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.

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.

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.

Respiratory syncytial virus (RSV) causes annual epidemics of acute respiratory disease in large part because antibody levels fall rapidly after infection. RSV is able to infect cultured dendritic cells (DCs) and persist in these cells. Given the importance of DCs in antigen presentation, RSV infection and persistence is likely to be an evolutionary adaptation that can subvert the host immune response. This study aimed to demonstrate infection and persistence of RSV in lung DCs using an in vivo model of RSV infection. Mice were infected with a modified strain of RSV which expresses a red fluorescent protein (RSV-RFP) when replicating. Clinical symptoms of infection were monitored using weight change and inflammatory cell counts from bronchoalveolar lavage, which were correlated to RSV viral titre (quantitative PCR). Lung tissues were collected at 3, 5, 7 and 21 days post-infection (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 observed in B cells and DCs. At 21 dpi, RSV-RFP remained evident in a subset of conventional DCs (CD103 CD11b ) even though clinical symptoms and pulmonary inflammation had resolved. This data indicates that RSV infects, replicates in and persists in a sub-population of lung cDCs after resolution of symptoms and clearance of virus from the airways. Understanding the implications of this adaptation is likely to provide crucial insights into the virus’s ability to generate annual epidemics of respiratory disease.

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

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. Five subjects aged 12–18 years (mean FEV 1 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. 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. 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.

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.

AbstractChildren with asthma face serious mental health risk, but the pathways remain unclear. This study aimed to examine bullying victimisation and perpetration in children with asthma and a comparison sample without a chronic health condition, and the role of bullying in moderating psychosocial adjustment outcomes for those with asthma. A sample of children with (n = 24) and without asthma (n = 39), and their parents, were recruited from hospital clinics. Parents rated children’s psychosocial adjustment; children provided self-report of bullying victimisation and perpetration; from which co-occurring bully/victim status was derived. No differences in mean perpetration or victimisation were found, but children with asthma were more likely to be bully/victims (involved both as target and perpetrator), compared to those without asthma. Children with asthma who were victims of bullying had greater peer problems and overall adjustment problems; bully/victims did not show this pattern. Children with asthma may be more likely to be bully/victims, and those who are victims of bullying may be at elevated risk for psychosocial adjustment problems and require particular support in this area from school counsellors and psychologists.

Bronchoalveolar lavage (BAL) is widely regarded as providing “gold standard” samples for infective lower respiratory tract disease. Current approaches have been adopted empirically without robust assessment and hence carry many assumptions that have not been tested. Many of these uncertainties were highlighted in the ATS pediatric bronchoscopy guidelines. This study was designed to explore some of these issues. BAL was undertaken via an endotracheal tube in 13 subjects aged less than 6 years with persistent bacterial bronchitis and five healthy controls. Aliquots of the same pooled BAL sample were sent to two accredited laboratories. one producing semiquantitative results and the other quantitative results. For five patients potentially pathogenic bacteria were grown by one laboratory but not the other, while in three more there were discrepancies in the organisms reported. Despite being symptomatic and off antibiotics, only 3 of 13 patients were reported to have a pathogen at a density of more than 1 × 104 colony forming unit. There was at best a poor correlation between semiquantitative and quantitative data. Potential pathogens were cultured in two of five control samples. The results suggest that the results from conventional microbiological assessment of BAL samples can be highly variable and that the proposal that a discrete cut‐off is of value in patients with chronic endobronchial infection is probably invalid.

The defining feature of asthma is loss of normal post-natal homeostatic control of airways smooth muscle (ASM). This is the key feature that distinguishes asthma from all other forms of respiratory disease. Failure to focus on impaired ASM homeostasis largely explains our failure to find a cure and contributes to the widespread excessive morbidity associated with the condition despite the presence of effective therapies. The mechanisms responsible for destabilizing the normal tight control of ASM and hence airways caliber in post-natal life are unknown but it is clear that atopic inflammation is neither necessary nor sufficient. Loss of homeostasis results in excessive ASM contraction which, in those with poor control, is manifest by variations in airflow resistance over short periods of time. During viral exacerbations, the ability to respond to bronchodilators is partially or almost completely lost, resulting in ASM being “locked down” in a contracted state. Corticosteroids appear to restore normal or near normal homeostasis in those with poor control and restore bronchodilator responsiveness during exacerbations. The mechanism of action of corticosteroids is unknown and the assumption that their action is solely due to “anti-inflammatory” effects needs to be challenged. ASM, in evolutionary terms, dates to the earliest land dwelling creatures that required muscle to empty primitive lungs. ASM appears very early in embryonic development and active peristalsis is essential for the formation of the lungs. However, in post-natal life its only role appears to be to maintain airways in a configuration that minimizes resistance to airflow and dead space. In health, significant constriction is actively prevented, presumably through classic negative feedback loops. Disruption of this robust homeostatic control can develop at any age and results in asthma. In order to develop a cure, we need to move from our current focus on immunology and inflammatory pathways to work that will lead to an understanding of the mechanisms that contribute to ASM stability in health and how this is disrupted to cause asthma. This requires a radical change in the focus of most of “asthma research.”

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 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.

Background: Inhaled therapies are used extensively in the treatment of patients with CF. With progressive impairment of lung function, aerosol deposition of inhaled drug occurs more centrally in the lung. The aim of this study was to determine whether long slow inhalations with a dosimetric nebuliser might improve penetration of drug aerosol into the peripheral lung areas. Methods: A comparison of two inhalation modes was undertaken in 5 subjects with moderately severe CF lung disease (aged 12-18 years; FEV1 63-80%) in a crossover study. The pattern of aerosol distribution was compared using a) long (6 – 8 secs) slow inhalations with the dosimetric AKITA delivery system with Pari LC Sprint nebuliser, and b) tidal breathing with a standard Pari LC Sprint nebuliser and compressor. Distribution and total aerosol dose deposited corrected for attenuation was obtained using gamma scintigraphy. Results: Slow, prolonged inhalation with the AKITA was associated with a higher proportion of the delivered dose depositing in the lungs (74.5%), when compared to tidal breathing (32.1%) with significantly less upper airway deposition with the AKITA. The mean peripheral to central deposition ratios for the 5 subjects were long slow breath 2.16 vs tidal breathing 2.13 (p=0.90). Conclusion: Given that the increased lung dose achieved with long slow inhalation is likely to contain a disproportionate amount of larger droplets that are likely to be deposited centrally, particularly in the presence of significant lung disease, the data supports the suggestion that a greater proportion of the finer droplets reach the lung periphery. Hence total and peripheral lung dose are increased by controlling the inspiratory profile.

There are many and varied devices currently approved for the administration of inhaled treatments for use in different parts of the world. Well-developed national and local guidelines and training programs for health professionals are important in ensuring that patients are prescribed the best available devices and formulations for their age and disease condition, as well as being trained adequately in their optimal use. Despite training, surveys have shown diverging practices between health care centers for using and testing efficacy of inhaled treatments. This demonstrates the confusion that arises due to the lack of consistency concerning advice from trained therapists and prescribers about the use of devices to administer inhaled treatments. This review aims to provide a summary of current inhalation devices, with advantages and caveats of each. This is done within the context of device development and how device options can be considered for appropriate treatment delivery for children with airway disease, such as asthma.