The function of the signaling protein Ras guanine releasing protein 4 (RasGRP4) in human mast cells

Mast cells have been implicated in the pathogenesis of both atopic and non-atopic asthma. Rasguanine nucleotide-releasing protein 4 (RasGRP4) is a mast cell-restricted guanine nucleotideexchange factor and diacylglycerol (DAG)/ phorbol ester receptor whose function has not beendeduced. RT-PCR analysis of 40 asthmatic patients and 40 non-asthmatic controls demonstrated ahigher hRasGRP4 mRNA expression in a subgroup of the asthmatics. A RasGRP4-defective variantof the human mast cell line HMC-1 was used to create stable clones expressing green fluorescentprotein-labeled human RasGRP4 for monitoring the movement of this signaling protein inside mastcells before and after exposure to phorbol-12-myristate 13-acetate (PMA) and for evaluating theprotein’s ability to control the development, phenotype, and function of mast cells.Transcript-profiling approaches revealed hRasGRP4 constitutively regulates the expression ofnumerous genes in the HMC-1 cell line. For example, expression of hRasGRP4 in HMC-1 cellssubstantially decreased GATA-1 levels without altering GATA-2 levels, suggesting that hRasGRP4regulates mast cell commitment of multipotential progenitors in part by controlling the intracellularlevels of at least one lineage-dependent transcription factor for hematopoietic cells. hRasGRP4resided primarily in the cytosol before HMC-1 cells were stimulated with PMA. After exposure toPMA, hRasGRP4 translocated to the inner leaflet of the cell’s plasma membrane and then toperinuclear and Golgi compartments. Extracellular signal-regulated kinases 1 and 2 were activatedduring this translocation process, and the PMA-treated cells transiently increased their expression ofthe transcripts encoding the interleukin 13 receptor IL-13Rá2 and numerous other proteins.The accumulated data in our mast cell model suggest hRasGRP4 translocates to various intracellularcompartments via its DAG/PMA-binding domain to regulate those signaling pathways that allow mastcells to respond quickly to changes in their tissue microenvironments

Severe asthma assessment, management and the organisation of care in Australia and New Zealand: expert forum roundtable meetings

Severe asthma imposes a significant burden on individuals, families and the healthcare system. Treatment is complex, due to disease heterogeneity, comorbidities and complexity in care pathways. New approaches and treatments improve health outcomes for people with severe asthma. However, emerging multidimensional and targeted treatment strategies require a reorganisation of asthma care. Consensus is required on how reorganisation should occur and what areas require further research. The Centre of Excellence in Severe Asthma convened 3 forums between 2015 and 2018, hosting experts from Australia, New Zealand and the UK. The forums were complemented by a survey of clinicians involved in the management of people with severe asthma. We sought to 1) identify areas of consensus among experts, 2) define activities and resources required for the implementation of findings into practice and 3) identify specific priority areas for future research. Discussions identified areas of unmet need including assessment and diagnosis of severe asthma, models of care and treatment pathways, add-on treatment approaches and patient perspectives. We recommend development of education and training activities, clinical resources and standards of care documents, increased stakeholder engagement and public awareness campaigns and improved access to infrastructure and funding. Further, we propose specific future research to inform clinical decision-making and develop novel therapies. A concerted effort is required from all stakeholders (including patients, healthcare professionals and organisations and government) to integrate new evidence-based practices into clinical care and to advance research to resolve questions relevant to improving outcomes for people with severe asthma. This article is protected by copyright. All rights reserved

Impact of Landscape Fire Smoke Exposure on Patients With Asthma With or Without Laryngeal Hypersensitivity

Background: Individuals with asthma experienced severe and prolonged symptoms after the Australian 2019 to 2020 landscape fire. Many of these symptoms, such as throat irritation, occur in the upper airway. This suggests that laryngeal hypersensitivity contributes to persistent symptoms after smoke exposure. Objective: This study examined the relationship between laryngeal hypersensitivity and symptoms, asthma control, and health impacts on individuals exposed to landscape fire smoke. Method: The study was a cross-sectional survey of 240 participants in asthma registries who were exposed to smoke during the 2019 to 2020 Australian fire. The survey, completed between March and May 2020, included questions about symptoms, asthma control, and health care use, as well as the Laryngeal Hypersensitivity Questionnaire. Daily concentration levels of particulate matter less than or equal to 2.5 μm in diameter were measured over the 152-day study period. Results: The 49 participants with laryngeal hypersensitivity (20%) had significantly more asthma symptoms (96% vs 79%; P = .003), cough (78% vs 22%; P \u3c .001), and throat irritation (71% vs 38%; P \u3c .001) during the fire period compared with those without laryngeal hypersensitivity. Participants with laryngeal hypersensitivity had greater health care use (P ≤ .02), more time off work (P = .004), and a reduced capacity to participate in usual activities (P \u3c .001) during the fire period, as well as poorer asthma control during the follow-up (P = .001). Conclusions: Laryngeal hypersensitivity is associated with persistent symptoms, reports of lower asthma control, and increased health care use in adults with asthma who were exposed to landscape fire smoke. Management of laryngeal hypersensitivity before, during, or immediately after landscape fire smoke exposure might reduce the symptom burden and health impact

Treatable traits can be identified in a severe asthma registry and predict future exacerbations

Background and objective: A new taxonomic and management approach, termed treatable traits, has been proposed for airway diseases including severe asthma. This study examined whether treatable traits could be identified using registry data and whether particular treatable traits were associated with future exacerbation risk. Methods: The Australasian Severe Asthma Web-Based Database (SAWD) enrolled 434 participants with severe asthma and a comparison group of 102 participants with non-severe asthma. Published treatable traits were mapped to registry data fields and their prevalence was described. Participants were characterized at baseline and every 6 months for 24 months. Results: In SAWD, 24 treatable traits were identified in three domains: pulmonary, extrapulmonary and behavioural/risk factors. Patients with severe asthma expressed more pulmonary and extrapulmonary treatable traits than non-severe asthma. Allergic sensitization, upper-airway disease, airflow limitation, eosinophilic inflammation and frequent exacerbations were common in severe asthma. Ten traits predicted exacerbation risk; among the strongest were being prone to exacerbations, depression, inhaler device polypharmacy, vocal cord dysfunction and obstructive sleep apnoea. Conclusion: Treatable traits can be assessed using a severe asthma registry. In severe asthma, patients express more treatable traits than non-severe asthma. Traits may be associated with future asthma exacerbation risk demonstrating the clinical utility of assessing treatable traits

The burden of mild asthma: Clinical burden and healthcare resource utilisation in the NOVELTY study

Background: Patients with mild asthma represent a substantial proportion of the population with asthma, yet there are limited data on their true burden of disease. We aimed to describe the clinical and healthcare resource utilisation (HCRU) burden of physician-assessed mild asthma.Methods: Patients with mild asthma were included from the NOVEL observational longiTudinal studY (NOVELTY; NCT02760329), a global, 3-year, real-world prospective study of patients with asthma and/or chronic obstructive pulmonary disease from community practice (specialised and primary care). Diagnosis and severity were based on physician discretion. Clinical burden included physician-reported exacerbations and patient-reported measures. HCRU included inpatient and outpatient visits.Results: Overall, 2004 patients with mild asthma were included; 22.8% experienced ≥1 exacerbation in the previous 12 months, of whom 72.3% experienced ≥1 severe exacerbation. Of 625 exacerbations reported, 48.0% lasted >1 week, 27.7% were preceded by symptomatic worsening lasting >3 days, and 50.1% required oral corticosteroid treatment. Health status was moderately impacted (St George's Respiratory Questionnaire score: 23.5 [standard deviation ± 17.9]). At baseline, 29.7% of patients had asthma symptoms that were not well controlled or very poorly controlled (Asthma Control Test score <20), increasing to 55.6% for those with ≥2 exacerbations in the previous year. In terms of HCRU, at least one unscheduled ambulatory visit for exacerbations was required by 9.5% of patients, including 9.2% requiring ≥1 emergency department visit and 1.1% requiring ≥1 hospital admission.Conclusions: In this global sample representing community practice, a significant proportion of patients with physician-assessed mild asthma had considerable clinical burden and HCRU

The burden of mild asthma: Clinical burden and healthcare resource utilisation in the NOVELTY study

Background: Patients with mild asthma represent a substantial proportion of the population with asthma, yet there are limited data on their true burden of disease. We aimed to describe the clinical and healthcare resource utilisation (HCRU) burden of physician-assessed mild asthma.Methods: Patients with mild asthma were included from the NOVEL observational longiTudinal studY (NOVELTY; NCT02760329), a global, 3-year, real-world prospective study of patients with asthma and/or chronic obstructive pulmonary disease from community practice (specialised and primary care). Diagnosis and severity were based on physician discretion. Clinical burden included physician-reported exacerbations and patient-reported measures. HCRU included inpatient and outpatient visits.Results: Overall, 2004 patients with mild asthma were included; 22.8% experienced ≥1 exacerbation in the previous 12 months, of whom 72.3% experienced ≥1 severe exacerbation. Of 625 exacerbations reported, 48.0% lasted >1 week, 27.7% were preceded by symptomatic worsening lasting >3 days, and 50.1% required oral corticosteroid treatment. Health status was moderately impacted (St George's Respiratory Questionnaire score: 23.5 [standard deviation ± 17.9]). At baseline, 29.7% of patients had asthma symptoms that were not well controlled or very poorly controlled (Asthma Control Test score <20), increasing to 55.6% for those with ≥2 exacerbations in the previous year. In terms of HCRU, at least one unscheduled ambulatory visit for exacerbations was required by 9.5% of patients, including 9.2% requiring ≥1 emergency department visit and 1.1% requiring ≥1 hospital admission.Conclusions: In this global sample representing community practice, a significant proportion of patients with physician-assessed mild asthma had considerable clinical burden and HCRU