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Bronchodilator responsiveness (BDR) in obstructive lung disease varies over time and may be associated with distinct clinical features.Is consistent BDR over time (always present) differentially associated with obstructive lung disease features relative to inconsistent (sometimes present) or never (never present) BDR in tobacco-exposed people with or without COPD?We retrospectively analyzed data from 2,269 tobacco-exposed participants in the Subpopulations and Intermediate Outcome Measures in COPD Study with or without COPD. We used various BDR definitions: change of ≥ 200 mL and ≥ 12% in FEVBoth consistent and inconsistent ATS-BDR were associated with asthma history and greater small airways disease (%parametric response mapping functional small airways disease) relative to never ATS-BDR in participants with GOLD stage 0 disease and the entire cohort. We observed similar findings using FEVDemonstration of BDR, even once, describes an obstructive lung disease phenotype with a history of asthma and greater small airways disease. Consistent demonstration of BDR indicated a high risk of lung function decline over time in the entire cohort and was associated with higher risk of progression to COPD in patients with GOLD stage 0 disease.

Background The long-term effects of SARS-CoV-2 infection on pulmonary structure and function remain incompletely characterized. Purpose To test whether SARS-CoV-2 infection leads to small airways disease in patients with persistent symptoms. Materials and Methods In this single-center study at a university teaching hospital, adults with confirmed COVID-19 who remained symptomatic more than 30 days following diagnosis were prospectively enrolled from June to December 2020 and compared with healthy participants (controls) prospectively enrolled from March to August 2018. Participants with post-acute sequelae of COVID-19 (PASC) were classified as ambulatory, hospitalized, or having required the intensive care unit (ICU) based on the highest level of care received during acute infection. Symptoms, pulmonary function tests, and chest CT images were collected. Quantitative CT analysis was performed using supervised machine learning to measure regional ground-glass opacity (GGO) and using inspiratory and expiratory image-matching to measure regional air trapping. Univariable analyses and multivariable linear regression were used to compare groups. Results Overall, 100 participants with PASC (median age, 48 years; 66 women) were evaluated and compared with 106 matched healthy controls; 67% (67 of 100) of the participants with PASC were classified as ambulatory, 17% (17 of 100) were hospitalized, and 16% (16 of 100) required the ICU. In the hospitalized and ICU groups, the mean percentage of total lung classified as GGO was 13.2% and 28.7%, respectively, and was higher than that in the ambulatory group (3.7%

Background Small airways are known to be affected early in the course of chronic obstructive pulmonary disease (COPD); however, traditional spirometric indices may not accurately identify small airways disease. Research Question Can FEV3/FEV6 identify early airflow abnormalities and predict future clinically important respiratory-related outcomes, including development of COPD? Study Design and Methods We included eight hundred thirty-two current and former smokers with post-bronchodilator FEV1/FVC ≥0.7 from the SPIROMICS cohort. Participants were classified as having a reduced pre-bronchodilator FEV3/FEV6 based on lower limit of normal (LLN) values. Repeatability analysis was performed for FEV3 and FEV6. Regression modeling was used to evaluate the relationship between baseline FEV3/FEV6 and outcome measures including functional small airways disease on thoracic imaging and respiratory exacerbations. Interval censored analysis was used to assess progression to COPD. Results FEV3/FEV6 Interpretation FEV3/FEV6 is a routinely available and repeatable spirometric index which can be useful in the evaluation of early airflow obstruction in current and former smokers without COPD. A reduced FEV3/FEV6 can identify those at risk for future development of COPD and respiratory exacerbations.

Rationale: Many patients with suspected chronic obstructive pulmonary disease (COPD) do not undergo spirometry to confirm the diagnosis. Underutilization is often attributed to barriers to accessing spirometry. Objective: Our objective wasto identify factors associated with spirometry underutilization for patients who are less likely to face access barriers related to travel, insurance, and availability of spirometry. Methods: A retrospective analysis was conducted of patients enrolled in the Veterans Health Administration and living in urban areas with a new diagnosis of COPD between 2012 to 2015, reducing out-of-pocket cost and travel barriers, respectively. We included only patients whose primary care clinic was located in an academically affiliated tertiary level facility with spirometry available. We used logistic regression to estimate associations between patient characteristics and receipt of spirometry within 2 years before or after COPD diagnosis. Results: Of 24,300 patients, 59.7% had spirometry. Compared to patients

Spyridon Fortis,1,2 Yubo Gao,1,3 Amy M J O’Shea,1,3 Brice Beck,1 Peter Kaboli,1,3 Mary Vaughan Sarrazin1,3 1Center for Access & Delivery Research & Evaluation (CADRE), Iowa City VA Health Care System, Iowa City, IA, USA; 2Department of Internal Medicine, Division of Pulmonary, Critical Care and Occupation Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA; 3Department of Internal Medicine, Division of General Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USACorrespondence: Spyridon FortisDepartment of Internal Medicine, Division of Pulmonary, Critical Care and Occupation Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, University of Iowa Hospitals and Clinics, 200 Hawkins Drive – C33 GH, Iowa City, IA, 52242, USAEmail spyridon-fortis@uiowa.eduBackground: Non-invasive mechanical ventilation (NIV) use in patients admitted with acute respiratory failure due to COPD exacerbations (AECOPDs) varies significantly between hospitals. However, previous literature did not account for patients’ illness severity. Our objective was to examine the variation in risk-standardized NIV use after adjusting for illness severity.Methods: We retrospectively analyzed AECOPD hospitalizations from 2011 to 2017 at 106 acute-care Veterans Health Administration (VA) hospitals in the USA. We stratified hospitals based on the percentage of NIV use among patients who received ventilation support within the first 24 hours of admission into quartiles, and compared patient characteristics. We calculated the risk-standardized NIV % using hierarchical models adjusting for comorbidities and severity of illness. We then stratified the hospitals by risk-standardized NIV % into quartiles and compared hospital characteristics between quartiles. We also compared the risk-standardized NIV % between rural and urban hospitals.Results: In 42,048 admissions for AECOPD over 6 years, the median risk-standardized initial NIV % was 57.3% (interquartile interval [IQI]=41.9– 64.4%). Hospitals in the highest risk-standardized NIV % quartiles cared for more rural patients, used invasive ventilators less frequently, and had longer length of hospital stay, but had no difference in mortality relative to the hospitals in the lowest quartiles. The risk-standardized NIV % was 65.3% (IQI=34.2– 84.2%) in rural and 55.1% (IQI=10.8– 86.6%) in urban hospitals (p=0.047), but hospital mortality did not differ between the two groups.Conclusion: NIV use varied significantly across hospitals, with rural hospitals having higher risk-standardized NIV % rates than urban hospitals. Further research should investigate the exact mechanism of variation in NIV use between rural and urban hospitals.Keywords: pulmonary disease, chronic obstructive, epidemiology, non-invasive ventilation

It is unclear whether the high burden of COPD in rural areas is related to worse outcomes in patients with COPD or is because the prevalence of COPD is higher in rural areas. We assessed the association of rural living with acute exacerbations of COPD (AECOPDs)-related hospitalization and mortality. We retrospectively analyzed Veterans Affairs (VA) and Medicare data of a nationwide cohort of veterans with COPD aged ≥ 65 years with a COPD encounter between 2011 and 2014 that had a follow-up until 2017. Patients were categorized based on residential location into urban, rural, and isolated rural. We used generalized linear and Cox proportional hazards models to assess the association of residential location with AECOPD-related hospitalizations and mortality. Age, sex, race, travel time to the nearest VA hospital, and comorbidity were included as covariates in the models. Of 165,996 patients with COPD, 45,045 (27.1%) experienced at least one AECOPD-related hospitalization over the study period. Rural (relative risk-RR) = 0.93; 95%CI:0.92 to 0.94;p

Introduction Substantial variation exists in telemedicine critical care (Tele-CC) effectiveness, which may be explained by heterogeneity in Tele-CC implementation and utilization. Methods We studied inpatient intensive care unit (ICU) admissions within the Veterans Health Administration from January 2005 to September 2018. Tele-CC affiliation was based on a facility's Tele-CC go-live date. Tele-CC interaction was quantified as the monthly number of video activations, recorded in the eCaremanager® (Phillips) system, per patient days. Tele-CC affiliated facilities were propensity-score matched to facilities without Tele-CC by hospital volume and average modified APACHE scores. We examined the effect of Tele-CC affiliation and the quantity of video interactions between Tele-CC and bedside on hospital outcomes. Results Comparing Tele-CC affiliated and control facilities, affiliated patients were, on average, younger (66.8 years vs 67.8 years; p Discussion Tele-CC interactions may occur more frequently for higher acuity patients. Increased Tele-CC interactions may improve health outcomes for the most acute and complex ICU cases.

Purpose To create a simplified critical illness severity scoring system with high prediction accuracy for 30-day mortality using only commonly available variables. Materials and methods This is a retrospective cohort study of ICU admissions 2010–2015 in 306 ICUs in 117 Veterans Affairs (VA) hospitals. We randomly divided our cohort into a training dataset (75%) and a validation dataset (25%). We created a critical illness severity scoring system (CISSS) using age, comorbidities, heart rate, mean arterial blood pressure, temperature, respiratory rate, hematocrit, white blood cell count, creatinine, sodium, glucose, albumin, bilirubin, bicarbonate, use of invasive mechanical ventilation, and whether the admission was surgical or not. We validated the performance of CISSS to predict 30-day mortality internally. Results After excluding 31,743 re-admissions, we divided our sample (n = 534,001) into a training (n = 400,613) and a validation dataset (n = 133,388). In the training dataset, the area under the curve (AUC) of CISSS was 0.847(95%CI = 0.845–0.850). In the validation dataset, the AUC was 0.848 (95%CI = 0.844–0.852), the standardized mortality ratio (SMR) was 1.00 (95%CI = 0.98–1.02), and Brier's score for 30-day mortality was 0.058 (95%CI = 0.057–0.059). CISSS calibration was acceptable. Conclusions CISSS has very good performance and requires only commonly used variables that can be easily extracted by electronic health records.

Spyridon Fortis,1,2 Amy MJ O’Shea,1,3 Brice F Beck,1 Alejandro Comellas,1,2 Mary Vaughan Sarrazin,1,3 Peter J Kaboli1,3 1Center for Access & Delivery Research & Evaluation (CADRE), Iowa City VA Health Care System, Iowa City, IA, USA; 2Pulmonary, Critical Care and Occupational Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA, USA; 3Department of Internal Medicine, Division of General Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USACorrespondence: Spyridon FortisPulmonary, Critical Care and Occupational Medicine, University of Iowa Hospitals and Clinics, 200 Hawkins Drive – C33 GH, Iowa City, IA 52242, USAEmail spyridon-fortis@uiowa.eduBackground: We explored the relationship between rural residency and in-hospital mortality in patients hospitalized with COPD exacerbations.Methods: We retrospectively analyzed COPD hospitalizations from 2011 to 2017 at 124 acute care Veterans Health Administration (VHA) hospitals in the US. Patient residence was classified using Rural Urban Commuting Area codes as urban, rural, or isolated rural. We stratified patient hospitalizations into quartiles by travel time from patient residence to the nearest VHA primary care provider clinic and hospital. Multivariate analyses utilized generalized estimating equations with a logit link accounting for repeated hospitalizations among patients and adjusting for patient- and hospital-level characteristics.Results: Of 64,914 COPD hospitalizations analyzed, 43,549 (67.1%) were for urban, 18,673 (28.8%) for rural, and 2,692 (4.1%) for isolated rural veterans. In-hospital mortality was 4.9% in urban, 5.5% in rural, and 5.2% in isolated rural veterans (P=0.008). Thirty-day mortality was 8.3% in urban, 9.9% in rural, and 9.2% in isolated rural veterans (P< 0.001). Travel time to a primary care provider and VHA hospital was not associated with in-hospital mortality among isolated rural and rural veterans. In the multivariable analysis, compared to urban veterans, isolated rural patients did not have increased mortality. Rural residence was not associated with in-hospital (OR=0.87; 95% CI=0.67– 1.12, P=0.28) but was associated with increased 30-day mortality (OR=1.13; 95% CI=1.04– 1.22, P=0.002). Transfer from another acute care hospital (OR=14.97; 95% CI=9.80– 17.16, P< 0.001) or an unknown/other facility (OR=33.05; 95% CI=22.66– 48.21, P< 0.001) were the strongest predictors of increased in-hospital mortality compared to patients coming from the outpatient sector. Transfer from another acute care facility was also a risk factor for 30-day mortality.Conclusion: Potential gaps in post-discharge care of rural veterans may be responsible for the rural–urban disparities. Further research should investigate the exact mechanism that inter-hospital transfers affect mortality.Keywords: pulmonary disease, chronic obstructive, epidemiology, mortality

BackgroundChronic bronchitis (CB) is strongly associated with cigarette smoking, but not all smokers develop CB. We aimed to evaluate whether measures of structural airway disease on CT are differentially associated with CB.MethodsIn smokers between ages 45 and 80 years, and with Global Initiative for Obstructive Lung Disease stages 0–4, CB was defined by the classic definition. Airway disease on CT was quantified by (i) wall area percent (WA%) of segmental airways; (ii) Pi10, the square root of the wall area of a hypothetical airway with 10 mm internal perimeter; (iii) total airway count (TAC) and (iv) airway fractal dimension (AFD), a measure of the complex branching pattern and remodelling of airways. CB was also assessed at the 5-year follow-up visit.Measurements and main resultsOf 8917 participants, 1734 (19.4%) had CB at baseline. Airway measures were significantly worse in those with CB compared with those without CB: WA% 54.5 (8.8) versus 49.8 (8.3); Pi10 2.58 (0.67) versus 2.28 (0.59) mm; TAC 156.7 (81.6) versus 177.8 (91.1); AFD 1.477 (0.091) versus 1.497 (0.092) (all pConclusionsHigher baseline AFD and TAC are associated with a lower risk of persistent CB, irrespective of changes in smoking status, suggesting preserved airway structure can confer a reserve against CB.

The effect of nonobstructive chronic bronchitis (CB) on mortality is unclear.Is nonobstructive CB associated with increased all-cause mortality?We conducted a systematic literature review and meta-analysis to assess the association of nonobstructive CB and all-cause mortality. We searched for articles that included both CB and mortality in the title, abstract, or both in PubMed and EMBASE. We excluded studies in which participants demonstrated obstructive spirometry findings and studies in which CB and mortality were not defined. We used the Newcastle-Ottawa Quality Assessment Scale to assess study quality. We pooled adjusted hazard ratios (HRs) using the random effects model and inverse variance weighting. We conducted stratified analysis by the definition of CB and smoking status. We used Cochran's Q and IOf 5,014 titles identified, eight fulfilled the inclusion and exclusion criteria. Overall nonobstructive CB was associated with all-cause mortality (HR, 1.37; 95% CI, 1.26-1.50) with no statistically significant heterogeneity (P = .14; INonobstructive CB is associated with increased all-cause mortality, and this association seems to be present only in current and former smokers. Further research should investigate whether this high-risk population may benefit from early therapeutic intervention.PROSPERO; No.: CRD42021253596; URL: www.crd.york.ac.uk/prospero.

BackgroundBody composition measures, specifically low weight or reduced muscle mass, are associated with mortality in COPD, but the effect of longitudinal body composition changes is undefined.Research questionIs the longitudinal loss of fat-free mass (FFM) associated with increased mortality, including in those with initially normal or elevated body composition metrics?Study design and methodsParticipants with complete data for at least one visit in the COPDGene study (n= 9,268) and the ECLIPSE study (n= 1,760) were included and monitored for 12 and 8 years, respectively. Pectoralis muscle area (PMA) was derived from thoracic CT scans and used as a proxy for FFM. A longitudinal mixed submodel for PMA and a Cox proportional hazards submodel for survival were fitted on a joint distribution, using a shared random intercept parameter and Markov chain Monte Carlo parameter estimation.ResultsBoth cohorts demonstrated a left-shifted distribution of baseline FFM, not reflected in BMI, and an increase in all-cause mortality risk associated with longitudinal loss of PMA. For each 1-cm2 PMA loss, mortality increased 3.1%(95%CI, 2.4%-3.7%; P< .001) in COPDGene, and 2.4%(95%CI, 0.9%-4.0%; P< .001) in ECLIPSE. Increased mortality risk was independent of enrollment values for BMI and disease severity [BODE (body mass, airflow obstruction, dyspnea, and exercise capacity) index quartiles] and was significant even in participants with initially greater than average PMA.InterpretationLongitudinal loss of PMA is associated with increased all-cause mortality, regardless of BMI or initial muscle mass. Consideration of novel screening tests and further research into mechanisms contributing to muscle decline may improve risk stratification and identify novel therapeutic targets in ever smokers.

To evaluate mortality, length of stay, and inter-hospital transfer in the Veteran Health Administration (VHA) among low complexity Intensive Care Unit (ICU) patients.Retrospective study of adult ICU admissions identified in VHA Medical SAS®; 2010-2015 at Veterans Affairs (VA) Medical Centers. Facilities classified by the Rural Urban Commuting Area code algorithm as large rural (referred to as rural) (N = 6) or urban (N = 33).In rural hospitals, patients (N = 9665) were less likely to have a respiratory (12.9% v. 18.9%; p .001) diagnosis, more likely diagnosed with sepsis (17.6% v. 4.9%), and had a higher illness severity score (42.0 vs. 41.4; p = .01) compared to urban (N = 65,846) counterparts. Mortality within ICU did not vary across facility rurality. In unadjusted analyses, facility rurality (rural vs. urban) was associated with reduced inter-hospital transfers (OR = 0.74; 95% CI = [0.69, 0.80]; p .001) and a shorter ICU length of stay (RR = 0.82; 95% CI = [0.74, 0.91]; p .001). This did not hold when the hierarchical data was accounted for.Despite challenges, low complexity ICUs in rural VA facilities fare similarly to urban counterparts. Being part of a national healthcare system may have benefits to explore in sustaining critical care access in rural areas outside the VA healthcare system.

Rationale: Increasing awareness of the prevalence and significance of Preserved Ratio Impaired Spirometry (PRISm), alternatively known as restrictive or Global Initiative for Chronic Obstructive Lu...

BACKGROUND: The objective of our study was to identify variables associated with inhaled medication use in smokers with normal spirometry (GOLD-0) and to examine the association of inhaled medication use with development of exacerbations and obstructive spirometry in the future. METHODS: We performed a retrospective multivariable analysis of GOLD-0 subjects identified in data from the COPDGene study to examine factors associated with medication use. Five categories were identified: (1) no medications, (2) short-acting bronchodilator, (3) long-acting bronchodilator; long-acting muscarinic antagonists and/or long-acting β agonist, (4) inhaled corticosteroids (ICS) with or without long-acting bronchodilator, and (5) dual bronchodilator with ICS. Sensitivity analysis was performed excluding subjects with history of asthma. We also evaluated whether long-acting inhaled medication use was associated with exacerbations and obstructive spirometry at the follow-up visit 5 y after enrollment. RESULTS: Of 4,303 GOLD-0 subjects within the analysis, 541 of them (12.6%) received inhaled medications. Of these, 259 (6%) were using long-acting inhaled medications and 282 (6.6%) were taking short-acting bronchodilator. Female sex (odds ratio [OR] 1.47, P = .003), numerous medical comorbidities, radiographic emphysema (OR 2.22, P = .02), chronic bronchitis (OR 1.77, P < .001), dyspnea (OR 2.24, P < .001), asthma history (OR 15.56, P < .001), prior exacerbation (OR 8.45, P < .001), and 6-min walk distance (OR 0.9, P < .001) were associated with medication use. Minimal changes were noted in a sensitivity analysis. Additionally, inhaled medications were associated with increased total (incidence rate ratio 2.83, P < .001) and severe respiratory exacerbations (incidence rate ratio 3.64, P < .001) and presence of obstructive spirometry (OR 2.83, P = .002) at follow-up. CONCLUSIONS: Respiratory symptoms, history of asthma, and radiographic emphysema were associated with inhaled medication use in smokers with normal spirometry. These individuals were more likely to develop obstructive spirometry, which suggests that health care providers may be able to identify obstructive lung disease prior to meeting the current criteria for COPD.

Background Although asthma is typically characterized by bronchodilator responsiveness (BDR), fixed airflow obstruction (FAO) occurs in ∼50% of patients with severe asthma. Objective Do FAO/BDR associate with efficacy of omalizumab, a monoclonal antibody that targets IgE? Methods In EXTRA, patients aged 12-75 years with inadequately controlled severe allergic asthma despite high-dose inhaled corticosteroids plus long-acting β2-agonists were randomized to omalizumab (n = 427) or placebo (n = 423) for 48 weeks of treatment. In this post hoc analysis, high/low BDR were defined as ≥12%/ Results In patients with high BDR, omalizumab reduced exacerbations more than placebo over the 48-week treatment period regardless of FAO status (RRR [95% confidence interval (CI)]: FAO+, 59.8% [17.7-80.4%]; FAO−, 44.3% [16.6-62.8%]). Omalizumab improved FEV1 compared with placebo in the FAO−, high BDR subgroup (FEV1 change from baseline [95% CI] for omalizumab vs placebo, 0.065 L [–0.071 to 0.201 L] to 0.236 L [0.112-0.359 L]) across 48 weeks. This was not observed in patients with low BDR, irrespective of FAO. Conclusion Omalizumab was more efficacious than placebo at reducing exacerbations in patients with high, but not low, BDR, regardless of the presence of FAO. Lung function improvement primarily occurred in FAO−, high BDR patients, suggesting that asthma with low BDR may represent a difficult-to-treat phenotype.

Iliya P Amaza,1 Amy MJ O’Shea,2,3 Spyridon Fortis,1,3 Alejandro P Comellas1 1University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Department of Internal Medicine, Division of Pulmonary, Critical Care, and Occupational Medicine, Iowa City, IA, USA; 2University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Department of Internal Medicine, Division of General Internal Medicine, Iowa City, IA, USA; 3Iowa City VA Health Care System, Center for Access & Delivery Research and Evaluation, Iowa City, IA, USACorrespondence: Alejandro P ComellasRoy J. and Lucille A. Carver College of Medicine, Department of Internal Medicine, Division of Pulmonary, Critical Care, and Occupational Medicine, 200 Hawkins Dr, W219B GH, Iowa City, Iowa City, 52242, USATel +1 319 384 6484Fax +1 319 353 6406Email alejandro-comellas@uiowa.eduPurpose: Visual assessment of computed tomography (CT) of the lung is routinely employed in the diagnosis of emphysema. Quantitative CT (QCT) can complement visual CT but must be well validated. QCT emphysema is defined as ≥ 5% of lung volume occupied by low attenuation areas ≤− 950 Hounsfield units (LAA-950). Discordant visual and QCT assessments are not uncommon. We examined the association between visual and quantitative chest CT evaluation within a large cohort of subjects to identify variables that may explain discordant visual and QCT findings.Materials and Methods: Volumetric inspiratory CT scans of 1221 subjects enrolled in phase 1 of the COPDGene study conducted at the University of Iowa were reviewed. Participants included never smokers, smokers with normal spirometry, preserved ratio impaired spirometry, and Global Initiative for Obstructive Lung Disease (GOLD) stages I–IV. CT scans were quantitatively scored and visually interpreted by both the COPDGene Imaging Center and the University of Iowa radiologists. Individual-level visual assessments were compared with QCT measurements. Agreement between the two sets of radiologists was calculated using kappa statistic. We assessed variables associated with discordant results using regression methods.Results: There was a fair agreement for the presence or absence of emphysema between our center’s radiologists and QCT (61% concordance, kappa 0.22 [0.17– 0.28]). Similar comparisons showed a slight agreement between the COPDGene Imaging Center and QCT (56% concordance, kappa 0.16 [0.11– 0.21]), and a moderate agreement between both sets of visual assessments (80% concordance, kappa 0.60 [0.54– 0.65]). Current smoking and female gender were significantly associated with QCT-negative but visually detectable emphysema.Conclusion: The slight-to-fair agreement between visual and quantitative CT assessment of emphysema highlights the need to utilize both modalities for a comprehensive radiologic evaluation. Discordant results may be attributable to one or more factors that warrant further exploration in larger studies.Clinical Trial Registration: ClinicalTrials.gov Identifier NCT000608764.Keywords: chest imaging, chronic obstructive pulmonary disease, interobserver agreement, Akaike information criterion

Background: Risk factor identification is a proven strategy in advancing treatments and preventive therapy for many chronic conditions. Quantifying the impact of those risk factors on health outcomes can consolidate and focus efforts on individuals with specific high-risk profiles. Using multiple risk factors and longitudinal outcomes in 2 independent cohorts, we developed and validated a risk score model to predict mortality in current and former cigarette smokers. Methods: We obtained extensive data on current and former smokers from the COPD Genetic Epidemiology (COPDGene(®)) study at enrollment. Based on physician input and model goodness-of-fit measures, a subset of variables was selected to fit final Weibull survival models separately for men and women. Coefficients and predictors were translated into a point system, allowing for easy computation of mortality risk scores and probabilities. We then used the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) cohort for external validation of our model. Results: Of 9867 COPDGene participants with standard baseline data, 17.6% died over 10 years of follow-up, and 9074 of these participants had the full set of baseline predictors (standard plus 6-minute walk distance and computed tomography variables) available for full model fits. The average age of participants in the cohort was 60 for both men and women, and the average predicted 10-year mortality risk was 18% for women and 25% for men. Model time-integrated area under the receiver operating characteristic curve statistics demonstrated good predictive model accuracy (0.797 average), validated in the external cohort (0.756 average). Risk of mortality was impacted most by 6-minute walk distance, forced expiratory volume in 1 second and age, for both men and women. Conclusions: Current and former smokers exhibited a wide range of mortality risk over a 10- year period. Our models can identify higher risk individuals who can be targeted for interventions to reduce risk of mortality, for participants with or without chronic obstructive pulmonary disease (COPD) using current Global initiative for chronic Obstructive Lung Disease (GOLD) criteria.

BACKGROUND: Mild expiratory flow limitation may not be recognized using traditional spirometric criteria based on the ratio of FEV(1)/FVC. RESEARCH QUESTION: Does slow vital capacity (SVC) instead of FVC increase the sensitivity of spirometry to identify patients with early or mild obstructive lung disease? STUDY DESIGN AND METHODS: We included 854 current and former smokers from the Subpopulations and Intermediate Outcome Measures in COPD Study cohort with a postbronchodilator FEV(1)/FVC ≥ 0.7 and FEV(1) % predicted of ≥ 80% at enrollment. We compared baseline characteristics, chest CT scan features, exacerbations, and progression to COPD (postbronchodilator FEV(1)/FVC, < 0.7) during the follow-up period between 734 participants with postbronchodilator FEV(1)/SVC of ≥ 0.7 and 120 with postbronchodilator FEV(1)/SVC < 0.7 at the enrollment. We performed multivariate linear and logistic regression models and negative binomial and interval-censored proportion hazards regression models adjusted for demographics and smoking exposure to examine the association of FEV(1)/SVC < 0.7 with those characteristics and outcomes. RESULTS: Participants with FEV(1)/SVC < 0.7 were older and had lower FEV(1) and more emphysema than those with FEV(1)/SVC ≥ 0.7. In adjusted analysis, individuals with postbronchodilator FEV(1)/SVC < 0.7 showed a greater percentage of emphysema by 0.45% (95% CI, 0.09%-0.82%), percentage of gas trapping by 2.52% (95% CI, 0.59%-4.44%), and percentage of functional small airways disease based on parametric response mapping by 2.78% (95% CI, 0.72%-4.83%) at baseline than those with FEV(1)/SVC ≥ 0.7. During a median follow-up time of 1,500 days, an FEV(1)/SVC < 0.7 was not associated with total exacerbations (incident rate ratio [IRR], 1.61; 95% CI, 0.97-2.64), but was associated with severe exacerbations (IRR, 2.60; 95% CI, 1.04-4.89). An FEV(1)/SVC < 0.7 was associated with progression to COPD during a 3-year follow-up even after adjustment for demographics and smoking exposure (hazard ratio, 3.93; 95% CI, 2.71-5.72). We found similar results when we examined the association of prebronchodilator FEV(1)/SVC < 0.7 or FEV(1)/SVC less than the lower limit of normal with chest CT scan features and progression to COPD. INTERPRETATION: Low FEV(1) to SVC in current and former smokers with normal spirometry results can identify individuals with CT scan features of COPD who are at risk for severe exacerbations and is associated with progression to COPD in the future. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01969344T4; URL: www.clinicaltrials.gov

One quarter of individuals with Preserved Ratio Impaired Spirometry (PRISm) will develop airflow obstruction, but there are no established methods to identify these individuals. We examined the utility of FVC/TLC in identifying features of obstructive lung disease. The ratio of post-bronchodilator FVC and TLCCT from chest CT (FVC/TLCCT) among current and former smokers with PRISm (FEV1/FVC ≥ 0.7 and FEV1 CT quartiles and (1) baseline characteristics, (2) respiratory exacerbations, (3) progression to COPD at 5 years, and (4) all-cause mortality. Among participants with PRISm at baseline (n = 1,131), the very low FVC/TLCCT quartile was associated with increased gas trapping and emphysema, and higher rates of progression to COPD at 5 years (36% versus 17%; p CT quartile was associated with increased total (IRR = 1.65; 95% CI [1.07–2.54]) and severe (IRR = 2.24; 95% CI [1.29–3.89]) respiratory exacerbations. Mortality was lower in the very high FVC/TLCCT quartile relative to the other quartiles combined. Reduced FVC/TLCCT ratio in PRISm is associated with increased symptoms, radiographic emphysema and gas trapping, exacerbations, and progression to COPD.

Background The effect of ICU telemedicine on transfers is not well studied. This study tests the hypothesis that ICU telemedicine decreases ICU patient interhospital transfers. Methods Data were retrieved for patients admitted to 306 Veterans Affairs ICUs in 117 acute care facilities between 2011 and 2015. Telemedicine was provided to 52 ICUs in 23 acute care facilities by two support centers located in Minneapolis and Cincinnati. We compared interhospital transfer rates in ICU telemedicine-affiliated hospitals with transfer rates of facilities with no telemedicine program. We used generalized linear mixed multivariable models to assess the association of ICU telemedicine with transfer rates and 30-day mortality. Results A total of 553,523 admissions to Veterans Affairs ICUs (97,256 to telemedicine hospitals; 456,267 to non-telemedicine hospitals) were analyzed. Transfers decreased from 3.46% to 1.99% in the telemedicine hospitals and from 2.03% to 1.68% in the non-telemedicine facilities between pre- and post-telemedicine implementation periods (P Conclusions ICU telemedicine was associated with a decrease in interhospital ICU transfers.

Background The burden of frequent respiratory exacerbations in COPD patients with mild-to-moderate spirometric impairment and smokers with preserved lung function is unknown. Methods We categorized COPD participants in COPDGene with post-bronchodilator FEV1%predicted≥50% by the annual exacerbation frequency into three groups: i)frequent exacerbators (top 5%; n = 109), ii)exacerbators (>0 but less than frequent exacerbators; n = 1,009), and iii)No exacerbation (n = 981). Exacerbations were defined as respiratory episodes requiring antibiotics and/or systemic steroids. We performed a Cox proportional hazards regression analysis to examine the association with mortality. We repeated the same process in current/former smokers with preserved spirometry (FEV1≥80%predicted and FEV1/FVC≥0.7). Results Among 2,099 COPD participants, frequent exacerbators had ≥1.8 exacerbations/year and were responsible for 34.3% of the total exacerbations. There were 102 (10.4%) deaths in the group with no exacerbations, 119 (11.8%) in the exacerbator group, and 24 (22%) in the frequent exacerbators. Adjusted mortality in frequent exacerbators was higher relative to individuals with no exacerbations (hazard ratio (HR) = 1.98; 95%CI = 1.25–3.13). An increase in frequency of exacerbations by one exacerbation/year was associated with increased mortality (HR = 1.40,95%CI = 1.21–1.62). Among 3,143 participants with preserved spirometry, frequent exacerbators had ≥0.8 exacerbations/year and were responsible for more than half of the exacerbations. There were 93 (4.2%) deaths in the group with no exacerbations, 28 (3.8%) in the exacerbator group, and 14 (7.6%) in the frequent exacerbators. The adjusted mortality was increased in frequent exacerbators with preserved spirometry relative to those with no exacerbations (HR = 2.25; 95%CI = 1.26–4.01). Conclusions In COPD participants with mild-to-moderate spirometric impairment and smokers with preserved spirometry, the frequent exacerbator phenotype is responsible for a large proportion of total exacerbations and associated with high mortality.

Background: Chronic obstructive pulmonary disease (COPD) remains a major cause of morbidity and mortality. Present-day diagnostic criteria are largely based solely on spirometric criteria. Accumulating evidence has identified a substantial number of individuals without spirometric evidence of COPD who suffer from respiratory symptoms and/or increased morbidity and mortality. There is a clear need for an expanded definition of COPD that is linked to physiologic, structural (computed tomography [CT]) and clinical evidence of disease. Using data from the COPD Genetic Epidemiology study (COPDGene(®)), we hypothesized that an integrated approach that includes environmental exposure, clinical symptoms, chest CT imaging and spirometry better defines disease and captures the likelihood of progression of respiratory obstruction and mortality. Methods: Four key disease characteristics – environmental exposure (cigarette smoking), clinical symptoms (dyspnea and/or chronic bronchitis), chest CT imaging abnormalities (emphysema, gas trapping and/or airway wall thickening), and abnormal spirometry – were evaluated in a group of 8784 current and former smokers who were participants in COPDGene(®) Phase 1. Using these 4 disease characteristics, 8 categories of participants were identified and evaluated for odds of spirometric disease progression (FEV(1) > 350 ml loss over 5 years), and the hazard ratio for all-cause mortality was examined. Results: Using smokers without symptoms, CT imaging abnormalities or airflow obstruction as the reference population, individuals were classified as Possible COPD, Probable COPD and Definite COPD. Current Global initiative for obstructive Lung Disease (GOLD) criteria would diagnose 4062 (46%) of the 8784 study participants with COPD. The proposed COPDGene(®) 2019 diagnostic criteria would add an additional 3144 participants. Under the new criteria, 82% of the 8784 study participants would be diagnosed with Possible, Probable or Definite COPD. These COPD groups showed increased risk of disease progression and mortality. Mortality increased in patients as the number of their COPD characteristics increased, with a maximum hazard ratio for all cause-mortality of 5.18 (95% confidence interval [CI]: 4.15–6.48) in those with all 4 disease characteristics. Conclusions: A substantial portion of smokers with respiratory symptoms and imaging abnormalities do not manifest spirometric obstruction as defined by population normals. These individuals are at significant risk of death and spirometric disease progression. We propose to redefine the diagnosis of COPD through an integrated approach using environmental exposure, clinical symptoms, CT imaging and spirometric criteria. These expanded criteria offer the potential to stimulate both current and future interventions that could slow or halt disease progression in patients before disability or irreversible lung structural changes develop.

Rationale: The American Thoracic Society (ATS)/European Respiratory Society defines a positive bronchodilator response (BDR) by a composite of BDR in either forced expiratory volume in 1 second (FEV(1)) and/or forced vital capacity (FVC) greater than or equal to 12% and 200 ml (ATS-BDR). We hypothesized that ATS-BDR components would be differentially associated with important chronic obstructive pulmonary disease (COPD) outcomes. Objectives: To examine whether ATS-BDR components are differentially associated with clinical, functional, and radiographic features in COPD. Methods: We included subjects with COPD enrolled in the COPDGene study. In the main analysis, we excluded subjects with self-reported asthma. We categorized BDR into the following: 1) No-BDR, no BDR in either FEV(1) or FVC; 2) FEV(1)-BDR, BDR in FEV(1) but no BDR in FVC; 3) FVC-BDR, BDR in FVC but no BDR in FEV(1); and 4) Combined-BDR, BDR in both FEV(1) and FVC. We constructed multivariable logistic, linear, zero-inflated negative binomial, and Cox hazards models to examine the association of BDR categories with symptoms, computed tomography findings, change in FEV(1) over time, respiratory exacerbations, and mortality. We also created models using the ATS BDR definition (ATS-BDR) as the main independent variable. Results: Of 3,340 COPD subjects included in the analysis, 1,083 (32.43%) had ATS-BDR, 182 (5.45%) had FEV(1)-BDR, 522 (15.63%) had FVC-BDR, and 379 (11.34%) had Combined-BDR. All BDR categories were associated with FEV(1) decline compared with No-BDR. Compared with No-BDR, both ATS-BDR and Combined-BDR were associated with higher functional residual capacity %predicted, greater internal perimeter of 10 mm, and greater 6-minute-walk distance. In contrast to ATS-BDR, Combined-BDR was independently associated with less emphysema (adjusted beta regression coefficient, −1.67; 95% confidence interval [CI], −2.68 to −0.65; P = 0.001), more frequent respiratory exacerbations (incidence rate ratio, 1.25; 95% CI, 1.03–1.50; P = 0.02) and severe exacerbations (incidence rate ratio, 1.34; 95% CI, 1.05–1.71; P = 0.02), and lower mortality (adjusted hazards ratio, 0.76; 95% CI, 0.58–0.99; P = 0.046). Sensitivity analysis that included subjects with self-reported history of asthma showed similar findings. Conclusions: BDR in both FEV(1) and FVC indicates a COPD phenotype with asthma-like characteristics, and provides clinically more meaningful information than current definitions of BDR.

In this chapter, we describe how to build a centralized tele-ICU program. We provide information regarding the various tele-ICU operational models, the roles of the tele-ICU staff, and the technological requirements. We provide suggestions for the optimal design of a tele-ICU hub and the ICUs participating in an ICU telemedicine program. We also describe what administrators and healthcare providers need to consider prior to starting a telemedicine program, common pitfalls, and few interesting cases of tele-ICU designs.

Background: Chronic obstructive pulmonary disease (COPD) remains a major cause of morbidity and mortality. Present-day diagnostic criteria are largely based solely on spirometric criteria. Accumulating evidence has identified a substantial number of individuals without spirometric evidence of COPD who suffer from respiratory symptoms and/or increased morbidity and mortality. There is a clear need for an expanded definition of COPD that is linked to physiologic, structural (computed tomography [CT]) and clinical evidence of disease. Using data from the COPD Genetic Epidemiology study (COPDGene®), we hypothesized that an integrated approach that includes environmental exposure, clinical symptoms, chest CT imaging and spirometry better defines disease and captures the likelihood of progression of respiratory obstruction and mortality. Methods: Four key disease characteristics – environmental exposure (cigarette smoking), clinical symptoms (dyspnea and/or chronic bronchitis), chest CT imaging abnormalities (emphysema, gas trapping and/or airway wall thickening), and abnormal spirometry – were evaluated in a group of 8784 current and former smokers who were participants in COPDGene® Phase 1. Using these 4 disease characteristics, 8 categories of participants were identified and evaluated for odds of spirometric disease progression (FEV1 > 350 ml loss over 5 years), and the hazard ratio for all-cause mortality was examined. Results: Using smokers without symptoms, CT imaging abnormalities or airflow obstruction as the reference population, individuals were classified as Possible COPD, Probable COPD and Definite COPD. Current Global initiative for obstructive Lung Disease (GOLD) criteria would diagnose 4062 (46%) of the 8784 study participants with COPD. The proposed COPDGene® 2019 diagnostic criteria would add an additional 3144 participants. Under the new criteria, 82% of the 8784 study participants would be diagnosed with Possible, Probable or Definite COPD. These COPD groups showed increased risk of disease progression and mortality. Mortality increased in patients as the number of their COPD characteristics increased, with a maximum hazard ratio for all cause-mortality of 5.18 (95% confidence interval [CI]: 4.15–6.48) in those with all 4 disease characteristics. Conclusions: A substantial portion of smokers with respiratory symptoms and imaging abnormalities do not manifest spirometric obstruction as defined by population normals. These individuals are at significant risk of death and spirometric disease progression. We propose to redefine the diagnosis of COPD through an integrated approach using environmental exposure, clinical symptoms, CT imaging and spirometric criteria. These expanded criteria offer the potential to stimulate both current and future interventions that could slow or halt disease progression in patients before disability or irreversible lung structural changes develop.