Background: Lung transplantation is an important option to treat patients with advanced Cystic Fibrosis (CF) lung disease. We report the outcomes of a large UK cohort of CF lung transplantation recipients.

Methods: Retrospective review of case notes and transplantation databases. Results 176 patients with CF underwent lung transplantation at our centre. The majority (168) had bilateral sequential lung transplantation. Median age at transplantation was 26 years. Diabetes was common pre-transplantation (40%). Polymicrobial infection was common in individual recipients. A diverse range of pathogens were encountered including the Burkholderia cepacia complex (BCC). The bronchial anastomotic complication rate was 2%. Pulmonary function (FEV1% predicted) improved from pre-transplantation median 0.8 litres (21% predicted) to 2.95 litres (78% predicted) at one year following transplantation. We noted an acute rejection rate of 41% within the first month. Our survival figures were 82% survival at one year, 70% at three years, 62% at five years and 51% at ten years. Patients with BCC infection had poorer outcomes and represented the majority of those who had a septic death. We present data on those free from these infections. Bronchiolitis Obliterans Syndrome (BOS) and sepsis were common causes of death. Freedom from BOS was 74% at five years and 38 % at ten years. Biochemical evidence of renal dysfunction was common though renal replacement was infrequently required (<5%).

Interpretation: Lung transplantation is an important therapeutic option in patients with CF even in those with more complex microbiology. Good functional outcomes are noted although transplantation-associated morbidities accrue with time.

Background: Patients with COPD walk less than healthy older people and their self-reported activity predicts exacerbation risk. The relationship between lower limb activity and total daily activity is not known nor is there data relating objectively assessed daily activity to laboratory assessments made before and after rehabilitation.

Methods: We measured lower limb activity by leg actigraphy over 3 days in 45 patients with moderate to severe COPD and 18 similar age controls. Thirty-three COPD patients entered an 8-week rehabilitation programme where we measured the change in leg activity and related this to other outcomes.

Results: In COPD patients mean activity level measured by whole body and leg activity monitors was closely related (r=0.92; p<0.001) but leg activity was consistently reduced compared with similar age controls (p=0.001). Mean leg activity, mean intensity of leg activity and the time that patients spent mobile at home were all related to FEV1 (r=0.57; p=0.001, r=0.5; p=0.003 and r=0.51; p=0.002 respectively) but intensity of activity and time spent mobile were not related. Subjects completing pulmonary rehabilitation showed significant improvements in mean activity (p=0.001) and spent more time moving (p=0.014). These changes were unrelated to improvement in muscle strength or walking distance but correlated with baseline FEV1 (r=0.8; p<0.001).

Conclusions: Total daily activity in COPD patients is closely related to leg activity which is reduced compared to similar age controls. Individuals differ in the time spent mobile during the day but both subjective and objectively assessed activity improves after rehabilitation and is predicted by FEV1. The change in activity is unrelated to improvements in corridor walking and health status.

Background: Impaired development in utero is suggested to increase the risk of poor respiratory health in adulthood, although a consensus has not been reached. A possible explanation for discrepancies between previous studies is inconsistent controlling for potential confounding factors, particularly childhood infections. Also, little is known regarding the relative importance of factors operating at different stages of the lifecourse. We have used detailed longitudinal data from the Newcastle Thousand Families cohort to assess the impact of birth weight, and various other factors acting throughout the lifecourse, on predicting forced expiratory volume in one second (FEV₁).

Methods: Detailed information was collected prospectively during childhood, including birth weight, childhood infections, and socio-economic circumstances. At age 49-51, 412 study members attended for clinical examination and measurement of FEV₁. These data were analysed in relation to a range of factors from across the lifecourse using linear regression models.

Results: After adjustment for all other significant variables, increasing birth weight - standardised for sex and gestational age - (p=0.011), being breast fed for more than four weeks (p=0.017), less frequent childhood lower respiratory tract infections (LRTI) (p=0.015), non smoking (p<0.001), lower body fat percentage (p=0.010), male sex (p<0.001), no history of asthma (p=0.013), and greater adult height (p<0.001) were all independently associated with higher adult FEV₁.

Conclusion:Adult lung function is influenced by numerous factors during an individual's lifetime, acting both directly and indirectly throughout the lifecourse. As expected, sex, height, and smoking were the most important predictors of FEV₁, but birth weight, breast feeding, and childhood LRTIs also contributed significantly.

Background: Breathlessness is a common and difficult symptom to treat in patients with cancer. Case reports suggest that nebulised furosemide can relieve breathlessness in such patients but few data are available.

Method: Patients with primary or secondary lung cancer and a Dyspnoea Exertion Scale score of >=3 were recruited. Following familiarisation patients received either nebulised furosemide 40mg or nebulised 0.9% saline under double-blind conditions or no treatment, in random order on three consecutive days. Patients undertook number reading and arm exercise tests to assess breathlessness and its impact, and were asked to report subjective benefit and any preference between nebulised treatments.

Results: Fifteen patients took part. There were no differences between furosemide, saline and no treatment in the outcomes of the number reading test (e.g. mean number read per breath was 6.7, 6.4 and 6.7 respectively) or arm exercise test (e.g. mean Borg score at maximum equivalent workload was 2.3, 2.5 and 2.7 respectively). No adverse effects were reported, although there was a small fall in FEV1 and FVC following saline. Six patients considered that their breathlessness improved with nebulised treatment, three preferring saline, one furosemide and two reporting they were of equal benefit.

Conclusions: Our findings do not support a beneficial effect from nebulised furosemide in patients with cancer-related breathlessness.

Objective: To estimate the cost-effectiveness of using continuous positive airway pressure (CPAP) in the management of patients suffering from severe obstructive sleep apnoea/hypopnoea syndrome (OSAHS), compared to no treatment, from the perspective of the UK's National Health Service (NHS).

Methods: A Markov model was constructed to assess the cost-effectiveness of CPAP compared to no treatment. The model depicted the management of a 55 year old patient with severe OSAHS as defined by an apnoea-hypopnoea index (AHI) >30 and daytime sleepiness (Epworth scale score >12). The model spans a period of 14 years.

Results: According to the model, 57% of untreated patients are expected to be alive at the end of 14 years compared to 72% of CPAP-treated patients. Untreated patients are expected to cost the NHS £10,645 (95% CI: £7,988; £14,098) per patient over 14 years compared to £9,672 (95% CI: £8,057; £12,860) per CPAP-treated patients. Treatment with CPAP for a period of one year was found not to be a cost-effective option since the cost per QALY gained is expected to be >£20,000, but after two years of treatment the cost per QALY gained is expected to be £10,000 or less and after 13 years of treatment, CPAP becomes a dominant treatment (i.e. more effective than no treatment for less cost).

Conclusion: Within the limitations of our model, CPAP was found to be clinically more effective than no treatment and the cost-effective strategy, from the perspective of the UK's NHS, after a minimum of 2 years' treatment.

Background: Infection with Burkholderia cepacia complex (BCC) is a life-threatening complication of cystic fibrosis (CF) often seen as a contraindication for lung transplantation.

Methods: We conducted a long-term retrospective study of all CF patients undergoing lung transplants from January 1990 to October 2006 in two French centers allowing transplantation in BCC-colonized patients.

Results: Twenty-two of the 247 lung transplant patients with CF were infected with BCC (B. cenocepacia genomovar III n=8, B. multivorans genomovar II n=11, B. vietnamiensis genomovar V n=2 and B. stabilis genomovar IV n=1). BCC colonization was not associated with any significant excess mortality (HR 1.5, 95% CI 0.7 to 3.2, p=0.58). However, early mortality rates tended to be higher in the BCC group than in the non BCC group (3-month survival: 85% vs 95%, respectively; log rank p=0.05). Univariate analysis showed that the risk of death was significantly higher for the eight patients infected with B. cenocepacia than for the other 14 colonized patients (HR 3.2, 95% CI 1.1 to 5.9, p=0.04). None of the other risk factors tested - primary graft failure, late extubation, septicemia - had a significant effect. The five-year cumulative incidence rate of bronchiolitis obliterans syndrome was not significantly higher in the BCC group than in the non BCC group (38% vs 24%, respectively, p=0.35).

Conclusion: Our results suggest that BCC infection with a non genomovar III organism may not be associated with excess mortality after lung transplantation in CF patients and should not been seen as sufficient reason to exclude lung transplantation. However, colonization with B. cenocepacia remains potentially detrimental.

Introduction: The association of murine asthma with adiposity may be mediated by adiponectin, an anti-inflammatory adipokine with reduced serum concentrations in the obese. We studied whether serum adiponectin concentration was associated with human asthma and explained the association between adiposity and asthma, particularly in women and in pre-menopausal women.

Methods: A cross-sectional analysis of 2,890 eligible subjects at year 15 of the Coronary Artery Risk Development in Young Adults (CARDIA) cohort and its YALTA ancillary study, and had either current asthma or never asthma at that evaluation, was performed. Obesity was defined as body mass index (BMI) ≥ 30 kg/m2. Multivariable logistic regression analysis was performed with dependent variable current asthma status.

Results: Women, but not men, with current asthma had lower mean unadjusted serum adiponectin concentration than those with never asthma (p < 0.001; p for sex interaction < 0.001). Similarly, current asthma was related to obese status only in women (OR 3.31, 95% CI 2.00, 5.46, p for sex interaction 0.004); this association was little affected by adjusting for serum adiponectin. Prevalence of current asthma in pre-menopausal women was reduced in the highest vs. lowest tertile of serum adiponectin concentration (OR 0.46, 95% CI 0.26, 0.84, p 0.03), after adjusting for BMI. However, the interaction between serum adiponectin concentration and BMI category on current asthma status was not significant in pre-menopausal women or women overall.

Discussion: High serum adiponectin concentration may protect against current asthma in pre-menopausal women, but does not explain the association between asthma and adiposity.

Background: Chemotherapy is the primary treatment option for patients with advanced non-small cell lung cancer (ANSCLC). We investigated whether the introduction of modern third-generation chemotherapy was associated with survival benefits in a national population of patients with ANSCLC, and explored geographic and temporary variations of the utilisation of chemotherapy.

Methods: We included all patients with ANSCLC in the national Cancer Registry of Norway during 1994-2005. Using sales of vinorelbine as an indicator for third-generation chemotherapy we calculated annual county utilisation rates. We compared survival before and after the general introduction of third-generation chemotherapy and investigated associations between survival and variations of chemotherapy utilisation in Norwegian counties. In a subgroup, we compared survival of patients with and without a registered chemotherapy procedure code and explored predictors of having received chemotherapy.

Results: Of 24875 registered patients with lung cancer, 13757 had ANSCLC. The annual utilisation of the indicator drug in Norway increased from 3.7 (1998) to 184.2 grams (2005). Variations in utilisation across counties diminished threefold during 1999-2005. Median survival increased from 149 to176 days (P<0.001). The adjusted hazard ratio (HR) for a diagnosis after the introduction of vinorelbine was 0.93 (95%CI 0.88-0.99). County utilisation rates of vinorelbine (increments of 100 mg/1000 inhabitants) were inversely associated with the risk of death (HR=0.84, 95%CI 0.73-0.98). One-year survival with and without chemotherapy was 33.8% and 22.4% (P<0.001); HR=0.63 (95%CI 0.60-0.66). County of residence predicted chemotherapy utilisation with odds ratios in the range 0.13 (95%CI 0.1-0.19) to 1.04 (95%CI 0.64-1.69; a county (Troms) with traditionally high utilisation as reference entity).

Conclusion: Utilisation of third-generation chemotherapy was associated with slightly increased survival of patients with ANSCLC in this national population. Geographic and temporal variations of chemotherapy utilisation indicate deficiencies of the quality of delivered care.

Rationale: There are many reference equations for the measurement of DLCO. However the testing methodologies vary and there are no well-documented studies that develop reference equations for DLCO and alveolar volume (VA) in middle aged and older populations.

Objectives: 1. Develop reference equations for DLCO in a middle aged population using the current ATS/ERS guidelines; 2. Compare the equations with those commonly used in laboratories around the world.

Methods: Healthy subjects (498 male and 474 female) aged 45 to 71 years were recruited as part of a larger epidemiological study. All participants completed a respiratory questionnaire and had spirometry and single breath DLCO (corrected for haemoglobin) measurements following ATS/ERS guidelines.

Results: The mean age was 58 years for males and 57 years for females. For males, factors that predicted DLCO were: Height, Age and Age * Height interaction and being an ex-smoker. For females, factors that predicted DLCO were: Height, Age, Weight and an Age * Height interaction.

Conclusion: We have described new prediction equations for DLCO in a middle-aged population that require validation in other populations.

Background: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is an accurate tool for lymph node staging of non-small lung cancer (NSCLC). The majority of NSCLC patients require systemic chemotherapy during their treatment, with relatively poor responses. If one could predict chemotherapy response, ideally at the time of initial bronchoscopic examination, one could maximize therapeutic benefit while limiting toxicity. Thus, we aimed to investigate the feasibility of EBUS-TBNA for obtaining tissue samples from mediastinal lymph nodes that can be utilized for immunohistochemical analysis; and to stratify, molecularly-based, pN2-NSCLC patients into chemoresponsive and chemoresistant subgroups who might benefit from chemotherapy-tailorment.

Methods: We examined the expression of six cell cycle-related proteins (pRb, cyclin D1, p16INK4A, p53, p21Waf1, Ki-67), in mediastinal lymph node specimens obtained by EBUS-TBNA, by immunohistochemistry in 36 pN2-NSCLC patients. We investigated their predictive role(s) for platinum-based chemotherapy response.

Results: Immunostaining was feasible in all studied specimens. Univariate analysis revealed that p53 and p21Waf1 expressions were significantly related to the chemotherapy response (p=0.002, p=0.011, respectively). Multivariate logistic regression analysis revealed that only p53 overexpression was associated with poor response to chemotherapy (p=0.021).

Conclusions: These results suggest that EBUS-TBNA is a feasible tool for obtaining mediastinal nodal tissue samples amenable for immunohistochemical analysis. Immunostaining of p53 in EBUS-TBNA guided specimens may be useful in predicting response to chemotherapy in N2-NSCLC patients, and help selection of those patients who might benefit from certain chemotherapeutic strategies.

The clinical impact of nocturnal desaturation on health-related quality of life (HRQL) and sleep in COPD has been little studied. We aimed to evaluate the prevalence and clinical impact of nocturnal desaturation in a typical outpatient population with COPD.

Between 2002 and 2005, consecutive patients with COPD attending outpatient services at the study centre underwent resting oximetry, if they were not on domiciliary oxygen therapy. If their resting saturations were less than 95%, overnight pulse oximetry was performed. Significant nocturnal desaturation was defined as spending more than 30% of at least one of two nights with a saturation of less than 90%. The Chronic Respiratory Questionnaire (CRQ) and SF-36 were used to assess HRQL, and the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Score (ESS) and Functional Outcomes of Sleep (FOSQ) questionnaires were used to assess sleep quality and daytime function.

Of 1104 patients, 803 underwent resting oximetry and 79 had resting oxygen saturations of less than 95%. Of these, 59 agreed to undergo overnight oximetry (mean age 70.5 years, FEV1 37.2% predicted, resting pO2 on air 8.9 kPa). Significant nocturnal desaturation was seen in 29 (49.2%) of the 59 subjects. The prevalence of nocturnal desaturation in the whole clinic population could therefore be estimated at 4.8%. There were no significant differences in CRQ, SF-36, PSQI, ESS or FOSQ scores for desaturators when compared with non-desaturators.

Significant nocturnal desaturation was common in COPD patients with resting saturations of less than 95%, but was estimated to have a prevalence of less than 5% in the whole outpatient population. Nocturnal desaturation was not associated with impairment of HRQL, sleep quality or daytime function.

Background: The Incremental Shuttle Walking Test (ISWT) is used to assess exercise capacity in chronic obstructive pulmonary disease (COPD) and is employed as an outcome measure for pulmonary rehabilitation. This study was designed to establish the minimum clinically important difference (MCID) for the ISWT.

Methods: 372 patients (205 male) performed an ISWT before and after a 7 week outpatient pulmonary rehabilitation programme. After completing the course subjects were asked to identify, from a 5-point Likert scale, the perceived change in their exercise performance immediately upon completion of the ISWT. The scale ranged from 'better' to 'worse'

Results: The mean (SD) age was 69.4 (8.4) years, FEV1 1.06 (0.53) litres, and FEV1/FVC ratio 50.8 (18.1) %. Baseline shuttle walking test distance was 168.5(14.6) m. After rehabilitation this increased to 234.7 (125.3) m. The mean difference and 95% confidence interval for the difference was 65.9 (58.9 to72.9) m. For a subject to feel they were 'slightly better' the mean improvement was 47.5 (38.6 to 56.5) m and to report feeling 'better' the mean increase was 78.7 (70.5 to 86.9) m. Patients who reported that their exercise tolerance was 'about the same' increased by a mean of 18.0 (4.5 - 31.5)m.

Conclusion: Two levels of improvement were identified . The minimum clinically important improvement for the ISWT is 47.5m. In addition patients were able to distinguish an additional benefit at 78.7m.

Background The obstructive sleep apnea/hypopnea syndrome (OSAHS) is associated with hypertension and increased cardiovascular risk, particularly when accompanied by marked nocturnal hypoxemia. The mechanisms of these associations are unclear. We hypothesised that OSAHS combined with severe nocturnal hypoxemia causes impaired vascular function that can be reversed by continuous positive airways pressure (CPAP) therapy.

Methods and Results We compared vascular function in two groups of patients with OSAHS: 27 with more than twenty 4% desaturations/hr (desaturator group) and 19 with no 4% and less than five 3% desaturations/hr (non-desaturator group). In a randomized double-blind placebo controlled crossover trial, the effect of 6-weeks CPAP therapy on vascular function was determined in the desaturator group. In all studies, vascular function was assessed invasively by forearm venous occlusion plethysmography during intra-arterial infusion of endothelium-dependent (acetylcholine, 5-20 µg/min, and substance P, 2-8 pmol/min) and independent (sodium nitroprusside, 2-8 µg/min) vasodilators. Compared to the non-desaturator group, patients with OSAHS and desaturations had reduced vasodilatation to all agonists (P≤0.007 for all). The apnea/hypopnea index and desaturation frequency were inversely related to peak vasodilatation with acetylcholine (r=-0.44, P=0.002 and r=-0.43, P=0.003) and sodium nitroprusside (r=-0.42, P=0.009 and r=-0.37, P=0.02). In comparison to placebo, CPAP therapy improved forearm blood flow to all vasodilators (P≤0.01).

Conclusions Patients with OSAHS and frequent nocturnal desaturations have impaired endothelial-dependent and endothelial-independent vasodilatation that is proportional to hypoxemia and is improved by CPAP therapy. Impaired vascular function establishes an underlying mechanism for the adverse cardiovascular consequences of OSAHS.

Background: Childhood obstructive sleep apnoea (OSA) is increasingly being recognized. Its effect on blood pressure (BP) elevation and hypertension is still controversial.

Objective: To evaluate the association between obstructive sleep apnoea and ambulatory BP in children.

Methods: Children aged 6 to 13 years from randomly selected schools were invited to undergo overnight sleep study and ambulatory BP monitoring after completing a validated OSA questionnaire. OSA was diagnosed if obstructive apnoea-hypopnoea index (AHI) > 1, and normal controls had AHI < 1 and snoring < 3 nights per week. Children with OSA were sub-stratified into mild group (AHI between 1 and 5) and moderate-to-severe group (AHI > 5).

Results: Three hundred and six subjects had valid sleep and daytime BP data. Children with OSA had significantly higher blood pressure than normal healthy children during both sleep and wakefulness. The BP levels increased with the severity of OSA, and children with moderate-to-severe disease (AHI > 5) were at significantly higher risk for nocturnal systolic (OR = 3.9 [95% CI: 1.4-10.5]) and diastolic hypertension (OR = 3.3 [95% CI: 1.4-8.1]). Multiple linear regression revealed a significant association between oxygen desaturation index and AHI with daytime and nocturnal BP respectively independent of obesity.

Conclusions: OSA was associated with elevated daytime and nocturnal BP, and it is an independent predictor of nocturnal hypertension. This has important clinical implications as childhood elevated BP predicts future cardiovascular risks. Future studies should examine the effect of therapy for OSA on BP changes.

OBJECTIVES: To target preventive strategies in old age, we investigated which very elderly are predisposed to developing lower respiratory tract infections.

DESIGN: Prospective observational follow-up study.

SETTING: General population.

PARTICIPANTS: Unselected cohort of 587 participants aged 85 years in Leiden, the Netherlands.

MEASUREMENTS: As reported in the literature, predictive factors were selected and assessed at baseline. During a five year follow-up period, information on the development of lower respiratory tract infections was obtained from general practitioners or nursing home physicians. Associations between predictive factors were analysed with Cox regression and population attributable risks were calculated.

RESULTS: The incidence of lower respiratory tract infections among persons aged 85 through 90 years was 94 (95% CI 80-108) per 1000 person-years. After multivariate analysis, history of COPD, smoking, oral glucocorticosteroid use, severe cognitive impairment, history of stroke and declined functional status remained independently associated with the occurrence of lower respiratory tract infections. Smoking was the greatest contributor with a population attributable risk of 32%.

CONCLUSION: In the very old, smoking, COPD, stroke and declined functional status were associated with the occurrence of lower respiratory tract infections and provide means to target patients at risk of severe health complications.

Background: OSA is associated with high cardiovascular morbidity and mortality. Randomised controlled trials have shown that on average CPAP treatment of OSA reduces blood pressure by about 3 to 5mmHg, although with considerable inter-individual variation. No predictors of BP change with CPAP have been convincingly identified. This prospective study aimed to determine predictors of BP change, which might provide insight into the aetiology of the raised blood pressure seen in untreated OSA.

Methods: Eighty-six patients with daytime hypersomnolence, warranting treatment with CPAP, were recruited. 24h mean BP (24hMBP), subjective sleepiness, fasting venous blood samples, and anthropometric measurements, were assessed at baseline and after 6 months CPAP treatment.

Results: The 24hMBP fell at 6 months from 101.0 (SD10.3) to 96.1 (9.1) mmHg (change = -4.92 (95%CI -2.8 to -7.1) mmHg). The Epworth sleepiness score (ESS) fell from a median of 16 (IQR 12 to 18) to 4 (2 to 7), with a mean fall of 9.7 (95% CI 8.6 to 10.8). Several factors correlated with the fall in 24hMBP but, after allowing for the baseline 24hMBP, only the fall in ESS and the BMI remained significant independent predictors (P= 0.006 and 0.007 respectively). There was also a correlation between the fall in 24hMBP and the fall in pulse rate (r= 0.44, p< 0.0001). There were no other independent predictors of 24hMBP fall, such as baseline OSA severity, overnight hypoxia, caffeine intake, or being on anti-hypertensive drugs.

Conclusion: Improvement in hypersomnolence and the BMI are independent correlates of the fall in 24hMBP following CPAP therapy. Markers of initial OSA severity did not predict 24hMBP fall. This suggests that sleep fragmentation and its effects may be more important than hypoxia in the pathogenesis of the hypertension associated with human sleep apnoea.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disorder with a poor prognosis. Epithelial instability is a crucial step in the development and progression of the disease including neoplastic transformation. Few tissue markers regarding epithelial instability have been reported in IPF. Squamous cell carcinoma antigen (SCCA) is a serine protease inhibitor typically expressed by dysplastic and neoplastic cells of epithelial origin, more often in squamous cell tumours. At present no information is available on its expression in IPF.

Methods: SCCA and transforming growth factor-β (TGF-β) expression in surgical lung biopsies from 22 IPF patients and 20 control cases. An in vitro study using A549 pneumocytes was also conducted to investigate the relationship between SCCA and TGF-β expression. SCCA and TGF-β epithelial expression were evaluated by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). SCCA values were correlated with different pathological and clinical parameters. Time course analysis of TGF-β expression in A549 pneumocytes incubated with different SCCA concentrations was assessed by real time RT-PCR.

Results: SCCA was expressed in many metaplastic alveolar epithelial cells in all IPF cases with a mean value of 24.9% while it was seen in only two control patients in up to 5% of metaplastic cells. In IPF patients SCCA correlated positively with the extension of fibroblastic foci (r = 0.49, p = 0.02), the expression of TGF-β(r = 0.78, p < 0.0001) and with DLCO decline at 9 months of follow-up (r = 0.59, p = 0.01). In vitro experiments showed that incubation of cultured cells with SCCA induced TGF-βexpression, with a peak at 24 hours.

Conclusion: Our findings provide for the first time a potential mechanism by which SCCA secreted from metaplastic epithelial cells may exert a profibrotic effect in IPF. SCCA could be an important biomarker in this incurable disease.

Rationale: Randomised data in men showed a small but significant reduction in risk of adult-onset asthma among those assigned to aspirin. Results from an observational study in women suggest that frequent use of aspirin decreased the risk of adult-onset asthma. Randomised data in women are lacking.

Objective: To test the effect of 100 mg of aspirin on alternate days or placebo on the risk of adult-onset asthma in the Women's Health Study.

Methods: Post-hoc analyses from a randomised, double-blind, placebo-controlled clinical trial of aspirin and vitamin E in apparently healthy US women with no indication or contraindication to aspirin therapy and free of a history of asthma at study entry.

Measurements: Female health professionals could self-report an asthma diagnosis on yearly questionnaires.

Results: Among 37,270 women without reported history of asthma prior to randomisation and during 10 years of follow-up, there were 872 new reports of asthma diagnosis in the aspirin group and 963 in the placebo group (hazard ratio=0.90; 95% confidence interval=0.82-0.99; P=0.027). This apparent 10% lower relative risk of incident adult-onset asthma among those assigned to aspirin was significantly modified by body mass index, indicating no effect among women with a body mass index of >30 kg/m2. There was no significant effect modification by age, smoking status, exercise levels, postmenopausal hormone use, or randomised vitamin E assignment.

Conclusions: In this large, randomised clinical trial of apparently healthy adult women, assignment of 100 mg of aspirin on alternate days reduced the relative risk of newly reported diagnosis of asthma. Key words: asthma, aspirin, randomised trial.

Can lay people deliver asthma self-management education as effectively as primary care-based practice nurses?

Objectives: To determine whether well-trained lay people could deliver asthma self-management education with comparable outcomes to that achieved by primary care-based practice nurses.

Design: Randomised equivalence trial.

Setting: Thirty nine general practices in West London and North West England.

Participants: 567 patients with asthma who were on regular maintenance therapy. Fifteen lay educators were recruited and trained to deliver asthma self-management education.

Intervention: An initial consultation of up to 45 minutes offered either by a lay educator or a practice-based primary care nurse, followed by a second shorter face-to-face consultation and telephone follow up for one year.

Main outcome measures: Unscheduled need for healthcare

Secondary outcome measures: Patient satisfaction and need for courses of oral steroids.

Results: 567 patients were randomised to care by a nurse (N=287) or a lay educator (N=280) and 146 and 171, respectively, attended the first face-to-face educational session. . During the first two consultations management changes were made in 35/146 patients seen by a practice nurse (24.0%) and in 56/171 patients (32.7%) seen by a lay educator. For 418/567 patients (73.7%), we have one year data on use of unscheduled healthcare. Under an intention to treat approach, 61/205 patients (29.8%) in the nurse-led group required unscheduled care, compared with 65/213 (30.5%) in the lay-led group (90% CI for difference -8.1% to 6.6%; 95% CI for difference -9.5% to 8.0%). The 90% CI contained the pre-determined equivalence region (-5% to +5%) giving an inconclusive result regarding the equivalence of the two approaches. Despite the fact that all patients had been prescribed regular maintenance therapy, 122/418 patients (29.2%) required courses of steroid tablets during the course of one year. Patient satisfaction following the initial face-to-face consultation was similar in both groups.

Conclusions: It is possible to recruit and train lay educators to deliver a discrete area of respiratory care, with comparable outcomes to those seen by nurses.

Background: There has been some concern that leukotriene-receptor antagonists might precipitate the onset of Churg-Strauss syndrome (CSS). Objective: To investigate the relationship between the leukotriene-receptor antagonist montelukast and CSS onset.

Methods: Medication histories of 78 CSS patients from France and Germany were retraced by questioning the patients, treating physicians and dispensing pharmacists, and from medical records. Using a case-crossover research design, we compared exposures to montelukast and other asthma medications during the 3-month 'index' period immediately preceding CSS onset with those of 4 previous 3-month 'control' periods. Odds ratios (OR) were computed by conditional logistic regression.

Results: OR (95% CI) for CSS onset were 4.5 (1.5-13.9) for montelukast, 3.0 (0.8-10.5) for inhaled long-acting β₂-agonists, 1.7 (0.5-5.4) for inhaled corticosteroids and 4.0 (1.3–12.5) for oral corticosteroids. Montelukast exposure during control periods increased temporally over 3 consecutive calendar periods of CSS onset from 1999 to 2003 (P_trend <.0001).

Conclusion: Montelukast use was associated with a 4.5-fold higher risk of CSS onset within 3 months. However, the positive estimates obtained for other long-term asthma-control medications suggest that this link is confounded by a general escalation of asthma therapy before CSS onset. The montelukast-CSS association observed herein is likely also explained by the increasing use of this medication over time.

Background: A Th1 predominant immune response has been shown in acute hypersensitivity pneumonitis. A Th2 predominance appears to favor the development of pulmonary fibrosis through the profibrotic process, and has been described as crucial in the progression of idiopathic pulmonary fibrosis (IPF). Chronic bird fancier's lung (cBFL) can present a histological pattern of usual interstitial pneumonia (UIP)-like lesions. Little is known about the Th1/Th2 balance in the pathogenesis of cBFL.

Methods: To evaluate the relevance of Th1-type (IP-10) and Th2-type (TARC) chemokines, and their receptors (CXCR3 and CCR4) with reference to histological patterns of cBFL We analyzed 40 patients with cBFL who underwent surgical lung biopsies, 12 acute BFL (aBFL) and 10 healthy volunteers. We measured IP-10 and TARC levels in serum and bronchoalveolar lavage fluid (BALF) by ELISA. Immunohistochemistry for CXCR3 and CCR4 was performed on surgical lung specimens.

Results: The ratio of TARC to IP-10 in serum of patients with UIP-like lesions was significantly higher than that with cNSIP/OP-like lesions, aBFL, and healthy volunteers. The ratio of CCR4 to CXCR3 in UIP-like lesions was significantly higher than that in cNSIP/OP-like lesions and fNSIP-like lesions. The ratio of CCR4- to CXCR3-positive cells correlated with the ratio of TARC to IP-10 in serum.

Conclusions: A Th2 predominant immune response may play an important role in the development of UIP-like lesions as already observed in IPF. A Th1 predominance may play a role in the development of cNSIP/OP-like lesions in cBFL.

Background: The indication of chest physical therapy as an adjunct to treatment of children hospitalized with acute pneumonia remains controversial and there is lack of robust scientific evidence on effectiveness of this modality in these patients.

Methods: A randomized controlled trial was conducted in two tertiary hospitals in southern Brazil. Children aged 29 days to 12 years, hospitalized with pneumonia between February and October of 2006 were recruited. Fifty-one patients were randomly allocated to the intervention group (chest physical therapy plus standard treatment for pneumonia) and 47 to the control group (standard treatment for pneumonia alone). The primary outcome was time to clinical resolution. The secondary outcomes were length of hospitalization and duration of respiratory symptoms and signs.

Results: There were no significant differences in terms of median time to clinical resolution (4.0 vs 4.0 days, p=0.84) and median length of hospital stay (6.0 vs 6.0 days, p=0.76) between the intervention and control groups. The intervention group had longer median duration of coughing (5.0 vs 4.0 days, p=0.04) and of rhonchi in lung auscultation (2.0 vs 0.5 days, p=0.03) than the control group.

Conclusions: Chest physical therapy as adjunct to the standard treatment does not hasten clinical resolution of children hospitalized with acute pneumonia and may prolong duration of coughing and rhonchi.

Rationale: There is little previous information of the effects of size-fractioned particulate air pollution and source-specific fine particles (PM2.5; <2.5 µm) on asthma and COPD among children, adults, and the elderly.

Objectives: To determine the effects of daily variation in levels of different particle size fractions and gaseous pollutants on asthma and COPD by age group.

Methods: We measured the levels of particulate air pollution, NO2, and CO in 1998-2004 at central outdoor monitoring sites in Helsinki, Finland. We evaluated associations between daily pollution levels and hospital emergency room visits for asthma (ICD10: J45+J46) in children <15 years old, and for asthma and COPD (ICD10: J41+J44) in adults (15-64 years) and the elderly (≥65).

Measurements and Main Results: We found 3 to 5 days lagged increases in the asthma visits among children in association with nucleation (<0.03µm), Aitken (0.03-0.1µm) and accumulation (0.1-0.29µm) mode particles, gaseous pollutants, and traffic-related PM2.5 (7.8% [95% CI 3.5-12.3] for 1.1µg/m3 increase in traffic-related PM2.5 at lag 4). Pooled asthma-COPD visits among elderly were associated with lag 0 of PM2.5, coarse particles, gaseous pollutants, and long-range transported and traffic-related PM2.5 (3.9% [95% CI 0.28-7.7] at lag 0). Only accumulation mode and coarse particles were associated with asthma and COPD among adults.

Conclusions: Among children traffic-related PM2.5 had delayed effects, whereas among elderly several types of particles had effects that were more immediate. These findings suggest that the mechanisms of the respiratory effects of air pollution, and responsible pollutants differ by age group.

Rationale: There is limited evidence for the role of air pollution in development of wheezing symptoms in young children.

Objectives: To study the impact of exposures to air pollution on wheezing symptoms in children under the age of three and with genetic susceptibility to asthma.

Methods and Measurements: Daily symptoms recordings were obtained for a panel of 205 children participating in the birth cohort study Copenhagen Prospective Study on Asthma in Children and living in Copenhagen in the first three years of life. Daily air pollution levels for particulate matter less than 10 µm in diameter(PM10), number concentration of ultrafine particles, nitrogen dioxide (NO2), nitrogen oxide (NOx), and carbon monoxide (CO) were available from a central background monitoring station in Copenhagen. The association between incident wheezing symptoms and air pollution on the concurrent and previous 4 days were estimated by logistic regression model (generalized estimating equation) controlling for temperature, season, gender, age, exposure to smoking, and paternal history of asthma.

Main Results: We found significant positive associations between concentrations of PM10, NO2, NOx, CO and wheezing symptoms in infants (age 0-1) with 3 to 4 days delay. Only the traffic related gasses, NO2, NOx showed significant effects throughout the three years of life, albeit attenuating after the age of one. Effects of ultrafine particles were comparable to those of NO2 and NOx in the first year of life, although estimated with less certainty due to missing data.

Conclusions: Air pollution related to traffic is significantly associated with wheezing symptoms development in the first three years of life.

Background: Varenicline, a new treatment for smoking cessation, has demonstrated significantly greater efficacy over placebo and sustained release bupropion (bupropion SR). Here we compare a 12-week standard regimen of varenicline with a 10-week standard regimen of transdermal nicotine replacement therapy (NRT) for smoking cessation.

Methods: In this 52-week, open-label, randomised, multicentre, phase 3 trial conducted in Belgium, France, the Netherlands, United Kingdom and United States, participants were randomly assigned (1:1) to receive varenicline up-titrated to 1 mg twice daily for 12 weeks or transdermal nicotine (21 mg/day reducing to 7 mg/day) for 10 weeks. Non-treatment follow-up continued to Week 52. The primary outcome was biochemically confirmed (exhaled carbon monoxide of ≤10 ppm) self-reported continuous abstinence rate (CAR) for the last 4 weeks of the treatment period in participants who had taken at least one dose of therapy. Secondary outcomes included CAR from the last 4 weeks of treatment through Weeks 24 and 52, and measures of craving, withdrawal and smoking satisfaction.

Results: In total, 376 and 370 participants assigned to varenicline and NRT respectively were eligible for analysis. The CAR for the last 4 weeks of treatment was significantly greater for varenicline (55.9%) than NRT (43.2%; odds ratio [OR] 1.70, 95% confidence interval [CI] 1.26 to 2.28, p<0.001). The Week 52 CAR (NRT,Weeks 8-52; varenicline,Weeks 9-52) was 26.1% for varenicline and 20.3% for NRT (OR 1.40, 95% CI, 0.99 to 1.99, p=0.056). Varenicline significantly reduced craving (p<0.001), withdrawal symptoms (p<0.001) and smoking satisfaction (p<0.001) versus NRT. The most frequent adverse event was nausea (varenicline, 37.2%, NRT, 9.7%).

Conclusions: The outcomes of this registered clinical trial (Clinical Trials Identification Number: NCT00143325) established that abstinence from smoking was greater, and craving, withdrawal symptoms and smoking satisfaction less, at the end of treatment with varenicline than with transdermal nicotine.

Background: Influenza-like illness (ILI) among elderly living in residential care homes (RCHE) is a common cause for hospitalization. We examined the incidence, underlying aetiology, natural history and associated healthcare resource utilization related to ILI in the RCHE population.

Methods: A prospective study of ILI in 4 RCHEs in Shatin, HK, from Apr 2006 to Mar 2007 was conducted. Each RCHE was monitored daily for ILI occurrence, and followed up until resolution of illness or death. Clinical features were recorded whereas sputum, nasopharyngeal aspirate, blood, and urine specimens were examined for underlying aetiology.

Results: 259 episodes of ILI occurred in 194 subjects, with mild peaks in winter and summer, over a sustained level throughout the year. Infection agent was identified in 61.4% of all episodes, comprising bacterial infection in 53.3% and viral in 46.7%. Multiple infections occurred in 16.2% of subjects. The most frequent organisms were Streptococcus pneumoniae, followed by respiratory syncytial virus, Pseudomonas aeruginosa, Metapneumovirus and parainfluenza viruses type 1 & 3. Clinical features did not vary according to underlying aetiology, the common presenting features being "decrease in general condition", cognitive and functional deterioration, and withholding of food in addition to fever and respiratory symptoms. Overall, mortality at 1 month/discharge was 9.7%. MRSA infection, low BMI, and poor function predisposed to mortality. No association between influenza vaccination status and underlying aetiology, clinical features or outcome, was observed.

Conclusions: Clinical presentation of ILI is non-specific and is mainly due to bacterial and other viral infections than influenza in the RCHE population.

Objectives:This study examined the effects of inhaled furosemide on the ventilatory and perceptual response to high intensity, constant-load cycle exercise in chronic obstructive pulmonary disease (COPD).

Methods: In a randomized, double-blind, placebo-controlled, cross-over study, 20 patients with COPD (forced expiratory volume in 1 sec 45 ± 15 % predicted; mean ± SD) received either nebulized furosemide 40 mg or placebo on two separate days. Thirty minutes after each treatment, patients performed pulmonary function tests and a symptom-limited cycle exercise test at 75% of their maximum incremental work-rate. Post-dose changes in spirometry, plethysmographic lung volumes, dynamic operating lung volumes, ventilation, breathing pattern, cardiovascular function, dyspnoea intensity and exercise endurance time were compared between-treatments.

Results: After treatment with furosemide compared with placebo, dyspnoea intensity at the highest equivalent exercise time (i.e., isotime for each patient) decreased by 0.9 ± 1.0 Borg units (p<0.01), with attendant improvement in exercise endurance time by 1.65 ± 0.63 min (p<0.05). These improvements were associated with increases in dynamic inspiratory capacity, tidal volume and mean tidal expiratory flow rates at isotime (p<0.01). The eight patients who improved exercise endurance time by >1 min had greater changes in operating lung volumes (p<0.05), submaximal oxygen pulse (p<0.05) and oxygen uptake (p=0.05) compared with those who did not.

Conclusion: Our results suggest that alleviation of exertional dyspnoea after single dose furosemide inhalation in COPD is multifactorial but that improvements in dynamic ventilatory mechanics are contributory in some individuals.

Background: In early childhood, the ability to mount protective immune responses in the airways is impaired, with increased risk of allergic sensitisation to inhaled allergens. Antigen-presenting cells (APC) and regulatory T cells (Tregs) are important modifiers of T-cell immunity, but little is known about their distribution in bronchial mucosa at this age. Here, we examined immunohistochemically the subset distribution of APC and the appearance of Foxp3+ Tregs and bronchus-associated lymphoid tissue (BALT) in children below the age of 2 years with chronic asthma-like symptoms of lower airways.

Methods: Immunophenotyping was performed in situ on bronchial biopsy specimens obtained from 45 infants 4-23 months of age under investigation for airway disease.

Results: A well-developed HLA-DR+ network of antigen presenting cells was present in all samples, approximately 50% of the cells being CD68+ macrophages and the remainder various subsets of dendritic cells. The density of HLA-DR+ cells increased significantly with age but was not related to atopy, clinical symptoms or lung function. Comparing the density of antigen-presenting cell subsets and clinical parameters, only the number of intraepithelial CD1a+ dendritic cells was significantly increased in infants who had recently suffered a respiratory infection. BALT structures were identified in 22 children, with no relation to lung function, atopic status or human rhinovirus positivity. Plasmacytoid dendritic cells and Foxp3+ Tregs were located primarily within these isolated lymphoid follicles.

Conclusion: A bronchial network of dendritic cells and macrophages develops quite rapidly after birth, apparently independent of clinical symptoms or atopy. The high frequency of BALT structures containing putative tolerogenic dendritic cells and Tregs suggests that these lymphoid follicles play an important role in bronchial immune homeostasis during infancy.

Background: The management of pulmonary disease caused by opportunist mycobacteria is bedevilled by a lack of randomized trials to provide an evidence-base for treatment. Rifampicin (R) and ethambutol (E) are the mainstay of treatment but the roles of macrolides and quinolones are not clear.

Aims: This trial was designed to compare clarithromycin (Clari) and ciprofloxacin (Cipro) as third drugs added to two years of rifampicin and ethambutol as treatment for pulmonary disease caused by M.avium-intracellulare (MAC), M.malmoense and M.xenopi. There was also an optional comparison of immunotherapy with M.vaccae with no immunotherapy.

Methods: Patients with pulmonary disease caused by these organisms were recruited to the trial once two positive cultures were confirmed. A factorial design permitted comparisons of clarithromycin and ciprofloxacin as well as immunotherapy/no immunotherapy. Information on clinical and bacteriological progress was obtained annually during the two years of treatment and for three years thereafter. If the patient was not improving at 1 year, the regimen was supplemented by the addition of the drug which he/she had not received in the original allocation of treatment.

Results: Three hundred and seventy-one patients (186 REClari, 185 RECipro) were entered by 191 physicians, 170 with MAC, 167 with M.malmoense and 34 with M.xenopi. Optional immunotherapy randomization was chosen by 170 patients of whom 84 received M.vaccae. No significant differences in outcomes were found between M.vaccae-treated patients and those who had not been randomised to M.vaccae. These patients were combined with the remaining 201 for purposes of comparison of REClari with RECipro.

All cause mortality was high for both groups (44% REClari, 43% RECipro). In patients with MAC the all-cause death rates were higher with REClari ( 48% ) than with RECipro (29 %), whereas for M.malmoense (42% vs 56% ) and M.xenopi (29% vs 47%) the rates were higher with RECipro (p=0.006). Most strikingly, only 3% died because of their mycobacterial disease (REClari = RECipro). At the end of treatment 4% of REClari and 10% of RECipro patients still had positive cultures. Among those with negative cultures at end of treatment 6% of REClari and 4% of RECipro patients relapsed. At 5 years 30% of REClari patients were known to have completed treatment as allocated and to be alive and cured, compared with 21% of the RECipro group (p=0.04), but this difference was principally due to those with M.malmoense (REClari 38%, RECipro 20%).

Patients with MAC or M.xenopi were more likely to have poor outcome (death due to mycobacterial disease, failure of treatment or relapse) than those with M.malmoense (p=0.004), there being no difference between REClari and RECipro in this respect. Overall, 20% in each group were unable to tolerate the regimen allocated, Cipro being associated with a trend towards more unwanted effects (16%) than Clari (9%), p=0.05.

Conclusion: Considering all three species together, there were no differences in outcome between the REClari and RECipro groups. Immunotherapy did not improve outcome. Mortality rates were high but only a small proportion died because of their mycobacterial disease. For M.malmoense and M.xenopi REClari appeared preferable to RECipro, whereas for MAC the opposite was true. Patients with MAC or M.xenopi had worse outcomes than those with M.malmoense, but there was no significant difference between REClari and RECipro. Comparison with other studies suggest that these triple-drug regimens, whilst having much the same beneficial effects as RE alone, resulted in twice as many unwanted effects and are consequently likely to reduce concordance. New therapies, optimised management of co-morbid conditions and a more holistic approach must be explored in the hope of improving outcome. Clinical trials.gov reg no: NCT 00367913

Neutrophil elastase (NE) activity is increased in lung diseases such as alpha-1-antitrypsin (A1AT) deficiency and pneumonia. We have recently demonstrated that NE can induce expression of cathepsin B and MMP 2 in vitro and in a mouse model. We postulated that increased Cathepsin B and MMP-2 in acute and chronic lung diseases are due to the presence of high levels of extracellular NE and that expression of these proteases could be inhibited by A1AT augmentation therapy. Cathepsin and MMP activities were assessed in bronchoalveolar lavage fluid (BAL) from A1AT deficient, pneumonia and control patients. Macrophages were exposed to BAL rich in free NE from pneumonia patients, following pre-treatment with A1AT. MMP-2, Cathepsin B, SLPI and lactoferrin levels were determined in BAL from A1AT deficient patients pre and post aerosolization of A1AT. BAL from both pneumonia and A1AT deficient patients, containing free neutrophil elastase, had increased cathepsin B and MMP-2 activities compared to BAL from healthy volunteers. Addition of A1AT to pneumonia BAL greatly reduced NE-induced cathepsin B and MMP-2 expression in macrophages in vitro. A1AT augmentation therapy to A1AT deficient individuals also reduced cathepsin B and MMP-2 activity in BAL in vivo. Furthermore, A1AT deficient patients had higher levels of SLPI and lactoferrin post A1AT augmentation therapy. This study describes a novel role for A1AT - inhibition of neutrophil elastase-induced up-regulation of expression of MMPs and cathepsins both in vitro and in vivo.

Rationale: TNF- is a cytokine recognized as a therapeutic target in chronic inflammatory diseases.

Objectives and Methods: We report a randomised double-blind placebo-controlled parallel group trial of etanercept (an IgG1-TNF p75 receptor fusion protein), administered once weekly for 12 weeks in 39 patients with symptomatic corticosteroid refractory asthma. Efficacy was measured by change from the pre-treatment baseline in Asthma Related Quality of Life (AQLQ) and Asthma Control (ACQ) Questionnaires scores (the primary end-points), lung function, PEF and bronchial hyperresponsiveness (BHR). We also assessed sputum and serum inflammatory cells and cytokines, serum albumin and C-reactive protein as biomarkers of inflammation.

Main results: There was a small but significant difference in reduction of ACQ scores between treatment and placebo (-1.11 (95%CI -1.56, -0.75) and -0.52 (95%CI -0.97, -0.07) respectively, p=0.030). There was no significant difference in improvements in AQLQ scores between groups (p=0.084), though sub group analyses restricted to 29 patients not taking antidepressants revealed significant improvements in both AQLQ and ACQ. There were no differences in lung function, PEF, BHR or exacerbation rates between groups. Minor adverse events including injection site pain and skin rashes were more frequent with etanercept. There was a significant reduction in sputum macrophages and CRP, and increases in serum TNF- and albumin following treatment, but not in other laboratory parameters.

Conclusion: ETanercept therapy over 12 weeks demonstrated only a small but significant improvement in asthma control and systemic inflammation as measured by serum albumin and CRP. Larger randomised placebo-controlled trials are required to clarify the role of TNF- antagonism in subjects with severe refractory asthma.

Rhinovirus infection is responsible for considerable morbidity and mortality as the major cause of exacerbations of asthma, and is also known to induce exacerbations of cystic fibrosis and chronic obstructive pulmonary disease. Exacerbations of these diseases are also frequently associated with bacterial and atypical bacterial infection. Alveolar macrophages are the major immune cells in the airways and are important in defence against bacterial infections. Therefore we investigated whether rhinovirus modifies cytokine release, the pattern recognition receptor (PRR) expression and phagocytosis by human alveolar macrophages in response to bacterial products. Viable rhinovirus was detected in macrophages up to 3 days after exposure and viral RNA expression persisted to 10 days. Infectious but not UV-inactivated rhinovirus increased TNF- and IL-8 release by macrophages. In contrast, infectious rhinovirus impaired lipopolysaccharide and lipoteichoic acid induced TNF- and IL-8 secretion by macrophages. Rhinovirus-induced impairment of macrophage antibacterial immune responses did not involve IL-10, PGE2, or down-regulation of TLR2. Furthermore the macrophage phagocytic response to labelled bacterial particles, but not to latex beads, was impaired. In conclusion, we have identified impairment of cytokine responses to bacterial lipopolysaccharide and lipoteichoic acid by alveolar macrophages in response to infectious rhinovirus. Virus induced impairment of antibacterial host defence has important implications in the pathogenesis of exacerbations of respiratory diseases.

Background: The combination of salmeterol and fluticasone propionate (SFC) and tiotropium bromide (TIO) are commonly used treatments in COPD but there is little data on their effectiveness when used together. We compared the effects of SFC 50/500mcg bd plus TIO 18mcg od with the individual treatments alone.

Methods: 41 COPD patients participated in a randomised, double-blind, double-dummy, 3-way cross-over study with 2-week wash-out periods between treatments. Lung function assessment included plethysmography and spirometry. The primary endpoint was post-dose specific airways conductance (sGaw) area-under the curve (AUC_0-4hr) on day 14.

Results: AUC_0-4hr sGaw was significantly higher on day 14 after SFC+TIO compared to TIO (22%) or SFC alone (27%), both p<0.001. SFC+TIO significantly improved trough FEV₁ compared with TIO alone (212mL, p<0.001) and SFC alone (110mL, p=0.017) on Day 14. Inspiratory capacity measurements also showed significant benefits for triple therapy over individual components on day 14. Subjects receiving SFC+TIO had clinically relevant improvements in TDI total score of 2.2 compared with TIO alone (p<0.001) (but not SFC alone, 0.7; p=ns) and used significantly less rescue medication (1.0 occasion less daily than TIO (p<0.001) and 0.6 less than SFC (p=0.01)).

Conclusion: SFC+TIO triple therapy led to greater improvements in bronchodilation compared with TIO and SFC alone. The advantages of triple therapy are observed across a range of physiologically important parameters, including airway conductance and lung volumes. Triple therapy also led to patient-related benefits by improving TDI and use of rescue medication.

Background: Interstitial lung disease (ILD) is characterised by exertional dyspnoea, exercise limitation and reduced quality of life. The role of exercise training in this diverse patient group is unclear. The aims of this study were to establish the safety of exercise training in ILD; its effects on exercise capacity, dyspnoea and quality of life; and whether patients with idiopathic pulmonary fibrosis (IPF) had similar responses to those with other types of ILD.

Methods: Fifty-seven subjects with ILD (thirty-four IPF) were randomised to receive eight weeks of supervised exercise training or weekly telephone support. The six-minute walk distance (6MWD), incremental exercise test, modified Medical Research Council (MRC) dyspnoea score and Chronic Respiratory Disease questionnaire (CRDQ) were performed at baseline, following intervention and at six months.

Results: Eighty percent of subjects completed the exercise program and no adverse events were recorded. The 6MWD increased following training (mean difference to control 35m, 95% confidence interval (CI) 6-64m). A significant reduction in MRC score was observed (0.7 points, 95% CI 0.1-1.3) along with improvements in dyspnoea (p=0.04) and fatigue (p<0.01) on the CRDQ. There was no change in VO2peak; however exercise training reduced heart rate at maximum workload (p=0.01). There were no significant differences in response between those with and without IPF. After six months there were no differences between the training and control group for any outcome variable.

Conclusions: Exercise training in ILD improves exercise capacity and symptoms in patients with ILD, however these benefits are not sustained six months following intervention. Clinicaltrials.gov NCT00168285

Background: Most cystic fibrosis (CF) patients die of respiratory failure due to chronic infection and destructive neutrophilic inflammation.

Objective: To identify potential therapeutic targets by characterising the neutrophil stimulating mediators in the CF airway.

Methods: Spontaneously expectorated CF sputum was extracted in phosphate buffered saline for assays of neutrophil chemotaxis, intracellular calcium mobilisation and cell shape change. Mediators were purified by ion exchange, C₁₈ reversed phase and size exclusion chromatography. Results: A pool of CF sputum contained considerable neutrophil stimulating activity but neutralisation of interleukin (IL)-8/CXCL8 had little inhibitory effect on neutrophil chemotactic (10149 ± 2023 migrating cells vs. 8661 ± 2597 at 62 mg sputum/ml, NS) or shape change (% FSC increase 46 ± 8 vs. 38 ± 5 at 19 mg sputum/ml, p<0.05) responses. Further, the CF sputum pool induced an elevation of intracellular calcium ions even after desensitisation of the neutrophils to IL-8. Chromatography identified contributions to the neutrophil shape change inducing activity from IL-8, other CXC chemokines, leukotriene (LT) B₄ and two formyl peptides. There was also suggestive evidence for contributions from platelet activating factor (PAF) and C5a. Using non-chromatographed individual sputum samples, anti-IL-8 alone did have an inhibitory effect on neutrophil chemotaxis (median inhibition 41%, p = 0.0002). However, even in this experiment, there were clearly significantly important, non-IL-8 mediated effects of CF sputum on neutrophils and an inhibitor cocktail of anti-IL-8 plus CXCR2, LTB₄, formyl peptide, PAF and C5a receptor antagonists inhibited chemotaxis by a median of 97% (p = 0.0002).

Conclusion: Many chemoattractants contribute to the neutrophil stimulating activity in CF sputum although the relative contribution of these mediators differs in different patients. The selective blockade of single mediators may not be sufficient to control neutrophil recruitment and activation in the CF airway.

Introduction: Lung function impairment may be a risk factor for cardiovascular disease (CVD) events.

Objective: To determine the relationship between the severity of airflow obstruction based on modified Global Initiative on Obstructive Lung Disease (GOLD) criteria and the prevalence, and incidence or recurrence of CVD in a cohort of U.S. adults ages 45-64 years from 1987 through 2001.

Methods: We analyzed data from 14,681 adults using logistic regression to determine the cross-sectional association between lung function impairment and prevalent CVD at baseline and Cox regression to examine the prospective association of lung function impairment at baseline with CVD over 15 years of follow-up. Models were adjusted for age, sex, race, smoking, comorbid hypertension and diabetes, cholesterol levels, and fibrinogen level.

Results: At baseline, the crude prevalence of CVD was higher among subjects with GOLD 2 (odds ratio [OR] 2.9, 95% confidence interval [CI] 2.0, 4.5) and GOLD 3 or 4 COPD (OR 3.0, 95% CI 0.8, 2.1), compared to normal subjects. These relative risks were greatly reduced after adjusting for covariates (OR 1.4, 95% CI 1.2, 1.8 for GOLD 2 and OR 1.3, 95% CI 0.8, 2.1 for GOLD 3 or 4). Similarly, the association between COPD and risk of incident or recurrent CVD was much stronger in the unadjusted models (hazard ratio [HR] 2.4, 95% CI 2.4, 2.7 for GOLD 2 and 2.9, 95% CI 2.2, 3.9 for GOLD 3 or 4) than in the adjusted ones (HR 1.2, 95% CI 1.03, 1.4 for GOLD 2 and 1.5, 95% CI 1.1, 2.0 for GOLD 3 or 4).

Conclusion: We observed a crude association between lung function impairment and prevalent and incident or recurrent CVD that was greatly reduced after adjusting for covariates including age, sex, race, smoking, comorbid hypertension and diabetes, cholesterol levels, and fibrinogen level. These data suggest that this association may be, in part, mediated through established CVD risk factors included in our adjusted models.

Background: There has been a recent increase in the number of reported cases of acute renal failure (ARF) in cystic fibrosis (CF). We conducted a case control study to determine the factors which are associated with an increased risk of ARF.

Methods: Our initial survey confirmed 24 cases of ARF, in CF patients from 20 UK CF Centres, presenting between 1997 & 2004. Using the UK CF database, we identified sex and age matched controls. Informed consent was sought from the control patients / parents for access to the case notes. Analysis of risk factors was by conditional logistic regression and Mantel Haenzsel analysis, using Stata (version 9).

Results: In the group of patients with ARF, 21/24 had received an aminoglycoside at the time of their episode of ARF or in the preceding week, compared with only 3/42 controls for the same time period (OR 81.8, 95% CI 4.7 to 1427, p<0.001). In the year prior to the episode of ARF, significantly more cases than controls received gentamicin (19/24 cases vs. 1/42 controls, p<0.001). The numbers receiving tobramycin were similar (9/24 cases vs. 15/42 controls, p=0.9). A known risk factor for renal impairment (prior renal disease, acute dehydration or long term nephrotoxic drug treatment) was present in 18/24 cases & 7/42 controls (OR 24.0, 95% CI 3.1 to 186.6, p = 0.002).

Conclusions: In CF patients, the use of an intravenous aminoglycoside is a risk factor for ARF and gentamicin is more nephrotoxic than tobramycin. The majority of patients who develop ARF have a risk factor which necessitates withholding aminoglycosides or more closely monitoring their use.

Obstructive sleep apnea hypopnea (OSAH) appears to be associated with an increased risk of motor vehicle crashes (MVC). However, its impact on crash patterns and particularly the severity of crashes has not been well described. We sought to determine whether OSAH severity influenced crash severity in patients referred for investigation of suspected sleep-disordered breathing. Objective crash data (including the nature of crashes) for patients with suspected OSAH for the 3 years prior to polysomnography were obtained from provincial insurance records and compared to an age and sex matched control group. Data were obtained for 783 patients with suspected OSAH and 783 matched controls. The patient group was 71% male, with a mean age of 50years, a mean apnea-hypopnea index (AHI) of 22 events/hour and a mean Epworth sleepiness scale score of 10. There were 375 crashes, of which 252 were in patients and 123 in controls in the 3-year period. When compared to controls, patients with mild, moderate, and severe OSAH had an increased rate of MVC with relative risks (95% CI) of 2.6 (1.7, 3.9), 1.9 (1.2, 2.8), and 2.0 (1.4, 3.0) respectively, whereas patients with suspected OSAH and normal polysomnography (AHI 0-5) did not with a relative risk (95% CI) of 1.5 (0.9, 2.5 p =0.21). When we examined the impact of OSAH on MVC associated with personal injury, patients with mild, moderate, and severe OSAH had a substantially increased rate of MVC compared to controls with relative risks of 4.8 (1.8, 12.4), 3.0 (1.3, 7.0), and 4.3 (1.8, 8.9) respectively, whereas patients without OSAH had similar crash rates to control with a relative risk of 0.6 (0.2, 2.5). Very severe MVCs (head-on collisions or those involving pedestrians or cyclists) were rare but 80% of these occurred in OSAH patients (p=0.06). Patients with OSAH have increased rates of MVC with disproportionately increased rates of MVC associated with personal injury.

Background: COPD is often associated with other chronic diseases. These patients are often admitted to hospital-based rehabilitation programs. Objectives. To determine the prevalence of chronic comorbidities in COPD patients undergoing pulmonary rehabilitation (PR) and to assess their influence on the outcomes.

Design: Observational retrospective cohort study. Setting. A single rehabilitation centre. Patients. 2,962 inpatients and outpatients with COPD (73% male, age 71 [SD 8] yr, FEV1 49.3 [SD14.8] % of predicted), graded 0, 1 or ≥2 according to the Comorbidity categories and included in a PR program. Measurements. We analyzed the number of self-reported comorbidities and recorded the Charlson index. We then calculated the percentage of patients with a predefined positive response to pulmonary rehabilitation (=minimally clinical important difference-MCID) as measured by improvement in exercise tolerance (6MWD), dyspnea (MRC), and/or health-related quality of life (SGRQ).

Results: 51% of the patients reported at least one chronic comorbidity added to COPD. Metabolic (systemic hypertension, diabetes, and/or dyslipidemia) and heart diseases (chronic heart failure and/or coronary heart disease) were the most frequently reported comorbid combinations (61 and 24%, respectively) among the overall diseases associated with COPD. The prevalence of patients with MCID was different across the Comorbidity categories and outcomes. In a multiple categorical logistic regression model, the Charlson index (OR 0.72, 96%CI 0.54 to 0.98 and 0.51, 96%CI 0.38 to 0.68, versus 6MWD and SGRQ respectively), metabolic diseases (OR 0.57, 96%CI 0.49-0.67 versus 6MWD) and heart diseases (OR 0.67, 96%CI 0.55 to 0.83 versus SGRQ) reduced the probability to improve outcomes of rehabilitation.

Conclusions: Most patients with COPD undergoing PR have one or more comorbidities. Despite the presence of comorbidities does not preclude the access to rehabilitation, the improvement in exercise tolerance and quality of life after rehabilitation may be reduced depending on comorbidity.

Background: Vascular endothelial growth factor (VEGF) and its receptor may play an important role in the pathogenesis of emphysema. But the effect of another angiogenic factor, placenta growth factor (PlGF), to chronic obstructive pulmonary disease (COPD) is unknown.

Methods: We measured the levels of VEGF and PlGF in serum from patients with COPD (n=184), smokers (n=212), nonsmokers (n=159), and in bronchoalveolar lavage (BAL) fluid from another group (COPD n=20, controls n=18). In vitro cell culture experiments were performed to investigate the effect of PlGF on VEGF.

Results: The serum levels of PlGF were significantly higher in COPD than in controls (27.1 (SE, 7.4) pg/ml vs. 12.3 (SE, 5.1) pg/ml in smokers and 10.8 (SE, 6.3) pg/ml in nonsmokers, p=0.005). The levels of PlGF in BAL fluids were also significantly higher in COPD than in controls (45.7 (SE, 12.3) pg/ml vs. 23.9 (SE, 7.6) pg/ml, p=0.005), associated with an increase of all measured cytokines, like tumor necrosis factor- (TNF-) and interleukin-8 (IL-8). In COPD patients, the levels of PlGF correlated inversely with forced expiratory volume in one second (FEV1) (in serum, r=-0.59, p=0.002; and in BAL fluids, r=-0.51, p=0.001). While the levels of VEGF in serum were the same between COPD and controls, the levels in BAL fluids were significantly lower in COPD than in controls (127.5 (SE, 30.1) pg/ml vs. 237.8 (SE, 36.1) pg/ml, p=0.002). In cultured bronchial epithelial cells, proinflammatory cytokines induced an increase in the protein expression of both PlGF and VEGF. Continuous concomitant treatment with PlGF, TNF- and IL-8 stimulation reduced VEGF expression and induced cell death. This phenomenon was suppressed by VEGF receptor inhibitor (CBO-P11).

Conclusions: PlGF was increased in serum and BAL fluids of COPD patients, and correlated inversely with FEV1. Concomitant treatment with PlGF, TNF- and IL-8 generate detrimental effects on airway epithelial cells. These data suggest that bronchial epithelial cells can express PlGF which may contribute to the pathogenesis of COPD.

Introduction: Dietary intake of specific nutrients or food groups during pregnancy could play a role in the risk of asthma and atopy in offspring, but specific dietary patterns have not been implicated. We evaluated the impact of maternal (during pregnancy) and child adherence to the Mediterranean Diet on asthma and atopy in childhood.

Methods: Women presenting for antenatal care at all general practices in Menorca, a Mediterranean island in Spain, over a 12-month period starting in mid-1997 were recruited. Four hundred and sixty children were included in the analysis after 6.5 years of follow-up. Maternal dietary intake during pregnancy and children’s dietary intake at age of 6.5 years were assessed by food frequency questionnaires and adherence to a Mediterranean Diet was evaluated through a priori defined scores. During follow-up, parents completed questionnaires on the child’s respiratory and allergic symptoms. Children underwent skin prick tests with 6 common aeroallergens.

Results: The prevalence of persistent wheeze, atopic wheeze, and atopy at age 6.5 years were 13.2%, 5.8%, and 17.0% respectively. One third (36.1%) of the mothers had low quality of Mediterranean Diet during pregnancy according to the Mediterranean Diet Score, while the rest had a high score. A high Mediterranean Diet Score during pregnancy (in two levels, using "low" score as reference) was found to be protective for persistent wheeze (OR, 0.22; 95% CI, 0.08-0.58), atopic wheeze (OR, 0.30; 95% CI, 0.10-0.90), and atopy (OR, 0.55; 95% CI, 0.31-0.97) at age 6.5 years after adjusting for potential confounders. Childhood adherence to the Mediterranean Diet was negatively associated with persistent wheeze and atopy though the associations did not reach statistical significance.

Conclusion: Our results support a protective effect of a high level of adherence to the Mediterranean Diet during pregnancy against asthma-like symptoms and atopy in childhood.

Rationale: Measurements of pulmonary biomarkers can be used to monitor airway inflammation in COPD but the variability of sampled biomarkers and their inter relationships are poorly understood.

Objectives: to describe the intra and inter-patient variability in spontaneous sputum samples from patients in the stable state and to describe the relationships between biomarkers, cell counts and markers of disease.

Methods: Sputum Interleukin-1beta, Tumour necrosis factor alpha, Interleukin 8, Myeloperoxidase, Leukotriene B4, Growth related oncogene alpha and differential cell counts were measured in patients with moderate to severe stable COPD (n = 14) on 11 occasions over one month.

Measurements and main results: There was significant variability in all inflammatory indices (median intra-patient coefficient of variation (CV) = 35% (IQR 22 - 69), median inter-patient CV = 102% (IQR 61 - 145)). Variability could be reduced by using a rolling mean of individual patient data points. Sample size calculations were undertaken to determine the number of patients required to detect a 50% reduction in neutrophil count. Utilising a cross-over design of a putative effective therapy, the number needed using one data point per patient was 72, reducing to 23 when the mean of 3 data points was used.

Significant correlations were demonstrated both between the inflammatory biomarkers themselves and between inflammatory biomarkers and markers of disease. Some relationships were not apparent when results from a single sample were used. The reliability of inter-relationships improved as more data points were used for each patient.

Conclusions: Clear relationships exist between inflammatory biomarkers in stable COPD patients. Sequential sampling reduced the variability of individual mediators and the potential number of patients needed to power proof of concept interventional studies.

Background: Although clinical N1 (cN1) non-small cell lung cancer (NSCLC) is considered to be locoregional, the postoperative outcome is disappointing, with a 5-year survival of less than 50%. One possible reason may underline that cN1disease diagnosed by current standard imaging modalities often contain unexpected N2 disease. This study was conducted to evaluate the surgical and pathological results of cN1 NSCLC patients.

Methods: Among 1782 NSCLC patients who underwent intended curative resection from 1993 to 2003, 143 patients were identified to have cN1 disease and were enrolled in this study. The clinico-pathological records and CT films of each patient were retrospectively reviewed to identify predictors for pN2-3 disease. Results: The pathological nodal status was pN0 in 23% (n = 33); pN1 in 47% (n = 67); and pN2-3 in 30% (n = 43). Patients with pN2-3 showed a significantly worse 5-year survival rate of 38% compared with pN0 (68%) and pN1 (60%) patients (p = 0.017 and 0.007, respectively). Multivariate analysis showed that adenocarcinoma histology was a significant predictor for pN2-3 disease (odds ratio [OR], 3.312; 95% confidence interval [CI], 1.439-7.784; p = 0.005). The presence of N1 node separate from the main tumour on CT scans tended to predict pN2-3 disease although it did not reach statistical significance (OR, 2.103; 95% CI, 0.955-4.693; p = 0.066). Pathological N2-3 disease was found in 53% of adenocarcinoma patients with separate N1 pattern and only in 12% of non-adenocarcinoma patients with continuous N1 pattern.

Conclusions: The diagnosis of N1 status by contrast-enhanced CT scans is unsatisfactory with a high rate of unexpected pN2 disease. To avoid infertile lung resection, CT-diagnosed N1 adenocarcinoma patients, especially with separate N1 pattern on CT, should be considered to undergo additional invasive node biopsy modalities, including mediastinoscopy.

Acoustic lung imaging offers a unique method for visualizing the lung. This study was designed to demonstrate reproducibility of acoustic lung images recorded from healthy individuals at different time points and to assess intra- and inter-rater agreement in the assessment of dynamically represented acoustic lung images. Recordings from 29 healthy volunteers were made on three separate occasions using Vibration Response Imaging. Reproducibility was measured using quantitative, computerized assessment of vibration energy. Dynamically represented acoustic lung images were scored by six blinded raters. Quantitative measurement of acoustic recordings was highly reproducible with an intra-class correlation score of 0.86 (very good agreement). Intra-class correlations for inter-rater agreement and reproducibility were 0.61 (good agreement) and 0.86 (very good agreement), respectively. There was no significant difference found between the six raters at any time point. Raters ranged from 88% to 95% in their ability to identically evaluate the different features of the same image presented to them blinded on two separate occasions. Acoustic lung imaging is reproducible in healthy individuals. Graphic representation of lung images can be interpreted with a high degree of accuracy by the same, and by different reviewers.

Background: Nitric oxide is released by immune, epithelial and endothelial cells, and plays important role in asthma pathophysiology. We sought to investigate the association of inducible NOS (NOS2A) gene repeat polymorphisms with asthma.

Methods: We recruited a total of 230 asthmatic families (842 individuals) to identify and establish genetic association of iNOS repeats with asthma and associated phenotypes. We measured serum NO levels of selected individuals and correlated with specific genotypes. Multiple logistic regression analysis was performed to see the effect of age and sex.

Results: A total of four repeats; a (CCTTT)n promoter repeat, a novel intron 2 (GT)n repeat (BV680047), an intron 4 (GT)n repeat (AFM311ZB1) and an intron 5 (CA)n repeat (D17S1878) were identified and genotyped. A significant transmission distortion to the asthmatic probands was seen for allele 3 of the AFM311ZB1 (p=0.006). This allele was also found to be significantly associated with percentage blood eosinophils (p=0.0006) and asthma severity (p=0.04). Moreover, it was functionally correlated with high serum NO levels (p=0.006). Similarly, the promoter repeat was found to be associated with serum total IgE (p=0.028). Individuals carrying allele 4 of this repeat have high serum IgE (p<0.0001) as well as NO levels (p=0.03).

Conclusion: This is the first study identifying the repeat polymorphisms in the iNOS gene that are associated with asthma severity and eosinophils. We also demonstrate the functional significance of the associated alleles with serum NO levels. Therefore, these results could be valuable in elucidating the role of NO in asthma pathogenesis.

Background: Reactive nitrogen species (RNS) are thought to be one of the important factors in the pathogenesis of chronic obstructive pulmonary disease (COPD). In this study, we examined the effects of theophylline and fluticasone propionate (FP) on RNS production in C