This issue coincides with the American Thoracic Society meeting, and we have tried to have a USA theme, showcasing work from North America to emphasise our wish to attract the best manuscripts from all round the world. These include a variety of topics: primary ciliary dyskinesia (with an attempt to recreate the cordial Anglo-American relationships extant at the time of the Boston Tea party in the correspondence columns!), COPD, interstitial lung disease and the basic science of lung development, reflecting the diversity of the Journal and the readership.
In days of yore, the MRC led the world in randomised controlled trials, not least in establishing the evidence base for the treatment of tuberculosis. Times change and increasing energy is devoted to process not outcome, and frenetic reforms of everything possible and impossible by those who make headless chickens seem like Einstein. While we...]]>
First, of course, is it necessary to make a specific diagnosis of PCD at all? There are several reasons why it is;...]]>
Not surprisingly, these QCT estimates of pathological changes were related to measures of clinical impact. More interestingly, the authors found that there were differences in the strength of the associations between measures of emphysema and airway disease and the composite indices. Measures of emphysema were more closely related with the BODE index while the airway wall abnormalities were better predictors of the SGRQ.
While it has long been recognised that there is a spectrum of changes in the airways and parenchyma in COPD,
Distal cell-type-specific regulatory elements may be located at very large distances from the genes that they control and are often hidden within intergenic regions or in introns of other genes. The development of methods that enable mapping of regions of open chromatin genome wide has greatly advanced the identification and characterisation of these elements.
Here we use DNase I hypersensitivity mapping followed by deep sequencing (DNase-seq) to generate a map of open chromatin in primary human tracheal epithelial (HTE) cells and use bioinformatic approaches to characterise the distribution of these sites within the genome and with respect to gene promoters, intronic and intergenic regions.
Genes with HTE-selective open chromatin at their promoters were associated with multiple pathways of epithelial function and differentiation. The data predict novel cell-type-specific regulatory elements for genes involved in HTE cell function, such as structural proteins and ion channels, and the transcription factors that may interact with them to control gene expression. Moreover, the map of open chromatin can identify the location of potentially critical regulatory elements in genome-wide association studies (GWAS) in which the strongest association is with single nucleotide polymorphisms in non-coding regions of the genome. We demonstrate its relevance to a recent GWAS that identifies modifiers of cystic fibrosis lung disease severity.
Since HTE cells have many functional similarities with bronchial epithelial cells and other differentiated cells in the respiratory epithelium, these data are of direct relevance to elucidating the molecular basis of normal lung function and lung disease.
Upregulation of glucocorticoid receptor β (GRβ) has been implicated in steroid resistance in severe asthma, although previous studies are conflicting. GRβ has been proposed as a dominant negative isoform of glucocorticoid receptor α (GRα) but it has also been suggested that GRβ can cause steroid resistance via reduced expression of histone deacetylase 2 (HDAC2), a key regulator of steroid responsiveness in the airway.
To examine GRβ, GRα, HDAC1 and HDAC2 expression at transcript and protein levels in bronchial biopsies from a large series of patients with severe asthma, and to compare the findings with those of patients with mild to moderate asthma and healthy volunteers.
Bronchoscopic study in two UK centres with real-time PCR and immunohistochemistry performed on biopsies, western blotting of bronchial epithelial cells and immunoprecipitation with anti-GRβ antibody.
Protein and mRNA expression for GRα and HDAC2 did not differ between groups. GRβ mRNA was detected in only 13 of 73 samples (seven patients with severe asthma), however immunohistochemistry showed widespread epithelial staining in all groups. Western blotting of bronchial epithelial cells with GRβ antibody detected an additional ‘cross-reacting’ protein, identified as clathrin. HDAC1 expression was increased in patients with severe asthma compared with healthy volunteers.
GRβ mRNA is expressed at low levels in a minority of patients with severe asthma. HDAC1 and HDAC2 expression was not downregulated in severe asthma. These data do not support upregulated GRβ and resultant reduced HDAC expression as the principal mechanism of steroid resistance in severe asthma. Conflicting GRβ literature may be explained in part by clathrin cross-reactivity with commercial antibodies.
The value of quantitative CT (QCT) to identify chronic obstructive pulmonary disease (COPD) phenotypes is increasingly appreciated. The authors hypothesised that QCT-defined emphysema and airway abnormalities relate to St George's Respiratory Questionnaire (SGRQ) and Body-Mass Index, Airflow Obstruction, Dyspnea and Exercise Capacity Index (BODE).
1200 COPDGene subjects meeting Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria for COPD with QCT analysis were included. Total lung emphysema was measured using the density mask technique with a –950 Hounsfield unit threshold. An automated programme measured mean wall thickness (WT), wall area percentage (WA%) and 10 mm lumenal perimeter (pi10) in six segmental bronchi. Separate multivariate analyses examined the relative influence of airway measures and emphysema on SGRQ and BODE.
In separate models predicting SGRQ score, a 1 unit SD increase in each airway measure predicted higher SGRQ scores (for WT, 1.90 points higher, p=0.002; for WA%, 1.52 points higher, p=0.02; for pi10, 2.83 points higher p<0.001). The comparable increase in SGRQ for a 1 unit SD increase in emphysema percentage in these models was relatively weaker, significant only in the pi10 model (for emphysema percentage, 1.45 points higher, p=0.01). In separate models predicting BODE, a 1 unit SD increase in each airway measure predicted higher BODE scores (for WT, 1.07-fold increase, p<0.001; for WA%, 1.20-fold increase, p<0.001; for pi10, 1.16-fold increase, p<0.001). In these models, emphysema more strongly influenced BODE (range 1.24–1.26-fold increase, p<0.001).
Emphysema and airway disease both relate to clinically important parameters. The relative influence of airway disease is greater for SGRQ; the relative influence of emphysema is greater for BODE.
Patients with active pulmonary tuberculosis screened or managed by the Find and Treat service between 2007 and 2010 (48 identified by mobile screening, 188 referred for case management support and 180 referred as lost to previous follow-up) were matched with 252 control patients who presented via London's enhanced tuberculosis surveillance system. A model was constructed based on various parameters such as the likelihood of completing treatment and quality of life with untreated and treated tuberculosis. The Find and Treat service was estimated to gain 220 quality-adjusted...]]>
Decline in forced vital capacity (FVC) over time reliably predicts mortality in patients with idiopathic pulmonary fibrosis. The use of this measure in clinical practice is recommended by current evidence-based guidelines. It is unknown if the method of calculating decline in FVC (relative vs absolute change) impacts its frequency or its ability to predict mortality.
Patients with idiopathic pulmonary fibrosis from two prospective cohorts were included if they had a baseline and 12-month follow-up FVC. A ≥10% decline in FVC from baseline was calculated in two ways: a relative decline of 10% (eg, from 60% predicted to 54% predicted) and an absolute decline of 10% (eg, from 60% predicted to 50% predicted). The frequency of a ≥10% decline in FVC and its ability to predict 2-year transplant-free survival were compared between these two methods. Declines in FVC of ≥5% and ≥15% were similarly compared. Analyses were performed unadjusted and adjusted for age, gender, use of oxygen, baseline FVC and baseline diffusion capacity for carbon monoxide.
The frequency of any given FVC decline was significantly greater using the relative change in FVC method. For ≥10% decline, both methods predicted 2-year transplant-free survival with similar accuracy, and remained significant predictors after adjusting for baseline characteristics. The absolute change method appeared more predictive for ≥5% decline.
Using the relative change in FVC maximises the chance of identifying a ≥10% decline in FVC without sacrificing prognostic accuracy. This may not hold true for ≥5% decline in FVC. These findings have important implications for clinical practice and the design of clinical trials.
Poor UK lung cancer survival rates may, in part, be due to late diagnosis.
To evaluate the effectiveness of a mixed-method community-based social marketing intervention on lung cancer diagnoses.
A public awareness campaign in conjunction with brief intervention training in general practices was piloted in six localities with a high lung cancer incidence. End points were self-reported awareness of lung cancer symptoms; intention to seek healthcare; chest x-ray referral rates in primary care; secular trends in the incidence of lung cancer and stage at diagnosis, compared before and after the intervention.
21% (128/600) (95% CI 18% to 25%) of the targeted population recalled something about the campaign. Compared with a responder in the control area, the odds of a responder in the intervention area saying that they would visit their general practitioner and request a chest x-ray for a cough was 1.97 times (95% CI 1.18 to 3.31, p=0.01). Primary care chest x-ray referral rates increased by 20% in the targeted practices in the year following the intervention compared with a 2% fall in the control practices. The difference was highly significant, with an incidence rate ratio of 1.22 (95% CI 1.12 to 1.33, p=0.001). There was a 27% increase in lung cancer diagnoses in the intervention area compared with a fall in the control area. The incidence rate ratio was 1.42 (95% CI 0.83 to 2.44 p=0.199).
This is encouraging early evidence that an awareness and early recognition initiative may facilitate lung cancer diagnosis.
Earlier diagnosis of lung cancer is key to reducing mortality. New evidence suggests that smokers have negative attitudes to screening and participation in lung cancer screening trials is poor (<1 in 6 of those eligible). Understanding participation is important since uptake in screening trials is likely to predict uptake in screening programmes. A qualitative study of people accepting and declining participation in the Lung-SEARCH screening trial was conducted. Two questions were addressed: Are the screening methods offered acceptable to patients? Why do some people take part and others decline?
The qualitative study used semi-structured interviews with 60 respondents from three groups: (a) trial participants providing an annual sputum sample; (b) trial participants with a sputum sample showing abnormal cytology and thus undergoing annual CT scanning and bronchoscopy; and (c) those declining trial participation.
Most respondents (48/60, 80%) viewed sputum provision, CT scanning and bronchoscopy as largely acceptable. Those declining trial participation described fear of bronchoscopy, inconvenience of travelling to hospitals for screening investigations and perceived themselves as having low susceptibility to lung cancer or being too old to benefit. Patients declining participation discounted their risk from smoking and considered negative family histories and good health to be protective. Four typological behaviours emerged within those declining: ‘too old to be bothered’, ‘worriers’, ‘fatalists’ and ‘avoiders’.
Sputum provision, CT scanning and bronchoscopy are largely acceptable to those participating in a screening trial. However, the decision to participate or decline reflects a complex balance of factors including acceptability and convenience of screening methods, risk perception, altruism and self-interest. Improving practical and changing cognitive aspects of participation will be key to improving uptake of lung cancer screening.
To develop and validate a Lung Cancer Awareness Measure (Lung CAM) and explore the demographical and social predictors of lung cancer awareness in the general population.
Symptoms and risk factors for lung cancer were identified from the medical literature and health professional expertise in an iterative process. Test–retest reliability, internal reliability, item analyses, construct validity and sensitivity to changes in awareness of the Lung CAM were assessed in three samples (total N=191).
The Lung CAM demonstrated good internal (Cronbach's α=0.88) and test–retest reliability (r=0.81, p<0.001). Validity was supported by lung cancer experts scoring higher than equally educated controls (t(106)=8.7, p<0.001), and volunteers randomised to read lung cancer information scoring higher than those reading a control leaflet (t(81)=3.66, p<0.001).
A population-based sample of 1484 adults completed the Lung CAM in a face-to-face, computer-assisted interview.
Symptom awareness was low (average recall of one symptom) and there was little awareness of risk factors other than smoking. Familiarity with cancer, and being from a higher socioeconomic group, were associated with greater awareness.
Using a valid and reliable tool for assessing awareness showed the UK population to have low awareness of lung cancer symptoms and risk factors. Interventions to increase lung cancer awareness are needed to improve early detection behaviour.
Primary ciliary dyskinesia (PCD) is an autosomal recessive, genetically heterogeneous disorder characterised by oto-sino-pulmonary disease and situs abnormalities (Kartagener syndrome) due to abnormal structure and/or function of cilia. Most patients currently recognised to have PCD have ultrastructural defects of cilia; however, some patients have clinical manifestations of PCD and low levels of nasal nitric oxide, but normal ultrastructure, including a few patients with biallelic mutations in dynein axonemal heavy chain 11 (DNAH11).
To test further for mutant DNAH11 as a cause of PCD, DNAH11 was sequenced in patients with a PCD clinical phenotype, but no known genetic aetiology.
82 exons and intron/exon junctions in DNAH11 were sequenced in 163 unrelated patients with a clinical phenotype of PCD, including those with normal ciliary ultrastructure (n=58), defects in outer and/or inner dynein arms (n=76), radial spoke/central pair defects (n=6), and 23 without definitive ultrastructural results, but who had situs inversus (n=17), or bronchiectasis and/or low nasal nitric oxide (n=6). Additionally, DNAH11 was sequenced in 13 subjects with isolated situs abnormalities to see if mutant DNAH11 could cause situs defects without respiratory disease.
Of the 58 unrelated patients with PCD with normal ultrastructure, 13 (22%) had two (biallelic) mutations in DNAH11; and two patients without ultrastructural analysis had biallelic mutations. All mutations were novel and private. None of the patients with dynein arm or radial spoke/central pair defects, or isolated situs abnormalities, had mutations in DNAH11. Of the 35 identified mutant alleles, 24 (69%) were nonsense, insertion/deletion or loss-of-function splice-site mutations.
Mutations in DNAH11 are a common cause of PCD in patients without ciliary ultrastructural defects; thus, genetic analysis can be used to ascertain the diagnosis of PCD in this challenging group of patients.
None.
Commissioned; internally peer reviewed.
AB and CH contributed equally to the manuscript.
None.
Commissioned; internally peer reviewed.
The defect in ion transport resulting from abnormal CF transmembrane conductance regulator protein leads to a dehydrated airway surface. Mucociliary clearance suffers and either shed bacterial components, such as flagella, or, more controversially, the bacteria themselves, trigger inflammatory responses via direct contact with cell surface glycoproteins. Increased expression of pro-inflammatory cytokines leads to neutrophil influx from the systemic circulation. Although at early...]]>
A 19-year-old student who had never smoked presented with a 6-month history of cough, wheeze, sputum production and generalised fatigue. His exercise tolerance was unaffected and he continued to play rugby competitively. He had a history of childhood asthma and received treatment with inhaled salbutamol with no effect. A chest x-ray revealed a round density at the base of the right lung. A CT chest was performed (
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