Dr Hayley Lewthwaite

Background 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. Methods 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. Results 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<0.001). Baseline predictors for assigned groups included lower OCS dose in Group 1; greater forced expiratory volume in 1 s percentage predicted, higher Asthma Quality of Life Questionnaire score, higher OCS dose and nasal polyps in Group 2; with Group 3 as the reference. Conclusions Treatment response to mepolizumab in severe eosinophilic asthma follows three 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 Exertional breathlessness is a key symptom in cardiorespiratory disease and can be quantified using incremental exercise testing, but its prognostic significance is unknown. We evaluated the ability of abnormally high breathlessness intensity during incremental cycle exercise testing to predict all-cause, respiratory, and cardiac mortality. Study design and methods Longitudinal cohort study of adults referred for exercise testing followed prospectively for mortality assessed using the Swedish National Causes of Death Registry. Abnormally high exertional breathlessness was defined as a breathlessness intensity response (Borg 0¿10 scale) > the upper limit of normal using published reference equations. Mortality was analyzed using multivariable Cox regression, unadjusted and adjusted for age, sex, and body mass index. A further mortality analysis was also done adjusted for select common comorbidities in addition to age, sex and body mass index. Results Of the 13,506 people included (46% female, age 59±15 years), 2,867 (21%) had abnormally high breathlessness during exercise testing. Over a median follow up of 8.0 years, 1,687 (12%) people died. No participant was lost to follow-up. Compared to those within normal predicted ranges, people with abnormally high exertional breathlessness had higher mortality from all causes (adjusted hazard ratio [aHR] 2.3, [95% confidence interval] 2.1¿2.6), respiratory causes (aHR 5.2 [3.4¿8.0]) and cardiac causes (aHR 3.0 [2.5¿3.6]). Even among people with normal exercise capacity (defined as peak Watt =75% of predicted exercise capacity, n = 10,284) those with abnormally high exertional breathlessness were at greater risk of all-cause mortality than people with exertional breathlessness within the normal predicted range (aHR 1.5 [1.2¿1.8]). Conclusion Among people referred for exercise testing, abnormally high exertional breathlessness, quantified using healthy reference values, independently predicted all-cause, respiratory and cardiac mortality.

Purpose of review Breathlessness is a common, distressing and limiting symptom in people with advanced disease, but is challenging to assess as the symptom intensity depends on the level of exertion (symptom stimulus) during the assessment. This review outlines how to use recently developed normative reference equations to evaluate breathlessness responses, accounting for level of exertion, for valid assessment in symptom research. Recent findings Published normative reference equations are freely available to predict the breathlessness intensity response (on a 0-10 Borg scale) among healthy people after a 6-minute walking test (6MWT) or an incremental cycle cardiopulmonary exercise test (iCPET). The predicted normal values account for individual characteristics (including age, sex, height, and body mass) and level of exertion (walk distance for 6MWT; power output, oxygen uptake, or minute ventilation at any point during the iCPET). The equations can be used to (1) construct a matched healthy control dataset for a study; (2) determine how abnormal an individual's exertional breathlessness is compared with healthy controls; (3) identify abnormal exertional breathlessness (rating > upper limit of normal); and (4) validly compare exertional breathlessness levels across individuals and groups. Summary Methods for standardized and valid assessment of exertional breathlessness have emerged for improved symptoms research.

Background: Up-to-date normative reference sets for cardiopulmonary exercise testing (CPET) are important to aid in the accurate interpretation of CPET in clinical or research settings. Research Question: This study aimed to (1) develop and externally validate a contemporary reference set for peak CPET responses in Canadian adults identified with population-based sampling; and (2) evaluate previously recommended reference equations for predicting peak CPET responses. Study Design and Methods: Participants were healthy adults who were =40 years old from the Canadian Cohort Obstructive Lung Disease who completed an incremental cycle CPET. Prediction models for peak CPET responses were estimated from readily available participant characteristics (age, sex, height, body mass) with the use of quantile regression. External validation was performed with a second convenience sample of healthy adults. Peak CPET parameters that were measured and predicted in the validation cohort were assessed for equivalence (two one-sided tests of equivalence for paired-samples and level of agreement (Bland-Altman analyses). Two one-sided tests of equivalence for paired samples assessed differences between responses in the derivation cohort using previously recommended reference equations. Results: Normative reference ranges (5th-95th percentiles) for 28 peak CPET parameters and prediction models for 8 peak CPET parameters were based on 173 participants (47% male) who were 64 ± 10 years old. In the validation cohort (n = 84), peak CPET responses that were predicted with the newly generated models were equivalent to the measured values. Peak cardiac parameters predicted by the previously recommended reference equations by Jones and colleagues and Hansen and colleagues were significantly higher. Interpretation: This study provides reference ranges and prediction models for peak cardiac, ventilatory, operating lung volume, gas exchange, and symptom responses to incremental CPET and presents the most comprehensive reference set to date in Canadian adults who were =40 years old to be identified with population-based sampling.