Atorvastatin versus Placebo in ICU Patients with COVID-19: Ninety-day Results of the INSPIRATION-S Trial.

BACKGROUND: In the INSPIRATION-S trial, atorvastatin versus placebo was associated with a nonsignificant 16% reduction in 30-day composite of venous/arterial thrombosis or death in intensive care unit (ICU) patients with COVID-19. Thrombo-inflammatory response in coronavirus disease 2019 (COVID-19) may last beyond the first 30 days. METHODS: This article reports the effects of atorvastatin 20 mg daily versus placebo on 90-day clinical and functional outcomes from INSPIRATION-S, a double-blind multicenter randomized trial of adult ICU patients with COVID-19. The main outcome for this prespecified study was a composite of adjudicated venous/arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause mortality. Functional status was assessed with the Post-COVID-19 Functional Scale. RESULTS: In the primary analysis, 587 patients were included (age: 57 [Q1-Q3: 45-68] years; 44% women). By 90-day follow-up, the main outcome occurred in 96 (33.1%) patients assigned to atorvastatin and 113 (38.0%) assigned to placebo (hazard ratio [HR]: 0.80, 95% confidence interval [CI]: 0.60-1.05, p = 0.11). Atorvastatin in patients who presented within 7 days of symptom onset was associated with reduced 90-day hazard for the main outcome (HR: 0.60, 95% CI: 0.42-0.86, p interaction = 0.02). Atorvastatin use was associated with improved 90-day functional status, although the upper bound CI crossed 1.0 (ORordinal: 0.64, 95% CI: 0.41-1.01, p = 0.05). CONCLUSION: Atorvastatin 20 mg compared with placebo did not significantly reduce the 90-day composite of death, treatment with ECMO, or venous/arterial thrombosis. However, the point estimates do not exclude a potential clinically meaningful treatment effect, especially among patients who presented within 7 days of symptom onset (NCT04486508).

Intermediate-Dose versus Standard-Dose Prophylactic Anticoagulation in Patients with COVID-19 Admitted to the Intensive Care Unit: 90-Day Results from the INSPIRATION Randomized Trial.

BACKGROUND: Thrombotic complications are considered among the main extrapulmonary manifestations of coronavirus disease 2019 (COVID-19). The optimal type and duration of prophylactic antithrombotic therapy in these patients remain unknown. METHODS: This article reports the final (90-day) results of the Intermediate versus Standard-dose Prophylactic anticoagulation In cRitically-ill pATIents with COVID-19: An opeN label randomized controlled trial (INSPIRATION) study. Patients with COVID-19 admitted to intensive care were randomized to intermediate-dose versus standard-dose prophylactic anticoagulation for 30 days, irrespective of hospital discharge status. The primary efficacy outcome was a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause death. The main safety outcome was major bleeding. RESULTS: Of 600 randomized patients, 562 entered the modified intention-to-treat analysis (median age [Q1, Q3]: 62 [50, 71] years; 237 [42.2%] women), of whom 336 (59.8%) survived to hospital discharge. The primary outcome occurred in 132 (47.8%) of patients assigned to intermediate dose and 130 (45.4%) patients assigned to standard-dose prophylactic anticoagulation (hazard ratio [HR]: 1.21, 95% confidence interval [CI]: 0.95-1.55, p = 0.11). Findings were similar for other efficacy outcomes, and in the landmark analysis from days 31 to 90 (HR: 1.59, 95% CI: 0.45-5.06). There were 7 (2.5%) major bleeding events in the intermediate-dose group (including 3 fatal events) and 4 (1.4%) major bleeding events in the standard-dose group (none fatal) (HR: 1.82, 95% CI: 0.53-6.24). CONCLUSION: Intermediate-dose compared with standard-dose prophylactic anticoagulation did not reduce a composite of death, treatment with ECMO, or venous or arterial thrombosis at 90-day follow-up.

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.

SP-A and TLR4 localization in lung tissue of SM-exposed patients.

INTRODUCTION: Long-term pulmonary complications are one of the major long-term consequences of sulfur mustard (SM) exposure. Toll-like receptor 4 (TLR4) involves in the pathogenesis of several pulmonary disorders. Surfactant protein-A (SP-A) regulates LPS-induced TLR4 localization and activation responses. However, the intensity and significance of TLR4 and SP-A expression by lung cells in SM-exposed patients is not clear. METHODS: The gene expression of TLR4 (through real-time PCR) and TLR4 and SP-A positive cells and alveolar type II cells, as SP-A producers, (using IHC) were assessed in formalin fixed paraffin embedded (FFPE) specimens from SM-exposed (n = 17), and non-SM exposed individuals (n = 12). RESULTS: TLR4 gene expression did not change between study groups. However, its cell surface presentation was significantly reduced in SM-exposed patients and particularly in which with constrictive bronchiolitis compared with the control group (P < 0.001 and P = 0.002, respectively). Frequency of alveolar type II cells was lower in the case group rather than the control group while the number of SP-A positive cells did not alter. CONCLUSIONS: These findings suggest that reduced TLR4 cell surface presentation may have anti-inflammatory function and SP-A may have a critical role in regulation of inflammatory responses in SM-exposed patients. Further investigation on other possible mechanisms involved in TLR4 internalization maybe help to illustrate the modulatory or inflammatory activity of TLR4 in these patients.

Logistic regression model for prediction of airway reversibility using peak expiratory flow.

BACKGROUND: Using peak expiratory flow (PEF) as an alternative to spirometry parameters (FEV1 and FVC), for detection of airway reversibility in diseases with airflow limitation is challenging. We developed logistic regression (LR) model to discriminate bronchodilator responsiveness (BDR) and then compared the results of models with a performance of >18%, >20%, and >22% increase in ΔPEF% (PEF change relative to baseline), as a predictor for bronchodilator responsiveness (BDR). MATERIALS AND METHODS: PEF measurements of pre-bronchodilator, post-bronchodilator and ΔPEF% of 90 patients with asthma (44) and chronic obstructive pulmonary disease (46) were used as inputs of model and the output was presence or absence of the BDR. RESULTS: Although ΔPEF% was a poor discriminator, LR model could improve the accuracy of BDR. Sensitivity, specificity, positive predictive value, and negative predictive value of LR were 68.89%, 67.27%, 71.43%, and 78.72%, respectively. CONCLUSION: The LR is a reliable method that can be used clinically to predict BDR based on PEF measurements.

Pulmonary function and methacholine challenge tests in patients with ulcerative colitis.

BACKGROUND: Ulcerative colitis is an inflammatory chronic disease which is believed to be a multi organ condition. The prevalence of ulcerative colitis is reportedly increasing in Iran presenting with the same clinical characteristics as in developing countries. Pulmonary manifestations of ulcerative colitis are increasingly reported. In this study, we investigated the incidence of bronchial hyper-responsiveness (BHR) in ulcerative colitis (UC) patients. MATERIALS AND METHODS: Fifty-one UC patients with definite diagnosis referred to Shariati Hospital, Tehran, Iran, were selected to be evaluated with methacholine challenge test from October 2010 to October 2011. Patients were compared for their methacholine test outcome and its association with age, sex, diagnosis time, and disease activity. RESULTS: The median age was 41 (range 15 to 65) years. The median time of diagnosis was 7 (range <1 to 16) years. Forty-five percent were females, 18% had active disease and 13% had comorbidity. Nine percent of patients with UC had abnormal PFT in our study. Three cases (5%) had bronchial hyper-responsiveness that was not correlated with sex, age, time of diagnosis, or disease activity. CONCLUSION: A small number of ulcerative colitis patients in our study had disturbed pulmonary function test which is in concord with the findings of other studies. However, higher rates of bronchial hyper-responsiveness have been reported in other studies. Confounding factors like cigarette smoking and medications, which were negative or minimal in our study, may influence the results.

Exercise-induced bronchospasm among students of Tehran University of Medical Sciences in 2004.

Exercise-induced bronchospasm (EIB) is a clinical syndrome that affects 8-20% of the general population and 11-50% of athletes. Although a variety of testing protocols for the diagnosis of EIB have been pursued, the optimal algorithm still is lacking. The aim of this study was to determine the prevalence of EIB among students of Tehran University of Medical Sciences and to find out whether self-reported symptoms are sufficient to establish the diagnosis of EIB. A total of 463 students completed an EIB symptoms-specific questionnaire, followed by a 9-minute exercise test. Spirometric measurements were performed before, and 6 and 15 minutes after exercise. In our study, decrements of >15% in forced expiratory volume in 1 second or 25% in peak expiratory flow or forced expiratory flow at 25-75% from baseline values were defined as positive indications of EIB. The overall prevalence of EIB was 10.8% (15.94% in men versus 8.62% in women; p = 0.02). There was no significant difference between the students with and without EIB regarding body mass index, family income, and allergy frequency. The frequency of at least two out of the four symptoms of coughing, wheezing, shortness of breathing, and chest pain/discomfort among students with EIB was significantly higher than those without EIB (26.5% versus 15.1%, respectively; p = 0.04). The sensitivity and specificity of self-reported symptoms for EIB diagnosis were 26.5 and 84.9%, respectively. Although among all determinants proposed for EIB, respiratory symptoms are closely related to the disease, diagnosis based on only these symptoms is not recommended because of high false positive and false negative results.