Clinical Significance of Bronchodilator Responsiveness Evaluated by Forced Vital Capacity in COPD: SPIROMICS Cohort Analysis.

ObjectiveBronchodilator responsiveness (BDR) is prevalent in COPD, but its clinical implications remain unclear. We explored the significance of BDR, defined by post-bronchodilator change in FEV1 (BDRFEV1) as a measure reflecting the change in flow and in FVC (BDRFVC) reflecting the change in volume.MethodsWe analyzed 2974 participants from a multicenter observational study designed to identify varying COPD phenotypes (SPIROMICS). We evaluated the association of BDR with baseline clinical characteristics, rate of prospective exacerbations and mortality using negative binomial regression and Cox proportional hazards models.ResultsA majority of COPD participants exhibited BDR (52.7%). BDRFEV1 occurred more often in earlier stages of COPD, while BDRFVC occurred more frequently in more advanced disease. When defined by increases in either FEV1 or FVC, BDR was associated with a self-reported history of asthma, but not with blood eosinophil counts. BDRFVC was more prevalent in subjects with greater emphysema and small airway disease on CT. In a univariate analysis, BDRFVC was associated with increased exacerbations and mortality, although no significance was found in a model adjusted for post-bronchodilator FEV1.ConclusionWith advanced airflow obstruction in COPD, BDRFVC is more prevalent in comparison to BDRFEV1 and correlates with the extent of emphysema and degree of small airway disease. Since these associations appear to be related to the impairment of FEV1, BDRFVC itself does not define a distinct phenotype nor can it be more predictive of outcomes, but it can offer additional insights into the pathophysiologic mechanism in advanced COPD.Clinical trials registrationClinicalTrials.gov: NCT01969344T4

Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease

Abstract: Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exome-sequencing and genome-wide genotyping in 145 patients (median age-at-diagnosis of 3.5 years), in whom no Mendelian disorders were clinically suspected. In five patients we detect a primary immunodeficiency or enteropathy, with clinical consequences (XIAP, CYBA, SH2D1A, PCSK1). We also present a case study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in CYBB. The mutation is present in ~70% of phagocytes and sufficient to result in defective bacterial handling but not life-threatening infections. Finally, we show that VEO-IBD patients have, on average, higher IBD polygenic risk scores than population controls (99 patients and 18,780 controls; P < 4 × 10−10), and replicate this finding in an independent cohort of VEO-IBD cases and controls (117 patients and 2,603 controls; P < 5 × 10−10). This discovery indicates that a polygenic component operates in VEO-IBD pathogenesis

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Rapid deployment of a community engagement study and educational trial via social media: implementation of the UC-COVID study.

BackgroundIn response to the COVID-19 pandemic and associated adoption of scarce resource allocation (SRA) policies, we sought to rapidly deploy a novel survey to ascertain community values and preferences for SRA and to test the utility of a brief intervention to improve knowledge of and values alignment with a new SRA policy. Given social distancing and precipitous evolution of the pandemic, Internet-enabled recruitment was deemed the best method to engage a community-based sample. We quantify the efficiency and acceptability of this Internet-based recruitment for engaging a trial cohort and describe the approach used for implementing a health-related trial entirely online using off-the-shelf tools.MethodsWe recruited 1971 adult participants (≥ 18 years) via engagement with community partners and organizations and outreach through direct and social media messaging. We quantified response rate and participant characteristics of our sample, examine sample representativeness, and evaluate potential non-response bias.ResultsRecruitment was similarly derived from direct referral from partner organizations and broader social media based outreach, with extremely low study entry from organic (non-invited) search activity. Of social media platforms, Facebook was the highest yield recruitment source. Bot activity was present but minimal and identifiable through meta-data and engagement behavior. Recruited participants differed from broader populations in terms of sex, ethnicity, and education, but had similar prevalence of chronic conditions. Retention was satisfactory, with entrance into the first follow-up survey for 61% of those invited.ConclusionsWe demonstrate that rapid recruitment into a longitudinal intervention trial via social media is feasible, efficient, and acceptable. Recruitment in conjunction with community partners representing target populations, and with outreach across multiple platforms, is recommended to optimize sample size and diversity. Trial implementation, engagement tracking, and retention are feasible with off-the-shelf tools using preexisting platforms.Trial registrationClinicalTrials.gov NCT04373135 . Registered on May 4, 2020

Factors Influencing CAM-ICU Documentation and Inappropriate "Unable to Assess" Responses.

BackgroundDetecting delirium with standardized assessment tools such as the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) is important, but such detection is frequently hampered by poor documentation and inappropriate "unable to assess" responses (in noncomatose patients).ObjectiveTo identify patient, clinical, and workplace factors that may impede or facilitate appropriate delirium assessment through use of the CAM-ICU, specifically documentation and inappropriate "unable to assess" responses.MethodsAn electronic health record-based data set was used to quantify CAM-ICU documentation and inappropriate "unable to assess" responses during 24 months. Associated patient (eg, age), clinical (eg, diagnosis), and workplace (eg, geographic location within the ICU, shift) factors were evaluated with multivariable regression.ResultsOf 28 586 CAM-ICU documentation opportunities, 66% were documented; 16% of documentations in alert or lightly sedated patients had inappropriate "unable to assess" responses. Night shift was associated with lower CAM-ICU documentation rates (P = .001), whereas physical restraints and location on side B (rather than side A) of the ICU were associated with higher documentation rates (P &lt; .05 for both). Age older than 80 years, non-White race, intubation, and physical restraints were associated with more inappropriate "unable to assess" responses (all P &lt; .05), as was infusion of propofol, midazolam, dexmedetomidine, or fentanyl (all P &lt; .05).ConclusionData from electronic health records can identify patient, clinical, and workplace factors associated with CAM-ICU documentation and inappropriate "unable to assess" responses, which can help target quality improvement efforts related to delirium assessment

Effects of Obstructive Sleep Apnea and Obesity on 30-Day Readmissions in Patients with Chronic Obstructive Pulmonary Disease: A Cross-Sectional Mediation Analysis.

Rationale: Comorbidity is a significant driver of health status and healthcare utilization in chronic obstructive pulmonary disease (COPD). Obstructive sleep apnea (OSA) portends poorer outcomes, whereas obesity is protective. Objectives: We describe the prevalence and influence of these comorbidities on COPD readmissions. Methods: We collated discharge records for COPD exacerbations spanning 2010-2016 from the Nationwide Readmissions Database using Medicare's Hospital Readmissions Reduction Program criteria, with OSA-COPD overlap identified by concomitant diagnosis code for OSA. We used mixed-effects logistic regression to predict readmission odds. A cross-sectional mediation analysis was performed to evaluate the extent that OSA attenuated obesity's impact on readmission. Results: Of 1,662,983 qualifying COPD discharges, 19.1% carried a diagnosis of obesity and 12.9% had OSA, with both diagnoses present in 7.8%. In unadjusted analyses, obesity (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.03-1.05; P &lt; 0.001) and OSA (OR, 1.11; 95% CI, 1.10-1.13; P &lt; 0.001) had increased readmission odds. In models adjusted for patient and hospital characteristics, 71% of readmission risk from obesity was attributable to OSA. When additionally adjusted for Charlson Comorbidity Index, we found that OSA remained a significant risk factor (OR, 1.05; 95% CI, 1.03-1.06; P &lt; 0.001), whereas obesity remained protective (OR, 0.96; 95% CI, 0.94-0.97; P &lt; 0.001) even after accounting for OSA. Conclusions: A significant proportion of patients with COPD suffer comorbid OSA and obesity with resultant readmission risk. Interestingly, obesity's protective effect attenuates readmission odds from OSA. Taken together, OSA and aggregate comorbidity influence readmissions in patients with COPD. Testing for and treating OSA-COPD overlap may provide a mechanism to reduce avoidable readmissions

Reduced COPD Exacerbation Risk Correlates With Improved FEV1: A Meta-Regression Analysis.

BackgroundThe mechanism by which various classes of medication reduce COPD exacerbation risk remains unknown. We hypothesized a correlation between reduced exacerbation risk and improvement in airway patency as measured according to FEV1.MethodsBy systematic review, COPD trials were identified that reported therapeutic changes in predose FEV1 (dFEV1) and occurrence of moderate to severe exacerbations. Using meta-regression analysis, a model was generated with dFEV1 as the moderator variable and the absolute difference in exacerbation rate (RD), ratio of exacerbation rates (RRs), or hazard ratio (HR) as dependent variables.ResultsThe analysis of RD and RR included 119,227 patients, and the HR analysis included 73,475 patients. For every 100-mL change in predose FEV1, the HR decreased by 21%&nbsp;(95%&nbsp;CI, 17-26; P&nbsp;&lt; .001; R2&nbsp;= 0.85) and the absolute exacerbation rate decreased by 0.06 per patient per year (95%&nbsp;CI, 0.02-0.11; P&nbsp;= .009; R2&nbsp;= 0.05), which corresponded to an RR of 0.86 (95%&nbsp;CI, 0.81-0.91; P&nbsp;&lt; .001; R2&nbsp;= 0.20). The relationship with exacerbation risk remained statistically significant across multiple subgroup analyses.ConclusionsA significant correlation between increased FEV1 and lower COPD exacerbation risk suggests that airway patency is an important mechanism responsible for this effect