Prevalence, Characteristics, and Outcomes of COVID-19-Associated Acute Myocarditis.

BACKGROUND: Acute myocarditis (AM) is thought to be a rare cardiovascular complication of COVID-19, although minimal data are available beyond case reports. We aim to report the prevalence, baseline characteristics, in-hospital management, and outcomes for patients with COVID-19-associated AM on the basis of a retrospective cohort from 23 hospitals in the United States and Europe. METHODS: A total of 112 patients with suspected AM from 56 963 hospitalized patients with COVID-19 were evaluated between February 1, 2020, and April 30, 2021. Inclusion criteria were hospitalization for COVID-19 and a diagnosis of AM on the basis of endomyocardial biopsy or increased troponin level plus typical signs of AM on cardiac magnetic resonance imaging. We identified 97 patients with possible AM, and among them, 54 patients with definite/probable AM supported by endomyocardial biopsy in 17 (31.5%) patients or magnetic resonance imaging in 50 (92.6%). We analyzed patient characteristics, treatments, and outcomes among all COVID-19-associated AM. RESULTS: AM prevalence among hospitalized patients with COVID-19 was 2.4 per 1000 hospitalizations considering definite/probable and 4.1 per 1000 considering also possible AM. The median age of definite/probable cases was 38 years, and 38.9% were female. On admission, chest pain and dyspnea were the most frequent symptoms (55.5% and 53.7%, respectively). Thirty-one cases (57.4%) occurred in the absence of COVID-19-associated pneumonia. Twenty-one (38.9%) had a fulminant presentation requiring inotropic support or temporary mechanical circulatory support. The composite of in-hospital mortality or temporary mechanical circulatory support occurred in 20.4%. At 120 days, estimated mortality was 6.6%, 15.1% in patients with associated pneumonia versus 0% in patients without pneumonia (P=0.044). During hospitalization, left ventricular ejection fraction, assessed by echocardiography, improved from a median of 40% on admission to 55% at discharge (n=47; P<0.0001) similarly in patients with or without pneumonia. Corticosteroids were frequently administered (55.5%). CONCLUSIONS: AM occurrence is estimated between 2.4 and 4.1 out of 1000 patients hospitalized for COVID-19. The majority of AM occurs in the absence of pneumonia and is often complicated by hemodynamic instability. AM is a rare complication in patients hospitalized for COVID-19, with an outcome that differs on the basis of the presence of concomitant pneumonia.

Dynamics of disease characteristics and clinical management of critically ill COVID-19 patients over the time course of the pandemic: an analysis of the prospective, international, multicentre RISC-19-ICU registry.

BACKGROUND: It remains elusive how the characteristics, the course of disease, the clinical management and the outcomes of critically ill COVID-19 patients admitted to intensive care units (ICU) worldwide have changed over the course of the pandemic. METHODS: Prospective, observational registry constituted by 90 ICUs across 22 countries worldwide including patients with a laboratory-confirmed, critical presentation of COVID-19 requiring advanced organ support. Hierarchical, generalized linear mixed-effect models accounting for hospital and country variability were employed to analyse the continuous evolution of the studied variables over the pandemic. RESULTS: Four thousand forty-one patients were included from March 2020 to September 2021. Over this period, the age of the admitted patients (62 [95% CI 60-63] years vs 64 [62-66] years, p < 0.001) and the severity of organ dysfunction at ICU admission decreased (Sequential Organ Failure Assessment 8.2 [7.6-9.0] vs 5.8 [5.3-6.4], p < 0.001) and increased, while more female patients (26 [23-29]% vs 41 [35-48]%, p < 0.001) were admitted. The time span between symptom onset and hospitalization as well as ICU admission became longer later in the pandemic (6.7 [6.2-7.2| days vs 9.7 [8.9-10.5] days, p < 0.001). The PaO2/FiO2 at admission was lower (132 [123-141] mmHg vs 101 [91-113] mmHg, p < 0.001) but showed faster improvements over the initial 5 days of ICU stay in late 2021 compared to early 2020 (34 [20-48] mmHg vs 70 [41-100] mmHg, p = 0.05). The number of patients treated with steroids and tocilizumab increased, while the use of therapeutic anticoagulation presented an inverse U-shaped behaviour over the course of the pandemic. The proportion of patients treated with high-flow oxygen (5 [4-7]% vs 20 [14-29], p < 0.001) and non-invasive mechanical ventilation (14 [11-18]% vs 24 [17-33]%, p < 0.001) throughout the pandemic increased concomitant to a decrease in invasive mechanical ventilation (82 [76-86]% vs 74 [64-82]%, p < 0.001). The ICU mortality (23 [19-26]% vs 17 [12-25]%, p < 0.001) and length of stay (14 [13-16] days vs 11 [10-13] days, p < 0.001) decreased over 19 months of the pandemic. CONCLUSION: Characteristics and disease course of critically ill COVID-19 patients have continuously evolved, concomitant to the clinical management, throughout the pandemic leading to a younger, less severely ill ICU population with distinctly different clinical, pulmonary and inflammatory presentations than at the onset of the pandemic.

Implications of early respiratory support strategies on disease progression in critical COVID-19: a matched subanalysis of the prospective RISC-19-ICU cohort.

BACKGROUND: Uncertainty about the optimal respiratory support strategies in critically ill COVID-19 patients is widespread. While the risks and benefits of noninvasive techniques versus early invasive mechanical ventilation (IMV) are intensely debated, actual evidence is lacking. We sought to assess the risks and benefits of different respiratory support strategies, employed in intensive care units during the first months of the COVID-19 pandemic on intubation and intensive care unit (ICU) mortality rates. METHODS: Subanalysis of a prospective, multinational registry of critically ill COVID-19 patients. Patients were subclassified into standard oxygen therapy ≥10 L/min (SOT), high-flow oxygen therapy (HFNC), noninvasive positive-pressure ventilation (NIV), and early IMV, according to the respiratory support strategy employed at the day of admission to ICU. Propensity score matching was performed to ensure comparability between groups. RESULTS: Initially, 1421 patients were assessed for possible study inclusion. Of these, 351 patients (85 SOT, 87 HFNC, 87 NIV, and 92 IMV) remained eligible for full analysis after propensity score matching. 55% of patients initially receiving noninvasive respiratory support required IMV. The intubation rate was lower in patients initially ventilated with HFNC and NIV compared to those who received SOT (SOT: 64%, HFNC: 52%, NIV: 49%, p = 0.025). Compared to the other respiratory support strategies, NIV was associated with a higher overall ICU mortality (SOT: 18%, HFNC: 20%, NIV: 37%, IMV: 25%, p = 0.016). CONCLUSION: In this cohort of critically ill patients with COVID-19, a trial of HFNC appeared to be the most balanced initial respiratory support strategy, given the reduced intubation rate and comparable ICU mortality rate. Nonetheless, considering the uncertainty and stress associated with the COVID-19 pandemic, SOT and early IMV represented safe initial respiratory support strategies. The presented findings, in agreement with classic ARDS literature, suggest that NIV should be avoided whenever possible due to the elevated ICU mortality risk.

Intrarenal Venous Doppler as a novel marker for optimal decongestion, patient management, and prognosis in Acute Decompensated Heart Failure.

AIMS: An increase in right atrial pressure is a common feature of acute decompensated heart failure (ADHF). Such increased pressure leads to persistent kidney congestion. A marker to guide optimal diuretic therapy is missing. We aim to correlate intrarenal Doppler (IRD) ultrasound in ADHF patients with clinical outcomes to assess whether renal haemodynamic parameter changes are useful for monitoring kidney congestion. METHODS AND RESULTS: Between December 2018 and January 2020, ADHF patients requiring intravenous diuretic therapy for at least 48 h were considered for study selection. An IRD blinded examination was performed on Days 1, 3, and 5, and clinical and laboratory parameters were recorded. Venous Doppler profiles (VDP) were classified as continuous (C), pulsatile (P), biphasic (B), or monophasic (M) according to the congestion degree; B and M profiles were considered deranged. A VDP improvement (VDPimp) was defined as a change of ≥1 pattern degree or maintenance of C or P patterns. An arterial resistive index (RI) > 0.8 was considered elevated. Outcomes of death and rehospitalization were gathered at 60 days. Data were assessed by regression and Kaplan-Meier analyses. All 177 ADHF patients admitted were screened, and 72 were enrolled [27 females-median age 81 (76-87) years-median ejection fraction 40% (30-52)]. The VDP derangement decreased from 79.2% on Day 1 to 51.4% on Day 5 (P < 0.05). The RI elevation decreased from 60.6% on Day 1 to 43.1% on Day 5 (P < 0.05). At Day 5, VDPimp was registered in over half of the patients (59.7%). At Day 5, signs of congestion (dyspnoea/oedema/rales), fluid accumulation (pleural/peritoneal fluid), haematocrit, and brain natriuretic peptide improved (P > 0.05). After 60 days, 12 (16.7%) patients were readmitted and 9 (12.5%) died. The VDPimp was identified as the unique independent factor associated with readmission [Hazard Ratio (HR) 0.22, 95% (confidence interval) CI 0.05-0.94, P = 0.04] and death (HR 0.07, 95% CI 0.01-0.68, P = 0.02), with significantly better outcomes identified in VDPimp patients (log-rank test, P < 0.05). CONCLUSION: Decongestion may be associated with improvements in many clinical and instrumental parameters, but only VDPimp was associated with better clinical outcomes. The VDPimp should be incorporated in ad hoc ADHF clinical trials to better define its role in everyday practice.

Dynamic angiopoietin-2 assessment predicts survival and chronic course in hospitalized patients with COVID-19.

This study examined the association between dynamic angiopoietin-2 assessment and COVID-19 short- and long-term clinical course. We included consecutive hospitalized patients from 1 February to 31 May 2020 with laboratory-confirmed COVID-19 from 2 Italian tertiary referral centers (derivation cohort, n = 187 patients; validation cohort, n = 62 patients). Serum biomarker levels were measured by sandwich enzyme-linked immunosorbent assay. Lung tissue from 9 patients was stained for angiopoietin-2, Tie2, CD68, and CD34. Cox model was used to identify risk factors for mortality and nonresolving pulmonary condition. Area under the receiver operating characteristic curve (AUROC) was used to assess the accuracy of 3- and 10-day angiopoietin-2 for in-hospital mortality and nonresolving pulmonary condition, respectively. Three-day angiopoietin-2 increase of at least twofold from baseline was significantly associated with in-hospital mortality by multivariate analysis (hazard ratio [HR], 6.69; 95% confidence interval [CI], 1.85-24.19; P = .004) with AUROC = 0.845 (95% CI, 0.725-0.940). Ten-day angiopoietin-2 of at least twofold from baseline was instead significantly associated with nonresolving pulmonary condition by multivariate analysis (HR, 5.33; 95% CI, 1.34-11.77; P ≤ .0001) with AUROC = 0.969 (95% CI, 0.919-1.000). Patients with persistent elevation of 10-day angiopoietin-2 levels showed severe reticular interstitial thickening and fibrous changes on follow-up computed tomography scans. Angiopoietin-2 and Tie2 were diffusely colocalized in small-vessel endothelia and alveolar new vessels and macrophages. Angiopoietin-2 course is strongly associated with COVID-19 in-hospital mortality and nonresolving pulmonary condition. Angiopoietin-2 may be an early and useful predictor of COVID-19 clinical course, and it could be a relevant part of disease pathogenesis. Angiopoietin-2 blockade may be a COVID-19 treatment option.

Right ventricular presystolic peak velocity represents right ventricular function in stable patients.

BACKGROUND: Right ventricular (RV) function is difficult to be measured but plays a role in morbility and mortality of patients with cardiopulmonary diseases, so many echocardiographic parameters have been developed from M-mode, B-mode and Doppler tissue imaging (DTI) evaluation. Right ventricular presystolic peak velocity (RVPrP) measured with DTI of the tricuspidal annulus and its changes in RV dysfunction have never been assessed in a patient's cohort of stable patients with cardiovascular risk factors. RVPrP velocity could have a role in RV function evaluation; this study addresses such issue. METHODS: Four hundred thirty-six consecutive patients were submitted to a complete echocardiographic examination with the contemporary evaluation of the following RV function indexes: Tricuspid Annulus Plane Systolic Excurtion (TAPSE), RV Systolic Peak (RVSyP) and RVPrP. Pulmonary artery systolic pressure (PASP), left ventricular and RV diastolic function were also evaluated. RESULTS: According to TAPSE and RVSyP taken alone or in combination, 113 patients had RV dysfunction, while 323 patients had normal RV function. RVPrP was reduced in patient's group with RV dysfunction with respect to patient's group with preserved RV function (16.48±7.3 cm/s vs. 23.98±8.4 cm/s, respectively, P<0.001). RVPrP was related with RVSyP (P<0.001) and with TAPSE (P=0.002). TAPSE and RVSyP revealed a poor concordance to define RV dysfunction. PASP was higher in patient's group with reduced RV function (P=0.033). CONCLUSIONS: The study showed RVPrP able to detect stable patients with RV dysfunction.

Effects of Cholecalciferol Supplementation in Patients with stable heart failure and LOw vITamin D levels (ECSPLOIT-D): a double-blind, randomized, placebo-controlled pilot study.

BACKGROUND: The aim of this study was to investigate the effects of vitamin D (VD) on the interaction among functional, echocardiographic and hormonal parameters in patients with heart failure (HF) and VD deficiency. METHODS: In a randomized, double blind trial, 35 patients with HF and VD<20 ng/mL, received either 300,000 U of oral cholecalciferol followed by 50,000 U/month for 6 months, or placebo treatment. RESULTS: Changes in the 6 Minute Walking Test (6MWT) assessed at 3 and 6 months in treatment group was the primary end point. Secondary endpoints were echocardiographic and hormonal changes. The same targets were compared in treated and placebo groups as secondary endpoints. In the treatment group the 6MWT improved at 3 (from 210±104 mt to 225±94 mt; P=0.033) but not at 6 months (from 210±104 mt to 217±94 mt; P=0.288) while PTH dropped at 3 (from 76.8±50.5 to 50.2±20.3 pg/mL; P=0.025), but not at 6 months. 6MWT improvement was negatively related to baseline VD levels. Variation in 6MWT did not significantly differ among groups at 3 (13.6±23.3 vs. 3.6±17.3; P 0.175) and 6 months (12.1±31.4 vs. 0.2±23.2; P 0.225). Left atrial size increased in the placebo group (from 50.8±20.7 to 61.7±36.0 mL/m2; P=0.010). Other hormonal parameters remained unchanged. CONCLUSIONS: In summary, the treatment of VD deficiency in patients with HF improved 6MWT after 3 months along with a decrease in PTH levels. However when compared with the placebo arm, treatment of VD deficiency did not influence the final outcomes.

Safety of dalteparin for the prophylaxis of venous thromboembolism in elderly medical patients with renal insufficiency: a pilot study.

The aim of this prospective cohort study was to determine the incidence of dalteparin bioaccumulation (measured using anti-Xa levels), and bleeding during thromboprophylaxis in elderly patients with renal failure who were admitted to hospital with an acute medical illness. Patients who met the criteria for being at high thromboembolic risk received dalteparin 5,000 IU subcutaneously once daily while the other patients (low risk) received 2,500 IU daily. Thromboprophylaxis was administered for at least 6 days. Anti-Xa activity was determined before the first dalteparin dose and again on day 6, 4 hours after the administration of the dalteparin dose. Bleeding was assessed daily. Compression ultrasonography was performed to identify any deep vein thromboses. There was no evidence of bioaccumulation on day 6 of therapy, irrespective of renal function. No episodes of major bleeding or venous thromboembolism occurred. Larger, randomized studies are warranted to confirm the safety of dalteparin in this patient population.

Does coronary Atherosclerosis Deserve to be Diagnosed earlY in Diabetic patients? The DADDY-D trial. Screening diabetic patients for unknown coronary disease.

OBJECTIVES: To evaluate if screening and treatment of asymptomatic coronary artery disease (CAD) are effective in preventing first cardiac event in diabetics. METHODS: Diabetic patients without known CAD were randomly assigned to undergo a screening for silent myocardial ischemia followed by revascularization or to continue follow-up. The reduction of cardiac death (CD) or nonfatal myocardial infarction (MI) represented the primary aim; secondary aim was the prevention of heart failure (HF). RESULTS: From September 2007 to May 2012, 520 patients (62 years; 104 female) were enrolled. Silent CAD was found in 20 of 262 patients (7.6%), revascularization was performed in 12 (4.6%). After a mean follow-up of 3.6 years 12 events (4.6%) occurred in the study group and 14 (5.4%) in the follow-up (HR=0.849, 95% CI: 0.393-1.827, P=0.678). The occurrence of first HF episode did not differ between groups: 2 (0.8%) in screened and 7 (2.7%) in follow-up (HR=0.273, 95% CI: 0.057-1.314, P=0.083). Subgroup analysis revealed a significantly lower HF episodes among patients with intermediate cardiovascular risk (Log rank P=0.022). Additionally, when CD and MI were analysed within subgroups, a significant lower number of CDs was observed among older than 60 years (P=0.044). CONCLUSION: Screening and revascularization of silent CAD in diabetics, failed to demonstrate a significant reduction in cardiac events and HF episodes. However, our data indicate that further research is warranted in patients older than 60 years and those with an intermediate cardiovascular risk. CLINICALTRIALS.GOV: NCT00547872.

[Locoregional treatment of hepatocellular carcinoma: comparison between percutaneous alcohol administration and intraarterial chemoembolization]. / Trattamento locoregionale del carcinoma epatocellulare: confronto tra alcolizzazione percutanea e chemioembolizzazione intrarteriosa.

Between 1991 and 1998, 45 cirrhotic patients with hepatocellular carcinoma (1 or 2 lesions smaller than 5 cm) were treated either with percutaneous ethanol injection (26 patients) or with trans arterial chemoembolization (19 patients) in our Department. Percutaneous ethanol injection was performed on 37 nodules: mean diameter of 3.1 +/- 0.8 cm. Transarterial chemoembolization was performed on 27 nodules: mean diameter of 2.8 +/- 0.7 cm. Therapeutic success at first treatment was obtained in 81.5% of percutaneous ethanol injection treated lesions and in 60.0% of trans arterial chemoembolization treated lesions. Local recurrence after first treatment occurred in 7 of 22 percutaneous ethanol injection patients (31.8%) and 8 of 15 transarterial chemoembolization patients (53.3%). Distant hepatic recurrence after first treatment occurred in 16 of 26 (61.5%) alcolization treated patients and in 14 of 25 (56.0%) chemoembolization treated. Multivariate analysis selected therapeutic success and modality of treatment as the best predictor of better survival probability in all treated patients. Survival probability at 12/24/36/48 months was 96.1/80.8/61.6/42.3% in percutaneous ethanol injection group and 89.5/68.4/36.8/15.8% in transarterial chemoembolization group (p < 0.05 Log rank). Few data are available comparing the efficacy of percutaneous ethanol injection and transarterial chemoembolization in patients with hepatocellular carcinoma. Our data confirm that percutaneous ethanol injection is better than trans arterial chemoembolization in the treatment of patients with one or two lesions of hepatocellular carcinoma.

Screening asymptomatic patients with diabetes for unknown coronary artery disease: does it reduce risk? An open-label randomized trial comparing a strategy based on exercise testing aimed at revascularization with management based on pharmacological/behavioural treatment of traditional risk factors. DADDY-D Trial (Does coronary Atherosclerosis Deserve to be Diagnosed and treated early in Diabetics?).

BACKGROUND: Coronary artery disease is the leading cause of morbidity and mortality in patients with type 2 diabetes. Screening for asymptomatic coronary artery disease with treatment by means of revascularization seems to be an appealing option for prevention. The utility of such a strategy has never been challenged in a randomized trial. METHODS/DESIGN: In the present study a cohort of diabetic patients without any symptoms and without known coronary artery disease will be screened at two diabetes outpatients services. Those with intermediate or high risk (equal or greater than 10% according to the Italian risk chart) will be asked to participate and enrolled. They will be seen and followed in order to provide the best adherence to medical therapy. Half of the patients will be randomized to undergo an exercise tolerance testing while the other group will continue to be regularly seen at diabetes outpatients services. Best medical/behavioral therapy will be offered to both groups. Those patients with a positive exercise tolerance testing will be studied by coronary angiography and treated according to the severity of coronary lesions by percutaneous stenting or surgery.The objective of the study is to evaluate the efficacy of the screening strategy aimed at revascularization. A cost-effectiveness analysis will be performed at the end of the follow up. DISCUSSION: The study will provide useful information about prevention and treatment of diabetic patients at high risk of coronary events. It will be made clearer if detection of silent coronary artery disease has to be recommended and followed by treatment. Given the simplicity of the study protocol, it will be easily transferable to the real world. TRIAL REGISTRATION: (ClinicalTrials.gov): NCT00547872.

Prevention and treatment of venous thromboembolism in the elderly patient.

Venous thromboembolism (VTE) is a common complication among hospitalized patients. Pharmacological thromboprophylaxis has emerged as the cornerstone for VTE prevention. As trials on thromboprophylaxis in medical patients have proven the efficacy of both low-molecular-weight heparins (LMWHs) and unfractionated heparin (UFH), all acutely medical ill patients should be considered for pharmacological thromboprophylaxis. Unlike in the surgical setting where the risk of associated VTE attributable to surgery is well recognized, and where widespread use of pharmacological thromboprophylaxis and early mobilization has resulted in significant reductions in the risk of VTE, appropriate VTE prophylaxis is under-used in medical patients. Many reasons for this under-use have been identified, including low perceived risk of VTE in medical patients, absence of optimal tools for risk assessment, heterogeneity of patients and their diseases, and fear of bleeding complications. A consistent group among hospitalized medical patients is composed of elderly patients with impaired renal function, a condition potentially associated with bleeding. How these patients should be managed is discussed in this review. Particular attention is devoted to LMWHs and fondaparinux and to measures to improve the safety and the efficacy of their use.