Improved lung function and body mass index associated with long-term use of Macrolide antibiotics

AbstractBackground: A number of studies have suggested that the non-antimicrobial actions of macrolide antibiotics may be valuable in treating patients with cystic fibrosis. The use of long-term macrolide antibiotics for the management of CF patients colonised by Pseudomonas aeruginosa and progressive pulmonary disease was introduced into our clinic in 1997. A retrospective study was undertaken to assess of the impact of this therapy. Methods: Twenty patients with progressive pulmonary disease (>10% fall in FEV1 over 12 months despite optimising conventional therapy) were commenced on Azithromycin, 250 mg daily during a 21-month period. At the time of assessment they had remained on therapy for a mean of 0.9 years. Changes in lung function, weight, body mass index (BMI) and frequency of pulmonary exacerbations were assessed. A group of 20 patients with stable lung function and matched as far as possible for age and sex was identified for comparison. Results: Pulmonary function increased significantly in the Azithromycin group with FEV1% predicted increasing from a mean of 50.2–59.1% (P=0.001) while FVC% predicted increase from 64.5 to 76.1% (P=0.002). There was small but non-significant fall in lung function in the comparison group. Body mass index increased by a mean of 1.1 in the Azithromycin group but remained unchanged in the comparison group. The number of pulmonary exacerbations requiring intravenous antibiotics declined by 48.3% in macrolide treated subjects compared to the pre-treatment period (P<0.025); frequency of exacerbations in the control group was unchanged. Conclusion: Long-term Azithromycin treatment in patients with progressive deterioration in lung function appears to have led to an improvement in pulmonary function, increased body mass index and decreased the frequency of pulmonary exacerbations requiring intravenous antibiotics

The Anti-Apoptotic Effect of Respiratory Syncytial Virus on Human Peripheral Blood Neutrophils is Mediated by a Monocyte Derived Soluble Factor

Respiratory Syncytial Virus (RSV) causes annual epidemics of respiratory disease particularly affecting infants. The associated airway inflammation is characterized by an intense neutrophilia. This neutrophilic inflammation appears to be responsible for much of the pathology and symptoms. Previous work from our group had shown that there are factors within the airways of infants with RSV bronchiolitis that inhibit neutrophil apoptosis. This study was undertaken to determine if RSV can directly affect neutrophil survival

Effect of inhaled corticosteroid particle size on asthma efficacy and safety outcomes: a systematic literature review and meta-analysis

BACKGROUND: Inhaled corticosteroids (ICS) are the primary treatment for persistent asthma. Currently available ICS have differing particle size due to both formulation and propellant, and it has been postulated that this may impact patient outcomes. This structured literature review and meta-analysis compared the effect of small and standard particle size ICS on lung function, symptoms, rescue use (when available) and safety in patients with asthma as assessed in head-to-head randomized controlled trials (RCTs). METHODS: A systematic literature search of MEDLINE was performed to identify RCTs (1998-2014) evaluating standard size (fluticasone propionate-containing medications) versus small particle size ICS medication in adults and children with asthma. Efficacy outcomes included forced expiratory volume in 1 s (FEV1), morning peak expiratory flow (PEF), symptom scores, % predicted forced expiratory flow between 25 and 75% of forced vital capacity (FEF25-75%), and rescue medication use. Safety outcomes were also evaluated when available. RESULTS: Twenty-three independent trials that met the eligibility criteria were identified. Benefit-risk plots did not demonstrate any clinically meaningful differences across the five efficacy endpoints considered and no appreciable differences were noted for most safety endpoints. Meta-analysis results, using a random-effects model, demonstrated no significant difference between standard and small size particle ICS medications in terms of effects on mean change from baseline FEV1 (L) (-0.011, 95% confidence interval [CI]: -0.037, 0.014 [N = 3524]), morning PEF (L/min) (medium/low doses: -3.874, 95% CI: -10.915, 3.166 [N = 1911]; high/high-medium doses: 5.551, 95% CI: -1.948, 13.049 [N = 749]) and FEF25-75% predicted (-2.418, 95% CI: -6.400; 1.564 [N = 115]). CONCLUSIONS: Based on the available literature, no clinically significant differences in efficacy or safety were observed comparing small and standard particle size ICS medications for the treatment of asthma. TRIAL REGISTRATION: GSK Clinical Study Register No: 202012

SABRE: a multicentre randomised control trial of nebulised hypertonic saline in infants hospitalised with acute bronchiolitis

Aim Acute bronchiolitis is the commonest cause for hospitalisation in infancy. Supportive care remains the cornerstone of current management and no other therapy has been shown to influence the course of the disease. It has been suggested that adding nebulised hypertonic saline to usual care may shorten the duration of hospitalisation. To determine whether hypertonic saline does have beneficial effects we undertook an open, multi-centre parallel-group, pragmatic RCT in ten UK hospitals. Methods Infants admitted to hospital with a clinical diagnosis of acute bronchiolitis and requiring oxygen therapy were randomised to receive usual care alone or nebulised 3% hypertonic saline (HS) administered 6-hourly. Randomisation was within 4 h of admission. The primary outcome was time to being assessed as ‘fit’ for discharge with secondary outcomes including time to discharge, incidence of adverse events together with follow up to 28 days assessing patient centred health related outcomes. Results A total of 317 infants were recruited to the study. 158 infants were randomised to HS (141 analysed) and 159 to standard care (149 analysed). There was no difference between the two arms in time to being declared fit for discharge (hazard ratio: 0−95, 95% CI: 0.75−1.20) nor to actual discharge (hazard ratio: 0.97, 95% CI: 0.76−1.23). There was no difference in adverse events. One infant in the HS group developed bradycardia with desaturation. Conclusion This study does not support the use of nebulised HS in the treatment of acute bronchiolitis over usual care with minimal handlings. ClinicalTrials.gov registration number NCT01469845

Key paediatric messages from Amsterdam

The Paediatric Assembly of the European Respiratory Society (ERS) maintained its high profile at the 2015 ERS International Congress in Amsterdam. There were symposia on preschool wheeze, respiratory sounds and cystic fibrosis; an educational skills workshop on paediatric respiratory resuscitation; a hot topic session on risk factors and early origins of respiratory diseases; a meet the expert session on paediatric lung function test reference values; and the annual paediatric grand round. In this report the Chairs of the Paediatric Assembly’s Groups highlight the key mess

Macrophages Are Required for Dendritic Cell Uptake of Respiratory Syncytial Virus from an Infected Epithelium

We have previously shown that the respiratory syncytial virus [RSV] can productively infect monocyte derived dendritic cells [MoDC] and remain dormant within the same cells for prolonged periods. It is therefore possible that infected dendritic cells act as a reservoir within the airways of individuals between annual epidemics. In the present study we explored the possibility that sub-epithelial DCs can be infected with RSV from differentiated bronchial epithelium and that in turn RSV from DCs can infect the epithelium. A dual co-culture model was established in which a differentiated primary airway epithelium on an Air Liquid Interface (ALI) was cultured on a transwell insert and MoDCs were subsequently added to the basolateral membrane of the insert. Further experiments were undertaken using a triple co-culture model in which in which macrophages were added to the apical surface of the differentiated epithelium. A modified RSV [rr-RSV] expressing a red fluorescent protein marker of replication was used to infect either the MoDCs or the differentiated epithelium and infection of the reciprocal cell type was assessed using confocal microscopy. Our data shows that primary epithelium became infected when rr-RSV infected MoDCs were introduced onto the basal surface of the transwell insert. MoDCs located beneath the epithelium did not become infected with virus from infected epithelial cells in the dual co-culture model. However when macrophages were present on the apical surface of the primary epithelium infection of the basal MoDCs occurred. Our data suggests that RSV infected dendritic cells readily transmit infection to epithelial cells even when they are located beneath the basal layer. However macrophages appear to be necessary for the transmission of infection from epithelial cells to basal dendritic cells

Fractional exhaled nitric oxide for the management of asthma in adults: Systematic review

The aim of this review was to evaluate the clinical effectiveness of fractional exhaled nitric oxide (FeNO) measured in a clinical setting for the management of asthma in adults. 13 electronic databases were searched and studies were selected against predefined inclusion criteria. Quality assessment was conducted using QUADAS-2. Class effect meta-analyses were performed. Six studies were included. Despite high levels of heterogeneity in multiple study characteristics, exploratory class effect meta-analyses were conducted. Four studies reported a wider definition of exacerbation rates (major or severe exacerbation) with a pooled rate ratio of 0.80 (95% CI 0.63–1.02). Two studies reported rates of severe exacerbations (requiring oral corticosteroid use) with a pooled rate ratio of 0.89 (95% CI 0.43–1.72). Inhaled corticosteroid use was reported by four studies, with a pooled standardised mean difference of −0.24 (95% CI −0.56–0.07). No statistically significant differences for health-related quality of life or asthma control were found. FeNO guided management showed no statistically significant benefit in terms of severe exacerbations or ICS use, but showed a statistically significant reduction in exacerbations of any severity. However, further research is warranted to clearly define which management protocols (including cut-off points) offer best efficacy and which patient groups would benefit the most

STAAR: a randomised controlled trial of electronic adherence monitoring with reminder alarms and feedback to improve clinical outcomes for children with asthma

Background Suboptimal adherence to inhaled steroids is common in children with asthma and is associated with poor disease control, reduced quality of life and even death. Previous studies using feedback of electronically monitored adherence data have demonstrated improved adherence, but have not demonstrated a significant impact on clinical outcomes. The aim of this study was to determine whether introduction of this approach into routine practice would result in improved clinical outcomes. Methods Children with asthma aged 6–16 years were randomised to the active intervention consisting of electronic adherence monitoring with daily reminder alarms together with feedback in the clinic regarding their inhaled corticosteroid (ICS) use or to the usual care arm with adherence monitoring alone. All children had poorly controlled asthma at baseline, taking ICS and long-acting β-agonists. Subjects were seen in routine clinics every 3 months for 1 year. The primary outcome was the Asthma Control Questionnaire (ACQ) score. Secondary outcomes included adherence and markers of asthma morbidity. Results 77 of 90 children completed the study (39 interventions, 38 controls). Adherence in the intervention group was 70% vs 49% in the control group (p≤0.001). There was no significant difference in the change in ACQ, but children in the intervention group required significantly fewer courses of oral steroids (p=0.008) and fewer hospital admissions (p≤0.001). Conclusions The results indicate that electronic adherence monitoring with feedback is likely to be of significant benefit in the routine management of poorly controlled asthmatic subjects

Respiratory Syncytial Virus infection promotes necroptosis and HMGB1 release by airway epithelial cells

Rationale: Respiratory syncytial virus (RSV) bronchiolitis causes significant infant mortality. Bronchiolitis is characterized by airway epithelial cell (AEC) death; however, the mode of death remains unknown. Objectives: To determine whether necroptosis contributes to RSV b r onchiolitis pathogenesis via HMGB1 (high mobility group box 1) release. Methods: Nasopharyngeal samples were collected from children presenting to the hospital with acute respiratory infection. Primary human AECs and neonatal mice were inoculated with RSV and murine Pneumovirus, respectively. Necroptosis was determined via viability assays and immunohistochemistry for RIPK1 (receptor-interacting protein kinase-1), MLKL (mixed lineage kinase domain-like pseudokinase) protein, and caspase-3. Necroptosis was blocked using pharmacological inhibitors and RIPK1 kinase-dead knockin mice. Measurements and Main Results: HMGB1 levels were elevated in nasopharyngeal samples of children with acute RSV infection. RSV-induced epithelial cell death was associated with increased phosphorylated RIPK1 and phosphorylated MLKL but not active caspase-3 expression. Inhibition of RIPK1 or MLKL attenuated RSV-induced HMGBI translocation and release, and lowered viral load. MLKL inhibition increased active caspase-3 expression in a caspase-8/9-dependent manner. In susceptible mice, Pneumovirus infection upregulated RIPK1 and MLKL expression in the airway epithelium at 8 to 10 days after infection, coinciding with AEC sloughing, HMGB1 release, and neutrophilic inflammation. Genetic or pharmacological inhibition of RIPK1 or MLKL attenuated these pathologies, lowered viral load, and prevented type 2 inflammation and airway remodeling. Necroptosis inhibition in early life ameliorated asthma progression induced by viral or allergen challenge in later life. Conclusions: Pneumovirus infection induces AEC necroptosis. Inhibition of necroptosis may be a viable strategy to limit the severity of viral bronchiolitis and break its nexus with asthma

Bacterial Signatures of Paediatric Respiratory Disease : An Individual Participant Data Meta-Analysis

Introduction: The airway microbiota has been linked to specific paediatric respiratory diseases, but studies are often small. It remains unclear whether particular bacteria are associated with a given disease, or if a more general, non-specific microbiota association with disease exists, as suggested for the gut. We investigated overarching patterns of bacterial association with acute and chronic paediatric respiratory disease in an individual participant data (IPD) meta-analysis of 16S rRNA gene sequences from published respiratory microbiota studies.Methods: We obtained raw microbiota data from public repositories or via communication with corresponding authors. Cross-sectional analyses of the paediatric (10 case subjects were included. Sequence data were processed using a uniform bioinformatics pipeline, removing a potentially substantial source of variation. Microbiota differences across diagnoses were assessed using alpha- and beta-diversity approaches, machine learning, and biomarker analyses.Results: We ultimately included 20 studies containing individual data from 2624 children. Disease was associated with lower bacterial diversity in nasal and lower airway samples and higher relative abundances of specific nasal taxa including Streptococcus and Haemophilus. Machine learning success in assigning samples to diagnostic groupings varied with anatomical site, with positive predictive value and sensitivity ranging from 43 to 100 and 8 to 99%, respectively.Conclusion: IPD meta-analysis of the respiratory microbiota across multiple diseases allowed identification of a non-specific disease association which cannot be recognised by studying a single disease. Whilst imperfect, machine learning offers promise as a potential additional tool to aid clinical diagnosis.Peer reviewe