The role of prone positioning in patients with SARS-CoV-2-related respiratory failure in non-intensive care unit.

BACKGROUND: Prone positioning (PP) is an established and commonly used lung recruitment method for intubated patients with severe acute respiratory distress syndrome, with potential benefits in clinical outcome. The role of PP outside the intensive care unit (ICU) setting is debated. OBJECTIVES: We aimed at assessing the role of PP in death and ICU admission in non-intubated patients with acute respiratory failure related to COronaVIrus Disease-19 (COVID-19) pneumonia. DESIGN: This is a retrospective analysis of a collaborative multicenter database obtained by merging local non-interventional cohorts. METHODS: Consecutive adult patients with COVID-19-related respiratory failure were included in a collaborative cohort and classified based on the severity of respiratory failure according to the partial arterial oxygen pressure to fraction of inspired oxygen ratio (PaO2/FiO2) and on clinical severity by the quick Sequential Organ Failure Assessment (qSOFA) score. The primary study outcome was the composite of in-hospital death or ICU admission within 30 days from hospitalization. RESULTS: PP was used in 114 of 536 study patients (21.8%), more commonly in patients with lower PaO2/FiO2 or receiving non-invasive ventilation and less commonly in patients with known comorbidities. A primary study outcome event occurred in 163 patients (30.4%) and in-hospital death in 129 (24.1%). PP was not associated with death or ICU admission (HR 1.17, 95% CI 0.78-1.74) and not with death (HR 1.01, 95% CI 0.61-1.67) at multivariable analysis; PP was an independent predictor of ICU admission (HR 2.64, 95% CI 1.53-4.40). The lack of association between PP and death or ICU admission was confirmed at propensity score-matching analysis. CONCLUSION: PP is used in a non-negligible proportion of non-intubated patients with COVID-19-related severe respiratory failure and is not associated with death but with ICU admission. The role of PP in this setting merits further evaluation in randomized studies.

Efficacy and safety of two heparin regimens for prevention of venous thromboembolism in hospitalized patients with COVID-19: a meta-analysis.

Venous thromboembolism (VTE) is common in patients with coronavirus disease-2019 (COVID-19). The optimal heparin regimen remains unknown and should balance thromboembolic and bleeding risks. The aim of this study was to evaluate the efficacy and safety of standard or higher heparin regimens for the prevention of VTE in patients hospitalized due to COVID-19. We performed a systematic literature search; studies reporting on hospitalized patients with COVID-19 who received standard heparin prophylaxis vs. high (intermediate or therapeutic) heparin regimens were included if outcome events were reported by treatment group and more than 10 patients were included. Primary study outcome was in-hospital VTE. Secondary study outcomes were major bleeding (MB), all-cause death, fatal bleeding and fatal pulmonary embolism. Overall, 33 studies (11,387 patients) were included. Venous thromboembolic events occurred in 5.2% and in 8.2% of patients who received heparin prophylaxis with at high-dose or standard-dose, respectively (RR 0.71, 95% CI 0.55-0.90, I2 48.8%). MB was significantly higher in patients who received high- compared to the standard-dose (4.2% vs 2.2%, RR 1.94, 95% CI 1.47-2.56, I2 18.1%). Sub-analyses showed a slight benefit associated with high-dose heparin in patients admitted to non-intensive care unit (ICU) but not in those to ICU. No significant differences were observed for mortality outcomes. Heparin prophylaxis at high-dose reduces the risk of VTE, but increased the risk of MB compared to the standard-dose. No clinical benefit for heparin high-dose was observed for ICU setting, but its role in the non-ICU deserves further evaluation. PROSPERO registration number: CRD42021252550.

A platelet lipidomics signature in patients with COVID-19.

Ischemic cardiovascular and venous thromboembolic events are a frequent cause of death in severe COVID-19 patients. Platelet activation plays a key role in these complications, however platelet lipidomics have not been studied yet. The aim of our pilot investigation was to perform a preliminary study of platelet lipidomics in COVID-19 patients compared to healthy subjects. Lipid extraction and identification of ultrapurified platelets from eight hospitalized COVID-19 patients and eight age- and sex-matched healthy controls showed a lipidomic pattern almost completely separating COVID-19 patients from healthy controls. In particular, a significant decrease of ether phospholipids and increased levels of ganglioside GM3 were observed in platelets from COVID-19 patients. In conclusion, our study shows for the first time that platelets from COVID-19 patients display a different lipidomics signature distinguishing them from healthy controls, and suggests that altered platelet lipid metabolism may play a role in viral spreading and in the thrombotic complications of COVID-19.

What is the context? Besides respiratory system involvement, venous thromboembolism is a severe complication of COVID-19, largely due to the strong derangement of hemostasis, with platelets playing a central role.Great attention has recently been devoted to lipid alterations in COVID-19, both because viruses by reprogramming cellular lipid metabolism remodel lipid membranes to fuel their replication, and because the COVID-19-associated cytokine storm may affect cell/plasma lipidomic signatures.Lipidomics studies in COVID-19 patients have been performed mainly in plasma and serum.To the best of our knowledge, platelet lipidomics have not been examined despite the central role played by platelets in COVID-19 complications.What is the aim of the study?The aim of our pilot study was to preliminarily explore whether platelet lipidomics is altered in COVID-19 patients compared to age- and sex-matched healthy subjects, analyzing lipidomic profile of ultrapurified platelets.What are the results of our study? Our study shows for the first time that platelets from COVID-19 patients display a different lipidomics signature distinguishing them from healthy controls.Ether phospholipids and, intriguingly, two phytoceramides were lower, while ganglioside GM3 was higher in COVID-19 samples compared to healthy controls.What is the impact?Despite the small number of COVID-19 patients enrolled, recognized as a limitation of our study, we show, for the first time, that platelets from COVID-19 patients present a different lipidomics signature and suggest that altered platelet lipid metabolism may play a significant role in viral spreading and in the thrombotic complications of COVID-19.

Illustrated State-of-the-Art Capsules of the ISTH 2020 Congress.

The 2020 Congress of the International Society of Thrombosis and Haemostasis (ISTH) was held virtually July 12-15, 2019, due to the coronavirus disease 2019 pandemic. The congress convenes annually to discuss clinical and basic topics in hemostasis and thrombosis. Each year, the program includes State of Art (SOA) lectures given by prominent scientists. Presenters are asked to create Illustrated Capsules of their talks, which are concise illustrations with minimal explanatory text. Capsules cover major themes of the presentation, and these undergo formal peer review for inclusion in this article. Owing to the shift to a virtual congress this year, organizers reduced the program size. There were 39 SOA lectures virtually presented, and 29 capsules (9 from talks omitted from the virtual congress) were both submitted and successful in peer review, and are included in this article. Topics include the roles of the hemostatic system in inflammation, infection, immunity, and cancer, platelet function and signaling, platelet function disorders, megakaryocyte biology, hemophilia including gene therapy, phenotype tests in hemostasis, von Willebrand factor, anticoagulant factor V, computational driven discovery, endothelium, clinical and basic aspects of thrombotic microangiopathies, fibrinolysis and thrombolysis, antithrombotics in pediatrics, direct oral anticoagulant management, and thrombosis and hemostasis in pregnancy. Capsule authors invite virtual congress attendees to refer to these capsules during the live presentations and participate on Twitter in discussion. Research and Practice in Haemostasis and Thrombosis will release 2 tweets from @RPTHJournal during each presentation, using #IllustratedReview, #CoagCapsule and #ISTH2020. Readers are also welcome to utilize capsules for teaching and ongoing education.

COVID-19 infection-associated platelet and neutrophil activation is blunted by previous anti-SARS-CoV-2 vaccination.

The effectiveness of vaccination against SARS-CoV-2 in preventing COVID-19 or in reducing severe illness in subjects hospitalized for COVID-19 despite vaccination has been unequivocally shown. However, no studies so far have assessed if subjects who get COVID-19 despite vaccination are protected from SARS-CoV-2-induced platelet, neutrophil and endothelial activation, biomarkers associated with thrombosis and worse outcome. In this pilot study, we show that previous vaccination blunts COVID-19-associated platelet activation, assessed by circulating platelet-derived microvesicles and soluble P-selectin, and neutrophil activation, assessed by circulating neutrophil extracellular trap (NET) biomarkers and matrix metalloproteinase-9, and reduces COVID-19-associated thrombotic events, hospitalization in intensive-care units and death.

Treatment with COLchicine in hospitalized patients affected by COVID-19: The COLVID-19 trial.

OBJECTIVE: To evaluate whether the addition of colchicine to standard of care (SOC) results in better outcomes in hospitalized patients with COVID-19. DESIGN: This interventional, multicenter, randomized, phase 2 study, evaluated colchicine 1.5 mg/day added to SOC in hospitalized COVID-19 patients (COLVID-19 trial) and 227 patients were recruited. The primary outcome was the rate of critical disease in 30 days defined as need of mechanical ventilation, intensive care unit (ICU), or death. RESULTS: 152 non-anti-SARS-CoV-2-vaccinated patients (colchicine vs controls: 77vs75, mean age 69.1±13.1 vs 67.9±15 years, 39% vs 33.3% females, respectively) were analyzed. There was no difference in co-primary end-points between patients treated with colchicine compared to controls (mechanical ventilation 5.2% vs 4%, ICU 1.3% vs 5.3%, death 9.1% vs 6.7%, overall 11 (14.3%) vs 10 (13.3%) patients, P=ns, respectively). Mean time to discharge was similar (colchicine vs controls 14.1±10.4 vs 14.7±8.1 days). Older age (>60 years, P=0.025), P/F<275 mmHg (P=0.005), AST>40 U/L (P<0.001), pre-existent heart (P=0.02), lung (P=0.003), upper-gastrointestinal (P=0.014), lower-gastrointestinal diseases (P=0.009) and cancer (P=0.008) were predictive of achieving the primary outcome. Diarrhoea (9.1% vs 0%, p=0.0031) and increased levels of AST at 6 days (76.9±91.8 vs 33.5±20.7 U/l, P=0.016) were more frequent in the colchicine group. CONCLUSION: Colchicine did not reduce the rate and the time to the critical stage. Colchicine was relatively safe although adverse hepatic effects require caution. We confirm that older (>60 years) patients with comorbidities are characterized by worse outcome.

Clinical prediction models in hospitalized patients with COVID-19: A multicenter cohort study.

BACKGROUND: Clinical spectrum of novel coronavirus disease (COVID-19) ranges from asymptomatic infection to severe respiratory failure that may result in death. We aimed at validating and potentially improve existing clinical models to predict prognosis in hospitalized patients with acute COVID-19. METHODS: Consecutive patients with acute confirmed COVID-19 pneumonia hospitalized at 5 Italian non-intensive care unit centers during the 2020 outbreak were included in the study. Twelve validated prognostic scores for pneumonia and/or sepsis and specific COVID-19 scores were calculated for each study patient and their accuracy was compared in predicting in-hospital death at 30 days and the composite of death and orotracheal intubation. RESULTS: During hospital stay, 302 of 1044 included patients presented critical illness (28.9%), and 226 died (21.6%). Nine out of 34 items included in different prognostic scores were independent predictors of all-cause-death. The discrimination was acceptable for the majority of scores (APACHE II, COVID-GRAM, REMS, CURB-65, NEWS II, ROX-index, 4C, SOFA) to predict in-hospital death at 30 days and poor for the rest. A high negative predictive value was observed for REMS (100.0%) and 4C (98.7%) scores; the positive predictive value was poor overall, ROX-index having the best value (75.0%). CONCLUSIONS: Despite the growing interest in prognostic models, their performance in patients with COVID-19 is modest. The 4C, REMS and ROX-index may have a role to select high and low risk patients at admission. However, simple predictors as age and PaO2/FiO2 ratio can also be useful as standalone predictors to inform decision making.

Early Variation of Respiratory Indexes to Predict Death or ICU Admission in Severe Acute Respiratory Syndrome Coronavirus-2-Related Respiratory Failure.

BACKGROUND: In severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-related respiratory failure, the prognostic value of clinically based or blood-gas-based respiratory indexes is unclear. OBJECTIVES: We aimed to assess the prognostic value of Respiratory Index (RI, oxygen saturation [SpO2]/respiratory rate [RR]), RR-oxygenation index (ROX, SpO2/fraction of inspired oxygen [FiO2]/RR), partial pressure of oxygen (PaO2)/FiO2 ratio (P/F), or standard PaO2/FiO2 ratio (STP/F) at admission and of their variation during hospitalization in SARS-CoV-2-related respiratory failure. METHODS: In 100 consecutive patients hospitalized due to SARS-CoV-2-related respiratory failure, we assessed the association of RI, ROX, P/F and STP/F, and death; secondary outcome was the composite of 7-day death or intensive care unit (ICU) admission. RESULTS: ROX <3.85 at admission (hazard ratio [HR] 2.95, 95% confidence interval [CI] 1.29-6.77) and decreasing RI or P/F during hospitalization (RI: HR 1.05, 95% CI: 1.00-1.09; P/F: HR 1.01, 95% CI: 1.00-1.02) were predictors of in-hospital death. RI ≤3.8, ROX <3.85, and P/F <100 at admission were predictors for death or ICU admission (RI: HR 3.77, 95% CI: 1.30-10.98; ROX: HR 4.56, 95% CI: 1.90-10.96; P/F: HR 7.37, 95% CI: 1.59-34.2). The decrease of RI (HR 1.14, 95% CI: 1.03-1.25), ROX (HR 1.45, 95% CI: 1.11-1.88), P/F (HR 1.08, 95% CI: 1.01-1.15), or STP/F (HR 1.05, 95% CI: 1.01-1.08) during hospitalization was associated with 7-day death or ICU admission. CONCLUSIONS: In patients with SARS-CoV-2-related respiratory failure, easy-to-calculate clinically based respiratory indexes at admission and their variation during hospital stay can be used to assess and monitor the risk for death or ICU admission.

Effect of awake prone position on diaphragmatic thickening fraction in patients assisted by noninvasive ventilation for hypoxemic acute respiratory failure related to novel coronavirus disease.

BACKGROUND: Awake prone position is an emerging rescue therapy applied in patients undergoing noninvasive ventilation (NIV) for acute hypoxemic respiratory failure (ARF) related to novel coronavirus disease (COVID-19). Although applied to stabilize respiratory status, in awake patients, the application of prone position may reduce comfort with a consequent increase in the workload imposed on respiratory muscles. Thus, we primarily ascertained the effect of awake prone position on diaphragmatic thickening fraction, assessed through ultrasound, in COVID-19 patients undergoing NIV. METHODS: We enrolled all COVID-19 adult critically ill patients, admitted to intensive care unit (ICU) for hypoxemic ARF and undergoing NIV, deserving of awake prone positioning as a rescue therapy. Exclusion criteria were pregnancy and any contraindication to awake prone position and NIV. On ICU admission, after NIV onset, in supine position, and at 1 h following awake prone position application, diaphragmatic thickening fraction was obtained on the right side. Across all the study phases, NIV was maintained with the same setting present at study entry. Vital signs were monitored throughout the entire study period. Comfort was assessed through numerical rating scale (0 the worst comfort and 10 the highest comfort level). Data were presented in median and 25th-75th percentile range. RESULTS: From February to May 2021, 20 patients were enrolled and finally analyzed. Despite peripheral oxygen saturation improvement [96 (94-97)% supine vs 98 (96-99)% prone, p = 0.008], turning to prone position induced a worsening in comfort score from 7.0 (6.0-8.0) to 6.0 (5.0-7.0) (p = 0.012) and an increase in diaphragmatic thickening fraction from 33.3 (25.7-40.5)% to 41.5 (29.8-50.0)% (p = 0.025). CONCLUSIONS: In our COVID-19 patients assisted by NIV in ICU, the application of awake prone position improved the oxygenation at the expense of a greater diaphragmatic thickening fraction compared to supine position. Trial registration ClinicalTrials.gov, number NCT04904731. Registered on 05/25/2021, retrospectively registered. https://clinicaltrials.gov/ct2/show/NCT04904731 .

Association of Neutrophil Activation, More Than Platelet Activation, With Thrombotic Complications in Coronavirus Disease 2019.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 infection is associated with hypercoagulability, which predisposes to venous thromboembolism (VTE). We analyzed platelet and neutrophil activation in patients with coronavirus disease 2019 (COVID-19) and their association with VTE. METHODS: Hospitalized patients with COVID-19 and age- and sex-matched healthy controls were studied. Platelet and leukocyte activation, neutrophil extracellular traps (NETs), and matrix metalloproteinase 9, a neutrophil-released enzyme, were measured. Four patients were restudied after recovery. The activating effect of plasma from patients with COVID-19 on control platelets and leukocytes and the inhibiting activity of common antithrombotic agents on it were studied. RESULTS: A total of 36 patients with COVID-19 and 31 healthy controls were studied; VTE developed in 8 of 36 patients with COVID-19 (22.2%). Platelets and neutrophils were activated in patients with COVID-19. NET, but not platelet activation, biomarkers correlated with disease severity and were associated with thrombosis. Plasmatic matrix metalloproteinase 9 was significantly increased in patients with COVID-19. Platelet and neutrophil activation markers, but less so NETs, normalized after recovery. In vitro, plasma from patients with COVID-19 triggered platelet and neutrophil activation and NET formation, the latter blocked by therapeutic-dose low-molecular-weight heparin, but not by aspirin or dypiridamole. CONCLUSIONS: Platelet and neutrophil activation are key features of patients with COVID-19. NET biomarkers may help to predict clinical worsening and VTE and may guide low-molecular-weight heparin treatment.

Shock and Diffuse ST-elevation in a Patient with Coronavirus Disease-2019 Disease.

The infection by the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is associated with significant cardiovascular morbidity and mortality. Cardiac events require prompt diagnosis and management, also in the SARS-CoV-2 era. A 58-year-old male, heavy smoker and with known SARS-CoV-2 infection, abruptly developed severe hypotension and asthenia. At patients' home, emergency physicians found hemodynamic compromise with diffuse ST-elevation at electrocardiography. The patient was rapidly moved to the cardiac catheterization laboratory, and any contact with other health-care workers was avoided. Coronary angiography excluded coronary artery disease. At admission to the coronavirus disease-2019 unit, an increase in inflammatory markers and liver enzymes with normal troponin levels were observed. Bedside lung ultrasonography showed interstitial syndrome and bilateral pleural effusion, whereas echocardiography showed large and diffuse pericardial effusion with a swinging heart. The hemodynamic status improved after gentle fluid therapy such suggesting potential concomitant sepsis and pericardiocentesis was not performed. At this time, a computed tomography scan showed a widespread neoplasm in the right lung involving the subclavian artery and vein and the thoracic lymph nodes. The histology confirmed the diagnosis of a locally advanced pulmonary adenocarcinoma. One week after admission, the patient died for worsening respiratory failure. Not delayed primary PCI remains the standard of care for patients with suspected ST-elevation myocardial infarction (STEMI) in the SARS-CoV-2 era. A diagnostic deepening for potential STEMI-mimicker (known to be associated with SARS-CoV-2 infection and to patients' comorbidities) should be considered, and a multidisciplinary approach is needed in these patients.

Search for SARS-CoV-2 RNA in platelets from COVID-19 patients.

The frequent finding of thrombocytopenia in patients with severe SARS-CoV-2 infection (COVID-19) and previous evidence that several viruses enter platelets suggest that SARS-CoV-2 might be internalized by platelets of COVID-19. Aim of our study was to assess the presence of SARS-CoV-2 RNA in platelets from hospitalized patients with aconfirmed diagnosis of COVID-19. RNA was extracted from platelets, leukocytes and serum from 24 COVID-19 patients and 3 healthy controls, real-time PCR and ddPCR for viral genes were carried out. SARS-CoV-2 RNA was not detected in any of the samples analyzed nor in healthy controls, by either RT-PCR or ddPCR, while RNA samples from nasopharyngeal swabs of COVID-19 patients were correctly identified. Viral RNA was not detected independently of viral load, of positive nasopharyngeal swabs, or viremia, the last detected in only one patient (4.1%). SARS-CoV-2 entry in platelets is not acommon phenomenon in COVID-19 patients, differently from other viral infections.