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In the 1990s, metered dose inhalers (MDIs) containing chlorofluorocarbons were replaced with dry-powder inhalers (DPIs) and MDIs containing hydrofluorocarbons (HFCs). While HFCs are not ozone depleting, they are potent greenhouse gases. Annual carbon footprint (CO2e), per patient were 17 kg for Relvar-Ellipta/Ventolin-Accuhaler; and 439 kg for Seretide-Evohaler/Ventolin-Evohaler. In 2017, 70% of all inhalers sold in England were MDI, versus 13% in Sweden. Applying the Swedish DPI and MDI distribution to England would result in an annual reduction of 550 kt CO2e. The lower carbon footprint of DPIs should be considered alongside other factors when choosing inhalation devices.

BackgroundThe genetic basis for developing asthma has been extensively studied. However, association studies to date have mostly focused on mild to moderate disease and genetic risk factors for severe asthma remain unclear.ObjectiveTo identify common genetic variants affecting susceptibility to severe asthma.MethodsA genome-wide association study was undertaken in 933 European ancestry individuals with severe asthma based on Global Initiative for Asthma (GINA) criteria 3 or above and 3346 clean controls. After standard quality control measures, the association of 480 889 genotyped single nucleotide polymorphisms (SNPs) was tested. To improve the resolution of the association signals identified, non-genotyped SNPs were imputed in these regions using a dense reference panel of SNP genotypes from the 1000 Genomes Project. Then replication of SNPs of interest was undertaken in a further 231 cases and 1345 controls and a meta-analysis was performed to combine the results across studies.ResultsAn association was confirmed in subjects with severe asthma of loci previously identified for association with mild to moderate asthma. The strongest evidence was seen for the ORMDL3/GSDMB locus on chromosome 17q12-21 (rs4794820, p=1.03×10(−8) following meta-analysis) meeting genome-wide significance. Strong evidence was also found for the IL1RL1/IL18R1 locus on 2q12 (rs9807989, p=5.59×10(−8) following meta-analysis) just below this threshold. No novel loci for susceptibility to severe asthma met strict criteria for genome-wide significance.ConclusionsThe largest genome-wide association study of severe asthma to date was carried out and strong evidence found for the association of two previously identified asthma susceptibility loci in patients with severe disease. A number of novel regions with suggestive evidence were also identified warranting further study.

Specifically, check for: reported wheeze, noisy breathing, cough, breathlessness or chest tightness, and any variation (for example, worse during the night or early morning, or seasonal) in these symptoms any triggers that make symptoms worse a personal or family history of asthma or allergic rhinitis symptoms to suggest alternative diagnoses (see the tables on alternative diagnoses in wheezy childrenandalternative diagnoses in adults in the BTS/SIGN British guideline on the management of asthma SIGN 158.) [BTS/NICE/SIGN 2024] For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on objective tests for diagnosing asthma in adults, young people and children aged 5 to 16 with a history suggestive of asthma. Full details of the evidence and the committee’s discussion are in: evidence review A: diagnostic test accuracy of spirometry in people suspected of asthma evidence review B: diagnostic test accuracy for bronchodilator reversibility in people suspected of asthma evidence review C: diagnostic test accuracy of peak expiratory flow variability for the diagnosis of asthma evidence review D: accuracy of skin prick test in children for the diagnosis of asthma evidence review E: diagnostic test accuracy of IgE in children evidence review F: diagnostic accuracy of fractional exhaled nitric oxide (FeNO) measures evidence review G: diagnostic accuracy of eosinophil blood count measures in the diagnosis of asthma evidence review H: bronchial challenge with histamine and methacholine for the diagnosis of asthma evidence review I: bronchial challenge test with mannitol evidence review J: bronchial challenge testing in response to exercise for the diagnosis of asthma evidence review K: diagnostic accuracy of combination of tests. [NICE 2017, BTS/SIGN 2019, amended BTS/NICE/SIGN 2024] Refer to a specialist respiratory paediatrician any preschool child with an admission to hospital, or two or more admissions to an emergency department, with wheeze in a 12 month period.

In those patients with asthma demonstrating nocturnal symptoms, the activity of the glucocorticoid receptor has been shown to demonstrate reduced steroid responsiveness overnight.6 The PER3 gene, which is linked to chronotype, had been demonstrated previously by Krakowiak et al to exhibit significantly greater rhythmicity in individuals with asthma compared to healthy controls.7 It therefore follows that aligning drug administration with the body’s circadian rhythm—known as chronotherapy—would likely enhance the efficacy of inhaled corticosteroid treatment in patients with asthma. Previous work by Gagnon et al had demonstrated in moderate asthma, managed with a twice-daily dose of inhaled beclomethasone, a single daily dose of beclomethasone administered in the late afternoon or evening offered equivalent asthma control over a 2 month period.9 In addition, Frezza et al had demonstrated a reduction in the nocturnal dip in FEV1 at 4 AM in steroid naïve patients with single-dose BDP/fluticasone propionate compared with placebo.10 However, no previous study had looked in detail at a combination of physiology and inflammation. If a more severe population was studied, then a different study design would have to be followed to prevent events during run-in or wash-out. Asthma: analysis of sudden deaths and ventilatory arrests in hospital.

BackgroundIn allergic asthma, exposure to relevant antigens leads to an early asthmatic response (EAR) followed, in certain subjects, by a late asthmatic response (LAR). Although many subjects with asthma consider LAR to be one of the defining symptoms of their disease, and despite its widespread use in the clinical assessment of new therapeutic entities, the mechanism underlying the LAR remains unclear.MethodA study was undertaken using ovalbumin-sensitised and challenged Brown Norway rat and C57BL/6J mouse models which recapitulate phenotypic features of allergic asthma including the LAR and its susceptibility to clinically effective agents.ResultsIn conscious animals an EAR was followed by a LAR. The LAR was subjectively evidenced by audible (wheeze) and visual signs of respiratory distress associated with quantifiable changes in non-invasive lung function assessment. Treatments that attenuated the EAR failed to impact on the LAR and, while anaesthesia did not impact on EAR, it abolished LAR. A key role for airway sensory neuronal reflexes in the LAR was therefore hypothesised, which was confirmed by the blockade observed after administration of ruthenium red (non-selective cation channel blocker), HC-030031 (TRPA1 inhibitor) and tiotropium bromide (anticholinergic) but not JNJ-17203212 (TRPV1 inhibitor).ConclusionThese results suggest that LAR involves the following processes: allergen challenge triggering airway sensory nerves via the activation of TRPA1 channels which initiates a central reflex event leading to a parasympathetic cholinergic constrictor response. These data are supported by recent clinical trials suggesting that an anticholinergic agent improved symptoms and lung function in patients with asthma.

Efficacy of omalizumab in severe asthma is well documented; however, the optimal duration of the treatment remains unclear. In an open prospective study, we sought to assess the persistence of response in subjects withdrawing from omalizumab treatment. We evaluated 49 patients who voluntarily accepted to discontinue omalizumab treatment after 6 years of therapy. Asthma relapse was defined as any severe asthma exacerbation associated with loss of asthma control. Twelve patients relapsed in the first year of follow-up, and 7 within 13 and 48 months. These results suggest that the effects of 6 years of omalizumab may persist after discontinuation of therapy in 60% of patients for at least 4 years.

BackgroundShort-term exposure to air pollution can trigger hospital admissions for asthma in children, but it is not known which components of air pollution are most important. There are no available studies on the particular effect of ultrafine particles (UFPs) on paediatric admissions for asthma.AimTo study whether short-term exposure to air pollution is associated with hospital admissions for asthma in children. It is hypothesised that (1) the association between asthma admissions and air pollution is stronger with UFPs than with coarse (PM10) and fine (PM2.5) particles, nitrogen oxides (NOx) or nitrogen dioxide (NO2); and (2) infants are more susceptible to the effects of exposure to air pollution than older children.MethodDaily counts of admissions for asthma in children aged 0–18 years to hospitals located within a 15 km radius of the central fixed background urban air pollution measurement station in Copenhagen between 2001 and 2008 were extracted from the Danish National Patient Registry. A time-stratified case crossover design was applied and data were analysed using conditional logistic regression to estimate the effect of air pollution on asthma admissions.ResultsA significant association was found between hospital admissions for asthma in children aged 0–18 years and NOx (OR 1.11; 95% CI 1.05 to 1.17), NO2 (1.10; 95% CI 1.04 to 1.16), PM10 (1.07; 95% CI 1.03 to 1.12) and PM2.5 (1.09; 95% CI 1.04 to 1.13); there was no association with UFPs. The association was stronger in infants than in older children for all pollutants, but no statistically significant interaction was detected.ConclusionShort-term exposure to air pollution can trigger hospital admission for asthma in children, with infants possibly being most susceptible. These effects seemed to be mediated by larger particles and traffic-related gases, whereas UFPs showed no effect.

BackgroundTwo distinct, stable inflammatory phenotypes have been described in adults with asthma: eosinophilic and non-eosinophilic. Treatment strategies based on these phenotypes have been successful. This study evaluated sputum cytology in children with asthma to classify sputum inflammatory phenotypes and to assess their stability over time.MethodsSputum induction was performed in 51 children with severe asthma and 28 with mild to moderate asthma. Samples were classified as eosinophilic (>2.5% eosinophils), neutrophilic (>54% neutrophils); mixed granulocytic (>2.5% eosinophils, >54% neutrophils); or paucigranulocytic (≤2.5% eosinophils, ≤54% neutrophils). Sputum induction was repeated every 3 months in children with severe asthma (n=42) over a 1-year period and twice in mild to moderate asthma (n=17) over 3–6 months.Results62 children (78%) had raised levels of inflammatory cells in at least one sputum sample. In the longitudinal analysis 37 of 59 children (63%) demonstrated two or more phenotypes. Variability in sputum inflammatory phenotype was observed in both the severe and the mild to moderate asthma groups. Change in phenotype was not related to change in inhaled corticosteroid (ICS) dose or asthma control, nor was it reflected in a change in exhaled nitric oxide (FENO). 24 children (41%) fulfilled the criteria for non-eosinophilic asthma on one occasion and eosinophilic on another. There were no differences in severity, asthma control, atopy, ICS dose or forced expiratory volume in 1 s between those who were always non-eosinophilic and those always eosinophilic.ConclusionRaised levels of inflammatory cells were frequently found in children with asthma of all severities. Sputum inflammatory phenotype was not stable in children with asthma.

Medication non-adherence and the clinical implications in difficult-to-control asthma were audited. Prescription issue data from 115 patients identified sub-optimal adherence (<80%) in 65% of patients on inhaled corticosteroids (ICS) or combined ICS/long-acting β2 agonist (LABA). In those using separate ICS and LABA, adherence to LABA (50%) was significantly better than to ICS (14.3%). Patients with sub-optimal ICS adherence had reduced FEV1 and higher sputum eosinophil counts. Adherence ratio was an independent predictor of previous ventilation for acute severe asthma (p=0.008). The majority of patients with difficult-to-control asthma are non-adherent with their asthma medication. Non-adherence is correlated with poor clinical outcomes.

BackgroundCurrent guidelines recommend treatment with one or more long-acting bronchodilators for patients with moderate or more severe chronic obstructive pulmonary disease (COPD). The authors investigated the approach of dual bronchodilation using indacaterol, a once-daily long-acting β2 agonist, and the long-acting muscarinic antagonist tiotropium, compared with tiotropium alone.MethodsIn two identically designed, double-blind, 12-week studies, patients with moderate to severe COPD were randomised to indacaterol 150 μg once daily or matching placebo. All patients concurrently received open-label tiotropium 18 μg once daily. The primary outcome was standardised area under the curve of forced expiratory volume in 1 s (FEV1) from 5 min to 8 h post dose at week 12. The key secondary outcome was 24 h post-dose (‘trough’) FEV1 at week 12. Resting inspiratory capacity (IC) was measured in a subgroup.Results1134 and 1142 patients were randomised in studies 1 and 2; 94% and 94% completed. Compared with monotherapy, concurrent therapy increased FEV1 (area under the curve by 130 and 120 ml, trough by 80 and 70 ml; all p<0.001) and trough IC (by 130 and 100 ml, p<0.01). Cough was more common with indacaterol plus tiotropium (10% and 9%) than with tiotropium alone (4% and 4%). Most cases (∼90%) of cough were mild. Other adverse events were similar for the treatment groups.ConclusionsCompared with tiotropium monotherapy, indacaterol plus tiotropium provided greater bronchodilation and lung deflation (reflected by increased resting IC). Adverse events were similar between treatments apart from mild cough being more common with indacaterol plus tiotropium. These results support COPD guideline recommendations to combine bronchodilators with different mechanisms of action.Trial registration numbersNCT00846586 and NCT00877383.