Tobacco use, self-reported professional dental cleaning habits, and lung adenocarcinoma diagnosis are associated with bronchial and lung microbiome alpha diversity.

RATIONALE: The lung microbiome is an inflammatory stimulus whose role in the development of lung malignancies is incompletely understood. We hypothesized that the lung microbiome associates with multiple clinical factors, including the presence of a lung malignancy. OBJECTIVES: To assess associations between the upper and lower airway microbiome and multiple clinical factors including lung malignancy. METHODS: We conducted a prospective cohort study of upper and lower airway microbiome samples from 44 subjects undergoing lung lobectomy for suspected or confirmed lung cancer. Subjects provided oral (2), induced sputum, nasopharyngeal, bronchial, and lung tissue (3) samples. Pathologic diagnosis, age, tobacco use, dental care history, lung function, and inhaled corticosteroid use were associated with upper and lower airway microbiome findings. MEASUREMENTS AND MAIN RESULTS: Older age was associated with greater Simpson diversity in the oral and nasopharyngeal sites (p = 0.022 and p = 0.019, respectively). Current tobacco use was associated with greater lung and bronchus Simpson diversity (p < 0.0001). Self-reported last profession dental cleaning more than 6 months prior (vs. 6 or fewer months prior) was associated with lower lung and bronchus Simpson diversity (p < 0.0001). Diagnosis of a lung adenocarcinoma (vs. other pathologic findings) was associated with lower bronchus and lung Simpson diversity (p = 0.024). Last professional dental cleaning, dichotomized as ≤ 6 months vs. >6 months prior, was associated with clustering among lung samples (p = 0.027, R2 = 0.016). Current tobacco use was associated with greater abundance of pulmonary pathogens Mycoplasmoides and Haemophilus in lower airway samples. Self-reported professional dental cleaning ≤ 6 months prior (vs. >6 months prior) was associated with greater bronchial Actinomyces and lung Streptococcus abundance. Lung adenocarcinoma (vs. no lung adenocarcinoma) was associated with lower Lawsonella abundance in lung samples. Inhaled corticosteroid use was associated with greater abundance of Haemophilus among oral samples and greater Staphylococcus among lung samples. CONCLUSIONS: Current tobacco use, recent dental cleaning, and a diagnosis of adenocarcinoma are associated with lung and bronchial microbiome α-diversity, composition (ß-diversity), and the abundance of several respiratory pathogens. These findings suggest that modifiable habits (tobacco use and dental care) may influence the lower airway microbiome. Larger controlled studies to investigate these potential associations are warranted.

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.

Sputum microbiome α-diversity is a key feature of the COPD frequent exacerbator phenotype.

Background: The lung microbiome is an inflammatory stimulus whose role in COPD pathogenesis is incompletely understood. We hypothesised that the frequent exacerbator phenotype is associated with decreased α-diversity and increased lung inflammation. Our objective was to assess correlations between the frequent exacerbator phenotype, the microbiome and inflammation longitudinally during exacerbation-free periods. Methods: We conducted a case-control longitudinal observational study of the frequent exacerbator phenotype and characteristics of the airway microbiome. 81 subjects (41 frequent and 40 infrequent exacerbators) provided nasal, oral and sputum microbiome samples at two visits over 2-4 months. Exacerbation phenotype, relevant clinical factors and sputum cytokine values were associated with microbiome findings. Results: The frequent exacerbator phenotype was associated with lower sputum microbiome α-diversity (p=0.0031). This decrease in α-diversity among frequent exacerbators was enhanced when the sputum bacterial culture was positive (p<0.001). Older age was associated with decreased sputum microbiome α-diversity (p=0.0030). Between-visit ß-diversity was increased among frequent exacerbators and those who experienced a COPD exacerbation between visits (p=0.025 and p=0.014, respectively). Sputum cytokine values did not differ based on exacerbation phenotype or other clinical characteristics. Interleukin (IL)-17A was negatively associated with α-diversity, while IL-6 and IL-8 were positively associated with α-diversity (p=0.012, p=0.012 and p=0.0496, respectively). IL-22, IL-17A and IL-5 levels were positively associated with Moraxella abundance (p=0.027, p=0.0014 and p=0.0020, respectively). Conclusions: Even during exacerbation-free intervals, the COPD frequent exacerbator phenotype is associated with decreased sputum microbiome α-diversity and increased ß-diversity. Decreased sputum microbiome α-diversity and Moraxella abundance are associated with lung inflammation.

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.

Levels of Urinary Mercapturic Acids of Acrolein, Methacrolein, Crotonaldehyde, and Methyl Vinyl Ketone in Relationship to Chronic Obstructive Pulmonary Disease in Cigarette Smokers of the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS).

Cigarette smoking is an established cause of chronic obstructive pulmonary disease (COPD). Numerous studies implicate acrolein, which occurs in relatively high concentrations in cigarette smoke and reacts readily with proteins, as one causative factor for COPD in smokers. Far less is known about the possible roles in COPD of the related α,ß-unsaturated carbonyl compounds of cigarette smoke crotonaldehyde, methacrolein, and methyl vinyl ketone. In the study reported here, we analyzed mercapturic acids of these α,ß-unsaturated compounds in the urine of 413 confirmed cigarette smokers in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS)─202 with COPD and 211 without COPD. The mercapturic acids analyzed were 3-hydroxypropyl mercapturic acid (3-HPMA) from acrolein, 3-hydroxy-1-methylpropyl mercapturic acid (HMPMA-1) from crotonaldehyde, 3-hydroxy-2-methylpropyl mercapturic acid (HMPMA-2) from methacrolein, and 3-hydroxy-3-methylpropyl mercapturic acid (HMPMA-3) from methyl vinyl ketone. In models adjusting for age, sex, race, pack years of tobacco use, and BMI, all four mercapturic acids were increased in individuals with COPD but not significantly. Stratified by the GOLD status, there were increased levels of the metabolites associated with GOLD 3-4 compared to that with GOLD 0, with the methacrolein metabolite HMPMA-2 reaching statistical significance (adjusted odds ratio 1.23 [95% CI: 1.00-1.53]). These results highlight the possible role of methacrolein, which has previously received little attention in this regard, as a causative factor in COPD in cigarette smokers.

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.

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.

Research Bronchoscopies in Critically Ill Research Participants: An Official American Thoracic Society Workshop Report.

Bronchoscopy for research purposes is a valuable tool to understand lung-specific biology in human participants. Despite published reports and active research protocols using this procedure in critically ill patients, no recent document encapsulates the important safety considerations and downstream applications of this procedure in this setting. The objectives were to identify safe practices for patient selection and protection of hospital staff, provide recommendations for sample procurement to standardize studies, and give guidance on sample preparation for novel research technologies. Seventeen international experts in the management of critically ill patients, bronchoscopy in clinical and research settings, and experience in patient-oriented clinical or translational research convened for a workshop. Review of relevant literature, expert presentations, and discussion generated the findings presented herein. The committee concludes that research bronchoscopy with bronchoalveolar lavage in critically ill patients on mechanical ventilation is valuable and safe in appropriately selected patients. This report includes recommendations on standardization of this procedure and prioritizes the reporting of sample management to produce more reproducible results between laboratories. This document serves as a resource to the community of researchers who endeavor to include bronchoscopy as part of their research protocols and highlights key considerations for the inclusion and safety of research participants.

Lung proteome and metabolome endotype in HIV-associated obstructive lung disease.

Purpose: Obstructive lung disease is increasingly common among persons with HIV, both smokers and nonsmokers. We used aptamer proteomics to identify proteins and associated pathways in HIV-associated obstructive lung disease. Methods: Bronchoalveolar lavage fluid (BALF) samples from 26 persons living with HIV with obstructive lung disease were matched to persons living with HIV without obstructive lung disease based on age, smoking status and antiretroviral treatment. 6414 proteins were measured using SomaScan® aptamer-based assay. We used sparse distance-weighted discrimination (sDWD) to test for a difference in protein expression and permutation tests to identify univariate associations between proteins and forced expiratory volume in 1 s % predicted (FEV1 % pred). Significant proteins were entered into a pathway over-representation analysis. We also constructed protein-driven endotypes using K-means clustering and performed over-representation analysis on the proteins that were significantly different between clusters. We compared protein-associated clusters to those obtained from BALF and plasma metabolomics data on the same patient cohort. Results: After filtering, we retained 3872 proteins for further analysis. Based on sDWD, protein expression was able to separate cases and controls. We found 575 proteins that were significantly correlated with FEV1 % pred after multiple comparisons adjustment. We identified two protein-driven endotypes, one of which was associated with poor lung function, and found that insulin and apoptosis pathways were differentially represented. We found similar clusters driven by metabolomics in BALF but not plasma. Conclusion: Protein expression differs in persons living with HIV with and without obstructive lung disease. We were not able to identify specific pathways differentially expressed among patients based on FEV1 % pred; however, we identified a unique protein endotype associated with insulin and apoptotic pathways.

Pneumoproteins and biomarkers of inflammation and coagulation do not predict rapid lung function decline in people living with HIV.

Chronic obstructive pulmonary disease (COPD) is among the leading causes of death worldwide and HIV is an independent risk factor for the development of COPD. However, the etiology of this increased risk and means to identify persons with HIV (PWH) at highest risk for COPD have remained elusive. Biomarkers may reveal etiologic pathways and allow better COPD risk stratification. We performed a matched case:control study of PWH in the Strategic Timing of Antiretoviral Treatment (START) pulmonary substudy. Cases had rapid lung function decline (> 40 mL/year FEV1 decline) and controls had stable lung function (+ 20 to - 20 mL/year). The analysis was performed in two distinct groups: (1) those who were virally suppressed for at least 6 months and (2) those with untreated HIV (from the START deferred treatment arm). We used linear mixed effects models to test the relationship between case:control status and blood concentrations of pneumoproteins (surfactant protein-D and club cell secretory protein), and biomarkers of inflammation (IL-6 and hsCRP) and coagulation (d-dimer and fibrinogen); concentrations were measured within ± 6 months of first included spirometry. We included an interaction with treatment group (untreated HIV vs viral suppression) to test if associations varied by treatment group. This analysis included 77 matched case:control pairs in the virally suppressed batch, and 42 matched case:control pairs in the untreated HIV batch (n = 238 total) who were followed for a median of 3 years. Median (IQR) CD4 + count was lowest in the controls with untreated HIV at 674 (580, 838). We found no significant associations between case:control status and pneumoprotein or biomarker concentrations in either virally suppressed or untreated PWH. In this cohort of relatively young, recently diagnosed PWH, concentrations of pneumoproteins and biomarkers of inflammation and coagulation were not associated with subsequent rapid lung function decline.Trial registration: NCT00867048 and NCT01797367.

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.

Lung and Plasma Metabolome in HIV-Associated Obstructive Lung Disease.

BACKGROUND: HIV is a risk factor for obstructive lung disease (OLD), independent of smoking. We used mass spectrometry (MS) approaches to identify metabolomic biomarkers that inform mechanistic pathogenesis of OLD in persons with HIV (PWH). METHODS: We obtained bronchoalveolar lavage fluid (BALF) samples from 52 PWH, in case:control (+OLD/-OLD) pairs matched on age, smoking status, and antiretroviral treatment. Four hundred nine metabolites from 8 families were measured on BALF and plasma samples using a MS-based Biocrates platform. After filtering metabolites with a high proportion of missing values and values below the level of detection, we performed univariate testing using paired t tests followed by false discovery rate corrections. We used distance-weighted discrimination (DWD) to test for an overall difference in the metabolite profile between cases and controls. RESULTS: After filtering, there were 252 BALF metabolites for analysis from 8 metabolite families. DWD testing found that collectively, BALF metabolites differentiated cases from controls, whereas plasma metabolites did not. In BALF samples, we identified 3 metabolites that correlated with OLD at the false discovery rate of 10%; all were in the phosphatidylcholine family. We identified additional BALF metabolites when analyzing lung function as a continuous variable, and these included acylcarnitines, triglycerides, and a cholesterol ester. CONCLUSIONS: Collectively, BALF metabolites differentiate PWH with and without OLD. These included several BALF lipid metabolites. These findings were limited to BALF and were not found in plasma from the same individuals. Phosphatidylcholine, the most common lipid component of surfactant, was the predominant lipid metabolite differentially expressed.

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.

Short Communication: A Pilot Study of the Effects of Losartan Versus Placebo on Pneumoproteins in HIV: A Secondary Analysis of a Randomized Double Blind Study.

HIV is an independent risk factor for lung disease, including chronic obstructive pulmonary disease (COPD) and emphysema. Angiotensin receptor blockers may be beneficial in COPD and emphysema through pathways that have been implicated in HIV-related lung disease. We performed a randomized comparison of the effects of losartan versus placebo on the plasma concentrations of the pneumoproteins, surfactant protein D (SPD) and club cell secretory protein (CCSP), in people living with HIV (PLWH). A total of 108 PLWH were included (52 assigned to losartan and 56 assigned to placebo). We found no difference in the change from baseline in log2 concentrations of CCSP or SPD over 1 year of follow-up. For SPD, we found a strong interaction by CD4+ counts, where those with CD4+ counts >350 cells/mm3 treated with losartan had more reduction (improvement) in SPD concentration than those treated with placebo (p value for interaction <.001). In conclusion, we did not find a beneficial effect of losartan on pneumoprotein concentrations in PLWH, but PLWH with higher CD4+ counts may have improvement in SPD when treated with losartan.

Metabolite profiles associated with disease progression in influenza infection.

BACKGROUND: We performed metabolomic profiling to identify metabolites that correlate with disease progression and death. METHODS: We performed a study of adults hospitalized with Influenza A(H1N1)pdm09. Cases (n = 32) were defined by a composite outcome of death or transfer to the intensive care unit during the 60-day follow-up period. Controls (n = 64) were survivors who did not require transfer to the ICU. Four hundred and eight metabolites from eight families were measured on plasma sample at enrollment using a mass spectrometry based Biocrates platform. Conditional logistic regression was used to summarize the association of the individual metabolites and families with the composite outcome and its major two components. RESULTS: The ten metabolites with the strongest association with disease progression belonged to five different metabolite families with sphingolipids being the most common. The acylcarnitines, glycerides, sphingolipids and biogenic metabolite families had the largest odds ratios based on the composite endpoint. The tryptophan odds ratio for the composite is largely associated with death (OR 17.33: 95% CI, 1.60-187.76). CONCLUSIONS: Individuals that develop disease progression when infected with Influenza H1N1 have a metabolite signature that differs from survivors. Low levels of tryptophan had a strong association with death. REGISTRY: ClinicalTrials.gov Identifier: NCT01056185.

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 .

Quantification of Perinodular Emphysema in High-risk Patients Offers No Benefit in Lung Nodule Risk-Stratification of Malignancy Potential.

PURPOSE: Pulmonary nodules, found either incidentally or on lung cancer screening, are common. Evaluating the benign or malignant nature of these nodules is costly in terms of patient risk and expense. The presence of both global and regional emphysema has been linked to increased lung cancer risk. We sought to determine whether the measurement of emphysema directly adjacent to a lung nodule could inform the likelihood of a nodule being malignant. MATERIALS AND METHODS: Within a population of Veterans at high risk for lung cancer, 58 subjects with malignant nodules found on computerized tomographic chest scans were matched by lobe and nodule size to 58 controls. Lung densitometry was measured via determination of the low attenuation area percentage at -950 Hounsfield units (LAA950) and the Hounsfield unit (HU) value at which 15% of lung voxels have a lower lung density (Perc15), at predefined lung volumes that encompassed the nodule to evaluate both perinodular and regional lung fields. The association between measured lung density and malignancy was investigated using conditional logistic regression models, with densitometry measurements used as the primary predictor, adjusting for age alone, or age and computerized tomographic scan characteristics. RESULTS: No significant differences in emphysema measurements between malignant and benign nodules were identified at lung volumes encompassing both perinodular and regional emphysema. Furthermore, emphysema quantification remained stable across lung volumes within individuals. CONCLUSIONS: In this study, quantifying the degree of perinodular or regional emphysema did not offer any benefit in the risk stratification of lung nodules.