These findings suggests that by identifying whether a patient infected with TB is in a high or reduced inflammatory state, as dictated by their LTA4H genotype and the detrimental effects of each extreme countered, patient morbidity and mortality would be improved. Blindly used ‘scatter-gun’ therapies may be either...]]>
None.
Not commissioned; internally peer...]]>
During a 9-month period 35, 510 influenza tests were performed in Alberta, of which 19% tested positive for pandemic H1N1 (pH1N1). Using mathematical transmission modelling, the study compared the confirmed cases of pH1N1 with weather patterns and the school calendar.
The results suggested that the end of the school term had a significant impact in reducing the first ‘wave’ of the pandemic; modelling showed transmission rates dropped in school children by more than 50% following school closure. A second wave of pH1N1 occurred shortly after school re-opening. Transmission was also affected by climate changes such as a low temperature, which correlated with increased transmission.
The study is limited in that it only takes into account cases of influenza that were confirmed virologically, meaning that data is...]]>
The genetic basis for developing asthma has been extensively studied. However, association studies to date have mostly focused on mild to moderate disease and genetic risk factors for severe asthma remain unclear.
To identify common genetic variants affecting susceptibility to severe asthma.
A genome-wide association study was undertaken in 933 European ancestry individuals with severe asthma based on Global Initiative for Asthma (GINA) criteria 3 or above and 3346 clean controls. After standard quality control measures, the association of 480 889 genotyped single nucleotide polymorphisms (SNPs) was tested. To improve the resolution of the association signals identified, non-genotyped SNPs were imputed in these regions using a dense reference panel of SNP genotypes from the 1000 Genomes Project. Then replication of SNPs of interest was undertaken in a further 231 cases and 1345 controls and a meta-analysis was performed to combine the results across studies.
An association was confirmed in subjects with severe asthma of loci previously identified for association with mild to moderate asthma. The strongest evidence was seen for the ORMDL3/GSDMB locus on chromosome 17q12-21 (rs4794820, p=1.03x10(–8) following meta-analysis) meeting genome-wide significance. Strong evidence was also found for the IL1RL1/IL18R1 locus on 2q12 (rs9807989, p=5.59x10(–8) following meta-analysis) just below this threshold. No novel loci for susceptibility to severe asthma met strict criteria for genome-wide significance.
The largest genome-wide association study of severe asthma to date was carried out and strong evidence found for the association of two previously identified asthma susceptibility loci in patients with severe disease. A number of novel regions with suggestive evidence were also identified warranting further study.
Impaired insulin sensitivity (ISx), increased visceral abdominal fat (VAF) and liver fat are all central components of the metabolic syndrome and characteristics of men with obstructive sleep apnoea (OSA). The reversibility of these observed changes with continuous positive airway pressure (CPAP) treatment in men with OSA has not been systematically studied in a randomised sham-controlled fashion.
65 men without diabetes who were CPAP naïve and had moderate to severe OSA (age=49±12 years, apnoea hypopnoea index (AHI)=39.9±17.7 events/h, body mass index=31.3±5.2 kg/m2) were randomised to receive either real (n=34) or sham (n=31) CPAP for 12 weeks. At 12 weeks, all subjects received real CPAP for an additional 12 weeks.
Main outcomes were the change at week 12 from baseline in VAF, ISx and liver fat. Other metabolic outcomes were changes in the disposition index, total fat, and blood leptin and adiponectin concentrations. The AHI was lower on CPAP compared with sham by 33 events/h (95% CI–43.9 to –22.2, p<0.0001) after 12 weeks. There were no between-group differences at 12 weeks in VAF (–13.0 cm3, –42.4 to 16.2, p=0.37), ISx (–0.13 (min–1)(μU/ml))–1, –0.40 to 0.14, p=0.33), liver fat (–0.5 cm3, –3.8 to 2.7, p=0.74) or any other cardiometabolic parameter. At 24 weeks, ISx (3.2x104 (min–1)(μU/ml))–1, 0.9x104 to 6.0x104, p=0.009), but not VAF (–1.4 cm3, –19.2 to 16.4, p=0.87) or liver fat (–0.2 Hounsfield units, –2.4 to 2.0, p=0.83) were improved compared with baseline in the whole study group.
Reducing visceral adiposity in men with OSA cannot be achieved with CPAP alone and is likely to require weight-loss interventions. Longer-term effects of CPAP on other cardiometabolic markers such as ISx require further investigation to fully examine time dependencies.
ACTRN12608000301369.
Some patients with obstructive sleep apnoea syndrome are at higher risk of being involved in road traffic accidents. It has not been possible to identify this group from clinical and polysomnographic information or using simple simulators. We explore the possibility of identifying this group from variables generated in an advanced PC-based driving simulator.
All patients performed a 90 km motorway driving simulation. Two events were programmed to trigger evasive actions, one subtle and an alert driver should not crash, while for the other, even a fully alert driver might crash. Simulator parameters including standard deviation of lane position (SDLP) and reaction times at the veer event (VeerRT) were recorded. There were three possible outcomes: ‘fail’, ‘indeterminate’ and ‘pass’. An exploratory study identified the simulator parameters predicting a ‘fail’ by regression analysis and this was then validated prospectively.
72 patients were included in the exploratory phase and 133 patients in the validation phase. 65 (32%) patients completed the run without any incidents, 45 (22%) failed, 95 (46%) were indeterminate. Prediction models using SDLP and VeerRT could predict ‘fails’ with a sensitivity of 82% and specificity of 96%. The models were subsequently confirmed in the validation phase.
Using continuously measured variables it has been possible to identify, with a high degree of accuracy, a subset of patients with obstructive sleep apnoea syndrome who fail a simulated driving test. This has the potential to identify at-risk drivers and improve the reliability of a clinician's decision-making.
Health status is impaired in patients with interstitial lung disease (ILD). There is a paucity of tools that assess health status in ILD. The objective of this study was to develop and validate the King's Brief Interstitial Lung Disease questionnaire (K-BILD), a new health status measure for patients with ILD.
Patients with ILD were recruited from outpatient clinics. The development of the questionnaire consisted of three phases: item generation; item reduction, allocation to domains by factor analysis, Rasch analysis to create unidimensional scales and validation; and repeatability testing.
173 patients with ILD (49 with idiopathic pulmonary fibrosis) completed a preliminary 71-item questionnaire. 56 items were removed due to redundancy, low factor loadings or poor fit to the Rasch model. The final version of the K-BILD questionnaire consisted of 15 items and three domains (breathlessness and activities, chest symptoms and psychological). Internal consistency assessed with Cronbach's α coefficient was 0.94 for the K-BILD total score. Concurrent validity of the K-BILD questionnaire was high compared with St George's Respiratory Questionnaire (r=0.90) and moderate with lung function (vital capacity, r=0.50). The K-BILD questionnaire was repeatable over 2 weeks (n=44), with intraclass correlation coefficients for domains and total score 0.86–0.94. The K-BILD construct validity for patients with idiopathic pulmonary fibrosis was similar to that of other ILDs.
The K-BILD questionnaire is a brief, valid, self-completed health status measure for ILD. It could be used in the clinic to assess ILD from the patients' perspective.
Forced expiratory volume in 1 s as a percentage of predicted (%FEV1) is a key outcome in cystic fibrosis (CF) and other lung diseases. As people with CF survive for longer periods, new methods are required to understand the way %FEV1 changes over time. An up to date approach for longitudinal modelling of %FEV1 is presented and applied to a unique CF dataset to demonstrate its utility at the clinical and population level.
The Danish CF register contains 70 448 %FEV1 measures on 479 patients seen monthly between 1969 and 2010. The variability in the data is partitioned into three components (between patient, within patient and measurement error) using the empirical variogram. Then a linear mixed effects model is developed to explore factors influencing %FEV1 in this population. Lung function measures are correlated for over 15 years. A baseline %FEV1 value explains 63% of the variability in %FEV1 at 1 year, 40% at 3 years, and about 30% at 5 years. The model output smooths out the short-term variability in %FEV1 (SD 6.3%), aiding clinical interpretation of changes in %FEV1. At the population level significant effects of birth cohort, pancreatic status and Pseudomonas aeruginosa infection status on %FEV1 are shown over time.
This approach provides a more realistic estimate of the %FEV1 trajectory of people with chronic lung disease by acknowledging the imprecision in individual measurements and the correlation structure of repeated measurements on the same individual over time. This method has applications for clinicians in assessing prognosis and the need for treatment intensification, and for use in clinical trials.
Exposure to cigarette smoke (CS) is associated with increased risk of pneumococcal infection. The mechanism for this association is unknown. We recently reported that the particulate matter from urban air simulates platelet-activating factor receptor (PAFR)-dependent adhesion of pneumococci to airway cells. We therefore sought to determine whether CS stimulates pneumococcal adhesion to airway cells.
Human alveolar (A549), bronchial (BEAS2-B), and primary bronchial epithelial cells (HBEpC) were exposed to CS extract (CSE), and adhesion of Streptococcus pneumoniae determined. The role of PAFR in mediating adhesion was determined using a blocker (CV-3988). PAFR transcript level was assessed by quantitative real-time PCR, and PAFR expression by flow cytometry. Lung PAFR transcript level was assessed in mice exposed to CS, and bronchial epithelial PAFR expression assessed in active-smokers by immunostaining.
In A549 cells, CSE 1% increased pneumococcal adhesion (p<0.05 vs control), PAFR transcript level (p<0.01), and PAFR expression (p<0.01). Pneumococcal adhesion to A549 cells was attenuated by CV-3988 (p<0.001). CSE 1% stimulated pneumococcal adhesion to BEAS2-B cells and HBEpC (p<0.01 vs control). CSE 1% increased PAFR expression in BEAS2-B (p<0.01), and in HBEpC (p<0.05). Lung PAFR transcript level was increased in mice exposed to CS in vivo (p<0.05 vs room air). Active smokers (n=16) had an increased percentage of bronchial epithelium with PAFR-positive cells (p<0.05 vs never smokers, n=11).
CSE stimulates PAFR-dependent pneumococcal adhesion to lower airway epithelial cells. We found evidence that CS increases bronchial PAFR in vivo.
Criteria for a clinically significant bronchodilator response (BDR) are mainly based on studies in patients with obstructive lung diseases. Little is known about the BDR in healthy general populations, and even less about the worldwide patterns.
10 360 adults aged 40 years and older from 14 countries in North America, Europe, Africa and Asia participated in the Burden of Obstructive Lung Disease study. Spirometry was used before and after an inhaled bronchodilator to determine the distribution of the BDR in population-based samples of healthy non-smokers and individuals with airflow obstruction.
In 3922 healthy never smokers, the weighted pooled estimate of the 95th percentiles (95% CI) for bronchodilator response were 284 ml (263 to 305) absolute change in forced expiratory volume in 1 s from baseline (FEV1); 12.0% (11.2% to 12.8%) change relative to initial value (%FEV1i); and 10.0% (9.5% to 10.5%) change relative to predicted value (%FEV1p). The corresponding mean changes in forced vital capacity (FVC) were 322 ml (271 to 373) absolute change from baseline (FVC); 10.5% (8.9% to 12.0%) change relative to initial value (FVCi); and 9.2% (7.9% to 10.5%) change relative to predicted value (FVCp). The proportion who exceeded the above threshold values in the subgroup with spirometrically defined Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 2 and higher (FEV1/FVC <0.7 and FEV1% predicted <80%) were 11.1%, 30.8% and 12.9% respectively for the FEV1-based thresholds and 22.6%, 28.6% and 22.1% respectively for the FVC-based thresholds.
The results provide reference values for bronchodilator responses worldwide that confirm guideline estimates for a clinically significant level of BDR in bronchodilator testing.
I could not resist your challenge in your Editorial, ‘Pre-drainage tension’, triggered by letters from Drs Simpson and Leigh Smith
My understanding of pneumothorax was that it is due to a loss of the negative intrapleural pressure that overcomes the elastic recoil of the pulmonary tissues. Once this vacuum is lost then air is free to enter the lungs or intrapleural space with impunity. The actual amounts will vary according to many factors, including the strength of elastic recoil of pulmonary tissues, exact sites of leak and depth of inspiration. Perhaps we need an engineer to explain this?
However, on first reading of the letters I was concerned that all texts on the issue including life support and trauma courses would have to be REPRINTED (Rapidly Expanding Pneumothorax Requiring Immediate...]]>
Small airways function studies in lung disease have used three promising multiple breath washout (MBW) derived indices: indices of ventilation heterogeneity in the acinar (Sacin) and conductive (Scond) lung zones, and the lung clearance index (LCI). Since peripheral lung structure is known to change with age, ventilation heterogeneity is expected to be affected too. However, the age dependence of the MBW indices of ventilation heterogeneity in the normal lung is unknown.
The authors systematically investigated Sacin, Scond or LCI as a function of age, testing also the robustness of these relationships across two laboratories.
MBW tests were performed by never-smokers (50% men) in the age range 25–65 years, with data gathered across two laboratories (n=120 and n=60). For comparison with the literature, the phase III slopes from classical single breath washout tests were also acquired in one group (n=120).
All three MBW indices consistently increased with age, representing a steady worsening of ventilation heterogeneity in the age range 25–65. Age explained 7–16% of the variability in Sacin and Scond and 36% of the variability in LCI. There was a small but significant gender difference only for Sacin. Classical single breath washout phase III slopes also showed age dependencies, with gender effects depending on the normalisation method used.
With respect to the clinical response, age is a small but consistent effect that needs to be factored in when using the MBW indices for the detection of small airways abnormality in disease.
Current guidelines recommend treatment with one or more long-acting bronchodilators for patients with moderate or more severe chronic obstructive pulmonary disease (COPD). The authors investigated the approach of dual bronchodilation using indacaterol, a once-daily long-acting β2 agonist, and the long-acting muscarinic antagonist tiotropium, compared with tiotropium alone.
In two identically designed, double-blind, 12-week studies, patients with moderate to severe COPD were randomised to indacaterol 150 μg once daily or matching placebo. All patients concurrently received open-label tiotropium 18 μg once daily. The primary outcome was standardised area under the curve of forced expiratory volume in 1 s (FEV1) from 5 min to 8 h post dose at week 12. The key secondary outcome was 24 h post-dose (‘trough’) FEV1 at week 12. Resting inspiratory capacity (IC) was measured in a subgroup.
1134 and 1142 patients were randomised in studies 1 and 2; 94% and 94% completed. Compared with monotherapy, concurrent therapy increased FEV1 (area under the curve by 130 and 120 ml, trough by 80 and 70 ml; all p<0.001) and trough IC (by 130 and 100 ml, p<0.01). Cough was more common with indacaterol plus tiotropium (10% and 9%) than with tiotropium alone (4% and 4%). Most cases (~90%) of cough were mild. Other adverse events were similar for the treatment groups.
Compared with tiotropium monotherapy, indacaterol plus tiotropium provided greater bronchodilation and lung deflation (reflected by increased resting IC). Adverse events were similar between treatments apart from mild cough being more common with indacaterol plus tiotropium. These results support COPD guideline recommendations to combine bronchodilators with different mechanisms of action.
NCT00846586 and NCT00877383.
This study evaluated the efficacy of a mindfulness training programme (mindfulness-based stress reduction (MBSR)) in improving asthma-related quality of life and lung function in patients with asthma.
A randomised controlled trial compared an 8-week MBSR group-based programme (n=42) with an educational control programme (n=41) in adults with mild, moderate or severe persistent asthma recruited at a university hospital outpatient primary care and pulmonary care clinic. Primary outcomes were quality of life (Asthma Quality of Life Questionnaire) and lung function (change from baseline in 2-week average morning peak expiratory flow (PEF)). Secondary outcomes were asthma control assessed by 2007 National Institutes of Health/National Heart Lung and Blood Institute guidelines, and stress (Perceived Stress Scale (PSS)). Follow-up assessments were conducted at 10 weeks, 6 and 12 months.
At 12 months MBSR resulted in clinically significant improvements from baseline in quality of life (differential change in Asthma Quality of Life Questionnaire score for MBSR vs control: 0.66 (95% CI 0.30 to 1.03; p<0.001)) but not in lung function (morning PEF, PEF variability and forced expiratory volume in 1 s). MBSR also resulted in clinically significant improvements in perceived stress (differential change in PSS score for MBSR vs control: –4.5 (95% CI –7.1 to –1.9; p=0.001)). There was no significant difference (p=0.301) in percentage of patients in MBSR with well controlled asthma (7.3% at baseline to 19.4%) compared with the control condition (7.5% at baseline to 7.9%).
MBSR produced lasting and clinically significant improvements in asthma-related quality of life and stress in patients with persistent asthma, without improvements in lung function.
Asthma and Mindfulness-Based Reduction (MBSR) Identifier: NCT00682669. clinicaltrials.gov.
The American and European cystic fibrosis (CF) guidelines recommend different diagnostic criteria. This study assessed diagnostic concordance between these recommendations.
Subjects with single organ manifestations suggestive of CF (chronic sinopulmonary disease (RESP), chronic/recurrent pancreatitis (PANC) or obstructive azoospermia (AZOOSP)) were prospectively evaluated by sweat test, nasal potential difference and genotyping. Concordance in diagnostic outcomes between the two algorithms was measured using observed agreement and statistics.
A total of 208 subjects were evaluated. Observed agreement was 84.8% and level of agreement was excellent (=0.87) between the American and European recommendations. The RESP phenotype was associated with the highest degree of concordance (observed agreement ≥90%, =0.92) compared with the PANC (observed agreement 86%, =0.65) and AZOOSP (observed agreement 80%, =0.87) phenotypes. Incorporation of nasal potential difference into the American algorithm failed to improve the overall degree of concordance (good agreement level; =0.75); the level of agreement was unchanged in RESP and PANC subjects, but reduced in AZOOSP subjects (from excellent to good). Extensive genotyping had limited clinical utility in the diagnosis of CF in both algorithms.
Despite inconsistencies between the American and European diagnostic recommendations, concordance in diagnostic outcomes among subjects presenting with single organ manifestations of CF was good to excellent. These diagnostic guidelines provide guidance and promote rigorous evaluation for the diagnosis of CF but neither guideline should be regarded as dogma.
A 58-year-old man who never smoked and was under follow-up for polymyositis associated with fibrotic interstitial lung disease was found to have an incidental opacity in the right upper lobe on a chest radiograph. He had been treated with daily azathioprine 200 mg and prednisolone 10 mg for 15 years. A CT chest revealed a mass-like lesion of relatively low attenuation suggesting necrosis (
Two months after the first CT, at presentation to our unit, the patient experienced small haemoptyses. Subsequent chest high resolution CT showed a marked increase in size of the lesion and eccentric cavitation (air crescent sign) (
Stem cells have the capacity for limitless self-renewal and differentiation. Mesenchymal stem cells (MSC) are multipotent adult stem cells with the capacity to differentiate into many different cell types, including alveolar cells. There are several mechanisms through which MSCs could potentially be used for attenuating lung injury and augmenting repair.
The death receptor ligand tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) shows considerable clinical promise as a therapeutic agent. TRAIL induces leukocyte apoptosis, reducing acute inflammatory responses in the lung. It is not known whether TRAIL modifies chronic lung injury or whether TRAIL has a role in human idiopathic pulmonary fibrosis (IPF). We therefore explored the capacity of TRAIL to modify chronic inflammatory lung injury and studied TRAIL expression in patients with IPF.
TRAIL–/– and wild-type mice were instilled with bleomycin and inflammation assessed at various time points by bronchoalveolar lavage and histology. Collagen deposition was measured by tissue hydroxyproline content. TRAIL expression in human IPF lung samples was assessed by immunohistochemistry and peripheral blood TRAIL measured by ELISA.
TRAIL–/– mice had an exaggerated delayed inflammatory response to bleomycin, with increased neutrophil numbers (mean 3.19±0.8 wild type vs 11.5±5.4x104 TRAIL–/–, p<0.0001), reduced neutrophil apoptosis (5.42±1.6% wild type vs 2.47±0.5% TRAIL–/–, p=0.0003) and increased collagen (3.45±0.2 wild type vs 5.8±1.3 mg TRAIL–/–, p=0.005). Immunohistochemical analysis showed induction of TRAIL in bleomycin-treated wild-type mice. Patients with IPF demonstrated lower levels of TRAIL expression than in control lung biopsies and their serum levels of TRAIL were significantly lower compared with matched controls (38.1±9.6 controls vs 32.3±7.2 pg/ml patients with IPF, p=0.002).
These data suggest TRAIL may exert beneficial, anti-inflammatory actions in chronic pulmonary inflammation in murine models and that these mechanisms may be compromised in human IPF.
In 1986 the American Thoracic Society (ATS) suggested an obstructive abnormality be present when FEV1/FVC is <0.75 independent of age and sex.
Antielastin autoimmunity has been hypothesised to drive disease progression in chronic obstructive pulmonary disease (COPD). The proposed mechanism is currently disputed by conflicting data. The authors aimed to explore antibody responses against elastin in a large and extensively characterised COPD population and to assess elastin-specific peripheral T-cell reactivity in a representative subgroup.
Antielastin antibodies were analysed with indirect ELISA on the plasma of 320 patients with COPD (Global Initiative for Chronic Obstructive Lung Disease 1–4) and 143 smoking controls. In a second group of 40 patients with COPD and smoking controls, T-cell responses against extracellular matrix (elastin, collagen I and collagen V) were determined with enzyme-linked immunosorbent spot (EliSpot) (interferon (IFN) and interleukin-2) on peripheral blood mononuclear cells and compared with the responses of 11 never-smoking controls.
Antielastin antibody titres were not elevated in patients with COPD compared with smoking controls and even decreased significantly with increasing severity of COPD (p<0.001). Lower antielastin antibody titres were also found in a subgroup of patients with CT-proven emphysema. Elastin-specific INF-mediated T helper 1 responses could not be revealed in smoking subjects with and without COPD. Collagen I-mediated T-cell responses were also absent, which contrasted with a significant increased anticollagen V response in the smoking controls and patients with COPD compared with the never smokers (p=0.008). Collagen V-mediated T-cell responses could not discriminate between patients with COPD and smoking controls.
A systemic immune response against elastin could not be identified in patients with COPD. By contrast, collagen V-mediated autoimmunity was increased in the subgroup of smokers and may potentially contribute to the pathogenesis of COPD.
Relationships between indoor air quality (IAQ) found in schools and the allergic and respiratory health of schoolchildren have been insufficiently explored. A survey was conducted in a large sample of classrooms of primary schools in France to provide objective assessments of IAQ to which young schoolchildren are exposed in classrooms, and to relate exposure to major air pollutants found in classrooms to asthma and allergies of schoolchildren.
Concentrations of fine particles with aerodynamic diameter ≤2.5 μm (PM2.5), nitrogen dioxide (NO2) and three aldehydes were objectively assessed in 401 randomly chosen classrooms in 108 primary schools attended by 6590 children (mean age 10.4 years, SD ±0.7) in the French 6 Cities Study. The survey incorporated a medical visit including skin prick testing (SPT) for common allergens, a test for screening exercise-induced asthma (EIA) and a standardised health questionnaire completed by parents.
Children were differently exposed to poor air quality in classrooms, with almost 30% being highly exposed according to available standards. After adjusting for confounders, past year rhinoconjunctivitis was significantly associated with high levels of formaldehyde in classrooms (OR 1.19; 95% CI 1.04 to 1.36). Additionally, an increased prevalence of past year asthma was found in the classrooms with high levels of PM2.5 (OR 1.21; 95% CI 1.05 to 1.39), acrolein (OR 1.22; 95% CI 1.09 to 1.38) and NO2 (OR 1.16; 95% CI 0.95 to 1.41) compared with others. The relationship was observed mostly for allergic asthma as defined using SPT. A significant positive correlation was found between EIA and the levels of PM2.5 and acrolein in the same week.
In this random sample, air quality in classrooms was poor, varied significantly among schools and cities, and was related to an increased prevalence of clinical manifestations of asthma and rhinitis in schoolchildren. Children with a background of allergies seemed at increased risk.
Tuberculous pleurisy is traditionally indicated by extreme lymphocytosis in pleural fluid and low yield of effusion culture. However, there is considerable inconsistency among previous study results. In addition, these data should be updated due to early effusion studies and advances in culture methods.
From January 2004 to June 2009, patients with tuberculous pleurisy were retrospectively identified from the mycobacteriology laboratories and the pathology and tuberculosis registration databases of two hospitals in Taiwan where tuberculosis is endemic. Pleural fluid characteristics and yields of mycobacterial cultures using liquid media were evaluated.
A total of 382 patients with tuberculous pleurisy were identified. The median lymphocyte percentage of total cells in pleural fluids was 84% (IQR 64–95%) and 17% of cases had a lymphocyte percentage of <50%. The lymphocyte percentage was negatively associated with the probability of a positive effusion culture (OR 0.97; 95% CI 0.96 to 0.99). The diagnostic yields were 63% for effusion culture, 48% for sputum culture, 79% for the combination of effusion and sputum cultures, and 74% for histological examination of pleural biopsy specimens.
The degree of lymphocyte predominance in tuberculous pleurisy was lower than was previously thought. The lymphocyte percentage in pleural fluid was negatively associated with the probability of a positive effusion culture. With the implementation of a liquid culture method, the sensitivity of effusion culture was much higher than has been previously reported, and the combination of effusion and sputum cultures provided a good diagnostic yield.
The distal trachea and proximal bronchi were resected for complete tumour removal. The airway was replaced with a synthetic bioartificial nanocomposite, tailor-made in the shape of the patient's airway. The graft was seeded with autologous bone-marrow cells and cultured in a bioreactor for 36 h prior to transplantation. An extracellular like matrix and proliferating cells were noted within the graft following incubation. To augment the regeneration process, the patient received granulocyte colony-stimulating factor and epoetin β subcutaneous injections for 2 weeks postoperatively. No major complications were encountered and the patient remained asymptomatic and tumour-free 5 months later. Postoperative investigations suggested integration...]]>
In this study, the authors recruited 182 patients into a double-blind, randomised, placebo-controlled trial exploring vitamin D supplementation and COPD exacerbations. One hundred and fifty patients completed the study. Patients recruited were either current or former smokers over the age of 50 years, with a diagnosis of moderate to severe COPD. They were randomised to receive...]]>
Risk of PE increased across all age groups in the first year post admission. Risk gradually decreased after hospitalisation but remained above the control group at 10 years post admission. Length of stay did not affect the risk. The thrombotic risk may have been related to active inflammation, side effects of the autoimmune treatment and/or immobilisation. The study postulated that the fall in risk over time was attributable to the inflammatory activity of autoimmune conditions decreasing with effective treatment. Overall risk of PE was lower during 1989–2008 than during 1964–1988. Interestingly, no difference was seen after the introduction of low molecular...]]>
α1-Antitrypsin (AAT) deficiency is one of the commonest rare respiratory disorders worldwide. Diagnosis, assessment of risk for developing chronic obstructive pulmonary disease (COPD), and management of replacement therapy require the availability of precise and updated ranges for protein serum levels.
This paper aims to provide ranges of serum AAT according to the main genotype classes in the general population.
The authors correlated mean AAT serum levels with the main SERPINA1 variants (M1Ala/M1Val (rs6647), M3 (rs1303), M2/M4 (rs709932), S (rs17580) and Z (rs28929474)) in 6057 individuals enrolled in the Swiss Cohort Study on Air Pollution and Lung Diseases in Adults (SAPALDIA) cohort.
The following ranges (5th–95th percentile) of AAT were found in the serum (g/litre): 1.050–1.640 for PI*MM, 0.880–1.369 for PI*MS, 0.730–1.060 for PI*SS, 0.660–0.997 for PI*MZ and 0.490–0.660 for PI*SZ. There was very little overlap in AAT serum levels between genotype classes generally not believed to confer an enhanced health risk (MM and MS) and those associated with an intermediate AAT deficiency and a potentially mildly enhanced health risk (SS, MZ).
This work resulted in three important findings: technically updated and narrower serum ranges for AAT according to PI genotype; a suggestion for a population-based ‘protective threshold’ of AAT serum level, used in decision-making for replacement therapy; and more precise ranges framing the intermediate AAT deficiency area, a potential target for future primary prevention.
An MDT with a high number of patients may reflect a high level of experience, but this may not be the case for every MDT. It would be helpful to see the actual numbers of patients per MDT in each quintile and the raw data for survival. Only the largest of MDTs may link to specialist qualities. MDTs reviewing a large number of patients, but outside the top quintile, may reflect those that are under-resourced and struggling to cope.
Other factors that may influence the...]]>
Although generally mild, the 2009–2010 influenza A/H1N1 pandemic caused two major surges in hospital admissions in the UK. The characteristics of patients admitted during successive waves are described.
Data were systematically obtained on 1520 patients admitted to 75 UK hospitals between May 2009 and January 2010. Multivariable analyses identified factors predictive of severe outcome.
Patients aged 5–54 years were over-represented compared with winter seasonal admissions for acute respiratory infection, as were non-white ethnic groups (first wave only). In the second wave patients were less likely to be school age than in the first wave, but their condition was more likely to be severe on presentation to hospital and they were more likely to have delayed admission. Overall, 45% had comorbid conditions, 16.5% required high dependency (level 2) or critical (level 3) care and 5.3% died. As in 1918–1919, the likelihood of severe outcome by age followed a W-shaped distribution. Pre-admission antiviral drug use decreased from 13.3% to 10% between the first and second waves (p=0.048), while antibiotic prescribing increased from 13.6% to 21.6% (p<0.001). Independent predictors of severe outcome were age 55–64 years, chronic lung disease (non-asthma, non-chronic obstructive pulmonary disease), neurological disease, recorded obesity, delayed admission (≥5 days after illness onset), pneumonia, C-reactive protein ≥100 mg/litre, and the need for supplemental oxygen or intravenous fluid replacement on admission.
There were demographic, ethnic and clinical differences between patients admitted with pandemic H1N1 infection and those hospitalised during seasonal influenza activity. Despite national policies favouring use of antiviral drugs, few patients received these before admission and many were given antibiotics.
When compared with those in the placebo arm, patients receiving continuous salbutamol infusion demonstrated significantly higher mortality rates at 28 days (34% vs 23%, RR 1.47, 95% CI 1.03 to 2.08). There was also a trend towards increased adverse rates necessitating drug withdrawal, including tachycardia (14% vs...]]>
The isolated domains of thermodynamic and kinetic destabilisation from isolated NBD1 variants by the F508 mutation were studied along with conformational stabilisation of F508 NBD1. Thermodynamic and kinetic destabilisations in combination were shown to be responsible for the F508 NBD1 misfolding. In full-length CFTR, the stability of NBD1 and NBD1-CL interface is needed for normal channel function. As F508 causes impairment of both these...]]>
The distribution of pneumococcal serotypes implicated in non-invasive community-acquired pneumonia (CAP) in adults is currently unknown.
A prospective observational cohort study was conducted over 2 years in a large UK teaching hospital trust. Urine samples, in addition to routine blood and sputum samples, were obtained from consecutive adults admitted to the hospital with CAP. Pneumococcal serotype was determined from urine samples using a validated multiplex immunoassay which detects 14 serotypes.
Of 920 patients with CAP, 366 had pneumococcal CAP; 242 had a serotype determined. Thirty-day mortality was 10% for all-cause CAP and 9.6% for pneumococcal CAP. Annual incidence of pneumococcal CAP was 36.5 per 100 000, increasing from 12.1 to 274.1 per 100 000 for ages 16–44 years and ≥85 years, respectively. The most prevalent serotypes were 14, 1, 8, 3 and 19A. Less invasive serotypes were significantly associated with increasing age (OR per increasing age group: 1.5, 95% CI 1.2 to 1.9, p<0.001) and co-morbidity (OR per increasing Charlson index group: 1.4, 95% CI 1.0 to 2.0, p=0.036), and with higher 30-day mortality (OR adjusted for age and co-morbidity: 5.5, 95% CI 1.2 to 25.3, p=0.028) compared with highly invasive serotypes. The proportion of patients in whom serotypes contained within the seven-valent childhood pneumococcal conjugate vaccine was identified increased with age (15.6% for patients aged 16–44 years, 41.0% for patients aged ≥85 years; p<0.05).
In adult invasive and non-invasive pneumococcal CAP, the most common serotypes implicated were 14, 1, 8, 3 and 19A. Age and co-morbidity were associated with the distribution of serotypes identified.
By day 5, the patient had become progressively breathless requiring high flow oxygen to maintain his oxygen saturations. Urine and blood cultures taken on admission were negative. A repeat chest radiograph revealed new bilateral pulmonary infiltrates (
The rapid spread of multidrug-resistant tuberculosis (MDR-TB) has attracted global concerns. This study aimed to identify factors contributing to the high prevalence of MDR-TB in China's Heilongjiang province.
A cross-sectional survey following the WHO/International Union Against Tuberculosis and Lung Disease guidelines was conducted with consecutive recruitment of patients with TB in 30 counties selected at random in Heilongjiang in 2004. A total of 1995 patients were tested for MDR-TB. Factors associated with MDR-TB were identified through multilevel models and traditional logistic regression analysis, along with in-depth interviews with nine patients, five healthcare managers and four doctors.
241 patients (12%) were identified with MDR-TB. The retreatment patients were 5.48 times (95% CI 4.04 to 7.44) more likely to have MDR-TB than newly diagnosed patients. The patients who were treated with isoniazid and rifampin for >180 days were 4.82 times (95% CI 2.97 to 7.81) more likely to develop MDR-TB than those treated <180 days. Age and delay in initiating TB treatment were associated with MDR-TB. Financial burden, poor knowledge and side effects of TB treatment were perceived by the interviewees as influencing factors. Lack of coordination of services, unsatisfactory supervision of treatment and infection control jeopardised the control of MDR-TB.
Inappropriate treatment is the most important influencing factor of MDR-TB. Increasing people's awareness of TB, early detection and appropriate treatment of patients with TB should become a priority, which requires strong commitment and collaboration among health organisations and greater compliance with TB treatment guidelines by service providers and patients.
Excess visceral adiposity and sleep apnoea are two conditions independently associated with cardiovascular diseases. The two conditions are often combined and are believed to interact in a vicious circle.
To compare the response of men with visceral obesity with or without sleep apnoea syndrome to a 1-year healthy eating, physical activity/exercise intervention programme.
77 men, selected on the basis of increased waist circumference (≥90 cm) and dyslipidaemia (triglycerides ≥1.69 and/or high-density lipoprotein (HDL) cholesterol <1.03 mmol/litre), participated in this study. Body composition and fat distribution were assessed by dual-emission X-ray absorptiometry or CT and sleep breathing disorders by home-based polygraphic recording. Cardiorespiratory fitness, plasma adipokines, plasma inflammatory markers, fasting lipoprotein–lipid profile and oral glucose tolerance test were assessed.
After the 1-year lifestyle intervention, the mean oxygen desaturation index (ODI) of the whole sample decreased (–3±13 events/h, p<0.05). Men with sleep apnoea syndrome at baseline (ODI ≥10 events/h, n=28) showed smaller reductions in body mass index, waist circumference, triglycerides and smaller increases in HDL cholesterol and adiponectin than men without sleep apnoea (ODI <10 events/h, n=49), despite similar compliance to the programme. The higher the baseline ODI and the time spent under 90% saturation, the lower the reductions in fat mass and visceral adiposity, and the smaller the improvement in glucose/insulin homeostasis indices after 1 year.
Men with sleep apnoea syndrome at baseline had smaller reduction in body weight and less metabolic improvements associated with the lifestyle intervention programme than men without sleep apnoea syndrome.
20–30% of patients with asthma have neutrophilic airway inflammation and reduced responsiveness to steroid therapy. They often have chronic airway bacterial colonisation and Haemophilus influenzae is one of the most commonly isolated bacteria. The relationship between chronic airway colonisation and the development of steroid-resistant neutrophilic asthma is unclear.
To investigate the relationship between H influenzae respiratory infection and neutrophilic asthma using mouse models of infection and ovalbumin (OVA)-induced allergic airways disease.
BALB/c mice were intratracheally infected with H influenzae (day 10), intraperitoneally sensitised (day 0) and intranasally challenged (day 12–15) with OVA. Treatment groups were administered dexamethasone intranasally during OVA challenge. Infection, allergic airways disease, steroid sensitivity and immune responses were assessed (days 11, 16 and 21).
The combination of H influenzae infection and allergic airways disease resulted in chronic lung infection that was detected on days 11, 16 and 21 (21, 26 and 31 days after infection). Neutrophilic allergic airways disease and T helper 17 cell development were induced, which did not require active infection. Importantly, all features of neutrophilic allergic airways disease were steroid resistant. Toll-like receptor 4 expression and activation of phagocytes was reduced, but most significantly the influx and/or development of phagocytosing neutrophils and macrophages into the airways was inhibited.
The combination of infection and allergic airways disease promotes bacterial persistence, leading to the development of a phenotype similar to steroid-resistant neutrophilic asthma and which may result from dysfunction in innate immune cells. This indicates that targeting bacterial infection in steroid-resistant asthma may have therapeutic benefit.
The argument for the increasing use of annual CT of the thorax as an outcome surrogate for measuring and monitoring the progression of lung disease in patients with CF is the ability of CT to detect subtle, salient lung parenchymal changes, as opposed to using conventional plain chest radiography...]]>
A 55-year-old patient with non-small-cell lung cancer suffered from productive cough due to bronchopulmonary fistula (BPF) following pneumectomy (
None.
Commissioned; externally peer reviewed.
This study identified a subset of IgE and IgG antibodies as HRF-interacting molecules in vitro. Through complex molecular research techniques it was confirmed that HRF together with HRF-reactive IgE triggered mast cell activation in vitro, confirming its pro-inflammatory role. Specific HRF inhibitor peptides were also characterised. Through several different intricate experiments these...]]>
In the study by Camargos et al, steroid naive asthmatic patients received fluticasone propionate either through a face mask, while breathing through their nose with their mouth closed, or through a spacer with a mouthpiece for oral inhalation. The latter group also received 0.9% sodium chloride intranasal spray.
Some previous studies suggest there are sex differences in susceptibility to, and prevalence of, chronic obstructive pulmonary disease (COPD) but findings are inconsistent. In this study, whether different diagnostic criteria for COPD may contribute to these conflicting findings was examined.
Cross sectional analysis of data from the 1995, 1996 and 2001 Health Survey for England was undertaken, including participants of white ethnicity, aged 40+ years with a valid smoking history and lung function data. COPD was defined using Global Initiative for Chronic Obstructive Lung Disease (GOLD), National Institute for Health and Clinical Excellence (NICE) and lower limit of normal (LLN) spirometric criteria, in the absence of a diagnosis of asthma.
COPD was present in 3035 (16.1%), 1304 (7.0%) and 1684 (9.0%) people, according to the GOLD, NICE and LLN criteria, respectively. With both the GOLD and NICE definitions, men had significant independent increased risks of COPD compared with women (OR 1.46 (95% CI 1.34 to 1.59) and 1.30 (1.15 to 1.48), respectively). With the LLN definition, this effect was removed (OR 0.96 (0.87 to 1.07). With the use of both the GOLD and NICE criteria, women had significantly greater susceptibility to COPD (25–30% higher risk) for the same level of pack years of exposure. This was not observed with the LLN criteria.
The study indicates that sex differences in risk of COPD reported in previous studies are influenced by the definition used for COPD. When using a statistically driven definition (LLN), no independent sex difference was found and there was no evidence of an increased susceptibility to COPD among female compared with male smokers.
I admitted a prematurely aged woman in a poor general condition. She presented with dyspnoea, right upper quadrant abdominal pain and back pain. A physical examination revealed stigmata of hypoxaemia, light crackles on both lungs, clinical signs for steroid use and an enlarged liver painful on palpation. She is a non-smoker and she has no history of cardiac diseases or cardiac involvement by...]]>
Automatic titration modes of non-invasive ventilation, including average volume assured pressure support (AVAPS), are hybrid technologies that target a set volume by automated adjustment of pressure support (PS). These automated modes could offer potential advantages over fixed level PS, in particular, in patients who are super obese.
Consecutive patients with obesity hypoventilation syndrome were enrolled in a two-centre prospective single-blind randomised controlled trial of AVAPS versus fixed-level PS using a strict protocolised setup.
The primary outcome was change in daytime arterial PCO2 (PaCO2) at 3 months. Body composition, physical activity (7-day actigraphy) and health-related quality of life (severe respiratory insufficiency questionnaire, SRI) were secondary outcome measures.
50 patients (body mass index 50±7 kg/m2; 55±11 years; 53% men) were enrolled with a mean PaCO2 of 6.9±0.8 kPa and SRI of 53±17. 46 patients (23 AVAPS and 23 PS) completed the trial. At 3 months, improvements in PaCO2 were observed in both groups (AVAPS 0.6 kPa, 95% CI 0.2 to 1.1, p<0.01 vs PS 0.6 kPa, 95% CI 0.1 to 1.1, p=0.02) but no between-group difference (–0.1 kPa, 95% CI –0.7 to 0.6, p=0.87). SRI also improved in both groups (AVAPS 11, 95% CI 6 to 17, p<0.001 vs PS 7, 95% CI 1 to 12, p=0.02; between groups 5, 95% CI –3 to 12, p=0.21). Secondary analysis of both groups combined showed improvements in daytime physical activity that correlated with reduction in fat mass (r=0.48; p=0.01).
The study demonstrated no differences between automated AVAPS mode and fixed-level PS mode using a strict protocolised setup in patients who were super obese. The data suggest that the management of sleep-disordered breathing may enhance daytime activity and promote weight loss in super-obese patients. Trial registration details available at http://www.controlled-trials.com/ISRCTN63940700
The primary outcome of the trial was the change in the forced expiratory volume in 1 s (FEV1). The secondary outcomes were time to the first pulmonary exacerbation and subject-reported respiratory symptoms. The trial included 161 subjects who were 12 years of age or above with the G551D mutation.
The study showed a treatment effect of 10.6% in FEV1 (p<0.001) in patients with a starting FEV1 <70% predicted. There was a 55% reduction in the risk of pulmonary exacerbation and a statistically significant improvement in subject-reported respiratory symptoms by 48 weeks. The study showed no significantly increased rate of adverse effects or dropout rate associated with ivacaftor. The study was not powered to assess the treatment effects in different demographic subgroups.
The G551D mutation is present only in approximately 4%–5% of cystic fibrosis patients and...]]>
Pseudomonas aeruginosa chronic pulmonary infection is an unfavourable event in cystic fibrosis. Bacterial clearance is possible with an early antibiotic treatment upon pathogen isolation. Currently, no best practice exists for early treatment. The efficacy of two different regimens against initial P aeruginosa infection was assessed.
In a randomised, open-label, parallel-group study involving 13 centres, the superiority of inhaled tobramycin/oral ciprofloxacin compared with inhaled colistin/oral ciprofloxacin (reference treatment) over 28 days was evaluated. Patients were eligible if they were older than 1 year with first or new P aeruginosa isolation. Treatments were assigned equally by centralised balanced randomisation, stratified by age and forced expiratory volume in 1 s values. The participants and those giving the intervention were not masked to arm assignments. The primary endpoint was P aeruginosa eradication, defined as three successive negative cultures in 6 months. Analysis was by intention to treat. This trial was registered with EudraCT, number 2008-006502-42.
105 patients were assigned to inhaled colistin/oral ciprofloxacin (arm A) and 118 to inhaled tobramycin/oral ciprofloxacin (arm B). All patients were analysed. P aeruginosa was eradicated in 66 (62.8%) patients in arm A and in 77 (65.2%) in arm B (OR 0.90, 95% CI 0.52 to 1.55, p=0.81). Following treatment, an increase in Stenotrophomonas maltophilia was noted (OR 3.97, 95% CI 2.27 to 6.94, p=0.001) with no differences between the two arms (OR 0.89, 95% CI 0.44 to 1.78, p=0.88).
No superiority of treatment under study was demonstrated in comparison to the reference treatment. Early eradication treatment was associated with an increase in S maltophilia.
Two distinct, stable inflammatory phenotypes have been described in adults with asthma: eosinophilic and non-eosinophilic. Treatment strategies based on these phenotypes have been successful. This study evaluated sputum cytology in children with asthma to classify sputum inflammatory phenotypes and to assess their stability over time.
Sputum induction was performed in 51 children with severe asthma and 28 with mild to moderate asthma. Samples were classified as eosinophilic (>2.5% eosinophils), neutrophilic (>54% neutrophils); mixed granulocytic (>2.5% eosinophils, >54% neutrophils); or paucigranulocytic (≤2.5% eosinophils, ≤54% neutrophils). Sputum induction was repeated every 3 months in children with severe asthma (n=42) over a 1-year period and twice in mild to moderate asthma (n=17) over 3–6 months.
62 children (78%) had raised levels of inflammatory cells in at least one sputum sample. In the longitudinal analysis 37 of 59 children (63%) demonstrated two or more phenotypes. Variability in sputum inflammatory phenotype was observed in both the severe and the mild to moderate asthma groups. Change in phenotype was not related to change in inhaled corticosteroid (ICS) dose or asthma control, nor was it reflected in a change in exhaled nitric oxide (FENO). 24 children (41%) fulfilled the criteria for non-eosinophilic asthma on one occasion and eosinophilic on another. There were no differences in severity, asthma control, atopy, ICS dose or forced expiratory volume in 1 s between those who were always non-eosinophilic and those always eosinophilic.
Raised levels of inflammatory cells were frequently found in children with asthma of all severities. Sputum inflammatory phenotype was not stable in children with asthma.
It has recently been found that the incidence of complicated pneumonia in children is increasing and that there is a concurrent increase in the incidence of community-associated methicillin-resistant S aureus (CA-MRSA) infections.
Risk scores that include genetic risk data may reach the parts that other risk scores fail to reach. In the lung-SEARCH screening trial, we found that a negative family history specifically led some smokers to decline participation in screening. Being told that risk of lung cancer is ‘in your genes’ may specifically counter perceptions of protection from a negative family history. This proposal could be tested with further qualitative exploration...]]>
Development of emphysema and vascular stiffness in chronic obstructive pulmonary disease (COPD) may be due to a common mechanism of susceptibility to pulmonary and systemic elastin degradation.
To investigate whether patients with COPD have evidence of systemic elastin degradation in the skin.
The authors measured cutaneous elastin degradation using immunohistochemistry (percentage area of elastin fibres) in sun-exposed (exposed) and non-sun-exposed (non-exposed) skin biopsies in 16 men with COPD and 15 controls matched for age and cigarette smoke exposure. Quantitative PCR of matrix metalloproteinase (MMP)-2, -9, -12 and tissue inhibitor of metalloproteinase-1 mRNA and zymography for protein expression of MMP-2 and -9 were performed on homogenised skin. Arterial stiffness and emphysema severity were measured using carotid-femoral pulse wave velocity and quantitative CT scanning.
Skin elastin degradation was greater in exposed and non-exposed skin of patients with COPD compared with controls (exposed, mean (SD); 43.5 (12.1)% vs 26.3 (6.9)%, p<0.001; non-exposed 22.4 (5.2)% vs 18.1 (4.3)%, p=0.02). Cutaneous expression of MMP-9 mRNA and proMMP-9 concentrations was increased in exposed skin of COPD patients (p=0.004 and p=0.02, respectively) and was also associated with increased skin elastin degradation (r=0.62, p<0.001 and r=0.47, p=0.01, respectively). In the entire cohort of ex-smokers, cutaneous elastin degradation was associated with emphysema severity, FEV1 and pulse wave velocity.
Patients with COPD have increased skin elastin degradation compared with controls, which is related to emphysema severity and arterial stiffness. Systemic elastin degradation due to increased proteolytic activity may represent a novel shared mechanism for the pulmonary, vascular and cutaneous features of COPD.
Although an increased concentration of degraded elastin products in patients with chronic obstructive pulmonary disease (COPD) has been reported for many years, its clinical validity and utility remain uncertain due to technical difficulties, small study groups and the unknown relationship between exacerbation and elastin degradation. The objectives of this study were to determine the validity of urinary and blood total desmosine/isodesmosine in patients with COPD and asthma and to evaluate their relationship to exacerbation status and lung function.
Urinary and blood desmosine levels were measured using validated isotopic dilution liquid chromatography–tandem mass spectrometry methods.
390 study participants were recruited from the following groups: healthy volunteers, stable asthma, stable and ‘during an exacerbation’ COPD. Compared with healthy non-smokers, we found increased urinary or blood desmosine levels in patients with COPD, but no differences in patients with asthma or healthy smokers. The elevation of urinary desmosine levels was associated with the exacerbation status in patients with COPD. Approximately 40% of patients with stable and ‘during an exacerbation’ COPD showed elevated blood desmosine levels. Blood desmosine levels were strongly associated with age and were negatively correlated with lung diffusing capacity for carbon monoxide.
The results suggest that urinary desmosine levels are raised by exacerbations of COPD whereas blood desmosine levels are elevated in a subgroup of patients with stable COPD and reduced lung diffusing capacity. The authors speculate that a raised blood desmosine level may identify patients with increased elastin degradation suitable for targeted therapy. Future prospective studies are required to investigate this hypothesis.
Considering its high frequency and association with poor control of asthma, among untreated and even treated subjects,
In their paper, however, de Groot et al stated that ‘One...]]>
Historically, S aureus has been the principal organism associated with necrotic or cavitary pneumonia in children, but recent data demonstrate Streptococcus pneumoniae is now a much more important cause.
To assess this, we analysed all 129 052 cases submitted to the NLCA (England only) between 2006 and 2010 inclusive, based on the ‘place first seen’ as a surrogate marker of the decision-making multidisciplinary team (MDT). After excluding cases with ‘negative survival’, no recorded place first seen and trusts with <100 cases over the 5-year time span, we divided the MDTs into quintiles based...]]>
Although women with severe non-allergic asthma may represent a substantial proportion of adults with asthma in clinical practice, gender differences in the incidence of allergic and non-allergic asthma have been little investigated in the general population.
Gender differences in asthma prevalence, reported diagnosis and incidence were investigated in 9091 men and women randomly selected from the general population and followed up after 8–10 years as part of the European Community Respiratory Health Survey. The protocol included assessment of bronchial responsiveness, IgE specific to four common allergens and skin tests to nine allergens.
Asthma was 20% more frequent in women than in men over the age of 35 years. Possible under-diagnosis of asthma appeared to be particularly frequent among non-atopic individuals, but was as frequent in women as in men. The follow-up of subjects without asthma at baseline showed a higher incidence of asthma in women than in men (HR 1.94; 95% CI 1.40 to 2.68), which was not explained by differences in smoking, obesity or lung function. More than 60% of women and 30% of men with new-onset asthma were non-atopic. The incidence of non-allergic asthma was higher in women than in men throughout all the reproductive years (HR 3.51; 95% CI 2.21 to 5.58), whereas no gender difference was observed for the incidence of allergic asthma.
This study shows that female sex is an independent risk factor for non-allergic asthma, and stresses the need for more careful assessment of possible non-allergic asthma in clinical practice, in men and women.
CD200, a cell-surface immunoglobulin-like molecule expressed by immune and stromal cells, dampens the pro-inflammatory activity of tissue-resident innate cells via its receptor, CD200R. This interaction appears critical for peripheral immune tolerance, particularly in the airways where excessive inflammation is undesirable. Vitamin D contributes to pulmonary health and promotes regulatory immune pathways, therefore its influence on CD200 and CD200R was investigated.
CD200 and CD200R expression were assessed by qPCR and immunoreactivity of human lymphoid, myeloid and epithelial cells following 1α,25-dihydroxyvitamin D3 (1α,25VitD3) exposure in vitro and in peripheral T cells following 1α,25VitD3 oral ingestion in vivo. The effect of 1α25VitD3 was also assessed in human airway-resident cells.
1α25VitD3 potently upregulated CD200 on peripheral human CD4+ T cells in vitro, and in vivo there was a trend towards upregulation in healthy, but not asthmatic individuals. CD200R expression was not modulated in any cells studied. CD200 induction was observed to a lesser extent in CD8+ T cells and not in B cells or airway epithelium. T cells isolated from the human airway also responded strongly to 1α25VitD3 to upregulate CD200.
The capacity of 1α,25-dihydroxyvitamin D3 to induce CD200 expression by peripheral and respiratory tract T cells identifies an additional pathway via which vitamin D can restrain inflammation in the airways to maintain respiratory health.
A chest x-ray showed a right sided ‘white out’, thought to be a pleural effusion (
However, further review of the CT images identified an unusual abnormality within the right hemithorax. Several of the thoracic spinal pedicles were absent and there was communication of fluid from a dilated spinal canal to the large fluid collection within the right hemithorax (
A thoracic MR image confirmed the appearance was due to a large cerebrospinal fluid collection within the right hemithorax, which directly communicated to the right side of the spinal canal (
Obstructive sleep apnoea (OSA) is associated with increased cardiovascular risk, however the mechanisms are not well established.
This study aimed to determine whether treatment of OSA with nasal continuous positive airway pressure (CPAP) would favourably alter coagulability across the sleep–wake cycle.
In a randomised crossover trial, 28 patients received therapeutic or placebo CPAP, each for 2 months with a 1 month washout between treatments. After each treatment period, a 24 h coagulation study was conducted in the laboratory. Plasminogen activator inhibitor-1 (PAI-1), D-dimer, fibrinogen, von Willebrand Factor (vWF), factor VIII (FVIII), factor VII (FVII) and factor V (FV) were determined at seven time points over the day and night.
At baseline, patients had severe OSA (Apnoea Hypopnoea Index 37.9±23.9 events/h). Treatment of OSA with CPAP compared with placebo resulted in lower 24 h levels of vWF (–3.9%, p=0.013), FVIII (–6.2%, p=0.007) and FV (–4.2%, p<0.001). The greatest difference occurred during the nocturnal and early morning periods. In contrast, fibrinogen, D-dimer, FVII and PAI-1 did not differ between treatments, however all markers displayed diurnal variability independent of treatment.
In this randomised, placebo-controlled crossover trial, treatment of OSA with CPAP reduced the early morning level of vWF, and nocturnal levels of FVIII and FV. These findings suggest that CPAP may reduce cardiovascular risk in OSA, in part through reducing risk of thrombosis.
One thousand one hundred and forty men, ex or current smokers (>16.5 pack year history), aged 50–75 years, already enrolled in a lung cancer screening trial, had low dose screening inspiratory CT scans, PFT and an additional expiratory scan. Pre-bronchodilatory forced expiratory volume in one second/forced vital capacity ratio <70% was used to diagnose COPD. Those with advanced disease, self-reported as unable to climb two flights stairs were excluded. CT emphysema, CT air trapping, body mass index, pack years and smoking status formed a diagnostic model to identify those with COPD.
Four hundred and thirty-seven (38%) subjects had COPD on PFT. The diagnostic model correctly diagnosed 274 patients with COPD, falsely...]]>
One area that this study did not address was the effect of the site of the smoking on exposure.
We have studied urinary cotinine levels in children attending an asthma clinic and correlated them with the self-reported smoking habits of their carers. Thirty-six girls and 64 boys aged between 30 and 164 months attending our asthma clinic were recruited if at least one carer smoked. The carers completed a questionnaire about their smoking habits and the child's urine was tested for cotinine using NicAlert, a commercially available reagent strip. Levels of 0–10 ng/ml correspond to minimal or no nicotine exposure, 10–100 ng/ml to moderate to high SHS exposure and >100 ng/ml to active smoking. Ten further...]]>
The study population comprised 86 CPAP naïve patients aged 30–65 who were recruited from a sleep laboratory in New Delhi, India. Exclusion criteria were previous or current treatment for hypertension, diabetes, dyslipidemia or any evidence of end-organ damage due to these conditions.
There were modest, statistically significant, reductions in systolic and diastolic blood pressure, glycated haemoglobin, triglycerides, low-density lipoprotein, non-high-density lipoprotein and total cholesterol after CPAP therapy as compared with sham therapy. Additionally, there were significant decreases in body mass index and visceral and subcutaneous fat. Carotid intimal thickness and insulin resistance did not differ significantly. Applying the authors' criteria for the metabolic syndrome, there...]]>
Four hundred and forty-three eligible participants received five telephone-counselling calls and 4 weeks of nicotine replacement therapy. They were randomised to receive continuing counselling and nicotine replacement therapy for 1 year (longitudinal care, LC) or to receive one additional call at 8 weeks (evidence-based usual care, UC). The primary outcome was 6 months of prolonged abstinence, measured at 18 months following initial quit date. Secondary outcomes included abstinence rates before 6 months and smoking reduction.
At 18 months, 30.2% of LC participants reported 6 months of abstinence from smoking, compared with 23.5% in UC. Prior to 6 months, abstinence rates were slightly higher with UC than LC. At all time points, those who did not quit had greater smoking...]]>
The value of pleural lavage cytology (PLC) in assessing the prognosis of early stage lung cancer is still controversial. No systematic review has investigated the relationship between PLC and lung cancer recurrence. Our primary goal was to investigate the association between positive pre-resection PLC and pleural, distant and overall tumour recurrence in patients undergoing surgical resection.
Medline, EMBASE and Google Scholar databases were searched up to 2011. All studies reporting relevant outcomes in both patient groups were included. Data were extracted for the following outcomes of interest: overall, local and distant recurrence; and freedom from death (survival—overall and patients with stage I disease only). Random effects meta-analysis was used to aggregate the data. Sensitivity and heterogeneity analysis were performed.
A meta-analysis of eight studies at maximum follow-up demonstrated a significant association between positive pre-resection PLC and increased risk of post-resection overall recurrence (OR 4.82, 95% CI 2.45 to 9.51), pleural recurrence (OR 9.89, 95% CI 5.95 to 16.44) and distant cancer recurrence (OR 3.18, 95% CI 1.57 to 6.46). Furthermore, a meta-analysis of 17 studies suggested that positive pre-resection PLC was also associated with unfavourable survival (HR 2.08, 95% CI 1.71 to 2.52). These findings were supported by sensitivity analysis.
Positive pre-resection PLC is associated with higher overall, distant and local tumour recurrence and unfavourable patient survival outcomes. This technique may therefore act as a predictor of tumour recurrence and adverse survival. Furthermore, its role in including adjuvant chemotherapy to the management protocol should be investigated within randomised controlled trials.
Collateral ventilation has been proposed as a mechanism of compensation of respiratory function in obstructive lung diseases but observations of it in vivo are limited. The assessment of collateral ventilation with an imaging technique might help to gain insight into lung physiology and assist the planning of new bronchoscopic techniques for treating emphysema.
To obtain images of delayed ventilation that might be related to collateral ventilation over the period of a single breath-hold in patients with chronic obstructive pulmonary disease (COPD).
Time-resolved breath-hold hyperpolarised 3He MRI was used to obtain images of the progressive influx of polarised gas into initially non-ventilated defects.
A time-series of images showed that 3He moves into lung regions which were initially non-ventilated. Ventilation defects with delayed filling were observed in 8 of the 10 patients scanned.
A method for direct imaging of delayed ventilation within a single breath-hold has been demonstrated in patients with COPD. Images of what is believed to be collateral ventilation and slow filling of peripheral airspaces due to increased flow resistance are presented. The technique provides 3D whole-lung coverage with sensitivity to regional information, and is non-invasive and non-ionising.
The main aim of our paper was to study the association between occupational exposure to organic dust and its constituents and lung cancer in the general population. For cumulative exposure to organic dust we observed a significantly increased risk of lung cancer. No associations were found between cumulative exposure to endotoxin and lung cancer. Exposures...]]>
The investigators carried out an open-label non-inferiority trial in which 3986 subjects were randomised to combination therapy and 3745 randomised to isoniazid monotherapy. Subjects were enrolled if they had a positive tuberculin skin test or were a close contact of a patient with tuberculosis. Contacts of patients with drug-resistant tuberculosis were excluded. Subjects were followed-up for 33 months from enrolment and the primary end point evaluated was the development of active tuberculosis in the study subjects.
The study demonstrated that 3 months directly observed weekly combination therapy is non-inferior to 9 months daily self-administered isoniazid. Seven patients developed...]]>
Bacterial pneumonia is the most common infectious cause of death worldwide and treatment is increasingly hampered by antibiotic resistance. Mesenchymal stem cells (MSCs) have been demonstrated to provide protection against acute inflammatory lung injury; however, their potential therapeutic role in the setting of bacterial pneumonia has not been well studied.
This study focused on testing the therapeutic and mechanistic effects of MSCs in a mouse model of Gram-negative pneumonia.
Syngeneic MSCs from wild-type mice were isolated and administered via the intratracheal route to mice 4 h after the mice were infected with Escherichia coli. 3T3 fibroblasts and phosphate-buffered saline (PBS) were used as controls for all in vivo experiments. Survival, lung injury, bacterial counts and indices of inflammation were measured in each treatment group. Treatment with wild-type MSCs improved 48 h survival (MSC, 55%; 3T3, 8%; PBS, 0%; p<0.05 for MSC vs 3T3 and PBS groups) and lung injury compared with control mice. In addition, wild-type MSCs enhanced bacterial clearance from the alveolar space as early as 4 h after administration, an effect that was not observed with the other treatment groups. The antibacterial effect with MSCs was due, in part, to their upregulation of the antibacterial protein lipocalin 2.
Treatment with MSCs enhanced survival and bacterial clearance in a mouse model of Gram-negative pneumonia. The bacterial clearance effect was due, in part, to the upregulation of lipocalin 2 production by MSCs.
A 58-year-old never-smoker man developed dyspnoea, cough, fevers, weight loss and tremulousness over 4 weeks. He had a brief history of asbestos exposure. Significant medical history included autosomal-dominant polycycstic kidney disease (APKD) and renal transplantation 7 years previously. He took mycophenolate mofetil and tacrolimus immune-suppressants. Examination revealed tachypnoea, a fine right arm tremor, bronchial breathing on the right and a superficial 1x2 cm non-fluctuant lump over the abdomen. Lymph nodes were impalpable.
Screening blood tests showed values of c reactive protein 115 mg/l (NR <6.0), urea 25.8 mmol/l, creatinine 254 umol/l (post-transplant baseline 220–230) and tacrolimus 25.5xµg/l (NR 5–10). Autoimmune profile was negative. PCR detected cytomegalovirus (CMV) levels at 31 338 copies/ml. Plain chest radiography showed right upper lobe consolidation (
The clinical response was slow. CT thoraco-abdominal scans noted a right upper lobe...]]>
Based on the studies to date, there is a consistent theme that smokers' participation in CT screening programmes for lung cancer is poor when their motivation is low and much greater when their perception of risk of lung cancer is high.
Regarding a decreased risk of lung cancer among cotton workers
For farmers we believe that the multicentre case–control study findings have the same shortcomings for the following reasons. In the Veneto region of Italy, where the first study reporting a decreased risk of lung cancer among farmers was carried out,
Asthma and allergic rhinitis are the two most common chronic disorders in childhood and adolescence. To date, no study has examined the impact of comorbid allergic rhinitis on asthma control in children.
To examine the prevalence of allergic rhinitis in children with asthma, and the impact of the disease and its treatment on asthma control.
A cross-sectional survey in 203 children with asthma (5–18 years) using validated questionnaires on rhinitis symptoms (stuffy or runny nose outside a cold) and its treatment, and the paediatric Asthma Control Questionnaire (ACQ). Fraction of nitric oxide in exhaled air (FeNO) was measured with a Niox Mino analyser; total and specific IgE levels were assessed by the Immunocap system.
157 children (76.2%) had symptoms of allergic rhinitis but only 88 of these (56.1%) had been diagnosed with the condition by a physician. ACQ scores were worse in children with allergic rhinitis than in those without the condition (p=0.012). An ACQ score ≥1.0 (incomplete asthma control) was significantly more likely in children with allergic rhinitis than in those without (OR 2.74, 95% CI 1.28 to 5.91, p=0.0081), also after adjustment for FeNO levels and total serum IgE. After adjustment for nasal corticosteroid therapy, allergic rhinitis was no longer associated with incomplete asthma control (OR 0.72, 95% CI 0.47 to 1.12, p=0.150).
Allergic rhinitis is common in children with asthma, and has a major impact on asthma control. The authors hypothesise that recognition and treatment of this condition with nasal corticosteroids may improve asthma control in children, but randomised clinical trials are needed to test this hypothesis.
Rhinoviruses are important triggers of pulmonary exacerbations and possible contributors to long-term respiratory morbidity in cystic fibrosis (CF), but mechanisms leading to rhinovirus-induced CF exacerbations are poorly understood. It is hypothesised that there is a deficient innate immune response of the airway epithelium towards rhinovirus infection in CF.
Early innate immune responses towards rhinoviruses (RV-16, major-type and RV-1B, minor-type) in CF and non-CF bronchial epithelial cell lines and primary nasal and bronchial epithelial cells from patients with CF (n=13) and healthy controls (n=24) were studied.
Rhinovirus RNA expression and virus release into supernatants was increased more than tenfold in CF cells compared with controls. CF cells expressed up to 1000 times less interferon (IFN) type I (β) and type III () mRNA and produced less than half of IFN-β and IFN- protein compared with controls. In contrast, interleukin 8 production was not impaired, indicating a selective deficiency in the innate antiviral defence system. Deficient IFN production was paralleled by lower expression of IFN-stimulated genes including myxovirus resistance A, 2',5'-oligoadenylate synthetase, viperin and nitric oxide synthase 2. Addition of exogenous type I and III IFNs, particularly IFN-β, restored antiviral pathways and virus control in CF cells, underscoring the crucial role of these molecules.
This study describes a novel mechanism to explain the increased susceptibility of patients with CF to rhinovirus infections. A profound impairment of the antiviral early innate response in CF airway epithelial cells was identified, suggesting a potential use of IFNs in the treatment of rhinovirus-induced CF exacerbations.
Cross-sectional studies implicate neutrophilic inflammation and pulmonary infection as risk factors for early structural lung disease in infants and young children with cystic fibrosis (CF). However, the longitudinal progression in a newborn screened population has not been investigated.
To determine whether early CF structural lung disease persists and progresses over 1 year and to identify factors associated with radiological persistence and progression.
143 children aged 0.2–6.5 years with CF from a newborn screened population contributed 444 limited slice annual chest CT scans for analysis that were scored for bronchiectasis and air trapping and analysed as paired scans 1 year apart. Logistic and linear regression models, using generalised estimating equations to account for multiple measures, determined associations between persistence and progression over 1 year and age, sex, severe cystic fibrosis transmembrane regulator (CFTR) genotype, pancreatic sufficiency, current respiratory symptoms, and neutrophilic inflammation and infection measured by bronchoalveolar lavage.
Once detected, bronchiectasis persisted in 98/133 paired scans (74%) and air trapping in 178/220 (81%). The extent of bronchiectasis increased in 139/227 (63%) of paired scans and air trapping in 121/264 (47%). Radiological progression of bronchiectasis and air trapping was associated with severe CFTR genotype, worsening neutrophilic inflammation and pulmonary infection.
CT-detected structural lung disease identified in infants and young children with CF persists and progresses over 1 year in most cases, with deteriorating structural lung disease associated with worsening inflammation and pulmonary infection. Early intervention is required to prevent or arrest the progression of structural lung disease in young children with CF.
We are unconvinced by the implication that the levels of normocarbia and hypercarbia (up to 50 mm Hg) demonstrated in this study are deleterious in acute asthma. Life-threatening respiratory failure in asthma is multifactorial, with ventilation–perfusion mismatch, lung hyperinflation and an increased work of breathing leading to respiratory muscle fatigue all being contributory factors.
We reviewed the contents of the new BTS guidelines relevant for physiotherapists. The timescale for literature search indicates that the relevant section was last updated in February 2006, with coverage in Medline extending from 1996 to 2005.
Thus, we searched PubMed for English language papers published between January 2006 and December 2010 and found 32 indexed as randomised controlled trials. In the Cochrane Database of Systematic Reviews we found updates or revisions to all cited documents, with those updated in 2004 and 2005 and not quoted in the guideline.
A corresponding document, not referred to in the BTS guidelines, the joint BTS and the Association of Chartered Physiotherapists in Respiratory Care (ACPRC) Guidelines...]]>
Contrary to the existing bleomycin-based models of pulmonary injury causing fibrosis, this murine H1N1 model sustains substantial airway damage and epithelial destruction, followed by viral clearing and histological recovery over several months. This represents a novel paradigm to investigate regenerative responses to infection.
Using molecular and immunohistochemical methods, the authors illustrate that following H1N1 infection, a cell population expressing p63, a known marker of stem cells in nasal and tracheal epithelia, emerges from distal bronchial epithelia in damaged lung and expands to form discrete ‘pods’ or islands of cells that concentrically surround distal airways. These pods assemble into novel alveoli-like structures bearing molecular markers and gene expression profiles of alveoli. Lineage tracing of these pods reveals a...]]>
The annual rate of decline in forced vital capacity (FVC), the primary end-point of this study, in the highest dose subgroup compared with the placebo subgroup failed to show statistical significance. However, the authors were able to demonstrate that the changes in FVC from baseline, total lung capacity, oxygen saturations, acute exacerbations and quality of life were statistically significantly better in the group receiving the highest dose of BIBF 1120. Serious adverse events were similar between groups, but lower in the highest dosing regimen compared with placebo. The most common reason for discontinuation of the medication was gastrointestinal upset.
Of note, only 33% of the patients recruited fulfilled the criteria for definite IPF with the remainder being...]]>
S1P1 receptor specific agonists were shown to significantly reduce cytokine responses and innate inflammation following infection of mice with mouse adapted influenza virus. Similar results were found using mice infected with a virulent isolate of the H1N1 pandemic influenza virus. S1P1 agonism also led to a reduction in mouse mortality.
Using an eGFP-S1P1 receptor knockin mouse and flow cytometry, high levels of S1P1 expression were detected in lung lymphatic and vascular endothelium, CD4 T cells and B cells. However, S1P1 agonist treatment of knockin mice did not alter the expression levels suggesting an effect through functional activation rather than receptor degradation. Furthermore, S1P1 treatment of...]]>
House dust mite (HDM) allergens have been reported to increase airway epithelial permeability, thereby facilitating access of allergens and allergic sensitisation.
The authors aimed to understand which biochemical properties of HDM are critical for epithelial immune and barrier responses as well as T helper 2-driven experimental asthma in vivo.
Three commercially available HDM extracts were analysed for endotoxin levels, protease and chitinase activities and effects on transepithelial resistance, junctional proteins and pro-inflammatory cytokine release in the bronchial epithelial cell line 16HBE and normal human bronchial cells. Furthermore, the effects on epithelial remodelling and airway inflammation were investigated in a mouse model.
The different HDM extracts varied extensively in their biochemical properties and induced divergent responses in vitro and in vivo. Importantly, the Greer extract, with the lowest serine protease activity, induced the most pronounced effects on epithelial barrier function and CCL20 release in vitro. In vivo, this extract induced the most profound epithelial E-cadherin delocalisation and increase in CCL20, CCL17 and interleukin 5 levels, accompanied by the most pronounced induction of HDM-specific IgE, goblet cell hyperplasia, eosinophilic inflammation and airway hyper-reactivity.
This study shows the ability of HDM extracts to alter epithelial immune and barrier responses is related to allergic sensitisation but independent of serine/cysteine protease activity.
A 55-year-old previously fit and well woman was admitted with a 4-week history of dry cough and 1-week history of progressive breathlessness. She had never smoked, was on no regular medications and there was no history of heart disease, malignancy, rheumatological disease or tuberculosis.
Physical examination revealed signs of a moderate right-sided pleural effusion but was otherwise unremarkable. Full blood count, clotting, and renal and liver function tests were normal. C reactive protein was <5 mg/l. Chest x-ray revealed a moderate right sided pleural effusion.
She underwent bedside diagnostic aspiration of 50 ml of pleural fluid which macroscopically appeared cloudy (
Pneumonectomy syndrome is a rare complication occurring after pneumonectomy, which was originally described in 1979.
The asthma-associated gene urokinase plasminogen activator receptor (uPAR) may be involved in epithelial repair and airway remodelling. These processes are not adequately targeted by existing asthma therapies. A fuller understanding of the pathways involved in remodelling may lead to development of new therapeutic opportunities. uPAR expression in the lung epithelium of normal subjects and patients with asthma was investigated and the contribution of uPAR to epithelial wound repair in vitro was studied using primary bronchial epithelial cells (NHBECs).
Bronchial biopsy sections from normal subjects and patients with asthma were immunostained for uPAR. NHBECs were used in a scratch wound model to investigate the contribution of the plasminogen pathway to repair. The pathway was targeted via blocking of the interaction between urokinase plasminogen activator (uPA) and uPAR and overexpression of uPAR. The rate of wound closure and activation of intracellular signalling pathways and matrix metalloproteinases (MMPs) were measured.
uPAR expression was significantly increased in the bronchial epithelium of patients with asthma compared with controls. uPAR expression was increased during wound repair in monolayer and air-liquid interface-differentiated NHBEC models. Blocking the uPA–uPAR interaction led to attenuated wound repair via changes in Erk1/2, Akt and p38MAPK signalling. Cells engineered to have raised levels of uPAR showed attenuated repair via sequestration of uPA by soluble uPAR.
The uPAR pathway is required for efficient epithelial wound repair. Increased uPAR expression, as seen in the bronchial epithelium of patients with asthma, leads to attenuated wound repair which may contribute to the development and progression of airway remodelling in asthma. This pathway may therefore represent a potential novel therapeutic target for the treatment of asthma.
In this randomised, double-blind, placebo-controlled study, lebrikizumab, a monoclonal antibody that binds to IL-13 thereby inhibiting its function, was used to investigate the effect on patients with uncontrolled asthma undergoing treatment with inhaled steroids. Lebrikizumab showed superior primary outcome to placebo, with an increase in pre-bronchodilator forced expiratory volume in one second (FEV1) by 5.5% at week 12. Patients with higher periostin levels had a relative increase in FEV1 of 8.2% compared with those receiving placebo, whereas the low periostin group had a relative increase in FEV1 of 1.6% over the placebo group. There was no significant improvement in secondary outcomes including rates of asthma exacerbation, asthma symptom scores or...]]>
A 64-year-old woman, never smoker, with a history of fully treated tuberculosis at 20 years of age attended our department for lung function testing. She had recently experienced several episodes of intermittent breathlessness and wheeze presumed to be due to asthma and was referred to a respiratory physician following an emergency department visit during one of these episodes. She did not have any recent weight loss, night sweats, purulent sputum or haemoptysis. Her dyspnoea and wheeze (inspiratory and expiratory) had been refractory to inhaled corticosteroids and both short and long acting β2 agonists.
Lung function using American Thoracic Society criteria
Bone-marrow derived mesenchymal stem cells (MSCs) reduce the severity of evolving acute lung injury (ALI), but their ability to repair the injured lung is not clear. A study was undertaken to determine the potential for MSCs to enhance repair after ventilator-induced lung injury (VILI) and elucidate the mechanisms underlying these effects.
Anaesthetised rats underwent injurious ventilation which produced severe ALI. Following recovery, they were given an intravenous injection of MSCs (2x106 cells) or vehicle immediately and a second dose 24 h later. The extent of recovery following VILI was assessed after 48 h. Subsequent experiments examined the potential for non-stem cells and for the MSC secretome to enhance VILI repair. The contribution of specific MSC-secreted mediators was then examined in a wound healing model.
MSC therapy enhanced repair following VILI. MSCs enhanced restoration of systemic oxygenation and lung compliance, reduced total lung water, decreased lung inflammation and histological lung injury and restored lung structure. They attenuated alveolar tumour necrosis factor α concentrations while increasing concentrations of interleukin 10. These effects were not seen with non-stem cells (ie, rat fibroblasts). MSC-secreted products also enhanced lung repair and attenuated the inflammatory response following VILI. The beneficial effect of the MSC secretome on repair of pulmonary epithelial wounds was attenuated by prior depletion of keratinocyte growth factor.
MSC therapy enhances lung repair following VILI via a paracrine mechanism that may be keratinocyte growth factor-dependent.
In vitro macrophages showed decreased degradation of phagosomes when exposed to azithromycin in both healthy controls and CF patients. This was demonstrated to be mainly due to lysosomal pH being raised to levels that inhibited destructive enzymes and also due to impaired phagosome–lysosome fusion. Further disruption to immune function was caused by inhibition of cytokine release, as evidenced by decreased levels of interferon (IFN). In vivo effects were verified by infecting mice with resistant strains of Mycobacterium abscessus. Control groups normally cleared the pathogen within 1 month whereas mice treated with azithromycin were...]]>
With regard to the patient selection in our study, we have acknowledged in the Discussion that the characteristics of patients with intrathoracic lymph node tuberculosis not submitted for EBUS-TBNA are unknown. This selection bias is an inherent problem in retrospective cohort studies, as only those patients suitable for EBUS-TBNA are included. Dr Tournoy would like to know the sensitivity of EBUS-TBNA for all cases in which tuberculous lymphadenitis is suspected; however, this is not reliably obtainable from a retrospective study. We have recently completed the recruitment to a prospective trial of EBUS-TBNA in patients with isolated mediastinal lymphadenopathy, which aims to answer this question (ClinicalTrials.gov identifier: NCT00932854).
We do not agree with Dr Tournoy's assertion that restricting the sample to patients with the...]]>
EBUS-TBNA has been validated for the assessment of mediastinal nodes in lung cancer
First, patients were selected in a peculiar way. The authors reviewed the files of all EBUS endoscopies and retrospectively selected those cases in which tuberculosis was finally found. Unfortunately, there is no information on how the patients were selected beforehand. The reported figure gives an indication of the sensitivity of EBUS in this particular...]]>
The primary outcome measure was sustained biochemically-verified smoking abstinence for 12 months after the end of treatment. Secondary outcomes were sustained abstinence for the first 6 months and point prevalence at 12 months. This study found that the rate of sustained 12-month abstinence was 8.4% (31 participants) in the cytisine group compared with 2.4% (9 participants) in the placebo group. The 7-day point prevalence for abstinence at the 12-month follow-up was 13.2% in the cytisine group and 7.3% in the placebo group. The relative difference in smoking cessation between cytisine and placebo was higher than previous...]]>
Non-cystic fibrosis bronchiectasis is characterised by irreversibly dilated bronchi usually associated with chronic sputum production, bacterial colonisation of the lower respiratory tract, inflammation and frequent exacerbations. Irrespective of the underlying cause, this represents failure of the host defence to maintain sterility of the respiratory tract.
To review the interactions and associations of non-cystic fibrosis bronchiectasis with the inate and adaptive immune systems with particular emphasis on known failure of local defences established deficiencies of the adaptive immune system. In addition we wished to explore potential subtle changes in the host defence which can lead to bacterial colonisation together with bacterial factors that aid colonisation of the lower respiratory tract and impair antibiotic response. This latter concept is considered with particular reference to Pseudomonas aeruginosa, which is often found in the airway secretions of patients with non-cystic fibrosis bronchiectasis and may act as a model for other organisms.
An extensive literature review was undertaken to provide a comprehensive review of immunity and bacterial colonisation in non-cystic fibrosis bronchiectasis, with focus on in vitro studies examining bacterial factors which may facilitate colonisation together with potential implications for management.
These themes provide a review of the current understanding of non-cystic fibrosis bronchiectasis together with areas for future research and potential therapeutic strategies.
The Thorax report focuses on adherence to local antibiotic guidelines. Nationally, 55.5% of patients received antibiotics in line with local prescribing policies (64% in severe CAP), but there was no association between adherence and mortality.
Smoking is the over-riding risk factor in lung cancer. Our measurements will provide further information concerning the potential for COPD as a useful factor in selecting populations that may benefit from screening. We do not have population-based spirometry in the UK to screen...]]>
First, cost-effectiveness is most likely to be achieved through optimising the risk assessment of those potentially eligible for CT screening
Studying the number of unnecessary lung biopsies, invasive procedures and surgeries due to cancer screening and the morbidity and mortality caused by these procedures. The risk of development of radiation-induced malignancy, both in patients undergoing routine yearly screening and in those subjected to serial CT scans for suspicious lesions. Some studies have shown significant risk of development of radiation-induced malignancies. Smoking abstinence behaviour in people undergoing...]]>
Severe bronchopulmonary dysplasia (BPD) might be associated with an accelerated age–related decline of lung function.
14 individuals were studied longitudinally at 15±4, 18±3 and 38±3.2 years. Information on personal history was completed, and lung function testing and skin prick testing were performed. Longitudinal data were compared intra-individually and with matched controls from the NHANES III dataset.
The ratio of residual volume/total lung capacity (RV/TLC) increased markedly from 25.9±7.0% to 39.3±6.8%. A significant time-effect was found compared to controls for the forced vital capacity (FVC) which decreased more rapidly than expected. Flow values were at the lower limit of normal range but remained relatively stable over time. Some individuals had completely normal lung function results.
Increasing static pulmonary hyperinflation with age is indicative of bronchiolar dysfunction or early emphysematous changes in survivors of severe BPD. Susceptibility for long-term sequelae shows significant variability.
Another point mentioned by Dr Konstantinou...]]>
The lung is the most commonly involved organ in WG, and the most representative CT findings are multiple nodules, occasionally with cavitation. Areas of consolidation and ground-glass attenuation are also frequent findings, which represent granulomatous changes and...]]>