John W. Upham

Description:Oral corticosteroids (OCS) are an effective treatment for severe uncontrolled asthma or asthma exacerbations, but frequent bursts or long-term use carry serious and sometimes irreversible adverse effects, or complications such as adrenal insufficiency upon discontinuation. Our aim was to survey people with asthma on their experiences of, and attitudes towards, using OCS. This study was a national descriptive cross-sectional survey of people with asthma in Australia. An anonymous survey was hosted online with invitations to participate distributed by national consumer peak bodies. Survey free-text responses were coded to the Theoretical Domains Framework (TDF) to elicit determinants of OCS use. 1808 people with asthma participated between 3 and 16 May 2022. Most common reasons for using OCS were severe asthma symptoms (40%), doctor prescription (38%) or asthma action plan recommendations (20%). Approximately 55% of people had experienced adverse effects from OCS use. Commonly reported adverse effects were trouble sleeping (69%), weight gain (56%) and mood problems (41%). Of people who had OCS at home or an OCS script, 44% did not have an action plan that described when and how they should take them. People (33%) did not feel well informed about OCS adverse effects from their healthcare team. People had varied awareness (3-65%) of current available strategies to reduce OCS use. 'Knowledge', 'Environmental context and resources' and 'Social influences' were the most coded TDF domains influencing OCS use. Adverse effects of OCS use are common. People with asthma are not adequately informed about optimal OCS use or strategies to reduce overuse. These findings can help guide the implementation of OCS stewardship initiatives.

Description:Background: For severe asthma (SA) management, real-world evidence on the effects of biologic therapies in reducing the burden of oral corticosteroid (OCS) use is limited. Objective: To estimate the efficacy of biologic initiation on total OCS (TOCS) exposure in SA patients from real-world specialist and primary care settings. Methods: From the International Severe Asthma Registry (ISAR, specialist care) and the Optimum Patient Care Research Database (OPCRD, primary care, UK), adult biologic initiators were identified and propensity score-matched with non-initiators (ISAR, 1:1; OPCRD, 1:2). The impact of biologic initiation on TOCS (including bursts for exacerbations) daily dose in the first and second year follow-up period was estimated using multivariable generalized linear models. Results: Among 5663 patients (ISAR 48%, OPCRD 52%), the odds ratios (ORs) of biologic initiators achieving TOCS cessation in the first and second year of follow-up were 2.38 (95% CI, 1.87-3.04) and 2.11 (95% CI, 1.65-2.70), whereas the ORs of low (0-5mg) TOCS intake were 1.62 (95% CI, 1.40-1.86) and 1.40 (95% CI, 1.21-1.61) respectively. Compared to non-initiators, biologic initiators had a substantially higher chance of achieving >75% reduction from baseline (OR [95% CI]: 2.35 [2.06-2.68] and 1.53 [1.35-1.73] in first and second year, respectively). These findings remained persistent and robust, when analyses were repeated with one country setting removed at a time. Conclusions: Biologic initiation in SA patients led to substantial reduction in TOCS exposure, in particular in the first year. Future analyses will explore the impact on OCS-related adverse health events.

Description:Asthma characterization using blood eosinophil count (BEC) (among other biomarkers and clinical indices) is recommended in severe asthma (SA), but the masking effect of oral corticosteroids (OCS), makes this challenging. Our aim was to explore the effect of OCS use (both intermittent [iOCS] and long-term [LTOCS]) prior to biologic initiation on SA phenotype and biomarker profile in real-life and to characterize the burden of SA among patients prescribed LTOCS by biomarker profile. This was a registry-based cohort study, including data from 23 countries collected between 2003 and 2023 and shared with the Internatonal Severe Asthma Registry (ISAR). Patients with SA were categorized into 3 cohorts, those with: (i) no prescription for OCS, (ii) prescription(s) for iOCS (ie, ≤90 days in previous 12-months, usually short courses for exacerbations), and (iii) prescriptions for LTOCS (ie, >90 days in previous 12-months). Biomarker distribution (ie, BEC, fractional exhaled nitric oxide [FeNO], and total Immunoglobulin E [IgE]) were quantified in the year prior to biologic initiation in patients with SA according to OCS prescription pattern. Phenotypes were characterized for those prescribed LTOCS according to BEC cut-off (<150 and ≥ 150 cells/μL). Of 4305 patients included, 5.0% (n = 215), 54.1% (n = 2330) and 40.9% (n = 1760) were prescribed no OCS, iOCS, and LTOCS, respectively. The BEC distribution varied by prescription pattern and LTOCS dose (<5 mg to ≥20 mg/day); BEC was <150 cells/μL in 28.6% (n = 369/1288) of LTOCS patients, compared to 19.5% (n = 284/1460) of iOCS patients and 14.0% (n = 21/150) of those in the no OCS group. Median BEC was also significantly lower in the LTOCS versus the iOCS group (310 vs 400 cells/μL; p < 0.001). A similar pattern was noted for IgE, but not FeNO. Among LTOCS patients with BEC <150 cells/μL, 39.9% experienced ≥4 exacerbations, 75.1% had uncontrolled asthma symptoms and 55.9% had evidence of persistent airflow obstruction (compared with 40.9%, 76.2% and 59.5% of those with BEC ≥150 cells/μL, respectively). OCS, whether prescribed intermittently or long term, affect BEC distribution potentially leading to heightened risk of phenotype misclassification and influencing subsequent treatment decisions. FeNO appears to be less susceptible to OCS-induced suppression. Disease burden was high for those in the LTOCS group and was high independent of dose and BEC. Our findings highlight the importance of considering OCS use, even intermittent use, when characterizing SA, and suggests the need for earlier phenotyping and alternative treatment strategies for LTOCS patients with low BEC.

Description: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.

Description:Objective: As children hospitalised with community-acquired pneumonia (CAP) are at risk of persistent chest radiograph (CXR) abnormalities and respiratory sequelae, we investigated factors associated with incomplete CXR resolution at 4 weeks and 12 months post-discharge in children from populations at high-risk of chronic lung disease. Methods: Secondary analysis-multicentre, placebo-controlled, randomised controlled trial. Methods: 324 children aged 3 months to ≤5 years hospitalised with radiographic-confirmed CAP were enrolled from seven hospitals in Australia, New Zealand and Malaysia. After 1-3 days of intravenous antibiotics, then 3 days of oral amoxicillin-clavulanate, they were randomised to extended (13-14 days) or standard (5-6 days) courses of antibiotics. Methods: CXRs were performed at admission, 4 weeks, and 12 months post-discharge and reviewed in a blinded manner. Methods: Radiographic changes of pneumonia at 4 weeks and 12 months post-discharge compared with admission CXRs. Results: Among children with interpretable CXRs, incomplete resolution was seen in 42/253 (17%) at 4 weeks, and 29/212 (14%) at 12 months. Characteristics at admission associated with incomplete CXR resolution at 4 weeks were previous pneumonia hospitalisation (adjusted odds ratio [ORadj])=6.46, 95% confidence interval [CI] 2.21 to 18.85) and increasing age (ORadj=0.60 per-year, 95% CI 0.38 to 0.94). Continuing respiratory symptoms/signs at 4 weeks post-discharge was also associated with incomplete resolution (OR=5.63, 95% CI 2.38 to 13.32). At 12 months, previous pneumonia hospitalisation was associated with persistent incomplete CXR resolution (OR=4.03, 95 % CI 1.25 to 13.02). Conclusions: In high-risk settings, younger age, those with previous pneumonia hospitalisation, or ongoing respiratory symptoms/signs 4 weeks post-discharge from hospitalised CAP may be associated with incomplete CXR resolution. Consequently, follow-up imaging and monitoring may be warranted in these children.