Comorbidity and sex-related differences in mortality in oxygen-dependent chronic obstructive pulmonary disease

Background

It is not known why survival differs between men and women in oxygen-dependent chronic obstructive pulmonary disease (COPD). The present study evaluates differences in comorbidity between men and women, and tests the hypothesis that comorbidity contributes to sex-related differences in mortality in oxygen-dependent COPD.

Methods

National prospective study of patients aged 50 years or older, starting long-term oxygen therapy (LTOT) for COPD in Sweden between 1992 and 2008. Comorbidities were obtained from the Swedish Hospital Discharge Register. Sex-related differences in comorbidity were estimated using logistic regression, adjusting for age, smoking status and year of inclusion. The effect of comorbidity on overall mortality and the interaction between comorbidity and sex were evaluated using Cox regression, adjusting for age, sex, Pa_O2 breathing air, FEV₁, smoking history and year of inclusion.

Results

In total, 8,712 patients (55% women) were included and 6,729 patients died during the study period. No patient was lost to follow-up. Compared with women, men had significantly more arrhythmia, cancer, ischemic heart disease and renal failure, and less hypertension, mental disorders, osteoporosis and rheumatoid arthritis (P<0.05 for all odds ratios). Comorbidity was an independent predictor of mortality, and the effect was similar for the sexes. Women had lower mortality, which remained unchanged even after adjusting for comorbidity; hazard ratio 0.73 (95% confidence interval, 0.68–0.77; P<0.001).

Conclusions

Comorbidity is different in men and women, but does not explain the sex-related difference in mortality in oxygen-dependent COPD.     

Population Pharmacodynamic Modeling and Simulation of the Respiratory Effect of Acetazolamide in Decompensated COPD Patients

Background

Chronic obstructive pulmonary disease (COPD) patients may develop metabolic alkalosis during weaning from mechanical ventilation. Acetazolamide is one of the treatments used to reverse metabolic alkalosis.

Methods

619 time-respiratory (minute ventilation, tidal volume and respiratory rate) and 207 time-PaCO₂ observations were obtained from 68 invasively ventilated COPD patients. We modeled respiratory responses to acetazolamide in mechanically ventilated COPD patients and then simulated the effect of increased amounts of the drug.

Results

The effect of acetazolamide on minute ventilation and PaCO₂ levels was analyzed using a nonlinear mixed effect model. The effect of different ventilatory modes was assessed on the model. Only slightly increased minute ventilation without decreased PaCO₂ levels were observed in response to 250 to 500 mg of acetazolamide administered twice daily. Simulations indicated that higher acetazolamide dosage (>1000 mg daily) was required to significantly increase minute ventilation (P<.001 vs pre-acetazolamide administration). Based on our model, 1000 mg per day of acetazolamide would increase minute ventilation by >0.75 L min⁻¹ in 60% of the population. The model also predicts that 45% of patients would have a decrease of PaCO2>5 mmHg with doses of 1000 mg per day.

Conclusions

Simulations suggest that COPD patients might benefit from the respiratory stimulant effect after the administration of higher doses of acetazolamide.     

FEV1 inversely correlates with metalloproteinases 1, 7, 9 and CRP in COPD by biomass smoke exposure

Background

Matrix metalloproteinases (MMPs) and C-reactive protein (CRP) are involved in chronic obstructive pulmonary disease (COPD) pathogenesis. The aim of the present work was to determine plasma concentrations of MMPs and CRP in COPD associated to biomass combustion exposure (BE) and tobacco smoking (TS).

Methods

Pulmonary function tests, plasma levels of MMP-1, MMP-7, MMP-9, MMP-9/TIMP-1 and CRP were measured in COPD associated to BE (n = 40) and TS (n =40) patients, and healthy non-smoking (NS) healthy women (controls, n = 40).

Results

Plasma levels of MMP-1, MMP-7, MMP-9, and MMP-9/TIMP-1 and CRP were higher in BE and TS than in the NS healthy women (p <0.01). An inverse correlation between MMP-1, MMP-7, MMP-9, MMP-9/TIMP-1 and CRP plasma concentrations and FEV₁ was observed.

Conclusions

Increase of MMPs and CRP plasma concentrations in BE suggests a systemic inflammatory phenomenon similar to that observed in COPD associated to tobacco smoking, which may also play a role in COPD pathogenesis.     

DNAH5 is associated with total lung capacity in chronic obstructive pulmonary disease

Background

Chronic obstructive pulmonary disease (COPD) is characterized by expiratory flow limitation, causing air trapping and lung hyperinflation. Hyperinflation leads to reduced exercise tolerance and poor quality of life in COPD patients. Total lung capacity (TLC) is an indicator of hyperinflation particularly in subjects with moderate-to-severe airflow obstruction. The aim of our study was to identify genetic variants associated with TLC in COPD.

Methods

We performed genome-wide association studies (GWASs) in white subjects from three cohorts: the COPDGene Study; the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE); and GenKOLS (Bergen, Norway). All subjects were current or ex-smokers with at least moderate airflow obstruction, defined by a ratio of forced expiratory volume in 1 second to forced vital capacity (FEV₁/FVC) <0.7 and FEV₁ < 80% predicted on post-bronchodilator spirometry. TLC was calculated by using volumetric computed tomography scans at full inspiration (TLC_CT). Genotyping in each cohort was completed, with statistical imputation of additional markers. To find genetic variants associated with TLC_CT, linear regression models were used, with adjustment for age, sex, pack-years of smoking, height, and principal components for genetic ancestry. Results were summarized using fixed-effect meta-analysis.

Results

Analysis of a total of 4,543 COPD subjects identified one genome-wide significant locus on chromosome 5p15.2 (rs114929486, β = 0.42L, P = 4.66 × 10⁻⁸).

Conclusions

In COPD, TLC_CT was associated with a SNP in dynein, axonemal, heavy chain 5 (DNAH5), a gene in which genetic variants can cause primary ciliary dyskinesia. DNAH5 could have an effect on hyperinflation in COPD.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-014-0097-y) contains supplementary material, which is available to authorized users.     

Efficacy and safety of AZD3199 vs formoterol in COPD: a randomized,double-blind study

Background

We investigated the efficacy and safety of AZD3199, a novel inhaled ultra-LABA, with the main aim of establishing a dose that would maintain 24-hour bronchodilation in patients with COPD.

Methods

Patients (n = 329) were randomized to AZD3199 (200, 400 or 800 μg o.d.), formoterol (9 μg b.i.d.) or placebo via Turbuhaler® in a parallel group study. The primary objective of the study was to compare the clinical efficacy of three doses of AZD3199 inhaled once daily with 9 μg formoterol twice daily and placebo, over a 4-week treatment period in adults with moderate-to-severe COPD. After 4 weeks, peak (0–4 h) and trough (24–26 h) forced expiratory volume in 1 second (FEV₁) were assessed as the primary efficacy outcome variables.

Results

All AZD3199 doses significantly increased mean peak and trough FEV₁ versus placebo (106–171 ml and 97–110 ml increases, respectively), but with no clear dose–response; the level of bronchodilation was comparable to or greater than that achieved with formoterol. Forced vital capacity (FVC) at peak bronchodilation also significantly increased with AZD3199 versus placebo (153–204 ml). COPD symptom scores and reliever use were reduced with AZD3199, while FEV₁ reversibility was unaltered. Adverse events were mild-to-moderate, with no safety concerns identified. Drug exposure was dose-proportional, but lower than predicted from healthy volunteers.

Conclusions

All three doses of AZD3199 produced 24-hour bronchodilation, but with no clear dose–response, suggesting that doses of 200 μg or less may be sufficient to maintain bronchodilation over 24 hours in patients with COPD. No safety concerns were identified. Further studies are required to determine the once-daily AZD3199 dose for COPD.

Trial registration

Clinicaltrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT00929708","term_id":"NCT00929708"}}NCT00929708     

Association of plasma sRAGE,but not esRAGE with lung function impairment in COPD

Rationale

Plasma soluble Receptor for Advanced Glycation End Product (sRAGE) is considered as a biomarker in COPD. The contribution of endogenous sRAGE (esRAGE) to the pool of plasma sRAGE and the implication of both markers in COPD pathogenesis is however not clear yet. The aim of the current study was therefore to measure plasma levels of esRAGE comparative to total sRAGE in patients with COPD and a control group. Further, we established the relations of esRAGE and total sRAGE with disease specific characteristics such as lung function and D_LCO, and with different circulating AGEs.

Methods

Plasma levels of esRAGE and sRAGE were measured in an 88 patients with COPD and in 55 healthy controls. FEV₁ (%predicted) and FEV₁/VC (%) were measured in both groups; D_LCO (%predicted) was measured in patients only. In this study population we previously reported that the AGE N^ϵ-(carboxymethyl) lysine (CML) was decreased, N^ϵ-(carboxyethyl) lysine (CEL) increased and pentosidine was not different in plasma of COPD patients compared to controls.

Results

Plasma esRAGE (COPD: 533.9 ± 412.4, Controls: 848.7 ± 690.3 pg/ml; p = 0.000) was decreased in COPD compared to controls. No significant correlations were observed between plasma esRAGE levels and lung function parameters or plasma AGEs. A positive correlation was present between esRAGE and total sRAGE levels in the circulation. Confirming previous findings, total sRAGE (COPD: 512.6 ± 403.8, Controls: 1834 ± 804.2 pg/ml; p < 0.001) was lower in patients compared to controls and was positively correlated FEV₁ (r = 0.235, p = 0.032), FEV₁/VC (r = 0.218, p = 0.047), and D_LCO (r = 0.308, p = 0.006). sRAGE furthermore did show a significant positive association with CML (r = 0.321, p = 0.003).

Conclusion

Although plasma esRAGE is decreased in COPD patients compared to controls, only total sRAGE showed a significant and independent association with FEV₁, FEV₁/VC and D_LCO, indicating that total sRAGE but not esRAGE may serve as marker of COPD disease state and severity.     

How air pollution influences clinical management of respiratory diseases. A case-crossover study in Milan

Background

Environmental pollution is a known risk factor for multiple diseases and furthermore increases rate of hospitalisations. We investigated the correlation between emergency room admissions (ERAs) of the general population for respiratory diseases and the environmental pollutant levels in Milan, a metropolis in northern Italy.

Methods

We collected data from 45770 ERAs for respiratory diseases. A time-stratified case-crossover design was used to investigate the association between air pollution levels and ERAs for acute respiratory conditions. The effects of air pollutants were investigated at lag 0 to lag 5, lag 0–2 and lag 3–5 in both single and multi-pollutant models, adjusted for daily weather variables.

Results

An increase in ozone (O₃) levels at lag 3–5 was associated with a 78% increase in the number of ERAs for asthma, especially during the warm season. Exposure to carbon monoxide (CO) proved to be a risk factor for pneumonia at lag 0–2 and in the warm season increased the risk of ERA by 66%. A significant association was found between ERAs for COPD exacerbation and levels of sulphur dioxide (SO₂), CO, nitrate dioxide (NO₂), and particulate matter (PM₁₀ and PM_2.5). The multipollutant model that includes all pollutants showed a significant association between CO (26%) and ERA for upper respiratory tract diseases at lag 0–2. For chronic obstructive pulmonary disease (COPD) exacerbations, only CO (OR 1.19) showed a significant association.

Conclusions

Exposure to environmental pollution, even at typical low levels, can increase the risk of ERA for acute respiratory diseases and exacerbation of obstructive lung diseases in the general population.     

Effects of Anabolic Steroids on Chronic Obstructive Pulmonary Disease: A Meta-Analysis of Randomised Controlled Trials

Background

Anabolic steroids are known to improve body composition and muscle strength in healthy people. However, whether anabolic steroids improve the physical condition and function in patients with chronic obstructive pulmonary disease (COPD) remains undetermined. A meta-analysis was conducted to review the current evidence regarding the effects of anabolic steroids on COPD patients.

Methods

A comprehensive literature search of PubMed and EMBASE was performed to identify randomised controlled trials that examine the effects of anabolic steroids on COPD patients. Weighted mean differences (WMDs) with 95% confidence intervals were calculated to determine differences between anabolic steroid administration and control conditions.

Results

Eight eligible studies involving 273 COPD patients were identified in this meta-analysis. Significant improvements were found in body weight (0.956 kg), fat-free mass (1.606 kg), St. George''s Respiratory Questionnaire total score (−6.336) and symptom score (−12.148). The apparent improvements in maximal inspiratory pressure (2.740 cmH₂O) and maximal expiratory pressure (12.679 cmH₂O) were not significant. The effects on handgrip strength, forced expiratory volume in one second (FEV₁), predicted FEV₁ percent, PaO₂, PaCO₂ and six-min walk distance were negative, with WMDs of −0.245 kg, −0.096 L/sec, −1.996% of predicted, −1.648 cmHg, −0.039 cmHg and −16.102 meters, respectively.

Conclusions

Limited evidence available from the published literature suggests that the benefit of anabolic steroids on COPD patients cannot be denied. However, further studies are needed to identify the specific benefits and adverse effects of anabolic steroids on COPD patients and to determine the optimal populations and regimes of anabolic steroids in COPD patients.     

How Does Socioeconomic Development Affect COPD Mortality? An Age-Period-Cohort Analysis from a Recently Transitioned Population in China

Background

Chronic obstructive pulmonary disease (COPD) is a leading cause of death, particularly in developing countries. Little is known about the effects of economic development on COPD mortality, although economic development may potentially have positive and negative influences over the life course on COPD. We took advantage of a unique population whose rapid and recent economic development is marked by changes at clearly delineated and identifiable time points, and where few women smoke, to examine the effect of macro-level events on COPD mortality.

Methods

We used Poisson regression to decompose sex-specific COPD mortality rates in Hong Kong from 1981 to 2005 into the effects of age, period and cohort.

Results

COPD mortality declined strongly over generations for people born from the early to mid 20th century, which was particularly evident for the first generation to grow up in a more economically developed environment for both sexes. Population wide COPD mortality decreased when air quality improved and increased with increasing air pollution. COPD mortality increased with age, particularly after menopause among women.

Conclusions

Economic development may reduce vulnerability to COPD by reducing long-lasting insults to the respiratory system, such as infections, poor nutrition and indoor air pollution. However, some of these gains may be offset if economic development results in increasing air pollution or increasing smoking.     

FEV1 Is a Better Predictor of Mortality than FVC: The PLATINO Cohort Study

Objective

To determine whether the presence of chronic obstructive lung disease (COPD) and reduction of lung function parameters were predictors of mortality in a cohort.

Materials/Patients and Methods

Population based cohorts were followed in Montevideo, Santiago and Sao Paulo during 5, 6 and 9 years, respectively. Outcomes included all-cause, cardiovascular, respiratory and cancer mortality; exposures were COPD, forced expiratory volume in one second (FEV₁) and forced vital capacity (FVC). Cox regression was used for analyses. Sensitivity, specificity, positive and negative predictive values, receiver operator characteristics curves and Youden''s index were calculated.

Results

Main causes of death were cardiovascular, respiratory and cancer. Baseline COPD was associated with overall mortality (HR = 1.43 for FEV₁/FVC<LLN; 2.01 for GOLD 2-4; 1.46 for GOLD 1-4; 1.50 for FEV₁/FEV₆ <LLN). For cardiovascular mortality, significant associations were found with GOLD 2-4 (HR = 2.68) and with GOLD 1-4 (HR = 1.78) for both genders together (not among women). Low FEV₁ was risk for overall and respiratory mortality (both genders combined). FVC was not associated with overall mortality. For most COPD criteria sensitivity was low and specificity high. The area under the curve for FEV₁ was greater than for FVC for overall and cardiovascular mortality.

Answer to the Question

COPD and low FEV₁ are important predictors for overall and cardiovascular mortality in Latin America.     

Absolute Lymphocyte Count as a Predictor of Mortality in Emergency Department Patients with Paraquat Poisoning

Background

Paraquat (PQ) is a potent, highly toxic and widely used herbicide. The major medical problems associated with PQ are accidental or suicidal ingestion. There are several prognostic markers of PQ poisoning, with the serum PQ concentration considered to be the best indicator of outcome. However, the measurement of such markers is limited in many hospitals.

Objective

The present study was conducted to investigate the association of absolute lymphocyte count (ALC) and the 30-day mortality rate in patients with PQ poisoning.

Methods

We performed a retrospective analysis of patients admitted to the emergency department after paraquat poisoning between January 2010 and April 2013. Independent risk factors including ALC for 30-day mortality were determined. The ALC was categorized in quartiles as ≤1700, 1700 to 3200, 3200 to 5000, and >5000. Univariate and multivariate Cox proportional hazard analysis were performed to determine the independent risk factors for mortality.

Results

A total of 136 patients were included in the study, and the 30-day mortality was 73.5%. ALC was significantly higher in nonsurvivors than in survivors. The highest ALC quartile (ALC>5000; hazard ratio, 2.58; 95% CI, 1.08–6.21) was associated with increased mortality in multivariate analysis. In addition, old age, lower arterial PaCO₂, increased peripheral neutrophil count, and high serum levels of creatinine were associated with mortality.

Conclusion

The absolute lymphocyte count is associated with the 30-day mortality rate in patients with paraquat poisoning.     

Correlating changes in lung function with patient outcomes in chronic obstructive pulmonary disease: a pooled analysis

Background

Relationships between improvements in lung function and other clinical outcomes in chronic obstructive pulmonary disease (COPD) are not documented extensively. We examined whether changes in trough forced expiratory volume in 1 second (FEV₁) are correlated with changes in patient-reported outcomes.

Methods

Pooled data from three indacaterol studies (n = 3313) were analysed. Means and responder rates for outcomes including change from baseline in Transition Dyspnoea Index (TDI), St. George''s Respiratory Questionnaire (SGRQ) scores (at 12, 26 and 52 weeks), and COPD exacerbation frequency (rate/year) were tabulated across categories of ΔFEV₁. Also, generalised linear modelling was performed adjusting for covariates such as baseline severity and inhaled corticosteroid use.

Results

With increasing positive ΔFEV₁, TDI and ΔSGRQ improved at all timepoints, exacerbation rate over the study duration declined (P < 0.001). Individual-level correlations were 0.03-0.18, but cohort-level correlations were 0.79-0.95. At 26 weeks, a 100 ml increase in FEV₁ was associated with improved TDI (0.46 units), ΔSGRQ (1.3-1.9 points) and exacerbation rate (12% decrease). Overall, adjustments for baseline covariates had little impact on the relationship between ΔFEV₁ and outcomes.

Conclusions

These results suggest that larger improvements in FEV₁ are likely to be associated with larger patient-reported benefits across a range of clinical outcomes.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00393458","term_id":"NCT00393458"}}NCT00393458, {"type":"clinical-trial","attrs":{"text":"NCT00463567","term_id":"NCT00463567"}}NCT00463567, and {"type":"clinical-trial","attrs":{"text":"NCT00624286","term_id":"NCT00624286"}}NCT00624286     

Two-year home-based nocturnal noninvasive ventilation added to rehabilitation in chronic obstructive pulmonary disease patients: A randomized controlled trial

Background

The use of noninvasive intermittent positive pressure ventilation (NIPPV) in chronic obstructive pulmonary disease (COPD) patients with chronic hypercapnic respiratory failure remains controversial as long-term data are almost lacking.The aim was to compare the outcome of 2-year home-based nocturnal NIPPV in addition to rehabilitation (NIPPV + PR) with rehabilitation alone (PR) in COPD patients with chronic hypercapnic respiratory failure.

Methods

Sixty-six patients could be analyzed for the two-year home-based follow-up period. Differences in change between the NIPPV + PR and PR group were assessed by a linear mixed effects model with a random effect on the intercept, and adjustment for baseline values. The primary outcome was health-related quality of life (HRQoL); secondary outcomes were mood state, dyspnea, gas exchange, functional status, pulmonary function, and exacerbation frequency.

Results

Although the addition of NIPPV did not significantly improve the Chronic Respiratory Questionnaire compared to rehabilitation alone (mean difference in change between groups -1.3 points (95% CI: -9.7 to 7.4)), the addition of NIPPV did improve HRQoL assessed with the Maugeri Respiratory Failure questionnaire (-13.4% (-22.7 to -4.2; p = 0.005)), mood state (Hospital Anxiety and Depression scale -4.0 points (-7.8 to 0.0; p = 0.05)), dyspnea (Medical Research Council -0.4 points (-0.8 to -0.0; p = 0.05)), daytime arterial blood gases (PaCO₂ -0.4 kPa (-0.8 to -0.2; p = 0.01); PaO₂ 0.8 kPa (0.0 to 1.5; p = 0.03)), 6-minute walking distance (77.3 m (46.4 to 108.0; p < 0.001)), Groningen Activity and Restriction scale (-3.8 points (-7.4 to -0.4; p = 0.03)), and forced expiratory volume in 1 second (115 ml (19 to 211; p = 0.019)). Exacerbation frequency was not changed.

Conclusions

The addition of NIPPV to pulmonary rehabilitation for 2 years in severe COPD patients with chronic hypercapnic respiratory failure improves HRQoL, mood, dyspnea, gas exchange, exercise tolerance and lung function decline. The benefits increase further with time.

Trial registration

ClinicalTrials.Gov (ID NCT00135538).     

Safety and tolerability of once-daily umeclidinium/vilanterol 125/25 mcg and umeclidinium 125 mcg in patients with chronic obstructive pulmonary disease: results from a 52-week,randomized, double-blind,placebo-controlled study

Background

The long-acting muscarinic antagonist (LAMA) umeclidinium (UMEC) and the combination of UMEC with the long-acting β₂-agonist (LABA) vilanterol (UMEC/VI) are approved maintenance treatments for chronic obstructive pulmonary disease (COPD) in the US and EU. They are not indicated for the treatment of asthma.

Methods

In this 52-week, double-blind, placebo-controlled, parallel-group safety study (GSK study DB2113359; {"type":"clinical-trial","attrs":{"text":"NCT01316887","term_id":"NCT01316887"}}NCT01316887), patients were randomized 2:2:1 to UMEC/VI 125/25 mcg, UMEC 125 mcg, or placebo. Study endpoints included adverse events (AEs), clinical chemistry and hematology parameters, vital signs, 12-lead, and 24-hour Holter electrocardiograms. COPD exacerbations and rescue medication use were assessed as safety parameters; lung function was also evaluated.

Results

The incidence of on-treatment AEs, serious AEs (SAEs), and drug-related AEs was similar between treatment groups (AEs: 52–58%; SAEs: 6–7%; drug-related AEs: 12–13%). Headache was the most common AE in each treatment group (8–11%). AEs associated with the LAMA and LABA pharmacologic classes occurred at a low incidence across treatment groups. No clinically meaningful effects on vital signs or laboratory assessments were reported for active treatments versus placebo. The incidences of atrial arrhythmias with UMEC/VI 125/25 mcg were similar to placebo; for UMEC 125 mcg, the incidences of ectopic supraventricular beats, sustained supraventricular tachycardia, and ectopic supraventricular rhythm were ≥2% greater than placebo. With active treatments, COPD exacerbations were fewer (13–15% of patients reporting ≥1 exacerbation) and on average less rescue medication was required (1.6–2.2 puffs/day) versus placebo (24% reporting ≥1 exacerbation, 2.6 puffs/day). Both active treatments improved lung function versus placebo.

Conclusion

UMEC/VI 125/25 mcg and UMEC 125 mcg were well tolerated over 12 months in patients with COPD.     

Serum Vitamin D in Patients with Chronic Obstructive Lung Disease Does Not Correlate with Mortality – Results from a 10-Year Prospective Cohort Study

Background

Recent studies have found vitamin D (25-OHD) deficiency and insufficiency to be common among patients with COPD. Serum level of 25-OHD seems to correlate to pulmonary function, COPD disease staging, and increased susceptibility to respiratory infections. We wanted to investigate whether vitamin D deficiency or insufficiency was associated with mortality rate in patients suffering from advanced COPD.

Methods

25-OHD serum levels were measured in 462 patients suffering from moderate to very severe COPD. Patients were stratified into three groups according to serum levels of 25-OHD. Outcome measure was mortality in a 10 year follow-up period. Kaplan-Meier curves (KM) were plotted and mortality hazard ratios (HR) were calculated using Cox Proportional Hazard regression (Cox PH).

Results

Serum 25-OHD deficiency and insufficiency were prevalent. We were unable to demonstrate any association between baseline serum levels of 25-OHD and mortality rate. We found an association between mortality and age [HR 1.05 (CI 95%: 1.03–1.06)], Charlson score [HR 1.49 (CI 95%: 1.06–2.09)], increasing neutrophil count [HR 1.05 (CI 95%: 1.02–1.09)], severe [HR 1.41 (CI 95%: 1.06–1.86)]/very severe COPD [HR 2.19 (CI 95%: 1.58–3.02)] and a smoking history of more than 40 pack years [HR 1.27 (CI 95%: 1.02–1.70)].

Conclusions

Serum level of 25-OHD does not seem to be associated with mortality rate, suggesting no or only a minor role of 25-OHD in disease progression in patients with moderate to very severe COPD.     

Association of 25-Hydroxyvitamin D status and genetic variation in the vitamin D metabolic pathway with FEV1 in the Framingham Heart Study

Background

Vitamin D is associated with lung function in cross-sectional studies, and vitamin D inadequacy is hypothesized to play a role in the pathogenesis of chronic obstructive pulmonary disease. Further data are needed to clarify the relation between vitamin D status, genetic variation in vitamin D metabolic genes, and cross-sectional and longitudinal changes in lung function in healthy adults.

Methods

We estimated the association between serum 25-hydroxyvitamin D [25(OH)D] and cross-sectional forced expiratory volume in the first second (FEV₁) in Framingham Heart Study (FHS) Offspring and Third Generation participants and the association between serum 25(OH)D and longitudinal change in FEV₁ in Third Generation participants using linear mixed-effects models. Using a gene-based approach, we investigated the association between 241 SNPs in 6 select vitamin D metabolic genes in relation to longitudinal change in FEV₁ in Offspring participants and pursued replication of these findings in a meta-analyzed set of 4 independent cohorts.

Results

We found a positive cross-sectional association between 25(OH)D and FEV₁ in FHS Offspring and Third Generation participants (P = 0.004). There was little or no association between 25(OH)D and longitudinal change in FEV₁ in Third Generation participants (P = 0.97). In Offspring participants, the CYP2R1 gene, hypothesized to influence usual serum 25(OH)D status, was associated with longitudinal change in FEV₁ (gene-based P < 0.05). The most significantly associated SNP from CYP2R1 had a consistent direction of association with FEV₁ in the meta-analyzed set of replication cohorts, but the association did not reach statistical significance thresholds (P = 0.09).

Conclusions

Serum 25(OH)D status was associated with cross-sectional FEV₁, but not longitudinal change in FEV₁. The inconsistent associations may be driven by differences in the groups studied. CYP2R1 demonstrated a gene-based association with longitudinal change in FEV₁ and is a promising candidate gene for further studies.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-015-0238-y) contains supplementary material, which is available to authorized users.     

Mortality in GOLD stages of COPD and its dependence on symptoms of chronic bronchitis

Background

The GOLD classification of COPD severity introduces a stage 0 (at risk) comprising individuals with productive cough and normal lung function. The aims of this study were to investigate total mortality risks in GOLD stages 0–4 with special focus on stage 0, and furthermore to assess the influence of symptoms of chronic bronchitis on mortality risks in GOLD stages 1–4.

Method

Between 1974 and 1992, a total of 22 044 middle-aged individuals participated in a health screening, which included a spirometry as well as recording of respiratory symptoms and smoking habits. Individuals with comorbidity at baseline (diabetes, stroke, cancer, angina pectoris, or heart infarction) were excluded from the analyses. Hazard ratios (HR 95% CI) of total mortality were analyzed in GOLD stages 0–4 with individuals with normal lung function and without symptoms of chronic bronchitis as a reference group. HR:s in smoking individuals with symptoms of chronic bronchitis within the stages 1–4 were calculated with individuals with the same GOLD stage but without symptoms of chronic bronchitis as reference.

Results

The number of deaths was 3674 for men and 832 for women based on 352 324 and 150 050 person-years respectively. The proportion of smokers among men was 50% and among women 40%. Self reported comorbidity was present in 4.6% of the men and 6.6% of the women. Among smoking men, Stage 0 was associated with an increased mortality risk, HR; 1.65 (1.32–2.08), of similar magnitude as in stage 2, HR; 1.41 (1.31–1.70). The hazard ratio in stage 0 was significantly higher than in stage 1 HR; 1.13 (0.98–1.29). Among male smokers with stage 1; HR: 2.04 (1.34–3.11), and among female smokers with stage 2 disease; HR: 3.16 (1.38–7.23), increased HR:s were found in individuals with symptoms of chronic bronchitis as compared to those without symptoms of chronic bronchitis.

Conclusion

Symptoms fulfilling the definition of chronic bronchitis were associated with an increased mortality risk among male smokers with normal pulmonary function (stage 0) and also with an increased risk of death among smoking individuals with mild to moderate COPD (stage 1 and 2).     

Impact of statins and ACE inhibitors on mortality after COPD exacerbations

Background

The purpose of our study was to examine the association of prior outpatient use of statins and angiotensin converting enzyme (ACE) inhibitors on mortality for subjects ≥ 65 years of age hospitalized with acute COPD exacerbations.

Methods

We conducted a retrospective national cohort study using Veterans Affairs administrative data including subjects ≥65 years of age hospitalized with a COPD exacerbation. Our primary analysis was a multilevel model with the dependent variable of 90-day mortality and hospital as a random effect, controlling for preexisting comorbid conditions, demographics, and other medications prescribed.

Results

We identified 11,212 subjects with a mean age of 74.0 years, 98% were male, and 12.4% of subjects died within 90-days of hospital presentation. In this cohort, 20.3% of subjects were using statins, 32.0% were using ACE inhibitors or angiotensin II receptor blockers (ARB). After adjusting for potential confounders, current statin use (odds ratio 0.51, 95% confidence interval 0.40–0.64) and ACE inhibitor/ARB use (0.55, 0.46–0.66) were significantly associated with decreased 90-day mortality.

Conclusion

Use of statins and ACE inhibitors prior to admission is associated with decreased mortality in subjects hospitalized with a COPD exacerbation. Randomized controlled trials are needed to examine whether the use of these medications are protective for those patients with COPD exacerbations.     

Three-year follow-up of Interleukin 6 and C-reactive protein in chronic obstructive pulmonary disease

Background

Past studies have shown that mean values of Interleukin-6 (IL-6) and C-reactive protein (CRP) do not change significantly in COPD patients over a one-year period. However, longer period follow-up studies are still lacking. Thus, the aim of this study is to evaluate plasma CRP and IL-6 concentration over three years in COPD patients and to test the association between these inflammatory mediators and disease outcome markers.

Methods

A cohort of 77 outpatients with stable COPD was evaluated at baseline, and 53 (mean FEV₁, 56% predicted) were included in the prospective study. We evaluated Interleukin-6 (IL-6), C-reactive protein (CRP), six-minute walking distance (6MWD), and body mass index (BMI) at baseline and after three years. Plasma concentration of IL-6 was measured by high sensitivity ELISA, and CRP was obtained by high sensitivity particle-enhanced immunonephelometry.

Results

IL-6 increased significantly after 3 years compared to baseline measurements [0.8 (0.5-1.3) vs 2.4 (1.3-4.4) pg/ml; p < 0.001] and was associated with worse 6MWD performance. In the Cox regression, increased IL-6 at baseline was associated with mortality [Hazard Ratio (95% CI) = 2.68 (0.13, 1.84); p = 0.02]. CRP mean values did not change [5 (1.6-7.9) vs 4.7 (1.7-10) pg/L; p = 0.84], although eleven patients (21%) presented with changes >3 mg/L in CRP after 3 years.

Conclusions

The systemic inflammatory process, evaluated by IL-6, seems to be persistent, progressive and associated with mortality and worse physical performance in COPD patients.

Trial registration

No.:{"type":"clinical-trial","attrs":{"text":"NCT00605540","term_id":"NCT00605540"}}NCT00605540     

TNF-α is associated with loss of lean body mass only in already cachectic COPD patients

Background

Systemic inflammation may contribute to cachexia in patients with chronic obstructive pulmonary disease (COPD). In this longitudinal study we assessed the association between circulating C-reactive protein (CRP), tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 levels and subsequent loss of fat free mass and fat mass in more than 400 COPD patients over three years.

Methods

The patients, aged 40–76, GOLD stage II-IV, were enrolled in 2006/07, and followed annually. Fat free mass and fat mass indexes (FFMI & FMI) were calculated using bioelectrical impedance, and CRP, TNF-α, IL-1ß, and IL-6 were measured using enzyme immunoassays. Associations with mean change in FFMI and FMI of the four inflammatory plasma markers, sex, age, smoking, FEV₁, inhaled steroids, arterial hypoxemia, and Charlson comorbidity score were analyzed with linear mixed models.

Results

At baseline, only CRP was significantly (but weakly) associated with FFMI (r = 0.18, p < 0.01) and FMI (r = 0.27, p < 0.01). Univariately, higher age, lower FEV₁, and use of beta2-agonists were the only significant predictors of decline in FFMI, whereas smoking, hypoxemia, Charlson score, and use of inhaled steroids predicted increased loss in FMI. Multivariately, high levels of TNF-α (but not CRP, IL-1ß or IL-6) significantly predicted loss of FFMI, however only in patients with established cachexia at entry.

Conclusion

This study does not support the hypothesis that systemic inflammation is the cause of accelerated loss of fat free mass in COPD patients, but suggests a role for TNF-α in already cachectic COPD patients.