Michael Fricker

Background: Treatment-induced clinical remission is an emerging therapeutic goal in severe asthma. Despite this, the perspectives of people with severe eosinophilic asthma (SEA) on remission remain unexplored. Objective: We sought to understand how people with SEA treated with mepolizumab perceive remission and to compare the perspectives of those who have achieved remission with those who have not. Methods: A qualitative study using one-to-one semi-structured interviews with 30 purposively sampled adult participants. Interview recordings were transcribed, audio verified and thematically analysed. Results: Participants were mostly female (60%), with a mean± sd age of 64.8±11.02 years in the remission group and 68.6±8.66 years in the non-remission group. Four themes emerged: (i) making sense of remission: participants perceived asthma remission as a discernible point where the disease progression stopped/ceased; (ii) getting my life back: described perceived improvements in daily functioning, psychological well-being and quality of life; (iii) treatment goals and discontinuation: participants expressed preference to be symptom-free over being off-treatment; (iv) communication and timing: shared their ideal timing to discuss remission and their views on the role of multidisciplinary team in the remission discourse. Conclusion: People with SEA defined asthma remission using individual metrics, including functional and emotional outcomes, highlighting restoration, normality and holistic well-being. Both groups consistently equated remission with freedom from OCS use and its negative consequences. Participants who achieved clinical remission described substantial perceived improvements in daily functioning, psychological well-being and quality of life. These findings can inform patient-clinician remission conversations, ensuring that it is discussed not only as a clinical outcome but also as a therapeutic goal shaped by patient priorities and expectations.

Background: The economic benefits of achieving remission in severe eosinophilic asthma (SEA) are unknown. Methods: Asthma-related healthcare resource and non-biologic medication use costs during the second year of mepolizumab treatment were calculated for patients in the Australian Mepolizumab Registry. In cost comparison analysis 1 (n=223), remission at 12-months was assessed with prospective evaluation of costs over the subsequent 12 months. Analysis 2 (n=222) evaluated remission at 24-months with retrospective evaluation of costs over the prior 12 months. Clinical remission was defined as: zero exacerbations [requiring hospitalisation, an emergency department (ED) visit or oral corticosteroid (OCS) use] and zero OCS use during the previous six months; and Asthma Control Questionnaire (ACQ)-5 ≤1. Results: Clinical remission was achieved in 28% (Analysis 1) and 33% (Analysis 2) of patients receiving mepolizumab. Analysis 1 (prospective): annual mean costs during the second year of mepolizumab treatment were 45% lower in patients who had achieved remission. Per patient costs [mean (95% CI) for remission were $1318.19 (972.45, 1663.93) versus non-remission $2405.63 (1712.56, 3098.70)]. Analysis 2: mean costs were 52% lower in the remission group [mean (95% CI) costs for remission $1231.22 (996.29, 1466.15) versus non-remission $2540.88 (1773.44, 3308.33)]. Across analyses, costs associated with hospitalisations and ED visits for exacerbations, asthma-related outpatient visits and medication use were lower in patients who achieved remission. Conclusion: Achieving clinical remission with mepolizumab in SEA is associated with additional cost savings from the health care payer's perspective, further highlighting the importance of timeliness and appropriateness of biologic treatments in severe asthma.

Neutrophils are innate immune effector cells that play a vital role in host defense against infection. They exert antimicrobial activities through degranulation, phagocytosis, intracellular killing, production of reactive oxygen species, and neutrophil extracellular traps. Dysregulation of neutrophil abundance, phenotype, and immune activity is a commonly observed inflammatory feature of chronic obstructive pulmonary disease (COPD), a chronic inflammatory disorder of the lungs with no effective cure. Here, we review the clinical association and involvement of neutrophils in COPD pathogenesis, progression, and exacerbation. The association between neutrophilia, airway microbial imbalance (dysbiosis), and clinical manifestations of COPD is described. We summarize the impact (or lack of) of current treatments, including inhaled corticosteroids, macrolide antibiotics, and phosphodiesterase inhibitors, on neutrophilic inflammation or neutrophilia-associated features. Finally, we review potential future therapeutic options to address neutrophilic inflammation in COPD currently in clinical development, including anti-alarmins and inhibitors of neutrophil mediators.

Treatment targets in severe asthma have evolved towards a remission‐focused paradigm guided by precision medicine. This novel concept requires a shift from evaluating the efficacy of therapies based on a single outcome at a single time point to an outcome that captures the complexity of asthma remission involving several domains assessed over a sustained period. Since the concept is still emerging, multiple definitions have been proposed, ranging from symptom control and exacerbation‐free to resolution of underlying pathobiology, with varying rigour in each parameter. Understanding the strengths and weaknesses of the current construct is needed to progress further. We conducted a roundtable discussion with 27 asthma experts to address this issue, and discussions were narratively synthesised and summarised. The participants observed that between one in three and one in five people treated with targeted biological therapies or macrolides experience low disease activity over a sustained period. They unanimously agreed that labelling the attained clinical state as clinical remission is useful as a clinical (e.g., facilitating a treat‐to‐target approach), policy (e.g., widening eligibility criteria for biologics), and scientific (e.g., a path to understanding cure) tool. Current remission rates vary significantly due to definition variability. When assessing remission, it is essential to consider confounding factors (e.g., steroid use for adrenal insufficiency). More research is required to reach an acceptable definition, and including the patient's voice in such research is essential. In conclusion, the concept of treatment‐induced clinical remission is possible and valuable in asthma. However, further refinement of the definition is required. image

Patients with severe eosinophilic asthma, characterised by a high disease burden, benefit from mepolizumab, which improves symptoms and reduces exacerbations, potentially leading to clinical remission in a subgroup. This study aimed to identify treatment response trajectories to mepolizumab for severe eosinophilic asthma and to assess the achievement of clinical remission. Data from the Australian Mepolizumab Registry were used to assess treatment responses at 3, 6, and 12 months. The treatment response trajectories were identified using a group-based trajectory model. The proportions achieving clinical remission at 12 months, which was defined as well-controlled symptoms, no exacerbations, and no oral corticosteroid (OCS) use for asthma management, were compared between trajectories, and baseline predictors of the trajectories were identified using logistic regression analysis. We identified three trajectory groups: group 1, responsive asthma with less OCS use (n=170); group 2, responsive late-onset asthma (n=58); and group 3, obstructed and less responsive asthma (n=70). Groups 1 and 2 demonstrated higher proportions achieving clinical remission at 36.5% and 25.9%, respectively, compared to group 3 with 5.7% (p 1% predicted, higher Asthma Quality of Life Questionnaire score, higher OCS dose, and nasal polyps in group 2; with group 3 as the reference. Treatment response to mepolizumab in severe eosinophilic asthma follows 3 trajectories with varying proportions achieving clinical remission and differing baseline characteristics. Treatment response variability may influence the achievement of clinical remission with mepolizumab therapy.

Background: IL5 promotes eosinophilia, a key therapeutic target in severe asthma (SA). The effect of IL5 blocking biologics on homeostatic (hEOs) and inflammatory (iEOs) eosinophil subsets is unknown. Objective: To determine the effect of mepolizumab and benralizumab treatment on eosinophil subsets in SA. Methods: Cross-sectional observational study of SA (eosinophilic [EA] n=32, non-eosinophilic [NEA] n=23, mepolizumab-treated n=25), with longitudinal follow-up of 30 EA participants at two timepoints (4-24 weeks, >24 weeks) post-commencement of mepolizumab (n=20) or benralizumab (n=10). Blood hEOs and iEOs assessed by flow cytometry measure of surface CD62L protein. The study was preregistered on ANZCTR: ACTRN12621000113853. Results: Mepolizumab treatment was associated with decreased iEO proportion in the cross-sectional and longitudinal studies. Depletion of iEOs was similar with mepolizumab and benralizumab, however hEO number was significantly greater in mepolizumab versus benralizumab at follow-up. Higher iEO proportion correlated with poorer asthma control in EA but not NEA. Higher residual iEO proportion correlated with poorer asthma control in mepolizumab-treated individuals. Reduced blood eosinophil viability was observed in some mepolizumab-treated SA participants, which was associated with improved clinical outcomes (better asthma control, spirometry, exacerbation rate). Conclusion: Mepolizumab depletes iEOs in SA but preserves a residual population of circulatory hEOs, while benralizumab depletes both iEOs and hEOs. Increased iEOs are associated with poorer asthma control in EA. Monitoring eosinophil phenotype and viability may be useful to predict biologic treatment response in SA.

Background: Eosinophils are key therapeutic targets in severe asthma that are suppressed by IL5 (mepolizumab) and IL5 receptor (benralizumab) blockade. The effect of IL5 pathway biologics on recently described homeostatic (hEOs) and inflammatory (iEOs) eosinophil subsets is unknown. We aimed to determine the relative impact of mepolizumab and benralizumab treatment on eosinophil subset and phenotype, and explore clinical associations of eosinophil subsets with severe asthma characteristics and treatment response.Methods: We performed a cross‐sectional observational study of severe asthma (eosinophilic n = 32, non‐eosinophilic n = 23, mepolizumab‐treated n = 25), with longitudinal follow‐up of 30 eosinophilic participants at two timepoints (4–24 weeks, >24 weeks) post‐commencement of mepolizumab (n = 20) or benralizumab (n = 10). Blood hEOs and iEOs were measured by flow cytometry assessment of surface CD62L protein.Results: iEO proportion was significantly lower in mepolizumab‐treated participants in both the cross‐sectional and longitudinal study. Mepolizumab and benralizumab depleted iEOs to a similar extent, however a significantly greater number of hEOs remained in mepolizumab participants at follow‐up. Greater iEO proportion correlated with poorer asthma control in eosinophilic but not non‐eosinophilic asthma. Higher residual iEO proportion correlated with poorer asthma control in mepolizumab‐treated individuals. Reduced blood eosinophil viability was observed in around half of mepolizumab‐treated participants, which was associated with significantly better asthma control and spirometry.Conclusions: Mepolizumab depletes iEOs and reduces circulating eosinophil viability in severe asthma but preserves a residual population of circulatory hEOs. In contrast benralizumab depleted both iEOs and hEOs. Higher iEO abundance and eosinophil viability are associated with poorer clinical outcomes following mepolizumab‐treatment. Monitoring circulating eosinophil phenotype and viability may be useful to predict biologic treatment response in severe asthma.