ABSTRACT
Background Prone positioning (PP) is routinely used among patients with COVID-19 requiring mechanical ventilation. However, its utility among spontaneously breathing patients is still debated. Methods In an open-label randomized controlled trial, we enrolled patients hospitalized with mild COVID-19 pneumonia, whose PaO2/FiO2 ratio was >200 mmHg and who did not require mechanical ventilation (MV) or non-invasive ventilation (NIV) at hospital admission. Patients were randomized 1:1 to PP on top of standard of care (intervention group) versus standard of care only (controls). The primary composite outcome included death, MV, NIV and PaO2/FiO2 <200 mmHg; secondary outcomes were oxygen weaning and hospital discharge. Results Sixty-one subjects were enrolled, 29 adjudicated to PP and 32 to the control group. By day 28, 11 patients required NIV, 4 MV and 3 died. Overall, 24/61 (39.3%) met the primary outcome. Using an intention-to-treat approach, 15/29 patients in PP group versus 9/32 controls met the primary outcome, corresponding to a significantly higher risk of progression among those randomized to PP (HR 2.38 95%CI 1.04-5.43; P=0.040). Using an as-treated approach, which included in the intervention group only patients who maintained PP for [≥]3 hours/day, no significant differences were found between the two groups (HR 1.77; 95%CI 0.79-3.94; P=0.165). Also, we did not find any statistically difference in terms of time to oxygen weaning or hospital discharge between study arms, in any of the analyses conducted. Conclusions We observed no clinical benefit from awake PP among spontaneously breathing patients with COVID-19 pneumonia requiring conventional oxygen therapy.
Subject(s)
COVID-19 , Pneumonia , DeathABSTRACT
It is uncertain whether higher doses of anticoagulants than recommended for thromboprophylaxis are necessary in COVID-19 patients hospitalized in general wards. This is a multicentre, open-label, randomized trial performed in 9 Italian centres, comparing 40 mg b.i.d. vs 40 mg o.d. enoxaparin in COVID-19 patients, between April 30, 2020 and April 25, 2021. Primary efficacy outcome was in-hospital incidence of venous thromboembolism (VTE): asymptomatic or symptomatic proximal deep vein thrombosis (DVT) diagnosed by serial compression ultrasonography (CUS), and/or symptomatic pulmonary embolism (PE) diagnosed by computed tomography angiography (CTA). Secondary endpoints included each individual component of the primary efficacy outcome and a composite of death, VTE, mechanical ventilation, stroke, myocardial infarction, admission to ICU. Safety outcomes included major bleeding. The study was interrupted prematurely due to slow recruitment. We included 183 (96%) of the 189 enrolled patients in the primary analysis (91 in b.i.d., 92 in o.d.). Primary efficacy outcome occurred in 6 patients (6.5%, 0 DVT, 6 PE) in the o.d. group and 0 in the b.id. group (Sto arrivando! 6.5, 95% CI, 1.5-11.6). Absence of concomitant DVT and imaging characteristics suggest that most pulmonary artery occlusions were actually caused by local thrombi rather than PE. Statistically non-significant differences in secondary and safety endpoints were observed, with two major bleeding events in each arm. In conclusion, no DVT developed in COVID-19 patients hospitalized in general wards, independently of enoxaparin dosing used for thromboprophylaxis. Pulmonary artery occlusions developed only in the o.d. group. Our trial is underpowered and with few events.
Subject(s)
Pulmonary Embolism , Myocardial Infarction , Hemorrhage , Retinal Artery Occlusion , Venous Thromboembolism , Death , COVID-19 , Stroke , Venous ThrombosisABSTRACT
Background: Understanding the cause of sex disparities in COVID-19 outcomes is a major challenge. We investigate sex hormone levels and their association with outcomes in COVID-19 patients, stratified by sex and age.Methods: This observational, retrospective, cohort study included 138 patients aged 18 years or older with COVID-19, hospitalized in Italy between February 1 and May 30, 2020. The association between sex hormones (testosterone, estradiol, progesterone, dehydroepiandrosterone) and outcomes (ARDS, severe COVID-19, in-hospital mortality) was explored in 120 patients aged 50 years and over. STROBE checklist was followed.Findings: The median age was 73·5 years [IQR 61, 82]; 55·8% were male. In older males, testosterone was lower if ARDS and severe COVID-19 were reported than if not (3·6 vs. 5·3 nmol/L, p =0·0378 and 3·7 vs. 8·5 nmol/L, p =0·0011, respectively). Deceased males had lower testosterone (2·4 vs. 4·8 nmol/L, p =0·0536) and higher estradiol than survivors (40 vs. 24 pg/mL, p = 0·0006). Testosterone was negatively associated with ARDS (OR 0·849 [95% CI 0·734, 0·982]), severe COVID-19 (OR 0·691 [95% CI 0·546, 0·874]), and in-hospital mortality (OR 0·742 [95% CI 0·566, 0·972]), regardless of potential confounders, though confirmed only in the regression model on males. Higher estradiol was associated with a higher probability of death (OR 1·051 [95% CI 1·018, 1.084]), confirmed in both sex models. Interpretation: In males, higher testosterone seems to be protective against any considered outcome. Higher estradiol was associated with a higher probability of death in both sexes.Funding Information: The research was funded by Italian Ministry of Health “Fondi Ricerca Corrente, Project L1P5” for IRCCS Sacro Cuore Don Calabria Hospital.Declaration of Interests: We declare there is no conflict of interest.Ethics Approval Statement: Ethical approval for data collection was obtained in accordance with local regulations at each participating site. The study protocol received ethical approval and consent from the competent Ethics Committee (Comitato Etico per la sperimentazione Clinica delle Province di Verona e Rovigo) on September 1st, 2020 (protocol #46555).
Subject(s)
COVID-19 , Cross InfectionABSTRACT
Due to the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), deepening the host genetic contribution to severe COVID-19 may further improve our understanding about underlying disease mechanisms. Here, we describe an extended GWAS meta-analysis of 3,260 COVID-19 patients with respiratory failure and 12,483 population controls from Italy, Spain, Norway and Germany, as well as hypothesis-driven targeted analysis of the human leukocyte antigen (HLA) region and chromosome Y haplotypes. We include detailed stratified analyses based on age, sex and disease severity. In addition to already established risk loci, our data identify and replicate two genome-wide significant loci at 17q21.31 and 19q13.33 associated with severe COVID-19 with respiratory failure. These associations implicate a highly pleiotropic ~0.9-Mb 17q21.31 inversion polymorphism, which affects lung function and immune and blood cell counts, and the NAPSA gene, involved in lung surfactant protein production, in COVID-19 pathogenesis.
Subject(s)
COVID-19 , Respiratory InsufficiencyABSTRACT
Background and objective. Long-term pulmonary sequelae following SARS-CoV-2 pneumonia are not yet confirmed, however preliminary observations suggests a possible relevant clinical, functional and radiological impairment. The aim of this study was to identify and characterise pulmonary sequelae caused by SARS-CoV-2 pneumonia at 6-month follow-up. Methods. In this multicenter, prospective, observational cohort study, patients hospitalised for SARS-CoV-2 pneumonia and without prior diagnosis of structural lung diseases were stratified by maximum ventilatory support (oxygen only, continuous positive airway pressure (CPAP) and invasive mechanical ventilation (IMV)) and followed up at 6 months from discharge. Pulmonary function tests and diffusion capacity for carbon monoxide (DLCO), 6 minutes walking test, chest X-ray, physical exam and modified Medical Research Council (mMRC) dyspnoea score were collected. Results. Between March and June 2020, 312 patients were enrolled (83, 27% women; median [IQR] age 61.1 [53.4,69.3] years). The parameters that showed the highest rate of impairment were DLCO and chest-X-ray, in 46% and 25% of patients, respectively. However, only a minority of patients reported dyspnoea (31%), defined as mMRC [≥] 1, or showed a restrictive ventilatory defects (9%). In the logistic regression model, having asthma as comorbidity was associated with DLCO impairment at follow-up, while prophylactic heparin administration during hospitalisation appeared as a protective factor. Need for invasive ventilatory support during hospitalisation was associated with chest imaging abnormalities. Conclusion. DLCO and radiological assessment appear to be the most sensitive tools to monitor patients with COVID-19 during follow-up. Future studies with longer follow-up are warranted to better understand pulmonary sequelae.
Subject(s)
Pulmonary Embolism , Lung Diseases , Dyspnea , Chest Pain , Severe Acute Respiratory Syndrome , Asthma , COVID-19ABSTRACT
Background: Long-term pulmonary sequelae following SARS-CoV-2 pneumonia are not yet confirmed, however preliminary observations suggests a possible relevant clinical, functional and radiological impairment. The aim of this study was to identify and characterise pulmonary sequelae caused by SARS-CoV-2 pneumonia at 6-month follow-up. Methods: . In this multicenter, prospective, observational cohort study, patients hospitalised for SARS-CoV-2 pneumonia and without prior diagnosis of structural lung diseases were stratified by maximum ventilatory support (“oxygen only”, “continuous positive airway pressure (CPAP)” and “invasive mechanical ventilation (IMV)”) and followed up at 6 months from discharge. Pulmonary function tests and diffusion capacity for carbon monoxide (DLCO), 6 minutes walking test, chest X-ray, physical exam and modified Medical Research Council (mMRC) dyspnoea score were collected. Results: . Between March and June 2020, 312 patients were enrolled (83, 27% women; median [IQR] age 61.1 [53.4,69.3] years). The parameters that showed the highest rate of impairment were DLCO and chest-X-ray, in 46% and 25% of patients, respectively. However, only a minority of patients reported dyspnoea (31%), defined as mMRC ≥ 1, or showed a restrictive ventilatory defects (9%). In the logistic regression model, having asthma as comorbidity was associated with DLCO impairment at follow-up, while prophylactic heparin administration during hospitalisation appeared as a protective factor. Need for invasive ventilatory support during hospitalisation was associated with chest imaging abnormalities. Conclusions: . DLCO and radiological assessment appear to be the most sensitive tools to monitor patients with COVID-19 during follow-up. Future studies with longer follow-up are warranted to better understand pulmonary sequelae. ClinicalTrials.gov Identifier: NCT04435327
Subject(s)
COVID-19 , Pneumonia , Lung DiseasesABSTRACT
Background: Evidence from COVID-19 outbreak shows that individuals with specific chronic diseases are at higher risk of severe prognosis after infection. Public health authorities are developing vaccination programmes with priorities that minimize the risk of mortality and severe events in individuals and communities. We propose an evidence-based strategy that targets the frailest subjects whose timely vaccination is likely to minimize future deaths and preserve the resilience of the health service by preventing infections. Methods: The cohort includes 146,087 cases with COVID-19 diagnosed in 2020 in Milan (3.49 million inhabitants). Individual level data on 42 chronic diseases and vital status updated as of January 21, 2021, were available in administrative data collected during the pandemic. Analyses were performed in three sub-cohorts of age (16-64, 65-79 and 80+ years) and comorbidities affecting mortality were selected by means of LASSO cross-validated conditional logistic regression. Simplified models based on previous results identified high-risk categories worth targeting with highest priority. Results adjusted by age and gender, were reported in terms of odds ratios and 95% confidence intervals. Findings: The final models include as predictors of mortality (7,667 deaths, 5.2%) 10, 12, and 5 chronic diseases, respectively. The older age categories shared, as risk factors, chronic renal failure, chronic heart failure, cerebrovascular disease, Parkinson disease and psychiatric diseases. In the younger age category, predictors included neoplasm, organ transplantation and psychiatric conditions. Results were consistent with those obtained on mortality at 60 days from diagnosis (6,968 deaths). Interpretation: This approach defines a two-level stratification for priorities in the vaccination that can easily be applied by health authorities, eventually adapted to local results in terms of number and types of comorbidities, and rapidly updated with current data. After the early phase of vaccination, data on effectiveness and safety will give the opportunity to revise prioritization and discuss the future approach in the remaining population. Funding: Agency for Health Protection, Metropolitan Area of Milan, ItalyDeclaration of Interests: None declared. Ethics Approval Statement: Ethics approval and consent to participate were not required, as this is an observational study based on data routinely collected by the Agency for Health Protection (ATS) of Milan, a public body of the Regional Health Service of Lombardy. Among the institutional functions of the ATS, established by the Lombardy regional legislation (R.L. 23/2015), is the management of individual care in the regional social and healthcare system, the evaluation of services provided to patients residing in the area covered by the ATS, and their health outcomes. This study is also ethically compliant with Italian law (Legislative Decree 101/2018) and the “General Authorisation to Process Personal Data for Scientific Research Purposes” (clauses no. 8 and 9/2016, referred to in the Data Protection Authority action of 13/12/2018). Data were anonymized with a unique identifier in the different datasets before being used for the analyses.
Subject(s)
Heart Failure , Mental Disorders , Cerebrovascular Disorders , Kidney Failure, Chronic , Parkinson Disease , Neoplasms , COVID-19ABSTRACT
Background. Respiratory failure is a key feature of severe Covid-19 and a critical driver of mortality, but for reasons poorly defined affects less than 10% of SARS-CoV-2 infected patients. Methods. We included 1,980 patients with Covid-19 respiratory failure at seven centers in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europe (Milan, Monza, Madrid, San Sebastian and Barcelona) for a genome-wide association analysis. After quality control and exclusion of population outliers, 835 patients and 1,255 population-derived controls from Italy, and 775 patients and 950 controls from Spain were included in the final analysis. In total we analyzed 8,582,968 single-nucleotide polymorphisms (SNPs) and conducted a meta-analysis of both case-control panels. Results. We detected cross-replicating associations with rs11385942 at chromosome 3p21.31 and rs657152 at 9q34, which were genome-wide significant (P<5x10-8) in the meta-analysis of both study panels, odds ratio [OR], 1.77; 95% confidence interval [CI], 1.48 to 2.11; P=1.14x10-10 and OR 1.32 (95% CI, 1.20 to 1.47; P=4.95x10-8), respectively. Among six genes at 3p21.31, SLC6A20 encodes a known interaction partner with angiotensin converting enzyme 2 (ACE2). The association signal at 9q34 was located at the ABO blood group locus and a blood-group-specific analysis showed higher risk for A-positive individuals (OR=1.45, 95% CI, 1.20 to 1.75, P=1.48x10-4) and a protective effect for blood group O (OR=0.65, 95% CI, 0.53 to 0.79, P=1.06x10-5). Conclusions. We herein report the first robust genetic susceptibility loci for the development of respiratory failure in Covid-19. Identified variants may help guide targeted exploration of severe Covid-19 pathophysiology.