Respiratory Medicine - Articles in Press

Validation of an electronic version of the Mini Asthma Quality of Life Questionnaire - Corrected Proof

2010-03-12

Summary: Background: The Mini Asthma Quality of Life Questionnaire (MiniAQLQ) is a validated disease-specific quality of life (QOL) paper (p) questionnaire. Electronic (e) versions enable inclusion of asthma QOL in electronic medical records and research databases.Purpose: To validate an e-version of the MiniAQLQ, compare time required for completion of e- and p-versions, and determine which version participants prefer.Methods: Adults with stable asthma were randomized to complete either the e- or p-MiniAQLQ, followed by a 2-h rest period before completing the other version. Agreement between versions was measured using the intraclass correlation coefficient (ICC) and Bland–Altman analysis.Results: Two participants with incomplete p-MiniAQLQ responses were excluded. Forty participants (85% female; age 47.7 ± 14.9 years; asthma duration 22.6 ± 16.1 years; FEV1 87.1 ± 21.6% predicted) with both AQLQ scores <6.0 completed the study. Agreement between e- and p-versions for the overall score was acceptable (ICC=0.95) with no bias (difference (Δ) p–e=0.1; P=0.21). ICCs for the symptom, activity limitation, emotional function and environmental stimuli domains were 0.94, 0.89, 0.90, and 0.91 respectively. A small but significant bias (Δ=0.3; P=0.004) was noted in the activity limitation domain. Completion time was significantly longer for the e-version (3.8 ± 1.9min versus 2.7 ± 1.1min; P<0.0001). The majority of patients (57.5%) preferred the e-MiniAQLQ; 35% had no preference.Conclusion: This e-version of the MiniAQLQ is valid and was preferred by most participants despite taking slightly longer to complete. Generalizabilty may be limited in younger (12–17) and older (>65) adults.

Link between COPD and lung cancer - Corrected Proof

Robert P. Young, Raewyn J. Hopkins — 2010-03-12

We read with interest the recent review on chronic obstructive pulmonary disease (COPD) and lung cancer by Potton et al. We agree with their conclusion that COPD and lung cancer are closely associated and outline here a possible pathogenic link that not only explains the basis of this relationship but also the potential for chemopreventive therapy.

Alpha-1-antitrypsin deficiency in the Cape Verde islands (Northwest Africa): High prevalence in a sub-Saharan population - Corrected Proof

Carla Spínola, António Brehm, Hélder Spínola — 2010-03-12

Summary: Alpha-1-antitrypsin (AAT) deficiency results from mutations on the Protease Inhibitor (PI) locus located in chromosome 14 and has been associated with pulmonary early-onset emphysema and chronic obstructive pulmonary disease (COPD). African populations show a lower prevalence of AAT deficiency compared to Europeans.Two hundred and two (202) unrelated samples from the Cape Verde archipelago (Northwest Africa) were genotyped for the two most common AAT deficiency alleles, PI*S and PI*Z, using PCR – Mediated Site-Directed Mutagenesis.PI*S mutation in Cape Verde (3.2%) presents one of the highest frequencies in sub-Saharans, similar to South Africa (3.3%) but lower than Angolans (18.8%), Namibians (14.7%), Nigerians (6.4%) and Botswains (4.5%). The PI*Z mutation shows lower values (0.2%) than other sub-Saharan populations, namely Somalia (1.15%), Mali (0.98%)or Nigeria (0.36%). However, many other sub-Saharan populations, like Botswana, Congo, Cameroon, Angola, Gambia, South Africa, Mozambique and Namibia, lack the PI*Z mutation.The frequency of all the AAT deficiency genotypes in the Cape Verde archipelago (PI*ZZ, PI*SS, and PI*SZ) was estimated to be one of the highest in sub-Saharans (15 per 1000), only lower than Angola (54 per 1000) and Namibia (22 per 1000).The results obtained show a high prevalence of the AAT deficiency in Cape Verdeans when compared to other sub-Saharans a condition that can be explained by a heavy European genetic influence, characteristic of that population.

Asthma Programme in Finland: Did the use of secondary care resources become more rational? - Corrected Proof

L.E. Tuomisto, M. Erhola, T. Luukkaala, H. Puolijoki, M.M. Nieminen, M. Kaila — 2010-03-08

Summary: Objectives: The aims were to evaluate the profile of newly diagnosed adult asthma cases and the approach adopted to the secondary care management at the launch of the Finnish asthma programme in 1994 and seven years later, in 2001.Methods: A retrospective medical record audit was made of non-acutely referred patients with asthma in 1994 (n=165) and in 2001 (n=133). Clinical profile data, numbers of out-patient visits and periods of in-patient care before and after asthma diagnosis were gathered from referral letters and secondary care records.Results: The newly diagnosed asthma patients in 2001 were older, more obese and had more co-morbidities. The main asthma symptoms, such as dyspnoea, wheezing and cough, occurred equally in both years but were more often periodic than daily in 2001. Wheezing during auscultation was significantly less common in 2001. The diagnostic process was associated to a history of asthma in first-degree relatives (OR 5.34, 95% CI 1.12–24.49) in 1994 and a visit to a nurse prior to that to a physician (OR 3.13, 95% CI 1.17–8.37) in 2001. Secondary care visits per new case of asthma (7.3 in 1994 vs. 5.4 in 2001) and days in hospital (3.6 in 1994 vs. 0.95 in 2001) decreased significantly.Conclusions: The profile of asthma diagnosed in secondary care indicates milder disease with more co-morbidities in 2001 than in 1994.Trends towards assigning a more active role on the part of primary care physicians and more rational use of secondary care resources in the management of asthma were found.

Controller medications and their effects on asthma exacerbations temporally associated with upper respiratory infections - Corrected Proof

2010-03-08

Summary: Background: Exacerbations are a major risk and a cause of asthma morbidity and healthcare utilization. Viral-induced upper respiratory tract infections are the most frequent trigger of asthma-related exacerbations. Studies have traditionally assessed exacerbations without documentation regarding exacerbation etiology. Therefore, it remains unknown whether asthma medications can alter exacerbation susceptibility based on a specific etiology.Objective: To examine whether treatment with inhaled corticosteroids plus long-acting beta2-agonists reduced the number of exacerbations associated with upper respiratory tract infections versus inhaled corticosteroids alone.Methods: Two large datasets comparing treatment with fluticasone propionate and fluticasone propionate plus salmeterol were analyzed, including the number of clinically reported upper respiratory tract infections, asthma-related exacerbations, and the presence of an exacerbation and concurrent report of an upper respiratory tract infection.Results: Both treatment groups had similar incidences of upper respiratory tract infections. Of those reporting an upper respiratory tract infection, statistically significantly fewer reported an asthma-related exacerbation comparing fluticasone propionate plus salmeterol with fluticasone propionate (p=0.0057).Discussion: This retrospective analysis suggests that therapy with fluticasone propionate plus salmeterol provides protection against asthma exacerbations temporally associated with upper respiratory tract infections. This retrospective analysis supports the hypothesis that specific therapeutic approaches to mitigate virus-associated exacerbations may benefit asthma care. Well-controlled prospective studies are warranted.

Chronic obstructive pulmonary disease in older persons: A comparison of two spirometric definitions - Corrected Proof

2010-03-04

Summary: Background: Among older persons, we previously endorsed a two-step spirometric definition of chronic obstructive pulmonary disease (COPD) that requires a ratio of forced expiratory volume in 1sec to forced vital capacity (FEV1/FVC) below .70, and an FEV1 below the 5th or 10th standardized residual percentile (“SR-tile strategy”).Objective: To evaluate the clinical validity of an SR-tile strategy, compared to a current definition of COPD, as published by the Global Initiative for Obstructive Lung Disease (GOLD-COPD), in older persons.Methods: We assessed national data from 2480 persons aged 65–80 years. In separate analyses, we evaluated the association of an SR-tile strategy with mortality and respiratory symptoms, relative to GOLD-COPD. As per convention, GOLD-COPD was defined solely by an FEV1/FVC<.70, with severity staged according to FEV1 cut-points at 80 and 50 percent predicted (%Pred).Results: Among 831 participants with GOLD-COPD, the risk of death was elevated only in 179 (21.5%) of those who also had an FEV1<5th SR-tile; and the odds of having respiratory symptoms were elevated only in 310 (37.4%) of those who also had an FEV1<10th SR-tile. In contrast, GOLD-COPD staged at an FEV1 50–79%Pred led to misclassification (overestimation) in terms of 209 (66.4%) and 77 (24.6%) participants, respectively, not having an increased risk of death or likelihood of respiratory symptoms.Conclusion: Relative to an SR-tile strategy, the majority of older persons with GOLD-COPD had neither an increased risk of death nor an increased likelihood of respiratory symptoms. These results raise concerns about the clinical validity of GOLD guidelines in older persons.

Point-of-care Arkansas method for measuring adherence to treatment with isoniazid - Corrected Proof

2010-03-04

Summary: We evaluated the accuracy of a point-of-care test designed to measure adherence to isoniazid (INH) preventive therapy in a hospital setting in Rio de Janeiro, Brazil. Patients on treatment with daily INH and patients not receiving INH were included. Sensitivity and specificity of the test were 84%/98% at the first minute, and 95%/98% at the fifth minute, respectively. Among smokers, sensitivity and specificity was reduced (80%/89% at the fifth minute, respectively), but only 17% smoked. This test accurately detected INH metabolites 24h following directly observed INH intake, though sensitivity and specificity may be compromised by tobacco smoke exposure.

Right ventricular dilation on CT pulmonary angiogram independently predicts mortality in pulmonary embolism - Corrected Proof

2010-03-04

Summary: Background: The aim of this study was to determine the prognostic significance of right ventricular dilation on CT pulmonary angiogram in acute pulmonary embolism and to distinguish if this feature predicts mortality independently of the Pulmonary Embolism Severity Index, an established admission severity score.Methods: A retrospective study of patients admitted with pulmonary embolism confirmed by CT pulmonary angiogram to three teaching hospitals in East Scotland between January 2005 and July 2007. Two radiologists judged presence of right ventricular dilation on CT pulmonary angiogram independently. The outcome of interest was 30 day mortality. Multivariable logistic regression was used to compare this outcome in patients with right ventricular dilation compared to those without right ventricular dilation, adjusting for Pulmonary Embolism Severity Index score.Results: There were 585 patients included and 30.4% had right ventricular dilation on CT pulmonary angiogram. Patients with right ventricular dilation had increased 30 day mortality rates compared to patients without right ventricular dilation (12.4% vs. 5.4%; p=0.006). Survival analysis showed that a significantly greater proportion of deaths in the right ventricular dilation group occurred within the first 48h after admission compared to the group without right ventricular dilation (45.5% deaths vs. 9.1%; p=0.016). On multivariable analysis, adjusting for Pulmonary Embolism Severity Index score, right ventricular dilation was independently associated with increased 30 day mortality (OR 2.98; 95% CI 1.54–5.75; p=0.001).Conclusion: Right ventricular dilation on CT pulmonary angiogram is an independent predictor of 30 day mortality in acute pulmonary embolism.

Prevalence and impact of coronary artery disease in idiopathic pulmonary fibrosis - Corrected Proof

2010-03-03

Summary: Introduction: Idiopathic Pulmonary Fibrosis (IPF) is a progressive disease with a poor prognosis for which there is no effective medical therapy. An awareness of comorbidities that are treatable and might impact outcomes in these patients is therefore very important. We sought to determine the prevalence of coronary artery disease (CAD) in IPF patients in comparison to a control group of patients with chronic obstructive pulmonary disease (COPD). We also sought to assess the impact of CAD on IPF patient outcomes.Patients and methods: IPF and COPD transplant candidates whose work-up included left heart catheterization were categorized as having significant CAD, non-significant CAD or no disease. The risk factor profile and prevalence of CAD in both groups was compared.Results: There were 73 IPF and 56 COPD patients. The prevalence of CAD was 65.8% in the IPF group compared to 46.1% in the COPD patients (p<0.028). Significant disease was present in 28.8% of IPF patients vs.16.1% of the COPD patients (p<0.081). Unsuspected significant CAD was found in 18% of IPF patients versus 10.9% of COPD patients (p<0.004). Outcomes of IPF patients with significant CAD was worse than those with no or non-significant disease (p<0.003) with a median survival of 572 days from the time of left heart catheterization.Conclusion: There is a higher prevalence of CAD in IPF patients compared to a similarly matched COPD group. This increased association appeared to be independent of common coronary artery risk factors. IPF patients with significant CAD appear to have worse outcomes.

Effects of beclomethasone and factors related to asthma on the growth of prepubertal children - Corrected Proof

Paulo A.M. Camargos, Laura M.L.B.F. Lasmar — 2010-03-02

Summary: Few studies on the concomitant effects of beclomethasone dipropionate and asthma-related factors on the growth of prepubertal asthmatic children have been published to date. In this prospective long-term ‘real-life’ cohort study we recruited 82 prepubertal steroid-naïve asthmatic patients aged 3 + years, excluding those with birth weight lower than 2500 g, malnutrition, and other concurrent chronic diseases. Height/age and weight/age Z scores were calculated every three months. Random effects multivariate longitudinal data analysis was used to adjust height/age and weight/age Z scores with independent variables. Among the studied patients, 63.4% were male, aged 4.7 ± 1.5 years, 68.3% suffered from severe persistent asthma and had normal values for height/age and weight/age Z scores at enrolment. They were followed for 5.2 years (range 2.3–6.1) and used a mean daily beclomethasone dipropionate dose of 351.8 mcg (range 137.3–1140.0). Height/age and weight/age Z scores were not affected by either duration of treatment or doses of beclomethasone dipropionate up to 500 mcg, 750 mcg and higher than 750 mcg (p-values > 0.17). The multivariate analysis final model showed that severe persistent asthma was associated to lower height for age Z score (p = 0.04), whereas hospitalizations because of acute asthma (before and during follow-up) were associated (p = 0.02) to lower weight for age Z score. Growth parameters were not affected by the use of beclomethasone dipropionate.

The link between exhaled NO and bronchomotor tone depends on the dose of inhaled steroid in asthma - Corrected Proof

2010-03-02

Summary: Background: Exhaled NO (FENO) is a steroid dose dependent eosinophilic inflammometer, but also a mediator of bronchomotor tone, but statistically significant relationships have infrequently been obtained with pulmonary function tests (PFT). The aim was to test the hypothesis that the relationships between FENO and PFT could be uncovered by inhaled corticosteroid (ICS) treatment, namely that a link between FENO and bronchodilator response (an index of bronchomotor tone) would appear under ICS.Methods: Exhaled NO, forced expiratory flows and lung volumes were measured in atopic asthmatic children without recent (one month) respiratory symptoms.Results: Two hundred and thirty children (mean±SD, age: 11.2±2.5 years, 69 girls) were included (% predicted, FEV1: 100±14; FEF50%: 76±23; RV: 107±29). The relationship between ICS dose (GINA classification) and FENO plateaued in children with an ICS dose higher than 200μg beclomethasone equipotent daily dose: FENO (median [25th–75th percentiles]), 43ppb [15–105] (no treatment, n=65), 33ppb [15–77] (low dose, n=70), 23ppb [12–57] (medium dose, n=57) and 26ppb [9–49] (high dose, n=38). Statistically significant relationships between FENO and PFT were only observed in children receiving more than 200μg/day ICS: with FEV1 (medium ICS dose: ρ=0.43, p=0.001; high dose: ρ=0.32, p=0.052) and bronchodilator (400μg salbutamol) response (medium dose: ρ=0.54, p=0.001; high dose: ρ=0.65, p=0.002).Conclusions: A positive correlation between FENO and bronchomotor tone appears with increasing ICS doses in atopic children with clinically controlled asthma, which further suggests that children depicting the highest FENO values may have lesser steroid sensitivity.

COPD patients with higher education are much less likely to adhere to prescribed daily inhaler use - Corrected Proof

Paul L. Enright — 2010-02-26

This was one of the results from a survey of 265 patients with COPD in Colorado. I agree with the 40% of patients who “vary their inhaler use from what is prescribed”. The only proven value of any of these medications is either to relieve dyspnea (for the duration of the bronchodilation) or slightly lower the risk of an exacerbation, but not to suppress the rapid loss of lung function. (Post hoc and subgroup analyses don't count.) Only smoking cessation halts progression of COPD, but it is much easier to write a prescription for an inhaler than to help a patient through the process of smoking cessation.

Sub-clinical left and right ventricular dysfunction in patients with COPD - Corrected Proof

2010-02-25

Summary: Background: Cardiovascular manifestations in COPD include increased arterial stiffness, ischaemic heart disease, chronic heart failure and cor pulmonale. We hypothesised that sub-clinical right (RV) and left ventricular (LV) dysfunction occurs in patients with COPD, related to the severity of airflow obstruction, arterial stiffness and systemic inflammation.Methods: Thirty six patients and 14 controls, all free of overt cardiovascular disease underwent tissue Doppler echocardiography, spirometry, measurement of aortic pulse wave velocity (PWV) and venous sampling for inflammatory markers.Results: Mean LV myocardial strain and strain rate were less in patients than controls, p<0.05. LV isovolumic relaxation time (IVRT) was prolonged in patients (125±15.2ms) compared with controls (98.2±21.1ms), p<0.01, indicating LV diastolic dysfunction. The RV free wall strain and strain rate were less in patients than controls, both p<0.05, indicating RV systolic dysfunction. Patients had sub-clinical pulmonary arterial hypertension with a greater RV myocardial relaxation time and Tei index, both p<0.01. Patients with mild airways obstruction had LV and RV dysfunction and evidence of increased RV afterload compared with controls. In multivariate analyses aortic PWV predicted LV IVRT, p<0.01, while FEV1 predicted RV Tei index and myocardial relaxation time, both p<0.01.Conclusions: Patients with COPD have sub-clinical left ventricular dysfunction related to arterial stiffness, and right ventricular dysfunction related to airways obstruction. Both right and left ventricular dysfunction are present in patients with mild airways obstruction suggesting that cardiac co-morbidities commence early in the development of COPD.

Risk factors for pneumonia in immunocompromised patients with influenza - Corrected Proof

2010-02-25

Summary: Background: Immunocompromised patients with influenza are at higher risk of pneumonia and death. However, risk factors for progression to pneumonia still need evaluation.Methods: Retrospective study in immunocompromised patients with influenza-related respiratory infections. Risk factors for pneumonia were identified by multivariable logistic regression.Results: We identified 100 immunocompromised patients infected with influenza (68 hematological malignancies, 11 HIV, 21 iatrogenic immunosuppression). Immunofluorescence was positive in 95% of patients, mainly on nasopharyngeal aspirates (84%). Influenza A virus was involved in 80% of patients. Associated infection was documented in 34 patients. All patients presented with upper respiratory tract infection and 53 progressed to pneumonia. Thirty-two patients were critically ill, 11 received mechanical ventilation, and 10 died. All the patients who died had pneumonia. Patients with pneumonia were older (46y (36–63) vs. 33y (13–51), P=0.003) and more often had influenza A (89% vs. 70%, P=0.04) and associated infection (56% vs. 9%, P<0.0001). Factors independently associated with progression to pneumonia were influenza A (OR 5.54, 95% CI [1.16–26.47]) and hematological malignancies (OR 3.85, 95% CI [1.1–14.5]).Conclusions: In our cohort of hospitalized immunocompromised patients, influenza progresses to pneumonia in more than half the patients. Patients with hematological malignancies and influenza A infection are at higher risk for pneumonia and should be included in preemptive antiviral therapy trials.

Efficacy and safety of ipratropium bromide/albuterol delivered via Respimat® inhaler versus MDI - Corrected Proof

2010-02-22

Summary: We compared the efficacy and safety of ipratropium bromide/albuterol delivered via Respimat® inhaler, a novel propellant-free inhaler, versus chlorofluorocarbon (CFC)-metered dose inhaler (MDI) and ipratropium Respimat® inhaler in patients with COPD.This was a multinational, randomized, double-blind, double-dummy, 12-week, parallel-group, active-controlled study. Patients with moderate to severe COPD were randomized to ipratropium bromide/albuterol (20/100mcg) Respimat® inhaler, ipratropium bromide/albuterol MDI [36mcg/206mcg (Combivent® Inhalation Aerosol MDI)], or ipratropium bromide (20mcg) Respimat® inhaler. Each medication was administered four times daily. Serial spirometry was performed over 6h (0.15min, then hourly) on 4 test days. The primary efficacy variable was forced expiratory volume in 1s (FEV1) change from test day baseline at 12 weeks.A total of 1209 of 1480 randomized, treated patients completed the study; the majority were male (65%) with a mean age of 64 yrs and a mean screening pre-bronchodilator FEV1 (percent predicted) of 41%. Ipratropium bromide/albuterol Respimat® inhaler had comparable efficacy to ipratropium bromide/albuterol MDI for FEV1 area under the curve at 0–6h (AUC0–6), superior efficacy to ipratropium Respimat® inhaler for FEV1 AUC0–4 and comparable efficacy to ipratropium Respimat® inhaler for FEV1 AUC4–6. All active treatments were well tolerated.This study demonstrates that ipratropium bromide/albuterol 20/100mcg inhaler® administered four times daily for 12 weeks had equivalent bronchodilator efficacy and comparable safety to ipratropium bromide/albuterol 36mcg/206mcg MDI, and significantly improved lung function compared with the mono-component ipratropium bromide 20 mcg Respimat® inhaler. [Clinical Trial Identifier Number: NCT00400153]

High BMI is related to higher incidence of asthma, while a fish and fruit diet is related to a lower– Results from a long-term follow-up study of three age groups in Sweden - Corrected Proof

2010-02-19

Summary: The causes of the worldwide increase in asthma seen during the last decades remain largely unexplained, but lifestyle and diet are suggested to play important roles. In this follow up of a large-scale population sample in Sweden, we wanted to identify modifiable risk factors for the cumulative incidence over a 13-year follow-up period.In 1990, a self-administered questionnaire was completed by 12,560 individuals from three age groups (16, 30–39 and 60–69 years of age) in two counties of Sweden. In 2003, the eligible subjects (n = 11,282) were sent a new postal questionnaire.In total 8150 (response rate 73%) answered the questionnaire. The prevalence of asthma in 2003 had increased in all ages. In the young adults, the asthma prevalence rose from 11.3% in 1990 to 25.0% in 2003. Adult asthma onset was identified in 791 of the participants. Smoking [RR (95% CI) = 1.37 (1.12–1.68)], BMI [1.49 (1.25–1.77 per inter quartile range)], and nocturnal gastro-oesophageal reflux (GOR) [2.16 (1.72–2.72)] were significant independent risk factors for the cumulative incidence of asthma. The impact of risk factors differed between the age groups where BMI and GOR had a significantly higher impact in the middle aged and the elderly (p < 0.05). High consumption of fruit and fish was protective especially in the elderly [0.52 (0.35–0.77)]. No significant difference was found in the impact of risk factors between men and women.Weight loss, smoking cessation and a diet rich in fruit and fish may be of importance in preventing onset of adult asthma.

Physical inactivity in patients with COPD, a controlled multi-center pilot-study - Corrected Proof

2010-02-18

Summary: Background: Physical activity (PA) has been reported to be reduced in severe chronic obstructive pulmonary disease (COPD). Studies in moderate COPD are currently scarce. The aim of the present study was to investigate physical activity in daily life in patients with COPD (n=70) and controls (n=30).Methods: A multi-center controlled study was conducted. PA was assessed using a multisensor armband device (SenseWear, BodyMedia, Pittsburgh, PA) and is reported as the average number of steps per day, and the time spent in mild and moderate physical activity.Results: Patients suffered from mild (n=9), moderate (n=28), severe (n=23) and very severe (n=10) COPD. The time spent in activities with mild (80±69min vs 160±89min, p<0.0001) and moderate intensity (24±29min vs 65±70min; p<0.0036) was reduced in patients compared to controls. The number of steps reached 87±34%, 71±32%, 49±34% and 29±20% of control values in GOLD-stages I to IV respectively. The time spent in activities at moderate intensity was 53±47%, 41±45%, 31±47% and 22±34% of the values obtained in controls respectively with increasing GOLD-stage. These differences reached statistical significance as of GOLD stage II (p<0.05). No differences were observed among centers.Conclusions: Physical activity is reduced early in the disease progression (as of GOLD-stage II). Reductions in physical activities at moderate intensity seem to precede the reduction in the amount of physical activities at lower intensity.

Pulmonary inflammation in asbestos-exposed subjects with borderline parenchymal changes on HRCT - Corrected Proof

2010-02-18

Summary: Many asbestos-exposed subjects have minor parenchymal changes on high resolution computed tomography (HRCT) that do not fulfil the diagnostic criteria for pulmonary fibrosis and asbestosis. We investigated if these borderline parenchymal changes in asbestos-exposed subjects are related to pulmonary inflammatory activity.Exhaled nitric oxide was measured, exhaled breath condensate collected and HRCT scanned in 104 subjects with moderate to high occupational asbestos exposure. Forty-one healthy unexposed subjects served as a comparison group.After excluding other pulmonary diseases, 35 asbestos-exposed subjects had normal parenchymal findings and 31 subjects had borderline parenchymal changes on HRCT. Lung function was poorer in the latter group, but there was no difference in the degree of asbestos exposure between these groups. As compared with the unexposed comparison group, asbestos-exposed subjects with borderline parenchymal changes had increased alveolar NO concentration (3.0 ± 0.2 vs. 2.3 ± 0.1 ppb, p = 0.008) and increased levels of leukotriene B4 (12.2 ± 1.1 vs. 3.3 ± 0.8 pg/ml, p < 0.001) and 8-isoprostane (9.4 ± 0.7 vs. 7.3 ± 0.6 pg/ml, p = 0.021) in breath condensate. Asbestos-exposed subjects with normal parenchymal findings had only increased breath condensate levels of leukotriene B4 (11.4 ± 0.9, p < 0.001).Borderline parenchymal changes on HRCT in asbestos-exposed subjects are associated with increased markers of pulmonary inflammation. Such borderline parenchymal changes are likely a mild or early form of the same pathological process that leads to asbestosis.

Continuous versus on-demand pharmacotherapy of allergic rhinitis: Evidence and practice - Corrected Proof

2010-02-17

Summary: This review aims to compare continuous with on-demand pharmacotherapy of allergic rhinitis by focusing on pharmacodynamic, pharmacokinetic, safety, effectiveness, cost and cost-effectiveness considerations. A working party of experts reviewed and discussed the literature and guidelines, and conducted a qualitative analysis of the Summary of Product Characteristics of specific medicines. With respect to medicines, the working party limited itself to antihistamines, nasal corticosteroids and leukotriene antagonists. Based on a review of the evidence from a multidisciplinary perspective, this article makes pharmacotherapeutic recommendations that are easy, functional and applicable to daily practice in primary care.The pharmacotherapeutic evidence for continuous versus on-demand treatment of allergic rhinitis was limited. Clearly, for corticosteroids, their mechanism of action in allergic rhinitis of reducing allergic inflammation requires continuous therapy at least for the duration of symptoms. For H1-antihistamines, some trials suggest that continuous treatment is preferable but more studies are needed to confirm this conclusion. For both H1-antihistamines and nasal corticosteroids safety data indicate that continuous treatment may be given without fears of adverse consequences, although a distinction can be made between the first and the second generation antihistamines. With regard to the cost and cost-effectiveness implications of continuous therapy versus on-demand therapy, more studies are necessary before definitive conclusions may be made.

PSMB8 (LMP7) but not PSMB9 (LMP2) gene polymorphisms are associated to pigeon breeder's hypersensitivity pneumonitis - Corrected Proof

2010-02-15

Summary: Hypersensitivity Pneumonitis (HP) is a lung inflammatory disorder caused by inhalation of organic particles by a susceptible host. However, only a small proportion of individuals exposed to HP-associated antigens develop the disease, suggesting that additional host/environmental factors may play a role. We have previously found that genetic susceptibility associated to the major histocompatibility complex (MHC) plays an important role in this disease. The low molecular weight proteosome (LMP, currently named PSMB) genes code for subunits of the proteosome, a multimeric enzymatic complex that degrades proteins into peptides in order to be presented in the MHC class I pathway. We hypothesized that polymorphisms in PSMB8 or PSMB9 genes could be involved in the susceptibility to HP. Thus, in this study we analyzed the polymorphic site at amino acid position 60 (Arg/His) of the fourth exon in the PSMB9 gene and the amino acid position 49 (Gln/Lys) in the second exon of PSMB8 gene in 50 Mexican patients with HP and 50 healthy ethnically matched controls. PSMB typing was performed using polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP). Our results demonstrated that HP patients had a significant increase of the PSMB8 KQ genotype frequency (OR = 7.25, CI = 2.61–21.3; p = 0.000034). No differences were found in the distribution of PSMB9 alleles/genotypes. However, PSMB9-RH/PSMB8 KQ haplotype was significantly increased in HP patients (OR = 6.77, CI = 1.34–65.31, p < 0.02). These findings suggest that PSMB8 KQ genotype could increase the risk to develop hypersensitivity pneumonitis.

Long-term therapy with inhaled iloprost in patients with pulmonary hypertension - Corrected Proof

2010-02-12

Summary: Aims: To investigate the long-term safety of inhaled iloprost in patients with pulmonary hypertension (pH), including idiopathic PAH (IPAH group) and other forms of pulmonary hypertension (PHother).Methods and results: Sixty-three patients (IPAH group, n=40, PHother n=23) were enrolled to receive inhaled iloprost either from baseline or after 3 months in a prospective, open-label 2-year study. Iloprost was inhaled 6–9 times daily with a night pause employing a jet nebulizer delivering an inhaled single dose of 4μg at the mouthpiece. In the case of side effects the single dose was reduced to 2μg. Sixty patients received at least 1 dose of inhaled iloprost. Thirty-six patients completed at least 630 days of therapy (25 IPAH, 11 PHother), 19 patients dropped out prematurely and 8 patients died (3 IPAH, 5 PHother). There were no drug-induced toxicities and only mild to moderate side effects. The most common side effects were coughing and flushing. Two-year survival was estimated at 85% (IPAH group 91%, PHother 78%). A modified analysis was performed to correct for differential drop-out. It included follow-up data from the premature discontinuations and revealed a 2-year survival of 87% [95% CI, 76%–98%] in the IPAH group while the predicted survival was 63%. The iloprost dose increased by 16% over 2 years.Conclusion: Inhaled iloprost is well tolerated as long-term therapy and no substantial dose increase is required. Although uncontrolled, the data suggest a long-term clinical benefit from continued therapy with inhaled iloprost.

Abnormalities of plethysmographic lung volumes in asthmatic children - Corrected Proof

Bruno Mahut, Plamen Bokov, Christophe Delclaux — 2010-02-12

Summary: Background: While lung hyperinflation is frequent in asthma, measurement of lung volumes is not recommended in current guidelines. The aim of this descriptive functional study was to assess whether systematic measurement of volumes by plethysmography may detect isolated hyperinflation with normal expiratory flows.Methods and patients: One hundred sixty asthmatic children (mean age±SD: 10.8±2.7 years; 50 girls) receiving inhaled corticosteroid underwent lung function tests before and after bronchodilation (BD). To avoid the problem of dysanaptic lung growth on predicted values in childhood, airflow limitation and hyperinflation were defined by ratios (FEV1,%pred/FVC%pred for the former, RV/TLC for the latter) and values below and above the 5th or 95th percentiles of reference values, were chosen as cut-off values.Results: Different functional phenotypes were evidenced, mainly normal lung function (142/160 [89%] after BD), but also isolated airflow limitation (35/160 [22%] before and 7/160 [4%] after BD) and isolated hyperinflation (17/160 [11%] before and 11/160 [7%] after BD), while the combination of both impairments before BD (13/160 [8%]) was never observed after BD. There was no statistical relationship between airflow limitation and hyperinflation, either before or after BD. Indices of spirometry (FEV1, FEF50%) were unable to predict isolated hyperinflation that corresponds to small airway obstructive syndrome.Conclusion: Isolated hyperinflation is not infrequent in asthmatic children (7–11%) and small airway obstruction is not detected by forced expiratory flows.

Burden of pulmonary arterial hypertension in Germany - Corrected Proof

2010-02-10

Summary: This study aimed to describe health care provision, resource consumption and related costs, as well as treatment patterns and quality of life in adult patients with pulmonary arterial hypertension (PAH) in Germany.Data for this retrospective and prospective cost-of-illness-study were derived from hospitals, general practitioners and patients. Costs were evaluated from the perspective of third party payer and patient. Quality of life data were collected by using three validated instruments.A total of 167 patients were enrolled at 10 hospitals. Time period from first occurrence of symptoms to confirmed diagnosis of PAH was 2.3 years on average. Mean number of GP visits was 1.5 per patient per month, and within 15 months, inpatient stays were reported for 50% of patients. The ratio of combination therapy to single-drug therapy for endothelin receptor antagonists, phosphodiesterase-5-inhibitor and prostacyclin analogues increased significantly during 15 months. Treatment costs were, on average, €47,400 per patient per year, arising mainly from drugs. Compared to the general population, quality of life of PAH patients was considerably impaired.This is the first study which evaluated aspects of the medical and economic consequences of PAH based on a large cohort of PAH patients in Germany.

Preselection of patients at risk for COPD by two simple screening questions - Corrected Proof

Harald Kögler, Norbert Metzdorf, Thomas Glaab, Tobias Welte — 2010-02-08

Abstract: Background: The Burden of Obstructive Lung Disease study showed that in Germany, to confirm the diagnosis of chronic obstructive lung disease (COPD) in one subject, eight people ≥40 years of age have to be screened. The number-needed-to-screen (NNS) increased to 18 for identifying a patient with COPD≥GOLD stage II. These high numbers limit the cost-effectiveness of COPD screening by population spirometry. We investigated in a primary care setting whether using two simple questions regarding smoking status and presence of cough and/or dyspnea may help to preselect patients for proper diagnosis of COPD.Methods: A total of 1088 patients aged ≥40 yrs without a history of chronic lung disease, who were either current or ex-smokers and complained of cough and/or dyspnea, were examined by respiratory physicians. Spirometry was carried out to confirm COPD diagnosis and severity.Results: A total of 61.6% of patients were male. Mean smoking history was 31.8 pack-yrs. In 516 patients (47.4%), a diagnosis of COPD was confirmed. Among these, 379 (34.8% of total) had at least GOLD stage II COPD, while 89 (8.2% of total) had advanced disease (GOLD stages III/IV). COPD prevalence was significantly associated with age and the extent of cigarette smoke exposure.Conclusions: Two questions regarding smoking status and presence of cough and/or dyspnea enabled general practitioners to select patients at risk for COPD for subsequent spirometry. This preselection reduced the NNS to 2.1 for identifying a COPD patient, and to 2.9 for identifying a patient of at least GOLD stage II.

Effects of CPAP therapy on the sympathovagal balance and arterial stiffness in obstructive sleep apnea - Corrected Proof

2010-02-08

Summary: Objective: Increased arterial stiffness and sympathovagal imbalance are noted in patients with obstructive sleep apnea (OSA). It has been thought that continuous positive airway pressure (CPAP) therapy can have beneficial effects on the vascular function in such cases. However, it is not yet clear whether the improvement of sympathovagal balance by CPAP might be related to reduction of the arterial stiffness, independent of changes in the blood pressure.Methods: In 50 consecutive eligible patients with OSA (apnea–hypopnea index≥20/hour) receiving CPAP therapy, the brachial-ankle pulse wave velocity (baPWV), heart rate variability (LF, HF and LF/HF ratio), baroreceptor sensitivity (BRS), plasma levels of C-reactive protein (CRP), and endothelial function as assessed by changes in the forearm blood flow before and after reactive hyperemia (END) were measured before and after 3-months' CPAP therapy.Results: Significant decrease of the LF/HF ratio, plasma levels of CRP, baPWV and heart rate were observed after 3 months' CPAP therapy. The change in the baPWV following 3-months' CPAP therapy was significantly correlated with the change in the LF/HF ratio and mean blood pressure (MBP), but not with that of the BRS, CRP or END after the therapy. Multivariate linear regression analysis demonstrated a significant correlation between the change in the LF/HF ratio and that in the baPWV (beta=0.305, p=0.041), independent of the changes in the MBP, plasma CRP levels and heart rate.Conclusions: Improvement of the sympathovagal balance by CPAP therapy may be significantly related to decreased stiffness of the central to middle-sized arteries, independent of the changes in the blood pressure and vascular endothelial status.

Mechanical ventilation induces changes in exhaled breath condensate of patients without lung injury - Corrected Proof

2010-02-08

Summary: Introduction: Measurement of biomarkers in exhaled breath condensate (EBC) may be useful for monitoring lung inflammation and injury in mechanically ventilated patients. The aim of this study was to analyze changes in biomarkers of inflammation in EBC associated with prolonged mechanical ventilation.Methods: EBC samples were collected from critically ill patients weaning from mechanical ventilation without lung disease and from healthy nonsmokers. The following parameters were measured: pH after helium deaeration, nitrogen oxide and 8-isoprostane concentrations.Results: EBC was obtained from 10 patients and 20 controls. Ventilation time before the start of sample collection was 250 (85–714)h. The post-deaeration pH of EBC samples was significantly lower in ventilated patients than controls (7.50 [7.28–7.70] vs 8.07 [7.60–8.40]; P=0.008). Ventilation time before sample collection inversely correlated with pH (r=−0.636; P=0.048). A significantly higher concentration of nitrogen oxide (μM) was seen in ventilated patients vs controls (66.22 [22.26–83.13] vs 15.06 [10.73–23.30]; P=0.002), whereas levels of 8-isoprostane (pg/mL) were not significantly different between both groups (5.73 [4.0–11.4] vs 9.09 [6.63–11.43]; P=0.169). The nitrogen oxide concentration correlated negatively with dynamic compliance (r=−0.952; P<0.001) and positively with respiratory rate (r=0.683; P=0.029).Conclusions: EBC analysis is a non-invasive technique that can be used to monitor ventilated patients. Mechanically ventilated patients had higher EBC acidity and nitrogen oxide concentrations. Duration of ventilation correlated with breath condensate pH.

Bronchitis-like symptoms and proximity air pollution in French elderly - Corrected Proof

2010-02-03

Summary: Background: Our aim was to explore the association between respiratory health and proximity air quality in elderly.Methods: The prevalence of respiratory conditions was linked in 2104 individuals aged ≥65 years recruited in Bordeaux (3C Study) to home address concentrations of NO2, CO, SO2, fine particles (PM10), VOCs and benzene, estimated through a dispersion model combining data on background air pollution, traffic characteristics, and conditions of topographical and meteorological dispersion of air pollutants.Results: Mean [minimum; maximum] values of the annual concentrations (μg/m3) of proximity air pollutants were respectively: 28 [18; 72.2] for NO2, 420 [350; 1337] for CO, 7.5[5; 13.7] for SO2, 23.1 [19; 51] for PM10, 8.1 [0.01; 116.6] for VOCs and 1.8 [1.5; 6.9] for benzene. Using a binary logistic regression model, PM10 were significantly associated with usual cough (Odds-Ratio=1.33 (95% confidence interval: 1.00–1.77) for exposed compared to non-exposed) and SO2 with usual cough (1.55 (1.16–2.08)) and phlegm (1.45 (1.04–2.01)). We found a 10% and a 23% increase in usual cough for a 10μg/m3 increment in PM10 and a 1μg/m3 increment in SO2 respectively, and a 23% increase in usual phlegm for a 1μg/m3 increase in SO2. A sensitivity analysis showed similar results when considering 3-year proximity pollution. A more pronounced effect of SO2 and PM10 on usual cough and phlegm was observed in woman.Conclusions: Our assessment of exposure to proximity air pollution has shown an increased prevalence of bronchitis-like symptoms in elderly living in areas polluted by SO2 and PM10.

Two variants of occupational asthma separable by exhaled breath nitric oxide level - Corrected Proof

2010-02-03

Summary: Exhaled nitric oxide (FENO) has been used as a marker of asthmatic inflammation in non-occupational asthma, but some asthmatics have a normal FENO. In this study we investigated whether, normal FENO variants have less reactivity in methacholine challenge and smaller peak expiratory flow (PEF) responses than high FENO variants in a group of occupational asthmatics.Methods: We measured FENO and PD20 in methacholine challenge in 60 workers currently exposed to occupational agents, who were referred consecutively to a specialist occupational lung disease clinic and whose serial PEF records confirmed occupational asthma. Bronchial responsiveness (PD20 in methacholine challenge) and the degree of PEF change to occupational exposures, (measured by calculating diurnal variation and the area between curves score of the serial PEF record in Oasys), were compared between those with normal and raised FENO. Potential confounding factors such as smoking, atopy and inhaled corticosteroid use were adjusted for.Results: There was a significant correlation between FENO and bronchial hyper-responsiveness in methacholine challenge (p = 0.011), after controlling for confounders. Reactivity to methacholine was significantly lower in the normal FENO group compared to the raised FENO group (p = 0.035). The two FENO variants did not differ significantly according to the causal agent, the magnitude of the response in PEF to the asthmagen at work, or diurnal variation.Conclusions: Occupational asthma patients present as two different variants based on FENO. The group with normal FENO have less reactivity in methacholine challenge, while the PEF changes in relation to work are similar.

HSP47 in lung fibroblasts is a predictor of survival in fibrotic nonspecific interstitial pneumonia - Corrected Proof

2010-02-03

Summary: Background: The histopathologic pattern is currently the most important prognostic marker for idiopathic interstitial pneumonia (IIP). However, more highly sensitive markers are now required. Heat shock protein (HSP) 47, a collagen-specific molecular chaperone, is involved in the processing and/or secretion of procollagens, and it has been demonstrated that HSP47 expression is significantly higher in the lung specimens of idiopathic UIP than in UIP associated with collagen vascular diseases (CVD). However, its expression in nonspecific interstitial pneumonia (NSIP), the other common pathological pattern of IIP, has not been well investigated. Therefore, the association between lung fibroblast HSP47 expression and prognosis in fibrotic NSIP was evaluated.Methods: Surgical lung biopsy specimens of 63 patients [idiopathic fibrotic NSIP=19, fibrotic NSIP associated with CVD=9, idiopathic UIP=26, and UIP associated with CVD=9] were reviewed, and a score for lung fibroblast HSP47 expression was assigned. These patients' clinical features and survival were also analyzed.Results: There was no significant difference in HSP47 expression between idiopathic fibrotic NSIP and fibrotic NSIP associated with CVD. The idiopathic fibrotic NSIP patients with higher HSP47 expression levels in their lung specimens had a poorer prognosis than patients with lower HSP47 expression levels.Conclusions: The present results suggest that lung fibroblast HSP47 expression may be a useful new prognostic marker for idiopathic fibrotic nonspecific interstitial pneumonia.

Tracheostomy in patients with long-term mechanical ventilation: A survey - Corrected Proof

2010-02-01

Summary: Background: Tracheostomy is increasingly performed in intensive care units (ICU), with many patients transferred to respiratory ICU (RICU). Indications/timing for closing tracheostomy are discussed.Aim and Method: We report results of a one-year survey evaluating: 1) clinical characteristics, types of tracheostomy, complications in patients admitted to Italian RICU in 2006; 2) clinical criteria and systems for performing decannulation, and outcome of patients undergoing tracheostomy (number decannulated; number non-decannulated/non-ventilated; number non-decannulated/ventilated; dead/lost patients).Results: 22/32 RICUs replied. There were 846 admissions of 719 patients (Mean age 64,3 (±14.2) years, 489 (68%) males). Causes of admission were: acute respiratory failure with underlying chronic co-morbidities 176 (24.4%); exacerbation of Chronic Obstructive Pulmonary Disease 222 (34.4%); neuromuscular diseases 200 (27.8%); surgical patients 77 (10.7%); thoracic dysmorphism 28 (3.8%); obstructive sleep apnea syndrome 16 (2.2%). Percutaneous tracheostomies were 65.9%. Major complications after tracheostomy were 2%. 427 tracheostomies were evaluated for decannulation: 96 (22.5%) were closed; 175 patients (41%) were discharged with home mechanical ventilation; 114 patients (26.5%) maintained the tracheostomy despite weaning from mechanical ventilation and 42 patients (10%) died or lost.The clinical criteria chosen for decannulation were: stability of respiratory conditions, effective cough, underlying diseases and ability to swallow. The systems for evaluating feasibility of decannulation were: closure of tracheostomy tube; laryngo-tracheoscopy; use of tracheal button and down-sizing.Conclusions: There were few major complications of tracheostomy. A substantial proportion of patients maintain the tracheostomy despite not requiring mechanical ventilation. There was no agreement on indications and systems for closing tracheostomy.

The MRC dyspnoea scale by telephone interview to monitor health status in elderly COPD patients - Corrected Proof

2010-01-29

Summary: Dyspnoea is the most common symptom associated with poor quality of life in patients affected by Chronic Obstructive Pulmonary Disease (COPD). While COPD severity is commonly staged by lung function, the Medical Research Council (MRC) dyspnoea scale has been proposed as a more clinically meaningful method of quantifying disease severity in COPD. We wished to assess whether this scale might also be useful during telephone surveys as a simple surrogate marker of perceived health status in elderly patients with COPD.We conducted a comprehensive health status assessment by telephone survey of 200 elderly patients who had a physician diagnosis of COPD. The telephone survey contained 71 items and explored such domains as educational level, financial status, living arrangements and social contacts, co-morbid illness, and the severity and the impact of COPD on health status. Patients were categorized according to the reported MRC score: mild dyspnoea (MRC scale of 1), moderate dyspnoea (MRC scale of 2 and 3), or severe dyspnoea (MRC of 4 and 5). Deterioration in most of the recorded indicators of health status correlated with an increasingly severe MRC score. This was most evident for instrumental activities of daily living (IADL), perceived health and emotional status, pain-related limitations, limitations in social life, hospital admissions in preceding year and prevalence of most co-morbidities.The MRC dyspnoea scale is a reliable index of disease severity and health status in elderly COPD patients which should prove useful for remote monitoring of COPD and for rating health status for epidemiological purposes.

Prognosis of COPD patients requiring frequent hospitalization: Role of airway infection - Corrected Proof

2010-01-27

Summary: Rationale: A subgroup of patients with chronic obstructive pulmonary disease require frequent hospitalization because of exacerbations of the disease. We hypothesized that airway infection by non-usual pathogens is a major factor driving hospitalization needs in these patients.Objectives: 1) To describe the clinical and functional characteristics of a cohort of COPD patients requiring ≥2 hospitalizations per year; 2) to determine prospectively their microbiological pattern during exacerbations; and, 3) to analyze the prognostic value of several clinical, functional and microbiological variables with respect to hospitalizations and mortality.Methods: Open cohort study of 116 COPD patients who had been hospitalized at least twice during the last 12 months. Patients were followed for an average of 21 months.Measurements and main results: Clinical data, forced spirometry and 6min walking distance were determined, and the BODE index was calculated, at the time of inclusion in the study. During follow-up, sputum culture was obtained during exacerbations, and hospitalization and mortality were collected every two months. Mean age was 71 yrs, and 94% of patients were male. Main findings show that: 1) not all patients had severe disease according to either the degree of airflow limitation or the BODE index; 2) non-usual pathogens, mainly Pseudomonas aeruginosa, other gram-negative non-fermentative rods and Enterobacteriaceae, were isolated among 71.1% of the sputum obtained during exacerbations; and, 3) these pathogens were associated with poor prognosis and frequent hospitalization.Conclusions: Airway infection by non-usual pathogens appears to be a key driver of frequent hospitalizations and mortality in COPD.

Alveolar and bronchial exhaled nitric oxide in chronic obstructive pulmonary disease - Corrected Proof

An Lehouck, Claudia Carremans, Kristien De Bent, Marc Decramer, Wim Janssens — 2010-01-25

Summary: Background: Fractional exhaled NO (Fe,NO) has yielded inconsistent results in COPD. Measuring exhaled NO at multiple flow rates however, allows to dissect exhaled NO in an alveolar (CAlv,NO) and bronchial (J'aw,NO) fraction, which are claimed to better reflect the bronchial and alveolar inflammation in COPD. We examined whether the use of Fe,NO, CAlv,NO and J'aw,NO may contribute to the clinical diagnosis of COPD.Methods: One hundred and fifty one patients were included in this case–control design: 28 healthy nonsmokers, 39 healthy smokers, 55 COPD nonsmokers and 29 COPD smokers. Prior to spirometry, exhaled NO was measured at three different flow rates (50, 100 and 200ml/s; NIOX-FLEX) from which Fe,NO, CAlv,NO and J'aw,NO were calculated.Results: Mean Fe,NO, mean CAlv,NO and mean J'aw,NO of healthy individuals were not significantly different from COPD patients and none of these variables correlated with FEV1. In both healthy and COPD patients, current smoking significantly reduced Fe,NO, J'aw,NO and CAlv,NO. Multivariate analysis demonstrated that in contrast to gender, age, BMI, GOLD stage and the use of inhaled corticosteroids, current smoking was the only variable affecting CAlv,NO. (p=0.0115)Conclusion: We conclude that similar to single breath exhaled NO, exhaled NO at different flow rates does not contribute to the diagnosis of COPD in standard respiratory practice.

Pulmonary hypertension in lung diseases: Survey of beliefs and practice patterns - Corrected Proof

2010-01-22

Summary: Introduction: Pulmonary hypertension can be associated with decreased functional capacity and poor prognosis in patients with parenchymal lung diseases (PLD). Yet, little attention has been given to current beliefs and practice patterns.Methods: An 18-question survey was submitted electronically to members of four Networks of the American College of Chest Physicians.Results: Analyzable responses were received from 453 physicians. Most (95%) respondents reported testing for PH in patients with PLD using transthoracic echocardiography (TTE) or right-heart catheterization (RHC) and believed that PH could occur in the absence of severe compromise in pulmonary function (70%) and hypoxemia (50%). Approximately 30% of physicians reported not performing RHC to confirm a diagnosis of PH before initiating therapy. Most respondents (92%) felt that medical therapy was effective and the medication of first choice was either bosentan or sildenafil. Most respondents believed that treating PH in these patients improves quality of life (63%) and dyspnea (67%), but were less sure about the impact on functional capacity and survival.Conclusions: Approximately 30% of physicians do not perform RHC to confirm this diagnosis prior to initiating therapy. Despite relatively little supportive evidence, most physicians treat with vasoactive medications and believe that medical therapy confers benefit.

Pharmacotherapy for pulmonary sarcoidosis: A delphi consensus study - Corrected Proof

Amanda C. Schutt, Wendy M. Bullington, Marc A. Judson — 2010-01-20

Summary: Background: Most issues concerning pharmacotherapy of pulmonary sarcoidosis have not been resolved in clinical trials. The objective was to survey sarcoidosis experts concerning the treatment of pulmonary sarcoidosis and attempt to reach a consensus by these experts using a Delphi method.Methods: A 6-item questionnaire was developed. Experts were identified at the Diffuse Lung Disease Network at the annual CHEST meeting in October 2008. Three rounds of questionnaires were presented to the experts. Respondent feedback and supporting literature was incorporated into the questionnaires of subsequent rounds.Results: Experts reached a consensus concerning the following issues: (a) corticosteroids are the initial therapy of choice; (b) initial use of inhaled corticosteroids are not recommended; (c) methotrexate was the preferred second-line drug; (d) 40mg of daily prednisone equivalent was the maximum dose recommended for the treatment of acute pulmonary sarcoidosis; (e) tapering to 10mg of daily prednisone equivalent for chronic pulmonary sarcoidosis was considered a successful taper. The experts could not resolve the following issues: (a) the initial corticosteroid dose for the treatment of acute pulmonary sarcoidosis; (b) the decision and timing of corticosteroid therapy in a patient with mild, Stage 2 pulmonary sarcoidosis.Conclusions: This Delphi study revealed that sarcoidosis experts reached a consensus concerning several aspects of the treatment of pulmonary sarcoidosis; these could be considered as appropriate approaches to therapy. Other issues concerning the therapy of pulmonary sarcoidosis remain unresolved by experts, and are areas where further clinical research could be directed.

Poor lung function and tonsillectomy in childhood are associated with mortality from age 18 to 44 - Corrected Proof

2010-01-15

Summary: Background: The aim of this analysis was to examine associations between lung health in childhood and mortality between ages 18 and 44 years in the Tasmanian Longitudinal Health Study (TAHS).Methods: The 1961 Tasmanian birth cohort who attended school in 1968 (n=8583) were linked to the Australian National Death Index (NDI) to identify deaths. Additional deaths were notified by families through a 37 year follow-up postal questionnaire. Information on lung health at age 7 years and on potential confounders was obtained from the original 1968 TAHS survey and school medical records. Cox proportional hazards modelling was used to assess determinants of mortality.Results: A total of 264 (3%) deaths were identified. The principal causes of death were external injury (56.1%, n=97) and cancer (17.9%, n=31). Males were more likely than females to have died (p=<0.1). Only two (1.1%) participants had died from respiratory conditions. Having an FEV1<80% predicted at 7 years of age was associated with a 2-fold increased incidence of death. Tonsillectomy before age 7 years was associated with a 1.5-fold increase in mortality (p=0.05); being male with a 3.6-fold increase in mortality (p=0.0001); and repeated chest illnesses at age 7 years causing >30 days confinement in the last year, was associated with a 2.2-fold increase in mortality (p=0.03).Conclusions: Childhood lung health appears to be associated with increased mortality in adulthood, perhaps by affecting the ability to survive trauma, major illnesses and other physical stresses.

A single dose of Sildenafil does not enhance FeNO: A randomised, cross-over and placebo-controlled study - Corrected Proof

Thomas Rothe, Werner Karrer, Christian Schindler — 2010-01-15

Summary: Monitoring of asthma control can be performed with different means including measurement of the concentration of nitric oxide (NO) in exhaled air. Due to its action on the NO-metabolism; we hypothesized that the intake of Sildenafil might augment and falsify the NO-values in exhaled air of subjects taking the drug to treat erectile dysfunction.This randomised, placebo-controlled cross-over study including 10 male non-asthmatic volunteers taking a single dose of 50 mg Sildenafil did not confirm this assumption in non-asthmatic subjects. We cannot think of any reason why asthmatics should behave differently.On the basis of these results, it does not seem necessary to ask asthma patients with elevated NO-values if they had taken any selective inhibitor of the cGMP-specific phosphodiesterase Type 5 as Sildenafil prior to the test.

Development and validation of the Asthma Life Impact Scale (ALIS) - Corrected Proof

2010-01-07

Summary: Background: Current asthma patient-reported outcome (PRO) measures focus on symptoms and functioning and may not capture the holistic impact of asthma on the quality of life of the patient.Objective: To develop a PRO measure capturing the overall impact of asthma on patient's quality of life.Methods: Items for the Asthma Life Impact Scale (ALIS) were generated from patients with asthma during interviews in the UK and focus groups in the US. The ALIS was tested with UK and US asthma patients during cognitive debriefing interviews and included in large, two-administration, validation studies in the UK and US.Results: Issues raised by asthma patients during interviews (n = 39 patients) and focus groups (n = 16 patients) were included in the draft ALIS. Cognitive debriefing interviews with 29 UK and US asthma patients showed that the scale was relevant and comprehensive. 140 UK and 185 US asthma patients participated in the validation study. The analysis showed that the ALIS measures a single construct, namely the overall impact of asthma on patients' quality of life. Internal consistency (Cronbach's Alpha) was high (UK = 0.94; US = 0.92) as was test-retest reliability (UK = 0.93; US = 0.83). Patients reporting worse general health or more severe asthma had significantly higher ALIS scores (p < 0.001) (indicating greater negative impact of asthma). Correlations with the Asthma Quality of Life Questionnaire were moderate to high.Conclusions: The final 22-item ALIS is unidimensional, reliable and valid, and a valuable tool for comprehensively assessing the holistic impact of asthma from the patient's perspective.

Correlation between airflow limitation and airway dimensions assessed by multidetector CT in asthma - Corrected Proof

2010-01-06

Summary: Background: Asthma is characterized by variable airflow obstruction and airway wall thickening. Multidetector-row computed tomography (MDCT) is useful for the evaluation of airway wall structural changes in asthma. The objective of the study is to assess the relationship between airflow limitation and airway dimensions from the third to fifth generation bronchi in asthma using MDCT.Methods: Thirty-eight subjects with asthma underwent MDCT to measure the airway wall area (WA) and luminal area (Ai), WA and Ai corrected by body surface area (BSA), up to the fifth generation of the apical bronchus (B1) and the posterior basal bronchus (B10) of the right lung.Results: WA/BSA, WA percentage (WA%) and Ai/BSA in the fifth generation were significantly correlated with forced expiratory volume in 1 s (FEV1)% predicted. The correlation coefficients between WA% and FEV1% predicted increased when tracking the airways from the third to the fifth generation (r=−0.25, p>0.05; r=−0.40, p<0.01; r=−0.63, p<0.001 for B1; r=−0.23, p>0.05; r=−0.47, p<0.01; r=−0.69, p<0.001 for B10). At the generation 5, WA% was greater and Ai/BSA was smaller in severe asthma than mild-to-moderate asthma.Conclusion: These results suggest that airway flow limitation in asthma is closely related to the more distal airways (third to fifth generation).

Spirometry guidelines influence lung function results in a longitudinal study of young adults - Corrected Proof

2010-01-04

Summary: Rationale: End of test criteria can influence spirometry results. Epidemiology studies initiated before adoption of the 1987 American Thoracic Society (ATS) guidelines typically used a 1 or 2 s plateau on the volume-time curve, not a minimum test duration of 6 s, to terminate a test.Objectives: To determine the effect of changing guidelines on FEV1, FVC and FEV1/FVC during a longitudinal study of young adults.Methods: Spirometry was performed on participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Values obtained at entry and 2, 5 and 10 years later using accepted procedures were re-evaluated using the 2005 ATS–ERS guidelines, which were in effect for the year 20 exam. Generalized estimating equations were used to adjust tests with short exhalations that were acceptable by then current end of test criteria.Results: The percentage of participants at years 0, 2, 5, and 10 with exhalations less than 6 s but with an acceptable plateau was 33%, 29%, 9%, and 2%, respectively. Exhalations less than 6 s occurred more frequently in younger and female participants, and were associated with lower FVC and higher FEV1/FVC. For short exhalations the adjusted FVC was 47 ml and 110 ml higher than the measured FVC when 6 and 8 s exhalation times were used.Conclusions: In longitudinal studies of young adults, changing end of test criteria may affect lung function, especially among younger and female participants. Determining adjusted values for tests with short exhalations may better represent the lung health of participants.

Bronchodilatory effects of aclidinium bromide, a long-acting muscarinic antagonist, in COPD patients - Corrected Proof

2009-12-31

Abstract: Background: Aclidinium bromide is a novel, long-acting, inhaled muscarinic antagonist bronchodilator currently in Phase III clinical development for the treatment of chronic obstructive pulmonary disease (COPD). This study evaluated the pharmacodynamics, pharmacokinetics, safety and tolerability of ascending doses of aclidinium bromide in patients with COPD.Methods: This double-blind, randomised, placebo-controlled, crossover study was conducted in patients with moderate to severe COPD (forced expiratory volume in 1s [FEV1] <65% predicted). Patients were randomly assigned to one of four treatment sequences of aclidinium bromide 100, 300, 900μg and placebo with a washout period between doses. The primary outcome was area under the FEV1 curve over the 0–24h time interval.Results: Seventeen patients with COPD were studied. Mean FEV1 over 24h was 1.583L for placebo, and 1.727L, 1.793L and 1.815L for aclidinium bromide 100, 300 and 900μg, respectively (p<0.001 vs. placebo, all doses). Significant changes from baseline in FEV1 were detected 15min post-dose for aclidinium bromide 300 and 900μg, with a peak effect 2h post-dose (all doses). Aclidinium bromide was undetected in plasma. The majority of adverse events was unrelated to study medication and did not result in discontinuation.Conclusion: Aclidinium bromide 100–900μg produced sustained bronchodilation over 24h in patients with COPD.

Comparison of eNO and histamine hyperresponsiveness in diagnosing asthma in new referrals - Corrected Proof

P. Munnik, I. van der Lee, J. Fijn, L.J. van Eijsden, J-W.J. Lammers, P. Zanen — 2009-12-28

Summary: The mainstay of the diagnosis of asthma is the presence of reversible airway obstruction. Exhaled NO levels are increased in asthma, in close relationship with the amount of airway inflammation, and may be used for monitoring the disease and adjusting therapy. In this study we investigated the role of eNO as a diagnostic for asthma, compared with the FEV1-reversibility and the PC20 (20% decrease of the FEV1 in the bronchial histamine provocation test), in two independent centers, on an unselected population. ENO measurements were performed with chemoluminesence technique in one center and with an electrochemical device in the other. Only after correction for so-called nuisance factors (allergy, use of inhaled steroids, recent infection, smoking, sex and the use of nitrate food) the eNO appeared as a diagnostic with equal power as the FEV1-reversibility and the PC20.Therefore, screening for asthma in our study population, with the eNO measurement, is a simple, fast and safe strategy.

Gender influences health-related Quality of Life in IPF - Corrected Proof

2009-12-25

Summary: Background: HRQL in IPF patients is impaired. Data from other respiratory diseases led us to hypothesize that significant gender differences in HRQL in IPF also exist.Methods: Data were drawn from the NIH-sponsored Lung Tissue Research Consortium (LTRC). Demographic and pulmonary physiology data along with MMRC, SF-12, and SGRQ scores from women vs. men were compared with two-sample t-tests. Multivariate linear regression was used to examine the association between SF-12 component scores and gender while adjusting for other relevant variables.Results: The study sample consisted of 147 men and 74 women. Among several baseline variables, only DLCO% predicted differed between women and men, (43.7 vs. 38.0, p=0.03). In general, men exhibited lower (better) MMRC scores (1.7 vs. 2.4, p=0.02), particularly those with milder disease as measured by DLCO% predicted. In an adjusted analysis, SF-12 PCS scores in men were lower (worse) than women (p=0.01), an effect that was more pronounced in men with greater dyspnea scores. In a similar analysis, SF-12 MCS scores in women were lower than men (worse) (48.3 vs. 54.4, p=0.0004), an effect that was more pronounced in women with greater dyspnea scores.Conclusions: Significant gender differences in HRQL exist in IPF. As compared to women, men reported less severe dyspnea, had worse SF-12 PCS scores, but better SF-12 MCS scores. Dyspnea appears to have a greater impact on the physical HRQL of men and the emotional HRQL of women. An improved understanding of the mechanism behind these differences is needed to better target interventions.

Add-on montelukast in inadequately controlled asthma patients in a 6-month open-label study: The MONtelukast In Chronic Asthma (MONICA) study - Corrected Proof

2009-12-23

Summary: Bronchial asthma often remains uncontrolled despite treatment with inhaled corticosteroids (ICS), long-acting β2-agonists (LABA) or both, necessitating additional treatment. Patients ≥18years (n=1681) with mild-to-moderate asthma received oral montelukast 10mg added to ICS or ICS+LABAs, and were followed for 6months in a prospective, open-label observational study. The primary endpoint was change in Asthma Control Test (ACT) score. Secondary endpoints included mini-Asthma Quality-of-Life Questionnaire (mini-AQLQ) and FEV1/PEF. Mean ACT scores improved from 14.6±4.6 (baseline) to 19.4±4.4 (month 6; p<0.0001). Using ACT score categories, the percentage of patients with uncontrolled (57.5%) or poorly controlled (25.0%) asthma at baseline decreased at month 6 (17.6 and 21.7%, respectively); the percentage of patients with well controlled (13.9%) or completely controlled (1.2%) asthma at baseline increased at month 6 (47.5 and 11.4%, respectively). The mini-AQLQ score (mean±SD) improved from 4.0±1.1 to 5.3±1.1 (p<0.0001); FEV1 increased from 2.46±0.89 to 2.60±0.92L (p<0.0001). Treatment with montelukast was generally well tolerated. In patients insufficiently controlled with ICS or ICS+LABAs, daily add-on montelukast improved both asthma control and asthma-related quality of life. Clinicaltrials.gov registry number NCT00802789.

Association of the CCR3 gene polymorphism with aspirin exacerbated respiratory disease - Corrected Proof

2009-12-21

Summary: Introduction: Aspirin hypersensitivity represents two distinct clinical syndromes, such as aspirin exacerbated respiratory disease (AERD) and aspirin-intolerant chronic urticaria/angioedema (AICU) which have different clinical phenotypes resulting from different genetic backgrounds in a Korean population. Persistent eosinophilic inflammation in airway is a characteristic feature of AERD and chemokine CC motif receptor 3 (CCR3) plays an important role in eosinophilic infiltration into the asthmatic airway.Objectives: The main objective of this study is to investigate the association between CCR3 gene polymorphisms and aspirin hypersensitivity, including AERD and AICU.Methods: CCR3 mRNA expression was measured after an aspirin provocation test by real-time PCR. In total, 330 patients with aspirin hypersensitivity (191 AERD and 139 AICU) and 217 normal healthy controls (NC) were genotyped for two CCR3 promoter polymorphisms (-520T/G and -174C/T), and the functional effects of the polymorphisms were analyzed applying a luciferase reporter assay and an electrophoretic mobility shift assay.Results: CCR3 mRNA expression was significantly increased after aspirin provocation in AERD patients (P=0.002) but not in AICU patients. An in vitro functional study showed that the reporter construct having a -520G allele exhibited significantly higher promoter activity compared with the construct having a -520T allele in human myeloid (U937), lymphoid (Jurkat), and mast (HMC-1) cell lines (P<0.001). We found -520G and -174T specific bands on EMSA.Conclusion: This result suggests that the CCR3 genetic polymorphisms may contribute to the development of the AERD phenotype and may be used as a genetic marker for differentiating between the two major aspirin hypersensitivity phenotypes.

Co-existence of COPD and left ventricular dysfunction in vascular surgery patients - Corrected Proof

2009-12-14

Summary: Background: The co-existence between chronic obstructive pulmonary disease (COPD) and heart failure has been previously described. However, the co-existence between COPD and subclinical left ventricular (LV) dysfunction, without the presence of heart failure symptoms, is less well understood. This study determined the relationship and clinical relevance of COPD and subclinical LV dysfunction in vascular surgery patients.Methods: 1005 consecutive vascular surgery patients were included in which COPD was determined using spirometry and LV function using echocardiography. Mild COPD was defined as FEV1≥80% of predicted+FEV1/FVC-ratio<0.70. Moderate/severe COPD was defined as FEV1<80% of predicted+FEV1/FVC-ratio<0.70. Systolic LV dysfunction was defined as LV ejection fraction <50% and diastolic LV dysfunction was diagnosed based on E/A-ratio, pulmonary vein flow and deceleration time. Multivariate regression analyses were used to evaluate the impact of COPD and LV dysfunction on all-cause mortality. The mean follow-up time was 2.2±1.8 years.Results: Both, mild and moderate/severe COPD were associated with increased risk for subclinical LV dysfunction with odds ratio of 1.6 (95%-CI=1.1–2.3) and 1.7 (95%-CI=1.2–2.4), respectively. mild- or moderate/severe COPD in combination with LV dysfunction was associated with increased risk for all-cause mortality (mild: hazard ratio 1.7; 95%-CI=1.1–3.6, moderate/severe: hazard ratio 2.5; 95%-CI=1.5–4.7).Conclusions: COPD was associated with increased risk for subclinical LV dysfunction. COPD+subclinical LV dysfunction was associated with increased risk for all-cause mortality compared to patients with COPD+normal LV function. Echocardiography may be useful to detect subclinical cardiovascular disease and risk-stratify COPD patients undergoing vascular surgery.

Chronic cough in upper airway diseases - Corrected Proof

J.B. Watelet, T. Van Zele, G. Brusselle — 2009-12-14

Summary: Background: The epidemiological, pathophysiological and clinical links between upper and lower airways are nowadays clearly demonstrated. Most of asthmatics are suffering from rhinitis while up to 40% of rhinitic patients have asthma. Asthmatics and COPD patients are also prone to develop concomitant chronic rhinosinusitis (CRS).This study aimed to determine the predictive value of cough for concomitant asthma in patients suffering from upper airway diseases.Methods: This cross-sectional study described a group of 143 consecutive patients suffering simultaneously from common upper and lower airway disorders. Both ENT-specialists and respiratory physicians consecutively examined the patients in Ghent University Hospital from October 2004 till October 2006. This study was based on the demographic characteristics, upper and lower airway conditions.Results: Forty-seven percent of the patients included in the study were males and the mean age of studied population was 43.6years. The major complaint was chronic cough. When present, patients with chronic cough have an increased risk of suffering from a concomitant asthma in both allergic rhinitis (OR=5.8) and CRS with nasal polyps (OR=10.4), but not in CRS without polyps.Conclusions: Chronic cough was found to be a key symptom of associated asthma in allergic rhinitis and CRS with nasal polyps. Interestingly, chronic cough in CRS without nasal polyps did not show the same predictive value: this suggests different pathophysiological mechanisms.

Plasma ammonia response to incremental cycling and walking tests in COPD - Corrected Proof

L.D. Calvert, M.C. Steiner, M.D. Morgan, S.J. Singh — 2009-12-09

Summary: Objective: It is well documented that plasma ammonia accumulates during exercise under conditions of metabolic stress. Metabolic stress (when skeletal muscle ATP supply fails to meet demand) occurs at low work rates during cycling in patients with COPD, but not been described during walking. Walking is an important activity for many patients with COPD and is commonly prescribed in pragmatic outpatient pulmonary rehabilitation programmes. In this study we explored whether metabolic stress occurs during incremental walking at the low work rates these patients achieve.Methods: Twenty-nine subjects with stable COPD [mean(SD) age 68(7)years, FEV1 50(19)% predicted] performed maximal cardiopulmonary exercise tests on a cycle ergometer and treadmill. Plasma ammonia concentration was measured at rest, 1 and 2min of exercise, peak exercise and 2min recovery.Results: Subjects achieved mean(SD) cycle work rate of 57(20)W with VO2max 15.5(4.6)ml/min per kg, and treadmill distance 284(175)m with VO2peak 16.8(4.2)ml/min per kg. Plasma ammonia concentration rose significantly (p<0.001) with walking [mean(SEM) change 24.7(3.8)μmol/l] and cycling [mean(SEM) change 35.2(4.3)μmol/l], but peak exercise ammonia was lower in walking (p<0.01). In a subgroup of subjects (n=7) plasma ammonia did not rise during either cycling or walking despite similar lactate rise and peak exercise indices.Conclusion: Our data indicate that failure of muscle ATP re-synthesis to meet demand and development of metabolic stress can occur during walking in COPD patients at the low work rates these patients achieve. This may therefore be a factor contributing to exercise limitation independent of ventilatory limitation.

Emitted dose and lung deposition of inhaled terbutaline from Turbuhaler at different conditions - Corrected Proof

Mohamed E. Abdelrahim — 2009-12-09

Summary: Turbuhaler has a very high resistance hence patient inhalation flow when using it would be low.The total emitted dose (TED) of 500μg terbutaline sulphate from a Bricanyl Turbuhaler was determined using a range of inhalation flows (10–60L min−1) with inhalation volume of 2 and 4L using a DPI sampling apparatus after one and two inhalations.The relative lung and systemic bioavailability of terbutaline from Bricanyl Turbuhaler when used by healthy subjects and COPD patients were determined after one and two inhalations at slow and fast inhalation flows using a novel urinary terbutaline pharmacokinetic method.The TED resulted from the one and two inhalations increased significantly (p<0.05) with the increase of the inhalation flow at both 2 and 4L inhalation volumes. The relative lung and systemic bioavailability after one inhalation at fast inhalation flow were significantly higher (p<0.01) than at slow inhalation flow in both healthy subjects and patients. Also the healthy subjects results were significantly higher (p<0.05) than the COPD patients after one inhalation.However after two inhalations there was no significant difference between slow and fast inhalation flow or healthy subjects and COPD patients.Hence it is essential to inhale twice and as deep and hard as possible from each dose of Turbuhaler for patients with low inspiratory flow and limited inhalation volume as they may not receive much benefit from one inhalation.

Economic implications of comorbid conditions among Medicaid beneficiaries with COPD - Corrected Proof

Pei-Jung Lin, Fadia T. Shaya, Steven M. Scharf — 2009-12-03

Summary: Objectives: To characterize a comprehensive comorbidity profile and to explore the economic implications of comorbidity among patients with chronic obstructive pulmonary disease (COPD).Methods: This retrospective cohort study analyzed medical claims from the Maryland Medicaid database. We employed a 1:2 case–control design to select COPD patients (n=1388) and demographically matched controls (n=2776) aged 40 to 64 years with 24 months of continuous enrollment. Odds ratios were employed to compare comorbidity differences, including 17 conditions defined by the Charlson Comorbidity Index (CCI) and 6 additional conditions commonly observed in COPD patients. We estimated the incremental medical utilization and medical cost by specific condition.Results: Compared with the controls, Medicaid COPD patients had higher comorbidity burden and were more likely to have myocardial infarction, congestive heart failure, cerebrovascular disease, peptic ulcer, mild liver disease, hypertension, sleep apnea, tobacco use, and edema. COPD patients on average had 24% more medical claims (81.4 vs. 65.4, p<0.001) and were 33% more expensive than controls ($7603 vs. $5732, p<0.001). Ten conditions defined by the CCI as well as hypertension, tobacco use, and edema were associated with incremental medical utilization and cost in COPD patients; depression was associated with incremental medical utilization but not cost.Conclusions: The high burden of comorbidity in COPD patients translates into additional medical utilization and cost. Effective disease management and treatment protocols are needed to reduce comorbidity burden. The development of a COPD-specific comorbidity measure may be used to identify high-risk subgroups and to predict utilization and cost.