Biomarkers of Inflammation and Longitudinal Evaluation of Lung Function, Physical Activity, and Grip Strength: A Secondary Analysis in the CASCADE Study.

Rationale: Physical activity, lung function, and grip strength are associated with exacerbations, hospitalizations, and mortality in people with chronic obstructive pulmonary disease (COPD). We tested whether baseline inflammatory biomarkers were associated with longitudinal outcomes of these physiologic measurements. Methods: The COPD Activity: Serotonin Transporter, Cytokines, and Depression (CASCADE) study was a prospective observational study of individuals with COPD. Fourteen inflammatory biomarkers were measured at baseline. Participants were followed for 2 years. We analyzed associations between baseline biomarkers and FEV1, physical activity, and grip strength. We used a hierarchical hypothesis testing procedure to reduce type I error. We used Pearson correlations to test associations between baseline biomarkers and longitudinal changes in the outcomes of interest. We used Fisher's linear discriminant analysis to test if linear combinations of baseline biomarkers predict rapid FEV1 decline. Finally, we used linear mixed modeling to test associations between baseline biomarkers and outcomes of interest at baseline, year 1, and year 2; models were adjusted for age, smoking status, baseline biomarkers, and FEV1. Results: 302 participants (age 67.5 ± 8.5 years, 19.5% female, 28.5% currently smoking) were included. Baseline biomarkers were not associated with longitudinal changes in grip strength, physical activity, or rapid FEV1 decline. Higher IL-6 and CRP were associated with lower physical activity at baseline and these relationships persisted at year 1 and year 2. Conclusion: Baseline inflammatory biomarkers did not predict changes in lung function or physical activity, but higher inflammatory biomarkers were associated with persistently low levels of physical activity.

Association between P-pulmonale and respiratory morbidity in COPD: a secondary analysis of the BLOCK-COPD trial.

RATIONALE: Pulmonary hypertension (PH) in COPD confers increased risk of exacerbations (ECOPD). Electrocardiogram (ECG) indicators of PH are prognostic both in PH and COPD. In the Beta-Blockers for the Prevention of Acute Exacerbations of COPD (BLOCK-COPD) trial, metoprolol increased risk of severe ECOPD through unclear mechanisms. OBJECTIVE: We evaluated whether an ECG indicator of PH, P-pulmonale, would be associated with ECOPD and whether participants with P-pulmonale randomized to metoprolol were at higher risk of ECOPD and worsened respiratory symptoms given the potential detrimental effects of beta-blockers in PH. METHODS: ECGs of 501 participants were analyzed for P-pulmonale (P wave enlargement in lead II). Cox proportional hazards models evaluated for associations between P-pulmonale and time to ECOPD (all and severe) for all participants and by treatment assignment (metoprolol vs. placebo). Linear mixed-effects models evaluated the association between treatment assignment and P-pulmonale on change in symptom scores (measured by CAT and SOBQ). RESULTS: We identified no association between P-pulmonale and risk of any ECOPD or severe ECOPD. However, in individuals with P-pulmonale, metoprolol was associated with increased risk for ECOPD (aHR 2.92, 95% CI: 1.45-5.85). There was no association between metoprolol and ECOPD in individuals without P-pulmonale (aHR 1.01, 95% CI: 0.77-1.31). Individuals with P-pulmonale assigned to metoprolol experienced worsening symptoms (mean increase of 3.95, 95% CI: 1.32-6.58) whereas those assigned to placebo experienced a mean improvement in CAT score of -2.45 (95% CI: -0.30- -4.61). CONCLUSIONS: In individuals with P-pulmonale, metoprolol was associated with increased exacerbation risk and worsened symptoms. These findings may explain the findings observed in BLOCK-COPD.

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.

Cardiovascular Autonomic Function and Incident Chronic Obstructive Pulmonary Disease Hospitalizations in Atherosclerosis Risk in Communities.

Rationale: The autonomic nervous system extensively innervates the lungs, but its role in chronic obstructive pulmonary disease (COPD) outcomes has not been well studied. Objective: We assessed relationships between cardiovascular autonomic nervous system measures (heart rate variability [HRV] and orthostatic hypotension [OH]) and incident COPD hospitalization in the multicenter ARIC (Atherosclerosis Risk In Communities) study. Methods: We used Cox proportional hazards regression models to estimate hazard ratios and 95% confidence intervals between baseline (1987-1989) autonomic function measures (HRV measures from 2-minute electrocardiograms and OH variables) and incident COPD hospitalizations through 2019. Adjusted analyses included demographic data, smoking status, lung function, comorbidities, and physical activity. We also performed analyses stratified by baseline airflow obstruction. Results: Of the 11,625 participants, (mean age, 53.8 yr), 56.5% were female and 26.3% identified as Black. Baseline mean percentage predicted forced expiratory volume in 1 second was 94 ± 17% (standard deviation), and 2,599 participants (22.4%) had airflow obstruction. During a median follow-up time of 26.9 years, there were 2,406 incident COPD hospitalizations. Higher HRV (i.e., better autonomic function) was associated with a lower risk of incident COPD hospitalization. Markers of worse autonomic function (OH and greater orthostatic changes in systolic and diastolic blood pressure) were associated with a higher risk of incident COPD hospitalization (hazard ratio for the presence of OH, 1.5; 95% confidence interval, 1.25-1.92). In stratified analyses, results were more robust in participants without airflow obstruction at baseline. Conclusions: In this large multicenter prospective community cohort, better cardiovascular autonomic function at baseline was associated with a lower risk of subsequent hospitalization for COPD, particularly among participants without evidence of lung disease at baseline.

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.

Lung Function and the Risk of Exacerbation in the ß-Blockers for the Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease Trial.

Rationale: The BLOCK COPD (ß-Blockers for the Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease) study found that metoprolol was associated with a higher risk of severe exacerbation. Objectives: To determine the mechanism underlying these results, we compared changes in lung function over the course of the study between treatment groups and evaluated whether baseline bronchodilator response or early reduction in forced expiratory volume in 1 second (FEV1) or forced vital capacity (FVC) was associated with exacerbation risk. Methods: We compared changes in lung function (FEV1 and FVC) over the treatment period between treatment groups using linear mixed-effect models. Cox proportional hazards models were used to evaluate the association between baseline bronchodilator responsiveness (FEV1, FVC, and combined FEV1 and FVC), early post-randomization (14 d) change in lung function, and the interaction between treatment assignment and these measures with risk of any or severe or very severe exacerbations. Negative binomial models were used to evaluate the relationship between bronchodilator responsiveness, the interaction between bronchodilator responsiveness and treatment assignment, and exacerbation rate. Results: Over the 336-day treatment period, individuals in the metoprolol group had a significantly greater decrease in logarithmic FEV1 from baseline to visit on Day 28 than individuals in the placebo group. Individuals in the metoprolol group had a significantly greater decrease in FVC from baseline to visits on Days 14 and 28, and also a significantly greater decrease in logarithmic FVC from baseline to visits on Days 42 and 112 than individuals in the placebo group. There were no associations between early lung function reduction or interactions between lung function reduction and treatment assignment and time to any or severe or very severe exacerbations. There were no interactions between treatment arm and baseline bronchodilator responsiveness measures on risk or rate of exacerbations. However, those with baseline FVC bronchodilator responsiveness had a higher rate of severe or very severe exacerbations (adjusted rate ratio, 1.62; 95% confidence interval, 1.04-2.48). Conclusions: Metoprolol was associated with reduced lung function during the early part of the treatment period, but these effects were modest and did not persist. Early lung function reduction and baseline bronchodilator responsiveness did not interact with the treatment arm to predict exacerbations; however, baseline FVC bronchodilator responsiveness was associated with a 60% higher rate of severe or very severe exacerbations. Clinical trial registered with www.clinicaltrials.gov (NCT02587351).

Heart Rate Variability on 10-Second Electrocardiogram and Risk of Acute Exacerbation of COPD: A Secondary Analysis of the BLOCK COPD Trial.

Introduction: Autonomic dysfunction is common in chronic obstructive pulmonary disease (COPD), and worse autonomic function may be a marker of risk for acute exacerbations of COPD (AECOPD). Heart rate variability (HRV) is a measure of autonomic function. Our objective was to test whether lower (worse) HRV is a risk factor for AECOPD. Methods: We measured standard deviation of normal RR intervals (SDNN) and root mean square of successive RR interval differences (RMSSD) on 10-second electrocardiograms (ECGs) performed at screening and day 42 in participants in the Beta Blockers for the Prevention of Acute Exacerbations of COPD trial ( BLOCK-COPD), a placebo-controlled trial of metoprolol for prevention of AECOPD. We used Cox-proportional hazards models to test if these HRV measures were associated with risk of any AECOPD, and separately, hospitalized AECOPD. We tested associations using baseline HRV measures and incorporating HRV measures from day 42 as a time-varying covariate. We also tested for interactions with metoprolol assignment. Results: Of 532 trial participants, 529 (forced expiratory volume in 1 second [FEV1 ]41 ± 16.3 % predicted) were included in this analysis. We did not find a significant association between HRV measures and risk of AECOPD when all participants were analyzed together. There was a significant interaction between RMSSD and assignment to metoprolol on time to first hospitalized AECOPD; in the placebo group greater RMSSD was associated with a lower risk of hospitalized AECOPD (adjusted hazard ratio0.71, 95% confidence interval: 0.52 to 0.96, per 10 ms increase) but there was no association in the metoprolol group. Conclusions: Autonomic dysfunction as measured by HRV may be a risk factor for AECOPD. Future studies should analyze longer HRV recordings and their performance in broader samples of people with COPD, including those on beta-blockers.

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.

Identifying a Heart Rate Recovery Criterion After a 6-Minute Walk Test in COPD.

BACKGROUND: Slow heart rate recovery (HRR) after exercise is associated with autonomic dysfunction and increased mortality. What HRR criterion at 1-minute after a 6-minute walk test (6MWT) best defines pulmonary impairment?. STUDY DESIGN AND METHODS: A total of 5008 phase 2 COPDGene (NCT00608764) participants with smoking history were included. A total of 2127 had COPD and, of these, 385 were followed-up 5-years later. Lung surgery, transplant, bronchiectasis, atrial fibrillation, heart failure and pacemakers were exclusionary. HR was measured from pulse oximetry at end-walk and after 1-min seated recovery. A receiver operator characteristic (ROC) identified optimal HRR cut-off. Generalized linear regression determined HRR association with spirometry, chest CT, symptoms and exacerbations. RESULTS: HRR after 6MWT (bt/min) was categorized in quintiles: ≤5 (23.0% of participants), 6-10 (20.7%), 11-15 (18.9%), 16-22 (18.5%) and ≥23 (18.9%). Compared to HRR≤5, HRR≥11 was associated with (p<0.001): lower pre-walk HR and 1-min post HR; greater end-walk HR; greater 6MWD; greater FEV1%pred; lower airway wall area and wall thickness. HRR was positively associated with FEV1%pred and negatively associated with airway wall thickness. An optimal HRR ≤10 bt/min yielded an area under the ROC curve of 0.62 (95% CI 0.58-0.66) for identifying FEV1<30%pred. HRR≥11 bt/min was the lowest HRR associated with consistently less impairment in 6MWT, spirometry and CT variables. In COPD, HRR≤10 bt/min was associated with (p<0.001): ≥2 exacerbations in the previous year (OR=1.76[1.33-2.34]); CAT≥10 (OR=1.42[1.18-1.71]); mMRC≥2 (OR=1.42[1.19-1.69]); GOLD 4 (OR=1.98[1.44-2.73]) and GOLD D (OR=1.51[1.18-1.95]). HRR≤10 bt/min was predicted COPD exacerbations at 5-year follow-up (RR=1.83[1.07-3.12], P=0.027). CONCLUSION: HRR≤10 bt/min after 6MWT in COPD is associated with more severe expiratory flow limitation, airway wall thickening, worse dyspnoea and quality of life, and future exacerbations, suggesting that an abnormal HRR≤10 bt/min after a 6MWT may be used in a comprehensive assessment in COPD for risk of severity, symptoms and future exacerbations.

Chronotropic Index and Acute Exacerbations of Chronic Obstructive Pulmonary Disease: A Secondary Analysis of BLOCK COPD.

Rationale: The chronotropic index quantifies the proportion of the expected heart rate increase that is attained during exercise. The relationship between the chronotropic index and acute exacerbations of chronic obstructive pulmonary disease (AECOPDs) has not been evaluated. Objectives: To determine whether a higher chronotropic index during a 6-minute walk (CI-6MW) is associated with lower risk of AECOPD and whether the CI-6MW is a marker of susceptibility to adverse effects of metoprolol in chronic obstructive pulmonary disease (COPD). Methods: We analyzed data from the BLOCK COPD (Beta-Blockers for the Prevention of AECOPDs) trial. We used Cox proportional hazards models to investigate the relationship between the CI-6MW and the time to AECOPDs. We also tested for interactions between study group assignment (metoprolol vs. placebo) and the CI-6MW on the time to AECOPDs. Results: Four hundred seventy-seven participants with exacerbation-prone COPD (mean forced expiratory volume in 1 second, 41% of predicted) were included in this analysis. A higher CI-6MW was independently associated with a decreased risk of AECOPDs of any severity (adjusted hazard ratio per 0.1 increase in CI-6MW of 0.88; 95% confidence interval, 0.80-0.96) but was not independently associated with AECOPDs requiring hospitalization (adjusted hazard ratio, 0.94; 95% confidence interval, 0.81-1.05). There was a significant interaction by treatment assignment, and in a stratified analysis, the protective effects of a higher CI-6MW on AECOPDs were negated by metoprolol use. Conclusions: A higher CI-6MW is associated with a decreased risk of AECOPDs and may be an indicator of susceptibility to the adverse effects of metoprolol.

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.

Best Practices in Resident Research- A National Survey of High Functioning Internal Medicine Residency Programs in Resident Research in USA.

PURPOSE: Meaningful participation in research for both faculty and residents is generally viewed to be an essential component of residency training. To better understand best practices in residency research, the authors conducted a survey among Internal Medicine (IM) Residency Programs with experience in research. METHODS: Phone interviews were conducted with a convenience sample of Residency Program Directors (PDs). Survey responses were analyzed across the following domains: size and makeup of the residency and research programs, resources for research, role of the PD/research director (RD), profile of trainees doing research, curriculum description, scope of research, role of mentors, career choices and determinants of success. RESULTS: Fifteen programs were included in the study. Across these programs, approximately two-thirds of residents were involved in research during their training . Eighty percent of the programs required an application for residents to engage in research. Ninety-two percent of the programs had a RD but only 58% had a formal research curriculum. Clinical research projects were the most common types of research. On average, two-thirds of residents involved in research submitted abstracts to regional and/or national meetings. The factor most frequently associated with resident research success was an effective faculty research mentor. CONCLUSIONS: Research success during residency is multifactorial. The authors propose that having a robust structure for research that is led by a residency RD, and the presence of effective mentors and strong administrative support are critical for success.

Observed controls on resilience of groundwater to climate variability in sub-Saharan Africa.

Groundwater in sub-Saharan Africa supports livelihoods and poverty alleviation1,2, maintains vital ecosystems, and strongly influences terrestrial water and energy budgets3. Yet the hydrological processes that govern groundwater recharge and sustainability-and their sensitivity to climatic variability-are poorly constrained4,5. Given the absence of firm observational constraints, it remains to be seen whether model-based projections of decreased water resources in dry parts of the region4 are justified. Here we show, through analysis of multidecadal groundwater hydrographs across sub-Saharan Africa, that levels of aridity dictate the predominant recharge processes, whereas local hydrogeology influences the type and sensitivity of precipitation-recharge relationships. Recharge in some humid locations varies by as little as five per cent (by coefficient of variation) across a wide range of annual precipitation values. Other regions, by contrast, show roughly linear precipitation-recharge relationships, with precipitation thresholds (of roughly ten millimetres or less per day) governing the initiation of recharge. These thresholds tend to rise as aridity increases, and recharge in drylands is more episodic and increasingly dominated by focused recharge through losses from ephemeral overland flows. Extreme annual recharge is commonly associated with intense rainfall and flooding events, themselves often driven by large-scale climate controls. Intense precipitation, even during years of lower overall precipitation, produces some of the largest years of recharge in some dry subtropical locations. Our results therefore challenge the 'high certainty' consensus regarding decreasing water resources4 in such regions of sub-Saharan Africa. The potential resilience of groundwater to climate variability in many areas that is revealed by these precipitation-recharge relationships is essential for informing reliable predictions of climate-change impacts and adaptation strategies.

Associations between baseline biomarkers and lung function in HIV-positive individuals.

OBJECTIVE: The aim of this study was to analyse the association of baseline biomarker data with cross-sectional lung function and subsequent decline in lung function in HIV-positive persons. DESIGN: Lung function was modelled in all START pulmonary substudy participants who had baseline biomarker data and good-quality spirometry. In longitudinal analyses, we restricted to those participants with at least one good-quality follow-up spirometry test. METHODS: We performed linear regression of baseline forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC and their longitudinal slopes on log2-transformed baseline biomarkers with adjustment for age, sex, race, region, smoking status, baseline CD4+ T-cell counts and baseline HIV-RNA. Biomarkers included D-dimer, high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, IL-27, serum amyloid A, soluble intercellular adhesion molecule (sICAM)-1, soluble vascular cell adhesion molecule (sVCAM)-1, albumin and total bilirubin. RESULTS: Among 903 included participants, baseline median age was 36 years, CD4+ cell count was 647 cells/µl, and 28.5% were current smokers. In adjusted analyses, elevated markers of systemic inflammation (hsCRP, IL-6 and serum amyloid A) were associated with lower baseline FEV1 and FVC. Elevated D-dimer and IL-6 were associated with worse airflow obstruction (lower FEV1/FVC). Despite these cross-sectional associations at baseline, no associations were found between baseline biomarkers and subsequent longitudinal lung function decline over a median follow-up time of 3.9 years (3293 spirometry-years of follow-up). CONCLUSION: Commonly available biomarkers, in particular markers of systemic inflammation, are associated with worse cross-sectional lung function, but do not associate with subsequent lung function decline among HIV-positive persons with early HIV infection and baseline CD4 T-cell counts more than 500 cells/µl.

Smoking and Accelerated Lung Function Decline in HIV-Positive Individuals: A Secondary Analysis of the START Pulmonary Substudy.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a leading cause of death and disability globally. Both cigarette smoking and HIV have been identified as independent risk factors for COPD. We used data from the strategic timing of antiretroviral treatment (START) Pulmonary Substudy to quantify the impact of smoking on rate of lung function decline in HIV. METHODS: We included START Pulmonary Substudy participants who contributed at least 2 good quality spirometry measures during the study. Slope of forced expiratory volume in 1 second (FEV1) was estimated using a repeated-measures model adjusted for the treatment group (immediate vs deferred treatment arm of START), age, sex, race, baseline COPD, and region. RESULTS: Of 1026 START Pulmonary Substudy participants, 915 (89%) were included in this analysis. Median follow-up time was 3.9 years. Smokers and nonsmokers were similar in baseline age (median 36 years), but smokers were more likely to be white, male, and from Europe/Israel/Australia. Smokers had faster average FEV1 decline compared with nonsmokers [-38.3 mL/yr vs -25.1 mL/yr; difference of -13.2 mL/yr (95% confidence interval: -23.6 to -2.7); P = 0.013], were more likely to meet criteria for rapid FEV1 decline [7.2%-11.7% more likely (P = 0.09-P = 0.002), depending on the definition of rapid decline], and had borderline, but not statistically significant, higher incident COPD during follow-up (9.7% vs 5.8%, P = 0.06). CONCLUSIONS: Compared to nonsmokers, HIV-positive smokers experience faster decline in lung function. These results underscore the need for a better understanding of how to best support smoking cessation among HIV-positive populations.