IL-5 antagonism reverses priming and activation of eosinophils in severe eosinophilic asthma.

Eosinophils are key effector cells mediating airway inflammation and exacerbation in patients with severe eosinophilic asthma. They are present in increased numbers and activation states in the airway mucosa and lumen. Interleukin-5 (IL-5) is the key eosinophil growth factor that is thought to play a role in eosinophil priming and activation. However, the mechanism of these effects is still not fully understood. The anti-IL-5 antibody mepolizumab reduces eosinophil counts in the airway modestly but has a large beneficial effect on the frequency of exacerbations of severe eosinophilic asthma, suggesting that reduction in eosinophil priming and activation is of central mechanistic importance. In this study, we used the therapeutic effect of mepolizumab and single-cell ribonucleic acid sequencing to investigate the mechanism of eosinophil priming and activation by IL-5. We demonstrated that IL-5 is a dominant driver of eosinophil priming and plays multifaceted roles in eosinophil function. It enhances eosinophil responses to other stimulators of migration, survival, and activation by activating phosphatidylinositol-3-kinases, extracellular signal-regulated kinases, and p38 mitogen-activated protein kinases signaling pathways. It also enhances the pro-fibrotic roles of eosinophils in airway remodeling via transforming growth factor-ß pathway. These findings provide a mechanistic understanding of eosinophil priming in severe eosinophilic asthma and the therapeutic effect of anti-IL-5 approaches in the disease.

Longitudinal changes in sputum and blood inflammatory mediators during FeNO suppression testing.

To explore whether fractional exhaled nitric oxide (FeNO) non-suppression identifies corticosteroid resistance, we analysed inflammatory mediator changes during a FeNO suppression test with monitored high-intensity corticosteroid therapy. In linear mixed-effects models analysed over time, the 15 clinically distinct 'suppressors' (ie, ≥42% FeNO suppression) normalised Asthma Control Questionnaire scores (mean±SD, start to end of test: 2.8±1.4 to 1.4±0.9, p<0.0001) and sputum eosinophil counts (median (IQR), start to end of test: 29% (6%-41%) to 1% (1%-5%), p=0.0003) while significantly decreasing sputum prostaglandin D2 (254 (89-894) to 93 (49-209) pg/mL, p=0.004) and numerically decreasing other type-2 cytokine, chemokine and alarmin levels. In comparison, the 19 non-suppressors had persistent sputum eosinophilia (10% (1%-67%) despite high-intensity therapy) with raised end-test inflammatory mediator levels (1.9 (0.9-2.8)-fold greater than suppressors). FeNO non-suppression during monitored treatment implies biological corticosteroid resistance.

An effective procedure skills training programme for GIM registrars.

BACKGROUND: The Royal College of Physicians' Acute care toolkit 8 recommends procedural training for medical registrars at all hospitals. We aimed to determine the interest and need, and to pilot the delivery of such training in the procedures outlined by the Joint Royal Colleges of Physicians Training Board (2017). METHODS: An online survey was sent to general internal medicine (GIM) trainees within the Thames Valley Deanery in January 2019. This identified a need for procedure skills training. Ninety per cent of trainees felt simulation training would improve their confidence in the outlined procedures.We trialled a simulation programme for GIM registrars between September 2019 and October 2019. Sessions lasted 3-3.5 hours and trainees rotated through four stations. Feedback was obtained from trainees and trainers during each pilot session. RESULTS: Thirty-two trainees attended across both sites. Excellent feedback was obtained and trainee confidence improved by visual analogue scale scoring post-training for all procedures. Almost 90% of trainees felt the sessions would improve safety on GIM on calls. CONCLUSION: Simulation training is an effective way to improve trainee confidence in procedural skills and this pilot shows such training is desired and necessitated in higher specialty training. Further work will assess its impact on maintaining trainee skillsets and impact on patient safety.

Successful awake proning is associated with improved clinical outcomes in patients with COVID-19: single-centre high-dependency unit experience.

The SARS-CoV-2 can lead to severe illness with COVID-19. Outcomes of patients requiring mechanical ventilation are poor. Awake proning in COVID-19 improves oxygenation, but on data clinical outcomes is limited. This single-centre retrospective study aimed to assess whether successful awake proning of patients with COVID-19, requiring respiratory support (continuous positive airways pressure (CPAP) or high-flow nasal oxygen (HFNO)) on a respiratory high-dependency unit (HDU), is associated with improved outcomes. HDU care included awake proning by respiratory physiotherapists. Of 565 patients admitted with COVID-19, 71 (12.6%) were managed on the respiratory HDU, with 48 of these (67.6%) requiring respiratory support. Patients managed with CPAP alone 22/48 (45.8%) were significantly less likely to die than patients who required transfer onto HFNO 26/48 (54.2%): CPAP mortality 36.4%; HFNO mortality 69.2%, (p=0.023); however, multivariate analysis demonstrated that increasing age and the inability to awake prone were the only independent predictors of COVID-19 mortality. The mortality of patients with COVID-19 requiring respiratory support is considerable. Data from our cohort managed on HDU show that CPAP and awake proning are possible in a selected population of COVID-19, and may be useful. Further prospective studies are required.

The role of interleukin-17 in asthma: a protective response?

While there now exist effective treatments for type 2 high, eosinophilic asthma, there are no specific therapies for 40-50% of people with asthma with other phenotypes, which result from poorly understood underlying pathological mechanisms. One such pathology is neutrophilic inflammation, which has been associated with interleukin (IL)-17 family cytokines. Human genetic studies identified IL-17 polymorphisms associated with asthma; in murine models of allergic airways disease, IL-17A contributes to airway hyperresponsiveness, and in humans, elevated airway IL-17A levels are repeatedly observed in severe asthma. However, the directionality of this association is unknown, and the assumption that IL-17 cytokines drive disease pathology remains speculative. Here, we explore the evidence underlying the relationship between IL-17 and asthma, we review lessons learned from investigating IL-17 in other inflammatory diseases, and discuss the possibility that IL-17 may even be protective in asthma rather than pathogenic. We also critically examine the newly proposed paradigm of a reciprocal relationship between type 2 and type 17 airways inflammation. In summary, we suggest an association between IL-17 and asthma, but research is needed examining the diverse functions of these cytokines, their longitudinal stability, their response to clinical interventions, and for mechanistic studies determining whether they are protective or pathogenic.

Targeted biologic therapy for asthma.

BACKGROUND: Asthma is a common and potentially serious condition affecting 300 million people worldwide. For many years, we have relied on a one-size-fits-all approach to its management, using corticosteroids and bronchodilators for all symptomatic patients. However, with more recent advances, it has become clear that asthma is a heterogeneous condition with multiple different underlying pathways. Understanding the different subtypes will be a key to giving us the ability to intervene in a targeted way to personalize care for patients with asthma. SOURCES OF DATA: Key published literature, guidelines and trials from clinicaltrials.gov. AREAS OF AGREEMENT: The most widely studied of these subtypes is T2 high eosinophilic asthma, for which there are an increasing number of biologic therapies available. T2 high asthma is associated with the cytokines interleukin (IL)-4, IL-5 and IL-13, for each of which biologics have been developed. AREAS OF CONTROVERSY: It is currently unclear which of the available biologics provides superior efficacy. It is also unclear how to select which biologic for which patient. GROWING POINTS: Head-to-head trials of the available T2 biologics will be important to determine superiority, and a suggested order for trialling biologics. Going further than this, we would like to see further analyses of available biologics to allow us to predict responders from non-responders in advance of administering therapy. AREAS TIMELY FOR DEVELOPING RESEARCH: Non-eosinophilic T2 low asthma is an area that is under-researched and for which there are few treatments available. It is likely that there are different subtypes in this category of asthma and unravelling what these are will be crucial to developing effective treatments.