Bipen D. Patel

Airway Wall Thickening and Emphysema Show Independent Familial Aggregation in Chronic Obstructive Pulmonary Disease

RATIONALE It is unclear whether airway wall thickening and emphysema make independent contributions to airflow limitation in chronic obstructive pulmonary disease (COPD) and whether these phenotypes cluster within families. OBJECTIVES To determine whether airway wall thickening and emphysema (1) make independent contributions to the severity of COPD and (2) show independent aggregation in families of individuals with COPD. METHODS Index cases with COPD and their smoking siblings underwent spirometry and were offered high-resolution computed tomography scans of the thorax to assess the severity of airway wall thickening and emphysema. MEASUREMENTS AND MAIN RESULTS A total of 3,096 individuals were recruited to the study, of whom 1,159 (519 probands and 640 siblings) had technically adequate high-resolution computed tomography scans without significant non-COPD-related thoracic disease. Airway wall thickness correlated with pack-years smoked (P < or = 0.001) and symptoms of chronic bronchitis (P < 0.001). FEV(1) (expressed as % predicted) was independently associated with airway wall thickness at a lumen perimeter of 10 mm (P = 0.0001) and 20 mm (P = 0.0013) and emphysema at -950 Hounsfield units (P < 0.0001). There was independent familial aggregation of both the emphysema (adjusted odds ratio, 2.1; 95% confidence interval, 1.1-4.0; P < or = 0.02) and airway disease phenotypes (P < 0.0001) of COPD. CONCLUSIONS Airway wall thickening and emphysema make independent contributions to airflow obstruction in COPD. These phenotypes show independent aggregation within families of individuals with COPD, suggesting that different genetic factors influence these disease processes.

Dietary antioxidants and asthma in adults

Background: Several antioxidant nutrients have been reported to be inversely associated with asthma. A study was undertaken to assess the independent associations of these nutrients with asthma in adults. Methods: A nested case-control study was performed in 515 adults with physician diagnosed asthma and 515 matched controls using dietary data obtained from 7 day food diaries. The main outcome measures were physician diagnosed asthma and current symptomatic asthma (diagnosed asthma and self-reported wheeze within the previous 12 months). Results: Cases were similar to controls in age, sex, social class, and daily energy intake but had a lower median intake of fruit (132.1 v 149.1 g/day, p⩽0.05). 51.5% of the population reported zero consumption of citrus fruit; relative to these individuals, people who consumed >46.3 g/day had a reduced risk of diagnosed and symptomatic asthma (OR adjusted for potential confounders 0.59 (95% CI 0.43 to 0.82) and 0.51 (95% CI 0.33 to 0.79), respectively). In nutrient analysis, dietary vitamin C and manganese were inversely and independently associated with symptomatic asthma (adjusted OR per quintile increase 0.88 (95% CI 0.77 to 1.00) for vitamin C and 0.85 (95% CI 0.74 to 0.98) for manganese), but only manganese was independently associated with diagnosed asthma (OR 0.86 (95% CI 0.77 to 0.95)). Adjusted plasma levels of vitamin C were significantly lower in symptomatic cases than in controls (54.3 v 58.2 μmol/l, p = 0.003). Conclusions: Symptomatic asthma in adults is associated with a low dietary intake of fruit, the antioxidant nutrients vitamin C and manganese, and low plasma vitamin C levels. These findings suggest that diet may be a potentially modifiable risk factor for the development of asthma.

Smoking related COPD and facial wrinkling: is there a common susceptibility?

Background: Cigarette smoking causes accelerated facial wrinkling and predisposes to chronic obstructive pulmonary disease (COPD). However, it has long been recognised that there is a subgroup of susceptible smokers who are at increased risk of developing airflow obstruction. We have tested the hypothesis that there is a common susceptibility for the development of COPD and facial wrinkling in cigarette smokers. Methods: One hundred and forty nine current and ex-smokers were recruited from a family based study of COPD genetics, 68 (45.6%) of whom fulfilled the definition of COPD. 124 (83.2%) had no or minor facial wrinkling (Daniell <IV) and 25 (16.8%) were wrinkled (Daniell score ⩾IV). Generalised estimating equations were used to adjust for familial correlations between related individuals and the potential confounding effects of age and pack years smoked. Results: Forced expiratory volume in 1 second (FEV1) was significantly lower in those with wrinkles than in those without (mean difference in FEV1 % predicted −13.7%, 95% CI −27.5 to 0.0, p = 0.05) and facial wrinkling was associated with a substantially increased risk of COPD (adjusted OR 5.0, 95% CI 1.3 to 18.5, p<0.02). The Daniell score correlated with the extent of emphysema on the CT scan (p<0.05) and facial wrinkling was also associated with a greater risk of more extensive emphysema (adjusted OR 3.0, 95% CI 1.0 to 9.3, p = 0.05). Conclusion: Facial wrinkling is associated with COPD in smokers, and both disease processes may share a common susceptibility. Facial wrinkling in smokers may therefore be a biomarker of susceptibility to COPD.

Childhood smoking is an independent risk factor for obstructive airways disease in women

Objective: To assess whether starting to smoke in childhood increases the risk of obstructive airways disease (OAD) in adult life. Methods: A retrospective cohort analysis was undertaken of 12 504 current and ex-smokers in the EPIC-Norfolk cohort. The main exposure was starting to smoke during childhood (age <16 years). Three definitions of OAD were used: doctor diagnosed asthma, doctor diagnosed bronchitis/emphysema, and “any OAD” (doctor diagnosed asthma or bronchitis/emphysema, or taking medication used in the treatment of OAD). Results: Childhood smokers had significantly more pack years of exposure and poorer lung function than subjects who started to smoke in adulthood (⩾16 years). Compared with starting in adulthood, starting to smoke in childhood was associated with a greater risk of bronchitis/emphysema in female smokers (OR 1.79, 95% CI 1.25 to 2.56) and ex-smokers of both sexes (OR 1.29, 95% CI 1.07 to 1.55 in men and OR 1.40, 95% CI 1.05 to 1.85 in women), and of “any OAD” in female smokers (OR 1.72, 95% CI 1.24 to 2.38) and male and female ex-smokers (OR 1.20, 95% CI 1.03 to 1.40 in men and 1.34, 95% CI 1.07 to 1.57 in women). After adjustment for pack years, childhood smoking was associated with poorer lung function (FEV1 92.3% predicted in adult smokers and 89.5% in childhood smokers, p = 0.03) and a greater risk of bronchitis/emphysema (adjusted OR 1.55, 95% CI 1.08 to 2.24) and for “any OAD” (OR 1.54, 95% CI 1.10 to 2.13) in female smokers but not in male and female ex-smokers. Conclusion: Starting to smoke in childhood is associated with an increased risk of airways disease because of the extra pack years smoked. In women, childhood smoking is itself an independent risk factor for the development of airways disease.

Case-based discussion from the Royal Devon and Exeter NHS Foundation Trust: a painful paradox

Tumour necrosis factor (TNF)-α inhibitors, despite being an effective treatment for granulomatous diseases such as sarcoidosis and Crohns, are recognised to trigger a paradoxical granulomatous response.1 ,2 Reported cases have predominantly described lymph node, pulmonary and skin manifestations. We present a case of a granulomatous thoracic spine lesion, leading to atraumatic fracture, arising as a consequence of etanarcept treatment of connective tissue disease with associated interstitial lung disease (ILD). Dr C Sharp (StR) A 50-year-old woman, a retired hairdresser, with rheumatoid arthritis/Jo-1 overlap syndrome, diagnosed 14 years earlier, and with associated but hitherto stable ILD, was referred to the ILD service with progressive dyspnoea and deteriorating lung function. Other relevant medical history included febrile neutrophilic dermatosis. The patient reported smoking 10–20 cigarettes per day, but had had no occupational or animal exposures and no past exposure to tuberculosis. At presentation, there was marked joint destruction though no active synovitis, and systemic symptoms were well controlled with the anti-TNFα monoclonal antibody etanercept which had been commenced in 2006. Prior to commencement of the etanercept, a Heaf test had been negative. There was no history of significant corticosteroid usage. Respiratory examination was remarkable only for fine bi-basal inspiratory crackles. Pulmonary function tests in January 2006 demonstrated a forced expiratory volume in 1 s (FEV1) of 2.62 L (95% predicted), forced vital capacity (FVC) 3.27 L (105% predicted), with diffusion coefficient for carbon monoxide (DLCO) 5.08 mL CO/Min/mm Hg (60% predicted). At presentation to the ILD service in May 2010, the values had fallen to FEV1 2.02 L (78%), FVC 2.53 L (86%) and DLco 3.73 (44%). Autoimmune profile demonstrated a positive rheumatoid factor (99 IU/mL), a positive antinuclear antibody and the presence of anti-Ro, anti-La and anti-Jo-1 antibodies. A high-resolution (HR) CT scan of the thorax and an echocardiogram were arranged. Dr A Spiers (Consultant Thoracic …

S113 The effect of small airways disease and emphysema on the association between smoking and lung function, and bronchodilator response

Introduction and objectives The airflow limitation of COPD results from small airway disease and emphysema. These phenotypes are likely to have independent genetic risk factors. It is not known if the heterogeneity of COPD accounts for the relatively weak association between pack-years smoked and forced expiratory volume in 1 s (FEV1) seen within smoking populations, or bronchodilator response (BDR). This study aimed to assess the effect of these phenotypes on the association between smoking and FEV1 and on BDR. Method The international COPD genetics network is a multi-centre study aimed at identifying genes that predispose to COPD, in which high resolution computed tomography (HRCT) was used to quantify components of the COPD phenotype: (i) emphysema detected by radiologists (RE), (ii) emphysema assessed as per cent low-attenuation area (%LAA) and (iii) airway wall thickness (AWT) for airways with an internal perimeter of 10 mm (Pi10), 20 mm (Pi20), and average per cent wall area (WA%). They were then assessed for their effect on the association between smoking and lung function (FEV1% predicted (FEV1%)), and on BDR. Results RE data were available for 1159 individuals, 745 had complete data for Pi10, Pi20, AWT% and %LAA. The association between pack-years smoked and FEV1% was greater in those without (r=−0.41), compared to those with, RE (r=−0.12, p<0.001 for difference in effect). AWT and RE correlated with FEV1% but had different relationships with smoking; AWT was positively associated with pack-years but there was no relationship between RE severity and pack-years smoked. RE, %LAA and AWT made independent contributions to FEV1%. Post-bronchodilator increase in FEV1 was inversely associated with severity of RE (Abstract S113 Table 1), even after adjustment for pre-bronchodilator FEV1 (p<0.01). BDR was also inversely associated with %LAA (p=0.02, and p≤0.05 adjusted for baseline FEV1).Abstract S113 Table 1 Severity of RE Mild (5–25%) Moderate (25–50%) Severe (>50%) p (trend) Number 228 185 266 – BDR, FEV1 (mls) 171.3±188.2 134.4±174.7 100.2±129.6 ≤0.0001 Conclusion The AWT component of COPD, but not the severity of RE, increases with pack-years smoked, and the association between pack-years and FEV1% is greatest in those with an airway predominant phenotype. This suggests different gene-smoking interactions between phenotypes. RE and %LAA independently contribute to FEV1% and therefore measure different components of emphysema, however both were inversely associated with BDR.