Pseudomonas aeruginosa is the most common bacterial pathogen in patients with cystic fibrosis (CF). Current infection control guidelines aim to prevent transmission via contact and respiratory droplet routes and do not consider the possibility of airborne transmission. It was hypothesised that subjects with CF produce viable respirable bacterial aerosols with coughing.
A cross-sectional study was undertaken of 15 children and 13 adults with CF, 26 chronically infected with P aeruginosa. A cough aerosol sampling system enabled fractioning of respiratory particles of different sizes and culture of viable Gram-negative non-fermentative bacteria. Cough aerosols were collected during 5 min of voluntary coughing and during a sputum induction procedure when tolerated. Standardised quantitative culture and genotyping techniques were used.
P aeruginosa was isolated in cough aerosols of 25 subjects (89%), 22 of whom produced sputum samples. P aeruginosa from sputum and paired cough aerosols were indistinguishable by molecular typing. In four cases the same genotype was isolated from ambient room air. Approximately 70% of viable aerosols collected during voluntary coughing were of particles <=3.3 µm aerodynamic diameter. P aeruginosa, Burkholderia cenocepacia, Stenotrophomonas maltophilia and Achromobacter xylosoxidans were cultivated from respiratory particles in this size range. Positive room air samples were associated with high total counts in cough aerosols (p = 0.003). The magnitude of cough aerosols was associated with higher forced expiratory volume in 1 s (r = 0.45, p = 0.02) and higher quantitative sputum culture results (r = 0.58, p = 0.008).
During coughing, patients with CF produce viable aerosols of P aeruginosa and other Gram-negative bacteria of respirable size range, suggesting the potential for airborne transmission.
For nearly 50 years the diagnosis of cystic fibrosis (CF) has depended on measurements of sweat chloride concentration. While the validity of this test is universally accepted, increasing diagnostic challenges and the search for adequate biomarker assays to support curative-orientated clinical drug trials have created a new demand for accurate, reliable and more practical CF tests. A novel concept is proposed that may provide a more efficient real-time method for assessing CFTR function in vivo.
Cholinergic and β-adrenergic agonists were iontophoresed to stimulate sweating. The bioelectric potential from stimulated sweat glands (SPD) was measured in vivo using a standard ECG electrode applied to the skin surface. SPD and sweat chloride concentrations were compared in cohorts predicted to express a range of CFTR function as presented by healthy controls (HC), heterozygotes (Hz), pancreatic sufficient (CFPS) and pancreatic insufficient patients with CF (CFPI).
The median SPD was hyperpolarised in patients with CF compared with control subjects (–47.4 mV vs –14.5 mV, p<0.001). In distinguishing between control and CF subjects, SPD (area under receiver operator curve (AUC) = 0.997) was similar to sweat chloride concentration (AUC = 0.986). Sequential cholinergic/β-adrenergic sweat stimulation dramatically depolarised the SPD in patients with CF (p<0.001) but had no effect in control subjects (p = 0.6) or on the sweat chloride concentration in either group (p>0.5). Furthermore, the positive SPD response was larger in CFPI than in CFPS subjects (p = 0.04).
These results support the concept that skin surface voltages arising from stimulated sweat glands can be exploited to assess expressed CFTR function in vivo and may prove to be a useful diagnostic tool.
Little is known about adherence to inhaled medication in chronic obstructive pulmonary disease (COPD) and the impact on mortality and morbidity.
Data on drug adherence from a randomised double-blind trial comparing inhaled salmeterol 50 µg + fluticasone propionate 500 µg twice daily with placebo and each drug individually in 6112 patients with moderate to severe COPD over 3 years in the TORCH study were used. All-cause mortality and exacerbations leading to hospital admission were primary and secondary end points. The study of adherence was not specified a priori as an ancillary study.
Of the 4880 patients (79.8%) with good adherence defined as >80% use of study medication, 11.3% died compared with 26.4% of the 1232 patients (20.2%) with poor adherence. The annual rates of hospital admission for exacerbations were 0.15 and 0.27, respectively. The association between adherence and mortality remained unchanged and statistically significant after adjusting for other factors related to prognosis (hazard ratio 0.40 (95% CI 0.35 to 0.46), p<0.001). The association was even stronger when analysing on-treatment deaths only. Similarly, the association between adherence and hospital admission remained unchanged and significant in a multivariate analysis (rate ratio 0.58 (95% CI 0.44 to 0.73, p<0.001). The association between increased adherence and improved mortality and reduction in hospital admission was independent of study treatment. The effect of treatment was more pronounced in patients with good adherence than in those with poor adherence.
Adherence to inhaled medication is significantly associated with reduced risk of death and admission to hospital due to exacerbations in COPD. Further research is needed to understand these strong associations.
A study was undertaken to determine if quantitative CT estimates of lung parenchymal overinflation and airway dimensions in smokers with a normal forced expiratory volume in 1 s (FEV1) can predict the rapid decline in FEV1 that leads to chronic obstructive pulmonary disease (COPD).
Study participants (n = 143; age 45–72 years; 54% male) were part of a lung cancer screening trial, had a smoking history of >30 pack years and a normal FEV1 and FEV1/forced vital capacity (FVC) at baseline (mean (SD) FEV1 99.4 (12.8)%, range 80.2–140.7%; mean (SD) FEV1/FVC 77.9 (4.4), range 70.0–88.0%). An inspiratory multislice CT scan was acquired for each subject at baseline. Custom software was used to measure airway lumen and wall dimensions; the percentage of the lung inflated beyond a predicted maximal lung inflation, the low attenuation lung area with an x ray attenuation lower than –950 HU and the size distribution of the overinflated lung areas and the low attenuation area were described using a cluster analysis. Multiple regression analysis was used to test the hypothesis that these CT measurements combined with other baseline characteristics might identify those who would develop an excessive annual decline in FEV1.
The mean (SD) annual change in FEV1 was –2.3 (4.7)% predicted (range –23.0% to +8.3%). Multiple regression analysis revealed that the annual change in FEV1%predicted was significantly associated with baseline percentage overinflated lung area measured on quantitative CT, FEV1%predicted, FEV1/FVC and gender.
Quantitative CT scan evidence of overinflation of the lung predicts a rapid annual decline in FEV1 in smokers with normal FEV1.
Fatigue is a prominent symptom in chronic obstructive pulmonary disease (COPD) and it has distinctive features; however, there is a need for a robust scale to measure fatigue in COPD.
At baseline, 122 patients with COPD (forced expiratory volume in 1 s (FEV1) 52%, women 38%, mean age 66 years) completed a pilot fatigue scale covering a pool of 57 items and underwent a range of tests, including indicators of mood and a short general fatigue questionnaire. All patients responded to the 57-item scale and it was readministered to a subset of 30 patients. The pilot scale was first subjected to constructive validated shortening steps and then to a principal components analysis.
The Manchester COPD fatigue scale (MCFS) consists of 27 items, loading into three dimensions: physical, cognitive and psychosocial fatigue. Internal consistency (Cronbach’s = 0.97) and test–retest repeatability (r = 0.97, p<0.001) were tested. It had significant convergent validity, correlating with the FACIT (Functional Assessment of Chronic Illness Therapy) fatigue scale and the fatigue in Borg scale at baseline and after a 6 minute walk distance (6MWD) test (r = –0.81, 0.53 and 0.63, respectively, p<0.001). Its scores were associated with BODE, SGRQ (St George’s Respiratory Questionnaire) and MRC (Medical Research Council) dyspnoea scores (r = 0.46, 0.8 and 0.51, respectively, p<0.001). The scale demonstrated meaningful discriminating ability; patients who walked <350 m in a 6MWD test as well as depressed patients (>=16 scores in the Center for Epidemiologic Study on Depression (CES-D) scale) had nearly twice as high fatigue scores as those who walked >=350 m or were not depressed (p<0.001).
The MCFS provides a simple, reliable and valid measurement of total and dimensional fatigue in moderate stable COPD.
Chronic obstructive pulmonary disease (COPD) is a chronic disease with a high prevalence and rapidly increasing incidence rates. The effect of self-treatment of COPD exacerbations on the severity of exacerbations during a 1-year period was examined and a cost-effectiveness analysis was performed.
Patients were randomly allocated to four 2-hour self-management sessions, with or without training in self-treatment of exacerbations. Patients in the self-treatment group received an action plan with the possibility to initiate a course of prednisolone (with or without antibiotics). During follow-up, all participants kept a daily symptom diary. These provided the data to calculate the frequency of exacerbations, the number of exacerbation days and mean daily severity scores.
Data were analysed for 142 randomised patients (self-treatment: n = 70; control: n = 72). The frequency of exacerbations was identical in both study groups (mean (SD) 3.5 (2.7)). Patients in the self-treatment group reported fewer exacerbation days (median 31 (interquartile range (IQR) 8.9–67.5) in the self-treatment group vs 40 (IQR 13.3–88.2) in the control group; p = 0.064); the difference was significant in the group of patients with a high number of exacerbation days per year (>137 (90th percentile of the whole study population); p = 0.028). The mean severity score of an exacerbation day was equal in both groups. No between-group differences were found in health-related quality of life. Cost-effectiveness analyses showed that applying self-treatment saved 154 per patient, with a trend towards a lower probability for hospital admissions (0.20/patient/year in the self-treatment group vs 0.33/patient/year in the control group; p = 0.388) and a significant reduction of health care contacts (5.37/patient/year in the self-treatment group vs 6.51/patient/year in the control group; p = 0.043).
Self-treatment of exacerbations incorporated in a self-management programme leads to fewer exacerbation days and lower costs.
Chronic obstructive pulmonary disease (COPD) is associated with an increased risk of lung cancer, independently of smoking. However, the relationship between COPD and total cancer mortality is less certain. A study was undertaken to investigate the association between COPD and total cancer mortality and to determine whether the use of statins, which have been associated with cancer risk in other settings, modified this relationship.
The study included 3371 patients with peripheral arterial disease who underwent vascular surgery between 1990 and 2006; 1310 (39%) had COPD and the rest did not. The primary end point was cancer mortality (lung and extrapulmonary) over a median follow-up of 5 years.
COPD was associated with an increased risk of both lung cancer mortality (hazard ratio (HR) 2.06; 95% CI 1.32 to 3.20) and extrapulmonary cancer mortality (HR 1.43; 95% CI 1.06 to 1.94). The excess risk was mostly driven by patients with moderate and severe COPD. There was a trend towards a lower risk of cancer mortality among patients with COPD who used statins compared with patients with COPD who did not use statins (HR 0.57; 95% CI 0.32 to 1.01). Interestingly, the risk of extrapulmonary cancer mortality was lower among statin users with COPD (HR 0.49; 95% CI 0.24 to 0.99).
COPD was associated with increased lung and extrapulmonary cancer mortality in this large cohort of patients with peripheral arterial disease undergoing vascular surgery. The risk of lung cancer mortality increased with progression of COPD. Statins were associated with a reduced risk of extrapulmonary cancer mortality in patients with COPD.
Increased numbers of activated neutrophils have been reported in the bronchial mucosa of patients with stable chronic obstructive pulmonary disease (COPD), particularly in severe disease.
To investigate the expression of neutrophilic chemokines and adhesion molecules in bronchial biopsies from patients with stable COPD of different severity (GOLD stages I–IV) compared with age-matched control subjects, smokers with normal lung function and never smokers.
The expression of CCL5, CXCL1, 5, 6, 7 and 8, CXCR1, CXCR2, CD11b and CD44 was measured in the bronchial mucosa using immunohistochemistry, confocal immunofluorescence, real-time quantitative polymerase chain reaction (RT-QPCR) and Western blotting (WB).
The numbers of CCL5+ epithelial cells and CCL5+ and CXCL7+ immunostained cells were increased in the bronchial submucosa of patients with stable severe COPD compared with control never smokers and smokers with normal lung function. This was also confirmed at the level of mRNA expression. The numbers of CCL5+ cells in the submucosa of patients with COPD were 2–15 times higher than any other chemokines. There was no correlation between the number of these cells and the number of neutrophils in the bronchial submucosa. Compared with control smokers, the percentage of neutrophils co-expressing CD11b and CD44 receptors was significantly increased in the submucosa of patients with COPD.
The increased expression of CCL5 and CXCL7 in the bronchial mucosa of patients with stable COPD, together with an increased expression of extracellular matrix-binding receptors on neutrophils, may be involved in the pathogenesis of COPD.
Hypercapnic acidosis exerts protective effects in acute lung injury but may also slow cellular repair. These effects may be mediated via inhibition of nuclear factor-B (NF-B), a pivotal transcriptional regulator in inflammation and repair.
To determine the effects of hypercapnic acidosis in pulmonary epithelial wound repair, to elucidate the role of NF-B and to examine the mechanisms by which these effects are mediated.
Confluent small airway epithelial cell, human bronchial epithelial cell and type II alveolar A549 cell monolayers were subjected to wound injury under conditions of hypercapnic acidosis (pH 7.0, carbon dioxide tension (P
Hypercapnic acidosis reduced wound closure (mean (SD) 33 (6.3)% vs 64 (5.9)%, p<0.01) and reduced activation of NF-B compared with normocapnia. Buffering of the acidosis did not alter this inhibitory effect. Prior inhibition of NF-B activation occluded the effect of hypercapnic acidosis. Inhibition of ERK, JNK and P38 did not modulate wound healing. Hypercapnic acidosis reduced epithelial cell migration but did not alter mitosis, and reduced matrix metalloproteinase-1 while increasing concentrations of tissue inhibitor of metalloproteinase-2.
Hypercapnic acidosis inhibits pulmonary epithelial wound healing by reducing cell migration via an NF-B dependent mechanism that may involve alterations in matrix metalloproteinase activity.
National analyses of mortality in England and Wales have repeatedly shown excess deaths from pneumonia in welders. During 1979–90 the excess was attributable largely to deaths from lobar pneumonia and pneumonias other than bronchopneumonia, limited to men of working age and apparent in other occupations with exposure to metal fumes. The findings for 1991–2000 were assessed and compared with the mortality pattern from asthma in occupations exposed to known respiratory sensitisers.
The Office of National Statistics supplied data on deaths by underlying cause among men aged 16–74 years in England and Wales during 1991–2000, including age and last held occupation. Data were abstracted on pneumonia for occupations with exposure to metal fumes and on asthma for occupations commonly reported to surveillance schemes as at risk of occupational asthma. The expected numbers of deaths were estimated by applying age-specific proportions of deaths by cause in the population to the total deaths by age in each occupational group. Observed and expected numbers were compared for each cause of death.
Among men of working age in occupations with exposure to metal fumes there was excess mortality from pneumococcal and lobar pneumonia (54 deaths vs 27.3 expected) and from pneumonias other than bronchopneumonia (71 vs 52.4), but no excess from these causes at older ages or from bronchopneumonia at any age. The attributable mortality from metal fume exposure was 45.3 excess deaths compared with an estimated 62.6 deaths from occupational asthma.
Exposure to metal fumes is a material cause of occupational mortality. The hazard deserves far more attention than it presently receives.
Biological markers as an expression of systemic inflammation have been recognised as useful for evaluating the host response in community-acquired pneumonia (CAP). The objective of this study was to evaluate whether the biological markers procalcitonin (PCT) and C-reactive protein (CRP) might reflect stability after 72 h of treatment and the absence of subsequent severe complications.
A prospective cohort study was performed in 394 hospitalised patients with CAP. Clinical stability was evaluated using modified Halm’s criteria: temperature <=37.2°C; heart rate <=100 beats/min; respiratory rate <=24 breaths/min; systolic blood pressure >=90 mm Hg; oxygen saturation >=90%; or arterial oxygen tension >=60 mm Hg. PCT and CRP levels were measured on day 1 and after 72 h. Severe complications were defined as mechanical ventilation, shock and/or intensive care unit (ICU) admission, or death after 72 h of treatment.
220 patients achieved clinical stability at 72 h and had significantly lower levels of CRP (4.2 vs 7 mg/dl) and of PCT (0.33 vs 0.48 ng/ml). Regression logistic analyses were performed to calculate several areas under the ROC curve (AUC) to predict severe complications. The AUC for clinical stability was 0.77, 0.84 when CRP was added (p = 0.059) and 0.77 when PCT was added (p = 0.45). When clinical stability was achieved within 72 h and marker levels were below the cut-off points (0.25 ng/ml for PCT and 3 mg/dl for CRP), no severe complications occurred.
Low levels of CRP and PCT at 72 h in addition to clinical criteria might improve the prediction of absence of severe complications.
Chronic cough is common, and medical treatment can be ineffective. Mindfulness is a psychological intervention that aims to teach moment-to-moment non-judgemental awareness of thoughts, feelings and sensations.
30 healthy subjects and 30 patients with chronic cough were studied in two sequential trials. For both studies, cough reflex sensitivity to citric acid (C5) was measured on two occasions, with urge to cough rated following each inhalation; between challenges subjects were randomised to (1) no intervention, (2) mindfulness or (3) no intervention but modified cough challenge (subjects suppress coughing). For the healthy volunteers, measures were 1 h apart and mindfulness was practised for 15 min. For the patients with chronic cough measures were 1 week apart and mindfulness was practised daily for 30 min.
In healthy volunteers, median change (interquartile range (IQR)) in cough reflex sensitivity (logC5) for no intervention, mindfulness and suppression was +1.0 (0.0 to +1.3), +2.0 (+1.0 to +3.0) and +3.0 (+2.8 to +3.0) doubling concentrations (p = 0.003); there were significant reductions for both mindfulness (p = 0.043) and suppression (p = 0.002) over no intervention. In patients with cough, median change (IQR) in logC5 for no intervention, mindfulness training and voluntary suppression was 0.0 (–1.0 to +1.0), +1.0 (–0.3 to +1.0) and +1.0 (+1.0 to +2.0) doubling concentrations (p = 0.046); there was a significant reduction for suppression (p = 0.02) but not mindfulness (p = 0.35). Urge to cough did not change after mindfulness compared with control in either healthy subjects (p = 0.33) or those with chronic cough (p = 0.47).
Compared with control, mindfulness decreased cough reflex sensitivity in healthy volunteers, but did not alter cough threshold in patients with chronic cough. Both groups were able to suppress cough responses to citric acid inhalation.