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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. 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. 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. NCT05922202 (www.clinicaltrials.gov).

Background Use of serum procalcitonin (PCT), an inflammatory biomarker for bacterial infections, has shown promising results for early stopping antibiotic treatment among patients with respiratory infections and sepsis. There is need for additional data regarding effectiveness and safety of this concept among patients with cancer. Methods Individual data of patients with a documented diagnosis of cancer and proven or suspected respiratory infection and/or sepsis were extracted from previous trials where adult patients were randomized to receive antibiotic treatment based on a PCT protocol or usual care (control group). The primary efficacy and safety endpoints were antibiotic exposure and 28-day all-cause mortality. Results This individual-patient data meta-analysis included 777 patients with a diagnosis of cancer from 15 randomized-controlled trials. Regarding efficacy, there was a 18% reduction in antibiotic exposure in patients randomized to PCT-guided care compared to usual care ([days] 8.2 ± 6.6 vs. 9.8 ± 7.3; adjusted difference, − 1.77 [95% CI, − 2.74 to − 0.80]; p  < 0.001). Regarding safety, there were 72 deaths in 379 patients in the PCT-guided group (19.0%) compared to 91 deaths in 398 participants in the usual care group (22.9%) resulting in an adjusted OR of 0.78 (95% CI, 0.60 to 1.02). A subgroup analysis showed a significant reduction in mortality in patients younger than 70 years (adjusted OR, 0.58 [95% CI, 0.40 to 0.86]). Conclusion Result of this individual patient meta-analysis from 15 previous trials suggests that among patients with cancer and suspected or proven respiratory infection or sepsis, use of PCT to guide antibiotic treatment decisions results in reduced antibiotic exposure with a possible reduction in mortality, particularly among younger patients.

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.

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.

The duration of antibiotic treatment of exacerbations of COPD (ECOPD) is controversial. Serum procalcitonin (PCT) is a biomarker of bacterial infection used to identify the cause of ECOPD. We investigated whether a PCT-guided plan would allow a shorter duration of antibiotic treatment in patients with severe ECOPD. For this multicenter, randomized, non-inferiority trial, we enrolled 184 patients hospitalized with ECOPD from 18 hospitals in Italy. Patients were assigned to receive antibiotics for 10 days (standard group) or for either 3 or 10 days (PCT group). The primary outcome was the rate of ECOPD at 6 months. Having planned to recruit 400 patients, we randomized only 183: 93 in the PCT group and 90 in the standard group. Thus, the completed study was underpowered. The ECOPD rate at 6 months between PCT-guided and standard antibiotic treatment was not significant (% difference, 4.04; 90% confidence interval [CI], -7.23 to 15.31), but the CI included the non-inferiority margin of 15. In the PCT-guided group, about 50% of patients were treated for 3 days, and there was no difference in primary or secondary outcomes compared to patients treated for 10 days. Although the primary and secondary clinical outcomes were no different for patients treated for 3 or 10 days in the PCT group, the conclusion that antibiotics can be safely stopped after 3 days in patients with low serum PCT cannot be substantiated statistically. Thus, the results of this study are inconclusive regarding the noninferiority of the PCT-guided plan compared to the standard antibiotic treatment. The study was funded by Agenzia Italiana del Farmaco (AIFA-FARM58J2XH). Clinical trial registered with www.clinicaltrials.gov (NCT01125098). ClinicalTrials.gov NCT01125098.

Abstract 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. It has been proposed that Non-Alcoholic Fatty Liver Disease should be renamed Metabolic Associated Fatty Liver Disease (MAFLD) with potential long-term cardiovascular complications. MAFLD was highly prevalent after hospital discharge in COVID-19 and may represent a specific PACS-cluster phenotype.

Background: Studies have highlighted long-term respiratory muscle dysfunction in COVID-19 survivors, although the underlying risk factors remain unclear. This single-centre study assessed respiratory muscle function and individual associated factors at follow-up in patients hospitalised with COVID-19 and related acute respiratory failure. Methods: Data were collected for consecutive patients, aged ≥ 18 years, at the post-COVID outpatient service of Hospital Policlinico in Modena (Italy) in the time frame of 3 to 6 months after discharge. Data were analysed using single and multiple logistic regression models. Correlations among MIP/MEP, hand-grip values, and lung function were further explored. Results: Out of 223 patients (mean age 67 years, 69% male) 121 (54.3%) exhibited MIP or MEP dysfunction, which was found to be associated with the use of non-invasive ventilation (aOR = 1.91 [1.07–3.49], p = 0.04) and female gender (aOR = 1.76 [1.09–4.16], p = 0.03) as independent risk factors. A positive correlation was observed between MIP dysfunction and hand-grip strength (p = 0.03 and 0.01), whereas both MIP and MEP were significantly associated with FEV1, FVC, TLC, and DLCO. Conclusions: Respiratory muscle dysfunction is consistently prevalent and parallels peripheral muscle weakness and the lung function level in patients at follow-up after severe COVID-19. The need for non-invasive ventilation during the acute phase and female gender might represent risk factors. MIP/MEP assessment should be recommended to observe respiratory muscle dysfunction in severe post-COVID survivors.

IntroductionThis 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 analysisOver 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 disseminationThis 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.

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.

Chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF) may coexist in elderly patients with a history of smoking. Low-grade systemic inflammation induced by smoking may represent the link between these 2 conditions. In this study, we investigated left ventricular dysfunction in patients primarily diagnosed with COPD, and nonreversible airflow limitation in patients primarily diagnosed with CHF. The levels of circulating high-sensitive C-reactive protein (Hs-CRP), pentraxin 3 (PTX3), interleukin-1β (IL-1 β), and soluble type II receptor of IL-1 (sIL-1RII) were also measured as markers of systemic inflammation in these 2 cohorts. Patients aged ≥ 50 years and with ≥ 10 pack years of cigarette smoking who presented with a diagnosis of stable COPD (n=70) or stable CHF (n=124) were recruited. All patients underwent echocardiography, N-terminal pro-hormone of brain natriuretic peptide measurements, and post-bronchodilator spirometry. Plasma levels of Hs-CRP, PTX3, IL-1 β, and sIL-1RII were determined by using a sandwich enzyme-linked immuno-sorbent assay in all patients and in 24 healthy smokers (control subjects). Although we were unable to find a single COPD patient with left ventricular dysfunction, we found nonreversible airflow limitation in 34% of patients with CHF. On the other hand, COPD patients had higher plasma levels of Hs-CRP, IL1 β, and sIL-1RII compared with CHF patients and control subjects (p < 0.05). None of the inflammatory biomarkers was different between CHF patients and control subjects. In conclusion, although the COPD patients had no evidence of CHF, up to one third of patients with CHF had airflow limitation, suggesting that routine spirometry is warranted in patients with CHF, whereas echocardiography is not required in well characterized patients with COPD. Only smokers with COPD seem to have evidence of systemic inflammation.