Showing papers in "Thorax in 2002"

Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease

Abstract: BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterised by both an accelerated decline in lung function and periods of acute deterioration in symptoms termed exacerbations. The aim of this study was to investigate whether these are related. METHODS: Over 4 years, peak expiratory flow (PEF) and symptoms were measured at home daily by 109 patients with COPD (81 men; median (IQR) age 68.1 (63-74) years; arterial oxygen tension (PaO(2)) 9.00 (8.3-9.5) kPa, forced expiratory volume in 1 second (FEV(1)) 1.00 (0.7-1.3) l, forced vital capacity (FVC) 2.51 (1.9-3.0) l); of these, 32 (29 men) recorded daily FEV(1). Exacerbations were identified from symptoms and the effect of frequent or infrequent exacerbations (> or < 2.92 per year) on lung function decline was examined using cross sectional, random effects models. RESULTS: The 109 patients experienced 757 exacerbations. Patients with frequent exacerbations had a significantly faster decline in FEV(1) and peak expiratory flow (PEF) of -40.1 ml/year (n=16) and -2.9 l/min/year (n=46) than infrequent exacerbators in whom FEV(1) changed by -32.1 ml/year (n=16) and PEF by -0.7 l/min/year (n=63). Frequent exacerbators also had a greater decline in FEV(1) if allowance was made for smoking status. Patients with frequent exacerbations were more often admitted to hospital with longer length of stay. Frequent exacerbations were a consistent feature within a patient, with their number positively correlated (between years 1 and 2, 2 and 3, 3 and 4). CONCLUSIONS: These results suggest that the frequency of exacerbations contributes to long term decline in lung function of patients with moderate to severe COPD.

Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids

Abstract: Background: The debate as to whether asthma is a single or heterogeneous disease remains unresolved although pathological studies, mostly using fibreoptic bronchoscopy on small numbers of subjects, have emphasised the similarities between different clinical phenotypes. Methods: Lower airway inflammation was assessed non-invasively using induced sputum in 34 normal controls and 259 adults with symptomatic asthma receiving treatment at steps 1–3 of the British Thoracic Society (BTS) guidelines. A subgroup of 49 patients treated with as required s2 agonists only who met BTS criteria for a step up in treatment were studied before and 2 months after treatment with inhaled budesonide 400 µg twice daily. Results: There was considerable heterogeneity in induced sputum cell counts, particularly in non-atopic patients. A subgroup of 60 patients had a distinctive sputum cell profile with a neutrophil count higher than our normal range (>65.3%) and a normal sputum eosinophil count (<1.9%). These patients were older, predominantly female, and were more likely to be non-atopic but otherwise had similar clinical and physiological features to the group as a whole. Among the 49 subjects studied before and after inhaled budesonide, 11 patients had an isolated sputum neutrophilia. Following treatment, these patients showed significantly less improvement in visual analogue symptom scores (–5.5 v –19.4 mm; mean difference 13.9; 95% CI 0.7 to 27.0), forced expiratory volume in 1 second (FEV1) (–0.08 v 0.13 l; mean difference 0.21; 95% CI 0.03 to 0.39), and concentration of methacholine provoking a fall in FEV1 of 20% or more (PC20) (0.15 v 1.29 doubling doses; mean difference 1.11; 95% CI 0.13 to 2.15) than the remaining 38 patients. Conclusions: These results suggest the presence of a distinct subgroup of patients with mild to moderate asthma who have predominantly neutrophilic airway inflammation and who respond less well to treatment with inhaled corticosteroids.

Relationship between bacterial colonisation and the frequency, character, and severity of COPD exacerbations

Abstract: Background: Patients with chronic obstructive pulmonary disease (COPD) are prone to frequent exacerbations which are a significant cause of morbidity and mortality. Stable COPD patients often have lower airway bacterial colonisation which may be an important stimulus to airway inflammation and thereby modulate exacerbation frequency. Methods: Twenty nine patients with COPD (21 men, 16 current smokers) of mean (SD) age 65.9 (7.84) years, forced expiratory volume in 1 second (FEV1) 1.06 (0.41) l, FEV1 % predicted 38.7 (15.2)%, FEV1/FVC 43.7 (14.1)%, inhaled steroid dosage 1.20 (0.66) mg/day completed daily diary cards for symptoms and peak flow over 18 months. Exacerbation frequency rates were determined from diary card data. Induced sputum was obtained from patients in the stable state, quantitative bacterial culture was performed, and cytokine levels were measured. Results: Fifteen of the 29 patients (51.7%) were colonised by a possible pathogen: Haemophilus influenzae (53.3%), Streptococcus pneumoniae (33.3%), Haemophilus parainfluenzae (20%), Branhamella catarrhalis (20%), Pseudomonas aeruginosa (20%). The presence of lower airway bacterial colonisation in the stable state was related to exacerbation frequency (p=0.023). Patients colonised by H influenzae in the stable state reported more symptoms and increased sputum purulence at exacerbation than those not colonised. The median (IQR) symptom count at exacerbation in those colonised by H influenzae was 2.00 (2.00–2.65) compared with 2.00 (1.00–2.00) in those not colonised (p=0.03). The occurrence of increased sputum purulence at exacerbation per patient was 0.92 (0.56–1.00) in those colonised with H influenzae and 0.33 (0.00–0.60) in those not colonised (p=0.02). Sputum interleukin (IL)-8 levels correlated with the total bacterial count (rho=0.459, p=0.02). Conclusion: Lower airway bacterial colonisation in the stable state modulates the character and frequency of COPD exacerbations.

Non-eosinophilic asthma: importance and possible mechanisms

Abstract: There is increasing evidence that inflammatory mechanisms other than eosinophilic inflammation may be involved in producing the final common pathway of enhanced bronchial reactivity and reversible airflow obstruction that characterises asthma. A review of the literature has shown that, at most, only 50% of asthma cases are attributable to eosinophilic airway inflammation. It is hypothesised that a major proportion of asthma is based on neutrophilic airway inflammation, possibly triggered by environmental exposure to bacterial endotoxin, particulate air pollution, and ozone, as well as viral infections. If there are indeed two (or more) subtypes of asthma, and if non-eosinophilic (neutrophil mediated) asthma is relatively common, this would have major consequences for the treatment and prevention of asthma since most treatment and prevention strategies are now almost entirely focused on allergic/eosinophilic asthma and allergen avoidance measures, respectively. It is therefore important to study the aetiology of asthma further, including the underlying inflammatory profiles.

A systematic review of the use of opioids in the management of dyspnoea

Abstract: Background Opioids are commonly used to treat dyspnoea in palliative medicine but there has been no formal evaluation of the evidence for their effectiveness in the treatment of dyspnoea. A systematic review was therefore carried out to examine this. Methods The criteria for inclusion required that studies were double blind, randomised, placebo controlled trials of opioids for the treatment of dyspnoea secondary to any cause. The methods used to identify suitable studies included electronic searching of the literature, hand searching of the literature, and personal contact with relevant individuals and organisations. Random effects meta-analyses were performed on all included studies and on various subgroups (studies involving nebulised opioids or patients with chronic obstructive pulmonary disease (COPD)). Subgroups were compared using meta-regression. Some studies included in the systematic review could not be included in the meta-analysis because insufficient data were presented. Results Eighteen studies fulfilled the criteria for the review. The meta-analysis showed a statistically significant positive effect of opioids on the sensation of breathlessness (p=0.0008). Meta-regression indicated a greater effect for studies using oral or parenteral opioids than for studies using nebulised opioids (p=0.02). The subgroup analysis failed to show a positive effect of nebulised opioids on the sensation of breathlessness. The results of the subgroup analysis of the COPD studies were essentially similar to the results of the main analysis. Conclusion This review supports the continued use of oral and parenteral opioids to treat dyspnoea in patients with advanced disease. There are insufficient data from the meta-analysis to conclude whether nebulised opioids are effective, but the results from included studies that did not contribute to the meta-analysis suggest that they are no better than nebulised normal saline.

Influence of cigarette smoking on inhaled corticosteroid treatment in mild asthma

Abstract: Background: Although inhaled corticosteroids have an established role in the treatment of asthma, studies have tended to concentrate on non-smokers and little is known about the possible effect of cigarette smoking on the efficacy of treatment with inhaled steroids in asthma. A study was undertaken to investigate the effect of active cigarette smoking on responses to treatment with inhaled corticosteroids in patients with mild asthma. Methods: The effect of treatment with inhaled fluticasone propionate (1000 μg daily) or placebo for 3 weeks was studied in a double blind, prospective, randomised, placebo controlled study of 38 steroid naive adult asthmatic patients (21 non-smokers). Efficacy was assessed using morning and evening peak expiratory flow (PEF) readings, spirometric parameters, bronchial hyperreactivity, and sputum eosinophil counts. Comparison was made between responses to treatment in non-smoking and smoking asthmatic patients. Results: There was a significantly greater increase in mean morning PEF in non-smokers than in smokers following inhaled fluticasone (27 l/min v –5 l/min). Non-smokers had a statistically significant increase in mean morning PEF (27 l/min), mean forced expiratory volume in 1 second (0.17 l), and geometric mean PC20 (2.6 doubling doses), and a significant decrease in the proportion of sputum eosinophils (–1.75%) after fluticasone compared with placebo. No significant changes were observed in the smoking asthmatic patients for any of these parameters. Conclusions: Active cigarette smoking impairs the efficacy of short term inhaled corticosteroid treatment in mild asthma. This finding has important implications for the management of patients with mild asthma who smoke.

A meta-analysis of the effect of Bacille Calmette Guérin vaccination on tuberculin skin test measurements

Abstract: Background: The accurate diagnosis of latent tuberculosis infection (LTBI) is an important component of any tuberculosis control programme and depends largely on tuberculin skin testing. The appropriate interpretation of skin test results requires knowledge of the possible confounding factors such as previous BCG vaccination. Uncertainty about the effect of BCG vaccination on tuberculin skin testing and the strength with which recommendations are made to individual patients regarding treatment of LTBI have identified a need to analyse the available data on the effect of BCG on skin testing. A meta-analysis of the evidence for the effect of BCG vaccination on tuberculin skin testing in subjects without active tuberculosis was therefore performed. Methods: Medline was searched for English language articles published from 1966 to 1999 using the key words “BCG vaccine”, “tuberculin test/PPD”, and “skin testing”. Bibliographies of relevant articles were reviewed for additional studies that may have been missed in the Medline search. Articles were considered for inclusion in the meta-analysis if they had recorded tuberculin skin test results in subjects who had received BCG vaccination more than 5 years previously and had a concurrent control group. Only prospective studies were considered. The geographical location, number of participants, type of BCG vaccine used, type of tuberculin skin test performed, and the results of the tuberculin skin test were extracted. Results: The abstracts and titles of 980 articles were identified, 370 full text articles were reviewed, and 26 articles were included in the final analysis. Patients who had received BCG vaccination were more likely to have a positive skin test (5 TU PPD: relative risk (RR) 2.12 (95% confidence interval (CI)1.50 to 3.00); 2 TU RT23: 26.50 (95% CI 1.83 to 3.85). The effect of BCG vaccination on PPD skin test results was less after 15 years. Positive skin tests with indurations of >15 mm are more likely to be the result of tuberculous infection than of BCG vaccination. Conclusions: In subjects without active tuberculosis, immunisation with BCG significantly increases the likelihood of a positive tuberculin skin test. The interpretation of the skin test therefore needs to be made in the individual clinical context and with evaluation of other risk factors for infection. The size of the induration should also be considered when making recommendations for treatment of latent infection.

Effect of long term treatment with azithromycin on disease parameters in cystic fibrosis: A randomised trial

Abstract: Background: Relentless chronic pulmonary inflammation is the major contributor to morbidity and mortality in patients with cystic fibrosis (CF). While immunomodulating therapies such as prednisolone and ibuprofen may be beneficial, their use is limited by side effects. Macrolides have immunomodulatory properties and long term use dramatically improves prognosis in diffuse panbronchiolitis, a condition with features in common with the lung disease of CF. Methods: To determine if azithromycin (AZM) improves clinical parameters and reduces inflammation in patients with CF, a 3 month prospective randomised double blind, placebo controlled study of AZM (250 mg/day) was undertaken in adults with CF. Monthly assessment included lung function, weight, and quality of life (QOL). Blood and sputum collection assessed systemic inflammation and changes in bacterial flora. Respiratory exacerbations were treated according to the policy of the CF Unit. Results: Sixty patients were recruited (29 men) of mean (SD) age 27.9 (6.5) years and initial forced expiratory volume in 1 second (FEV1) 56.6 (22.3)% predicted. FEV1% and forced vital capacity (FVC)% predicted were maintained in the AZM group while in the placebo group there was a mean (SE) decline of –3.62 (1.78)% (p=0.047) and –5.73 (1.66)% (p=0.001), respectively. Fewer courses of intravenous antibiotics were used in patients on AZM (0.37 v 1.13, p=0.016). Median C reactive protein (CRP) levels declined in the AZM group from 10 to 5.4 mg/ml but remained constant in the placebo group (p<0.001). QOL improved over time in patients on AZM and remained unchanged in those on placebo (p=0.035). Conclusion: AZM in adults with CF significantly improved QOL, reduced CRP levels and the number of respiratory exacerbations, and reduced the rate of decline in lung function. Long term AZM may have a significant impact on morbidity and mortality in patients with CF. Further studies are required to define frequency of dosing and duration of benefit.

Airway inflammation, basement membrane thickening and bronchial hyperresponsiveness in asthma

Abstract: Background: There are few data in asthma relating airway physiology, inflammation and remodelling and the relative effects of inhaled corticosteroid (ICS) treatment on these parameters. A study of the relationships between spirometric indices, airway inflammation, airway remodelling, and bronchial hyperreactivity (BHR) before and after treatment with high dose inhaled fluticasone propionate (FP 750 μg bd) was performed in a group of patients with relatively mild but symptomatic asthma. Methods: A double blind, randomised, placebo controlled, parallel group study of inhaled FP was performed in 35 asthmatic patients. Bronchoalveolar lavage (BAL) and airway biopsy studies were carried out at baseline and after 3 and 12 months of treatment. Twenty two normal healthy non-asthmatic subjects acted as controls. Results: BAL fluid eosinophils, mast cells, and epithelial cells were significantly higher in asthmatic patients than in controls at baseline (p 20 improved throughout the study. BAL inflammatory cells decreased following 3 months of treatment with no further improvement at 12 months (p v placebo). Rbm thickness decreased in the FP group, but only after 12 months of treatment (mean change –1.9, 95% CI –3 to –0.7 μm; p v baseline, p v placebo). A third of the improvement in BHR with FP was associated with early changes in inflammation, but the more progressive and larger improvement was associated with the later improvement in airway remodelling. Conclusion: Physiology, airway inflammation and remodelling in asthma are interrelated and improve with ICS. Changes are not temporally concordant, with prolonged treatment necessary for maximal benefit in remodelling and PD 20 . Determining the appropriate dose of inhaled steroids only by reference to symptoms and lung function, as specified in current international guidelines, and even against indices of inflammation may be over simplistic. The results of this study support the need for early and long term intervention with ICS, even in patients with relatively mild asthma.

Risk of depression in patients with chronic obstructive pulmonary disease and its determinants

Abstract: Background: Although it has been repeatedly suggested that chronic obstructive pulmonary disease (COPD) is associated with depression, no conclusion has so far been reached. A study was undertaken to investigate whether depression occurs more often in patients with COPD than in controls. The demographic and clinical variables associated with depression were also determined. Methods: Patients with a registered diagnosis of obstructive airway disease in general practice, aged ≥40 years, forced expiratory volume in 1 second (FEV1) <80% predicted, FEV1 reversibility ≤12%, FEV1/VC ≤ predicted – 1.64 x SD, and a history of smoking were selected. A random sample of subjects without a registered diagnosis of asthma or COPD aged 40 years or older acted as controls. Depression was assessed using the Centers for Epidemiologic Studies Depression (CES-D) scale. Results: In patients with severe COPD (FEV1 <50% predicted), the prevalence of depression was 25.0% compared with 17.5% in controls and 19.6% in patients with mild to moderate COPD. When the results were adjusted for demographic variables and comorbidity, the risk for depression was 2.5 times greater for patients with severe COPD than for controls (OR 2.5, 95% CI 1.2 to 5.4). In patients with mild to moderate COPD this increased risk of depression was not seen. Living alone, reversibility of FEV1 % predicted, respiratory symptoms and physical impairment were significantly associated with the scores on the CES-D scale. Conclusion: Patients with severe COPD are at increased risk of developing depression. The results of this study underscore the importance of reducing symptoms and improving physical functioning in patients with COPD.

beta-Actin and GAPDH housekeeping gene expression in asthmatic airways is variable and not suitable for normalising mRNA levels.

Abstract: Background: The use of reverse transcription-polymerase chain reaction (RT-PCR) to measure mRNA levels has led to the common use of β-actin and GAPDH housekeeping genes as denominators for comparison of samples Expression of these genes is assumed to remain constant, so normalising for variations in processing and signal quantitation However, it is well documented that β-actin and GAPDH expression is upregulated with proliferation, activation, and differentiation We hypothesised that airway samples which differ in their cellular profiles and activation status have different levels of expression of GAPDH and β-actin Methods: The mRNA for β-actin, GAPDH, and interleukin (IL)-2 was measured in bronchoalveolar lavage (BAL) fluid cells and endobronchial biopsy tissue by competitive RT-PCR in a cross sectional study of 26 normal controls and 92 asthmatic subjects Results: For both BAL fluid cells and biopsy tissue, asthmatics overall had reduced expression of GAPDH and β-actin mRNA In asthmatic subjects not using inhaled corticosteroids (ICS), GAPDH mRNA levels in both BAL fluid and biopsy tissue, and β-actin mRNA in BAL fluid cells were 10 times lower than samples from both normal controls and from asthmatic subjects using ICS β-Actin mRNA in biopsy specimens showed the same pattern of expression, but asthmatic subjects not using ICS were not significantly different from those receiving ICS treatment IL-2 mRNA levels did not differ between the subject or treatment groups but, when expressed as a ratio with β-actin, significant differences were seen Conclusions: β-Actin and GAPDH used as denominators of gene expression quantitation in asthma research can cause confounding Housekeeping genes need careful validation before their use in such quantitative mRNA assays

Increased levels of the chemokines GROalpha and MCP-1 in sputum samples from patients with COPD.

Abstract: Background: Patients with chronic obstructive pulmonary disease (COPD) have increased numbers of neutrophils and macrophages in their lungs. Growth related oncogene-α (GROα) attracts neutrophils, whereas monocyte chemoattractant protein-1 (MCP-1) attracts monocytes that can differentiate into macrophages. The aim of this study was to determine the concentration of GROα and MCP-1 in bronchoalveolar lavage (BAL) fluid and sputum from non-smokers, healthy smokers and patients with COPD, and to see if there was a correlation between the concentrations of these chemokines, lung function, and numbers of inflammatory cells. Methods: BAL fluid and sputum from non-smokers (n=32), healthy smokers (n=36), and patients with COPD (n=40) were analysed for the presence of GROα and MCP-1 using ELISA. Cells counts were performed on the samples and correlations between the concentrations of these chemokines, lung function, and inflammatory cells observed. Results: Median (SE) GROα and MCP-1 levels were significantly increased in sputum from patients with COPD compared with non-smokers and healthy smokers (GROα: 31 (11) v 2 (2) v 3 (0.8) ng/ml; MCP-1: 0.8 (0.4) v 0.2 (0.1) v 0.1 (0.04) ng/ml, p<0.05), but not in BAL fluid. There were significant negative correlations between both GROα and MCP-1 levels in sputum and forced expiratory volume in 1 second (FEV1) % predicted (GROα: r=–0.5, p<0.001; MCP-1: r=–0.5, p<0.001), together with significant positive correlations between GROα and MCP-1 and neutrophil numbers in sputum (GROα: r=0.6, p<0.001; MCP-1: r=0.4, p<0.01). Conclusion: These results suggest that GROα and MCP-1 are involved in the migration of inflammatory cells, thus contributing to the inflammatory load associated with COPD.

Differentiation of bacterial and viral pneumonia in children

Abstract: Background A study was undertaken to investigate the differential diagnostic role of chest radiographic findings, total white blood cell count (WBC), erythrocyte sedimentation rate (ESR), and serum C reactive protein (CRP) in children with community acquired pneumonia of varying aetiology. Methods The study population consisted of 254 consecutive children admitted to hospital with community acquired pneumonia diagnosed between 1993 and 1995. WBC, ESR, and CRP levels were determined on admission. Seventeen infective agents (10 viruses and seven bacteria) were searched for. Chest radiographs were retrospectively and separately reviewed by three paediatric radiologists. Results A potential causative agent was found in 215 (85%) of the 254 cases. Bacterial infection was found in 71% of 137 children with alveolar infiltrates on the chest radiograph, while 72% of the 134 cases with a bacterial pneumonia had alveolar infiltrates. Half of the 77 children with solely interstitial infiltrates on the chest radiograph had evidence of bacterial infection. The proportion of patients with increased WBC or ESR did not differ between bacterial and viral pneumonias, but differences in the CRP levels of >40 mg/l, >80 mg/l, and >120 mg/l were significant although the sensitivity for detecting bacterial pneumonia was too low for use in clinical practice. Conclusions Most children with alveolar pneumonia, especially those with lobar infiltrates, have laboratory evidence of a bacterial infection. Interstitial infiltrates are seen in both viral and bacterial pneumonias.

Home based neuromuscular electrical stimulation as a new rehabilitative strategy for severely disabled patients with chronic obstructive pulmonary disease (COPD)

Abstract: Background: Passive training of specific locomotor muscle groups by means of neuromuscular electrical stimulation (NMES) might be better tolerated than whole body exercise in patients with severe chronic obstructive pulmonary disease (COPD). It was hypothesised that this novel strategy would be particularly effective in improving functional impairment and the consequent disability which characterises patients with end stage COPD. Methods: Fifteen patients with advanced COPD (nine men) were randomly assigned to either a home based 6 week quadriceps femoris NMES training programme (group 1, n=9, FEV 1 =38.0 (9.6)% of predicted) or a 6 week control period before receiving NMES (group 2, n=6, FEV 1 =39.5 (13.3)% of predicted). Knee extensor strength and endurance, whole body exercise capacity, and health related quality of life (Chronic Respiratory Disease Questionnaire, CRDQ) were assessed. Results: All patients were able to complete the NMES training programme successfully, even in the presence of exacerbations (n=4). Training was associated with significant improvements in muscle function, maximal and endurance exercise tolerance, and the dyspnoea domain of the CRDQ (p Conclusions: For severely disabled COPD patients with incapacitating dyspnoea, short term electrical stimulation of selected lower limb muscles involved in ambulation can improve muscle strength and endurance, whole body exercise tolerance, and breathlessness during activities of daily living.

British Thoracic Society Guidelines for the Management of Community Acquired Pneumonia in Childhood.

Abstract: Community acquired pneumonia (CAP) can be defined clinically as the presence of signs and symptoms of pneumonia in a previously healthy child due to an infection which has been acquired outside hospital. In developed countries this can be verified by the radiological finding of consolidation. In the developing world a more practical term—acute lower respiratory infection—is preferred, reflecting the difficulties in obtaining a chest radiograph. Ideally, the definition would include the isolation of a responsible organism. However, it is apparent from many studies that a pathogen is not identified in a significant proportion of cases that otherwise meet the clinical definition (see Section 3 on Aetiology). As it is assumed that CAP is caused by infection, the presumption is that current techniques have insufficient sensitivity to detect all relevant pathogens. Treatment guidelines therefore have to assume that, where pathogens are isolated, they represent all likely pathogens. There is a clear need for better diagnostic methods. In creating guidelines it is necessary to assess all available evidence with consideration of the quality of that evidence. This we have endeavoured to do. We have then produced key points and management guidelines based on the available evidence supplemented by consensus clinical opinion where no relevant evidence was found. A summary of the key points and a further summary prepared specifically for use in primary care are also available on the Thorax website (www.thoraxjnl.com) and the British Thoracic Society website (www.brit-thoracic.org.uk).

Bacterial colonisation in patients with bronchiectasis: microbiological pattern and risk factors.

Abstract: Background: A study was undertaken to investigate the incidence, diagnostic yield of non-invasive and bronchoscopic techniques, and risk factors of airway colonisation in patients with bronchiectasis in a stable clinical situation. Methods: A 2 year prospective study of 77 patients with bronchiectasis in a stable clinical condition was performed in an 800 bed tertiary university hospital. The interventions used were pharyngeal swabs, sputum cultures and quantitative protected specimen brush (PSB) bacterial cultures (cut off point ≥102 cfu/ml) and bronchoalveolar lavage (BAL) (cut off point ≥103 cfu/ml). Results: The incidence of bronchial colonisation with potential pathogenic microorganisms (PPMs) was 64%. The most frequent PPMs isolated were Haemophilus influenzae (55%) and Pseudomonas spp (26%). Resistance to antibiotics was found in 30% of the isolated pathogens. When the sample was appropriate, the operative characteristics of the sputum cultures were similar to those obtained with the PSB taken as a gold standard. Risk factors associated with bronchial colonisation by PPMs in the multivariate analysis were: (1) diagnosis of bronchiectasis before the age of 14 years (odds ratio (OR)=3.92, 95% CI 1.29 to 11.95), (2) forced expiratory volume in 1 second (FEV1) <80% predicted (OR=3.91, 95% CI 1.30 to 11.78), and (3) presence of varicose or cystic bronchiectasis (OR=4.80, 95% CI 1.11 to 21.46). Conclusions: Clinically stable patients with bronchiectasis have a high prevalence of bronchial colonisation by PPMs. Sputum culture is a good alternative to bronchoscopic procedures for evaluation of this colonisation. Early diagnosis of bronchiectasis, presence of varicose-cystic bronchiectasis, and FEV1 <80% predicted appear to be risk factors for bronchial colonisation with PPMs.

Regular use of inhaled corticosteroids and the long term prevention of hospitalisation for asthma.

Abstract: Background: Inhaled corticosteroids are effective at preventing asthma morbidity and mortality. Most studies, however, have focused on short term effects, raising uncertainty about their effectiveness in the long term. Methods: The Saskatchewan Health databases were used to form two population based cohorts of asthma patients aged 5–44 between 1975 and 1991. The first cohort included all subjects from the start of asthma treatment, while the second included subjects hospitalised for asthma from the date of discharge. Subjects were followed up, starting 1 year after cohort entry and continuing until 1997, 54 years of age, or death. The outcome was the first asthma hospital admission and readmission, respectively, to occur during follow up. A nested case-control design was used by which all cases were matched on calendar time and several markers of asthma severity to all available controls within the cohort. Results: The full cohort included 30 569 asthmatic subjects of which 3894 were admitted to hospital for asthma and 1886 were readmitted. The overall rate of asthma hospitalisation was 42.4 per 1000 asthma patients per year. Regular use of inhaled corticosteroids was associated with reductions of 31% in the rate of hospital admissions for asthma (95% confidence interval (CI) 17 to 43) and 39% in the rate of readmission (95% CI 25 to 50). The rate reduction found during the first 4 years of follow up was sustained over the longer term. Regular use of inhaled corticosteroids can potentially prevent between five hospital admissions and 27 readmissions per 1000 asthma patients per year. Conclusion: Regular use of low dose inhaled corticosteroids prevents a large proportion of hospital admissions with asthma, both early and later on in the course of the disease.

Exhaled nitric oxide correlates with airway eosinophils in childhood asthma

Abstract: Background: Exhaled nitric oxide has been proposed as a marker for airway inflammation in asthma. The aim of this study was to compare exhaled nitric oxide levels with inflammatory cells and mediators in bronchoalveolar lavage fluid from asthmatic and normal children. Methods: Children were recruited from elective surgical lists and a non-bronchoscopic bronchoalveolar lavage (BAL) was performed after induction of anaesthesia. Exhaled nitric oxide (parts per billion) was measured by two techniques: tidal breathing and restricted breath. Results: Median (interquartile range) exhaled nitric oxide measured by restricted breath was increased in asthmatics compared with normal children (24.3 (10.5–66.5) v 9.7 (6.5–16.5), difference between medians 14.6 (95% CI 5.1 to 29.9), p=0.001). In asthmatic children exhaled nitric oxide correlated significantly with percentage eosinophils ( r =0.78, p<0.001 (tidal breathing) and r =0.78, p<0.001 (restricted breath)) and with eosinophilic cationic protein ( r =0.53, p<0.01 (restricted breath)), but not with other inflammatory cells in the BAL fluid. The area under the receiver operator characteristic curves for the prediction of the presence of eosinophilic airways inflammation by exhaled nitric oxide (tidal and restricted) was 0.80 and 0.87, respectively. Conclusions: Exhaled nitric oxide correlates closely with percentage eosinophils in BAL fluid in asthmatic children and is therefore likely to be a useful non-invasive marker of airway inflammation.

Relationship between nutritional status and lung function in cystic fibrosis: cross sectional and longitudinal analyses from the German CF quality assurance (CFQA) project

Abstract: Background: The German cystic fibrosis (CF) quality assurance (CFQA) project is a patient registry for CF which was founded in 1995. Relevant clinical and laboratory data, respiratory function test results, complications, and CF treatments are entered into the database once a year for each patient. Using the database, a study was undertaken to elucidate the relationship between nutrition and lung function in a large patient cohort by cross sectional and longitudinal analysis. Methods: A cohort of 3298 patients above 2 years of age was analysed. Patients were grouped according to the presence or absence of malnutrition (wasting and/or stunting). Cross sectional and longitudinal analyses over 2 and 3 years including mixed model analyses were performed. Results: The prevalence of abnormal weight for height ( 5% predicted decrease in weight for height had a concomitant mean loss of FEV1 of 16.5% predicted during that year, whereas patients who gained relative weight had a parallel increase in FEV1 of 2.1% predicted. Conclusions: These data emphasise the close relationship between nutrition, lung function, and clinical course in CF. Normal body weight and absence of P aeruginosa infection was associated with better preservation of lung function.

Clinical audit indicators of outcome following admission to hospital with acute exacerbation of chronic obstructive pulmonary disease

Abstract: Background: The 1997 BTS/RCP national audit of acute chronic obstructive pulmonary disease (COPD) in terms of process of care has previously been reported. This paper describes from the same cases the outcomes of death, readmission rates within 3 months of initial admission, and length of stay. Identification of the main pre-admission predictors of outcome may be used to control for confounding factors in population characteristics when comparing performance between units. Methods: Data on 74 variables were collected retrospectively using an audit proforma from patients admitted to UK hospitals with acute COPD. Important prognostic variables for the three outcome measures were identified by relative risk and logistic regression was used to place these in order of predictive value. Results: 1400 admissions from 38 acute hospitals were collated. 14% of cases died within 3 months of admission with variation between hospitals of 0–50%. Poor performance status, acidosis, and the presence of leg oedema were the best significant independent predictors of death. Age above 65, poor performance status, and lowest forced expiratory volume in 1 second (FEV1) tertile were the best predictors of length of stay (median 8 days). 34% of patients were readmitted (range 5–65%); lowest FEV1 tertile, previous admission, and readmission with five or more medications were the best predictors for readmission. Conclusions: Important predictors of outcome have been identified and formal recording of these may assist in accounting for confounding patient characteristics when making comparisons between hospitals. There is still wide variation in outcome between hospitals that remains unexplained by these factors. While some of this variance may be explained by incomplete recording of data or patient factors as yet unidentified, it seems likely that deficiencies in the process of care previously identified are responsible for poor outcomes in some units.

Randomised trial of intrapleural urokinase in the treatment of childhood empyema

Abstract: Background: The role of intrapleural fibrinolytic agents in the treatment of childhood empyema has not been established. A randomised double blind placebo controlled trial of intrapleural urokinase was performed in children with parapneumonic empyema. Methods: Sixty children (median age 3.3 years) were recruited from 10 centres and randomised to receive either intrapleural urokinase 40 000 units in 40 ml or saline 12 hourly for 3 days. The primary outcome measure was length of hospital stay after entry to the trial. Results: Treatment with urokinase resulted in a significantly shorter hospital stay (7.4 v 9.5 days; ratio of geometric means 1.28, CI 1.16 to 1.41 p=0.027). A post hoc analysis showed that the use of small percutaneous drains was also associated with shorter hospital stay. Children treated with a combination of urokinase and a small drain had the shortest stay (6.0 days, CI 4.6 to 7.8). Conclusion: Intrapleural urokinase is effective in treating empyema in children and significantly shortens hospital stay.

A defective type 1 response to rhinovirus in atopic asthma

Abstract: Background: Rhinoviruses (RVs) are the most frequent precipitants of the common cold and asthma exacerbations, but little is known about the immune response to these viruses and its potential implications in the pathogenesis of asthma Methods: Peripheral blood mononuclear cells (PBMC) from patients with atopic asthma and normal subjects were exposed to live or inactivated RV preparations Levels of interferon (IFN)γ and interleukins IL-12, IL-10, IL-4, IL-5 and IL-13 were evaluated in the culture supernatants with specific immunoassays Results: Exposure of PBMC to RVs induced the production of IFNγ, IL-12, IL-10, and IL-13 Cells from asthmatic subjects produced significantly lower levels of IFNγ and IL-12 and higher levels of IL-10 than normal subjects IL-4 was induced only in the asthmatic group, while the IFNγ/IL-4 ratio was more than three times lower in the asthmatic group Conclusions: This evidence suggests that the immune response to RVs is not uniquely of a type 1 phenotype, as previously suggested The type 1 response is defective in atopic asthmatic individuals, with a shift towards a type 2 phenotype in a way similar, but not identical, to their aberrant response to allergens A defective type 1 immune response to RVs may be implicated in the pathogenesis of virus induced exacerbations of asthma

Sahaja yoga in the management of moderate to severe asthma: a randomised controlled trial

Abstract: Background: Sahaja Yoga is a traditional system of meditation based on yogic principles which may be used for therapeutic purposes. A study was undertaken to assess the effectiveness of this therapy as an adjunctive tool in the management of asthma in adult patients who remained symptomatic on moderate to high doses of inhaled steroids. Methods: A parallel group, double blind, randomised controlled trial was conducted. Subjects were randomly allocated to Sahaja yoga and control intervention groups. Both the yoga and the control interventions required the subjects to attend a 2 hour session once a week for 4 months. Asthma related quality of life (AQLQ, range 0–4), Profile of Mood States (POMS), level of airway hyperresponsiveness to methacholine (AHR), and a diary card based combined asthma score (CAS, range 0–12) reflecting symptoms, bronchodilator usage, and peak expiratory flow rates were measured at the end of the treatment period and again 2 months later. Results: Twenty one of 30 subjects randomised to the yoga intervention and 26 of 29 subjects randomised to the control group were available for assessment at the end of treatment. The improvement in AHR at the end of treatment was 1.5 doubling doses (95% confidence interval (CI) 0.0 to 2.9, p=0.047) greater in the yoga intervention group than in the control group. Differences in AQLQ score (0.41, 95% CI –0.04 to 0.86) and CAS (0.9, 95% CI –0.9 to 2.7) were not significant (p>0.05). The AQLQ mood subscale did improve more in the yoga group than in the control group (difference 0.63, 95% CI 0.06 to 1.20), as did the summary POMS score (difference 18.4, 95% CI 0.2 to 36.5, p=0.05). There were no significant differences between the two groups at the 2 month follow up assessment. Conclusions: This randomised controlled trial has shown that the practice of Sahaja yoga does have limited beneficial effects on some objective and subjective measures of the impact of asthma. Further work is required to understand the mechanism underlying the observed effects and to establish whether elements of this intervention may be clinically valuable in patients with severe asthma.

Association of serum leptin with hypoventilation in human obesity

Abstract: Background: Leptin is a protein hormone produced by fat cells of mammals. It acts within the hypothalamus via a specific receptor to reduce appetite and increase energy expenditure. Plasma leptin levels correlate closely with total body fat mass operating via a central feedback mechanism. In human obesity serum leptin levels are up to four times higher than in lean subjects, indicating a failure of the feedback loop and central leptin resistance. In leptin deficient obese mice ( ob/ob mice) leptin infusion reverses hypoventilation. It was hypothesised that a relative deficiency in CNS leptin, indicated by high circulating leptin levels, may be implicated in the pathogenesis of obesity hypoventilation syndrome (OHS). Methods: Fasting morning leptin levels were measured in obese and non-obese patients with and without daytime hypercapnia (n=56). Sleep studies, anthropometric data, spirometric parameters, and awake arterial blood gas tensions were measured in each patient. Results: In the whole group serum leptin levels correlated closely with % body fat ( r =0.77). Obese hypercapnic patients (mean (SD) % body fat 43.8 (6.0)%) had higher fasting serum leptin levels than eucapnic patients (mean % body fat 40.8 (6.2)%), with mean (SD) leptin levels of 39.1 (17.9) and 21.4 (11.4) ng/ml, respectively (p<0.005). Serum leptin (odds ratio (OR) 1.12, 95% CI 1.03 to 1.22) was a better predictor than % body fat (OR 0.92, 95% CI 0.76 to 1.1) for the presence of hypercapnia. Conclusions: Hyperleptinaemia is associated with hypercapnic respiratory failure in obesity. Treatment with leptin or its analogues may have a role in OHS provided central leptin resistance can be overcome.

Dose-dependent onset and cessation of action of inhaled budesonide on exhaled nitric oxide and symptoms in mild asthma

Abstract: Background: Dose dependent anti-inflammatory effects of inhaled corticosteroids in asthma are difficult to demonstrate in clinical practice. The anti-inflammatory effect of low dose inhaled budesonide on non-invasive exhaled markers of inflammation and oxidative stress were assessed in patients with mild asthma. Methods: 28 patients entered a double blind, placebo controlled, parallel group study and were randomly given either 100 or 400 µg budesonide or placebo once daily, inhaled from a dry powder inhaler (Turbohaler), for 3 weeks followed by 1 week without treatment. Exhaled nitric oxide (NO), exhaled carbon monoxide (CO), nitrite/nitrate, S-nitrosothiols, and 8-isoprostanes in exhaled breath condensate were measured four times during weeks 1 and 4, and once a week during weeks 2 and 3. Results: A dose-dependent speed of onset and cessation of action of budesonide was seen on exhaled NO and asthma symptoms. Treatment with 400 µg/day reduced exhaled NO faster (–2.06 (0.37) ppb/day) than 100 µg/day (–0.51 (0.35) ppb/day; p<0.01). The mean difference between the effect of 100 and 400 µg budesonide was –1.55 ppb/day (95% CI –2.50 to –0.60). Pretreatment NO levels were positively related to the subsequent speed of reduction during the first 3–5 days of treatment. Faster recovery of exhaled NO was seen after stopping treatment with budesonide 400 µg/day (1.89 (1.43) ppb/day) than 100 µg/day (0.49 (0.34) ppb/day, p<0.01). The mean difference between the effect of 100 and 400 µg budesonide was 1.40 ppb/day (95% CI –0.49 to 2.31). Symptom improvement was dose-dependent, although symptoms returned faster in patients treated with 400 µg/day. A significant reduction in exhaled nitrite/nitrate and S-nitrosothiols after budesonide treatment was not dose-dependent. There were no significant changes in exhaled CO or 8-isoprostanes in breath condensate. Conclusion: Measurement of exhaled NO levels can indicate a dose-dependent onset and cessation of anti-inflammatory action of inhaled corticosteroids in patients with mild asthma.

Patterns and predictors of sleep disordered breathing in primary myopathies.

Abstract: Background: Sleep disordered breathing (SDB) is common in neuromuscular diseases but its relationship to respiratory function is poorly defined. A study was undertaken to identify distinct patterns of SDB, to clarify the relationships between SDB and lung and respiratory muscle function, and to identify daytime predictors for SDB at its onset, for SDB with continuous hypercapnic hypoventilation, and for diurnal respiratory failure. Methods: Upright and supine inspiratory vital capacity (IVC, % predicted), maximal inspiratory muscle pressure (PImax), respiratory drive (P0.1), respiratory muscle effort (P0.1/PImax), and arterial blood gas tensions were prospectively compared with polysomnography and capnometry (PtcCO2) in 42 patients with primary myopathies. Results: IVC correlated with respiratory muscle function and gas exchange by day and night. SDB evolved in three distinct patterns from REM hypopnoeas, to REM hypopnoeas with REM hypoventilation, to REM/non-REM (continuous) hypoventilation, and preceded diurnal respiratory failure. SDB correlated with IVC and PImax which yielded highly predictive thresholds for SDB onset (IVC <60%, PImax <4.5 kPa), SDB with continuous hypoventilation (IVC <40%, PImax <4.0 kPa), and SDB with diurnal respiratory failure (IVC <25%, PImax <3.5 kPa). Conclusion: Progressive ventilatory restriction in neuromuscular diseases correlates with respiratory muscle weakness and results in progressive SDB which, by pattern and severity, can be predicted from daytime lung and respiratory muscle function.

Relation of bronchial responsiveness to body mass index in the ECRHS

Abstract: Background: There is substantial evidence for an association between symptoms of asthma and overweight or obesity. However, a study that reported no association between bronchial responsiveness (BHR) and body mass index (BMI) suggested that the relation of symptoms to obesity was due to increased diagnosis of asthma. The relation of BHR to BMI was therefore investigated in a large multicentre study. Methods: Data were obtained for 11 277 participants in stage II of the European Community Respiratory Health Survey (ECRHS). BHR to methacholine was analysed in relation to BMI adjusted for a number of factors known to be associated with BHR, including baseline lung function and allergen sensitisation, and combined across 34 centres using random effects meta-analysis. Results: BHR increased with increasing BMI in men (ECRHS slope changed by –0.027 for each unit increase in BMI, 95% confidence interval –0.044 to –0.010, p=0.002), but the relation in women was weak (–0.014, 95% CI –0.033 to 0.005, p=0.14). There was no evidence for an interaction of sex with BMI (p=0.41). Conclusions: BHR is related to BMI in the ECRHS. This suggests that the association is not due to greater diagnosis or perception of symptoms in obese people compared with those of normal weight. The data do not support the finding by some studies of a relation between asthma and obesity in women but not in men.

Airways in cystic fibrosis are acidified: detection by exhaled breath condensate

Abstract: CF. Results: The pH of EBC was significantly lower in patients with stable CF than in controls (5.88 (0.32) v 6.15 (0.16), p=0.017), and was further reduced in CF patients with an exacerbation (5.32 (0.38), p=0.001) compared with stable CF patients. EBC pH increased significantly following antibiotic treat- ment from 5.27 (0.42) to 5.71 (0.42), p=0.049). Nitrite levels in EBC were increased in CF patients with an exacerbation compared with control subjects (4.4 (4.0) µm v 1.6 (1.6) µm p=0.047). No cor- relation was found between EBC pH and nitrite levels. Conclusions: These findings support the hypothesis that airway acidification occurs in CF. This acid- ity is in part a function of inflammation as the pH of the EBC of patients increased significantly with treatment of an exacerbation, although not to control levels. Acidic pH of the ELF may play a role in the pathophysiology of CF lung disease and requires further investigation.

Nationwide prevalence of sporadic and familial idiopathic pulmonary fibrosis: evidence of founder effect among multiplex families in Finland

Abstract: Background: The prevalence of sporadic and familial idiopathic pulmonary fibrosis (IPF) cases in Finland was evaluated according to the revised recommendations of the American Thoracic Society. Methods: All Finnish pulmonary clinics (n=29) were included in the primary screening. Hospital data bases were used to identify patients with the diagnosis “alveolitis fibroticans idiopathica” (J84.1 in ICD-10 classification). The total number of patients with IPF was extrapolated based on the evaluation of random samples of case records in different centres. Families with more than one potentially affected member were identified from a questionnaire study and the diagnosis was verified from the medical records. Results: Using this approach, the nationwide prevalence of IPF in Finland was estimated to be 16–18/100 000. In 90% of the patients lung involvement was assessed by high resolution computed tomographic (HRCT) scanning and in 31% a surgical biopsy specimen was available, further confirming the diagnosis. Seventeen multiplex families with 2–5 affected family members were identified, giving a prevalence of 5.9/million for familial IPF in Finland. Both multiplex and sporadic families were clustered in Eastern Finland. This clustering reflects the demographic history of Finland in the 16th century and suggests that multiplex families may share a common ancestor in the last 20–25 generations. Conclusion: The familial form explained 3.3–3.7% of all Finnish cases of IPF diagnosed according to the revised international guidelines. Geographical clustering of multiplex families suggests a recent founder effect in patients with familial IPF.

High resolution computed tomographic assessment of airway wall thickness in chronic asthma: reproducibility and relationship with lung function and severity.

Abstract: Background: In some patients chronic asthma results in irreversible airflow obstruction. High resolution computed tomography (HRCT) has been advocated for assessing the structural changes in the asthmatic lung and permits investigation of the relationships between airway wall thickening and clinical parameters in this condition. Methods: High resolution CT scanning was performed in 49 optimally controlled asthmatic patients and measurements of total airway and lumen diameter were made by two independent radiologists using electronic callipers. Wall area as % total airway cross sectional area (WA%) and wall thickness to airway diameter ratio (T/D) were calculated for all airways clearly visualised with a transverse diameter of more than 1.5 mm, with a mean value derived for each patient. Intra- and inter-observer variability was assessed for scope of agreement in a subgroup of patients. Measurements were related to optimum forced expiratory volume in 1 second (FEV1), forced mid expiratory flow, carbon monoxide gas transfer, two scores of asthma severity, airway inflammation as assessed with induced sputum, and exhaled nitric oxide. Results: Neither observer produced a statistically significant difference between measurements performed on two occasions but there was a significant difference between observers (limits of agreement –2.6 to 6.8 for WA%, p<0.0001). However, mean WA% measured on two occasions differed by no more than 5.4% (limits of agreement –4.0 to 5.4; mean (SD) 0.7 (2.4)). Statistically significant positive associations were observed between both WA% and T/D ratio and asthma severity (rS=0.29 and 0.30, respectively, for ATS score), and an inverse association with gas transfer coefficient was observed (rS=–0.43 for WA% and rS=–0.41 for T/D). No association was identified with FEV1 or airway inflammation. Conclusions: The airway wall is thickened in more severe asthma and is associated with gas transfer coefficient. This thickening does not relate directly to irreversible airflow obstruction as measured with FEV1.