‘Oh – let no-one ever, ever doubt, What nobody is sure about!’ (Hilaire Belloc)
Hot off the Breath: the PANTHER-IPF trial dared to go where no man has gone before (at least for a very long time) and have a PLACEBO limb in a randomised controlled trial of treatment for IPF, and lo! Those randomised to the gold standard triple therapy arm did substantially worse, and this limb has rightly been terminated by the data monitoring board. On page
Increasing recognition of the clinical need for effective IPF therapy has finally led to a number of clinical trials evaluating potential anti-inflammatory and anti-fibrotic agents. IFIGENIA demonstrated that triple therapy with NAC, azathioprine and prednisolone was better...]]>
Readers from these countries may be surprised to learn that elsewhere the production, sale and use of asbestos continue to flourish and even increase. In 1994, one of us (NP) edited...]]>
In the 18-month intervention, we compared two budesonide regimens with a control group treated with a fixed dose of disodium cromoglycate (DSCG). The study evaluated the antiasthmatic efficacy...]]>
The intermittent approach is attractive to patients and families for a variety of reasons, including fear of corticosteroid side effects,
This practice...]]>
This 37-year prospective cohort study was undertaken to provide additional evidence for mortality risks associated with exposure to chrysotile asbestos.
577 asbestos workers and 435 control workers in original cohorts were followed from 1972 to 2008, achieving a follow-up rate of 99% and 73%, respectively. Morality rates were determined based on person-years of observation. Cox proportional hazard models were constructed to estimate HRs of cause-specific mortality, while taking into account age, smoking and asbestos exposure level.
There were 259 (45%) deaths identified in the asbestos cohort, and 96 died of all cancers. Lung cancer (n=53) and non-malignant respiratory diseases (n=81) were major cause-specific deaths, in contrast to nine lung cancers and 11 respiratory diseases in the controls. Age and smoking-adjusted HRs for mortality by all causes and all cancers in asbestos workers were 2.05 (95% CI 1.56 to 2.68) and 1.89 (1.25 to 2.87), respectively. The risks for lung cancer and respiratory disease deaths in asbestos workers were over threefold that in the controls (HR 3.31(95% CI 1.60 to 6.87); HR 3.23 (95% CI 1.68 to 6.22), respectively). There was a clear exposure–response trend with asbestos exposure level and lung cancer mortality in both smokers and non-smokers.
Data from this prospective cohort provide strong evidence for increased mortality risks, particularly from lung cancer and non-malignant respiratory diseases, associated with exposure to chrysotile asbestos, while taking into account of the smoking effect.
Organic dust is a complex mixture of particulate matter from microbial, plant or animal origin. Occupations with exposure to animal products have been associated with an increased lung cancer risk, while exposure to microbial components (eg, endotoxin) has been associated with a decreased risk. To date there has not been a comprehensive evaluation of the possible association between occupational organic dust exposure (and its specific constituents) and lung cancer risk in the general population.
The SYNERGY project has pooled information on lifetime working and smoking from 13 300 lung cancer cases and 16 273 controls from 11 case–control studies conducted in Europe and Canada. A newly developed general population job-exposure matrix (assigning no, low or high exposure to organic dust, endotoxin, and contact with animals or fresh animal products) was applied to determine level of exposure. ORs for lung cancer were estimated by logistic regression, adjusted for age, sex, study, cigarette pack-years, time since quitting smoking, and ever employment in occupations with established lung cancer risk.
Occupational organic dust exposure was associated with increased lung cancer risk. The second to the fourth quartile of cumulative exposure showed significant risk estimates ranging from 1.12 to 1.24 in a dose-dependent manner (p<0.001). This association remained in the highest quartile after restricting analyses to subjects without chronic obstructive pulmonary disease or asthma. No association was observed between lung cancer and exposure to endotoxin or contact with animals or animal products.
Occupational exposure to organic dust was associated with increased lung cancer risk in this large pooled case–control study.
Journal Club articles are summaries of papers that have been selected from these journals, printing the title of the paper with a short commentary of about 200–250 words, summarising the main message or learning point from the paper. These articles will be attributed to the reviewer and may include a personal view on the paper, especially if the topic is controversial. The articles, usually reporting original research rather than reviews or meta-analyses, are selected by the Journal Club editor from papers published within the last month and are then sent by email to the reviewers. We are keen to expand the bank...]]>
Rates of mortality and readmission are high in patients hospitalised with acute exacerbations of chronic obstructive pulmonary disease (AECOPD). In this population, the prognostic value of the Medical Research Council Dyspnoea Scale (MRCD) is uncertain, and an extended MRCD (eMRCD) scale has been proposed to improve its utility. Coexistent pneumonia is common and, although the CURB-65 prediction tool is used, its discriminatory value has not been reported.
Clinical and demographic data were collected on consecutive patients hospitalised with AECOPD. The relationship of stable-state dyspnoea severity to in-hospital mortality and 28-day readmission was assessed. The discriminatory value of CURB-65, MRCD and eMRCD, in the prediction of in-hospital mortality, was assessed and compared.
920 patients were recruited. 10.4% died in-hospital and 19.1% of the 824 survivors were readmitted within 28 days of discharge. During their stable state prior to admission, 34.2% of patients were too breathless to leave the house. Mortality was significantly higher in pneumonic than in non-pneumonic exacerbations (20.1% vs 5.8%, p<0.001). eMRCD was a significantly better discriminator than either CURB-65 or the traditional MRCD scale for predicting in-hospital mortality, and was a stronger prognostic tool than CURB-65 in the subgroup of patients with pneumonic AECOPD.
The severity of dyspnoea in the stable state predicts important clinical outcomes in patients hospitalised with AECOPD. The eMRCD scale identifies a subgroup of patients at a particularly high risk of in-hospital mortality and is a better predictor of mortality risk than CURB-65 in exacerbations complicated by pneumonia.
The mechanisms underlying chronic obstructive pulmonary disease (COPD) remain unclear. MicroRNAs (miRNAs or miRs) are small non-coding RNA molecules that modulate the levels of specific genes and proteins. Identifying expression patterns of miRNAs in COPD may enhance our understanding of the mechanisms of disease. A study was undertaken to determine if miRNAs are differentially expressed in the lungs of smokers with and without COPD. miRNA and mRNA expression were compared to enrich for biological networks relevant to the pathogenesis of COPD.
Lung tissue from smokers with no evidence of obstructive lung disease (n=9) and smokers with COPD (n=26) was examined for miRNA and mRNA expression followed by validation. We then examined both miRNA and mRNA expression to enrich for relevant biological pathways.
70 miRNAs and 2667 mRNAs were differentially expressed between lung tissue from subjects with COPD and smokers without COPD. miRNA and mRNA expression profiles enriched for biological pathways that may be relevant to the pathogenesis of COPD including the transforming growth factor β, Wnt and focal adhesion pathways. miR-223 and miR-1274a were the most affected miRNAs in subjects with COPD compared with smokers without obstruction. miR-15b was increased in COPD samples compared with smokers without obstruction and localised to both areas of emphysema and fibrosis. miR-15b was differentially expressed within GOLD classes of COPD. Expression of SMAD7, which was validated as a target for miR-15b, was decreased in bronchial epithelial cells in COPD.
miRNA and mRNA are differentially expressed in individuals with COPD compared with smokers without obstruction. Investigating these relationships may further our understanding of the mechanisms of disease.
To determine differences in aetiologies, initial antimicrobial treatment choices and outcomes in patients with nursing-home-acquired pneumonia (NHAP) compared with patients with community-acquired pneumonia (CAP), which is a controversial issue.
Data from the prospective multicentre Competence Network for Community-acquired pneumonia (CAPNETZ) database were analysed for hospitalised patients aged ≥65 years with CAP or NHAP. Potential differences in baseline characteristics, comorbidities, physical examination findings, severity at presentation, initial laboratory investigations, blood gases, microbial investigations, aetiologies, antimicrobial treatment and outcomes were determined between the two groups.
Patients with NHAP presented with more severe pneumonia as assessed by CRB-65 (confusion, respiratory rate, blood pressure, 65 years and older) score than patients with CAP but received the same frequency of mechanical ventilation and less antimicrobial combination treatment. There were no clinically relevant differences in aetiology, with Streptococcus pneumoniae the most important pathogen in both groups, and potential multidrug-resistant pathogens were very rare (<5%). Only Staphylococcus aureus was more frequent in the NHAP group (n=12, 2.3% of the total population, 3.1% of those with microbial sampling compared with 0.7% and 0.8% in the CAP group, respectively). Short-term and long-term mortality in the NHAP group was higher than in the CAP group for patients aged ≥65 years (26.6% vs 7.2% and 43.8% vs 14.6%, respectively). However, there was no association between excess mortality and potential multidrug-resistant pathogens.
Excess mortality in patients with NHAP cannot be attributed to a different microbial pattern but appears to result from increased comorbidities, and consequently, pneumonia is frequently considered and managed as a terminal event.
Two hundred and seventy-six CF patients whose FEV1 was first observed to be less than 30% predicted between 1990 and 2003 were included in the cohort. The patients were followed up in 2-year subcohorts until 2007 and their survival was assessed. The authors showed an important improvement in the average survival of CF patients with severely impaired lung function. Median survival for patients who entered the cohort most recently (2002–2003) was 5.3 years, more than four times that for those who entered the study in the...]]>
The development of organ fibrosis after injury requires activation of transforming growth factor β1 which regulates the transcription of profibrotic genes. The systemic administration of a proteasomal inhibitor has been reported to prevent the development of fibrosis in the liver, kidney and bone marrow. It is hypothesised that proteasomal inhibition would prevent lung and skin fibrosis after injury by inhibiting TGF-β1-mediated transcription.
Bortezomib, a small molecule proteasome inhibitor in widespread clinical use, was administered to mice beginning 7 days after the intratracheal or intradermal administration of bleomycin and lung and skin fibrosis was measured after 21 or 40 days, respectively. To examine the mechanism of this protection, bortezomib was administered to primary normal lung fibroblasts and primary lung and skin fibroblasts obtained from patients with idiopathic pulmonary fibrosis and scleroderma, respectively.
Bortezomib promoted normal repair and prevented lung and skin fibrosis when administered beginning 7 days after the initiation of bleomycin. In primary human lung fibroblasts from normal individuals and patients with idiopathic pulmonary fibrosis and in skin fibroblasts from a patient with scleroderma, bortezomib inhibited TGF-β1-mediated target gene expression by inhibiting transcription induced by activated Smads. An increase in the abundance and activity of the nuclear hormone receptor PPAR, a repressor of Smad-mediated transcription, contributed to this response.
Proteasomal inhibition prevents lung and skin fibrosis after injury in part by increasing the abundance and activity of PPAR. Proteasomal inhibition may offer a novel therapeutic alternative in patients with dysregulated tissue repair and fibrosis.
Idiopathic pulmonary fibrosis (IPF) is characterised by the aberrant epithelial to mesenchymal transition (EMT) and myofibroblast accumulation. Sphingosine-1-phosphate (S1P) and sphingosine kinase 1 (SPHK1) have been implicated in lung myofibroblast transition, but their role in EMT and their expression in patients with IPF is unknown.
S1P levels were measured in serum (n=27) and bronchoalveolar lavage (BAL; n=15) from patients with IPF and controls (n=30 for serum and n=15 for BAL studies). SPHK1 expression was measured in lung tissue from patients with IPF (n=12) and controls (n=15). Alveolar type II transformation into mesenchymal cells was studied in response to S1P (10–9–10–5 M). The median (IQR) of S1P serum levels was increased in patients with IPF (1.4 (0.4) μM) versus controls (1 (0.26) μM; p<0.0001). BAL S1P levels were increased in patients with IPF (1.12 (0.53) μM) versus controls (0.2 (0.5); p<0.0001) and correlated with diffusion capacity of the lung for carbon monoxide, forced expiratory volume in 1 s and forced vital capacity (Spearman's r=–0.87, –0.72 and –0.68, respectively) in patients with IPF. SPHK1 was upregulated in lung tissue from patients with IPF and correlated with α-smooth muscle actin, vimentin and collagen type I (Spearman's r=0.82, 0.85 and 0.72, respectively). S1P induced EMT in alveolar type II cells by interacting with S1P2 and S1P3, as well as by the activation of p-Smad3, RhoA-GTP, oxidative stress and transforming growth factor-β1 (TGF-β1) release. Furthermore, TGF-β1-induced EMT was partially conducted by the S1P/SPHK1 activation, suggesting crosstalk between TGF-β1 and the S1P/SPHK1 axis.
S1P is elevated in patients with IPF, correlates with the lung function and mediates EMT.
Two cross-sectional studies are described (PARSIFAL n=489 and GABRIELA n=444) in which the prevalence of asthma and atopy in children who live on farms are compared with a control group. Samples of dust were collected from children's bedrooms and analysed for bacteria and fungi. Results showed that the farm-dwelling children were exposed to a greater diversity of micro-organisms, even in an indoor environment. Furthermore, the prevalence of asthma was inversely related to the greater diversity of microbial exposure, independent of whether the children lived on a farm or not....]]>
Respiratory failure is a life-threatening and unpredictable complication of systemic sclerosis (SSc). A study was undertaken to assess the value of alveolar nitric oxide (NO) in predicting the risk of lung function deterioration leading to respiratory failure or death in patients with SSc.
105 patients with SSc were enrolled in this prospective cohort and were followed longitudinally over a 3-year period during which the risk of occurrence of deleterious events was analysed according to alveolar concentration (CA
The area under the receiver operating characteristic curve of CA
Increased CA
Mice were infected with two influenza viruses that differ in the degree of glycosylation of the surface glycoprotein haemagluttinin. Infection with the poorly glycosylated H1N1 virus PR8 resulted in rapid weight loss and a 100% 5-day mortality, whereas the highly glycosylated PR8 reassortant BJx109 resulted in no significant weight loss and a 0% 10-day mortality. This result was replicated in knockout mice with impaired B and T cell function demonstrating that the innate immune system was sufficient to limit disease.
In vitro only the highly glycosylated BJx109 (H3N2) virus infected airway macrophages to high levels and was neutralised by mouse bronchoalveolar lavage and a soluble lectin present in respiratory...]]>
Studies in cystic fibrosis (CF) generally focus on inflammation present in the airway lumen. Little is known about inflammation occurring in the airway wall, the site ultimately destroyed in end-stage disease.
To test the hypothesis that inflammatory patterns in the lumen do not reflect those in the airway wall of children with CF.
Bronchoalveolar lavage (BAL) fluid and endobronchial biopsies were obtained from 46 children with CF and 16 disease-free controls. BAL cell differential was assessed using May-Gruenwald-stained cytospins. Area profile counts of bronchial tissue immunopositive inflammatory cells were determined.
BAL fluid from children with CF had a predominance of neutrophils compared with controls (median 810x103/ml vs 1x103/ml, p<0.0001). In contrast, subepithelial bronchial tissue from children with CF was characterised by a predominance of lymphocytes (median 961 vs 717 cells/mm2, p=0.014), of which 82% were (CD3) T lymphocytes. In chest exacerbations, BAL fluid from children with CF had more inflammatory cells of all types compared with those with stable disease whereas, in biopsies, only the numbers of lymphocytes and macrophages, but not of neutrophils, were higher. A positive culture of Pseudomonas aeruginosa was associated with higher numbers of T lymphocytes in subepithelial bronchial tissue (median 1174 vs 714 cells/mm2, p=0.029), but no changes were seen in BAL fluid. Cell counts in BAL fluid and biopsies were positively correlated with age but were unrelated to each other.
The inflammatory response in the CF airway is compartmentalised. In contrast to the neutrophil-dominated inflammation present in the airway lumen, the bronchial mucosa is characterised by the recruitment and accumulation of lymphocytes.
Ksr1 deficiency impairs the bactericidal activity of alveolar macrophages and, as a consequence, Ksr1-deficient mice were found to die of sepsis from failed clearance of P aeruginosa. The bactericidal activity of alveolar macrophages and neutrophils is mediated by the formation and release of nitric oxide (NO) and peroxynitrite, which is triggered by Ksr1. This occurs through a previously unidentified pathway where Ksr1 functions as a unique scaffold and mediates the interaction between inducible NO synthase (iNOS) and heat shock protein 90, thereby activating iNOS and releasing NO, which kills the bacteria.
The authors...]]>
We would like to raise concerns about the procedure in adults as well. From 1987 to 2011, Regamey et al found five independent studies in which bronchial biopsies were performed in only 25 adults with CF.
None.
All authors contributed to this letter equally.
Not commissioned; internally peer reviewed.
However, a potential important confounding factor may explain a part of their results: undiagnosed pulmonary embolism (PE), mimicking (or induced by) COPD exacerbation. Troponin and BNP are factors associated with poor prognosis in PE.
Thromboprophylaxis was administered to some patients during their admission depending on their immobility and other risk factors, but this would not have influenced the NT-proBNP or troponin T results obtained on presentation. We did not collect information on pre-existing anticoagulation therapy on admission to the study.
Further...]]>
In a CT image, pulmonary hamartomas are typically well-defined nodules occasionally containing fat or regions of calcification or both.