Background

Little evidence on the validity of simple and widely applicable tools to predict mortality in patients with chronic obstructive pulmonary disease (COPD) exists.

Objective

To conduct a large international study to validate the ADO index that uses age, dyspnoea and FEV1 to predict 3-year mortality and to update it in order to make prediction of mortality in COPD patients as generalisable as possible.

Design

Individual subject data analysis of 10 European and American cohorts (n=13 914).

Setting

Population-based, primary, secondary and tertiary care.

Patients

COPD GOLD stages I–IV.

Measurements

We validated the original ADO index. We then obtained an updated ADO index in half of our cohorts to improve its predictive accuracy, which in turn was validated comprehensively in the remaining cohorts using discrimination, calibration and decision curve analysis and a number of sensitivity analyses.

Results

1350 (9.7%) of all subjects with COPD (60% male, mean age 61 years, mean FEV1 66% predicted) had died at 3 years. The original ADO index showed high discrimination but poor calibration (p<0.001 for difference between predicted and observed risk). The updated ADO index (scores from 0 to 14) preserved excellent discrimination (area under curve 0.81, 95% CI 0.80 to 0.82) but showed much improved calibration with predicted 3-year risks from 0.7% (95% CI 0.6% to 0.9%, score of 0) to 64.5% (61.2% to 67.7%, score of 14). The ADO index showed higher net benefit in subjects at low-to-moderate risk of 3-year mortality than FEV1 alone.

Interpretation

The updated 15-point ADO index accurately predicts 3-year mortality across the COPD severity spectrum and can be used to inform patients about their prognosis, clinical trial study design or benefit harm assessment of medical interventions.

Rationale

Though matrix metalloproteinases (MMPs) are critical in the pathogenesis of COPD, their utility as a disease biomarker remains uncertain. This study aimed to determine whether bronchoalveolar lavage (BALF) or plasma MMP measurements correlated with disease severity or functional decline in emphysema.

Methods

Enzyme-linked immunosorbent assay and luminex assays measured MMP-1, -9, -12 and tissue inhibitor of matrix metalloproteinase-1 in the BALF and plasma of non-smokers, smokers with normal lung function and moderate-to-severe emphysema subjects. In the cohort of 101 emphysema subjects correlative analyses were done to determine if MMP or TIMP-1 levels were associated with key disease parameters or change in lung function over an 18-month time period.

Main Results

Compared to non-smoking controls, MMP and TIMP-1 BALF levels were significantly elevated in the emphysema cohort. Though MMP-1 was elevated in both the normal smoker and emphysema groups, collagenase activity was only increased in the emphysema subjects. In contrast to BALF, plasma MMP-9 and TIMP-1 levels were actually decreased in the emphysema cohort compared to the control groups. Both in the BALF and plasma, MMP and TIMP-1 measurements in the emphysema subjects did not correlate with important disease parameters and were not predictive of subsequent functional decline.

Conclusions

MMPs are altered in the BALF and plasma of emphysema; however, the changes in MMPs correlate poorly with parameters of disease intensity or progression. Though MMPs are pivotal in the pathogenesis of COPD, these findings suggest that measuring MMPs will have limited utility as a prognostic marker in this disease.

Background

Information comparing subjective and objective measurements of adherence to study medications and the effects of adherence on treatment-related differences in asthma clinical trials are limited.

Objective

We sought to compare subjective and objective measurements of children’s adherence to inhaled corticosteroids or placebo and to determine whether adherence to study medications modified treatment-related differences in outcomes.

Methods

In an ancillary study conducted in 3 of 8 Childhood Asthma Management Program Clinical Centers, adherence was assessed by using self-reported and objective data in 5- to 12-year-old children with mild or moderate asthma who were randomly assigned to 200 μg of inhaled budesonide twice per day (n = 84) or placebo (n = 56) for 4 years. The κ statistic was used to evaluate agreement between self-reported adherence (daily diary cards) and objectively measured adherence (number of doses left in study inhalers). Multivariable analyses were used to determine whether adherence to study treatment modified treatment-related differences in outcomes.

Results

Adherence of less than 80% was seen in 75% of 140 children when adherence was measured objectively but only in 6% of children when measured by means of self-report. There was poor agreement between objective and subjective measurements of adherence of at least 80% (κ = 0.00; 95% CI, −0.05 to 0.04); self-reported adherence over the 4-year period generally overestimated objectively measured adherence (93.6% vs 60.8%, P < .0001). There was little evidence to indicate that adherence modified treatment-related differences in outcomes.

Conclusion

Researchers should use objective rather than self-reported adherence data to identify clinical trial participants with low levels of adherence to study treatment.

Asthma in the elderly (AIE) is under diagnosed and under treated and there is a paucity of knowledge. The National Institute on Aging convened this workshop to identify what is known, what gaps in knowledge remain and suggest research directions needed to improve the understanding and care of AIE. Asthma presenting at an advanced age often has similar clinical and physiologic consequences as seen with younger individuals but co-morbid illnesses and the psychosocial effects of aging may affect the diagnosis, clinical presentation and care of asthma in this population. At least two phenotypes exist among elderly asthma; those with long-standing asthma have more severe airflow limitation and less complete reversibility than those with late-onset asthma. Many challenges exist in the recognition and treatment of asthma in the elderly. Furthermore, the pathophysiological mechanisms of AIE are likely to be different from those seen in young asthmatics and these differences may influence the clinical course and outcomes of asthma in this population.

The extent by which early postnatal lung injury contributes to the development of chronic obstructive pulmonary disease (COPD) in the adult is unclear. We hypothesized that exposure to hyperoxia during early postnatal life can augment lung changes caused by adult chronic cigarette smoke (CS) exposure. C57BL/6J mice (1 d old) were exposed to hyperoxia (O2) for 5 days. At 1 month of age, half of the O2–exposed mice and half of the control mice were placed in a CS chamber for 6 months. After exposure to CS, mice underwent quasi-static pressure–volume curve and mean chord length measurements; quantification of pro–Sp-c expression; and measurement of lung IL-8/ KC, CXCR2/IL8Rα, TNF-α, and IL-6 mRNA by real-time PCR. Adult mice exposed to O2+CS had significantly larger chord length measurements (P < 0.02) and lung volumes at 35 cm H2O (P < 0.05) compared with all other groups. They also had significantly less pro–Sp-c protein and surfactant protein C mRNA expression (P < 0.003). Mice exposed to O2+CS and CS-only mice had significantly higher lung resistance and longer mean time constants (P < 0.01), significantly more inflammatory cells in the bronchoalveolar lavage fluid (P < 0.03), and significantly higher levels of lung CXCR2/IL8Rα mRNA compared with mice not exposed to smoke (P < 0.02). We conclude that exposure to early postnatal hyperoxia contributed additively to CS-induced COPD changes in adult mice. These results may be relevant to a growing population of preterm children who sustained lung injury in the newborn period and may be exposed to CS in later life.

Rationale: There are no accepted blood-based biomarkers in chronic obstructive pulmonary disease (COPD). Pulmonary and activation-regulated chemokine (PARC/CCL-18) is a lung-predominant inflammatory protein that is found in serum.

Objectives: To determine whether PARC/CCL-18 levels are elevated and modifiable in COPD and to determine their relationship to clinical end points of hospitalization and mortality.

Methods: PARC/CCL-18 was measured in serum samples from individuals who participated in the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) and LHS (Lung Health Study) studies and a prednisolone intervention study.

Measurements and Main Results: Serum PARC/CCL-18 levels were higher in subjects with COPD than in smokers or lifetime nonsmokers without COPD (105 vs. 81 vs. 80 ng/ml, respectively; P < 0.0001). Elevated PARC/CCL-18 levels were associated with increased risk of cardiovascular hospitalization or mortality in the LHS cohort and with total mortality in the ECLIPSE cohort.

Conclusions: Serum PARC/CCL-18 levels are elevated in COPD and track clinical outcomes. PARC/CCL-18, a lung-predominant chemokine, could be a useful blood biomarker in COPD.

Clinical trial registered with www.clinicaltrials.gov (NCT 00292552).

Background

Proximity to roadways increases the risk of asthma in developed countries; however, relatively little is known about this relationship in developing countries, where rapid and uncontrolled growth of cities has resulted in urban sprawl and heavy traffic volumes.

Objective

Determine the effect of distance from a heavily transited avenue on asthma symptoms and quantitative respiratory outcome measures in a peri-urban shanty town in Lima, Peru.

Methods

We enrolled 725 adolescents aged 13–15 years, administered a survey on asthma symptoms and measured spirometry, response to allergy skin testing and eNO. We calculated distances from the main avenue for all households and measured indoor PM in 100 households. We used multivariable regression to model the risk of asthma symptoms, risk of atopy, eNO and FEV1/FVC as a function of distance.

Results

Compared against 384 meters, the odds of current asthma symptoms in households living within 100 meters increased by a factor of 2 (p<0.05). The odds of atopy increased by a factor of 1.07 for every 100 meters difference in the distance from the avenue (p=0.03). We found an inverse relationship in pre-bronchodilator FEV1/FVC and distance to the avenue in females (p=0.01) but not in males. We did not find an association between eNO or household PM levels and distance.

Conclusion

Living in close proximity to a high traffic-density avenue in a peri-urban community in Peru was associated with a greater risk of asthma symptoms and atopy. Regulation of mobile source pollutants in peri-urban areas of developing countries may help reduce the burden of asthma symptoms and atopy.

Objectives

According to a large-scale international survey, Peru has one of the highest prevalences of asthma worldwide; however, data from this survey were limited to participants from urban Lima. The authors sought to characterise the epidemiology of asthma in Peru in two regions with disparate degrees of urbanisation. In this manuscript, the authors summarise the study design and implementation.

Design

A cross-sectional study.

Participants

Using census data of 13–15-year-old adolescents from two communities in Peru, the authors invited a random sample of participants in Lima (n=725) and all adolescents in Tumbes (n=716) to participate in our study.

Primary and secondary outcome measures

The authors asked participants to complete a questionnaire on asthma symptoms, environmental exposures and socio-demographics and to undergo spirometry before and after bronchodilator, skin allergy testing and exhaled nitric oxide testing. The authors obtained blood samples for haematocrit, total IgE levels, vitamin D levels and DNA in all participants and measured indoor particulate matter concentrations for 48 h in a random subset of 70–100 households at each site.

Results

Of 1851 eligible participants, 1441 (78%) were enrolled and 1159 (80% of enrolled) completed all physical tests. 1283 (89%) performed spirometry according to standard guidelines, of which 86% of prebronchodilator tests and 92% of postbronchodilator tests were acceptable and reproducible. 92% of allergy skin tests had an adequate negative control. The authors collected blood from 1146 participants (79%) and saliva samples from 148 participants (9%). Overall amounts of DNA obtained from blood or saliva were 25.8 μg, with a 260/280 ratio of 1.86.

Conclusions

This study will contribute to the characterisation of a variety of risk factors for asthma, including urbanisation, total IgE levels, vitamin D levels and candidate genes, in a resource-poor setting. The authors present data to support high quality of survey, allergic, spirometric and genetic data collected in our study.

Article summary

Article focus

We sought to characterise the epidemiology of asthma in Peru by studying two regions with disparate degrees of urbanisation.

We summarise the study design, implementation and standard operating procedures and provide quality control data for important outcome and exposure variables.

Key messages

We present data to support high quality of survey, allergic, spirometric and genetic data collected in our study.

Strengths and limitations of this study

This study will contribute to the characterisation of a variety of risk factors for asthma, including urbanisation, total IgE levels, vitamin D levels and candidate genes, in a resource-poor setting.

This study is cross-sectional and therefore does not track symptoms over time to directly determine causality. In addition, we did not collect stool samples to assess parasitic infections nor do we have information on respiratory infections in early childhood.

Background

Little is known about how drug presentation influences medication adherence.

Objective

Examine the effect of an educational program aimed at increasing expectations of treatment benefit on medication adherence.

Methods

Data are analyzed from 99 participants who underwent electronic drug monitoring during TAPE (Trial of Asthma Patient Education), a randomized placebo-controlled multi-center trial. Participants with suboptimally-controlled asthma were randomized to placebo or montelukast in conjunction with a presentation mode that was either neutral or designed to increase outcome expectancy. Adherence was monitored electronically over 4 weeks, and was defined as ≥ 80% use of prescribed doses. Outcome expectancy, peak expiratory flow, pre-bronchodilator forced expiratory volume, asthma control (ACQ), and asthma-related quality of life were assessed at baseline and at the 4-week follow-up.

Results

Average electronic medication adherence was 69.9%. There was a significant interaction between presentation mode and drug assignment, with participants in the enhanced/montelukast group having a higher change in outcome expectancy (Δ 2.1 points, p < 0.001) and better medication adherence (odds ratio 4.0, CI 1.1, 14.3) compared to those in the neutral/placebo group. There was no difference in asthma symptoms, quality of life, or clinical outcomes based on presentation mode. Rather, increased outcome expectancy was associated with modest improvements in asthma symptoms after adjusting for presentation mode, drug assignment, and medication adherence.

Conclusion

The use of an enhanced presentation aimed at increasing outcome expectancy may lead to improved medication adherence.

α-1 Antitrypsin (A1AT) is a serpin with a major protective effect against cigarette smoke–induced emphysema development, and patients with mutations of the A1AT gene display a markedly increased risk for developing emphysema. We reported that A1AT protects lung endothelial cells from apoptosis and inhibits caspase-3 activity. It is not clear if cigarette smoking or A1AT mutations alter the caspase-3 inhibitory activity of A1AT and if this serpin alters the function of other caspases. We tested the hypothesis that the caspase-3 inhibitory activity of A1AT is impaired by cigarette smoking and that the A1AT RCL, the key antiprotease domain of the serpin, is required for its interaction with the caspase. We examined the caspase-3 inhibitory activity of human A1AT purified from plasma of actively smoking and nonsmoking individuals, either affected or unaffected with chronic obstructive pulmonary disease. We also tested the caspase inhibitory activity of two mutant forms of A1AT, the recombinant human piZZ and the RCL–deleted (RCL-null) A1AT forms. A1AT purified from the blood of active smokers exhibited marked attenuation in its caspase-3 inhibitory activity, independent of disease status. In vitro exposure of the normal (MM) form of A1AT to cigarette smoke extract reduced its ability to interact with caspase-3, measured by isothermal titration calorimetry, as did the deletion of the RCL, but not the ZZ point mutation. In cell-free assays A1AT was capable of inhibiting all executioner caspases, -3, -7 and especially -6, but not the initiator or inflammatory caspases. The inhibitory effect of A1AT against caspase-6 was tested in vivo, where overexpression of both human MM and ZZ-A1AT via adeno-associated virus transduction significantly protected against apoptosis and against airspace damage induced by intratracheal instillation of caspase-6 in mice. These data indicate a specific inhibitory effect of A1AT on executioner caspases, which is profoundly attenuated by active exposure to cigarette smoking and is dependent on the protein RCL, but is not affected by the PiZZ mutation.

Objective

To determine whether asthma-specific quality of life during pregnancy is related to asthma exacerbations and to perinatal outcomes.

Methods

This was a secondary analysis of data from a randomized controlled trial of inhaled beclomethasone versus theophylline in the treatment of moderate asthma during pregnancy. The Juniper Asthma Quality of Life Questionnaire (AQLQ) was administered to patients at enrollment. Exacerbations were defined as asthma symptoms requiring a hospitalization, unscheduled medical visit, or oral corticosteroid course.

Results

Quality of life assessments were provided by 310 of the 385 participants who completed the study. There was more than a 25% decrease in the odds of a subsequent asthma exacerbation for every 1-point increase in AQLQ score for the overall score (odds ratio [OR] 0.73, 95% confidence interval [CI] 0.55–0.96), emotion domain (OR 0.72, 95% CI 0.59–0.88), and symptoms domain (OR 0.73, 95% CI 0.57–0.94). These relationships were not significantly influenced by initial symptom frequency or forced expiratory volume in 1 s (FEV1). No significant relationships were demonstrated between enrollment AQLQ scores and preeclampsia, preterm birth, low birth weight, or small for gestational age.

Conclusion

Asthma-specific quality of life in early pregnancy is related to subsequent asthma morbidity during pregnancy but not to perinatal outcomes.

Chronic obstructive pulmonary disease (COPD) is a prevalent smoking-related disease for which no disease-altering therapies currently exist. As dysregulated TGF-β signaling associates with lung pathology in patients with COPD and in animal models of lung injury induced by chronic exposure to cigarette smoke (CS), we postulated that inhibiting TGF-β signaling would protect against CS-induced lung injury. We first confirmed that TGF-β signaling was induced in the lungs of mice chronically exposed to CS as well as in COPD patient samples. Importantly, key pathological features of smoking-associated lung disease in patients, e.g., alveolar injury with overt emphysema and airway epithelial hyperplasia with fibrosis, accompanied CS-induced alveolar cell apoptosis caused by enhanced TGF-β signaling in CS-exposed mice. Systemic administration of a TGF-β–specific neutralizing antibody normalized TGF-β signaling and alveolar cell death, conferring improved lung architecture and lung mechanics in CS-exposed mice. Use of losartan, an angiotensin receptor type 1 blocker used widely in the clinic and known to antagonize TGF-β signaling, also improved oxidative stress, inflammation, metalloprotease activation and elastin remodeling. These data support our hypothesis that inhibition of TGF-β signaling through angiotensin receptor blockade can attenuate CS-induced lung injury in an established murine model. More importantly, our findings provide a preclinical platform for the development of other TGF-β–targeted therapies for patients with COPD.

Chronic obstructive pulmonary disease (COPD), which is caused primarily by cigarette smoking, is a major health problem worldwide. The progressive decline in lung function that occurs in COPD is a result of persistent inflammation of the airways and destruction of the lung parenchyma. Despite the key role of inflammation in the pathogenesis of COPD, treatment with corticosteroids — normally highly effective antiinflammatory drugs — has little therapeutic benefit. This corticosteroid resistance is largely caused by inactivation of histone deacetylase 2 (HDAC2), which is critical for the transrepressive activity of the glucocorticoid receptor (GR) that mediates the antiinflammatory effect of corticosteroids. Here, we show that in alveolar macrophages from patients with COPD, S-nitrosylation of HDAC2 is increased and that this abolishes its GR-transrepression activity and promotes corticosteroid insensitivity. Cys-262 and Cys-274 of HDAC2 were found to be the targets of S-nitrosylation, and exogenous glutathione treatment of macrophages from individuals with COPD restored HDAC2 activity. Treatment with sulforaphane, a small-molecule activator of the transcription factor nuclear factor erythroid 2–related factor 2 (NRF2), was also able to denitrosylate HDAC2, restoring dexamethasone sensitivity in alveolar macrophages from patients with COPD. These effects of sulforaphane were glutathione dependent. We conclude that NRF2 is a novel drug target for reversing corticosteroid resistance in COPD and other corticosteroid-resistant inflammatory diseases.

Background

Chronic obstructive pulmonary disease (COPD) is a leading cause of death and 70% of the cost of COPD is due to hospitalizations. Self-reported daily physical activity and health status have been reported as predictors of a hospitalization in COPD but are not routinely assessed.

Objectives

We tested the hypothesis that self-reported daily physical activity and health status assessed by a simple question were predictors of a hospitalization in a well-characterized cohort of patients with severe emphysema.

Methods

Investigators gathered daily physical activity and health status data assessed by a simple question in 597 patients with severe emphysema and tested the association of those patient-reported outcomes to the occurrence of a hospitalization in the following year. Multiple logistic regression analyses were used to determine predictors of hospitalization during the first 12 months after randomization.

Results

The two variables tested in the hypothesis were significant predictors of a hospitalization after adjusting for all univariable significant predictors: >2 h of physical activity per week had a protective effect [odds ratio (OR) 0.60; 95% confidence interval (95% CI) 0.41–0.88] and self-reported health status as fair or poor had a deleterious effect (OR 1.57; 95% CI 1.10–2.23). In addition, two other variables became significant in the multivariate model: total lung capacity (every 10% increase) had a protective effect (OR 0.88; 95% CI 0.78–0.99) and self-reported anxiety had a deleterious effect (OR 1.75; 95% CI 1.13–2.70).

Conclusion

Self-reported daily physical activity and health status are independently associated with COPD hospitalizations. Our findings, assessed by simple questions, suggest the value of patient-reported outcomes in developing risk assessment tools that are easy to use.

Background

Obstructive lung disease (OLD) is frequently unrecognized and undertreated. Urban drug users are at higher risk for OLD due to race, behavioral, and socioeconomic characteristics, yet little data exist on prevalence and risk factors associated with unrecognized OLD in this population.

Objective

The objective of this study is to determine the prevalence of unrecognized OLD in an urban population and identify the characteristics associated with lack of physician-diagnosed OLD.

Design

Cross-sectional analysis from the Acquired Immunodeficiency Syndrome Linked to the Intravenous Experience (ALIVE) study, an observational study of current and former injection drug users in Baltimore, Maryland, USA.

Participants

All participants with spirometry-defined airflow obstruction were stratified by the presence or absence of physician diagnosis of OLD.

Main measures

Using cross-sectional demographic, clinical, and spirometric measurements, multivariable regression models were generated to identify factors independently associated with unrecognized OLD.

Key results

Of the 1083 participants evaluated in the ALIVE lung substudy, 176 (16.3%) met spirometric criteria for OLD. Of those, only 88 (50%) had a physician diagnosis of OLD. The prevalence of unrecognized OLD decreased as severity of airflow obstruction increased. Factors independently associated with unrecognized OLD were absence of respiratory symptoms (prevalence ratio [PR], 1.70; 95% confidence interval [CI]: 1.29–2.23; P < 0.01) and less severe dyspnea (PR, 0.83; 95% CI: 0.72–0.96, per point increase in dyspnea scale; P = 0.01). In the subset of human immunodeficiency virus (HIV)–infected participants, the use of antiretroviral therapy (ART) was independently associated with an increased prevalence of unrecognized OLD (PR, 1.93; 95% CI: 1.05–3.56; P = 0.03).

Conclusions

In a cohort of current and former urban drug users, OLD is substantially underrecognized and associated with lack of respiratory symptoms. Relying on the presence of respiratory symptoms as a trigger to perform spirometry may result in a substantial underdiagnosis of OLD in this population. HIV-infected individuals receiving ART are a population particularly vulnerable to unrecognized OLD.

Background:

Scleroderma (SSc) patients with active interstitial lung disease (ILD) experience a decline in lung function and increased mortality; cyclophosphamide (CYC) therapy may stabilize lung function at one and two years follow-up. Long-term lung function and survival outcomes of SSc patients with ILD following CYC treatment remain largely unknown.

Methodology:

We reviewed records of SSc patients with active ILD who had received at least six months of CYC treatment and had pulmonary function tests (PFTs) performed at least two years from the onset of treatment.

Principal Findings:

Thirty eight patients meeting eligibility criteria had a mean follow-up period from start of CYC to the last follow-up PFT of 5.1 years (range 2.3 -10.8 years). At a median of 4.1 years (range 9 months - 8.4 years), 12/38 (32%) patients had a significant decline in % predicted Forced Vital Capacity from their baseline PFT. At a median of 3.9 years (range 7 months - 8.4 years); 12/36 (33%) patients experienced a significant decline in their % predicted carbon monoxide diffusing capacity. Three patients died at a follow-up between 4.5-6 years and two received bilateral lung transplants because of severe restrictive lung disease.

Conclusions:

While the majority of SSc patients treated with CYC for active ILD experience long-term lung function stability and survive, greater than 1/3 of patients will experience either lung function decline, death, or require a lung transplant. This suggests that despite aggressive immune suppressing therapy, a subset of patients will have continued lung function decline, highlighting the need for ongoing monitoring and better therapeutic options.

Rationale: Nuclear factor erythroid 2–related factor 2 (Nrf2), an important regulator of lung antioxidant defenses, declines in chronic obstructive pulmonary disease (COPD). However, Nrf2 also regulates the proteasome system that degrades damaged and misfolded proteins. Because accumulation of misfolded proteins in the endoplasmic reticulum (ER) causes ER stress and ER stress-induced apoptosis, Nrf2 may potentially prevent ER stress-mediated apoptosis in COPD.

Objectives: To determine whether Nrf2-regulated proteasome function affects ER stress-mediated apoptosis in COPD.

Methods: We assessed the expression of Nrf2, Nrf2-dependent proteasomal subunits, proteasomal activity, markers of ER stress, and apoptosis in emphysematous lungs of mice exposed to cigarette smoke (CS) as well as peripheral lung tissues from normal control subjects and patients with COPD.

Measurements and Main Results: Compared with wild-type mice, emphysematous lungs of CS-exposed Nrf2-deficient mice exhibited markedly lower proteasomal activity and elevated markers of ER stress and apoptosis. Furthermore, compared with normal control subjects, lungs of patients with mild and advanced COPD showed a marked decrease in the expression of Nrf2-regulated proteasomal subunits and total proteasomal activity. However, they were associated with greater levels of ER stress and apoptosis markers. In vitro studies have demonstrated that enhancing proteasomal activity in Beas2B cells either by sulforaphane, an activator of Nrf2, or overexpression of Nrf2-regulated proteasomal subunit PSMB6, significantly inhibited cigarette smoke condensate (CSC)-induced ER stress and cell death.

Conclusions: Impaired Nrf2 signaling causes significant decline in proteasomal activity and heightens ER stress response in lungs of patients with COPD and CS-exposed mice. Accordingly, pharmacological approaches that augment Nrf2 activity may protect against COPD progression by both up-regulating antioxidant defenses and relieving ER stress.

Rationale

Aquaporin-5 (AQP5) can cause mucus overproduction and lower lung function. Genetic variants in the AQP5 gene might be associated with rate of lung function decline in chronic obstructive pulmonary disease (COPD).

Methods

Five single nucleotide polymorphisms (SNPs) in AQP5 were genotyped in 429 European American individuals with COPD randomly selected from the NHLBI Lung Health Study. Mean annual decline in FEV1 % predicted, assessed over five years, was calculated as a linear regression slope, adjusting for potential covariates and stratified by smoking status. Constructs containing the wildtype allele and risk allele of the coding SNP N228K were generated using site-directed mutagenesis, and transfected into HBE-16 (human bronchial epithelial cell line). AQP5 abundance and localization were assessed by immunoblots and confocal immunofluoresence under control, shear stress and cigarette smoke extract (CSE 10%) exposed conditions to test for differential expression or localization.

Results

Among continuous smokers, three of the five SNPs tested showed significant associations (0.02>P>0.004) with rate of lung function decline; no associations were observed among the group of intermittent or former smokers. Haplotype tests revealed multiple association signals (0.012>P>0.0008) consistent with the single-SNP results. In HBE16 cells, shear stress and CSE led to a decrease in AQP5 abundance in the wild-type, but not in the N228K AQP5 plasmid.

Conclusions

Polymorphisms in AQP5 were associated with rate of lung function decline in continuous smokers with COPD. A missense mutation modulates AQP-5 expression in response to cigarette smoke extract and shear stress. These results suggest that AQP5 may be an important candidate gene for COPD.

Background

Gastroesophageal reflux (GER) is common in asthma patients but often has mild or no symptoms. It is not known whether treatment of GER with proton pump inhibitors (PPIs) in poorly-controlled asthmatics without GER symptoms can substantially improve asthma control.

Methods

402 asthmatics with inadequate asthma control despite inhaled corticosteroids and absent or minimal GER symptoms were randomly assigned to either esomeprazole 40mg b.i.d. or matching placebo in a parallel-group double-masked clinical trial. Participants were followed for 24 weeks with daily asthma diaries, every 4-week spirometry, and asthma symptom questionnaires. Participants were classified with respect to GER status with ambulatory pH probe monitoring. The primary outcome was the rate of episodes of poor asthma control (EPACs) based on asthma diaries.

Results

Episodes of poor asthma control occurred with similar frequency in the placebo and esomeprazole treatment groups (2.3 vs 2.5 events/person-year, respectively, P=0.66). There was no treatment effect with respect to components of the EPACs, or secondary outcomes including pulmonary function, airways reactivity, asthma control, symptom scores, nocturnal awakenings, or quality of life. GER documented by pH probe studies in 40% of participants with absent or minimal symptoms did not identify a subgroup benefitting from PPI treatment.

Conclusion

Despite a high prevalence of asymptomatic GER in patients with poorly controlled asthma, treatment with proton pump inhibitors does not improve control. Silent GER is not a likely cause of poorly controlled asthma.

Rationale: Silent gastroesophageal reflux (GER) is common in patients with asthma, but it is unclear whether GER is associated with worse asthma symptoms or reduced lung function.

Objectives: To determine in patients with poorly controlled asthma, whether proximal or distal esophageal reflux is associated with asthma severity, symptoms, physiology, or functional status.

Methods: Baseline asthma characteristics were measured in patients with asthma enrolled in a multicenter trial assessing the effectiveness of esomeprazole on asthma control. All participants underwent 24-hour esophageal pH probe monitoring. Lung function, methacholine responsiveness, asthma symptoms, and quality-of-life scores were compared in subjects with and without GER.

Measurements and Main Results: Of 304 participants with probe recordings, 53% had reflux. Of 242 participants with recordings of proximal pH, 38% had proximal reflux. There was no difference in need for short-acting bronchodilators, nocturnal awakenings, dose of inhaled corticosteroid, use of long-acting β-agonists, lung function, or methacholine reactivity between individuals with and without proximal or distal GER. Participants with GER reported more use of oral corticosteroids and had worse asthma quality of life and subjects with proximal GER had significantly worse asthma quality of life and health-related quality of life compared with participants without GER.

Conclusions: Asymptomatic GER is not associated with distinguishing asthma symptoms or lower lung function in individuals with suboptimal asthma control who are using inhaled corticosteroids. Patients with proximal reflux report significantly worse asthma and health-related quality of life despite lack of physiologic impairment or increase in asthma symptoms.

Clinical trial registered with www.clinicaltrials.gov (NCT00069823).

Background

Information that enhances expectations about drug effectiveness improves the response to placebos for pain. Although asthma often improves with placebo, it is not known whether the response to placebo or active treatment can be augmented by increasing expectation of benefit.

Objective

The study objective was to determine if response to placebo or a leukotriene antagonist (montelukast) can be augmented by messages that increase expectation of benefit.

Methods

A randomized 20-center controlled trial enrolled 601 asthmatics with poor symptom control were assigned to one of five study groups. Participants were randomly assigned to either four treatment groups in a factorial design: placebo with enhanced messages, placebo with neutral messages, montelukast with enhanced messages, or montelukast with neutral messages; or to usual care. Assignment to study drug was double-masked; assignment to message content was single-masked; usual care was not masked. The enhanced message aimed to increase expectation of benefit from the drug. The primary outcome was mean change in daily peak-flow over 4 weeks. Secondary outcomes included lung function and asthma symptom control.

Results

Peak flow and other lung function measures were not improved in participants assigned to the enhanced message groups versus neutral messages groups for either montelukast or placebo; no differences were noted between neutral placebo and usual care groups. Placebo-treated participants had improved asthma control with the enhanced message, but not montelukast-treated participants; neutral placebo did have improved asthma control compared to usual care after adjusting for baseline difference. Headaches were more common in participants provided messages that mentioned headache as a montelukast side effect.

Conclusions

Optimistic drug presentation augments the placebo effect for patient-reported outcomes (asthma control), but not lung function. However, the effect of montelukast was not enhanced by optimistic messages regarding treatment effectiveness.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous syndrome, including emphysema and airway disease. Phenotypes defined on the basis of chest computed tomography (CT) may decrease disease heterogeneity and aid in the identification of candidate genes for COPD subtypes. To identify these genes, we performed genome-wide linkage analysis in extended pedigrees from the Boston Early-Onset COPD Study, stratified by emphysema status (defined by chest CT scans) of the probands, followed by genetic association analysis of positional candidate genes. A region on chromosome 1p showed strong evidence of linkage to lung function traits in families of emphysema-predominant probands in the stratified analysis (LOD score = 2.99 in families of emphysema-predominant probands versus 1.98 in all families). Association analysis in 949 individuals from 127 early-onset COPD pedigrees revealed association for COPD-related traits with an intronic single-nucleotide polymorphism (SNP) in transforming growth factor-β receptor-3 (TGFBR3) (P = 0.005). This SNP was significantly associated with COPD affection status comparing 389 cases from the National Emphysema Treatment Trial to 472 control smokers (P = 0.04), and with FEV1 (P = 0.004) and CT emphysema (P = 0.05) in 3,117 subjects from the International COPD Genetics Network. Gene-level replication of association with lung function was seen in 427 patients with COPD from the Lung Health Study. In conclusion, stratified linkage analysis followed by association testing identified TGFBR3 (betaglycan) as a potential susceptibility gene for COPD. Published human microarray and murine linkage studies have also demonstrated the importance of TGFBR3 in emphysema and lung function, and our group and others have previously found association of COPD-related traits with TGFB1, a ligand for TGFBR3.

Rationale: In studies that address health-related quality of life (QoL) and survival, subjects who die are usually censored from QoL assessments. This practice tends to inflate the apparent benefits of interventions with a high risk of mortality. Assessing a composite QoL-death outcome is a potential solution to this problem.

Objectives: To determine the effect of lung volume reduction surgery (LVRS) on a composite endpoint consisting of the occurrence of death or a clinically meaningful decline in QoL defined as an increase of at least eight points in the St. George's Respiratory Questionnaire total score from the National Emphysema Treatment Trial.

Methods: In patients with chronic obstructive pulmonary disease and emphysema randomized to receive medical treatment (n = 610) or LVRS (n = 608), we analyzed the survival to the composite endpoint, the hazard functions and constructed prediction models of the slope of QoL decline.

Measurements and Main Results: The time to the composite endpoint was longer in the LVRS group (2 years) than the medical treatment group (1 year) (P < 0.0001). It was even longer in the subsets of patients undergoing LVRS without a high risk for perioperative death and with upper-lobe-predominant emphysema. The hazard for the composite event significantly favored the LVRS group, although it was most significant in patients with predominantly upper-lobe emphysema. The beneficial impact of LVRS on QoL decline was most significant during the 2 years after LVRS.

Conclusions: LVRS has a significant effect on the composite QoL-survival endpoint tested, indicating its meaningful palliative role, particularly in patients with upper-lobe–predominant emphysema.

Background

Assessment of asthma via spirometry in children is challenging due to often normal FEV1 values.

Objective

We used Mead’s slope ratio ( (dV•∕dV)∕(V•∕V) ) to analyze the shape of the flow volume loop.

Methods

We analyzed the effects of time, albuterol, and budesonide on FEV1, FEV1/FVC, FEF25-75%, and Mead’s slope ratio, early (between 75% and 50% of FVC, SR61) and late (between 75% and 50% of FVC, SR35) in exhalation, in the Childhood Asthma Management Program cohort at baseline, 4 months, and end of study in participants who received either inhaled placebo or budesonide BID.

Results

In the placebo group, both SR61 and SR35 improved over time. Bronchodilator consistently improved both SR61 and SR35, without change in degree of improvement over time. Similarly, in the budesonide group, time and bronchodilator each independently improved both SR61 and SR35. At 4 months and end of study, budesonide patients had significant improvements in SR61 relative to placebo patients, independent of bronchodilator effect. Budesonide and placebo were not different with respect to pre or post-bronchodilator SR35.

Conclusion

Budesonide-treated patients have less concave flow-volume loops when compared to placebo-treated patients. Time and bronchodilator also make the flow-volume loop less concave. Furthermore, it appears that there are discrete bronchodilator responsive and corticosteroid responsive components of airflow obstruction in pediatric asthma.

Clinical Implications

Changes in flow-volume loop shape in children with asthma may reflect changes in airflow for which slope ratio may be more sensitive than conventional measures.

Background

Injection drug use is associated with an increased risk of human immunodeficiency virus (HIV) infection and with obstructive lung diseases (OLD). Understanding how HIV and OLD may impact respiratory symptoms among injection drug users (IDUs) is important to adequately care for this high-risk population. We characterized the independent and joint effects of HIV and OLD on respiratory symptoms of a cohort of inner-city IDUs.

Methods

Demographics, risk behavior and spirometric measurements were collected from a cross-sectional analysis of the Acquired Immunodeficiency Syndrome Link to the IntraVenous Experience study, an observational cohort of IDUs followed in Baltimore, MD since 1988. Participants completed a modified American Thoracic Society respiratory questionnaire and the Medical Research Council (MRC) dyspnea score to assess respiratory symptoms of cough, phlegm, wheezing and dyspnea.

Results

Of 974 participants, 835 (86%) were current smokers and 288 (29.6%) were HIV-infected. The prevalence of OLD (FEV1/FVC ≤ 0.70) was 15.5%, and did not differ by HIV status. OLD, but not HIV, was associated with increased frequency of reported respiratory symptoms. There was a combined effect of OLD and HIV on worsening of MRC scores. OLD and HIV were independently associated with an increased odds of reporting an MRC ≥ 2 (OR 1.83 [95%CI 1.23-2.73] and 1.50 [95%CI 1.08-2.09], respectively). COPD, but not HIV, was independently associated with reporting an MRC ≥ 3 (OR 2.25 [95%CI 1.43-3.54] and 1.29 [95%CI 0.87-1.91], respectively).

Conclusions

While HIV does not worsen cough, phlegm or wheezing, HIV significantly increases moderate but not severe dyspnea in individuals of similar OLD status. Incorporating the MRC score into routine evaluation of IDUs at risk for OLD and HIV provides better assessment than cough, phlegm and wheezing alone.