Steve Cunningham

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These guidelines have been replaced by British Guideline on the Management of Asthma.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 Superseded By 2012 Revision Of 2008 Guideline: British Guideline on the Management of Asthma.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.

Transcutaneous oxygen levels in retinopathy of prematurity

Retinopathy of prematurity (ROP) is a potentially blinding disease of preterm infants. 21 days of computer-recorded transcutaneous oxygen (TcPO2) data were compared in 31 infants with stage 3 or greater ROP and 38 infants with no ROP or stage 1 or 2. In a multiple logistic regression adjusted for significant perinatal factors (birthweight, gestation, and intraventricular haemorrhage), babies with stage 3 or higher ROP showed an increased variability of TcPO2 in week 1 (p < 0.01) and 2 (p = 0.012) but not week 3. Variability of TcPO2 in the first 2 weeks of life is a significant predictor of severe ROP.

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.

Effect of Oxygen Supplementation on Length of Stay for Infants Hospitalized With Acute Viral Bronchiolitis

OBJECTIVE. The goal was to establish the final supportive therapy determinants of hospital length of stay for bronchiolitis. METHODS. A retrospective case study of a randomly selected 25% of subjects <1 year of age who were hospitalized with bronchiolitis between April 1, 2003, and June 15, 2005 (n = 129), was performed. Records of 102 admissions to the general wards were reviewed (77 respiratory syncytial virus positive). Length of stay, pulse oxygen saturation profile, oxygen supplementation, feeding support, and nasal suction were determined. Infants admitted to the PICU (27 admissions) were excluded. RESULTS. The majority of patients presented with feeding difficulties (82% at admission). Oxygen supplementation was not indicated initially for the majority of infants (22% with mean pulse oxygen saturation of 94%). However, oxygen treatment was required by 70% of infants by 6 hours, whereas the mean pulse oxygen saturation decreased by an average of only 2%. Feeding problems were resolved for 98% of infants by 96 hours, followed by oxygen supplementation resolving with an average lag of 66 hours. The mean pulse oxygen saturation at discharge was 95%. There was no significant correlation between pulse oxygen saturation at arrival at the emergency department and subsequent oxygen requirements or length of stay. CONCLUSIONS. Oxygen supplementation is the prime determinant of the length of hospitalization for infants with bronchiolitis. Infants remaining in the hospital for oxygen supplementation once feeding difficulties had resolved did not experience deterioration to the extent of needing PICU support.

Bronchoconstriction following nebulised colistin in cystic fibrosis

Nebulised colistin is regularly used as antipseudomonal therapy in children with cystic fibrosis. We assessed bronchoconstriction in response to nebulised colistin in 58 children. Nebulised colistin significantly reduced FEV1, MEF25%, and Sao 2 for 15 minutes. In 20 children the reduction was greater than 10% from baseline FEV1, and was still at that level in five at 30 minutes. Subjective assessment, baseline FEV1, and serum IgE were unable to identify susceptible children. It is recommended that children receiving colistin should be carefully assessed for bronchoconstriction.

Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2–5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study

BACKGROUND Ivacaftor has been shown to be a safe, effective treatment for cystic fibrosis in patients aged 6 years or older with a CFTR gating mutation. We aimed to assess the safety, pharmacokinetics, and pharmacodynamics of ivacaftor in children aged 2-5 years. METHODS In the two-part KIWI study, we enrolled children aged 2-5 years weighing 8 kg or more with a confirmed diagnosis of cystic fibrosis and a CFTR gating mutation on at least one allele from 15 hospitals in the USA, UK, and Canada. Participants received oral ivacaftor 50 mg (if bodyweight <14 kg) or 75 mg (if bodyweight ≥14 kg) every 12 h for 4 days in part A (to establish the short-term safety of doses for subsequent assessment in part B), and then for 24 weeks in part B (to assess safety and longer-term pharmacodynamics). Children could participate in both or just one part of the study. Primary outcomes were pharmacokinetics and safety, analysed in all patients who received at least one dose of ivacaftor. Secondary outcomes were absolute change from baseline in sweat chloride concentrations and bodyweight, body-mass index (BMI), and height Z scores, and pharmacokinetic parameter estimation of ivacaftor. This study is registered with ClinicalTrials.gov, number NCT01705145. FINDINGS Between Jan 8, 2013, and March 1, 2013, nine patients were enrolled onto part A of the study, all of whom completed the 4 day treatment period, and eight of whom took part in part B. Between June 28, 2013, and Sept 26, 2013, 34 patients were enrolled in part B, 33 of whom completed the 24 week treatment period. All patients received at least one dose of ivacaftor. Results of ivacaftor pharmacokinetics suggested that exposure was similar to that reported in adults (median Cmin were 536 ng/mL for the 50 mg dose; 580 ng/mL for the 75 mg dose; median ivacaftor AUC values were 9840 ng × h/mL and 10 200 ng × h/mL, respectively). Common adverse events in part B included cough (in 19 [56%] of 34 patients) and vomiting (in ten [29%]). Five (15%) patients had liver function test (LFT) results that were more than eight times higher than the upper limit of normal, four of whom had study drug interrupted, and one of whom had study drug discontinued. Six (18%) of 34 patients had seven serious adverse events; a raised concentration of transaminases was the only serious adverse event regarded as related to ivacaftor and the only adverse event that resulted in study treatment discontinuation. At week 24, in patients for whom we had data, sweat chloride had changed from baseline by a mean of -46·9 mmol/L (SD 26·2, p<0·0001), weight Z score by 0·2 (0·3; p<0·0001), BMI Z score by 0·4 (0·4, p<0·0001), and height Z score by -0·01 (0·3; p=0·84). INTERPRETATION Ivacaftor at doses of 50 mg and 75 mg seems to be safe in children aged 2-5 years with cystic fibrosis with a gating mutation followed up for 24 weeks, although the frequency of elevated LFTs suggests that monitoring should be frequent in young children, particularly those with a history of elevated LFTs. Results of an ongoing extension study assessing durability of these effects and longer-term safety are warranted. FUNDING Vertex Pharmaceuticals Incorporated.

Effect of an Integrated Care Pathway on Acute Asthma/Wheeze in Children Attending Hospital: Cluster Randomized Trial

OBJECTIVE To determine whether an integrated care pathway (ICP) could improve care delivered to patients coming to an emergency department only or to patients who were subsequently admitted. STUDY DESIGN Children (age, 2-16 years; n = 298) coming to the ED with acute asthma/wheeze, were randomized by using a cluster design to either standard care or care delivered by an ICP. RESULTS Children discharged from the ED who received care with an ICP (n = 118) received more prednisolone (81%; standard, 63%; P = .03) and increased advice to obtain primary care review (72%; standard, 33%; P < .0001). A total of 180 children were admitted (94 ICP, 86 standard). The rate of recovery was unchanged by ICP. The mean ICP length of stay (37.6 hours; range, 33.5-42.4 hours), was 93% of the mean standard length of care (40.7 hours; range, 35.9-46; P = .36). When a discharge checklist was completed (60 of 94 cases), the mean ICP length of stay was 34.2 hours (range, 30.5-38.4 hours; P = .07 versus standard). An ICP resulted in a 30% reduction in prescribing errors (mean, 10.4; standard, 14.8; P = .002). Eighty-four of 94 children with an ICP received a 48-hour discharge plan (89%) versus 35 of 86 children with standard care (41%). More clinical contacts were observed in children receiving care by an ICP (mean, 22, versus standard, 19.2: P = .0004). CONCLUSION An acute asthma/wheeze ICP improved education and prescribing errors, modestly reduced the length of stay when discharge criteria were adhered to, but did not influence recovery time. Further consideration of the effect on staff workload is required.

A randomised, double-blind, placebo-controlled phase IIB clinical trial of repeated application of gene therapy in patients with cystic fibrosis

The UK Cystic Fibrosis Gene Therapy Consortium has been working towards clinical gene therapy for patients with cystic fibrosis for several years. We have recently embarked on a large, multi-dose clinical trial of a non-viral, liposome-based formulation powered for the first time to detect clinical benefit. The article describes the details of the protocol.