Alex Horsley

British guideline on the management of asthma: A national clinical guideline

These guidelines have been replaced by British Guideline on the Management of Asthma. A national clinical guideline. Superseded By 2012 Revision Of 2008 Guideline: British Guideline on the Management of Asthma. Thorax 2008 May; 63(Suppl 4): 1–121.

Consensus statement for inert gas washout measurement using multiple- and single- breath tests

Inert gas washout tests, performed using the single- or multiple-breath washout technique, were first described over 60 years ago. As measures of ventilation distribution inhomogeneity, they offer complementary information to standard lung function tests, such as spirometry, as well as improved feasibility across wider age ranges and improved sensitivity in the detection of early lung damage. These benefits have led to a resurgence of interest in these techniques from manufacturers, clinicians and researchers, yet detailed guidelines for washout equipment specifications, test performance and analysis are lacking. This manuscript provides recommendations about these aspects, applicable to both the paediatric and adult testing environment, whilst outlining the important principles that are essential for the reader to understand. These recommendations are evidence based, where possible, but in many places represent expert opinion from a working group with a large collective experience in the techniques discussed. Finally, the important issues that remain unanswered are highlighted. By addressing these important issues and directing future research, the hope is to facilitate the incorporation of these promising tests into routine clinical practice.

Lung clearance index is a sensitive, repeatable and practical measure of airways disease in adults with cystic fibrosis

Background: Lung clearance index (LCI) is a sensitive marker of early lung disease in children but has not been assessed in adults. Measurement is hindered by the complexity of the equipment required. The aims of this study were to assess performance of a novel gas analyser (Innocor) and to use it as a clinical tool for the measurement of LCI in cystic fibrosis (CF). Methods: LCI was measured in 48 healthy adults, 12 healthy school-age children and 33 adults with CF by performing an inert gas washout from 0.2% sulfur hexafluoride (SF6). SF6 signal:noise ratio and 10–90% rise time of Innocor were compared with a mass spectrometer used in similar studies in children. Results: Compared with the mass spectrometer, Innocor had a superior signal:noise ratio but a slower rise time (150 ms vs 60 ms) which may limit its use in very young children. Mean (SD) LCI in healthy adults was significantly different from that in patients with CF: 6.7 (0.4) vs 13.1 (3.8), p<0.001. Ten of the patients with CF had forced expiratory volume in 1 s ⩾80% predicted but only one had a normal LCI. LCI repeats were reproducible in all three groups of subjects (mean intra-visit coefficient of variation ranged from 3.6% to 5.4%). Conclusions: Innocor can be adapted to measure LCI and affords a simpler alternative to a mass spectrometer. LCI is raised in adults with CF with normal spirometry, and may prove to be a more sensitive marker of the effects of treatment in this group.

Ventilation heterogeneity in children with well controlled asthma with normal spirometry indicates residual airways disease

Background: In adults with asthma, ventilation heterogeneity, independent of inflammation, has been hypothesised to be associated with airway remodelling. Bronchial biopsy in preschool children with wheeze demonstrates early structural changes. Ventilation heterogeneity is sensitive to airway disease in other paediatric respiratory conditions such as cystic fibrosis, so may be sensitive to early airway disease in asthma. An observational study was performed in which it was hypothesised that ventilation heterogeneity (lung clearance index (LCI) and phase III slope indices (Scond and Sacin)) were more sensitive than conventional measurements (forced expiratory volume in 1 s (FEV1) and exhaled nitric oxide (Feno)) for detecting residual airways disease in children with well controlled asthma. Methods: In 31 children with asthma of mean age 10.6 years (range 5–15), FEV1, LCI, Scond and Sacin were measured at two separate visits, before and after blinded salbutamol or placebo, with Feno measured once. 29 healthy volunteers of mean age 11.2 years (range 5–16) completed measurements at one visit only. Results: Baseline mean (SD) LCI was significantly higher in children with asthma than in controls (6.69 (0.91) vs 6.24 (0.47), p = 0.02). There were no significant differences in FEV1 or median Feno. Following salbutamol there was a small significant change in mean (SD) FEV1 (from −1.26 (1.25) to −0.93 (0.23), p = 0.03) but not in LCI, Scond or Sacin. Importantly, LCI remained significantly higher after bronchodilator in children with asthma than in controls (6.64 (0.69), p = 0.01). Conclusion: This study identifies the presence of residual ventilation heterogeneity in children with well controlled asthma and normal FEV1. The role of LCI in measuring early airway disease in children with asthma requires further exploration, possibly as a surrogate of structural remodelling.

Changes in physiological, functional and structural markers of cystic fibrosis lung disease with treatment of a pulmonary exacerbation

Background Clinical trials in cystic fibrosis (CF) have been hindered by the paucity of well characterised and clinically relevant outcome measures. Aim To evaluate a range of conventional and novel biomarkers of CF lung disease in a multicentre setting as a contributing study in selecting outcome assays for a clinical trial of CFTR gene therapy. Methods A multicentre observational study of adult and paediatric patients with CF (>10 years) treated for a physician-defined exacerbation of CF pulmonary symptoms. Measurements were performed at commencement and immediately after a course of intravenous antibiotics. Disease activity was assessed using 46 assays across five key domains: symptoms, lung physiology, structural changes on CT, pulmonary and systemic inflammatory markers. Results Statistically significant improvements were seen in forced expiratory volume in 1 s (p<0.001, n=32), lung clearance index (p<0.01, n=32), symptoms (p<0.0001, n=37), CT scores for airway wall thickness (p<0.01, n=31), air trapping (p<0.01, n=30) and large mucus plugs (p=0.0001, n=31), serum C-reactive protein (p<0.0001, n=34), serum interleukin-6 (p<0.0001, n=33) and serum calprotectin (p<0.0001, n=31). Discussion We identify the key biomarkers of inflammation, imaging and physiology that alter alongside symptomatic improvement following treatment of an acute CF exacerbation. These data, in parallel with our study of biomarkers in patients with stable CF, provide important guidance in choosing optimal biomarkers for novel therapies. Further, they highlight that such acute therapy predominantly improves large airway parameters and systemic inflammation, but has less effect on airway inflammation.

Effects of Ivacaftor in Patients With Cystic Fibrosis Who Carry the G551D Mutation and Have Severe Lung Disease

BACKGROUND The development of ivacaftor represents a significant advance in therapeutics for patients with cystic fibrosis (CF) who carry the G551D mutation. Patients with an FEV1 < 40% predicted represent a considerable proportion of eligible patients but were excluded from phase 3 clinical trials, and the effectiveness of the drug in this population is, therefore, unknown. METHODS Data were collected from adult CF centers in the United Kingdom and Ireland with patients enrolled in an ivacaftor compassionate use program (FEV1 < 40% or on lung transplant waiting list). Clinically recorded data were collated from patient records for 1 year prior and for a period of 90 to 270 days following ivacaftor commencement. Each patient was matched to two control subjects who would have met the requirements for the compassionate use program with the exception of genotype. RESULTS Twenty-one patients received ivacaftor for a median of 237 days. Mean FEV1 improved from 26.5% to 30.7% predicted (P = .01), representing a 16.7% relative improvement. Median weight improved from 49.8 to 51.6 kg (P = .006). Median inpatient IV antibiotic days declined from 23 to 0 d/y (P = .001) and median total IV treatment days decreased from 74 to 38 d/y (P = .002) following ivacaftor. Changes in pulmonary function and IV antibiotic requirements were significant compared with control subjects. CONCLUSIONS Ivacaftor was clinically effective in patients with CF who carry the G551D mutation and have severe pulmonary disease. The reductions in treatment requirements were clinically and statistically significant and have not been described in less severe populations.

Effects of cystic fibrosis lung disease on gas mixing indices derived from alveolar slope analysis.

S(cond) and S(acin) are derived from analysis of concentration-normalized phase III slopes (Sn(III)) of a multiple breath inert gas washout. Studies in healthy and COPD subjects suggest these reflect ventilation heterogeneity in conducting and acinar airway zones respectively, but similar studies in cystic fibrosis (CF) are lacking. S(cond), S(acin) and lung clearance index (LCI, a measure of overall gas mixing efficiency) were measured in 22 adults and 18 children with CF and 17 adult and 29 child controls. Plethysmography and gas transfer measurements were performed in adults, and spirometry in all subjects. S(cond) was elevated in almost all CF patients, including children with mild disease and normal LCI. However, S(cond) did not correlate with other measurements and appeared to reach a maximum; further increase in ventilation heterogeneity being restricted to S(acin). The nature and/or severity of CF lung disease may invalidate assumptions underlying the ability to separate phase III slope analysis of ventilation heterogeneity into proximal and peripheral components, and LCI may be a better indicator of gas mixing in this population.

Lung Clearance Index Is a Repeatable and Sensitive Indicator of Radiological Changes in Bronchiectasis

RATIONALE In bronchiectasis there is a need for improved markers of lung function to determine disease severity and response to therapy. OBJECTIVES To assess whether the lung clearance index is a repeatable and more sensitive indicator of computed tomography (CT) scan abnormalities than spirometry in bronchiectasis. METHODS Thirty patients with stable bronchiectasis were recruited and lung clearance index, spirometry, and health-related quality of life measures were assessed on two occasions, 2 weeks apart when stable (study 1). A separate group of 60 patients with stable bronchiectasis was studied on a single visit with the same measurements and a CT scan (study 2). MEASUREMENTS AND MAIN RESULTS In study 1, the intervisit intraclass correlation coefficient for the lung clearance index was 0.94 (95% confidence interval, 0.89 to 0.97; P < 0.001). In study 2, the mean age was 62 (10) years, FEV1 76.5% predicted (18.9), lung clearance index 9.1 (2.0), and total CT score 14.1 (10.2)%. The lung clearance index was abnormal in 53 of 60 patients (88%) and FEV1 was abnormal in 37 of 60 patients (62%). FEV1 negatively correlated with the lung clearance index (r = -0.51, P < 0.0001). Across CT scores, there was a relationship with the lung clearance index, with little evidence of an effect of FEV1. There were no significant associations between the lung clearance index or FEV1 and health-related quality of life. CONCLUSIONS The lung clearance index is repeatable and a more sensitive measure than FEV1 in the detection of abnormalities demonstrated on CT scan. The lung clearance index has the potential to be a useful clinical and research tool in patients with bronchiectasis.

Lung clearance index in cystic fibrosis subjects treated for pulmonary exacerbations

Pulmonary exacerbations are important clinical events for cystic fibrosis (CF) patients. Studies assessing the ability of the lung clearance index (LCI) to detect treatment response for pulmonary exacerbations have yielded heterogeneous results. Here, we conduct a retrospective analysis of pooled LCI data to assess treatment with intravenous antibiotics for pulmonary exacerbations and to understand factors explaining the heterogeneous response. A systematic literature search was performed to identify prospective observational studies. Factors predicting the relative change in LCI and spirometry were evaluated while adjusting for within-study clustering. Six previously reported studies and one unpublished study, which included 176 pulmonary exacerbations in both paediatric and adult patients, were included. Overall, LCI significantly decreased by 0.40 units (95% CI −0.60– −0.19, p=0.004) or 2.5% following treatment. The relative change in LCI was significantly correlated with the relative change in forced expiratory volume in 1 s (FEV1), but results were discordant in 42.5% of subjects (80 out of 188). Higher (worse) baseline LCI was associated with a greater improvement in LCI (slope: −0.9%, 95% CI −1.0– −0.4%). LCI response to therapy for pulmonary exacerbations is heterogeneous in CF patients; the overall effect size is small and results are often discordant with FEV1. Lung clearance index response to therapy for pulmonary exacerbations is heterogeneous in cystic fibrosis patients http://ow.ly/Mnvtd

Can early Burkholderia cepacia complex infection in cystic fibrosis be eradicated with antibiotic therapy

Introduction: Organisms of the Burkholderia cepacia complex (BCC) are important pathogens in cystic fibrosis (CF). The majority of those who acquire BCC develop chronic infection but it can also result in rapid decline in a significant minority. In addition, chronic infection with Burkholderia cenocepacia in particular is regarded as a contraindication to lung transplantation in many units. Whilst aggressive antibiotic therapy is employed in CF to eradicate Pseudomonas aeruginosa before infection becomes irreversibly established, no formal assessment of such strategies has been previously reported for BCC, despite the apparent widespread adoption of this practice. Methods: UK adult CF centers were surveyed about their current approach to new BCC infection. Outcomes of eradication therapy were assessed in patients attending the Manchester Adult CF Center with new BCC isolates between 1st January 2002 and 1st May 2011. Patients with previous infection with the same strain of BCC were excluded. BCC were identified at the national reference laboratories and confirmed by species-specific PCR and RecA sequencing. Results: Routine use of therapies to attempt eradication of new BCC is commonly used in the UK (12/17 centers who responded). This typically involves a combination of intravenous and nebulised antibiotics. Of 19 eligible cases of new BCC infection, the organism has been eradicated in 7 (37%). Three of these did not receive specific eradication therapy. Of 14 patients who have received eradication therapy and completed follow up, BCC were cleared in only 4 (29%). Conclusions: Attempted eradication of new BCC is a common practice in UK adult CF centers. A minority of patients clear the infection spontaneously and the effects of eradication therapies are at best modest. Early treatment may be associated with better outcomes, though there are insufficient data to support the use of any specific treatment regimen. A prospective, systematic evaluation of treatments and outcomes is required.