ABSTRACT
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
Introduction: SARS-CoV-2 infection was first identified at the end of 2019 in China, and subsequently spread globally. COVID-19 disease frequently affects the lungs leading to bilateral viral pneumonia, progressing in some cases to severe respiratory failure requiring ICU admission and mechanical ventilation. Risk stratification at ICU admission is fundamental for resource allocation and decision making, considering that baseline comorbidities, age, and patient conditions at admission have been associated to poorer outcomes. Supervised machine learning techniques are increasingly diffuse in clinical medicine and can predict mortality and test associations reaching high predictive performance. We assessed performances of a machine learning approach to predict mortality in COVID-19 patients admitted to ICU using data from the Lombardy ICU Network.Methods: this is a secondary analysis of prospectively collected data from Lombardy ICU network. To predict survival at 7-,14- and 28 days we built two different models; model A included patient demographics, medications before admission and comorbidities, while model B also included the data of the first day since ICU admission. 10-fold cross validation was repeated 2500 times, to ensure optimal hyperparameter choice. The only constrain imposed to model optimization was the choice of logistic regression as final layer to increase clinical interpretability. Different imputation and over-sampling techniques were employed in model training.Results 1503 patients were included, with 766 deaths (51%). Exploratory analysis and Kaplan-Meier curves demonstrated mortality association with age and gender. Model A and B reached the greatest predictive performance at 28 days (AUC 0.77 and 0.79), with lower performance at 14 days (AUC 0.72 and 0.74) and 7 days (AUC 0.68 and 0.71). Male gender, age and number of comorbidities were strongly associated with mortality in both models. Among comorbidities, chronic kidney disease and chronic obstructive pulmonary disease demonstrated association. Mode of ventilatory assistance at ICU admission and Fraction of Inspired oxygen were associated with mortality in model B.Conclusions Supervised machine learning models demonstrated good performance in prediction of 28-day mortality. 7-days and 14-days predictions demonstrated lower performance. Machine learning techniques may be useful in emergency phases to reach higher predictive performance with reduced human supervision using complex data.
Subject(s)
COVID-19ABSTRACT
Background: Neuromuscular blocking agents (NMBA) have been previously used in patients with acute respiratory distress syndrome (ARDS). It is unknown if NMBA are useful in COVID-19 patients who require invasive mechanical ventilation (IMV).Methods: We investigated use of NMBA in COVID-19 patients on IMV from February 1 to November 24, 2020, in 147 hospitals across 6 continents, comprising the COVID-19 Critical Care Consortium. We performed propensity score (PS) matched Cox proportional hazards analysis to appraise the impact of NMBA use for ≥2 days, continuously or discontinuously (treatment), vs. no use of NMBA or only upon commencement of IMV (control) on 28-day intensive care unit (ICU) mortality.Findings: 1548 (72%) patients received any NMBA therapy; 1165 (54%) of patients were stratified in the treatment group, with a median (IQR) time from ICU admission to commencement of NMBA therapy of 0 (0-2) days. The median (IQR) duration of NMBA therapy was 3 (2-6) days (N=1548). Upon commencement of IMV, patients who received NMBA therapy had a lower mean (±SD) PaO2/FiO2 (139±75 vs 157±93; P<0.001). After PS matching, Cox proportional hazard model demonstrated that NMBA therapy was significantly associated with higher 28-day ICU mortality (adjusted HR 2.20, 95% CI 1.67, 2.89, P<0.001). Sensitivity analyses testing various NMBA therapeutic regimens confirmed similar associations with mortality.Interpretation: Use of NMBA is common in COVID-19 patients on IMV and associated with a 2.2-fold increase in risk of 28-day mortality. Until further randomised evidence is available, NMBA should be applied cautiously in routine clinical practice.Funding Statement: University of Queensland, Wesley Medical Research, The Prince Charles Hospital Foundation, The Health Research Board of Ireland; Biomedicine international training research programme for excellent clinician-scientists; European Union’s research and innovation programme (Horizon 2020); la Caixa Foundation. Finally, Carol Hodgson is funded by a National Health and Medical Research Council Grant.Declaration of Interests: Dr. Li Bassi received research support from Fisher & Paykel outside the submitted work. Dr. Dalton has consulting from Innovative ECMO Concepts, Abiomed and Instrumentation Labs , none which affect the current work. Dr. Brodie receives research support from ALung Technologies and he has been on the medical advisory boards for Baxter, Abiomed, Xenios and Hemovent. Dr. Fan reports personal fees from ALung Technologies, Baxter, Fresenius Medical Care, Getinge, and MC3Cardiopulmonary outside the submitted work. Dr. Laffey reports consulting fees from Baxter and Cala Medical, both outside the submitted work. Dr Nichol is supported by a health Research Board of Ireland award (CTN-2014-012). Dr. Fraser receives research support from Fisher & Paykel outside the submitted work. Remaining authors do not have any competing interest to declare. Ethics Approval Statement: Participating hospitals obtained local ethics committee approval and a waiver of informed consent was granted in all cases.De-identified patient data were collected and stored via the REDCap (Vanderbilt/NIH/NCATS UL1 TR000445 v.10.0.23) electronic data capture tool, hosted at the University of Oxford, United Kingdom and University of Queensland.
Subject(s)
COVID-19 , Respiratory Distress SyndromeABSTRACT
Background: Limited data are available on the use of prone position in intubated, invasively ventilated patients with Coronavirus disease-19 (COVID-19). Aim of this study is to investigate the use and effect of prone position in this population during the first 2020 pandemic wave.Methods: Retrospective, multicentre, national cohort study conducted between February 24 and June 14, 2020 in 24 Italian Intensive Care Units (ICU) on adult patients needing invasive mechanical ventilation for respiratory failure caused by COVID-19.Clinical data were collected on the day of ICU admission. Information regarding the use of prone position were collected daily. Follow-up for patient outcomes was performed on July 15, 2020. The respiratory effects of the first prone position were studied in a subset of 78 patients. Patients were classified as Responders if the PaO2/FiO2 ratio increased ≥ 20 mmHg during prone position. Results: Of 1057 included patients, mild, moderate and severe ARDS was present in 15, 50 and 35% of patients, respectively and had a resulting mortality of 25, 33 and 41%. Prone position was applied in 61% of the patients. Patients placed prone had a more severe disease and died significantly more (45% vs 33%, p<0.001). Overall, prone position induced a significant increase in PaO2/FiO2 ratio, while no change in respiratory system compliance was observed. Seventy-eight % of patients were Responders to prone position. Non-Responders had a more severe respiratory failure and died more often in the ICU (65% vs. 38%, p=0.047).Conclusions: During the COVID-19 pandemic, prone position has been widely adopted to treat mechanically ventilated patients with respiratory failure. The majority of patients improved their oxygenation during prone position, most likely due to a better ventilation perfusion matching.Trial registration: clinicaltrials.gov number: NCT04388670
Subject(s)
COVID-19 , Respiratory Insufficiency , Respiratory Distress Syndrome , Jaundice, ObstructiveABSTRACT
Background Heterogeneous respiratory system static compliance (CRS) values and levels of hypoxemia in patients with novel coronavirus disease (COVID-19) requiring mechanical ventilation have been reported in previous small-case series or studies conducted at a national level.Methods We designed a retrospective observational cohort study with rapid data gathering from the international COVID-19 Critical Care Consortium study to comprehensively describe the impact of CRS on the ventilatory management and outcomes of COVID-19 patients on mechanical ventilation (MV), admitted to intensive care units (ICU) worldwide.Results We enrolled 318 COVID-19 patients enrolled into the study from January 14th through September 31th, 2020 in 19 countries and stratified into two CRS groups. CRS was calculated as: tidal volume/[airway plateau pressure-positive end-expiratory pressure (PEEP)] and available within 48 h from commencement of MV in 318 patients. Patients were mean ± SD of 58.0 ± 12.2, predominantly from Europe (54%) and males (68%). Median CRS (IQR) was 34.1 mL/cmH2O (26.5–45.5) and PaO2/FiO2 was 119 mmHg (87.1–164) and was not correlated with CRS. Female sex presented lower CRS than in males (95% CI: -13.8 to -8.5 P < 0.001) and higher body mass index (34.7 ± 10.9 vs 29.1 ± 6.0, p < 0.001). Median (IQR) PEEP was 12 cmH2O (10–15), throughout the range of CRS, while median (IQR) driving pressure was 12.3 (10–15) cmH2O and significantly decreased as CRS improved (p < 0.001). No differences were found in comorbidities and clinical management between CRS strata. In addition, 28-day ICU mortality and hospital mortality did not differ between CRS groups.Conclusions This multicentre report provides a comprehensive account of CRS in COVID-19 patients on MV – predominantly males or overweight females, in their late 50 s – admitted to ICU during the first international outbreaks. Phenotypes associated with different CRS upon commencement of MV could not be identified. Trial documentation: Available at https://www.covid-critical.com/study.Trial registration ACTRN12620000421932.
Subject(s)
Coronavirus Infections , Craniosynostoses , Hypoxia , COVID-19ABSTRACT
BACKGROUND. Aim of the study is to evaluate the incidence of DVT in COVID-19 patients and its correlation with the severity of the disease and with clinical and laboratory findings.METHODS. 234 symptomatic patients with COVID-19, diagnosed according to the World Health Organization guidelines, were included in the study. The severity of the disease was classified as moderate, severe and critical. Doppler ultrasound (DUS) was performed in all patients. DUS findings, clinical, laboratory’s and therapeutic variables were investigated by contingency tables, Pearson chi square test and by Student T test and Fisher's exact test. ROC curve analysis was applied to study significant continuous variables.RESULTS. Overall incidence of DVT was 10.7% (25/234): 1.6% (1/60) among moderate cases, 13.8% (24/174) in severely and critically ill patients. Prolonged bedrest and intensive care unit admission were significantly associated with the presence of DVT (19.7%). Fraction of inspired oxygen, P/F ratio, respiratory rate, heparin administration, D-dimer, IL-6, ferritin and CRP showed correlation with DVT. CONCLUSIONS. DUS may be considered a useful and valid tool for early identification of DVT. In less severely affected patients, DUS as screening of DVT might be unnecessary. High rate of DVT found in severe patients and its correlation with respiratory parameters and some significant laboratory findings suggests that these can be used as a screening tool for patients who should be getting DUS.
Subject(s)
COVID-19 , Critical IllnessABSTRACT
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.
Subject(s)
Severe Acute Respiratory Syndrome , COVID-19 , Respiratory InsufficiencyABSTRACT
Objective. To describe the radiographic key patterns on CXR in patients with SARS-CoV-2 infection, assessing the prevalence of radiographic signs of interstitial pneumonia. To evaluate pattern variation between a baseline and a follow-up CXR.Materials and methods. 1117 patients tested positive for SARS-CoV-2 infection were retrospectively enrolled from four centers in Lombardy region. All patients underwent a CXR at presentation. Follow-up CXR was performed when clinically indicated.Two radiologists in each center reviewed CXR images and classified them as suggestive or not for interstitial pneumonia, recording the presence of ground-glass opacity (GGO), reticular pattern or consolidation and their distribution.Pearson’s chi-square test for categorical variables and McNemar test (chi-square for paired data) were performed.Results. Patients mean age 63.3 years, 767 were males (65.5%). The main result is the large proportion of positive CXR in COVID-19 patients.Baseline CXR was positive in 940 patients (80.3%), with significant differences in age and sex distribution between patients with positive and negative CXR. 382 patients underwent a follow-up CXR. The most frequent pattern on baseline CXR was the GGO (66.1%), on follow-up was consolidation (53.4%). The most common distributions were peripheral and middle-lower lung zone.Conclusions. We described key-patterns and their distribution on CXR in a large cohort of COVID-19 patients: GGO was the most frequent finding on baseline CXR, while we found an increase in the proportion of lung consolidation on follow-up CXR. CXR proved to be a reliable tool in our cohort obtaining positive results in 80.3% of the baseline cases.