Heat and Cold Wave-Related Mortality Risk among United States Veterans with Chronic Obstructive Pulmonary Disease: A Case-Crossover Study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous pulmonary disease affecting 16 million Americans. Individuals with COPD are susceptible to environmental disturbances including heat and cold waves that can exacerbate disease symptoms. OBJECTIVE: Our objective was to estimate heat and cold wave-associated mortality risks within a population diagnosed with a chronic respiratory disease. METHODS: We collected individual level data with geocoded residential addresses from the Veterans Health Administration on 377,545 deceased patients with COPD (2016 to 2021). A time stratified case-crossover study was designed to estimate the incidence rate ratios (IRR) of heat and cold wave mortality risks using conditional logistic regression models examining lagged effects up to 7 d. Attributable risks (AR) were calculated for the lag day with the strongest association for heat and cold waves, respectively. Effect modification by age, gender, race, and ethnicity was also explored. RESULTS: Heat waves had the strongest effect on all-cause mortality at lag day 0 [IRR: 1.04; 95% confidence interval (CI): 1.02, 1.06] with attenuated effects by lag day 1. The AR at lag day 0 was 651 (95% CI: 326, 975) per 100,000 veterans. The effect of cold waves steadily increased from lag day 2 and plateaued at lag day 4 (IRR: 1.04; 95% CI: 1.02, 1.07) with declining but still elevated effects over the remaining 7-d lag period. The AR at lag day 4 was 687 (95% CI: 344, 1,200) per 100,000 veterans. Differences in risk were also detected upon stratification by gender and race. DISCUSSION: Our study demonstrated harmful associations between heat and cold waves among a high-risk population of veterans with COPD using individual level health data. Future research should emphasize using individual level data to better estimate the associations between extreme weather events and health outcomes for high-risk populations with chronic medical conditions. https://doi.org/10.1289/EHP13176.

Individual Risk Factors of PM2.5 Associated With Wintertime Mortality in Urban Patients With COPD.

BACKGROUND: Air pollution contributes to premature mortality, but potential impacts differ in populations with existing disease, particularly for individuals with multiple risk factors. Although COPD increases vulnerability to air pollution, individuals with COPD and other individual risk factors are at the intersection of multiple risks and may be especially susceptible to the effect of acute outdoor air pollution. RESEARCH QUESTION: What is the association between wintertime air pollution and mortality in patients with COPD and the modifying role of individual risk factors? STUDY DESIGN AND METHODS: This study evaluated 19,243 deceased veterans with prior COPD diagnosis who had resided in 25 US metropolitan regions (2016-2019). Electronic health records included patient demographic characteristics; smoking status; and comorbidities such as asthma, coronary artery disease (CAD), obesity, and diabetes. Using geocoded addresses, individuals were assigned wintertime fine particulate matter (particulate matter smaller than 2.5 µg in diameter [PM2.5]) and nitrogen dioxide air pollution exposures. Associations between acute air pollution and mortality were estimated by using a time-stratified case-crossover design with a conditional logistic model, and individual risk differences were assessed according to stratified analysis. RESULTS: A 1.05 (95% CI, 1.02-1.09) mortality risk was estimated for each 10 µg/m3 increase in daily wintertime PM2.5). Older patients and Black individuals displayed elevated risk. Obesity was a substantial air pollution-related mortality risk factor (OR, 1.11; 95% CI, 1.01-1.23), and the estimated risk for individuals with obesity plus CAD or obesity plus diabetes was 16% higher. INTERPRETATION: Wintertime PM2.5 exposure was associated with elevated mortality risk in people with COPD, but individuals with multiple comorbidities, notably obesity, had high vulnerability. Our study suggests that obesity, CAD, and diabetes are understudied modifiers of air pollution-related risks for people with existing COPD.

Early Evidence of Chronic Obstructive Pulmonary Disease Obscured by Race-Specific Prediction Equations.

Rationale: The identification of early chronic obstructive pulmonary disease (COPD) is essential to appropriately counsel patients regarding smoking cessation, provide symptomatic treatment, and eventually develop disease-modifying treatments. Disease severity in COPD is defined using race-specific spirometry equations. These may disadvantage non-White individuals in diagnosis and care. Objectives: Determine the impact of race-specific equations on African American (AA) versus non-Hispanic White individuals. Methods: Cross-sectional analyses of the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) cohort were conducted, comparing non-Hispanic White (n = 6,766) and AA (n = 3,366) participants for COPD manifestations. Measurements and Main Results: Spirometric classifications using race-specific, multiethnic, and "race-reversed" prediction equations (NHANES [National Health and Nutrition Examination Survey] and Global Lung Function Initiative "Other" and "Global") were compared, as were respiratory symptoms, 6-minute-walk distance, computed tomography imaging, respiratory exacerbations, and St. George's Respiratory Questionnaire. Application of different prediction equations to the cohort resulted in different classifications by stage, with NHANES and Global Lung Function Initiative race-specific equations being minimally different, but race-reversed equations moving AA participants to more severe stages and especially between the Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 0 and preserved ratio impaired spirometry groups. Classification using the established NHANES race-specific equations demonstrated that for each of GOLD stages 1-4, AA participants were younger, had fewer pack-years and more current smoking, but had more exacerbations, shorter 6-minute-walk distance, greater dyspnea, and worse BODE (body mass index, airway obstruction, dyspnea, and exercise capacity) scores and St. George's Respiratory Questionnaire scores. Differences were greatest in GOLD stages 1 and 2. Race-reversed equations reclassified 774 AA participants (43%) from GOLD stage 0 to preserved ratio impaired spirometry. Conclusions: Race-specific equations underestimated disease severity among AA participants. These effects were particularly evident in early disease and may result in late detection of COPD.

Guideline-discordant inhaler regimens after COPD hospitalization: associations with rurality, drive time to care, and fragmented care - a United States cohort study.

Background: Many patients receive guideline-discordant inhaler regimens after chronic obstructive pulmonary disease (COPD) hospitalization. Geography and fragmented care across multiple providers likely influence prescription of guideline-discordant inhaler regimens, but these have not been comprehensively studied. We assessed patient-level differences in guideline-discordant inhaler regimens by rurality, drive time to pulmonary specialty care, and fragmented care. Methods: Retrospective cohort analysis using national Veterans Health Administration (VA) data among patients who received primary care and prescriptions from the VA. Patients hospitalized for COPD exacerbation between 2017 and 2020 were assessed for guideline-discordant inhaler regimens in the subsequent 3 months. Guideline-discordant inhaler regimens were defined as short-acting inhaler/s only, inhaled corticosteroid (ICS) monotherapy, long-acting beta-agonist (LABA) monotherapy, ICS + LABA, long-acting muscarinic antagonist (LAMA) monotherapy, or LAMA + ICS. Rural residence and drive time to the closest pulmonary specialty care were obtained from geocoded addresses. Fragmented care was defined as hospitalization outside the VA. We used multivariable logistic regression models to assess associations between rurality, drive time, fragmentated care, and guideline-discordant inhaler regimens. Models were adjusted for age, sex, race/ethnicity, Charlson Comorbidity Index, Area Deprivation Index, and region. Findings: Of 33,785 patients, 16,398 (48.6%) received guideline-discordant inhaler regimens 3 months after hospitalization. Rural residents had higher odds of guideline-discordant inhalers regimens compared to their urban counterparts (adjusted odds ratio [aOR] 1.18 [95% CI: 1.12-1.23]). The odds of receiving guideline-discordant inhaler regimens increased with longer drive time to pulmonary specialty care (aOR 1.38 [95% CI: 1.30-1.46] for drive time >90 min compared to <30 min). Fragmented care was also associated with higher odds of guideline-discordant inhaler regimens (aOR 1.56 [95% CI: 1.48-1.63]). Interpretation: Rurality, long drive time to care, and fragmented care were associated with greater prescription of guideline-discordant inhaler regimens after COPD hospitalization. These findings highlight the need to understand challenges in delivering evidence-based care. Funding: NIHNCATS grants KL2TR002492 and UL1TR002494.

Bilirubin-associated single nucleotide polymorphism (SNP) and respiratory health outcomes: a mendelian randomization study.

BACKGROUND: Observational studies have shown an association between higher bilirubin levels and improved respiratory health outcomes. Targeting higher bilirubin levels has been proposed as a novel therapeutic strategy in COPD. However, bilirubin levels are influenced by multiple intrinsic and extrinsic factors, and these observational studies are prone to confounding. Genetic analyses are one approach to overcoming residual confounding in observational studies. OBJECTIVES: To test associations between a genetic determinant of bilirubin levels and respiratory health outcomes. METHODS: COPDGene participants underwent genotyping at the baseline visit. We confirmed established associations between homozygosity for rs6742078 and higher bilirubin, and between higher bilirubin and decreased risk of acute respiratory events within this cohort. For our primary analysis, we used negative binomial regression to test associations between homozygosity for rs6742078 and rate of acute respiratory events. RESULTS: 8,727 participants (n = 6,228 non-Hispanic white and 2,499 African American) were included. Higher bilirubin was associated with decreased rate of acute respiratory events [incidence rate ratio (IRR) 0.85, 95% CI 0.75 to 0.96 per SD increase in bilirubin intensity]. We did not find significant associations between homozygosity for rs6742078 and acute respiratory events (IRR 0.94, 95% CI 0.70 to 1.25 for non-Hispanic white and 1.09, 95% CI 0.91 to 1.31 for African American participants). CONCLUSIONS: A genetic determinant of higher bilirubin levels was not associated with better respiratory health outcomes. These results do not support targeting higher bilirubin levels as a therapeutic strategy in COPD.

Race-Specific Spirometry Equations Do Not Improve Models of Dyspnea and Quantitative Chest CT Phenotypes.

BACKGROUND: Race-specific spirometry reference equations are used globally to interpret lung function for clinical, research, and occupational purposes, but inclusion of race is under scrutiny. RESEARCH QUESTION: Does including self-identified race in spirometry reference equation formation improve the ability of predicted FEV1 values to explain quantitative chest CT abnormalities, dyspnea, or Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification? STUDY DESIGN AND METHODS: Using data from healthy adults who have never smoked in both the National Health and Nutrition Survey (2007-2012) and COPDGene study cohorts, race-neutral, race-free, and race-specific prediction equations were generated for FEV1. Using sensitivity/specificity, multivariable logistic regression, and random forest models, these equations were applied in a cross-sectional analysis to populations of individuals who currently smoke and individuals who formerly smoked to determine how they affected GOLD classification and the fit of models predicting quantitative chest CT phenotypes or dyspnea. RESULTS: Race-specific equations showed no advantage relative to race-neutral or race-free equations in models of quantitative chest CT phenotypes or dyspnea. Race-neutral reference equations reclassified up to 19% of Black participants into more severe GOLD classes, while race-neutral/race-free equations may improve model fit for dyspnea symptoms relative to race-specific equations. INTERPRETATION: Race-specific equations offered no advantage over race-neutral/race-free equations in three distinct explanatory models of dyspnea and chest CT scan abnormalities. Race-neutral/race-free reference equations may improve pulmonary disease diagnoses and treatment in populations highly vulnerable to lung disease.

Sociodemographic and Geographic Risk Factors for All-Cause Mortality in Patients with COPD.

Background: Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. Identifying both individual and community risk factors associated with higher mortality is essential to improve outcomes. Few population-based studies of mortality in COPD include both individual characteristics and community risk factors. Objective: We used geocoded, patient-level data to describe the associations between individual demographics, neighborhood socioeconomic status, and all-cause mortality. Methods: We performed a nationally representative retrospective cohort analysis of all patients enrolled in the Veteran Health Administration with at least one ICD-9 or ICD-10 code for COPD in 2016-2019. We obtained demographic characteristics, comorbidities, and geocoded residential address. Area Deprivation Index and rurality were classified using individual geocoded residential addresses. We used logistic regression models to assess the association between these characteristics and age-adjusted all-cause mortality. Results: Of 1,106,163 COPD patients, 33.4% were deceased as of January 2021. In age-adjusted models, having more comorbidities, Black/African American race (OR 1.09 [95% CI: 1.08-1.11]), and higher neighborhood disadvantage (OR 1.30 [95% CI: 1.28-1.32]) were associated with all-cause mortality. Female sex (OR 0.67 [95% CI: 0.65-0.69]), Asian race (OR 0.64, [95% CI: 0.59-0.70]), and living in a more rural area were associated with lower odds of all-cause mortality. After adjusting for age, comorbidities, neighborhood socioeconomic status, and rurality, the association with Black/African American race reversed. Conclusion: All-cause mortality in COPD patients is disproportionately higher in patients living in poorer neighborhoods and urban areas, suggesting the impact of social determinants of health on COPD outcomes. Black race was associated with higher age-adjusted all-cause mortality, but this association was abrogated after adjusting for gender, socioeconomic status, comorbidities, and urbanicity. Future studies should focus on exploring mechanisms by which disparities arise and developing interventions to address these.

Association of rural living with COPD-related hospitalizations and deaths in US veterans.

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 COPD diagnosis between 2011 and 2014 that had follow-up data 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 long-term mortality. Of 152,065 patients, 80,162 (52.7%) experienced at least one AECOPD-related hospitalization. After adjusting for demographics and comorbidities, rural living was associated with fewer hospitalizations (relative risk-RR = 0.90; 95% CI: 0.89-0.91; P < 0.001) but isolated rural living was not associated with hospitalizations. Only after accounting for travel time to the closest VA medical center, neighborhood disadvantage, and air quality, isolated rural living was associated with more AECOPD-related hospitalizations (RR = 1.07; 95% CI: 1.05-1.09; P < 0.001). Mortality did not vary between rural and urban living patients. Our findings suggest that other aspects than hospital care may be responsible for the excess of hospitalizations in isolated rural patients like poor access to appropriate outpatient care.

Use of the Spirometric "Fixed-Ratio" Underdiagnoses COPD in African-Americans in a Longitudinal Cohort Study.

BACKGROUND: COPD diagnosis is tightly linked to the fixed-ratio spirometry criteria of FEV1/FVC < 0.7. African-Americans are less often diagnosed with COPD. OBJECTIVE: Compare COPD diagnosis by fixed-ratio with findings and outcomes by race. DESIGN: Genetic Epidemiology of COPD (COPDGene) (2007-present), cross-sectional comparing non-Hispanic white (NHW) and African-American (AA) participants for COPD diagnosis, manifestations, and outcomes. SETTING: Multicenter, longitudinal US cohort study. PARTICIPANTS: Current or former smokers with ≥ 10-pack-year smoking history enrolled at 21 clinical centers including over-sampling of participants with known COPD and AA. Exclusions were pre-existing non-COPD lung disease, except for a history of asthma. MEASUREMENTS: Subject diagnosis by conventional criteria. Mortality, imaging, respiratory symptoms, function, and socioeconomic characteristics, including area deprivation index (ADI). Matched analysis (age, sex, and smoking status) of AA vs. NHW within participants without diagnosed COPD (GOLD 0; FEV1 ≥ 80% predicted and FEV1/FVC ≥ 0.7). RESULTS: Using the fixed ratio, 70% of AA (n = 3366) were classified as non-COPD, versus 49% of NHW (n = 6766). AA smokers were younger (55 vs. 62 years), more often current smoking (80% vs. 39%), with fewer pack-years but similar 12-year mortality. Density distribution plots for FEV1 and FVC raw spirometry values showed disproportionate reductions in FVC relative to FEV1 in AA that systematically led to higher ratios. The matched analysis demonstrated GOLD 0 AA had greater symptoms, worse DLCO, spirometry, BODE scores (1.03 vs 0.54, p < 0.0001), and greater deprivation than NHW. LIMITATIONS: Lack of an alternative diagnostic metric for comparison. CONCLUSIONS: The fixed-ratio spirometric criteria for COPD underdiagnosed potential COPD in AA participants when compared to broader diagnostic criteria. Disproportionate reductions in FVC relative to FEV1 leading to higher FEV1/FVC were identified in these participants and associated with deprivation. Broader diagnostic criteria for COPD are needed to identify the disease across all populations.

Prevalence of abnormal spirometry in individuals with a smoking history and no known obstructive lung disease.

INTRODUCTION: Recent evidence suggests a high prevalence of undiagnosed chronic obstructive pulmonary disease (COPD). These individuals are at risk of exacerbations and delayed treatment. We analyzed an at-risk population for the prevalence of abnormal spirometry to provide clarity into who should undergo early spirometry. METHODS: We analyzed data from the COPDGene study. Participants with ≥10 pack-years of smoking were included. Individuals with self-reported or physician-diagnosed COPD, asthma, chronic bronchitis, emphysema and/or were on inhalers were excluded. Parsimonious multivariable logistic regression models identified factors associated with abnormal spirometry, defined as either airflow obstruction (AFO) or preserved ratio impaired spirometry. Variables were selected for the final model using a stepwise backward variable elimination process which minimized Akaike information criterion (AIC). Similarly, during the 5-year follow-up period, we assessed factors associated with incident diagnosis of COPD. RESULTS: Of 5055 individuals, 1064 (21%) had undiagnosed AFO. Age, pack-years, current smoking and a history of acute bronchitis were associated with AFO while body mass index, female sex, and Black race were inversely associated. Among 2800 participants with 5-year follow-up, 532 (19%) had an incident diagnosis of COPD. Associated risk factors included mMRC ≥2, chronic productive cough, respiratory exacerbations during the follow-up period, and abnormal spirometry. Age was inversely associated. CONCLUSIONS: The prevalence of undiagnosed COPD is high in at-risk populations. We found multiple factors associated with undiagnosed COPD and incident diagnosis of COPD at follow up. These results can be used to identify those at risk for undiagnosed COPD to facilitate earlier diagnosis and treatment.

Drive Time and Receipt of Guideline-Recommended Screening, Diagnosis, and Treatment.

Importance: Many patients do not receive recommended services. Drive time to health care services may affect receipt of guideline-recommended care, but this has not been comprehensively studied. Objective: To assess associations between drive time to care and receipt of guideline-recommended screening, diagnosis, and treatment interventions. Design, Setting, and Participants: This cohort study used administrative data from the National Veterans Health Administration (VA) data merged with Medicare data. Eligible participants were patients using VA services between January 2016 and December 2019. Women ages 65 years or older without underlying bone disease were assessed for osteoporosis screening. Patients with new diagnosis of chronic obstructive pulmonary disease (COPD) indicated by at least 2 encounter codes for COPD or at least 1 COPD-related hospitalization were assessed for receipt of diagnostic spirometry. Patients hospitalized for ischemic heart disease were assessed for cardiac rehabilitation treatment. Exposures: Drive time from each patient's residential address to the closest VA facility where the service was available, measured using geocoded addresses. Main Outcomes and Measures: Binary outcome at the patient level for receipt of osteoporosis screening, spirometry, and cardiac rehabilitation. Multivariable logistic regression models were used to assess associations between drive time and receipt of services. Results: Of 110 780 eligible women analyzed, 36 431 (32.9%) had osteoporosis screening (mean [SD] age, 66.7 [5.4] years; 19 422 [17.5%] Black, 63 403 [57.2%] White). Of 281 130 patients with new COPD diagnosis, 145 249 (51.7%) had spirometry (mean [SD] age, 68.2 [11.5] years; 268 999 [95.7%] men; 37 834 [13.5%] Black, 217 608 [77.4%] White). Of 73 146 patients hospitalized for ischemic heart disease, 11 171 (15.3%) had cardiac rehabilitation (mean [SD] age, 70.0 [10.8] years; 71 217 [97.4%] men; 15 213 [20.8%] Black, 52 144 [71.3%] White). The odds of receiving recommended services declined as drive times increased. Compared with patients with a drive time of 30 minutes or less, patients with a drive time of 61 to 90 minutes had lower odds of receiving osteoporosis screening (adjusted odds ratio [aOR], 0.90; 95% CI, 0.86-0.95) and spirometry (aOR, 0.90; 95% CI, 0.88-0.92) while patients with a drive time of 91 to 120 minutes had lower odds of receiving cardiac rehabilitation (aOR, 0.80; 95% CI, 0.74-0.87). Results were similar in analyses restricted to urban patients or patients whose primary care clinic was in a tertiary care center. Conclusions and Relevance: In this retrospective cohort study, longer drive time was associated with less frequent receipt of guideline-recommended services across multiple components of care. To improve quality of care and health outcomes, health systems and clinicians should adopt strategies to mitigate travel burden, even for urban patients.

Beyond Access: Factors Associated With Spirometry Underutilization Among Patients With a Diagnosis of COPD in Urban Tertiary Care Centers.

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 <55 years, patients 75-84 years had an adjusted odds ratio (aOR) of undergoing spirometry of 0.80 (95% confidence interval [CI]:0.72-0.90), while patients ≥85 years had an aOR of 0.47 (95%CI: 0.40-0.54). Compared to patients with a Charlson Comorbidity Index (CCI) ≥3, patients with a CCI of 0 had an aOR of 0.60 (95%CI:0.54-0.67). Patients who had not seen a pulmonary specialist had lower odds of receiving spirometry (aOR 0.38 [95%CI:0.35-0.41]). Conclusion: Spirometry underutilization persists among patients who are less likely to have access barriers related to travel, insurance, and availability of spirometry. Spirometry underutilization is associated with older age, not having received pulmonary care, and having fewer comorbidities. COPD care quality initiatives will need to address these factors.

Chronotropic index during 6-minute walk and acute respiratory events in COPDGene.

BACKGROUND: Lower heart rate (HR) increases during exercise and slower HR recovery (HRR) after exercise are markers of worse autonomic function that may be associated with risk of acute respiratory events (ARE). METHODS: Data from 6-min walk testing (6MWT) in COPDGene were used to calculate the chronotropic index (CI) [(HR immediately post 6MWT - resting HR)/((220 - age) - resting HR)] and HRR at 1 min after 6MWT completion. We used zero-inflated negative binomial regression to test associations of CI and HRR with rates of any ARE (requiring steroids and/or antibiotics) and severe ARE (requiring emergency department visit or hospitalization), among all participants and in spirometry subgroups (normal, chronic obstructive pulmonary disease [COPD], and preserved ratio with impaired spirometry). RESULTS: Among 4,484 participants, mean follow-up time was 4.1 years, and 1,966 had COPD. Among all participants, CI-6MWT was not associated with rate of any ARE [adjusted incidence rate ratio (aIRR) 0.98 (0.95-1.01)], but higher CI-6MWT was associated with lower rate of severe ARE [0.95 (0.92-0.99)]. Higher HRR was associated with a lower rate of both any ARE [0.97 (0.95-0.99)] and severe ARE [0.95 (0.92-0.98)]. Results were similar in the COPD spirometry subgroup. CONCLUSION: Heart rate measures derived from 6MWT tests may have utility in predicting risk of acute respiratory events and COPD exacerbations.

Effectiveness and Harms of High-Flow Nasal Oxygen for Acute Respiratory Failure: An Evidence Report for a Clinical Guideline From the American College of Physicians.

BACKGROUND: Use of high-flow nasal oxygen (HFNO) for treatment of adults with acute respiratory failure (ARF) has increased. PURPOSE: To assess HFNO versus noninvasive ventilation (NIV) or conventional oxygen therapy (COT) for ARF in hospitalized adults. DATA SOURCES: English-language searches of MEDLINE, Embase, CINAHL, and Cochrane Library from January 2000 to July 2020; systematic review reference lists. STUDY SELECTION: 29 randomized controlled trials evaluated HFNO versus NIV (k = 11) or COT (k = 21). DATA EXTRACTION: Data extraction by a single investigator was verified by a second, 2 investigators assessed risk of bias, and evidence certainty was determined by consensus. DATA SYNTHESIS: Results are reported separately for HFNO versus NIV, for HFNO versus COT, and by initial or postextubation management. Compared with NIV, HFNO may reduce all-cause mortality, intubation, and hospital-acquired pneumonia and improve patient comfort in initial ARF management (low-certainty evidence) but not in postextubation management. Compared with COT, HFNO may reduce reintubation and improve patient comfort in postextubation ARF management (low-certainty evidence). LIMITATIONS: Trials varied in populations enrolled, ARF causes, and treatment protocols. Trial design, sample size, duration of treatment and follow-up, and results reporting were often insufficient to adequately assess many outcomes. Protocols, clinician and health system training, cost, and resource use were poorly characterized. CONCLUSION: Compared with NIV, HFNO as initial ARF management may improve several clinical outcomes. Compared with COT, HFNO as postextubation management may reduce reintubations and improve patient comfort; HFNO resulted in fewer harms than NIV or COT. Broad applicability, including required clinician and health system experience and resource use, is not well known. PRIMARY FUNDING SOURCE: American College of Physicians. (PROSPERO: CRD42019146691).

Serum bilirubin and chronic obstructive pulmonary disease (COPD): a systematic review.

BACKGROUND: Bilirubin is a potent antioxidant and higher serum bilirubin levels have been associated with improved COPD outcomes. We performed a systematic review to evaluate the association between serum bilirubin levels and lung function (FEV1), prevalence/incidence of COPD, acute exacerbations of COPD, respiratory health status, and mortality. METHODS: MEDLINE® and Embase were searched using Ovid® (search updated October 1st, 2019). We included studies that measured serum bilirubin levels and outcomes of interest in adults with or without underlying lung disease. We excluded studies of those with liver disease or drug-induced elevations in bilirubin. We used the Newcastle-Ottawa scale to assess individual study risk of bias (ROB) and the US Agency for Healthcare Research and Quality-Evidence Based Practice tool to assess overall strength of evidence (SOE). Two authors independently determined eligibility, performed data abstraction, assessed ROB, and determined SOE. RESULTS: Thirteen studies (5 low risk of bias, 3 moderate and 5 high risk) were included. We found low strength of evidence for the association between higher bilirubin levels and lower risk of acute exacerbations of COPD (2 studies), mortality (3 studies), COPD diagnosis (4 studies), and lung function (FEV1) (8 studies). We found insufficient evidence on the relationship between serum bilirubin and respiratory health status/exercise capacity (1 study) and airflow obstruction (FEV1/FVC ratio) (4 studies). CONCLUSION: Higher bilirubin levels may be associated with lower mortality and improved COPD outcomes. Randomized trials are needed to evaluate the effect of medications that raise serum bilirubin on COPD outcomes. PROSPERO registration: CRD42019145747.

Impact of gastroesophageal reflux on longitudinal lung function and quantitative computed tomography in the COPDGene cohort.

RATIONALE: Gastroesophageal reflux disease (GERD) is a common comorbidity in chronic obstructive pulmonary disease (COPD) and has been associated with increased risk of acute exacerbations, hospitalization, emergency room visits, costs, and quality-of-life impairment. However, it remains unclear whether GERD contributes to the progression of COPD as measured by lung function or computed tomography. OBJECTIVE: To determine the impact of GERD on longitudinal changes in lung function and radiographic lung disease in the COPDGene cohort. METHODS: We evaluated 5728 participants in the COPDGene cohort who completed Phase I (baseline) and Phase II (5-year follow-up) visits. GERD status was based on participant-reported physician diagnoses. We evaluated associations between GERD and annualized changes in lung function [forced expired volume in 1 s (FEV1) and forced vital capacity (FVC)] and quantitative computed tomography (QCT) metrics of airway disease and emphysema using multivariable regression models. These associations were further evaluated in the setting of GERD treatment with proton-pump inhibitors (PPI) and/or histamine-receptor 2 blockers (H2 blockers). RESULTS: GERD was reported by 2101 (36.7%) participants at either Phase I and/or Phase II. GERD was not associated with significant differences in slopes of FEV1 (difference of - 2.53 mL/year; 95% confidence interval (CI), - 5.43 to 0.37) or FVC (difference of - 3.05 mL/year; 95% CI, - 7.29 to 1.19), but the odds of rapid FEV1 decline of ≥40 mL/year was higher in those with GERD (adjusted odds ratio (OR) 1.20; 95%CI, 1.07 to 1.35). Participants with GERD had increased progression of QCT-measured air trapping (0.159%/year; 95% CI, 0.054 to 0.264), but not other QCT metrics such as airway wall area/thickness or emphysema. Among those with GERD, use of PPI and/or H2 blockers was associated with faster decline in FEV1 (difference of - 6.61 mL/year; 95% CI, - 11.9 to - 1.36) and FVC (difference of - 9.26 mL/year; 95% CI, - 17.2 to - 1.28). CONCLUSIONS: GERD was associated with faster COPD disease progression as measured by rapid FEV1 decline and QCT-measured air trapping, but not by slopes of lung function. The magnitude of the differences was clinically small, but given the high prevalence of GERD, further investigation is warranted to understand the potential disease-modifying role of GERD in COPD pathogenesis and progression. CLINICAL TRIALS REGISTRATION: NCT00608764 .

The Oral-Lung Axis: The Impact of Oral Health on Lung Health.

Poor oral health has long been recognized as a clinical risk factor for developing lung infections. Recent data using culture-independent techniques assessing the microbiome in healthy subjects have demonstrated that chronic microaspiration establishes a very similar microbial community between the mouth and lung, suggesting these 2 anatomic regions are closely intertwined. Dental disease is driven and aided by a dysbiosis in the oral microbiome, and evidence is mounting that implicates the microbiome in a variety of lung diseases including asthma, COPD, pulmonary fibrosis, and pneumonia. This review describes common dental conditions and potential mechanisms by which poor oral health may contribute to lung disease. We also review the current literature drawing associations between poor oral health and lung disease.

Effectiveness and harms of high-flow nasal oxygen (HFNO) for acute respiratory failure: a systematic review protocol.

INTRODUCTION: High-flow nasal oxygen (HFNO) use in adults hospitalised with acute respiratory failure (ARF) is increasing. However, evidence to support widespread use of HFNO compared with non-invasive ventilation (NIV) and conventional oxygen therapy (COT) is unclear. This protocol describes the methods for a systematic evidence review regarding the comparative effectiveness and harms of HFNO compared with NIV or COT for the management of ARF in hospitalised adult patients. METHODS AND ANALYSIS: We will search MEDLINE, Embase, CINAHL and Cochrane Library for randomised-controlled trials (RCTs) of adult patients hospitalised with ARF or who developed ARF while hospitalised. ARF will be defined as SpO 2 <90%, PaO 2 :FiO 2 ratio ≤300, PaO 2 ≤60 mm Hg, or PaCO 2 ≥45 mm Hg. The intervention is HFNO (humidified oxygen, flow rate ≥20 L/min) compared separately to NIV or COT. The critical outcomes are: all-cause mortality, hospital-acquired pneumonia, intubation/reintubation (days of intubation), intensive care unit admission/transfers, patient comfort and hospital length of stay. The important outcomes are: delirium, 30-day hospital readmissions, barotrauma, compromised nutrition (enteral or parenteral nutrition), gastric dysfunction, functional independence at discharge and skin breakdown or pressure ulcers. We will calculate risk ratios and Peto ORs (for rare events) and corresponding 95% CIs for categorical outcomes. Mean and standardised mean difference will be calculated for continuous outcomes. Where possible and appropriate, meta-analysis will be performed for each outcome. CONCLUSION: This systematic review will provide a comprehensive evaluation of the evidence regarding the comparative effectiveness and harms of HFNO compared with NIV or COT for the management of ARF in hospitalised adult patients to inform clinical practice and to identify research gaps in the management of ARF in hospitalised adults. The results will inform the work of the American College of Physicians-Clinical Guidelines Committee in their development of a clinical guideline related to use of HFNO in adult patients with ARF. ETHICS AND DISSEMINATION: No ethical approval will be needed because we will be using data from previously published studies in which informed consent was obtained by the primary investigators. We will publish our results in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42019146691.