Frailty and comorbidity burden in Atrial Fibrillation

Background: With the aging of the population, the characterization of frailty and comorbidity burden is increasingly taking on particular importance. The aims of the present study are to analyze such conditions in a population affected by Atrial Fibrillation (AF), matching it with a population without AF, and to recognize potential independent factors associated with such common cardiovascular disease. Methods: This study included subjects consecutively evaluated over 5 years at the Geriatric Outpatient Service, University Hospital of Monserrato, Cagliari, Italy. A sum of 1981 subjects met the inclusion criteria. The AF-group was made up of 330 people, and another 330 people were randomly selected to made up the non-AF-group. The sample was subjected to Comprehensive Geriatric Assessment (CGA). Results: In our sample, severe comorbidity burden (p = 0.01) and frailty status (p = 0.04) were significantly more common in patients with AF than without AF, independently on gender and age. Furthermore, the 5-years follow-up demonstrated that survival probability was significantly higher in AF-group (p = 0.03). The multivariate analysis (AUC: 0.808) showed that the presence of AF was independently positively associated with a history of coronary heart disease (OR: 2.12) and cerebrovascular disease (OR: 1.64), with the assumption of Beta Blockers (OR: 3.39), and with the number of drugs taken (OR: 1.12), and negatively associated with the assumption of antiplatelets (OR: 0.09). Conclusions: Elderly people with AF are frailer, have more severe comorbidities, and take more drugs, in particular beta blockers, than people without AF, who conversely have a higher survival probability. Furthermore, it is necessary to pay attention to antiplatelets, especially in AF-group, in order to avoid dangerous under- or over-prescriptions

Emergency department: risk stratification in the elderly

Background & aims. The older adults have very frequent access to the Emergency Department (ED). The aim of this study is to explore the ability of some geriatric screening tools validated for the ED to predict outcomes (mortality, hospitalization, ED readmission and institutional-ization) at 6 months. Methods. Older adults consecutively admitted to Cagliari University’s ED between May and December of 2017 were enrolled. In ED older patients were screened with three tools: Identification of Seniors at Risk tool (ISAR); Triage Risk Screening Tool (TRST); International Resident Assessment Instrument Emergency Department Screener (InterRAI ED Screener). At 6 months patients were contacted by phone to verify: mortality, ED readmission, hospital admission, and institutionalization. Results. Of the 421 patients (median age 77, Interquartile Range 71-83; 55.8% women) enrolled, 72.4% were positive at the ISAR, 50.1% at the TRST; moreover 44.9% of enrolled subjects needed a urgent geriatric evaluation at the InterRAI ED Screener. The dead subjects had ISAR, TRST and InterRAI ED Screener with greater severity compared to the alive ones. The ISAR and the TRST were also more severe in subjects who had ED readmission, while those hospitalized, in addition to the ISAR, had the more severe Inter-RAI ED Screener. However, applying stepwise logistic regression, of the three tools used, only the ISAR was a predictor for hospitalization (OR = 1.23; CI = 1.03-1.48; P = 0.02; AUC = 0.63). Conclusions. The association of ISAR and InterRAI ED Screener may be useful in ED to intercept both critical issues typical of the elderly, and the need and priority of the geriatric evaluation

Human Leukocyte Antigen Complex and Other Immunogenetic and Clinical Factors Influence Susceptibility or Protection to SARS-CoV-2 Infection and Severity of the Disease Course. The Sardinian Experience

Aim: SARS-CoV-2 infection is a world-wide public health problem. Several aspects of its pathogenesis and the related clinical consequences still need elucidation. In Italy, Sardinia has had very low numbers of infections. Taking advantage of the low genetic polymorphism in the Sardinian population, we analyzed clinical, genetic and immunogenetic factors, with particular attention to HLA class I and II molecules, to evaluate their influence on susceptibility to SARS-CoV-2 infection and the clinical outcome. Method and Materials: We recruited 619 healthy Sardinian controls and 182 SARS-CoV-2 patients. Thirty-nine patients required hospital care and 143 were without symptoms, pauci-symptomatic or with mild disease. For all participants, we collected demographic and clinical data and analyzed the HLA allele and haplotype frequencies. Results: Male sex and older age were more frequent in hospitalized patients, none of whom had been vaccinated during the previous seasonal flu vaccination campaignes. Compared to the group of asymptomatic or pauci-symptomatic patients, hospitalized patients also had a higher frequency of autoimmune diseases and glucose-6-phosphate-dehydrogenase (G6PDH) deficiency. None of these patients carried the beta-thalassemia trait, a relatively common finding in the Sardinian population. The extended haplotype HLA-A*02:05, B*58:01, C*07:01, DRB1*03:01 [OR 0.1 (95% CI 0–0.6), Pc = 0.015] was absent in all 182 patients, while the HLA-C*04:01 allele and the three-loci haplotype HLA-A*30:02, B*14:02, C*08:02 [OR 3.8 (95% CI 1.8–8.1), Pc = 0.025] were more frequently represented in patients than controls. In a comparison between in-patients and home care patients, the HLA-DRB1*08:01 allele was exclusively present in the hospitalized patients [OR > 2.5 (95% CI 2.7–220.6), Pc = 0.024]. Conclusion: The data emerging from our study suggest that the extended haplotype HLA-A*02:05, B*58:01, C*07:01, DRB1*03:01 has a protective effect against SARS-CoV-2 infection in the Sardinian population. Genetic factors that resulted to have a negative influence on the disease course were presence of the HLA-DRB1*08:01 allele and G6PDH deficiency, but not the beta-thalassemic trait. Absence of influenza vaccination could be a predisposing factor for more severe disease

Natural killer-cell immunoglobulin-like receptors trigger differences in immune response to SARS-CoV-2 infection

Background: The diversity in the clinical course of COVID-19 has been related to differences in innate and adaptative immune response mechanisms. Natural killer (NK) lymphocytes are critical protagonists of human host defense against viral infections. It would seem that reduced circulating levels of these cells have an impact on COVID-19 progression and severity. Their activity is strongly regulated by killer-cell immuno-globulin-like receptors (KIRs) expressed on the NK cell surface. The present study's focus was to investigate the impact of KIRs and their HLA Class I ligands on SARS-CoV-2 infection. Methods: KIR gene frequencies, KIR haplotypes, KIR ligands and combinations of KIRs and their HLA Class I ligands were investigated in 396 Sardinian patients with SARS-CoV-2 infection. Comparisons were made between 2 groups of patients divided according to disease severity: 240 patients were symptomatic or paucisymptomatic (Group A), 156 hospitalized patients had severe disease (Group S). The immunogenetic characteristics of patients were also compared to a population group of 400 individuals from the same geographical areas. Results: Substantial differences were obtained for KIR genes, KIR haplotypes and KIR-HLA ligand combinations when comparing patients of Group S to those of Group A. Patients in Group S had a statistically significant higher frequency of the KIR A/A haplotype compared to patients in Group A [34.6% vs 23.8%, OR = 1.7 (95% CI 1.1-2.6); P = 0.02, Pc = 0.04]. Moreover, the KIR2DS2/HLA C1 combination was poorly represented in the group of patients with severe symptoms compared to those of the asymptomatic-paucisymptomatic group [33.3% vs 50.0%, OR = 0.5 (95% CI 0.3-0.8), P = 0.001, Pc = 0.002]. Multivariate analysis confirmed that, regardless of the sex and age of the patients, the latter genetic variable correlated with a less severe disease course [ORM = 0.4 (95% CI 0.3-0.7), PM = 0.0005, PMC = 0.005]. Conclusions: The KIR2DS2/HLA C1 functional unit resulted to have a strong protective effect against the adverse outcomes of COVID-19. Combined to other well known factors such as advanced age, male sex and concomitant autoimmune diseases, this marker could prove to be highly informative of the disease course and thus enable the timely intervention needed to reduce the mortality associated with the severe forms of SARS-CoV-2 infection. However, larger studies in other populations as well as experimental functional studies will be needed to confirm our findings and further pursue the effect of KIR receptors on NK cell immune-mediated response to SARS-Cov-2 infection

STOPP/START antiaggregation and anticoagulation alerts in atrial fibrillation

BACKGROUND Atrial Fibrillation (AF) is common in the elderly. A key component of AF management is Oral Anticoagulant Therapy (OAT), consisting of Vitamin K Antagonists (VKAs) or Direct Oral Anticoagulants (DOACs). The aim of the present study is to check, using STOPP (Screening Tool of Older Persons’ Prescriptions)/START (Screening Tool to Alert to Right Treatment) Criteria, if such drugs are potentially inappropriately prescribed/omitted in an elderly population with AF, and to determine their impact on mortality. METHODS This study included patients (n=427) with nonvalvular AF consecutively evaluated between 2013 and 2019 at the Geriatric Outpatient Service, University Hospital of Monserrato, Cagliari, Italy, and followed-up for 36 months. The OAT-group included 330 patients; the other 97 patients constituted the non-OAT-group. The sample was assessed for STOPP/START criteria. RESULTS We found no difference (p>0.1) in comorbidity burden, frailty, and cardio-cerebro-vascular disease prevalence in the two groups, who also did not present difference in 36-month mortality (p=0.97). OAT was overall appropriately taken, and 62.4% of OAT-group presented the START criterion to take antiplatelets but also the STOPP criterion not to take them, because of the simultaneous anticoagulant intake. In the non-OAT-group, 69.1% presented the START criterion to take anticoagulants, and 21.6% the START criterion to take antiplatelets. CONCLUSIONS Patients with AF are often prone to under- or over-prescription, particularly of antithrombotic drugs. The STOPP/START criteria are a valid tool to assess and correct wrong therapeutic choices. In frail and comorbid subjects, survival is not correlated with the assumption of OAT

Heparin in COVID-19 patients is associated with reduced in-hospital mortality: the multicentre Italian CORIST Study

INTRODUCTION: A hypercoagulable condition was described in patients with COVID-19 and proposed as a possible pathogenic mechanism contributing to disease progression and lethality.AIM: We evaluated if in-hospital administration of heparin improved survival in a large cohort of Italian COVID-19 patients.METHODS: In a retrospective observational study, 2,574 unselected patients hospitalised in 30 clinical centres in Italy from February 19, 2020 to May 23, 2020 with laboratory-confirmed SARS-CoV-2 infection, were analysed. The primary end-point in a time-to event analysis was in-hospital death, comparing patients who received heparin (low-molecular weight heparin (LMWH) or unfractionated heparin (UFH)) with patients who did not. We used multivariable Cox proportional-hazards regression models with inverse probability for treatment weighting by propensity scores.RESULTS: Out of 2,574 COVID-19 patients, 70.1% received heparin. LMWH was largely the most used formulation (99.5%). Death rates for patients receiving heparin or not were 7.4 and 14.0 per 1,000 person-days, respectively. After adjustment for propensity scores, we found a 40% lower risk of death in patients receiving heparin (HR=0.60; 95%CI: 0.49 to 0.74; E-value=2.04). This association was particularly evident in patients with a higher severity of disease or strong coagulation activation.CONCLUSIONS: In-hospital heparin treatment was associated with lower mortality, particularly in severely ill COVID-19 patients and in those with strong coagulation activation. The results from randomised clinical trials are eagerly awaited to provide clear-cut recommendations

Disentangling the Association of Hydroxychloroquine Treatment with Mortality in Covid-19 Hospitalized Patients through Hierarchical Clustering

The efficacy of hydroxychloroquine (HCQ) in treating SARS-CoV-2 infection is harshly debated, with observational and experimental studies reporting contrasting results. To clarify the role of HCQ in Covid-19 patients, we carried out a retrospective observational study of 4,396 unselected patients hospitalized for Covid-19 in Italy (February-May 2020). Patients' characteristics were collected at entry, including age, sex, obesity, smoking status, blood parameters, history of diabetes, cancer, cardiovascular and chronic pulmonary diseases, and medications in use. These were used to identify subtypes of patients with similar characteristics through hierarchical clustering based on Gower distance. Using multivariable Cox regressions, these clusters were then tested for association with mortality and modification of effect by treatment with HCQ. We identified two clusters, one of 3,913 younger patients with lower circulating inflammation levels and better renal function, and one of 483 generally older and more comorbid subjects, more prevalently men and smokers. The latter group was at increased death risk adjusted by HCQ (HR[CI95%] = 3.80[3.08-4.67]), while HCQ showed an independent inverse association (0.51[0.43-0.61]), as well as a significant influence of cluster*HCQ interaction (p<0.001). This was driven by a differential association of HCQ with mortality between the high (0.89[0.65-1.22]) and the low risk cluster (0.46[0.39-0.54]). These effects survived adjustments for additional medications in use and were concordant with associations with disease severity and outcome. These findings suggest a particularly beneficial effect of HCQ within low risk Covid-19 patients and may contribute to clarifying the current controversy on HCQ efficacy in Covid-19 treatment

RAAS inhibitors are not associated with mortality in COVID-19 patients: Findings from an observational multicenter study in Italy and a meta-analysis of 19 studies

Objective: The hypothesis that been set forward that use of Renin Angiotensin Aldosterone System (RAAS) inhibitors is associated with COVID-19 severity. We set-up a multicenter Italian collaboration (CORIST Project, ClinicalTrials.gov ID: NCT04318418) to retrospectively investigate the relationship between RAAS inhibitors and COVID-19 in-hospital mortality. We also carried out an updated meta-analysis on the relevant studies.Methods: We analyzed 4069 unselected patients with laboratory-confirmed SARS-CoV-2 infection and hospitalized in 34 clinical centers in Italy from February 19, 2020 to May 23, 2020. The primary end-point in a time-to event analysis was in-hospital death, comparing patients who received angiotensin-converting-enzyme inhibitors (ACEeI) or angiotensin-receptor blockers (ARB) with patients who did not. Articles for the meta-analysis were retrieved until July 13th, 2020 by searching in web-based libraries, and data were combined using the general variance-based method.Results: Out of 4069 COVID-19 patients, 13.5% and 13.3% received ACE-I or ARB, respectively. Use of neither ACE-I nor ARB was associated with mortality (multivariable hazard ratio (HR) adjusted also for COVID-19 treatments: 0.96, 95% confidence interval 0.77-1.20 and HR = 0.89, 0.67-1.19 for ACE-I and ARB, respectively). Findings were similar restricting the analysis to hypertensive (N = 2057) patients (HR = 1.00, 0.78-1.26 and HR = 0.88, 0.65-1.20) or when ACE-I or ARB were considered as a single group. Results from the meta-analysis (19 studies, 29,057 COVID-19 adult patients, 9700 with hypertension) confirmed the absence of association.Conclusions: In this observational study and meta-analysis of the literature, ACE-I or ARB use was not associated with severity or in-hospital mortality in COVID-19 patients