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Purpose: Patients hospitalized for community-acquired pneumonia (CAP) may have a higher risk of new-onset atrial fibrillation (NOAF). The C2HEST score was developed to evaluate the NOAF risk in the general population. Data on the value of the C2HEST score in acute patients admitted with CAP are lacking. We want to establish the predictive value of C2HEST score for NOAF in patients with CAP. Methods: Patients with CAP enrolled in the SIXTUS cohort were enrolled. C2HEST score was calculated at baseline. In-hospital NOAF was recorded. Receiver-operating Characteristic (ROC) curve and multivariable Cox proportional hazard regression analysis were performed. Results: We enrolled 473 patients (36% women, mean age 70.6 ± 16.5 years), and 54 NOAF occurred. Patients with NOAF were elderly, more frequently affected by hypertension, heart failure, previous stroke/transient ischemic attack, peripheral artery disease and hyperthyroidism. NOAF patients had also higher CURB-65, PSI class and CHA2DS2-VASc score. The C-index of C2HEST score for NOAF was 0.747 (95% confidence interval [95%CI] 0.705–0.786), higher compared to CURB-65 (0.611, 95%CI 0.566–0.655, p = 0.0016), PSI (0.665, 95%CI 0.621–0.708, p = 0.0199) and CHA2DS2-VASc score (0.696, 95%CI 0.652–0.737, p = 0.0762). The best combination of sensitivity (67%) and specificity (70%) was observed with a C2HEST score ≥ 4. This result was confirmed by the multivariable Cox analysis (Hazard Ratio [HR] for C2HEST score ≥ 4 was 10.7, 95%CI 2.0–57.9; p = 0.006), independently from the severity of pneumonia. Conclusion: The C2HEST score was a useful predictive tool to identify patients at higher risk for NOAF during hospitalization for CAP. Clinical Trial Registration: www.clinicaltrials.gov (NCT01773863) [ABSTRACT FROM AUTHOR]

Community-acquired pneumonia (CAP) is associated with low-grade endotoxemia but its relationship with cardiovascular events (CVE) has not been investigated. We evaluated the incidence of CVE including myocardial infarction, stroke, and cardiovascular death in 523 adult patients hospitalized for CAP. Serum lipopolysaccharide (LPS) and zonulin, a marker of gut permeability, were analyzed in the cohort, that was followed-up during hospitalization and up to 43 months thereafter. During the hospital-stay, 55 patients experienced CVE with a progressive increase from the lowest (0.6%) to highest LPS tertile (23.6%, p < 0.001). Logistic regression analyses showed that higher LPS tertile was independently associated with CVE; LPS significantly correlated with age, hs-CRP and zonulin. In a sub-group of 23 CAP patients, blood E. coli DNA was higher in patients compared to 24 controls and correlated with LPS. During the long-term follow-up, 102 new CVE were registered; the highest tertile of LPS levels was associated with incident CVE; Cox regression analysis showed that LPS tertiles, age, history of CHD, and diabetes independently predicted CVE. In CAP low-grade endotoxemia is associated to short- and long-term risk of CVE. Further study is necessary to assess if lowering LPS by non-absorbable antibiotics may result in improved outcomes. [ABSTRACT FROM AUTHOR]

Background and Purpose: Corticosteroids are often prescribed to community‐acquired pneumonia (CAP) patients, but the relationship with major cardiovascular events (MACEs) is unclear. Experimental Approach 541 CAP patients were recruited (334 males, mean age 71.9 ± 16.2 years). High‐sensitivity troponin T (hs‐cTnT) was measured at admission, during the hospital stay and at discharge. MACE occurrence was registered during a long‐term follow‐up. Key Results: Overall, 318 patients (59%) showed hs‐cTnT elevation >99th percentile (>0.014 μg/L). Age, heart failure and the increasing quintiles of hs‐cTnT (hazard ratio [HR] 2.16, 95% confidence interval [CI] 1.82‐2.58, P <.001) predicted MACEs. Among patients with hs‐cTnT >0.014 μg/L at admission, 102 patients (31%) were on corticosteroids and showed lower hs‐cTnT increase (P =.021), (NADPH) oxidase‐2 (Nox2) activation (P =.005) and incidence of MACEs than untreated ones (HR 0.64, 95% CI 0.41‐0.97, P =.038); no effect of corticosteroids on MACEs was observed in CAP patients with normal troponin. In vitro study showed that glucocorticoids have an antioxidant effect via downregulation of Nox2 activity. Conclusion and Implications: The study provides evidence that corticosteroid use is associated with lower increase of hs‐cTnT and incidence of MACEs in CAP patients. [ABSTRACT FROM AUTHOR]

Hypoalbuminemia complicates acute diseases and infections and is associated with a worst prognosis. The aim is to evaluate whether hypoalbuminemia is associated with higher incidence and risk of thrombotic events in community-acquired pneumonia. We retrospectively collected data from a prospective study investigating the incidence of thrombotic events in community-acquired pneumonia hospitalized patients from 2011 to 2016 at University-Hospital Policlinico Umberto I. Baseline characteristics and outcomes were collected. Incidence of outcomes were calculated. Kaplan-Meier curves were created, Cox model used to identify predictors for the outcomes, and competing risk analysis performed. From a total of 231 patients, 130 (56.3%) and 101 (43.7%) had or not hypoalbuminemia. Age, proportion of female, BMI, major comorbidities, and severity of pneumonia were similar between two subgroups. A less proportion of patients with hypoalbuminemia received antithrombotic and statin therapy. Median hospital stay was 11 days in both subgroups. Patients with hypoalbuminemia had higher D-dimer and high- sensitivity C-reactive-protein values with an inverse relation between albumin values and these markers. Incidence of thrombotic events was 26 and 11 per 1000 patient-days in patient with and without hypoalbuminemia. At Cox model, hypoalbuminemia was associated with thrombotic events development in univariable (hazard ratio; 2.67, 95% confidence intervals, 1.30–5.40) and multivariable (hazard ratio 3.19; 95% confidence intervals, 1.48–6.89) analysis. More than a half of patients with community acquired pneumonia had hypoalbuminemia that is associated with a doubled incidence and a three-fold increased risk of thrombotic events. The inverse relation between baseline albumin and D-dimer values confirms this association. [Display omitted] • If hypoalbuminemia is associated with the thrombotic risk of community-acquired pneumonia in unknown. • About 50% of patients with community-acquired pneumonia had hypoalbuminemia. • Hypoalbuminemia is associated with a 3-fold increased risk of thrombotic events. • The inverse relation between albumin and D-dimer values confirms this association. [ABSTRACT FROM AUTHOR]

Previous reports suggest that community-acquired pneumonia (CAP) is associated with an enhanced risk of myocardial infarction (MI) and that enhanced platelet activation may play a role. Aims of this study were to investigate if urinary excretion of 11-dehydro-thromboxane (Tx) B 2 , a reliable marker of platelet activation in vivo, was elevated in CAP and whether glucocorticoid administration reduced platelet activation. Three-hundred patients hospitalized for CAP were recruited and followed-up until discharge. Within the first 2 days from admission, urinary 11-dehydro-TxB 2 and serum levels of methylprednisolone and betamethasone were measured. 11-Dehydro-TxB 2 was also measured in a control group of 150 outpatients, matched for age, sex, and comorbidities. Finally, in-vitro studies were performed to assess if glucocorticoids affected platelet activation, at the same range of concentration found in the peripheral circulation of CAP patients treated with glucocorticoids. Compared to controls, CAP patients showed significantly higher levels of 11-dehydro-TxB 2 (110 [69–151] vs. 163 [130–225] pg/mg creatinine; p < 0.001). During the in-hospital stay, 31 patients experienced MI (10%). A COX regression analysis showed that 11-dehydro-TxB 2 independently predicted MI (p = .005). CAP patients treated with glucocorticoids showed significantly lower levels of 11-dehydro-TxB 2 compared to untreated ones (147 [120–201] vs. 176 [143–250] pg/mg creatinine; p < 0.001). In vitro, glucocorticoids-treated platelets showed a dose-dependent decrease of ADP-induced platelet aggregation, TxB 2 production, cPLA 2 phosphorylation and arachidonic acid release from the platelet membrane. In conclusion, platelet TxB 2 is overproduced in CAP patients and may be implicated in MI occurrence. Glucocorticoids reduce platelet release of TxB 2 in vitro and urinary excretion of 11-dehydro-TxB 2 in vivo and may be a novel tool to decrease platelet activation in this setting. [ABSTRACT FROM AUTHOR]

Background. Previous reports suggest that community-acquired pneumonia (CAP) is associated with an enhanced risk of cardiovascular complications. However, a contemporary and comprehensive characterization of this association is lacking. Methods. In this multicenter study, 1182 patients hospitalized for CAP were prospectively followed for up to 30 days after their hospitalization for this infection. Study endpoints included myocardial infarction, new or worsening heart failure, atrial fibrillation, stroke, deep venous thrombosis, cardiovascular death, and total mortality. Results. Three hundred eighty (32.2%) patients experienced intrahospital cardiovascular events (CVEs) including 281 (23.8%) with heart failure, 109 (9.2%) with atrial fibrillation, 89 (8%) with myocardial infarction, 11 (0.9%) with ischemic stroke, and 1 (0.1%) with deep venous thrombosis; 28 patients (2.4%) died for cardiovascular causes. Multivariable Cox regression analysis showed that intrahospital Pneumonia Severity Index (PSI) class (hazard ratio [HR], 2.45, P = .027; HR, 4.23, P < .001; HR, 5.96, P < .001, for classes III, IV, and V vs II, respectively), age (HR, 1.02, P = .001), and preexisting heart failure (HR, 1.85, P < .001) independently predicted CVEs. One hundred three (8.7%) patients died by day 30 postadmission. Thirty-day mortality was significantly higher in patients who developed CVEs compared with those who did not (17.6% vs 4.5%, P < .001). Multivariable Cox regression analysis showed that intrahospital CVEs (HR, 5.49, P < .001) independently predicted 30-day mortality (after adjustment for age, PSI score, and preexisting comorbid conditions). Conclusions. CVEs, mainly those confined to the heart, complicate the course of almost one-third of patients hospitalized for CAP. More importantly, the occurrence of CVEs is associated with a 5-fold increase in CAP-associated 30-day mortality. [ABSTRACT FROM AUTHOR]

Background Community-acquired pneumonia (CAP) is complicated by cardiovascular events as myocardial infarction and stroke but the underlying mechanism is still unclear. We hypothesized that endothelial dysfunction may be implicated and that endotoxemia may have a role. Methods Fifty patients with CAP and 50 controls were enrolled. At admission and at discharge, flow-mediated dilation (FMD), serum levels of endotoxins and oxidative stress, as assessed by serum levels of nitrite/nitrate (NOx) and isoprostanes, were studied. Results At admission, a significant difference between patients with CAP and controls was observed for FMD (2.1 ± 0.3 vs 4.0 ± 0.3%, p < 0.001), serum endotoxins (157.8 ± 7.6 vs 33.1 ± 4.8 pg/ml), serum isoprostanes (341 ± 14 vs 286 ± 10 pM, p = 0.009) and NOx (24.3 ± 1.1 vs 29.7 ± 2.2 μM). Simple linear correlation analysis showed that serum endotoxins significantly correlated with Pneumonia Severity Index score (Rs = 0.386, p = 0.006). Compared to baseline, at discharge CAP patients showed a significant increase of FMD and NOx (from 2.1 ± 0.3 to 4.6 ± 0.4%, p < 0.001 and from 24.3 ± 1.1 to 31.1 ± 1.5 μM, p < 0.001, respectively) and a significant decrease of serum endotoxins and isoprostanes (from 157.8 ± 7.6 to 55.5 ± 2.3 pg/ml, p < 0.001, and from 341 ± 14 to 312 ± 14 pM, p < 0.001, respectively). Conversely, no changes for FMD, NOx, serum endotoxins and isoprostanes were observed in controls between baseline and discharge. Changes of FMD significantly correlated with changes of serum endotoxins (Rs = − 0.315; p = 0.001). Conclusions The study provides the first evidence that CAP is characterized by impaired FMD with a mechanism potentially involving endotoxin production and oxidative stress. [ABSTRACT FROM AUTHOR]

ABSTRACT Background and objective Community-acquired pneumonia ( CAP) is associated with an increased risk of arterial and venous thrombosis but the underlying pathophysiological mechanisms are still unclear. We investigated if, in patients with CAP, a pro-thrombotic state does exist and its relationship with serum levels of endotoxins. Methods A total of 104 consecutive patients with CAP were prospectively recruited and followed up until discharge. At admission and at discharge, serum endotoxins, systemic markers of clotting activation and zonulin, a marker of gut permeability, were analysed. Hospitalized patients matched for gender, age and comorbidities but without infections were used as control. Results At admission, CAP patients showed higher plasma levels of F1 +2, a marker of thrombin generation ( P = 0.023), and lower levels of protein C ( PC; P < 0.001) and activated PC ( aPC) ( P < 0.001) compared with controls. At discharge, plasma levels of both PC and aPC significantly increased while F1 +2 significantly decreased ( P < 0.001). Baseline serum endotoxins and zonulin were higher in CAP patients than controls ( P < 0.001) and significantly decreased at discharge; a significant correlation between serum endotoxins and zonulin was detected (R = 0.575; P < 0.001) Conclusion This study provides the first evidence that CAP patients disclose an ongoing pro-thrombotic state and suggests a role for endotoxemia in determining enhanced thrombin generation. [ABSTRACT FROM AUTHOR]

Community-acquired pneumonia (CAP) is complicated by cardiac events in the early phase of the disease. Aim of this study was to assess if these intrahospital cardiac complications may account for overall mortality and cardiovascular events occurring during a long-term follow-up. Three hundred one consecutive patients admitted to the University-Hospital, Policlinico Umberto I, with community-acquired pneumonia were prospectively recruited and followed up for a median of 17.4 months. Primary end point was the occurrence of death for any cause, and secondary end point was the occurrence of cardiovascular events (cardiovascular death, nonfatal myocardial infarction [MI], and stroke). During the intrahospital stay, 55 patients (18%) experienced a cardiac complication. Of these, 32 had an MI (29 non-ST-elevation MI and 3 ST-elevation MI) and 30 had a new episode of atrial fibrillation (7 nonmutually exclusive events). During the follow-up, 89 patients died (51% of patients with an intrahospital cardiac complication and 26% of patients without, p <0.001) and 73 experienced a cardiovascular event (47% of patients with and 19% of patients without an intrahospital cardiac complication, p <0.001). A Cox regression analysis showed that intrahospital cardiac complications, age, and Pneumonia Severity Index were significantly associated with overall mortality, whereas intrahospital cardiac complications, age, hypertension, and diabetes were significantly associated with cardiovascular events during the follow-up. In conclusion, this prospective study shows that intrahospital cardiac complications in the early phase of pneumonia are associated with an enhanced risk of death and cardiovascular events during long-term follow-up. [ABSTRACT FROM AUTHOR]

The article presents the authors' reply in response to their article on the incidence of cardiovascular events (CVEs) after community-acquired pneumonia (CAP). The authors say that in patients hospitalized with CAP, CVEs such as myocardial infarction, heart failure, stroke, atrial fibrillation, and cardiovascular death occurred in nearly 30 percent of patients, and such complications were associated with 30-day mortality.

Endothelial dysfunction, assessed by flow-mediated dilation (FMD), is related to poor prognosis in patients with COVID-19 pneumonia (CP). In this study, we explored the interplay among FMD, NADPH oxidase type 2 (NOX-2) and lipopolysaccharides (LPS) in hospitalised patients with CP, community acquired pneumonia (CAP) and controls (CT). We enrolled 20 consecutive patients with CP, 20 hospitalised patients with CAP and 20 CT matched for sex, age, and main cardiovascular risk factors. In all subjects we performed FMD and collected blood samples to analyse markers of oxidative stress (soluble Nox2-derived peptide (sNOX2-dp), hydrogen peroxide breakdown activity (HBA), nitric oxide (NO), hydrogen peroxide (H2O2)), inflammation (TNF-α and IL-6), LPS and zonulin levels. Compared with controls, CP had significant higher values of LPS, sNOX-2-dp, H2O2,TNF-α, IL-6 and zonulin; conversely FMD, HBA and NO bioavailability were significantly lower in CP. Compared to CAP patients, CP had significantly higher levels of sNOX2-dp, H2O2, TNF-α, IL-6, LPS, zonulin and lower HBA. Simple linear regression analysis showed that FMD inversely correlated with sNOX2-dp, H2O2, TNF-α, IL-6, LPS and zonulin; conversely FMD was directly correlated with NO bioavailability and HBA. Multiple linear regression analysis highlighted LPS as the only predictor of FMD. This study shows that patients with COVID-19 have low-grade endotoxemia that could activate NOX-2, generating increased oxidative stress and endothelial dysfunction. • Patients with COVID-19 have low-grade endotoxemia. • Compared to patients with community acquired pneumonia, COVID-19 patients had significant higher values of NADPH oxidase type 2. • Lipopolysaccharides could activate NADPH oxidase type 2 generating increased oxidative stress and endothelial dysfunction. [ABSTRACT FROM AUTHOR]