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.

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 .

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.

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.

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.

In Vivo Evidence of Respiratory Syncytial Virus Persistence in a Subset of Pulmonary Dendritic Cells Following a Primary Infection.

Respiratory syncytial virus (RSV) causes annual epidemics of infections affecting the whole population. In vitro, it has been shown to infect and persist in human dendritic cells (DCs) for prolonged periods. Initially persistence is associated with low levels of replication before the virus becomes dormant. Reactivation of viral replication can be triggered many months later. Infection of DCs is likely to influence the host's ability to generate effective long-term memory responses. A well-established animal was utilized to confirm that RSV both infects and persists in pulmonary DCs in vivo. Mice were infected with a modified strain of RSV expressing red fluorescent protein (RSV-RFP) when replicating. Clinical symptoms of infection were monitored using weight change and inflammatory cell counts from bronchoalveolar lavage, which correlated with the RSV viral titer (quantitative polymerase chain reaction). Lung tissues were collected at 3, 5, 7, and 21 days postinfection (dpi) to assess leukocyte populations by flow cytometry. Clinical symptoms and RSV viral load peaked at 5 dpi. RSV-RFP was most prevalent in macrophages at 3 dpi and also observed in B cells and DCs. At 21 dpi, RSV-RFP remained evident in a subset of conventional DCs (CD103+CD11b+) even though both clinical symptoms and pulmonary inflammation had resolved. These results confirm that in this well-established mouse model, RSV persists in lung conventional DCs following resolution of the acute infection. Further work is required to explore whether the virus continues with low-level replication before becoming dormant in vivo, as has been described in vitro.

'Recurrent lower respiratory tract infections' - going around in circles, respiratory medicine style.

Recurrent lower respiratory tract infections are very common in childhood, particularly the pre-school years. The term lower respiratory tract infection [LTRI] is, as with many terms used in respiratory medicine, used very loosely and carries little more information than the often decried term 'chest infections'. LRTIs should more accurately be characterised by the type of infection [viral or bacterial], the site of infection [conducting airways, or respiratory compartment or both - bronchitis/pneumonia/bronchopneumonia], the nature of the episode [acute or acute on chronic (exacerbation)], the interaction with co-morbidities such as asthma. The limited nature of the responses of the lower airways to any insult whether it is infective or irritation due to inhaled or aspirated chemicals means that almost any aetiology can lead to cough, shortness of breath and noisy breathing. We lack good non-invasive techniques to study the nature of the inflammation in the lower airways and hence the cause of chronic and recurrent symptoms in patients is frequently mis-diagnosed.

Precision Medicine and Childhood Asthma: A Guide for the Unwary.

Many thousands of articles relating to asthma appear in medical and scientific journals each year, yet there is still no consensus as to how the condition should be defined. Some argue that the condition does not exist as an entity and that the term should be discarded. The key feature that distinguishes it from other respiratory diseases is that airway smooth muscles, which normally vary little in length, have lost their stable configuration and shorten excessively in response to a wide range of stimuli. The lungs' and airways' limited repertoire of responses results in patients with very different pathologies experiencing very similar symptoms and signs. In the absence of objective verification of airway smooth muscle (ASM) lability, over and underdiagnosis are all too common. Allergic inflammation can exacerbate symptoms but given that worldwide most asthmatics are not atopic, these are two discrete conditions. Comorbidities are common and are often responsible for symptoms attributed to asthma. Common amongst these are a chronic bacterial dysbiosis and dysfunctional breathing. For progress to be made in areas of therapy, diagnosis, monitoring and prevention, it is essential that a diagnosis of asthma is confirmed by objective tests and that all co-morbidities are accurately detailed.

Challenging the paradigm.

While advocating for addressing "treatable traits" is admirable in that it reminds clinicians to consider the patient and not the disease, the use of this idea to promote dangerous changes in practice should be challenged. https://bit.ly/30VkP8Q.

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 (<18 years) microbiota in acute and chronic respiratory conditions, with >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.

Time to Say Goodbye to Bronchiolitis, Viral Wheeze, Reactive Airways Disease, Wheeze Bronchitis and All That.

The diagnosis and management of infants and children with a significant viral lower respiratory tract illness remains the subject of much debate and little progress. Over the decades various terms for such illnesses have been in and fallen out of fashion or have evolved to mean different things to different clinicians. Terms such as "bronchiolitis," "reactive airways disease," "viral wheeze," and many more are used to describe the same condition and the same term is frequently used to describe illnesses caused by completely different dominant pathologies. This lack of clarity is due, in large part, to a failure to understand the basic underlying inflammatory and associated processes and, in part, due to the lack of a simple test to identify a condition such as asthma. Moreover, there is a lack of insight into the fact that the same pathology can produce different clinical signs at different ages. The consequence is that terminology and fashions in treatment have tended to go around in circles. As was noted almost 60 years ago, amongst pre-school children with a viral LRTI and airways obstruction there are those with a "viral bronchitis" and those with asthma. In the former group, a neutrophil dominated inflammation response is responsible for the airways' obstruction whilst amongst asthmatics much of the obstruction is attributable to bronchoconstriction. The airways obstruction in the former group is predominantly caused by airways secretions and to some extent mucosal oedema (a "snotty lung"). These patients benefit from good supportive care including supplemental oxygen if required (though those with a pre-existing bacterial bronchitis will also benefit from antibiotics). For those with a viral exacerbation of asthma, characterized by bronchoconstriction combined with impaired b-agonist responsiveness, standard management of an exacerbation of asthma (including the use of steroids to re-establish bronchodilator responsiveness) represents optimal treatment. The difficulty is identifying which group a particular patient falls into. A proposed simplified approach to the nomenclature used to categorize virus associated LRTIs is presented based on an understanding of the underlying pathological processes and how these contribute to the physical signs.