Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality among Patients with COVID-19 Admitted to the Intensive Care Unit: The INSPIRATION Randomized Clinical Trial

Importance: Thrombotic events are commonly reported in critically ill patients with COVID-19. Limited data exist to guide the intensity of antithrombotic prophylaxis. Objective: To evaluate the effects of intermediate-dose vs standard-dose prophylactic anticoagulation among patients with COVID-19 admitted to the intensive care unit (ICU). Design, Setting, and Participants: Multicenter randomized trial with a 2 � 2 factorial design performed in 10 academic centers in Iran comparing intermediate-dose vs standard-dose prophylactic anticoagulation (first hypothesis) and statin therapy vs matching placebo (second hypothesis; not reported in this article) among adult patients admitted to the ICU with COVID-19. Patients were recruited between July 29, 2020, and November 19, 2020. The final follow-up date for the 30-day primary outcome was December 19, 2020. Interventions: Intermediate-dose (enoxaparin, 1 mg/kg daily) (n = 276) vs standard prophylactic anticoagulation (enoxaparin, 40 mg daily) (n = 286), with modification according to body weight and creatinine clearance. The assigned treatments were planned to be continued until completion of 30-day follow-up. Main Outcomes and Measures: The primary efficacy outcome was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days, assessed in randomized patients who met the eligibility criteria and received at least 1 dose of the assigned treatment. Prespecified safety outcomes included major bleeding according to the Bleeding Academic Research Consortium (type 3 or 5 definition), powered for noninferiority (a noninferiority margin of 1.8 based on odds ratio), and severe thrombocytopenia (platelet count <20 �103/µL). All outcomes were blindly adjudicated. Results: Among 600 randomized patients, 562 (93.7) were included in the primary analysis (median interquartile range age, 62 50-71 years; 237 42.2% women). The primary efficacy outcome occurred in 126 patients (45.7%) in the intermediate-dose group and 126 patients (44.1%) in the standard-dose prophylaxis group (absolute risk difference, 1.5% 95% CI,-6.6% to 9.8%; odds ratio, 1.06 95% CI, 0.76-1.48; P =.70). Major bleeding occurred in 7 patients (2.5%) in the intermediate-dose group and 4 patients (1.4%) in the standard-dose prophylaxis group (risk difference, 1.1% 1-sided 97.5% CI,-� to 3.4%; odds ratio, 1.83 1-sided 97.5% CI, 0.00-5.93), not meeting the noninferiority criteria (P for noninferiority >.99). Severe thrombocytopenia occurred only in patients assigned to the intermediate-dose group (6 vs 0 patients; risk difference, 2.2% 95% CI, 0.4%-3.8%; P =.01). Conclusions and Relevance: Among patients admitted to the ICU with COVID-19, intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic anticoagulation, did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days. These results do not support the routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients admitted to the ICU with COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04486508. © 2021 American Medical Association. All rights reserved

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Exertional-induced bronchoconstriction: Comparison between cardiopulmonary exercise test and methacholine challenging test

Introduction: Exertional-induced bronchoconstriction is a condition in which the physical activity causes constriction of airways in patients with airway hyper- responsiveness. In this study, we tried to study and evaluate any relationship between the findings of cardiopulmonary exercise testing (CPET) and the response to methacholine challenge test (MCT) in patients with dyspnea after activity. Materials and Methods: Thirty patients with complaints of dyspnea following activity referred to "Lung Clinic" of Baqiyatallah Hospital but not suffering from asthma were entered into the study. The subjects were excluded from the study if: Suffering from any other pulmonary diseases, smoking more than 1 cigarette a week in the last year, having a history of smoking more than 10 packets of cigarettes/year, having respiratory infection in the past 4 weeks, having abnormal chest X-ray or electrocardiogram, and cannot discontinue the use of medicines interfering with bronchial provocation. Baseline spirometry was performed for all the patients, and the values of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV/FVC were recorded. The MCT and then the CPET were performed on all patients. Results: The mean VO 2 (volume oxygen) in patients with positive methacholine test (20.45 mL/kg/min) was significantly lower than patients with negative MCT (28.69 mL/kg/min) (P = 0.000). Respiratory rates per minute (RR) and minute ventilation in the group with positive MCT (38.85 and 1.636 L) were significantly lower than the group with negative methacholine test (46.78 and 2.114 L) (P < 0.05). Also, the O 2 pulse rate in the group with negative methacholine test (116.27 mL/beat) was significantly higher than the group with positive methacholine test (84.26 mL/beat) (P < 0.001). Conclusion: Pulmonary response to exercise in patients with positive methacholine test is insufficient. The dead space ventilation in these patients has increased. Also, dynamic hyperinflation in patients with positive methacholine test causes the reduced stroke volume and O 2 pulse in these patients

Pulmonary Scintiscan Findings in Sulfur Mustard Injured Patients Suspected for Gastroesophageal Reflux; a Descriptive Cross-Sectional Study

Background:Gastroesophageal reflux disease (GERD) prevalence in patients with sulfur mustard (SM)-induced bronchiolitis obliterans (BO) is higher than exposed cases with mild lung injuries. In this study, we aimed to evaluate the prevalence of microaspirations using nuclear scintiscan among BO patients with SM exposure. Methods: This was a prospective cross-sectional study conducted on patients with SM-induced BO and pulmonary symptom exacerbation referred to the Baqiyatallah Hospital, Tehran, Iran during the year 2009. Following the endoscopy-based diagnosis of GERD by a gastroenterologist, anti-reflux medications were withdrawn for 72 hours and then the patients underwent nuclear scintigraphy scan following 12 hour ingestion of fat containing food as radionuclide dinner. High resolution computed tomography (HRCT), spirometry and bronchoscopy were also performed for all patients. Results: In this study, 39 patients (94.9% men) with mean (± SD) age of 45.1 ± 6.2 years were enrolled. The most common clinical complaints of the patients were thick sputum (97.4%) and dyspepsia (94.7%), followed by chest tightness (89.7%), nocturnal cough (82.1%), and nocturnal dyspnea (66.7%). In HRCT, air-trapping was the most common pulmonary finding (92.1%). In spirometry, mean (±SD) FEV1 and FEV1/FVC were 52.7 ± 22.4% and 70.4 ± 13.9%, respectively. In bronchoscopy, the most common finding was airway remodeling (62.2%), followed by false vocal cord hypertrophy (24.3%). In scintigraphic imaging, only 1 patient had a remarkable finding, in whom, the radionuclide material was seen in the pharynx (proximal GERD), but did not produce marked microaspiration of gastric substances into the airways. Conclusion:Although previous reports demonstrated high prevalence of GERD and microaspiration in patients with SM-induced BO, we did not find remarkable evidence for microaspiration in scintiscan in patients included in this study

Comparison of corticosteroids types, dexamethasone, and methylprednisolone in patients hospitalized with COVID-19: A systematic review and network meta-analysis

Background: COVID-19 is associated with severe pneumonia lung damage, acute respiratory distress syndrome (ARDS), and mortality. In this study, we aimed to compare corticosteroids' effect on the mortality risk in patients hospitalized with COVID-19. Methods: PubMed, Web of Science, Scopus, Cochrane Library, and Embase, were searched using a predesigned search strategy. Randomized controlled trials (RCTs) that had compared the corticosteroid drugs were included. The hazard ratio (HR) with a 95% confidence interval (CI) was used to summarize the effect size from the network meta-analysis (NMA). Results: Out of 329 retrieved references, 12 RCTs with 11,455 participants met the eligibility criteria in this review. The included RCTs formed one network with six treatments. In addition, five treatments in two RCTs were not connected to the network. Methylprednisolone + usual care (UC) versus UC decreased the risk of death by 0.65 (95% CI: 0.47, 0.90). Among treatments in the network the highest P-score (0.89) was related to Methylprednisolone + UC. Conclusion: Based on the results of this NMA it seems Methylprednisolone + UC to be the best treatment option in patients with COVID-ARDS and COVID pneumonia

Frequency distribution of gastro esophageal reflux disease in inhalation injury: A historical cohort study

Background: There is no data on the prevalence and the association of gastro esophageal reflux disease (GERD) with toxic fume inhalation. Therefore, we aimed to evaluate the frequency distribution of GERD symptoms among the individuals with mild respiratory disorder due to the past history of toxic fume exposure to sulfur mustard (SM). Materials and Methods: In a historical cohort study, subjects were randomly selected from 7000 patients in a database of all those who had a history of previous exposure to a single high dose of SM gas during war. The control group was randomly selected from adjacent neighbors of the patients, and two healthy male subjects were chosen per patient. In this study, we used the validated Persian translation of Mayo Gastroesophageal Reflux Questionnaire to assess the frequency distribution of reflux disease. Results: Relative frequency of GERD symptoms, was found to be significantly higher in the inhalation injury patients with an odds ratio of 8.30 (95% confidence interval [CI]: 4.73-14.55), and after adjustment for cigarette smoking, tea consumption, age, and body mass index, aspirin and chronic cough the odds ratio was found to be 4.41 (95% CI: 1.61-12.07). Conclusion: The most important finding of our study was the major GERD symptoms (heartburn and/or acid regurgitation once or more per week) among the individuals with the past history of exposure to SM toxic gas is substantially higher (4.4-fold) than normal populations