Therapeutic relevance of eosinophilic inflammation and airway viral interactions in severe asthma.

The role of eosinophils in airway inflammation and asthma pathogenesis is well established, with raised eosinophil counts in blood and sputum associated with increased disease severity and risk of asthma exacerbation. Conversely, there is also preliminary evidence suggesting antiviral properties of eosinophils in the airways. These dual roles for eosinophils are particularly pertinent as respiratory virus infections contribute to asthma exacerbations. Biologic therapies targeting key molecules implicated in eosinophil-associated pathologies have been approved in patients with severe asthma and, therefore, the effects of depleting eosinophils in a clinical setting are of considerable interest. This review discusses the pathological and antiviral roles of eosinophils in asthma and exacerbations. We also highlight the significant reduction in asthma exacerbations seen with biologic therapies, even at the height of the respiratory virus season. Furthermore, we discuss the implications of these findings in relation to the role of eosinophils in inflammation and antiviral responses to respiratory virus infection in asthma.

Contemporary Concise Review 2023: Asthma.

Asthma research and management needs to meet the priorities of the end user-patients, carers and clinicians. A better understanding of the natural history of asthma and the progression of disease has highlighted the importance of early identification of patients with asthma and the potential role of early intervention. Management of mild asthma requires a consistent approach with the same detail and consideration used when managing severe disease. Evidence around treatable traits approaches continues to evolve, supporting the role of a personalized medicine in asthma. Oral corticosteroid (OCS) stewardship continues to be an urgent issue in asthma management. Strategies to taper OCS doses and the implementation of biologic therapies for their steroid sparing benefits will be important steps to address this problem. The concept of remission in asthma provides an ambitious target and treatment outcome.

Oral corticosteroid stewardship: key insights from the Australasian Severe Asthma Registry.

BACKGROUND: People with severe asthma remain at risk of toxicity from maintenance oral corticosteroid (OCS) use and/or frequent OCS burst therapy. Cumulative exposures above 500-1000 mg prednisolone are associated with adverse effects, and recently OCS stewardship principles were promulgated to guide OCS prescription. AIMS: To examine real-world registry data to quantify OCS burden, ascertain trends over time in prescription and assess whether opportunities to implement steroid-sparing strategies were utilised. METHODS: Participants were enrolled in the Australasian Severe Asthma Registry for the period 2013-2021. Assessments were taken at enrolment and then annual follow-up, which included asthma control and OCS use. Descriptive analyses were performed, and subgroups were compared at baseline and over time. RESULTS: Nine hundred and twenty-four participants were evaluated and 215/924 (23%) were taking maintenance OCS at baseline, with 44% and 32% of participants having exposure to ≥500 or 1000 mg of OCS respectively in the prior year. Twelve months later, an additional 10% and 9% of participants reached cumulative doses of 500 or 1000 mg. People exceeding thresholds had ongoing poor asthma control. At baseline, 240/924 (26%) people were treated with asthma biological therapy. An additional 83 (12%) participants were identified as potentially benefiting from this steroid-sparing medication. Of these patients, only 23% commenced a biologic agent in the next 12 months. CONCLUSIONS: A large national asthma registry identifies exposure to toxic cumulative doses of OCS in more than a third of participants, with further subsequent cumulative dose escalation over 2 years. Steroid-sparing strategies were often not employed, highlighting the need for implementation of OCS stewardship initiatives.

Living With Asthma and Vocal Cord Dysfunction/Inducible Laryngeal Obstruction: "I Just Can't Get Air In".

BACKGROUND: Asthma and vocal cord dysfunction (VCD), also known as inducible laryngeal obstruction (ILO), may coexist, resulting in worse outcomes for patients. The experience of people with VCD/ILO and coexisting asthma is unknown. OBJECTIVE: We sought to determine whether coexistent VCD/ILO and asthma have deleterious impacts on quality of life. METHODS: We undertook a descriptive qualitative study using one-to-one semistructured interviews with 30 purposively recruited adult participants with a prior confirmed doctor asthma diagnosis and laryngoscopy-confirmed VCD/ILO. A thematic and content analysis was conducted to explore the data. RESULTS: Participants were mostly female (63%), mean ± SD age 63 ± 12 years. Four themes were identified: trapped voice, altered life, knowledge about VCD/ILO, and looking for solutions. Participants reported their voice being trapped in their throat or the voice being suddenly cut off when talking or singing. Self-reported VCD/ILO symptoms including throat tightness and breathlessness were highlighted by participants. The second theme described how patients struggle to communicate or tended to shorten conversations. Insufficient knowledge and existing confusion regarding whether asthma was causing the breathlessness was described in the third theme. Looking for solutions depicted participants' diagnostic journey and how they sought an explanation for the symptoms. CONCLUSIONS: People with asthma and coexisting VCD/ILO experience a substantial burden affecting the quality of life. These data describe the impact on patients with coexisting conditions and should be used to increase clinician awareness of the experience of VCD/ILO from patients' perspectives to support a personalized approach to care.

Biologics (mepolizumab and omalizumab) induced remission in severe asthma patients.

BACKGROUND: Asthma remission has emerged as a potential treatment goal. This study evaluated the effectiveness of two biologics (mepolizumab/omalizumab) in achieving asthma remission. METHODS: This observational study included 453 severe asthma patients (41% male; mean age ± SD 55.7 ± 14.7 years) from two real-world drug registries: the Australian Mepolizumab Registry and the Australian Xolair Registry. The composite outcome clinical remission was defined as zero exacerbations and zero oral corticosteroids during the previous 6 months assessed at 12 months and 5-item Asthma Control Questionnaire (ACQ-5) ≤1 at 12 months. We also assessed clinical remission plus optimization (post-bronchodilator FEV1 ≥80%) or stabilization (post-bronchodilator FEV1 not greater than 5% decline from baseline) of lung function at 12 months. Sensitivity analyses explored various cut-offs of ACQ-5/FEV1 scores. The predictors of clinical remission were identified. RESULTS: 29.3% (73/249) of AMR and 22.8% (37/162) of AXR cohort met the criteria for clinical remission. When lung function criteria were added, the remission rates were reduced to 25.2% and 19.1%, respectively. Sensitivity analyses identified that the remission rate ranged between 18.1% and 34.9% in the AMR cohort and 10.6% and 27.2% in the AXR cohort. Better lung function, lower body mass index, mild disease and absence of comorbidities such as obesity, depression and osteoporosis predicted the odds of achieving clinical remission. CONCLUSION: Biologic treatment with mepolizumab or omalizumab for severe asthma-induced asthma remission in a subgroup of patients. Remission on treatment may be an achievable treatment target and future studies should consider remission as an outcome measure.

Vocal cord dysfunction/inducible laryngeal obstruction cannot be diagnosed from symptoms.

Vocal cord dysfunction/inducible laryngeal obstruction is highly variable. Standard clinical symptoms and questionnaires cannot predict laryngoscopic diagnosis in a "lung disease" population. https://bit.ly/3QUtsbB.

Benralizumab and mepolizumab treatment outcomes in two severe asthma clinics.

BACKGROUND AND OBJECTIVE: This study compared the clinical outcomes of severe asthmatics treated with mepolizumab and benralizumab in a tertiary care severe asthma service setting. METHODS: Patient data at baseline, six and 12 months were collected prospectively at two large tertiary hospital severe asthma clinics following treatment initiation. Two hundred and four patients received treatment with mepolizumab (117) or benralizumab (87). Baseline characteristics between groups were similar in regard to age, gender, body mass index, steroid dose and blood eosinophil count. However, the mepolizumab cohort had a higher Asthma Control Questionnaire Score (ACQ) at baseline (4.0 ± 1.1 vs. 3.6 ± 0.9, p = 0.018), accompanied by more frequent reliever medication usage and lower prebronchodilator FEV1 % (56.0 ± 20.1 vs. 63.8 ± 18.9, p = 0.008). RESULTS: After 6 months treatment, both treatments induced significant improvements in (i) ACQ of 2.3 ± 0.1 (p < 0.001), (ii) oral steroid requiring exacerbations (incident rate ratio 0.26 (0.18-0.37), p < 0.001) and (iii) FEV1 . However, the improvement in FEV1 was 0.18 (0.05-0.30) litres greater with benralizumab than with mepolizumab (p = 0.002) even when adjusting statistically for baseline differences between groups. These differences were even more pronounced at 12 months post-treatment initiation, when the improvement in exacerbation frequency with benralizumab was 64% greater than with mepolizumab (p = 0.01). Whilst both treatments significantly reduced the blood eosinophil count at 6 and 12 months, this reduction was substantially greater with benralizumab than mepolizumab (-260 cells/µL [-400 to -110, p = 0.001]). CONCLUSION: In this large group of severe eosinophilic asthmatics, mepolizumab and benralizumab both improved disease parameters. However, benralizumab treatment appeared significantly more effective than mepolizumab in reducing exacerbations, improving FEV1 and depleting blood eosinophils.

Elevated blood lactate in COPD exacerbations associates with adverse clinical outcomes and signals excessive treatment with ß2 -agonists.

BACKGROUND AND OBJECTIVE: Raised blood lactate secondary to high dose ß2 -agonist treatment has been reported in asthma exacerbations but has not been investigated during acute exacerbations of COPD (AECOPD). We explored associations of blood lactate measurements with disease outcomes and ß2 -agonist treatments during AECOPD. METHODS: Retrospective (n = 199) and prospective studies (n = 142) of patients hospitalized with AECOPD were conducted. The retrospective cohort was identified via medical records and the prospective cohort was recruited during hospitalization for AECOPD. Baseline demographics, comorbidities, ß2 -agonist treatment, biochemical measurements and clinical outcomes were compared between patients with normal (≤2.0 mmol/L) versus elevated lactate (>2.0 mmol/L). Regression analyses examined associations of lactate measurements with ß2 -agonist dosages. RESULTS: Demographic data and comorbidities were similar between high versus normal lactate groups in both cohorts. The populations were elderly (mean >70 years), predominantly male (>60%) with reduced FEV1 (%) 48.2 ± 19 (prospective cohort). Lactate was elevated in approximately 50% of patients during AECOPD and not related to evidence of sepsis. In the prospective cohort, patients with high lactate had more tachypnoea, tachycardia, acidosis and hyperglycaemia (p < 0.05) and received more non-invasive ventilation (37% vs. 9.7%, p < 0.001, prospective cohort). There was a trend to longer hospitalization (6 vs. 5 days, p = 0.06, prospective cohort). Higher cumulative ß2 -agonist dosages were linked to elevated lactate levels (OR 1.04, p = 0.01). CONCLUSION: Elevated lactate during AECOPD was common, unrelated to sepsis and correlated with high cumulative doses of ß2 -agonists. Raised lactate may indicate excessive ß2 -agonist treatment and should now be investigated as a possible biomarker.

Diagnosis of vocal cord dysfunction/inducible laryngeal obstruction: An International Delphi Consensus Study.

BACKGROUND: Vocal cord dysfunction/inducible laryngeal obstruction (VCD/ILO) is characterized by breathing difficulties in association with excessive supraglottic or glottic laryngeal narrowing. The condition is common and can occur independently; however, it may also be comorbid with other disorders or mimic them. Presentations span multiple specialties and misdiagnosis or delayed diagnosis is commonplace. Group-consensus methods can efficiently generate internationally accepted diagnostic criteria and descriptions to increase clinical recognition, enhance clinical service availability, and catalyze research. OBJECTIVES: We sought to establish consensus-based diagnostic criteria and methods for VCD/ILO. METHODS: We performed a modified 2-round Delphi study between December 7, 2021, and March 14, 2022. The study was registered at ANZCTR (Australian New Zealand Clinical Trials Registry; ACTRN12621001520820p). In round 1, experts provided open-ended statements that were categorized, deduplicated, and amended for clarity. These were presented to experts for agreement ranking in round 2, with consensus defined as ≥70% agreement. RESULTS: Both rounds were completed by 47 international experts. In round 1, 1102 qualitative responses were received. Of the 200 statements presented to experts across 2 rounds, 130 (65%) reached consensus. Results were discussed at 2 international subject-specific conferences in June 2022. Experts agreed on a diagnostic definition for VCD/ILO and endorsed the concept of VCD/ILO phenotypes and clinical descriptions. The panel agreed that laryngoscopy with provocation is the gold standard for diagnosis and that ≥50% laryngeal closure on inspiration or Maat grade ≥2 define abnormal laryngeal closure indicative of VCD/ILO. CONCLUSIONS: This Delphi study reached consensus on multiple aspects of VCD/ILO diagnosis and can inform clinical practice and facilitate research.

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 < .001), and throat irritation (71% vs 38%; P < .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 < .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.

Vocal cord dysfunction/inducible laryngeal obstruction: novel diagnostics and therapeutics.

INTRODUCTION: Vocal cord dysfunction/inducible laryngeal obstruction (VCD/ILO) is an important medical condition but understanding of the condition is imperfect. It occurs in healthy people but often co-exists with asthma. Models of VCD/ILO pathophysiology highlight predisposing factors rather than specific mechanisms and disease expression varies between people, which is seldom appreciated. Diagnosis is often delayed, and the treatment is not evidence based. AREAS COVERED: A unified pathophysiological model and disease phenotypes have been proposed. Diagnosis is conventionally made by laryngoscopy during inspiration with vocal cord narrowing >50% Recently, dynamic CT larynx was shown to have high specificity (>80%) with potential as a noninvasive, swift, and quantifiable diagnostic modality. Treatment entails laryngeal retraining with speech pathology intervention and experimental therapies such as botulinum toxin injection. Multidisciplinary team (MDT) clinics are a novel innovation with demonstrated benefits including accurate diagnosis, selection of appropriate treatment, and reductions in oral corticosteroid exposure. EXPERT OPINION: Delayed diagnosis of VCD/ILO is pervasive, often leading to detrimental treatments. Phenotypes require validation and CT larynx can reduce the necessity for laryngoscopy, thereby fast-tracking diagnosis. MDT clinics can optimize management. Randomized controlled trials are essential to validate speech pathology intervention and other treatment modalities and to establish international standards of care.