Controlled inhalation improves central and peripheral deposition in cystic fibrosis patients with moderate lung disease.

AIM: With progressive impairment of lung function, deposition of inhaled drug in the lungs becomes progressively more central, limiting its effectiveness. This pilot study explored the possibility that long slow inhalations might improve delivery of aerosol to the lung periphery in cystic fibrosis patients with moderate lung disease. METHODS: Five subjects aged 12-18 years (mean FEV1 72%; range 63-80%) inhaled a radiolabelled aerosol from a jet nebuliser on two occasions. Two inhalation techniques were compared: breathing tidally from a standard continuous output nebuliser and using long slow inhalations from the AKITA® JET system. RESULTS: Long slow breaths resulted in much lower oropharyngeal deposition with higher lung doses. Importantly, the peripheral lung increased proportionately. The increased lung dose is attributable to more of the larger inhaled droplets passing into the lower airways. This would be expected to increase the central deposition unless significantly more of the smaller droplets were able to penetrate deeper into the lungs. The data support improved delivery of drug to the distal lung when compared with tidal breathing. CONCLUSION: These pilot data suggest that this approach may prove to be clinically relevant in improving the efficacy of inhaled medication in those with moderate-severe lung disease.

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 bronchiolitis 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 HMGB1 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.

The role of ecosystems in mitigation and management of Covid-19 and other zoonoses.

There is rising international concern about the zoonotic origins of many global pandemics. Increasing human-animal interactions are perceived as driving factors in pathogen transfer, emphasising the close relationships between human, animal and environmental health. Contemporary livelihood and market patterns tend to degrade ecosystems and their services, driving a cycle of degradation in increasingly tightly linked socio-ecological systems. This contributes to reductions in the natural regulating capacities of ecosystem services to limit disease transfer from animals to humans. It also undermines natural resource availability, compromising measures such as washing and sanitation that may be key to managing subsequent human-to-human disease transmission. Human activities driving this degrading cycle tend to convert beneficial ecosystem services into disservices, exacerbating risks related to zoonotic diseases. Conversely, measures to protect or restore ecosystems constitute investment in foundational capital, enhancing their capacities to provide for greater human security and opportunity. We use the DPSIR (Drivers-Pressures-State change-Impact-Response) framework to explore three aspects of zoonotic diseases: (1) the significance of disease regulation ecosystem services and their degradation in the emergence of Covid-19 and other zoonotic diseases; and of the protection of natural resources as mitigating contributions to both (2) regulating human-to-human disease transfer; and (3) treatment of disease outbreaks. From this analysis, we identify a set of appropriate response options, recognising the foundational roles of ecosystems and the services they provide in risk management. Zoonotic disease risks are ultimately interlinked with biodiversity crises and water insecurity. The need to respond to the Covid-19 pandemic ongoing at the time of writing creates an opportunity for systemic policy change, placing scientific knowledge of the value and services of ecosystems at the heart of societal concerns as a key foundation for a more secure future. Rapid political responses and unprecedented economic stimuli reacting to the pandemic demonstrate that systemic change is achievable at scale and pace, and is also therefore transferrable to other existential, global-scale threats including climate change and the 'biodiversity crisis'. This also highlights the need for concerted global action, and is also consistent with the duties, and ultimately the self-interests, of developed, donor nations.

ERS statement on tracheomalacia and bronchomalacia in children.

Tracheomalacia and tracheobronchomalacia may be primary abnormalities of the large airways or associated with a wide variety of congenital and acquired conditions. The evidence on diagnosis, classification and management is scant. There is no universally accepted classification of severity. Clinical presentation includes early-onset stridor or fixed wheeze, recurrent infections, brassy cough and even near-death attacks, depending on the site and severity of the lesion. Diagnosis is usually made by flexible bronchoscopy in a free-breathing child but may also be shown by other dynamic imaging techniques such as low-contrast volume bronchography, computed tomography or magnetic resonance imaging. Lung function testing can provide supportive evidence but is not diagnostic. Management may be medical or surgical, depending on the nature and severity of the lesions, but the evidence base for any therapy is limited. While medical options that include bronchodilators, anti-muscarinic agents, mucolytics and antibiotics (as well as treatment of comorbidities and associated conditions) are used, there is currently little evidence for benefit. Chest physiotherapy is commonly prescribed, but the evidence base is poor. When symptoms are severe, surgical options include aortopexy or posterior tracheopexy, tracheal resection of short affected segments, internal stents and external airway splinting. If respiratory support is needed, continuous positive airway pressure is the most commonly used modality either via a face mask or tracheostomy. Parents of children with tracheobronchomalacia report diagnostic delays and anxieties about how to manage their child's condition, and want more information. There is a need for more research to establish an evidence base for malacia. This European Respiratory Society statement provides a review of the current literature to inform future study.

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 ß-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. TRIAL REGISTRATION NUMBER: NCT02451709; pre-result.

ERS statement on protracted bacterial bronchitis in children.

This European Respiratory Society statement provides a comprehensive overview on protracted bacterial bronchitis (PBB) in children. A task force of experts, consisting of clinicians from Europe and Australia who manage children with PBB determined the overall scope of this statement through consensus. Systematic reviews addressing key questions were undertaken, diagrams in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement constructed and findings of relevant studies summarised. The final content of this statement was agreed upon by all members.The current knowledge regarding PBB is presented, including the definition, microbiology data, known pathobiology, bronchoalveolar lavage findings and treatment strategies to manage these children. Evidence for the definition of PBB was sought specifically and presented. In addition, the task force identified several major clinical areas in PBB requiring further research, including collecting more prospective data to better identify the disease burden within the community, determining its natural history, a better understanding of the underlying disease mechanisms and how to optimise its treatment, with a particular requirement for randomised controlled trials to be conducted in primary care.

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

CORRECTION: After publication of this work [1] it was noticed that the author name Rachael L. DiSantostefano was not spelt correctly as there was a space in her surname between 'Di' and 'Santostefano'. The publisher apologises for this error.

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 .

Towards the standardisation of lung sound nomenclature.

Auscultation of the lung remains an essential part of physical examination even though its limitations, particularly with regard to communicating subjective findings, are well recognised. The European Respiratory Society (ERS) Task Force on Respiratory Sounds was established to build a reference collection of audiovisual recordings of lung sounds that should aid in the standardisation of nomenclature. Five centres contributed recordings from paediatric and adult subjects. Based on pre-defined quality criteria, 20 of these recordings were selected to form the initial reference collection. All recordings were assessed by six observers and their agreement on classification, using currently recommended nomenclature, was noted for each case. Acoustical analysis was added as supplementary information. The audiovisual recordings and related data can be accessed online in the ERS e-learning resources. The Task Force also investigated the current nomenclature to describe lung sounds in 29 languages in 33 European countries. Recommendations for terminology in this report take into account the results from this survey.

Fractional exhaled nitric oxide for the management of asthma in adults: a 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 inhaled corticosteroid 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.

Cytokine responses in primary and secondary respiratory syncytial virus infections.

BACKGROUND: Primary respiratory syncytial virus (RSV) infections are characterized by high levels of IL-8 and an intense neutrophilia. Little is known about the cytokine responses in secondary infections. Preschool children experiencing RSV secondary infections were recruited from the siblings of infants admitted to hospital with RSV acute bronchiolitis. METHODS: Fifty-one infants with acute bronchiolitis (39 RSV positive, 12 RSV negative) and 20 age-matched control infants were recruited. In addition, seven older siblings of infants from the RSV-positive cohort and confirmed RSV infection were recruited. Samples of nasal secretions were obtained using a flocked swab, and secretions extracted using centrifugation. Cytokine bead array was used to obtain levels of interleukin (IL)-17A, IL-8, IL-6, IL-21, and tumor necrosis factor-α. RESULTS: Levels of IL-8 and IL-6 were significantly lower in the RSV-positive siblings compared with the RSV-positive infants. There were no significant differences between levels of the other cytokines in the primary and secondary infections. CONCLUSION: The very high levels of IL-8 and IL-6 response characteristic of the primary RSV infection was not observed in secondary RSV-positive infections and this did not appear to be due to a global reduction in cytokine production.

Getting to grips with 'dysfunctional breathing'.

Dysfunctional breathing (DB) is common, frequently unrecognised and responsible for a substantial burden of morbidity. Previously lack of clarity in the use of the term and the use of multiple terms to describe the same condition has hampered our understanding. DB can be defined as an alteration in the normal biomechanical patterns of breathing that result in intermittent or chronic symptoms. It can be subdivided into thoracic and extra thoracic forms. Thoracic DB is characterised by breathing patterns involving relatively inefficient, excessive upper chest wall activity with or without accessory muscle activity. This is frequently associated with increased residual volume, frequent sighing and an irregular pattern of respiratory effort. It may be accompanied by true hyperventilation in the minority of subjects. Extra thoracic forms include paradoxical vocal cord dysfunction and the increasingly recognised supra-glottic 'laryngomalacia' commonly seen in young sportsmen and women. While the two forms would appear to be two discreet entities they often share common factors in aetiology and respond to similar interventions. Hence both forms are considered in this review which aims to generate a more coherent approach to understanding, diagnosing and treating these conditions.

Hypertonic saline (HS) for acute bronchiolitis: Systematic review and meta-analysis.

BACKGROUND: Acute bronchiolitis is the commonest cause of hospitalisation in infancy. Currently management consists of supportive care and oxygen. A Cochrane review concluded that, "nebulised 3 % saline may significantly reduce the length of hospital stay". We conducted a systematic review of controlled trials of nebulised hypertonic saline (HS) for infants hospitalised with primary acute bronchiolitis. METHODS: Searches to January 2015 involved: Cochrane Central Register of Controlled Trials; Ovid MEDLINE; Embase; Google Scholar; Web of Science; and, a variety of trials registers. We hand searched Chest, Paediatrics and Journal of Paediatrics on 14 January 2015. Reference lists of eligible trial publications were checked. Randomised or quasi-randomised trials which compared HS versus either normal saline (+/- adjunct treatment) or no treatment were included. Eligible studies involved children less than 2 years old hospitalised due to the first episode of acute bronchiolitis. Two reviewers extracted data to calculate mean differences (MD) and 95 % Confidence Intervals (CIs) for length of hospital stay (LoS-primary outcome), Clinical Severity Score (CSS) and Serious Adverse Events (SAEs). Meta-analysis was undertaken using a fixed effect model, supplemented with additional sensitivity analyses. We investigated statistical heterogeneity using I(2). Risk of bias, within and between studies, was assessed using the Cochrane tool, an outcome reporting bias checklist and a funnel plot. RESULTS: Fifteen trials were included in the systematic review (n = 1922), HS reduced mean LoS by 0.36, (95 % CI 0.50 to 0.22) days, but with considerable heterogeneity (I(2) = 78 %) and sensitivity to alternative analysis methods. A reduction in CSS was observed where assessed [n = 516; MD -1.36, CI -1.52, -1.20]. One trial reported one possible intervention related SAE, no other studies described intervention related SAEs. CONCLUSIONS: There is disparity between the overall combined effect on LoS as compared with the negative results from the largest and most precise trials. Together with high levels of heterogeneity, this means that neither individual trials nor pooled estimates provide a firm evidence-base for routine use of HS in inpatient acute bronchiolitis.

Aging effects in cueing tasks as assessed by the ideal observer: peripheral cues.

Previous aging and cueing studies suggest that automatic orienting driven by peripheral cues is preserved with aging; however, inconsistencies can be found. One issue might be the use of response times (RT) to assess cueing effects (invalid RT--valid RT), which, in many cases, may not have clear quantitative predictions. We propose an ideal observer (IO) analysis of accuracy estimating participants' internal value of cue validity, or weight, which should equal the actual cue validity. The weight measures the use of information provided by the cue and is insensitive to variations in set size and difficulty, thus potentially providing advantages to RT. Older (n = 54) and younger (n = 58) participants performed a yes/no detection task of a two-dimensional (2-D) Gaussian (60 ms). Square peripheral precues (150 ms) indicated likely target locations (70% valid) across two or six locations (set sizes). For cueing effects, (valid--invalid hit rates), younger participants had set-size effects (larger cueing effects for set size 6), while older participants did not. The opposite pattern was found for weights (younger: no set-size effects, older: set-size effects) due to the IO predicting larger cueing effects for larger set sizes. Comparisons to the ideal weight (cue validity) suggested that older participants used the cue information effectively with set size 2 (as or more so than younger participants), but not with set size 6. These results suggest that attentional deficits from aging in peripheral cueing tasks may only arise as difficulty increases, such as larger set sizes.

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. CLINICALTRIALSGOV REGISTRATION NUMBER: NCT01469845.

Methodological innovations within the RAWES framework for use in development scenarios.

Built development changes the nature of land and its ecosystems, with diverse ramifications for human well-being and the resilience of the socioecological system. Robust and replicable approaches are required to assess ecosystem services generated by sites both predevelopment and for evaluation of postdevelopment options, to assess change and to support a paradigm shift from a "do less harm" to a "regenerative" approach. The Rapid Assessment of Wetland Ecosystem Services (RAWES) approach provides an internationally recognized methodology for systemic assessment of the ecosystem services generated by a site, taking account of all ecosystem services and service categories across multiple spatial scales. The RAWES assessments of constituent ecosystem services can be combined into Ecosystem Service Index scores. This article outlines innovations in RAWES methods to assess changes in ecosystem services likely to result from differing development scenarios in the context of a case study site in eastern England. These adaptations of the RAWES approach include revised methods for the analysis of ecosystem service beneficiaries across multiple spatial scales, the establishment of a common baseline against which to compare likely ecosystem service outcomes under a range of development scenarios, and a standardized method for accounting for supporting services through their contributions to other more directly exploited services. Integr Environ Assess Manag 2024;20:189-200. © 2023 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

The efficacy of biodiversity and ecosystem assessment approaches for informing a regenerative approach to built development.

The built environment, even at its "greenest," inevitably entails changing ecosystem structure and function. Multiple sustainable development tools and approaches are available to reduce environmental harm from built development. However, the reality that society exists within fully integrated socioecological systems, wholly interdependent on supporting ecosystems, is not yet adequately represented in regulation or supporting tools. Regenerative development seeks to address this interdependence in part by improving the health of supporting socioecological systems through the development process. We demonstrate the relevance of a series of approaches-Local Nature-Related Planning Policy (LNRPP), Biodiversity Net Gain (BNG), the Environmental Benefits from Nature Tool (EBN Tool), Nature Assessment Tool for Urban and Rural Environments (NATURE Tool), and Rapid Assessment of Wetland Ecosystem Services+ (RAWES+)-for their ability to meet their stated aims and objectives and how these relate to wider regenerative themes. A comparative analysis of the five approaches is done by applying them to a practical case study site, resulting in policy- and practice-relevant learning and recommendations. The research reveals current gaps in methodology, which can lead to adverse outcomes for sustainability. This is particularly clear for the spatial and temporal scales across which each approach operates. In addition, this research discusses the inherent limitations of taking a reductionist approach to examining complex systems. Integr Environ Assess Manag 2024;20:248-262. © 2023 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Time to re-set our thinking about airways disease: lessons from history, the resurgence of chronic bronchitis / PBB and modern concepts in microbiology.

In contrast to significant declines in deaths due to lung cancer and cardiac disease in Westernised countries, the mortality due to 'chronic obstructive pulmonary disease' (COPD) has minimally changed in recent decades while 'the incidence of bronchiectasis' is on the rise. The current focus on producing guidelines for these two airway 'diseases' has hindered progress in both treatment and prevention. The elephant in the room is that neither COPD nor bronchiectasis is a disease but rather a consequence of progressive untreated airway inflammation. To make this case, it is important to review the evolution of our understanding of airway disease and how a pathological appearance (bronchiectasis) and an arbitrary physiological marker of impaired airways (COPD) came to be labelled as 'diseases'. Valuable insights into the natural history of airway disease can be obtained from the pre-antibiotic era. The dramatic impacts of antibiotics on the prevalence of significant airway disease, especially in childhood and early adult life, have largely been forgotten and will be revisited as will the misinterpretation of trials undertaken in those with chronic (bacterial) bronchitis. In the past decades, paediatricians have observed a progressive increase in what is termed 'persistent bacterial bronchitis' (PBB). This condition shares all the same characteristics as 'chronic bronchitis', which is prevalent in young children during the pre-antibiotic era. Additionally, the radiological appearance of bronchiectasis is once again becoming more common in children and, more recently, in adults. Adult physicians remain sceptical about the existence of PBB; however, in one study aimed at assessing the efficacy of antibiotics in adults with persistent symptoms, researchers discovered that the majority of patients exhibiting symptoms of PBB were already on long-term macrolides. In recent decades, there has been a growing recognition of the importance of the respiratory microbiome and an understanding of the ability of bacteria to persist in potentially hostile environments through strategies such as biofilms, intracellular communities, and persister bacteria. This is a challenging field that will likely require new approaches to diagnosis and treatment; however, it needs to be embraced if real progress is to be made.

The Emperor's New Clothes II--time for regulators to wake up and take responsibility for unnecessary asthma morbidity: time for the second aerosol 'transition'.

The rate of technological improvement continues to accelerate. Regulators in every field dealing with consumer products continue to set ever higher standards to protect consumers from adverse events and use 'recalls' to remove products that prove to be harmful from the market. In the field of medical products in general the issues of 'human factors' and 'usability' are now, quite rightly, a major issue at least among regulators in the USA. The elephant in the inhaled therapy room is of course the continued use of obsolete, portable inhalers which few patients can use effectively for the treatment of asthma. Countless studies have demonstrated that the inability of patients to use these devices effectively is a major factor in perpetuating unnecessarily high levels of morbidity. They fail to meet basic usability standards and do not incorporate the facility to provide feedback to patient and clinician. More than 20 years ago regulators deemed that pressurised metered dose inhalers containing chlorofluorocarbons should be removed from the market on environmental grounds even though their use accounted for less than 0.5% of chlorofluorocarbon use. Surely asthmatic patients require the same level of protection. Unfortunately regulators appear determined to fossilise the field in a 1950's time warp by ensuring that the failings of obsolete technology are perpetuated in any 'generic' device. The time has come for regulators to meet their obligations to 'protect the public health by assuring the safety, effectiveness, and security of drugs, vaccines and other biological products, medical devices….' and mandate the phasing out of these antiquated devices within the next decade in order to reduce the unacceptably high burden of preventable morbidity and death associated with their use.

Breathing exercises for dysfunctional breathing/hyperventilation syndrome in children.

BACKGROUND: Dysfunctional breathing is described as chronic or recurrent changes in breathing pattern causing respiratory and non-respiratory symptoms. It is an umbrella term that encompasses hyperventilation syndrome and vocal cord dysfunction. Dysfunctional breathing affects 10% of the general population. Symptoms include dyspnoea, chest tightness, sighing and chest pain which arise secondary to alterations in respiratory pattern and rate. Little is known about dysfunctional breathing in children. Preliminary data suggest 5.3% or more of children with asthma have dysfunctional breathing and that, unlike in adults, it is associated with poorer asthma control. It is not known what proportion of the general paediatric population is affected. Breathing training is recommended as a first-line treatment for adults with dysfunctional breathing (with or without asthma) but no similar recommendations are available for the management of children. As such, breathing retraining is adapted from adult regimens based on the age and ability of the child. OBJECTIVES: To determine whether breathing retraining in children with dysfunctional breathing has beneficial effects as measured by quality of life indices.To determine whether there are any adverse effects of breathing retraining in young people with dysfunctional breathing. SEARCH METHODS: We identified trials for consideration using both electronic and manual search strategies. We searched CENTRAL, MEDLINE and EMBASE. We searched the National Research Register (NRR) Archive, Health Services Research Projects in Progress (HSRProj), Current Controlled Trials register (incorporating the metaRegister of Controlled Trials and the International Standard Randomised Controlled Trial Number (ISRCTN) to identify research in progress and unpublished research. The latest search was undertaken in October 2013. SELECTION CRITERIA: We planned to include randomised, quasi-randomised or cluster-randomised controlled trials. We excluded observational studies, case studies and studies utilising a cross-over design. The cross-over design was considered inappropriate due to the purported long-lasting effects of breathing retraining. Children up to the age of 18 years with a clinical diagnosis of dysfunctional breathing were eligible for inclusion. We planned to include children with a primary diagnosis of asthma with the intention of undertaking a subgroup analysis. Children with symptoms secondary to cardiac or metabolic disease were excluded.We considered any type of breathing retraining exercise for inclusion in this review, such as breathing control, diaphragmatic breathing, yoga breathing, Buteyko breathing, biofeedback-guided breathing modification and yawn/sigh suppression. We considered programmes where exercises were either supervised (by parents or a health professional, or both) or unsupervised. We also considered relaxation techniques and acute episode management as long as it was clear that breathing exercises were a component of the intervention.Any intervention without breathing exercises or where breathing exercises were not key to the intervention were excluded. DATA COLLECTION AND ANALYSIS: We planned that two authors (NJB and MJ) would extract data independently using a standardised form. Any discrepancies would be resolved by consensus. Where agreement could not be reached a third review author (MLE) would have considered the paper. MAIN RESULTS: We identified 264 potential trials and reviews from the search. Following removal of duplicates, we screened 224 papers based on title and abstract. We retrieved six full-text papers and further evaluated them but they did not meet the inclusion criteria. There were, therefore, no studies suitable for inclusion in this review. AUTHORS' CONCLUSIONS: The results of this systematic review cannot inform clinical practice as no suitable trials were identified for inclusion. Therefore, it is currently unknown whether these interventions offer any added value in this patient group or whether specific types of breathing exercise demonstrate superiority over others. Given that breathing exercises are frequently used to treat dysfunctional breathing/hyperventilation syndrome, there is an urgent need for well-designed clinical trials in this area. Future trials should conform to the CONSORT statement for standards of reporting and use validated outcome measures. Trial reports should also ensure full disclosure of data for all important clinical outcomes.