The Reverend Sydney Smith remarked that he ‘must believe in the Apostolic succession, there being no other way of accounting for the descent of the Bishop of Exeter from Judas Iscariot’. The decision to exclude plain packaging of cigarettes from the Queen's speech suggests that this Apostolic succession is not confined to the episcopate. Everyone knows that legislating against smoking works and indeed in this issue, Sims et al (Hot Topic; see
Pirfenidone works. There have been four randomised placebo-control trials of pirfenidone for the treatment of idiopathic pulmonary fibrosis (IPF); a phase II and phase III study in Japan, and two international multicentre phase III studies.
IPF is a chronic progressive disease of unknown aetiology, it is fatal with a median survival of approximately 3 years,
Unfortunately, several clinical trials of novel therapy for IPF have yielded negative results. In 1999, the therapeutic potential of pirfenidone as the first antifibrotic pharmacologic agent with promises/hopes that it would improve outcomes for IPF patients was demonstrated in a phase II study.
The approval of ivacaftor by the European Medicines Agency (EMA) and the US Food and Drug Administration (US FDA) and the ongoing development of other drugs that target the underlying defect that causes cystic fibrosis (CF) have generated a great deal of excitement and hope for patients with CF.
Starting this month in Thorax, we have a new feature in which we will briefly summarise important original articles published in general journals or mainstream specialist journals that are likely to be of interest to Thorax readers. We recognise that it is becoming increasingly difficult to keep up to date with all the available literature, and that sometimes good articles are published in places that our readers may miss. Our intention is to keep this selection topical and up to date, and to this end we have enlisted the help of four enthusiastic Respiratory Trainees who will trawl the medical literature on a monthly basis on our readers’ behalf! Additionally, if we can persuade the authors of our favourite original articles published elsewhere each month to record a podcast, we will link this to the summary. We hope that Thorax readers find this new section useful; it will...]]>
Objective measures are required that may be used as a proxy for exacerbations in asthma. The aim was to determine the sensitivity and specificity of electronic diary data to detect severe exacerbations (SEs) of asthma. A secondary aim was to identify phenotypic variables associated with a higher risk of exacerbation.
In the BIOAIR study, 169 patients with asthma (93 severe (SA); 76 mild to moderate (MA)) recorded lung function, symptoms and medication use in electronic diaries for 1 year. Data were analysed using receiver-operator characteristics curves and related to physician-diagnosed exacerbations. Medical history and baseline clinical data were used to assess risk of exacerbation.
Of 122 physician-diagnosed exacerbations, 104 occurred in the SA group (1.1 per patient/year), 18 in the MA group (0.2 per patient/year) and 63 were severe using American Thoracic Society/European Respiratory Society criteria. During exacerbations, peak expiratory flow (PEF) and forced expiratory volume in 1 s significantly decreased, whereas day and night symptoms significantly increased. An algorithm combining a 20% decrease in PEF or a 20% increase in day symptoms on 2 consecutive days was able to detect SEs with 65% sensitivity and 95% specificity. The strongest risk factors for SEs were low Asthma Control Questionnaire score, sputum eosinophils ≥3%, body mass index >25 and low quality of life (St George's Respiratory Questionnaire), with ORs between 3.61 and 2.22 (p<0.05).
Regular electronic monitoring of PEF and asthma symptoms provides an acceptable sensitivity and specificity for the detection of SEs and may be suitable for personal internet-based monitoring of asthma control.
In this national database study from the USA, the short-term outcomes following thoracoscopic lobectomy were compared with open thoracotomy lobectomy.
From the Nationwide Inpatient Sample database, maintained by the Agency for Healthcare Research and Quality, all adult patients who underwent lobectomy as the principal procedure, by either thoracoscopy or thoracotomy during 2007 and 2008, were included. Patients with prior thoracotomy, or if both thoracoscopic and open lobectomy were listed as the approach, were excluded. All 68 350 patients were included, and 15% underwent a thoracoscopic lobectomy. Propensity score matching was used to reduce confounding by indication, and 10 173 thoracoscopic lobectomy patients were matched to 30 866 patients in the open lobectomy group.
There was no difference regarding in-hospital mortality between the open lobectomy group and the thoracoscopic lobectomy group (2.3% vs 1.6%). There were modest differences regarding postoperative complications, and 2 days shorter in hospital stay, favouring thoracoscopic lobectomy. Interestingly, about...]]>
Comprehensive smokefree laws have now been introduced in several jurisdictions. Few studies have examined the association between smokefree laws and asthma in adults and these have limitations, such as lacking appropriate adjustment for long-term trends or having limited statistical power due to small study populations. This study addresses these limitations and evaluates the short-term impact of smokefree legislation in England. It aims to investigate whether the introduction of smokefree legislation on 1 July 2007 was associated with an immediate reduction in emergency hospital admissions for asthma in the adult population, and whether any association differs across regions.
We identified monthly numbers of emergency admissions for asthma (primary diagnosis, 10th revision of the International Classification of Diseases code J45 and J46) in the nine Government Office Regions from April 1997 to December 2010 in the population aged 16 and over. A generalised additive model was fitted that adjusted for seasonality, variation in population size and region-specific, non-linear, long-term trends.
Smokefree legislation was associated with an immediate 4.9% (95% CI 0.6% to 9.0%) reduction in emergency admissions for asthma in the adult population. This implies that approximately 1900 emergency admissions for asthma were prevented in each of the first 3 years after legislation was introduced. The reduction in admissions did not vary significantly across regions.
Our findings add to the expanding body of evidence that smokefree policies are associated with positive health outcomes. Further research evaluating the impact of legislation in other jurisdictions is needed to support these findings.
Skeletal muscle dysfunction is a systemic feature of chronic obstructive pulmonary disease (COPD), contributing to morbidity and mortality. Physical training improves muscle mass and function in COPD, but the molecular regulation therein is poorly understood.
Candidate genes and proteins regulating muscle protein breakdown (ubiquitin proteasome pathway), muscle protein synthesis (phosphatidylinositol 3 kinase/Akt/mammalian target of rapamycin pathway), myogenesis (MyoD, myogenin and myostatin) and transcription (FOXO1, FOXO3 and RUNX1) were determined in quadriceps muscle samples taken at four time points over 8 weeks of knee extensor resistance training (RT) in patients with COPD and healthy controls (HCs). Patients with COPD were randomly allocated to receive protein/carbohydrate or placebo supplements during RT.
59 patients with COPD (mean (SD) age 68.0 (9.3) years, forced expiratory volume in 1 s (FEV1) 46.9 (17.8) % predicted) and 21 HCs (66.1 (4.8) years, 105.0 (21.6) % predicted) were enrolled. RT increased lean mass (~5%) and strength (~20%) in all groups. Absolute work done during RT was lower throughout in patients with COPD compared with HCs. RT resulted in increases (from basal) in catabolic, anabolic, myogenic and transcription factor protein expression at 24 h, 4 weeks and 8 weeks of exercise in HCs. This response was blunted in patients with COPD, except for myogenic signalling, which was similar. Nutritional supplementation did not augment functional or molecular responses to RT.
The potential for muscle rehabilitation in response to RT is preserved in COPD. Except for markers of myogenesis, molecular responses to RT are not tightly coupled to lean mass gains but reflect the lower work done during RT, suggesting some caution when identifying molecular targets for intervention. Increasing post-exercise protein and carbohydrate intake is not a prerequisite for a normal training response in COPD.
Cigarette smoking is the major cause of chronic obstructive pulmonary disease and emphysema. Recent studies suggest that susceptibility to cigarette smoke may vary by race/ethnicity; however, they were generally small and relied on self-reported race/ethnicity.
To test the hypothesis that relationships of smoking to lung function and per cent emphysema differ by genetic ancestry and self-reported race/ethnicity among Caucasians, African-Americans, Hispanics and Chinese-Americans.
Cross-sectional population-based study of adults age 45–84 years in the USA.
Principal components of genetic ancestry and continental ancestry estimated from one million genome-wide single nucleotide polymorphisms; pack-years of smoking; spirometry measured for 3344 participants; and per cent emphysema on computed tomography for 8224 participants.
The prevalence of ever-smoking was: Caucasians, 57.6%; African-Americans, 56.4%; Hispanics, 46.7%; and Chinese-Americans, 26.8%. Every 10 pack-years was associated with –0.73% (95% CI –0.90% to –0.56%) decrement in the forced expiratory volume in 1 s to forced vital capacity (FEV1 to FVC) and a 0.23% (95% CI 0.08% to 0.38%) increase in per cent emphysema. There was no evidence that relationships of pack-years to the FEV1 to FVC, airflow obstruction and per cent emphysema varied by genetic ancestry (all p>0.10), self-reported race/ethnicity (all p>0.10) or, among African-Americans, African ancestry. There were small differences in relationships of pack-years to the FEV1 among male Chinese-Americans and to the FEV1 to FVC ratio with African and Native American ancestry among male Hispanics only.
In this large cohort, there was little to no evidence that the associations of smoking to lung function and per cent emphysema differed by genetic ancestry or self-reported race/ethnicity.
Newborn screening allows novel treatments for cystic fibrosis (CF) to be trialled in early childhood before irreversible lung injury occurs. As respiratory exacerbations are a potential trial outcome variable, we determined their rate, duration and clinical features in preschool children with CF; and whether they were associated with growth, lung structure and function at age 5 years.
Respiratory exacerbations were recorded prospectively in Australasian CF Bronchoalveolar Lavage trial subjects from enrolment after newborn screening to age 5 years, when all participants underwent clinical assessment, chest CT scans and spirometry.
168 children (88 boys) experienced 2080 exacerbations, at an average rate of 3.66 exacerbations per person-year; 80.1% were community managed and 19.9% required hospital admission. There was an average increase in exacerbation rate of 9% (95% CI 4% to 14%; p<0.001) per year of age. Exacerbation rate differed by site (p<0.001) and was 26% lower (95% CI 12% to 38%) in children receiving 12 months of prophylactic antibiotics. The rate of exacerbations in the first 2 years was associated with reduced forced expiratory volume in 1 s z scores. Ever having a hospital-managed exacerbation was associated with bronchiectasis (OR 2.67, 95% CI 1.13 to 6.31) in chest CT scans, and lower weight z scores at 5 years of age (coefficient –0.39, 95% CI –0.74 to –0.05).
Respiratory exacerbations in young children are markers for progressive CF lung disease and are potential trial outcome measures for novel treatments in this age group.
Pseudomonas aeruginosa and Aspergillus fumigatus frequently co-colonise the airways of patients with cystic fibrosis (CF). This study aimed to assess the impact of short-term administration of intravenous antipseudomonal antibiotics during CF exacerbations on the presence of Aspergillus.
Pre- and post-antibiotic sputum samples from 26 adult patients with CF and chronic Pseudomonas colonisation were analysed for the presence of Aspergillus by fungal culture, real-time PCR and galactomannan antigen (GM). Lung function (forced expiratory volume in 1 s and forced vital capacity % predicted) and blood levels of total IgE, specific A fumigatus IgE and specific A fumigatus IgG were measured at the start and end of antibiotics. Respiratory viral real-time PCR and bacterial community profiling using ribosomal intergenic spacer analysis (RISA) were performed to estimate concurrent changes in the lung microbiome.
Aspergillus PCR and GM were more sensitive than culture in detecting Aspergillus species (culture 8%, GM 31%, PCR 77%). There was a significant decline in the presence of Aspergillus, measured both by PCR and GM index, following antibacterial therapy (PCR: median increase in crossing threshold 1.7 (IQR 0.5–3.8), p<0.001; GM: median fall in GM index 0.7 (IQR 0.4–1.6), p=0.016). All patients improved clinically with a significant increase in lung function (p<0.0001). RISA community analysis showed large changes in bacterial community similarity in 67% of patients following antibiotics. Viral RT-PCR demonstrated the presence of a concurrent respiratory virus in 27% of patients.
Intravenous antibiotics targeting Pseudomonas during CF pulmonary exacerbations have a negative impact on the presence of Aspergillus in sputum samples.
Guidelines recommend influenza vaccinations in all diabetic adults, but there is limited evidence to support vaccinating working-age adults (<65 years) with diabetes. We examined the effectiveness of influenza vaccine in this subgroup, compared with elderly adults (≥65 years) for whom vaccination recommendations are well accepted.
We identified all adults with diabetes, along with a sample of age-matched and sex-matched comparison subjects without diabetes, from 2000 to 2008, using administrative data from Manitoba, Canada. With multivariable Poisson regression, we estimated vaccine effectiveness (VE) on influenza-like illnesses (ILIs), pneumonia and influenza (PI) hospitalisations and all-cause (ALL) hospitalisations during periods of known circulating influenza. Analyses were replicated outside of influenza season to rule out residual confounding.
We included 543 367 person-years of follow-up, during which 223 920 ILI, 5422 PI and 94 988 ALL occurred. The majority (58%) of adults with diabetes were working age. In this group, influenza vaccination was associated with relative reductions in PI (43%, 95% CI 28% to 54%) and ALL (28%, 95% CI 24% to 32%) but not ILI (–1%, 95% CI –3% to 1%). VE was similar in elderly adults for ALL (33–34%) and PI (45–55%), although not ILI (12–13%). However, similar estimates of effectiveness were also observed for all three groups during non-influenza control periods.
Working-age adults with diabetes experience similar benefits from vaccination as elderly adults, supporting current diabetes-specific recommendations. However, these benefits were also manifest outside of influenza season, suggesting residual bias. Vaccination recommendations in all high-risk adults would benefit from randomised trial evidence.
Spontaneous pneumothorax (SP) is broken down into primary (PSP: no known underlying lung disease), secondary (SSP: known lung disease) and from trauma or iatrogenic pneumothorax (IP). Current treatments include a conservative approach, needle aspiration, chest drain, suction and surgery. A Heimlich valve (HV) is a lightweight one-way valve designed for the ambulatory treatment of pneumothorax (with an intercostal catheter).
We performed a systematic review across nine electronic databases for studies reporting the use of HV for adults with pneumothorax. Randomised controlled trials (RCT), case control studies and case series were included, unrestricted by year of publication. Measures of interest included the use only of a HV to manage SP or IP, (ie, avoidance of further procedures), successful treatment as outpatient (OP) and complications.
Eighteen studies were included reporting on the use of HV in 1235 patients, 992 cases of SP (of which 413 were reported as PSP) and 243 IP. The overall quality of the reports was moderate to poor with high risk of bias. Success with HV alone was 1060/1235 (85.8%) and treatment as OP successful in 761/977 (77.9%). Serious complications are rare. Long-term outcomes are comparable with current treatments.
High-quality data to support the use of HV for ambulatory treatment of pneumothorax is sparse. The use of HV in such circumstances may have benefits for patient comfort, mobility and avoidance of hospital admission, with comparable outcomes to current practice. There is urgent need for a carefully designed RCT to answer his question.
Chronic obstructive pulmonary disease (COPD) is a multicomponent condition that is characterised by airflow obstruction that is not fully reversible and is a major global cause of morbidity and mortality. The most widely used marker of disease severity and progression is FEV1. However, FEV1 correlates poorly with both symptoms and other measures of disease progression and thus there is an urgent need for other biological markers to better characterise individuals with COPD. Fibrinogen is an acute phase plasma protein that has emerged as a promising biomarker in COPD. Here we review the current clinical evidence linking fibrinogen with COPD and its associated co-morbidities and discuss its potential utility as a biomarker.
Searches for appropriate studies were undertaken on PubMed using search terms fibrinogen, COPD, emphysema, chronic bronchitis, FEV1, cardiovascular disease, exacerbation and mortality.
There is strong evidence of an association between fibrinogen and the presence of COPD, the presence and frequency of exacerbations and with mortality. Fibrinogen is associated with disease severity but does not predict lung function decline, a measure used as a surrogate for disease activity. The role of fibrinogen in identifying inflammatory co morbidities, particularly cardiovascular disease, remains unclear. Fibrinogen is reduced by p38 mitogen-activated protein kinase inhibitors in individuals with stable disease and by oral corticosteroids during exacerbations.
Fibrinogen is likely to be a useful biomarker to stratify individuals with COPD into those with a high or low risk of future exacerbations and may identify those with a higher risk of mortality.
Chronic thromboembolic pulmonary hypertension (CTEPH) is a complication of pulmonary embolism potentially curable by surgery. Perfusion scintigraphy is currently advocated as the imaging modality of choice to exclude CTEPH due to its high sensitivity. We have evaluated the diagnostic utility of lung perfusion MRI.
Consecutive patients attending a pulmonary hypertension referral centre undergoing lung perfusion MRI, perfusion scintigraphy, CT pulmonary angiography (CTPA) and right heart catheterisation within 14 days were identified.
Of 132 patients, 78 were diagnosed as having CTEPH. Lung perfusion MRI correctly identified 76 patients as having CTEPH with an overall sensitivity of 97%, specificity 92%, positive predictive value 95% and negative predictive value 96% compared with perfusion scintigraphy (sensitivity 96%, specificity 90%) and CTPA (sensitivity 94%, specificity 98%). No cases of surgically accessible CTEPH were missed with either modality.
Lung perfusion MRI has high sensitivity equivalent to perfusion scintigraphy in diagnosing CTEPH but does not require ionising radiation, making it an attractive initial imaging modality to assess patients with suspected CTEPH.
One possibility that the authors have not considered is that hypovitaminosis D may be a consequence rather than cause of disease. Vitamin D deficiency has been associated with an ever-expanding list of diseases.
Our study was cross-sectional and was unable to establish whether vitamin D deficiency is a cause or consequence of bronchiectasis.
The acute phase response is unlikely to be the only explanation for the observed association with severity. We previously reported only a weak association between C reactive protein (CRP) and erythrocyte sedimentation rate, as acute phase reactants, and bacterial colonisation...]]>
The British Thoracic Society has recently updated the air travel recommendations suggesting that patients with precapillary pulmonary hypertension (PCPH) in functional classes (FCs) 3 and 4 should have inflight oxygen.
We have recently published the effect a HCT would have on arterial oxygen levels in 36 patients with PCPH and baseline Sp02>90%.
We thank Burns et al
To improve is to change; to be perfect is to change often. Sir Winston Churchill (1874–1965)
We thoroughly enjoyed reading the succinct review article by Vallieres et al
An association has been demonstrated between obstructive sleep apnoea (OSA) and both hypertension and cardiovascular events. Although observational studies suggest that treatment with continuous positive airways pressure (CPAP) can reduce blood pressure and the incidence of fatal and non-fatal cardiovascular events in patients with severe and moderate OSA, short term randomised controlled trials have failed to demonstrate a similar effect in non-sleepy patients.
The primary objective of this large, multicentre randomised controlled trial was to investigate the effect of CPAP on the incidence of hypertension and cardiovascular events in non-sleepy patients (Epworth Sleepiness Score of ≤10, range 0–24) with OSA (apnoea-hypopnoea index of 20 h–1 or greater). The secondary objective was to assess an association between OSA severity and the incidence of hypertension or cardiovascular events.
Although a statistically significant reduction in the incidence of hypertension and cardiovascular events was not observed in the treatment group, there was a...]]>
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease whose assessment and management have traditionally been based on the severity of airflow limitation (forced expiratory volume in 1 s (FEV1)). Yet, it is now clear that FEV1 alone cannot describe the complexity of the disease. In fact, the recently released Global Initiative for Chronic Obstructive Lung Disease (GOLD), 2011 revision has proposed a new combined assessment method using three variables (symptoms, airflow limitation and exacerbations).
Here, we go one step further and propose that in the near future physicians will need a ‘control panel’ for the assessment and optimal management of individual patients with complex diseases, including COPD, that provides a path towards personalised medicine.
We propose that such a ‘COPD control panel’ should include at least three different domains of the disease: severity, activity and impact. Each of these domains presents information on different ‘elements’ of the disease with potential prognostic value and/or with specific therapeutic requirements. All this information can be easily incorporated into an ‘app’ for daily use in clinical practice.
We recognise that this preliminary proposal needs debate, validation and evolution (eg, including ‘omics’ and molecular imaging information in the future), but we hope that it may stimulate debate and research in the field.
The rising disease burden from chronic obstructive pulmonary disease (COPD) requires new approaches.
We suggest an approach based around three elements: inflammometry and multidimensional assessment to identify therapeutic targets and case management to design and implement an individualised treatment programme based on these assessments.
This tailored approach to treatment would maximise efficacy, limit cost and permit a better risk–benefit ratio of treatment. The advantages include the ability to add up the benefits of individual therapies leading to a cumulative therapeutic benefit that is greater than each individual therapy alone. We can now design a multifaceted inflammometry intervention for airway diseases based on targeting eosinophilic inflammation, non-eosinophilic pathways and systemic inflammation. COPD is a complex and challenging disease. The use of inflammometry and multidimensional assessment is necessary to identify relevant treatment targets and maximise the scope of therapy while limiting unnecessary use of drugs. An individualised programme of management can be designed and coordinated by using a case manager. This new approach may provide tangible benefits to people with COPD.
A 51-year-old woman presented to the chest clinic with history of progressive dyspnoea and dry cough for 8 weeks. Her past medical history was remarkable for sleeve gastrectomy 3 months ago, which resulted in loss of three stones. She also reported migraines for which she had an implanted occipital nerve stimulator and had undergone hysterectomy with bilateral salpingo-oophorectomy 18 months ago. Other history included hypothyroidism, hypertension and depression. Her medications were Hormone Replacement Therapy (HRT), Nifedipine, Losartan, Levothyroxine, Lansoprazole, Simvastatin and Fluoxetine. She had smoked for 3 years in her 20s, no more than 3–5 cigarettes per day and had no noteworthy occupational exposure. She had a family history of maternal myelodysplasia and paternal cerebral malignancy.
Examination revealed right-sided thoracic dullness and reduced breath sounds. Blood results were unremarkable. A chest radiograph was performed confirming a right-sided effusion (
This multicentre, randomised, double-blind placebo-controlled trial was designed to address the effectiveness of the antioxidant, N-Acetylcysteine (NAC), alone and in ‘triple’ therapy (prednisolone, azathioprine and NAC) in idiopathic pulmonary fibrosis (IPF). Patients with IPF and mild to moderate lung function impairment (FVC≥50% and TLCO≥30%) were assigned to receive triple therapy, NAC alone or matched placebo for 60 weeks.
Target recruitment was 130 patients per group, however, following a planned interim analysis (mean follow-up 32 weeks) the triple therapy arm (n=77) was halted. Compared with placebo (n=78), increased risks of death (8 vs 1), hospitalisation (23 vs 7), and serious adverse events (24 vs 8) were seen. The placebo and triple therapy groups had no significant differences in demographic and clinical characteristics. No clinical or physiological benefit was seen with triple therapy.
This is the first trial to compare triple therapy with placebo, and provides evidence that as a treatment for...]]>
Completion of a full treatment programme for the management of tuberculosis is pivotal in achieving successful disease treatment and preventing development of drug resistant disease. In this study (Epidemiol Infect 2013;141:1223–1231), investigators compared characteristics of patients in the UK between 2001 and 2007 who completed TB therapy to those who were lost to follow-up. Factors associated with an increased risk of loss to follow-up included being male; adjusted odds ratio (aOR 1.29); having sputum smear-positive disease (aOR 1.25), and arriving in the UK within two years (aOR 3.58) particularly those of White ethnic origin (aOR 6.39).
This Europe-wide study (BMJ 2013;346:f2450 doi:10.1136/bmj.f2450) of patients presenting to primary care with acute cough investigated...]]>