Cardiac Involvement in Patients With Multisystem Inflammatory Syndrome in Adults.

Multisystemic inflammatory syndrome in adults is a hyperinflammatory condition following (within 4-12 weeks) SARS-CoV-2 infection. Here, the dysregulation of the immune system leads to a multiorgan involvement often affecting the heart. Cardiac involvement in multisystemic inflammatory syndrome in adults has been described mainly in young men without other comorbidities and may present with different clinical scenarios, including acute heart failure, life-threatening arrhythmias, pericarditis, and myocarditis, with a nonnegligible risk of mortality (up to 7% of all cases). The heterogeneity of its clinical features and the absence of a clear case definition make the differential diagnosis with other postinfectious (eg, infective myocarditis) and hyperinflammatory diseases (eg, adult Still disease and macrophage activation syndrome) challenging. Moreover, the evidence on the efficacy of specific treatments targeting the hyperinflammatory response underlying this clinical condition (eg, glucocorticoids, immunoglobulins, and other immunomodulatory agents) is sparse and not supported by randomized clinical trials. In this review article, we aim to provide an overview of the clinical features and the diagnostic workup of multisystemic inflammatory syndrome in adults with cardiac involvement, highlighting the possible pathogenetic mechanisms and the therapeutic management, along with remaining knowledge gaps in this field.

Novel therapeutic insights into the treatment of pericarditis: Targeting the innate immune system.

Acute pericarditis is characterized by pericardial inflammation which can be treated with anti-inflammatory drugs. A considerable percentage of patients develops recurrent pericarditis with several relapses. In developed countries, the idiopathic form is the most frequent and has a high risk of recurrences. Two pathophysiological mechanisms have been described for idiopathic recurrent pericarditis, autoimmune and autoinflammatory. The autoimmune mechanism is more frequently encountered in patients with rheumatologic disorders, especially systemic lupus erythematosus. The innate immune system plays a central role in the pathophysiology of pericarditis, especially in the autoinflammatory phenotype. Current evidence highlights the central role played by interleukin 1 (IL-1) and NLRP3 (NACHT, leucine-rich repeat, and pyrin domain-containing protein 3) in idiopathic recurrent pericarditis. Accordingly, IL-1 blockers have been approved for the treatment of this condition. Neutrophils are likely to be important in such setting, however their role has only been partially investigated. In the present review we have collected the current knowledge on the role of innate immune system in pericarditis pathophysiology and how this can be used to provide targeted treatments for patients with recurrent pericarditis.

Adiponectin/leptin ratio predicts the remission of metabolic syndrome: A pilot study.

BACKGROUND: Adipokines are key mediators of inflammation in metabolic syndrome perpetuating the effect of excess nutrient intake by setting a self-maintaining vicious circle. Here, we assess levels of adiponectin and leptin in a cohort of individuals with MetS undergoing dietary and behavioral counselling. Specifically, we investigate their role as predictors of metabolic syndrome remission after 1 year. METHODS: Patients with MetS (n = 127) received behavioral and dietary recommendations and were followed-up for 1 year. Serum was available for 108 individuals, levels of adiponectin and leptin were tested at baseline, at 6 months (t1) and after 1 year (t2). Adiponectin/leptin (A/L) ratio was also calculated and tested for predictive ability. RESULT: At the end of the follow-up period, 59 patients did not show enough criteria to define MetS anymore. When considered alone, adiponectin and leptin levels did not show difference over follow-up. Their ratio instead was significantly reduced at t1 and t2 with respect to baseline. Remitters also showed lowers level of leptin and A/L ratio as compared to non-remitters at t1. At this timepoint, A/L ratio independently predicted MetS remission at 1 year [OR 9.082 95%CI (1.394-59.160), p = 0.021]. Bootstrap resampling analysis internally validated our findings. CONCLUSIONS: Preliminary results from our pilot study suggest that MetS remission after counselling associates with changes in adipokine balance. A/L ratio decreases overtime and its value at 6 months can independently predict MetS remission.

The Use of Risk Scores for Thromboprophylaxis in Medically Ill Patients-Rationale and Design of the RICO trial.

Background Venous thromboembolism (VTE) in hospitalized medically ill patients is a significant cause of morbidity and mortality. Guidelines suggest that VTE and bleeding risk assessment models (RAMs) should be integrated into the clinical decision-making process on thromboprophylaxis. However, poor evidence is available comparing the use of a RAM versus clinical judgement in evaluating VTE and bleeding occurrence. Methods Reducing Important Clinical Outcomes in hospitalized medical ill patients (RICO) is a multicenter, cluster-randomized, controlled clinical trial (ClinicalTrials.gov Identifier: NCT04267718). Acutely ill patients hospitalized in Internal Medicine wards are randomized to the use of RAMs-namely the Padua Prediction Score and the International Medical Prevention Registry on Venous Thromboembolism Bleeding Score-or to clinical judgement. The primary study outcome is a composite of symptomatic objectively confirmed VTE and major bleeding at 90-day follow-up. Secondary endpoints include the evaluation of clinical outcomes at hospital discharge and the assessment of VTE prophylaxis prescription during the study period. In order to demonstrate a 50% reduction in the primary outcome in the experimental group and assuming an incidence of the primary outcome of 3.5% in the control group at 90-day; 2,844 patients across 32 centers will be included in the study. Discussion The RICO trial is a randomized study of clinical management assessing the role of RAMs in hospitalized medical ill patients with the aim of reducing VTE and bleeding occurrence. The study has the potential to improve clinical practice since VTE still represents an important cause of morbidity and mortality in this setting.

Pathogenic pathways and therapeutic targets of inflammation in heart diseases: A focus on Interleukin-1.

BACKGROUND: An exuberant and dysregulated inflammatory response contributes to the development and progression of cardiovascular diseases (CVDs). METHODS: This narrative review includes original articles and reviews published over the past 20 years and found through PubMed. The following search terms (or combination of terms) were considered: "acute pericarditis," "recurrent pericarditis," "myocarditis," "cardiac sarcoidosis," "atherosclerosis," "acute myocardial infarction," "inflammation," "NLRP3 inflammasome," "Interleukin-1" and "treatment." RESULTS: Recent evidence supports the role of inflammation across a wide spectrum of CVDs including myocarditis, pericarditis, inflammatory cardiomyopathies (i.e. cardiac sarcoidosis) as well as atherosclerotic CVD and heart failure. Interleukins (ILs) are the signalling mediators of the inflammatory response. The NACHT, leucine-rich repeat and pyrin-domain containing protein 3 (NLRP3) inflammasome play a key role in producing IL-1ß, the prototypical pro-inflammatory cytokine involved in CVDs. Other pro-inflammatory cytokines (e.g. tumour necrosis factor) have been implicated in cardiac sarcoidosis. As a proof of this, IL-1 blockade has been proven efficacious in pericarditis and chronic coronary syndrome. CONCLUSION: Tailored strategies aiming at quenching the inflammatory response have emerged as promising to treat CVDs. In this review article, we summarize recent evidence regarding the role of inflammation across a broad spectrum of CVDs. We also review novel evidence regarding targeted therapeutic strategies.

IL-1 blockade in cardiovascular disease: an appraisal of the evidence across different inflammatory paradigms.

Pre-clinical and clinical studies suggest a role for inflammation in the pathophysiology of cardiovascular (CV) diseases. The NLRP3 (NACHT, leucine-rich repeat, and pyrin domain-containing protein 3) inflammasome is activated during tissue injury and releases interleukin-1ß (IL-1ß). We describe three paradigms in which the NLRP3 inflammasome and IL-1ß contribute to CV diseases. During acute myocardial infarction (AMI), necrotic cell debris, including IL-1α, induce NLRP3 inflammasome activation and further damage the myocardium contributing to heart failure (HF) (acute injury paradigm). In chronic HF, IL-1ß is induced by persistent myocardial overload and injury, neurohumoral activation and systemic comorbidities favoring infiltration and activation of immune cells into the myocardium, microvascular inflammation, and a pro-fibrotic response (chronic inflammation paradigm). In recurrent pericarditis, an autoinflammatory response triggered by cell injury and maintained by the NLRP3 inflammasome/IL-1ß axis is present (autoinflammatory disease paradigm). Anakinra, recombinant IL-1 receptor antagonist, inhibits the acute inflammatory response in patients with ST elevation myocardial infarction (STEMI) and acute HF. Canakinumab, IL-1ß antibody, blunts systemic inflammation and prevents complications of atherosclerosis in stable patients with prior AMI. In chronic HF, anakinra reduces systemic inflammation and improves cardiorespiratory fitness. In recurrent pericarditis, anakinra and rilonacept, a soluble IL-1 receptor chimeric fusion protein blocking IL-1α and IL-1ß, treat and prevent acute flares. In conclusion, the NLRP3 inflammasome and IL-1 contribute to the pathophysiology of CV diseases, and IL-1 blockade is beneficial with different roles in the acute injury, chronic inflammation and autoinflammatory disease paradigms. Further research is needed to guide the optimal use of IL-1 blockers in clinical practice.

A new score to predict Clostridioides difficile infection in medical patients: a sub-analysis of the FADOI-PRACTICE study.

Medical divisions are at high risk of Clostridioides difficile infection (CDI) due to patients' frailty and complexity. This sub-analysis of the FADOI-PRACTICE study included patients presenting with diarrhea either at admission or during hospitalization. CDI diagnosis was confirmed when both enzyme immunoassay and A and B toxin detection were found positive. The aim of this sub-analysis was the identification of a new score to predict CDI in hospitalized, medical patients. Five hundred and seventy-two patients with diarrhea were considered. More than half of patients was female, 40% on antibiotics in the previous 4 weeks and 60% on proton pump inhibitors (PPIs). CDI diagnosis occurred in 103 patients (18%). Patients diagnosed with CDI were older, more frequently of female sex, recently hospitalized and bed-ridden, and treated with antibiotics and PPIs. Through a backward stepwise logistic regression model, age > 65 years, female sex, recent hospitalization, recent antibiotic therapy, active cancer, prolonged hospital stay (> 12 days), hypoalbuminemia (albumin < 3 g/dL), and leukocytosis (white blood cells > 9 × 10^9/L) were found to independently predict CDI occurrence. These variables contributed to building a clinical prognostic score with a good sensitivity and a modest specificity for a value > 3 (79% and 58%, respectively; AUC 0.75, 95% CI 0.71-0.79, p < 0.001), that identified low-risk (score ≤ 3; 42.5%) and high-risk (score > 3; 57.5%) patients. Although some classical risk factors were confirmed to increase CDI occurrence, the changing landscape of CDI epidemiology suggests a reappraisal of common risk factors and the development of novel risk scores based on local epidemiology.

Interleukin-1 blockers for the treatment of recurrent pericarditis: pathophysiology, patient reported outcomes and perspectives.

ABSTRACT: Recurrent pericarditis (RP) is the most troublesome complication of acute pericarditis reflecting an unresolving inflammation of the pericardial sac around the heart and associated with significant morbidity. Recent studies have shown interleukin-1 (IL-1) signaling to be central to the pathophysiology of cases of RP with evidence of activation of systemic inflammation. We herein review the literature and clinical trials discussing the utility of IL-1 blockade for RP. The early experience of IL-1 blockade with anakinra (Kineret) and its favorable safety profile paved the way for the clinical development of rilonacept (Arcalyst) and subsequent approval by the US FDA for RP. In patients with RP who have become colchicine-resistant and glucocorticoid-dependent, IL-1 blockade with rilonacept or anakinra effectively treats recurrences and prevents future flares, and significantly improves quality of life.

NLRP3 inflammasome and interleukin-1 contributions to COVID-19-associated coagulopathy and immunothrombosis.

Immunothrombosis-immune-mediated activation of coagulation-is protective against pathogens, but excessive immunothrombosis can result in pathological thrombosis and multiorgan damage, as in severe coronavirus disease 2019 (COVID-19). The NACHT-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome produces major proinflammatory cytokines of the interleukin (IL)-1 family, IL-1ß and IL-18, and induces pyroptotic cell death. Activation of the NLRP3 inflammasome pathway also promotes immunothrombotic programs including release of neutrophil extracellular traps and tissue factor by leukocytes, and prothrombotic responses by platelets and the vascular endothelium. NLRP3 inflammasome activation occurs in patients with COVID-19 pneumonia. In preclinical models, NLRP3 inflammasome pathway blockade restrains COVID-19-like hyperinflammation and pathology. Anakinra, recombinant human IL-1 receptor antagonist, showed safety and efficacy and is approved for the treatment of hypoxaemic COVID-19 patients with early signs of hyperinflammation. The non-selective NLRP3 inhibitor colchicine reduced hospitalization and death in a subgroup of COVID-19 outpatients but is not approved for the treatment of COVID-19. Additional COVID-19 trials testing NLRP3 inflammasome pathway blockers are inconclusive or ongoing. We herein outline the contribution of immunothrombosis to COVID-19-associated coagulopathy, and review preclinical and clinical evidence suggesting an engagement of the NLRP3 inflammasome pathway in the immunothrombotic pathogenesis of COVID-19. We also summarize current efforts to target the NLRP3 inflammasome pathway in COVID-19, and discuss challenges, unmet gaps, and the therapeutic potential that inflammasome-targeted strategies may provide for inflammation-driven thrombotic disorders including COVID-19.

Early sclerostin assessment in frail elderly patients with sepsis: insights on short- and long-term mortality prediction.

Unmet needs challenge clinical management of sepsis especially concerning patient profiling, enhancing recovery, and long-term sequelae. Here, we preliminarily focused on sclerostin (SOST) as a candidate biomarker to encompass such a broad range of clinical needs related to sepsis. Seventy-three septic patients were enrolled at internal medicine wards between January 2017 and December 2019 in this pilot study. Clinical examination and blood sample analyses were collected at enrollment and after 7 and 14 days. SOST levels were assessed on serum by ELISA. Thirty-day mortality was set as primary outcome. In-hospital and long-term mortality (2.5 years of median follow-up) were assessed as secondary outcomes. Patients were frail, elderly, and heterogeneous in terms of comorbidity burden. SOST levels were associated with age, cardiovascular comorbidities, and time to early death (30 days). When regression models were built, SOST displayed a high predictive value toward 30-day mortality (OR 13.459 with 95% CI 1.226-148.017) with ever better performance than validated scoring scales for critical ill patients. Such a predictive value of SOST was further confirmed for in-hospital (HR 10.089 with 95% CI 1.375-74.013) and long-term mortality (HR 5.061 with 95% CI 1.379-18.570). SOST levels generally decreased over 7 to 14 days after enrollment (p for trend < 0.001). The degree of this variation further predicted long-term mortality (HR for Δ SOST T0-day 14: 1.006 with 95% CI 1.001-1.011). Our results suggest a role for SOST in both short- and long-time prediction of worse outcome in septic elderly admitted to internal medicine wards.

Relapsing pericarditis: Peripheral blood neutrophilia, lymphopenia and high neutrophil-to-lymphocyte ratio herald acute attacks, high-grade inflammation, multiserosal involvement, and predict multiple recurrences.

AIMS: To identify peripheral blood cellular correlates of active pericarditis and to verify whether peripheral blood neutrophils, lymphocytes and the neutrophil to-lymphocyte ratio (NLR) are associated with disease phenotype or prognosis. METHODS: Observational prospective study on a cohort of 63 patients with idiopathic pericarditis followed for 12 months after each pericarditis recurrence. Two distinct analyses were performed: the "index attack" analysis focused on the first pericarditis episode in each patient, while the "all attacks" analysis included all episodes occurring during the study. RESULTS: Absolute and relative neutrophilia and lymphopenia, together with high NLR, were observed during active pericarditis, as compared with disease remission, at both analyses. Neutrophils showed a positive correlation with plasma C-reactive protein levels, while lymphocyte count showed a negative correlation. Relative neutrophil count was higher, and lymphocyte count lower in patients with pleural effusion; a higher NLR and lower absolute lymphocyte count were observed in those with peritoneal involvement. No correlations were found between peripheral blood neutrophil or lymphocyte counts and size of pericardial effusion, or with the presence of myocardial involvement. Peripheral neutrophilia, lymphopenia and NLR during acute attacks predicted the number of recurrences in the following 12 months. CONCLUSIONS: Peripheral blood neutrophilia and lymphopenia are typical of acute idiopathic pericarditis. Acute attacks of pericarditis are associated with neutrophilia and lymphopenia, as compared with disease remission. During acute attacks, neutrophilia and lymphopenia reflect the extent of serosal inflammation and could help to customize therapeutic management after remission has been achieved.

Among biomarkers of neutrophil activity, matrix metalloproteinases 8 independently predicts remission of metabolic syndrome.

BACKGROUND AND AIMS: Inflammation due to the excess of nutrient intake plays an important role in the pathophysiology of metabolic syndrome (MetS). Here, the potential influence of neutrophils and their degranulation markers on MetS improvement upon dietary and behavioral counselling, has been investigated. Specifically, we aimed at investigating their role as potential predictors of metabolic syndrome improvements. METHODS AND RESULTS: patients with MetS (n = 127) received behavioral and dietary recommendations before follow-up at 6 months. Serum levels of matrix metalloproteinases (MMP)8, MMP9, myeloperoxidase (MPO), tissue inhibitor of MMP (TIMP)-1, TIMP-2, TIMP-3 and resistin were tested at baseline. In the whole cohort, baseline levels of proinflammatory MMP8, MMP9 and MPO increased together with the number of MetS criteria. Seventy-three (57%) patients experienced a reduction in MetS-defining criteria at follow-up. With respect to those with no improvement, such individuals showed lower weight and waist circumference at enrolment, less frequent smoking habits, higher levels of triglycerides and lower circulating MMP8. At logistic regression analysis, baseline MMP8 showed negative predictive ability (odds ratio (OR) 0.979 [0.961-0.997]; p = 0.025) against MetS improvement. Such findings hold true even when included in the backward stepwise logistic regression model confirming MMP8 as an independent predictor (OR 0.970 [0.949-0.993]; p = 0.009). Receiver operating characteristic (ROC) curve confirmed the predictive ability of MMP8 combined in a model including baseline MetS criteria and waist circumference. Bootstrap resampling analysis internally validated our findings. CONCLUSION: Improvement of MetS is independently associated with baseline low MMP-8 levels, suggesting a pivotal role for inflammation in metabolic alteration.

Interleukin-1 and the NLRP3 inflammasome in COVID-19: Pathogenetic and therapeutic implications.

A hyperinflammatory response during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection crucially worsens clinical evolution of coronavirus disease 2019 (COVID-19). The interaction between SARS-CoV-2 and angiotensin-converting enzyme 2 (ACE2) triggers the activation of the NACHT, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome. Enhanced inflammasome activity has been associated with increased disease severity and poor prognosis. Evidence suggests that inflammasome activation and interleukin-1ß (IL-1ß) release aggravate pulmonary injury and induce hypercoagulability, favoring progression to respiratory failure and widespread thrombosis eventually leading to multiorgan failure and death. Observational studies with the IL-1 blockers anakinra and canakinumab provided promising results. In the SAVE-MORE trial, early treatment with anakinra significantly shortened hospital stay and improved survival in patients with moderate-to-severe COVID-19. In this review, we summarize current evidence supporting the pathogenetic role of the NLRP3 inflammasome and IL-1ß in COVID-19, and discuss clinical trials testing IL-1 inhibition in COVID-19.

Lipoprotein(a) Modulates Carotid Atherosclerosis in Metabolic Syndrome.

Background and Aim: High lipoprotein(a) [Lp(a)] is a well-established cardiovascular (CV) risk factor, but the effect of mildly elevated Lp(a) on CV health is largely unknown. Our aim was to evaluate if Lp(a) is associated with the severity of carotid atherosclerosis (CA) in the specific subset of metabolic syndrome (MetS). Patients and Methods: Subjects with diagnosed MetS and ultrasound-assessed CA were enrolled. Those patients were categorized according to the severity of CA (moderate vs. severe), and the circulating levels of Lp(a) alongside with clinical, anthropometric, and biochemical data were collected. Results: Sixty-five patients were finally included: twenty-five with moderate and forty with severe CA (all with asymptomatic disease). Intergroup comparison showed Lp(a) as the only significantly different variable [6 (2-12) mg/dl vs. 11.5 (6-29.5) mg/dl; p = 0.018]. Circulating levels of Lp(a) were also confirmed as the only variable independently associated with severity of CA at logistic regression analysis [OR 2.9 (95% CI 1.1-7.8); p = 0.040]. ROC curve analysis for Lp(a) confirmed a serum level of 10 mg/dl as the best cut-off value [AUC 0.675 (95% CI 0.548-0.786)]. Although sensitivity and specificity were suboptimal (69.0 and 70.4%, respectively)-likely due to the small sample size-this result is in line with those previously reported in the literature. Conclusion: Lp(a) is independently associated with severity of CA in the subgroup of MetS patients.

Correlation of SpO2/FiO2 and PaO2/FiO2 in patients with symptomatic COVID-19: An observational, retrospective study.

Some patients affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) experience acute hypoxemic respiratory failure progressing toward atypical acute respiratory distress syndrome (ARDS). The aim of the study is to evaluate whether a correlation between ratio of peripheral saturation of oxygen (SpO2) and fraction of inspired oxygen (S/F) and ratio of arterial partial pressure of oxygen and fraction of inspired oxygen (P/F) exists in COVID-19-related ARDS as already known in classical ARDS. In this multicenter, retrospective, observational study, consecutive, adult (≥ 18 years) patients with symptomatic coronavirus disease 2019 (COVID-19) admitted to different COVID-19 divisions in Italy between March and December 2020 were included. Patients with SpO2 > 97% or missing information were excluded. We included 1,028 patients (median age 72 years, prevalence of males [62.2%]). A positive correlation was found between P/F and S/F (r = 0.938, p < 0.0001). A receiver operating characteristic (ROC) curve analysis showed that S/F accurately recognizes the presence of ARDS (P/F ≤ 300 mmHg) in COVID-19 patients, with a cut-off of ≤ 433% showing good sensitivity and specificity. S/F was also tested against P/F values ≤ 200 and ≤ 100 mmHg (suggestive for moderate and severe ARDS, respectively), the latter showing great accuracy for S/F ≤ 178%. S/F was accurate in predicting ARDS for SpO2 ≥ 92%. In conclusion, our findings support the routine use of S/F as a reliable surrogate of P/F in patients with COVID-19-related ARDS.

Advances in pharmacotherapy for acute and recurrent pericarditis.

INTRODUCTION: Aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine are first-line treatments for acute and recurrent pericarditis. Drugs blocking the NACHT, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome/interleukin-1ß (IL-1ß) axis are beneficial in patients with multiple recurrences. AREAS COVERED: In this review, the role of the NLRP3 inflammasome/IL-1ß axis in the pathophysiology of pericarditis is discussed. Updates about novel therapies targeting IL-1 for recurrent pericarditis (RP) and practical considerations for their use are provided. EXPERT OPINION: IL-1 inhibitors have been increasingly studied for RP in recent years. NLRP3 inflammasome is a key mediator in the pathophysiology of RP. IL-1ß, its main product, can sustain its own production and feeds local and systemic inflammation. Randomized clinical trials testing anakinra (a recombinant form of the IL-1 receptor antagonist blocking IL-1α and IL-1ß) and rilonacept (an IL-1α and IL-1ß trap) have shown that IL-1 blockade reduces recurrences. These trials also helped in phenotyping patients with RP. Patients with multiple recurrences and signs of pericardial and/or systemic inflammation might benefit from IL-1 blockers in order to interrupt cyclic flares of auto-inflammation. Given this evidence, guidelines should consider incorporating IL-1 blockers.