Reasons for the excess risk for cardiovascular disease among people with chronic obstructive pulmonary disease remain unclear. Our objective was to examine the cardiovascular risk profile for adults with obstructive and restrictive impairments of lung functioning in a representative sample of adults from the United States.
We used data from adults aged 20–79 years who participated in the National Health and Nutrition Examination Survey from 2007 to 2010 and had a pulmonary function test. The severity of obstructive impairment was defined by adapting the Global Initiative for Chronic Obstructive Lung Disease criteria.
Among 7249 participants, 80.9% had a normal pulmonary function test, 5.7% had a restrictive impairment, 7.9% had mild obstructive impairment, and 5.5% had moderate or severe/very severe obstructive impairment. Participants with obstructive impairment had high rates of smoking and increased serum concentrations of cotinine. Compared to participants with normal pulmonary functioning, participants with at least moderate obstructive impairment had elevated concentrations of C-reactive protein but lower concentrations of total cholesterol and non-high-density lipoprotein cholesterol. Among participants aged 50–74 years, participants with at least a moderate obstructive impairment or a restrictive impairment had an elevated predicted 10-year risk for cardiovascular disease.
The high rates of smoking among adults with impaired pulmonary functioning, particularly those with obstructive impairment, point to a need for aggressive efforts to promote smoking cessation in these adults. In addition, adults with restrictive impairment may require increased attention to and fine-tuning of their cardiovascular risk profile.
Chronic obstructive pulmonary disease; Cardiovascular diseases; Risk factors; Spirometry
Chronic obstructive pulmonary disease (COPD) is predominantly the consequence of chronic smoking exposure, but its development may be influenced by genetic variants that affect lung remodelling, inflammation, and defence from oxidant stress. A study was undertaken to determine whether genetic variants within genes encoding the antioxidant enzymes superoxide dismutase (SOD) and catalase may be associated with the development of impaired lung function.
In a case‐control study, the allele and genotype frequencies of functional polymorphisms from SOD1 (CuZnSOD), SOD2 (MnSOD), SOD3 (extracellular SOD), and catalase (CAT) were compared in chronic smokers with normal lung function (resistant smokers) and in those with COPD.
Significantly higher frequencies of the G allele and CG/GG genotype of the 213 SOD3 polymorphism were found in resistant smokers (odds ratios (ORs) 4.3 (95% CI 1.5 to 13.3) and 4.2, 95% CI 1.4 to 13.3), Bonferroni corrected p = 0.02 and p = 0.02, respectively) than in those with COPD. There were no differences between the COPD and resistant smokers for the SOD1, SOD2, or CAT polymorphisms tested.
The 213Gly variant of the SOD3 gene may, through antioxidant or anti‐inflammatory effects, confer a degree of resistance in some smokers to the development of COPD.
antioxidant; chronic obstructive pulmonary disease; genes; smokers; lung function
Genetic variation may underlie phenotypic variation in chronic obstructive pulmonary disease (COPD) in subjects with and without alpha 1 antitrypsin deficiency (AATD). Genotype specific sub-phenotypes are likely and may underlie the poor replication of previous genetic studies. This study investigated subjects with AATD to determine the relationship between specific phenotypes and TNFα polymorphisms.
424 unrelated subjects of the PiZZ genotype were assessed for history of chronic bronchitis, impairment of lung function and radiological presence of emphysema and bronchiectasis. A subset of subjects with 3 years consecutive lung function data was assessed for decline of lung function. Four single nucleotide polymorphisms (SNPs) tagging TNFα were genotyped using TaqMan® genotyping technologies and compared between subjects affected by each phenotype and those unaffected. Plasma TNFα levels were measured in all PiZZ subjects.
All SNPs were in Hardy-Weinberg equilibrium. A significant difference in rs361525 genotype (p = 0.01) and allele (p = 0.01) frequency was seen between subjects with and without chronic bronchitis, independent of the presence of other phenotypes. TNFα plasma level showed no phenotypic or genotypic associations.
Variation in TNFα is associated with chronic bronchitis in AATD.
To determine the extent to which the co-occurrence of chronic obstructive pulmonary disease (COPD) and cognitive impairment affect adverse health outcomes in older adults.
Multi-center longitudinal cohort study.
California, Pennsylvania, Maryland, and North Carolina.
Three thousand ninety-three community-dwelling adults aged ≥65 from the Cardiovascular Health Study. Four hundred thirty-one participants had chronic obstructive pulmonary disease (COPD) at study baseline.
Follow-up began at the second CHS visit and continued for three years. Spirometric criteria for airflow limitation served to establish COPD, using the Lambda-Mu-Sigma method, which accounts for age-related changes in lung function. Cognitive impairment was evaluated by the modified Mini Mental State Exam and claims data. Outcomes were respiratory-related and all-cause hospitalizations and death.
Participants with co-existing COPD and cognitive impairment had the highest rates of respiratory-related (adjusted hazard ratio [HR]=4.10, 95%CI=1.86–9.05) and all-cause hospitalizations (HR= 1.34, 95%CI=1.00–1.80) and death (HR=2.29, 95%CI=1.18–4.45). In particular, individuals with both conditions had a 48% higher rate of all-cause hospitalizations (adjusted synergy index [SI]=1.48, 95%CI=0.19–11.31) and nearly a three-fold higher rate of death (SI=2.74, 95%CI=0.43–17.32) than the sum of risks for each respective outcome associated with having COPD or cognitive impairment alone. However, tests for interaction were not statistically significant for the presence of synergism between both conditions relative to any of the outcomes. Therefore, we cannot conclude that the combined effect of COPD and cognitive impairment is greater than additive.
Co-existing COPD and cognitive impairment have an additive effect on respiratory-related and all-cause hospitalizations and death. Optimizing outcomes in older adults with COPD and cognitive impairment will require that we determine how to improve concurrent management of both conditions.
Chronic obstructive pulmonary disease; cognitive impairment; health outcomes; hospitalizations; disability; death
To determine the extent to which disease-related symptoms and impairments, which constitute measures of disease severity or targets of therapy, account for the associations between chronic diseases and universal health outcomes.
Cardiovascular Health Study (CHS) and Health ABC.
5,654 CHS, and 2,706 Health ABC, members.
Diseases included heart failure (HF), chronic obstructive pulmonary disease (COPD), osteoarthritis, and cognitive impairment. The universal health outcomes included self-rated health, basic and instrumental activities of daily living (BADLs-IADLs), and death. Disease-related symptoms/impairments included HF symptoms and ejection fraction (EF) for HF; Dyspnea Scale and FEV1 for COPD; joint pain for osteoarthritis, and executive function for cognitive impairment.
The diseases were associated with the universal health outcomes (p<0.001) except osteoarthritis with death (both cohorts) and cognitive impairment with self-rated health (Health ABC). Symptoms/impairments accounted for ≥30% of each disease’s effect on the universal health outcomes. In CHS, for example, HF, compared with no HF, was associated with one fewer (0.918) BADLs-IADL performed without difficulty; 27% of this effect was accounted for by HF symptoms, only 5% by EF. The hazard ratio for death with HF was 6.5 (95% CI, 4.7, 8.9) with 40% accounted for by EF and only 14% by HF symptoms.
Disease-related symptoms/impairments accounted for much of the significant associations between the 4 chronic diseases and the universal health outcomes. Results support considering universal health outcomes as common metrics across diseases in clinical decision-making, perhaps by targeting the disease-related symptoms/impairments that contribute most strongly to the effect of the disease on the universal health outcomes.
chronic diseases; universal health outcomes; patient-reported outcomes; clinical decision-making
Five to thirty percent of patients undergoing cardiac surgery present with chronic obstructive pulmonary disease (COPD) and have a 2- to 10-fold higher 30-day mortality risk. Cardiopulmonary bypass (CPB) creates a whole body systemic inflammatory response syndrome (SIRS) that could impair pulmonary function. Impaired pulmonary function can, however, be attenuated by pulmonary perfusion with oxygenated blood or custodiol HTK (histidine-tryptophan-ketoglutarate) solution.
The Pulmonary Protection Trial (PP-Trial) randomizes 90 patients undergoing CPB-dependent cardiac surgery to evaluate whether pulmonary perfusion with oxygenated blood or custodiol HTK solution reduces postoperative pulmonary dysfunction in COPD patients. Further, we aim for a non-randomized evaluation of postoperative pulmonary function after transcatheter aortic-valve implantation (TAVI). The primary outcome measure is the oxygenation index measured from anesthesia induction to the end of surgery and until 24 hours after anesthesia induction for a total of six evaluations.
Patients with COPD may be impaired by hypoxemia and SIRS. Thus, prolonged recovery and even postoperative complications and death may be reflected by the degree of hypoxemia and SIRS. The limited sample size does not aim for confirmatory conclusions on mortality, cardiovascular complications or risk of pneumonia and sepsis, but the PP-Trial is considered an important feasibility trial paving the road for a multicenter confirmatory trial.
Cardiopulmonary bypass; Inflammation; Systemic inflammatory response syndrome; Pulmonary function; Pulmonary perfusion; Pulmoplegia; Transcatheter aortic-valve implantation
Although impaired lung function in general has been associated with an increased risk of lung cancer, past studies typically have not attempted to investigate separately the obstructive and restrictive components of respiratory impairment. To deal with this question further, data from a large (n = 176 997) cohort of male Swedish construction workers, for whom spirometry measurements before follow‐up were available, were analysed.
Cancer incidence for 1971–2001 was obtained through linkage with the national cancer registry. Using a modification of the Global Initiative for Chronic Obstructive Lung Disease criteria for chronic obstructive pulmonary disease (COPD), subjects were classified into five categories of lung function: normal, mild COPD, moderate COPD, severe COPD and restrictive lung disease (RLD). Rate ratios (RR) and 95% confidence intervals (CI) for lung cancer across lung function categories were calculated using Poisson regression, adjusted for age and smoking. Other end points (histological types of lung cancer, non‐lung tobacco‐related cancers, other cancers, total mortality) were also investigated.
834 incident cases of lung cancer were identified. Increased rates of lung cancer were observed for both COPD (mild: RR 1.5, 95% CI 1.2 to 1.9; moderate/severe: RR 2.2, 95% CI 1.8 to 2.7) and RLD (RR 2.0, 95% CI 1.6 to 2.5) relative to normal lung function. These associations did not meaningfully change on applying follow‐up lag times of 5, 10 and 15 years after spirometry. When analysed by histological type, associations with both COPD and RLD were stronger for squamous cell carcinoma and small cell carcinoma, and weaker for adenocarcinoma. Both COPD and RLD were associated with increased rates of total mortality.
Obstructive and restrictive impairments in lung function are associated with increased lung cancer risk.
Systemic inflammation is associated with various complications in chronic obstructive pulmonary disease including weight loss, cachexia, osteoporosis, cancer and cardiovascular diseases. Inhaled corticosteroids attenuate airway inflammation, reduce exacerbations, and improve mortality in chronic obstructive pulmonary disease. Whether inhaled corticosteroids by themselves or in combination with a long-acting β2-adrenoceptor agonist repress systemic inflammation in chronic obstructive pulmonary disease is unknown. The Advair Biomarkers in COPD (ABC) study will determine whether the effects of inhaled corticosteroids alone or in combination with a long-acting β2-adrenoceptor agonist reduce systemic inflammation and improve health status in patients with chronic obstructive pulmonary disease.
After a 4-week run-in phase during which patients with stable chronic obstructive pulmonary disease will receive inhaled fluticasone (500 micrograms twice daily), followed by a 4-week withdrawal phase during which all inhaled corticosteroids and long acting β2-adrenoceptor agonists will be discontinued, patients will be randomized to receive fluticasone (500 micrograms twice daily), fluticasone/salmeterol combination (500/50 micrograms twice daily), or placebo for four weeks. The study will recruit 250 patients across 11 centers in western Canada. Patients must be 40 years of age or older with at least 10 pack-year smoking history and have chronic obstructive pulmonary disease defined as forced expiratory volume in one second to vital capacity ratio of 0.70 or less and forced expiratory volume in one second that is 80% of predicted or less. Patients will be excluded if they have any known chronic systemic infections, inflammatory conditions, history of previous solid organ transplantation, myocardial infarction, or cerebrovascular accident within the past 3 months prior to study enrolment. The primary end-point is serum C-reactive protein level. Secondary end-points include circulating inflammatory cytokines such as interleukin-6 and interleukin-8 as well as health-related quality of life and lung function.
If inhaled corticosteroids by themselves or in combination with a long-acting β2-adrenoceptor agonist could repress systemic inflammation, they might greatly improve clinical prognosis by reducing various complications in chronic obstructive pulmonary disease.
The World Health Organization has estimated that by 2030, chronic obstructive pulmonary disease will be the third leading cause of death worldwide. Most knowledge of chronic obstructive pulmonary disease is based on studies performed in Europe or North America and little is known about the prevalence, patient characteristics and change in lung function over time in patients in developing countries, such as those of Latin America. This lack of knowledge is in sharp contrast to the high levels of tobacco consumption and exposure to biomass fuels exhibited in Latin America, both major risk factors for the development of chronic obstructive pulmonary disease. Studies have also demonstrated that most Latin American physicians frequently do not follow international chronic obstructive pulmonary disease diagnostic and treatment guidelines. The PRISA Study will expand the current knowledge regarding chronic obstructive pulmonary disease and risk factors in Argentina, Chile and Uruguay to inform policy makers and health professionals on the best policies and practices to address this condition.
PRISA is an observational, prospective cohort study with at least four years of follow-up. In the first year, PRISA has employed a randomized three-staged stratified cluster sampling strategy to identify 6,000 subjects from Marcos Paz and Bariloche, Argentina, Temuco, Chile, and Canelones, Uruguay. Information, such as comorbidities, socioeconomic status and tobacco and biomass exposure, will be collected and spirometry, anthropometric measurements, blood sampling and electrocardiogram will be performed. In year four, subjects will have repeat measurements taken.
There is no longitudinal data on chronic obstructive pulmonary disease incidence and risk factors in the southern cone of Latin America, therefore this population-based prospective cohort study will fill knowledge gaps in the prevalence and incidence of chronic obstructive pulmonary disease, patient characteristics and changes in lung function over time as well as quality of life and health care resource utilization. Information gathered during the PRISA Study will inform public health interventions and prevention practices to reduce risk of COPD in the region.
Chronic Obstructive Pulmonary Disease; Risk Factors; South America; Cohort
BACKGROUND: The consequences of chronic obstructive pulmonary disease (COPD) on daily life, encapsulated by the term "health-related quality of life" (HRQL), are important in determining appropriate home care. There is a need to understand the relative contribution of respiratory impairment, physical disability, coping, age, and socioeconomic variables on HRQL. METHODS: Patients with COPD were recruited on admission to a pulmonary rehabilitation centre. Respiratory impairment was assessed by lung function tests and physical disability was evaluated by a 12 minute walking test. HRQL was assessed by means of the St George's Respiratory Questionnaire (SGRQ) measuring "symptoms", "activity", and "impact". Because the SGRQ does not include a measure of "well being", this was taken from the medical psychological questionnaire for lung diseases. The COPD coping questionnaire and a questionnaire covering basic socioeconomic variables were also used. RESULTS: One hundred and twenty six patients of mean (SD) age 65 (9) years and mean (SD) forced expiratory volume in one second (FEV1) 39 (9)% predicted were included. The scores on the SGRQ indicated severe impairment. Correlations were found between lung function parameters, 12 minute walking test, and the HRQL "activity" and "impact" components. Coping strategies were correlated with the "activity", "impact", and "well being" components. No correlations were found between age, socioeconomic variables, and HRQL. FEV1, 12 minute walking test, and the coping strategies "avoidance" and "emotional reaction" were the best predictors of HRQL. CONCLUSION: In patients with COPD methods of improving physical performance and teaching adequate coping strategies should be considered in order to improve HRQL.
In the Eastern Highlands of Papua New Guinea 46 men and 24 women with chronic lung disease underwent clinical and lung function investigations. In all cases the sole or predominant abnormality was irreversible airways obstruction, probably from chronic bronchitis with variable amounts of acompanying emphysema. There were close similarities to chronic obstructife lung disease in European populations in terms of symptoms, airways obstruction, transfer factor, and radiographic emphysema and inflammatory changes. Bronchiectasis and local fibrosis were present in a few subjects, but previous reports that pulmonary and pleural fibrosis are features of the disease were not confirmed. Possibly environmental and genetic factors may increase the associated blood gas disturbances leading to pulmonary hypertension. Unlike chronic obstructive lung disease in European populations, tobacco smoking is not an important aetiological factor. Although there is no direct evidence, the most likely possibilities are domestic wood smoke and acute chest infections.
New paradigms have been recently proposed in the pathogenesis of both chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), evidencing surprising similarities between these deadly diseases, despite their obvious clinical, radiological and pathologic differences. There is growing evidence supporting a "double hit" pathogenic model where in both COPD and IPF the cumulative action of an accelerated senescence of pulmonary parenchyma (determined by either telomere dysfunction and/or a variety of genetic predisposing factors), and the noxious activity of cigarette smoke-induced oxidative damage are able to severely compromise the regenerative potential of two pulmonary precursor cell compartments (alveolar epithelial precursors in IPF, mesenchymal precursor cells in COPD/emphysema). The consequent divergent derangement of signalling pathways involved in lung tissue renewal (mainly Wnt and Notch), can eventually lead to the distinct abnormal tissue remodelling and functional impairment that characterise the alveolar parenchyma in these diseases (irreversible fibrosis and bronchiolar honeycombing in IPF, emphysema and airway chronic inflammation in COPD).
COPD; IPF; precursor cell senescence; telomere dysfunction; Wnt; Notch; Caveolin-1
Chronic obstructive pulmonary disease, metabolic syndrome and diabetes mellitus are common and underdiagnosed medical conditions. It was predicted that chronic obstructive pulmonary disease will be the third leading cause of death worldwide by 2020. The healthcare burden of this disease is even greater if we consider the significant impact of chronic obstructive pulmonary disease on the cardiovascular morbidity and mortality.
Chronic obstructive pulmonary disease may be considered as a novel risk factor for new onset type 2 diabetes mellitus via multiple pathophysiological alterations such as: inflammation and oxidative stress, insulin resistance, weight gain and alterations in metabolism of adipokines.
On the other hand, diabetes may act as an independent factor, negatively affecting pulmonary structure and function. Diabetes is associated with an increased risk of pulmonary infections, disease exacerbations and worsened COPD outcomes. On the top of that, coexistent OSA may increase the risk for type 2 DM in some individuals.
The current scientific data necessitate a greater outlook on chronic obstructive pulmonary disease and chronic obstructive pulmonary disease may be viewed as a risk factor for the new onset type 2 diabetes mellitus. Conversely, both types of diabetes mellitus should be viewed as strong contributing factors for the development of obstructive lung disease. Such approach can potentially improve the outcomes and medical control for both conditions, and, thus, decrease the healthcare burden of these major medical problems.
COPD; Dysglycemia; Insulin resistance; Obesity; Metabolic syndrome; Diabetes mellitus endothelial dysfunction; Vasculopathy
TP53 gene mutations can lead to the expression of a dysfunctional protein that in turn may enable genetically unstable cells to survive and change into malignant cells. Mutant p53 accumulates early in cells and can precociously induce circulating anti-p53 antibodies (p53Abs); in fact, p53 overexpression has been observed in pre-neoplastic lesions, such as bronchial dysplasia, and p53Abs have been found in patients with Chronic Obstructive Pulmonary Disease, before the diagnosis of lung and other tobacco-related tumors.
A large prospective study was carried out, enrolling non-smokers, ex-smokers and smokers with or without the impairment of lung function, to analyze the incidence of serum p53Abs and the correlation with clinicopathologic features, in particular smoking habits and impairment of lung function, in order to investigate their possible role as early markers of the onset of lung cancer or other cancers. The p53Ab levels were evaluated by a specific ELISA in 675 subjects.
Data showed that significant levels of serum p53Abs were present in 35 subjects (5.2%); no difference was observed in the presence of p53Abs with regard to age and gender, while p53Abs correlated with the number of cigarettes smoked per day and packs-year. Furthermore, serum p53Abs were associated with the worst lung function impairment. The median p53Ab level in positive subjects was 3.5 units/ml (range 1.2 to 65.3 units/ml). Only fifteen positive subjects participated in the follow-up, again resulting positive for serum p53Abs, and no evidence of cancer was found in these patients.
The presence of serum p53Abs was found to be associated with smoking level and lung function impairment, both risk factors of cancer development. However, in our study we have not observed the occurrence of lung cancer or other cancers in the follow-up of positive subjects, therefore we cannot directly correlate the presence of serum p53Abs with cancer risk.
Impaired lung function; Smoking habits; Serum p53 antibodies; Biomarkers; Lung cancer
A previously reported computer analysis has been used to provide numerical ventilation-perfusion lung scan data, for comparison with tests of airways function and results of arterial blood gas analysis in 11 patients with pulmonary embolism, 18 with asthma, and 37 with chronic obstructive lung disease. In pulmonary embolism an index of underperfusion showed high sensitivity, and an index of ventilation-perfusion mismatching correlated well with severity (hypoxaemia). In asthma an index of underventilation was sensitive and correlated well with severity of airways obstruction. In chronic obstructive lung disease the same index was sensitive but correlated poorly with severity. This was attributed to heterogeneity of the lung disease (airways obstruction plus emphysema) in chronic obstructive lung disease. Ventilation-perfusion mismatching was frequently present in airways disease, and was often of great severity in chronic obstructive lung disease. Discrimination between pulmonary embolism and either type of airways disease was possible by using a combination of underfusion and underventilation indices. The technique offers the prospect of increasing the information derived from lung scans and of automating the reporting of scans.
obstructive pulmonary disease (COPD) is common although often poorly
characterised, particularly in primary care. However, application of
guidelines to the management of such patients needs a clear
understanding of the phenotype. In particular, the British guidelines
for the management of COPD recommend that the diagnosis is based on
appropriate symptoms and evidence of airflow obstruction as determined
by a forced expiratory volume in one second (FEV1) of
<80% of the predicted value and an FEV1/VC ratio of
was undertaken of 110 patients aged 40-80 years who had presented to
their general practitioner with an acute exacerbation of COPD. The
episode was treated at home and, when patients had recovered to the
stable state (two months later), they were characterised by full lung
function tests and a high resolution computed tomographic (HRCT) scan
of the chest.
RESULTS—There was a
wide range of impairment of FEV1 which was in the normal
range (⩾80%) in 30%, mildly impaired (60-79%) in 18%, moderately
impaired (40-59%) in 33%, and severely impaired (<40%) in 19% of
patients. A reduced FEV1/VC ratio was present in all patients with an FEV1 of <80% predicted but also in 41%
of those with an FEV1 of ⩾80% predicted. Only 5% of
patients had a substantial bronchodilator response suggesting a
diagnosis of asthma. Emphysema was present in 51% of patients and
confined to the upper lobes in most (73% of these patients). HRCT
evidence of bronchiectasis was noted in 29% of patients and was
predominantly tubular; most (81%) were current or ex-smokers. A
solitary pulmonary nodule was seen on 9% of scans and unsuspected lung
malignancy was diagnosed in two patients.
confirms that COPD in primary care is a heterogeneous condition. Some
patients do not fulfil the proposed diagnostic criteria with
FEV1 of ⩾80% predicted but they may nevertheless have
airflow obstruction. Bronchiectasis is common in this group of
patients, as is unsuspected malignancy. These findings should be
considered when developing recommendations for the investigation and
management of COPD in the community.
α1-Antitrypsin (AAT) secreted from hepatocytes is an inhibitor of neutrophil elastase. Its normal circulating concentration functions to maintain the elasticity of the lung by preventing the hydrolytic destruction of elastin fibers. Severely diminished circulating concentrations of AAT, resulting from the impaired secretion of genetic variants that exhibit distinct polypeptide folding defects, can function as an etiologic agent for the development of chronic obstructive pulmonary disease. In addition, the inappropriate accumulation of structurally aberrant AAT within the hepatocyte endoplasmic reticulum can contribute to the etiology of liver disease. This article focuses on the discovery and characterization of a biosynthetic quality control system that contributes to the secretion of AAT by first facilitating its proper structural maturation, and then by orchestrating the selective elimination of those molecules that fail to attain structural maturation. Mechanistic elucidation of these interconnected quality control events recently led to the identification of an underlying genetic modifier capable of accelerating the onset of end-stage liver disease by impairing the efficiency of an initial step in the protein disposal process.
endoplasmic reticulum; glycoproteins; biosynthetic quality control; proteolysis; autophagy
With rapid advances in our knowledge of the human genome and increasing availability of high-throughput investigative technology, genome-wide association (GWA) studies have recently gained marked popularity. As an unbiased approach to identifying genomic regions of importance in complex human disease, the results of such studies have the potential to illuminate novel causal pathways, guide mechanistic research, and aid in prediction of disease risk. The use of a genome-wide approach presents considerable methodological and statistical challenges, and properly conducted studies are essential to avoid false-positive results. A total of 22 GWA studies have been published in pulmonary medicine thus far, implicating several intriguing genomic regions in the determination of pulmonary function measures, onset of asthma, and susceptibility to chronic obstructive pulmonary disease. Many questions remain, however, as most identified genetic variants contribute only nominally to overall disease risk, genetic disease mechanisms remain uncertain, and disease-associated variants are not consistent across studies. Perhaps most fundamentally, the association signals identified have not yet been traced to causal variants. This perspective will review the current state of GWA studies in pulmonary disease. We begin with an introduction to the hypothesis, principles, and limitations of this type of genome-wide approach, highlight key points from available studies, and conclude by addressing future approaches to better understand the genetics of complex pulmonary disease.
genetics; chronic obstructive pulmonary disease; asthma
Introduction. Fabry disease is a rare X-linked lysosomal storage disorder, characterized by an α-galactosidase A deficiency resulting in globotriaosylceramide storage within cells. Subsequently, various organ systems are involved, clinically the most important are kidneys, the heart, and the peripheral and central nervous systems. Although obstructive lung disease is a common pathological finding in Fabry disease, pulmonary involvement is a clinically disregarded feature. Case Presentation. We report a patient with a diagnosis of chronic obstructive pulmonary disease (COPD) who received a single lung transplant in 2007. Later, a kidney biopsy revealed the diagnosis of Fabry disease, which was confirmed by enzymatic and genetic testing. Ultrastructural changes in a native lung biopsy were consistent with the diagnosis. Although the association of a lung transplant and Fabry disease appears far-fetched on first sight, respiratory impairment cannot be denied in Fabry disease. Conclusion. With this case presentation, we would like to stimulate discussion about rare differential diagnoses hidden beneath widespread disease and that a correct diagnosis is the base of an optimal treatment strategy for each patient. Overall, the patient might have benefited from specific enzyme replacement therapy, especially in view of the chronic kidney disease.
Muscle dysfunction represents a pathophysiological feature of chronic obstructive pulmonary disease (COPD). Muscle impairment contributes to decreased effort capacity in these patients at least in the same proportion as pulmonary function limitation. Maximal inspiratory pressure (MIP) is a reliable, noninvasive parameter for assessing the respiratory muscle capacity. The aim of the present study was to determine the role of MIP in effort capacity decrease in COPD patients. MIP was measured in 121 COPD patients without hyperinflation (RV < 150%) together with the following investigations: body plethysmography, body impedance analysis, dynamometry, 6-minute walking test (6MWT), determination of SaO2 and serum levels of highly sensitive C-reactive protein (hsCRP). MIP (kPa) was significantly decreased in moderate-severe stages (6.19 ± 2.42, COPD II; 5.35 ± 2.49, COPD III; 4.56 ± 1.98, COPD IV vs 7.90 ± 2.61 in controls, P < 0.001), whereas the muscle force assessed by dynamometry was decreased only in advanced stages of disease (0.47 ± 0.12, COPD III; 0.41 ± 0.07, COPD IV vs 0.71 ± 0.16 in controls, P < 0.001). The values of MIP correlated (r = 0.53, P = 0.0003) with the distance walked in 6MWT. MIP may provide additive information concerning the general profile of muscle dysfunction in COPD patients.
COPD; MIP; exacerbation
Alpha-1-antitrypsin deficiency is a genetic condition associated with severe, early-onset chronic obstructive pulmonary disease (COPD). However, there is significant variability in lung function impairment among persons with the protease inhibitor ZZ genotype. Early identification of persons at highest risk of developing lung disease could be beneficial in guiding monitoring and treatment decisions. Using a multicenter, family-based study sample (2002–2005) of 372 persons with the protease inhibitor ZZ genotype, the authors developed prediction models for forced expiratory volume in 1 second (FEV1) and the presence of severe COPD using demographic, clinical, and genetic variables. Half of the data sample was used for model development, and the other half was used for model validation. In the training sample, variables found to be predictive of both FEV1 and severe COPD were age, sex, pack-years of smoking, bronchodilator responsiveness, chronic bronchitis symptoms, and index case status. In the validation sample, the predictive model for FEV1 explained 50% of the variance in FEV1, and the model for severe COPD exhibited excellent discrimination (c statistic = 0.88).
alpha-1-antitrypsin deficiency; genetics; polymorphism, single nucleotide; pulmonary disease, chronic obstructive
Chronic subclinical inflammation may contribute to impaired physical function in older adults; however, more data are needed to determine whether inflammation is a common mechanism for functional decline, independent of disease or health status.
We examined associations between physical function and inflammatory biomarkers in 542 older men and women enrolled in four clinical studies at Wake Forest University between 2001 and 2006. All participants were at least 55 years and had chronic obstructive pulmonary disease, congestive heart failure, high cardiovascular risk, or self-reported physical disability. Uniform clinical assessments were used across studies, including grip strength; a Short Physical Performance Battery (SPPB; includes balance, 4-m walk, and repeated chair stands); inflammatory biomarker assays for interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and C-reactive protein (CRP); and anthropometric measures.
Higher levels of CRP and IL-6, but not TNF-α, were associated with lower grip strength and SPPB scores and longer times to complete the 4-m walk and repeated chair stands tests, independent of age, gender, and race. More importantly, these relationships were generally independent of disease status. Further adjustment for fat mass, lean mass, or percent body fat altered some of these relationships but did not significantly change the overall results.
Elevated CRP and IL-6 levels are associated with poorer physical function in older adults with various comorbidities, as assessed by a common battery of clinical assessments. Chronic subclinical inflammation may be a marker of functional limitations in older persons across several diseases/health conditions.
Inflammation; Physical function; Aging; Comorbidities
Chronic obstructive pulmonary disease/emphysema (COPD/emphysema) is characterized by chronic inflammation and premature lung aging. Anti-aging sirtuin 1 (SIRT1), a NAD+-dependent protein/histone deacetylase, is reduced in lungs of patients with COPD. However, the molecular signals underlying the premature aging in lungs, and whether SIRT1 protects against cellular senescence and various pathophysiological alterations in emphysema, remain unknown. Here, we showed increased cellular senescence in lungs of COPD patients. SIRT1 activation by both genetic overexpression and a selective pharmacological activator, SRT1720, attenuated stress-induced premature cellular senescence and protected against emphysema induced by cigarette smoke and elastase in mice. Ablation of Sirt1 in airway epithelium, but not in myeloid cells, aggravated airspace enlargement, impaired lung function, and reduced exercise tolerance. These effects were due to the ability of SIRT1 to deacetylate the FOXO3 transcription factor, since Foxo3 deficiency diminished the protective effect of SRT1720 on cellular senescence and emphysematous changes. Inhibition of lung inflammation by an NF-κB/IKK2 inhibitor did not have any beneficial effect on emphysema. Thus, SIRT1 protects against emphysema through FOXO3-mediated reduction of cellular senescence, independently of inflammation. Activation of SIRT1 may be an attractive therapeutic strategy in COPD/emphysema.
OBJECTIVE--To assess the prevalence of distal airway obstruction and its risk factors in agricultural areas. METHODS--A cross sectional study of respiratory symptoms and lung function was performed among French farmers and their spouses (1122 subjects) who came for preventive medicine examinations. They answered a respiratory questionnaire and performed pulmonary function tests on a portable spirometer. Diagnoses of chronic bronchitis were made on the basis of reported chronic respiratory symptoms. Airway obstruction was determined from predicted values. Odds ratio (OR) and linear regression coefficients were calculated after stratification by smoking and history of cardiac and other respiratory diseases. RESULTS--Of respiratory symptoms prevalence of chronic cough was 8.47%, and chronic bronchitis 7.66%. Prevalence of distal airway obstruction was 11.4%, and overall airflow obstruction 3.2%. Smokers were 20.2% men, and 5.7% women. Linear regressions showed high association between pack-years in smokers or exsmokers and forced expiratory volume in one second/forced vital capacity (FEV1/VC) and forced expiratory flow between 25% and 75% of vital capacity (FEF25-75). In non-smokers without any history of cardiac or respiratory diseases, age and the size of farms had the highest correlations with these variables. OR for distal airway obstruction was 2.1 in subjects > 50 years old v the younger ones and 3.02 in the smaller farms v the larger ones. CONCLUSION--After stratification by smoking and history of cardiac and respiratory diseases, distal airway obstruction is present in agricultural areas. The age, and the size of farm are the highest respiratory risk factors in non-smokers.
The authors’ objective was to analyze the impact of respiratory impairment on the risk of physical functional limitations among adults with chronic obstructive pulmonary disease (COPD). They hypothesized that greater pulmonary function decrement would result in a broad array of physical functional limitations involving organ systems remote from the lung, a key step in the pathway leading to overall disability. The authors used baseline data from the Function, Living, Outcomes, and Work (FLOW) study, a prospective cohort study of adults with COPD recruited from northern California in 2005–2007. They studied the impact of pulmonary function impairment on the risk of functional limitations using validated measures: lower extremity function (Short Physical Performance Battery), submaximal exercise performance (6-Minute Walk Test), standing balance (Functional Reach Test), skeletal muscle strength (manual muscle testing with dynamometry), and self-reported functional limitation (standardized item battery). Multiple variable analysis was used to control for confounding by age, sex, race, height, educational attainment, and cigarette smoking. Greater pulmonary function impairment, as evidenced by lower forced expiratory volume in 1 second (FEV1), was associated with poorer Short Physical Performance Battery scores and less distance walked during the 6-Minute Walk Test. Lower forced expiratory volume in 1 second was also associated with weaker muscle strength and with a greater risk of self-reported functional limitation (p < 0.05). In conclusion, pulmonary function impairment is associated with multiple manifestations of physical functional limitation among COPD patients. Longitudinal follow-up can delineate the impact of these functional limitations on the prospective risk of disability, guiding preventive strategies that could attenuate the disablement process.
pulmonary disease; chronic obstructive