Lower Levels Of Lung Function Research Articles

Impact of society and national guidelines on patient selection for lung cancer surgery in the United Kingdom.

We sought to evaluate the impact of different national clinical guidelines (with consistent and conflicting recommendations) on clinician's practice in the UK. In this cohort study, we analysed data from National Lung Cancer Audit comprising all patients diagnosed with lung cancer between 2008 and 2013 within England and Wales for consistent (British Thoracic Society and National Institute of Clinical Excellence) recommendations for lower/more permissive lung function but opposing stage (N2) selection parameters for surgery. From 2008 to 2013, data from 167192 patients with primary lung cancers were included. The proportion of patients undergoing surgery for lung cancer increased from 9.5% to 20.5% in 2013 (P < 0.001) as the number of general thoracic surgeons in the UK increased from 40 to 81 in the corresponding timeframe. Mean forced expiratory volume in 1 s of surgical patients increased from 76% (22) to 81% (22) in 2013 (P < 0.001). Of the patients undergoing surgery, the proportion of patients with N2 disease across the 6-year interval was broadly consistent between 8% and 11% without any evidence of trend (P = 0.125). Within 3 years of new clinical guideline recommendations, we did not observe any overall change suggesting greater selection for surgery on lower levels of lung function. When presented with conflicting recommendation, no observable change in selection was noted on surgery for N2 disease. The observed increase in surgical resection rates is more likely due to greater access to surgery (by increasing number of surgeons) rather than any impact of guideline recommendations.

Impact of society and national guidelines on patient selection for lung cancer surgery in the United Kingdom.

8544 Background: In 2010 the British Thoracic Society (BTS) guidelines introduced clinical decision based on patient perception of risk to make surgery more permissive and revised recommendations for broader oncologic criteria such as surgery for N2 disease to improve surgical resection rates. In 2011 the National Institute for Health and Care Excellence (NICE) guidelines were updated with similar recommendations, but notable disagreement on surgery for N2 disease. We sought to conduct one of the largest cross-sectional studies to ascertain the impact of national clinical guidelines (with conflicting recommendations) on clinician behaviour. Methods: We analysed data from the UK national registry (National Lung Cancer Audit) comprising all patients diagnosed with lung cancer between 2008 to 2013 within England and Wales. Categorical data was summarised as frequency (%) and continuous data was summarised as mean (SD). Linear and logistic regression analyses were used with each year as an independent categorical outcome to determine global and year specific changes in FEV1 and proportions with N2 undergoing surgery respectively. Results: From January 2008 to December 2013, data from 167,192 patients with primary lung cancers were submitted to the NLCA. In 2008, 23,293 new lung cancers were diagnosed in England and Wales increasing annually by 2013 to 29,224. The most common presentation was advanced disease stage IV (49.7%), IIIB (13.2%) and IIIA (12.0%) and early-stage disease was less frequent with presentations IA (7.0%), IB (6.7%), IIA (2.9%) and IIB (4.27%). Lung function tests were undertaken in a subset of 53,905 of all diagnosed patients from 2008 to 2013. The mean FEV1 (SD) increased annually from 67 (22)% in 2008 to 71 (24)% in 2013 (p &lt; 0.001). Overall, 28% (n = 46,742) of the patients were preoperatively staged as N2 disease at diagnosis. The proportion of patients with N2 disease increased from 24 to 29% in this timeframe (P = 0.003). The proportion of patients undergoing surgery for lung cancer increased from 9.5% in 2008 to 20.5% in 2013 (p &lt; 0.001). Mean FEV1 of surgical patients were higher at 79 (22)% than the population average of 69 (23)%, an accepted reflection of surgical selection. Over time, mean FEV1 of surgical patients increased from 76 (22)% in 2008 to 81 (22)% in 2013 (p &lt; 0.001). Of the patients undergoing surgery, the proportion of patients across the 6-year interval were broadly consistent between 8 to 11% without any evidence of trend (P = 0.125). Conclusions: Within 3 years of new clinical guidelines, we did not observe any overall change in selection based on lower levels of lung function and when presented with conflicting recommendation no observable change in attitudes of clinicians on surgery for N2 disease. The observed increase in surgical resection rates is more likely due to (greater access to surgery by) increasing number of surgeons rather than any impact of guideline recommendations.

Blood eosinophils associate with reduced lung function growth in adolescent asthmatics.

Background and ObjectiveSome children with asthma have low lung growth, putting them at increased risk for COPD later in life. However, it is currently not clear who will experience this adverse growth pattern. We therefore investigated the predictive role of blood eosinophils as a type 2 inflammation marker in lung growth, focusing on the presence and severity of asthma.MethodsWe investigated blood eosinophils and lung function growth (percentage of predicted values) using linear mixed models in children and adolescents from two longitudinal cohorts. One cohort was hospital‐based and consisted of asthmatic children at their first outpatient clinic visit after referral by the general practitioner (n = 133, mean age 9.8), while the second was a general population‐based birth cohort (PIAMA, asthma n = 52 and non‐asthma n = 433, mean age 8.1). The hospital‐based cohort had not been treated with inhaled corticosteroids (ICS) before referral.ResultsSubjects in the hospital‐based asthma cohort had more severe asthma compared with the asthmatic subjects in the population‐based cohort, defined by lower lung function levels and a higher prevalence of bronchial hyper‐responsiveness. In the asthma cohort, higher blood eosinophil numbers were associated with less growth in FEV1 (estimated change in lung function per 1 unit increase in ln blood eosinophils (B): −0.66%/year (95% confidence interval (CI): −1.11 to −0.20, p < .01)) and FVC (B: −0.40%/year (95% CI: −0.75 to −0.05), p = .025)) during follow‐up in adolescence (min 7, max 17 years). These associations were not observed in the general population‐based birth cohort, regardless of asthma status during follow‐up (age 8–16).Conclusions and Clinical RelevanceBlood eosinophil counts in children with asthma not treated with ICS at referral were predictive of lower growth in FEV1 and FVC during follow‐up in adolescence. Our findings indicate that this association is dependent on the degree of asthma severity. Future studies should address whether anti‐eosinophilic treatments preserve lung function growth in children with asthma.

Biomarkers for Overweight in Adult-Onset Asthma.

PurposeOverweight and obesity are associated with one of the severe phenotypes of asthma, with an increased rate of exacerbations, low level of lung function, and reduced response to corticosteroid therapy. The present study focused on identifying useful biomarkers of severity in overweight patients with adult-onset asthma using real-world data.Patients and MethodsA total of 56 patients with adult-onset asthma who visited Saga University Hospital between 2018 and 2019 were retrospectively reviewed. Overweight was defined as a body mass index (BMI) greater than 25 kg/m2. Blood eosinophils, cytokines, and chemokines were compared between non-overweight asthma and overweight asthma patients.ResultsOverweight asthma patients had a higher annual exacerbation rate, lower pulmonary function even when treated frequently with high-dose inhaled corticosteroids, and a significantly lower percentage of eosinophils and lower eosinophil count compared to non-overweight asthma patients (p<0.01, p=0.03). Moreover, the percentage of eosinophils was significantly negatively correlated with BMI (ρ=−0.38, p<0.01) (Figure 1). On serum cytokine and chemokine analyses, the overweight asthma group included significantly more patients with a lower level of tissue growth factor α (TGF-α) (1.1 pg/mL) and higher levels of hsIL-6 (2.5 pg/mL), RANTES/CCL5 (298.5 pg/mL), and vascular endothelial growth factor A (VEGF-A) (63.7 pg/mL), than the non-overweight asthma group (p=0.02, p<0.01, p=0.02, p=0.01, respectively).ConclusionThe present study showed that overweight patients with adult-onset asthma were characterized by a higher rate of annual exacerbations and worse lung function despite treatment with high-dose inhaled corticosteroids and lower blood eosinophil counts than non-overweight patients with asthma. On blood cytokine and chemokine analyses, a low level of TGF-α and high levels of hsIL-6, RANTES/CCL5, and VEGF-A might be biomarkers reflecting the pathophysiology in overweight patients with asthma.

Determination of the phenotypic age in residents of Mexico City: effect of accelerated ageing on lung function and structure.

IntroductionPhenotypic age better represents age-related biological dysregulation than chronological age. Recently, a multisystem-based ageing measure, which integrates chronological age and nine biomarkers, was proposed.MethodsPhenotypic age was determined in 774 residents of Mexico City over 60 years old and without respiratory problems. We arbitrarily classified as “accelerated” ageing, those showing >4 years compared with their chronological age, and “slowed” ageing, those with <4 years compared with chronological age. Demographic risk factors were analysed with structured questionnaires. Lung structure was evaluated by high-resolution computed tomography and functional competence was analysed by forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), diffusion capacity of carbon monoxide (DLCO), and the 6-minute walk test (6MWT).ResultsOverall, 13% of this cohort showed accelerated ageing, which was corroborated with four independent biomarkers of ageing, 42% had normal ageing and 46% had slowed ageing. Risk factors associated with accelerated ageing were male sex (OR 4.4, 95% CI 2.4–7.9; p<0.01), diabetes mellitus (OR 9.7, 95% CI 5.5–17.2; p<0.01), and long-term sleep duration (OR 2.9 95% CI 1.34–6.35, p<0.01). Among smokers, there was a slight but significant association with the number of pack-years. Subjects with accelerated ageing showed decreased FVC (p<0.0001), FEV1 (p<0.0001), DLCO (p<0.02) and walking distance in the 6MWT (p=0.0001). Slowed-ageing subjects presented less frequently with emphysematous lesions compared with those with accelerated ageing.ConclusionsA small but significant proportion of residents of Mexico City age rapidly, which is associated with male sex, diabetes, and long-term sleep duration. They exhibit lower levels of lung function and develop emphysema more frequently.

Occupational exposure to solvents and lung function decline: A population based study

RationaleWhile cross-sectional studies have shown associations between certain occupational exposures and lower levels of lung function, there was little evidence from population-based studies with repeated lung function measurements.ObjectivesWe aimed to...

Results from an online survey of adults with cystic fibrosis: Accessing and using life expectancy information.

Cystic fibrosis (CF) is the one of the most common inherited diseases. It affects around 10,000 people in the UK, and the median survival age is 47. Recent developments making use of longitudinal patient registry data are producing more detailed and relevant information about predicted life expectancy in CF based on current age and clinical measurements. The objective of this study was toconduct an online survey of adults with CF living in the UK using a web-based questionnaire to investigate: (i) if and how they access information on life expectancy; (ii) what they use it for; (iii) if they want more personalised information on life expectancy or the time until other milestones. The survey was advertised through the Cystic Fibrosis Trust using social media. There were 85 respondents, covering men (39%) and women (61%) aged 16–65. 75% had received information on life expectancy either from their CF care team (34%) or other sources (71%), the most common being the Cystic Fibrosis Trust website and research literature. Most people who received information found it to be beneficial and reported using it in a variety of ways, including to plan strategies for maintaining as best health as possible and to psychologically manage current health status. 82% of respondents were interested in more personalised information about their life expectancy, and participants also noted interest in other outcomes, including time to needing transplant or reaching a low level of lung function. Themes arising in text responses included the importance of good communication of information, the difficulty of relating general information to one’s own circumstances, and a desire for increased information on factors that impact on survival in CF. As an outcome from this work, research is underway to establish how information on life expectancy can be presented to people with CF in an accessible way.

A Meta-analysis of Arsenic Exposure and Lung Function: Is There Evidence of Restrictive or Obstructive Lung Disease?

Hundreds of millions of people worldwide are exposed to arsenic via contaminated water. The goal of this study was to identify whether arsenic-associated lung function deficits resemble obstructive- or restrictive-like lung disease, in order to help illuminate a mechanistic pathway and identify at-risk populations. We recently published a qualitative systematic review outlining the body of research on arsenic and non-malignant respiratory outcomes. Evidence from several populations, at different life stages, and at different levels of exposure showed consistent associations of arsenic exposure with chronic lung disease mortality, respiratory symptoms, and lower lung function levels. The published review, however, only conducted a broad qualitative description of the published studies without considering specific spirometry patterns, without conducting a meta-analysis, and without evaluating the dose-response relationship. We searched PubMed and Embase for studies on environmental arsenic exposure and lung function. We performed a meta-analysis using inverse-variance-weighted random effects models to summarize adjusted effect estimates for arsenic and forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio. Across nine studies, median water arsenic levels ranged from 23 to 860μg/L. The pooled estimated mean difference (MD) comparing the highest category of arsenic exposure (ranging from > 11 to > 800μg/L) versus the lowest (ranging from < 10 to < 100μg/L) for each study for FEV1 was -42mL (95% confidence interval (CI) - 70, - 16) and for FVC was -50mL (95% CI - 63, - 37). Three studies reported effect estimates for FEV1/FVC, for which there was no evidence of an association; the pooled estimated MD was 0.01 (95% CI - 0.005, 0.024). This review supports that arsenic is associated with restrictive impairments based on inverse associations between arsenic and FEV1 and FVC, but not with FEV1/FVC. Future studies should confirm whether low-level arsenic exposure is a restrictive lung disease risk factor in order to identify at-risk populations in the USA.

A cross-sectional study with an improved methodology to assess occupational air pollution exposure and respiratory health in motorcycle taxi driving

IntroductionMotorcycle taxi driving is common in many African cities. This study tested whether this occupation is associated with more respiratory disorders in a context of widespread urban air pollution with an improved methodology. MethodsIn a cross sectional study we compared 85 male motorcycle taxi drivers in the capital city of the Republic of Benin (Cotonou) with an age and neighborhood matched control group. All participants carried a portable carbon monoxide data logger for 8 hours per day to assess exposure to air pollution. Respiratory symptoms were obtained using a standardized questionnaire and pulmonary function was assessed by spirometry. ResultsThe two groups did not differ significantly (p>0.10) in their age, height, educational level, and exposures to smoke from biomass fuels and tobacco products. The taxi drivers were exposed to higher mean (SD) levels of carbon monoxide (7.6±4.9ppmvs. 5.4±3.8ppm p=0.001). They reported more phlegm and tended to have slightly lower levels of lung function, although these differences were not statistically significant. ConclusionIn this cross sectional study of young motorcycle taxi drivers with substantial exposure to urban traffic and a matched control group, we found no evidence for respiratory impairment. A follow-up of such study population with other pollution exposure surrogate and other clinical endpoint may provide a more robust conclusion regarding the exposure response in this professional group.

Anxiety Sensitivity and Reactivity to Asthma-Like Sensations Among Young Adults With Asthma.

Anxiety sensitivity, particularly the physical concerns domain, is associated with more problematic asthma symptoms and greater functional limitations. It has been theorized that anxiety sensitivity fosters greater reactivity to asthma-related physical sensations; however, this theory has yet to be empirically tested. Thus, the present investigation sought to examine the role of anxiety sensitivity-physical concerns in terms of affective and physical reactivity to asthma-like symptoms. Participants were 101 undergraduates with asthma (76.2% female, Mage = 19.69 years, SD = 3.77 years, range = 18-49 years) who completed self-report measures and a straw-breathing task. Results indicated that after controlling for the effects of gender, asthma control (i.e., how well one's asthma symptoms are managed or controlled), and negative affectivity, greater levels of anxiety sensitivity-physical concerns significantly predicted greater anxiety (4.7% unique variance) and asthma symptoms (6.9% unique variance) and lower levels of lung function (4.4% unique variance) after the straw-breathing task. These findings suggest that individuals with asthma who are fearful of physiological arousal are a particularly "at-risk" population for poor asthma outcomes because of this greater reactivity and could benefit from interventions targeting anxiety sensitivity.

The emerging role of Vitamin D in asthma management

Vitamin D deficiency and asthma share risk factors. Epidemiologists suggest that the U.S. prevalence of Vitamin D deficiency has increased as a result of the Westernization of culture and less time spent outdoors. Numerous studies support a patient's Vitamin D deficiency as a contributing cause to increased asthma symptoms, lower lung function levels, increased airway reactivity, and worsening asthma control. The purpose of the review article is to discuss the emerging role of Vitamin D in asthma management. A review of original research identified through MEDLINE and CINAHL and published in English was performed. Research suggests promising benefits of Vitamin D supplementation in asthma patients with low (<30 ng/mL) Vitamin D levels. Evidence supports several possible mechanisms, including downregulation of allergen sensitivity and enhanced steroid responsiveness. Studies demonstrate that Vitamin D modifies airway hyperresponsiveness by minimizing airway inflammation. Ongoing studies seek to further evaluate the effects of Vitamin D supplementation on asthma and asthma morbidity. While there is no consensus on the use of Vitamin D as a mainstay in asthma treatment, research supports its consideration for use in asthma patients with low Vitamin D levels. Current evidence reinforces the need to measure Vitamin D levels for all asthma patients.

A prudent diet attenuates lung function decline in cigarette smokers

BackgroundMost previous studies of diet and lung function focus on individual nutrients and/or foods. Dietary pattern analysis is a strong alternative approach, but very few studies examine the dietary pattern—lung function decline association.MethodsThe association between dietary patterns and decline of forced expiratory volume in 1 s (FEV1) was investigated in 2,560 male adults. Dietary patterns were derived from food frequency data using principal component analysis, and linear mixed‐effects models examined these patterns with FEV1 decline over ~3 years, adjusting for confounders. Given the importance of smoking, dietary pattern × smoking interactions were tested.ResultsA more prudent pattern (higher intake of fruits, vegetables and whole grains) was associated with a slower decline in FEV1 in smokers only (top vs. bottom tertile of pattern: +37.8 mL/y; trend Pinteraction = 0.0008). A more Western pattern (higher intake of meat, potatoes and snacks) was associated with a lower FEV1 at study baseline (top vs. bottom quintile: −162.4 mL; P for trend = 0.001), but not with FEV1 decline either overall or by smoking.ConclusionsIn males, a prudent dietary pattern was associated with a slower decline in lung function in smokers only, and a Western dietary pattern was associated with lower levels of lung function, but not change over time.Grant Funding Source: NHLBI R01HL071022 (PAC), and, in part, NCI/DCP CA37429, NCCAM.

SERPINE1 -675 4G/5G polymorphism is associated with asthma severity and inhaled corticosteroid response

Asthma is characterised by chronic airway inflammation and remodelling, which can be (partially) suppressed by inhaled corticosteroids (ICSs). Plasminogen activator inhibitor-1, encoded by the SERPINE1 gene, is the key inhibitor of the plasminogen activator system, which affects tissue repair and remodelling. We studied associations between a functional SERPINE1 -675 4G/5G promoter polymorphism and asthma development, severity and response to ICSs. Longitudinal cohorts of 281 asthmatics and their nonasthmatic spouses, and the general population (n=1,390) were studied. No significant associations were found with asthma development and immunoglobulin (Ig)E levels, or with forced expiratory volume in 1 s (FEV₁) in nonasthmatic controls. Asthmatic subjects carrying the SERPINE1 5G allele had higher IgE and lower lung function levels at follow-up, lower maximally attained lung function levels, and faster lung function decline compared with individuals with the 4G/4G genotype. ICS treatment showed an immediate improvement in FEV₁ in asthmatics carrying the 5G allele. However, these asthmatics still had the fastest rate of FEV₁ decline after initiating ICS treatment. Finally, the 5G allele was associated with a lower prevalence of complete asthma remission at follow-up. These findings suggest that SERPINE1 is not an asthma susceptibility gene, but rather affects the severity, progression and long-term ICS response in asthma.

The Influence of Neonatal Lung Function on Rhinovirus-associated Wheeze

Several studies have shown that the occurrence of wheezing illnesses during the first year of life is associated with lower levels of lung function shortly after birth and before any respiratory illness. It has been suggested that reduced lung function early in life predisposes infants to wheezing during viral respiratory infections, but the association between neonatal lung function and subsequent confirmed viral infections has never been investigated. To study the influence between neonatal lung function and the occurrence of human rhinovirus (HRV)-associated wheeze. In a prospective birth cohort study, infants were followed from birth through the first year of life with daily questionnaires about respiratory symptoms. Neonatal lung function was performed within the first 2 months of life. Nose and throat swabs were collected during episodes with respiratory symptoms. Polymerase chain reaction was used to detect single HRV infections. In 176 of the 202 infants (87%) with a single HRV infection, valid lung function measurements were obtained. The risk of wheeze was 1.49 times higher for each SD increase of airway resistance. The adjusted risk (corrected for possible important confounders) for wheeze was 1.77 (95% confidence interval, 1.16-2.69; P = 0.01) times higher for each SD increase of airway resistance. Maternal smoking during pregnancy was independently associated with wheeze (odds ratio 4.42; 95% confidence interval, 1.27-15.5; P = 0.02). This study showed that total lung resistance is clearly associated with HRV-associated wheeze. Moreover, HRV-associated wheeze might be the first sign to recognize infants with reduced neonatal lung function.

Epidemiology of the Origins of Airflow Limitation in Asthma

There is now conclusive evidence that, as a group, subjects with asthma have lower levels of lung function as compared with their peers and that a significant proportion of subjects with persistent asthma are at risk of developing non-fully reversible airflow limitation, the clinical hallmark of chronic obstructive pulmonary disease. Although at the population level the most conspicuous form of airflow limitation in asthma seems to be that of subjects who wheeze during the first years of life and whose symptoms persist into adult life, asthma-related lung deficits can be related to both acquired deficits in growth of lung function in childhood and steeper decline of lung function in adult life. These trajectories of lung function are likely to differ across subgroups of individuals with asthma, suggesting that different windows of opportunity may exist to modify the natural course of the disease before irreversible deficits are established. These observations indicate the importance of identifying biomarkers that can be used to target children and adults with asthma at increased risk for airflow limitation and determining whether pharmacological interventions can protect these patients from the development of chronic obstructive pulmonary disease.

Genetic associations with asthma and virus-induced wheezing: a systematic review

Various wheezing phenotypes can be identified based on differences in natural histories, risk factors and responses to treatment. In epidemiologic studies, atopic asthma or virus-induced wheezing can be discriminated by the presence or the absence of sensitization to allergens. Children with asthma have been shown to present lower levels of lung function. Patients with viral respiratory infections evolve from normal lung function to enhanced airway reactivity. The objective of this study was to identify genes and polymorphisms associated with different wheezing phenotypes. Using data obtained from the Genetic Association Database, we systematically reviewed studies on genes and polymorphisms that have been associated with virus-induced wheezing or atopic asthma. The research was carried out in February of 2009. Genes associated with the studied outcomes in more than three studies were included in the analysis. We found that different genes and loci have been associated with virus-induced wheezing or atopic asthma. Virus-induced wheezing has frequently been associated with IL-8 polymorphisms, whereas atopic asthma and atopy have frequently been associated with Th2 cytokine gene (CD14 and IL-13) polymorphisms on chromosome 5. This review provides evidence that different wheezing disorders in childhood can be differently affected by genetic variations, considering their role on airway inflammation and atopy. Future studies of genetic associations should consider the different wheezing phenotypes in infancy. In addition, stratified analyses for atopy can be useful for elucidating the mechanisms of the disease.

Risk factors for adult‐onset asthma: A 14‐year longitudinal study

Few longitudinal studies have examined the risk factors and natural history of adult-onset asthma. This study assessed the subject characteristics and lifestyle factors that predicted the new diagnosis of asthma in adulthood and how these factors changed over time in those who developed asthma compared with those who do not. The study enrolled 1554 adults from the Busselton Health Study seen in 1981 and again in 1994-1995 who initially reported never having had doctor-diagnosed asthma. Questionnaire measures were used to assess doctor-diagnosed asthma, respiratory history and tobacco smoking. Height, weight and spirometric measures of lung function were measured. Atopy was assessed by skin prick tests. Logistic regression analysis was used to identify risk factors for adult-onset asthma and changes over time. Reported wheeze, rhinitis, chronic cough, smoking and lower levels of lung function in 1981 each predicted asthma diagnosis by 1994-1995. Neither initial skin-prick reactivity nor newly positive skin-prick tests at follow up were associated with adult-onset asthma. Those diagnosed with asthma were more likely to have new wheeze, new rhinitis, new habitual snoring, weight gain and excess decline in lung function. Adult-onset asthma has risk factors that are distinct from those observed in childhood asthma. The presence of upper airway symptoms including rhinitis, as well as lifestyle factors, such as smoking, predicts those at greatest risk. However, neither pre-existing atopy nor new atopy as measured by skin prick tests was associated with adult-onset asthma.

Lung Function Loss, Smoking, Vitamin C Intake, and Polymorphisms of the Glutamate-Cysteine Ligase Genes

Smoking-induced oxidative stress contributes to chronic obstructive pulmonary disease, a lung disease characterized by low lung function and increasing mortality worldwide. The counterbalance for this effect may be provided by, for example, increased intake of the antioxidant vitamin C or endogenously acting antioxidant enzymes like glutamate-cysteine ligase (GCL), which is responsible for glutathione biosynthesis. To investigate associations of functional polymorphisms in GCL subunits (GCLM and GCLC) with lung function level and its longitudinal course, with vitamin C and smoking habits as potential interactive factors. Two independent general population samples (Doetinchem, n = 1,152, and Vlagtwedde-Vlaardingen, n = 1,390) with multiple lung function (FEV(1), VC) measurements were genotyped for three polymorphisms (C[-129]T, C[-588]T, and a trinucleotide GAG repeat [TNR]) in the subunits of GCL. Genetic effects on lung function level and decline were estimated using linear regression and linear mixed effect models adjusted for confounders. Findings were further investigated for interactions with vitamin C intake in the Doetinchem cohort. GCLC polymorphisms were significantly associated with lower lung function levels in interaction with pack-years smoked in both cohorts. TNR variants in GCLC were associated with accelerated FEV(1) decline in both cohorts in interaction with pack-years. All significant effects were specifically present in subjects within the lowest tertile of vitamin C intake. GCLC is a novel susceptibility gene for low level of lung function in two independent populations. We provide suggestive evidence that this occurs due to an interaction between GCLC polymorphisms, smoking, and low vitamin C intake, which all contribute to the oxidative burden.

Influence of polymorphic metabolic enzymes on biotransformation and effects of diphenylmethane diisocyanate

To identify effect modification produced by genetic traits found in metabolic enzymes, to investigate how these affect the levels of different biomarkers of sprayed and thermo-degraded polyurethane (PUR) based on 4,4'-diphenylmethane diisocyanate (MDI) and to determine how associated respiratory disorders are affected. Two partly overlapping groups of 141 and 158 factory employees exposed to sprayed or heated MDI-PUR glue were examined in years 0 and 2, respectively, for occurrence of polymorphisms in five genes (N-acetyltransferase NAT2 and the glutathione S-transferases GSTM1, GSTM3, GSTP1 [codon 105 and 114] and GSTT1) on the basis of the polymerase chain reaction, exposure biomarkers in plasma and urine (P- and U-MDX), by means of gas chromatography-mass spectrometry, specific serum IgG antibodies against MDI (S-IgG-MDI) by means of ELISA, total S-IgE, symptoms in the eyes, nose and lower airways as assessed by questionnaire and interview, and lung function as measured by spirometry. Both the GSTP1 (105) isoleucine/isoleucine and GSTP1 (114) alanine/alanine genotypes showed higher levels of U-MDX than the other genotypes and the GSTP1 (114) genotype modified the P-MDX/U-MDX relationship. GSTP1 (105) isoleucine/isoleucine was found to be associated with lower levels of S-IgG-MDI and fewer eye symptoms, but with an increased risk of symptoms in the airways, as well as with atopy. Presence of the GSTT1 gene resulted in somewhat lower lung function levels than did the null genotype. A slow NAT2 acetylating capacity was associated with lower P- and U-MDX and S-IgG-MDI levels, and better lung function, but a higher risk of eye and airway symptoms. Analysing the effects of combinations of the different genes provided no further information. Although our study has clear limitations, it reveals various effect modifications produced by the GST and NAT2 genotypes. Gene-environment interactions are highly complex. Further research is needed to obtain a more comprehensive understanding of them.

The natural history of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality in the USA, and it remains one of the few diseases that continues to increase its numbers. The development and progression of COPD can vary dramatically between individuals. A low level of lung function remains the cornerstone of COPD diagnosis and is a key predictor of prognosis. Lung function, however, is not the only factor in determining morbidity and mortality related to COPD, with factors such as body mass index, exercise capability and comorbid disease being important predictors of poor outcomes. Exacerbations of COPD are additional important indicators of both quality of life and outcomes in COPD patients. Definitions of exacerbations can vary, ranging from an increase in symptoms to COPD-related hospitalisations and death. COPD exacerbations are more common in patients with lower levels of lung function and may lead to more rapid declines in lung function. Better understanding of the natural history of COPD may lead to better definitions of specific COPD phenotypes, better interventions and improved outcomes.