with COVID-19, aged ≥ 65 (79.9 ± 8.1) years were included in the study, with 98.5% having fully completed CFS. The total prevalence of frailty (CFS ≥ 5) was 66.9%, being higher in women than men (75.2% vs. 59.4%, p < 0.001). Frailty was found in 161 (44%) patients aged 65-74 years, 352 (69%) in 75-84 years, and 341 (85%) in ≥85 years groups, and increased across the age groups (<0.0001, test for trend). Conclusion: Frailty was prevalent in our cohort of older people admitted to hospital with COVID-19. This indicates that older people who are also frail, who go on to contract COVID-19 may have disease severity significant enough to warrant hospitalization. These data may help inform health care planners and targeted interventions and appropriate management for the frail older person.

The influence of ACE inhibitors and ARBs on hospital length of stay and survival in people with COVID-19.

OBJECTIVE: During the COVID-19 pandemic the continuation or cessation of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) has been contentious. Mechanisms have been proposed for both beneficial and detrimental effects. Recent studies have focused on mortality with no literature having examined length of hospital stay. The aim of this study was to determine the influence of ACEi and ARBs on COVID-19 mortality and length of hospital stay. METHODS: COPE (COVID-19 in Older People) is a multicenter observational study including adults of all ages admitted with either laboratory or clinically confirmed COVID-19. Routinely generated hospital data were collected. Primary outcome: mortality; secondary outcomes: Day-7 mortality and length of hospital stay. A mixed-effects multivariable Cox's proportional baseline hazards model and logistic equivalent were used. RESULTS: 1371 patients were included from eleven centres between 27th February to 25th April 2020. Median age was 74 years [IQR 61-83]. 28.6% of patients were taking an ACEi or ARB. There was no effect of ACEi or ARB on inpatient mortality (aHR = 0.85, 95%CI 0.65-1.11). For those prescribed an ACEi or ARB, hospital stay was significantly reduced (aHR = 1.25, 95%CI 1.02-1.54, p = 0.03) and in those with hypertension the effect was stronger (aHR = 1.39, 95%CI 1.09-1.77, p = 0.007). CONCLUSIONS: Patients and clinicians can be reassured that prescription of an ACEi or ARB at the time of COVID-19 diagnosis is not harmful. The benefit of prescription of an ACEi or ARB in reducing hospital stay is a new finding.

The effect of frailty on survival in patients with COVID-19 (COPE): a multicentre, European, observational cohort study.

BACKGROUND: The COVID-19 pandemic has placed unprecedented strain on health-care systems. Frailty is being used in clinical decision making for patients with COVID-19, yet the prevalence and effect of frailty in people with COVID-19 is not known. In the COVID-19 in Older PEople (COPE) study we aimed to establish the prevalence of frailty in patients with COVID-19 who were admitted to hospital and investigate its association with mortality and duration of hospital stay. METHODS: This was an observational cohort study conducted at ten hospitals in the UK and one in Italy. All adults (≥18 years) admitted to participating hospitals with COVID-19 were included. Patients with incomplete hospital records were excluded. The study analysed routinely generated hospital data for patients with COVID-19. Frailty was assessed by specialist COVID-19 teams using the clinical frailty scale (CFS) and patients were grouped according to their score (1-2=fit; 3-4=vulnerable, but not frail; 5-6=initial signs of frailty but with some degree of independence; and 7-9=severe or very severe frailty). The primary outcome was in-hospital mortality (time from hospital admission to mortality and day-7 mortality). FINDINGS: Between Feb 27, and April 28, 2020, we enrolled 1564 patients with COVID-19. The median age was 74 years (IQR 61-83); 903 (57·7%) were men and 661 (42·3%) were women; 425 (27·2%) had died at data cutoff (April 28, 2020). 772 (49·4%) were classed as frail (CFS 5-8) and 27 (1·7%) were classed as terminally ill (CFS 9). Compared with CFS 1-2, the adjusted hazard ratios for time from hospital admission to death were 1·55 (95% CI 1·00-2·41) for CFS 3-4, 1·83 (1·15-2·91) for CFS 5-6, and 2·39 (1·50-3·81) for CFS 7-9, and adjusted odds ratios for day-7 mortality were 1·22 (95% CI 0·63-2·38) for CFS 3-4, 1·62 (0·81-3·26) for CFS 5-6, and 3·12 (1·56-6·24) for CFS 7-9. INTERPRETATION: In a large population of patients admitted to hospital with COVID-19, disease outcomes were better predicted by frailty than either age or comorbidity. Our results support the use of CFS to inform decision making about medical care in adult patients admitted to hospital with COVID-19. FUNDING: None.