Long-Term Effectiveness of Benralizumab in Eosinophilic Granulomatosis With Polyangiitis.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a multisystemic disease characterized by eosinophilic tissue inflammation. Benralizumab, an anti-IL-5 receptor (anti-IL-5R) monoclonal antibody, induces rapid depletion of eosinophils; its longer-term effect in EGPA is unknown. OBJECTIVE: To assess the real-world effectiveness and clinical remission rates of anti-IL-5R therapy in EGPA. METHODS: We performed a retrospective cohort analysis of patients with EGPA, who commenced treatment with benralizumab. Clinical remission, assessed at 1 year and 2 years after the initiation of benralizumab, was defined as an absence of active vasculitis (Birmingham Vasculitis Activity Score of 0) and an oral corticosteroid (OCS) dose of ≤4 mg/d of prednisolone. "Super-responders" were defined as patients in remission and free of any significant relapses (asthma or extrapulmonary) over the preceding 12 months. The corticosteroid-sparing capacity of benralizumab, patient-reported outcome measures, and characteristics associated with clinical remission and super-responder status were also analyzed. RESULTS: A total of 70 patients completed at least 1 year of treatment with benralizumab, of whom 53 completed 2 years. Of 70 patients, 47 (67.1%) met the definition for clinical remission at 1 year, with a similar proportion in remission at 2 years. Excluding asthma-related relapses, 61 of 70 (87.1%) patients were relapse free at 1 year, and of the 53 who completed 2 years, 45 (84.9%) were relapse free. A total of 67.9% of patients no longer needed any OCS for disease control. No significant difference was seen between antineutrophilic cytoplasmic antibody (ANCA)-positive and ANCA-negative subgroups. CONCLUSIONS: In this real-world setting of patients with EGPA, treatment with benralizumab was well tolerated and resulted in corticosteroid-free clinical remission for the majority of patients.

Reduction of daily maintenance inhaled corticosteroids in patients with severe eosinophilic asthma treated with benralizumab (SHAMAL): a randomised, multicentre, open-label, phase 4 study.

BACKGROUND: Stepwise intensification of inhaled corticosteroids (ICS) is routine for severe eosinophilic asthma, despite some poor responses to high-dose ICS. Dose reductions are recommended in patients responding to biologics, but little supporting safety evidence exists. METHODS: SHAMAL was a phase 4, randomised, open-label, active-controlled study done at 22 study sites in four countries. Eligible participants were adults (aged ≥18 years) with severe eosinophilic asthma and a five-item Asthma Control Questionnaire score below 1·5 and who received at least three consecutive doses of benralizumab before screening. We randomly assigned patients (3:1) to taper their high-dose ICS to a medium-dose, low-dose, and as-needed dose (reduction group) or continue (reference group) their ICS-formoterol therapy for 32 weeks, followed by a 16-week maintenance period. The primary endpoint was the proportion of patients reducing their ICS-formoterol dose by week 32. The primary outcome was assessed in the reduction group, and safety analyses included all randomly assigned patients receiving study treatment. This study is registered at ClinicalTrials.gov, NCT04159519. FINDINGS: Between Nov 12, 2019, and Feb 16, 2023, we screened and enrolled in the run-in period 208 patients. We randomly assigned 168 (81%) to the reduction (n=125 [74%]) and reference arms (n=43 [26%]). Overall, 110 (92%) patients reduced their ICS-formoterol dose: 18 (15%) to medium-dose, 20 (17%) to low-dose, and 72 (61%) to as-needed only. In 113 (96%) patients, reductions were maintained to week 48; 114 (91%) of patients in the reduction group had zero exacerbations during tapering. Rates of adverse events were similar between groups. 91 (73%) patients had adverse events in the reduction group and 35 (83%) in the reference group. 17 patients had serious adverse events in the study: 12 (10%) in the reduction group and five (12%) in the reference group. No deaths occurred during the study. INTERPRETATION: These findings show that patients controlled on benralizumab can have meaningful reductions in ICS therapy while maintaining asthma control. FUNDING: AstraZeneca.

Diagnosing and managing pleural disease.

This issue of Breathe focuses on the management of pleural disease https://bit.ly/4a7dh1S.

The changing face of the modern respiratory clinician.

This issue of Breathe examines both the integral role multidisciplinary care has in managing respiratory disease, and the changing faces of the respiratory clinicians providing that care. https://bit.ly/47MsW5R.

Climate change, the environment and respiratory disease.

Respiratory clinicians are no strangers to the concept of both occupational and recreational exposures affecting the lung, but evolving factors like climate change and air quality can also play a critical role in respiratory health. https://bit.ly/42XFCUA.

Nocturnal Hypoxemia Associates With Symptom Progression and Mortality in Patients With Progressive Fibrotic Interstitial Lung Disease.

BACKGROUND: OSA and nocturnal hypoxemia (NH) are common in patients with fibrotic interstitial lung disease (F-ILD), but their relationship with disease outcomes remains unclear. RESEARCH QUESTION: What is the relationship between NH and OSA and clinical outcomes in patients with F-ILD? STUDY DESIGN AND METHODS: This was a prospective observational cohort study of patients with F-ILD and without daytime hypoxemia. Patients underwent home sleep study at baseline and were followed up for at least 1 year or until death. NH was defined as ≥ 10% of sleep with oxygen saturation of < 90%. OSA was defined as an apnea-hypopnea index of ≥ 15 events/h. RESULTS: Among 102 participants (male, 74.5%; age, 73.0 ± 8.7 years; FVC, 2.74 ± 0.78 L; 91.1% idiopathic pulmonary fibrosis), 20 patients (19.6%) demonstrated prolonged NH and 32 patients (31.4%) showed OSA. No significant differences were found between those with and without NH or OSA at baseline. Despite this, NH was associated with a more rapid decline in both quality of life as measured by the King's Brief Interstitial Lung Disease questionnaire (change, -11.3 ± 5.3 points in the NH group vs -6.7 ± 6.5 in those without NH; P = .005) and higher all-cause mortality at 1 year (hazard ratio, 8.21; 95% CI, 2.40-28.1; P < .001). No statistically significant difference was seen between the groups in annualized change in measures of pulmonary function testing. INTERPRETATION: Prolonged NH, but not OSA, is associated with worsening disease-related quality of life and increased mortality in patients with F-ILD.

Use of digital measurement of medication adherence and lung function to guide the management of uncontrolled asthma (INCA Sun): a multicentre, single-blinded, randomised clinical trial.

BACKGROUND: The clinical value of using digital tools to assess adherence and lung function in uncontrolled asthma is not known. We aimed to compare treatment decisions guided by digitally acquired data on adherence, inhaler technique, and peak flow with existing methods. METHODS: A 32-week prospective, multicentre, single-blinded, parallel, randomly controlled trial was done in ten severe asthma clinics across Ireland, Northern Ireland, and England. Participants were 18 years or older, had uncontrolled asthma, asthma control test (ACT) score of 19 or less, despite treatment with high-dose inhaled corticosteroids, and had at least one severe exacerbation in the past year despite high-dose inhaled corticosteroids. Patients were randomly assigned in a 1:1 ratio to the active group or the control group, by means of a computer-generated randomisation sequence of permuted blocks of varying sizes (2, 4, and 6) stratified by fractional exhaled nitric oxide (FeNO) concentration and recruitment site. In the control group, participants were masked to their adherence and errors in inhaler technique data. A statistician masked to study allocation did the statistical analysis. After a 1-week run-in period, both groups attended three nurse-led education visits over 8 weeks (day 7, week 4, and week 8) and three physician-led treatment adjustment visits at weeks 8, 20, and 32. In the active group, treatment adjustments during the physician visits were informed by digital data on inhaler adherence, twice daily digital peak expiratory flow (ePEF), patient-reported asthma control, and exacerbation history. Treatment was adjusted in the control group on the basis of pharmacy refill rates (a measure of adherence), asthma control by ACT questionnaire, and history of exacerbations and visual management of inhaler technique. Both groups used a digitally enabled Inhaler Compliance Assessment (INCA) and PEF. The primary outcomes were asthma medication burden measured as proportion of patients who required a net increase in treatment at the end of 32 weeks and adherence rate measured in the last 12 weeks by area under the curve in the intention-to-treat population. The safety analyses included all patients who consented for the trial. The trial is registered with ClinicalTrials.gov, NCT02307669 and is complete. FINDINGS: Between Oct 25, 2015, and Jan 26, 2020, of 425 patients assessed for eligibility, 220 consented to participate in the study, 213 were randomly assigned (n=108 in the active group; n=105 in the control group) and 200 completed the study (n=102 in the active group; n=98 in the control group). In the intention-to-treat analysis at week 32, 14 (14%) active and 31 (32%) control patients had a net increase in treatment compared with baseline (odds ratio [OR] 0·31 [95% CI 0·15-0·64], p=0·0015) and 11 (11%) active and 21 (21%) controls required add-on biological therapy (0·42 [0·19-0·95], p=0·038) adjusted for study site, age, sex, and baseline FeNO. Three (16%) of 19 active and 11 (44%) of 25 control patients increased their medication from fluticasone propionate 500 µg daily to 1000 µg daily (500 µg twice a day; adjusted OR 0·23 [0·06-0·87], p=0·026). 26 (31%) of 83 active and 13 (18%) of 73 controls reduced their medication from fluticasone propionate 1000 µg once daily to 500 µg once daily (adjusted OR 2·43 [1·13-5·20], p=0·022. Week 20-32 actual mean adherence was 64·9% (SD 23·5) in the active group and 55·5% (26·8) in the control group (between-group difference 11·1% [95% CI 4·4-17·9], p=0·0012). A total of 29 serious adverse events were recorded (16 [55%] in the active group, and 13 [45%] in the control group), 11 of which were confirmed as respiratory. None of the adverse events reported were causally linked to the study intervention, to the use of salmeterol-fluticasone inhalers, or the use of the digital PEF or INCA. INTERPRETATION: Evidence-based care informed by digital data led to a modest improvement in medication adherence and a significantly lower treatment burden. FUNDING: Health Research Board of Ireland, Medical Research Council, INTEREG Europe, and an investigator-initiated project grant from GlaxoSmithKline.

What we do and do not know about managing respiratory disease in pregnancy.

Respiratory disorders are common in pregnant women, but their exclusion from clinical trials makes decisions around pharmacotherapy challenging. Developing programmes designed to improve evidence in pregnancy should be a priority for respiratory research. https://bit.ly/3n6aX42.

Infectious disease in respiratory medicine.

COVID-19 has brought respiratory infections into the spotlight, but other infectious diseases remain important causes of respiratory illness and death https://bit.ly/36t6Rhf.

Pulmonary vascular disease for the general respiratory clinician.

Pulmonary vascular disease is relevant to many practising respiratory clinicians: ∼1% of the world's population is estimated to have PH, and it is an important consequence of many other respiratory diseases (e.g. COPD, ILD, sleep breathing disorders) https://bit.ly/3hLqUx1.

Using Fractional Exhaled Nitric Oxide Measurement in Clinical Asthma Management.

Asthma is a common and heterogeneous disease characterized by lower airway inflammation and airflow limitation. Critical factors in asthma management include establishing an accurate diagnosis and ensuring appropriate selection and dosage of antiinflammatory therapies. Most patients with asthma exhibit type 2 inflammation, with increased IL-4, IL-5, and IL-13 signalling, often with associated eosinophilia. Identifying lower airway eosinophilia with sputum induction improves asthma outcomes, but is time-consuming and costly. Increased type 2 inflammation leads to upregulation of nitric oxide (NO) release into the airway, with increasing fractional exhaled NO (Feno) reflecting greater type 2 inflammation. Feno can be measured easily and quickly in the clinic, offering a point-of-care surrogate measurement of the degree of lower airway inflammation. Feno testing can be used to help confirm an asthma diagnosis, to guide inhaled corticosteroid therapy, to assess adherence to treatment, and to aid selection of appropriate biologic therapy. However, Feno levels also may be influenced by a variety of intrinsic and extrinsic factors other than asthma, including nasal polyposis and cigarette smoking, and must be interpreted in the broader clinical context, rather than viewed in isolation. This review discusses the clinical application of Feno measurement in asthma care, from diagnosis to treatment selection, and describes its place in current international expert guidelines.

Emergency medical admissions and COVID-19: impact on 30-day mortality and hospital length of stay.

BACKGROUND: The COVID-19 pandemic has put considerable strain on healthcare systems. AIM: To investigate the effect of the COVID-19 pandemic on 30-day in-hospital mortality, length of stay (LOS) and resource utilization in acute medical care. METHODS: We compared emergency medical admissions to a single secondary care centre during 2020 to the preceding 18 years (2002-2019). We investigated 30-day in-hospital mortality with a multiple variable logistic regression model. Utilization of procedures/services was related to LOS with zero truncated Poisson regression. RESULTS: There were 132,715 admissions in 67,185 patients over the 19-year study. There was a linear reduction in 30-day in-hospital mortality over time; over the most recent 5 years (2016-2020), there was a relative risk reduction of 36%, from 7.9 to 4.3% with a number needed to treat of 27.7. Emergency medical admissions increased 18.8% to 10,452 in 2020 with COVID-19 admissions representing 3.5%. 18.6% of COVID-19 cases required ICU admission with a median stay of 10.1 days (IQR 3.8, 16.0). COVID-19 was a significant univariate predictor of 30-day in-hospital mortality, 18.5% (95%CI: 13.9, 23.1) vs. 3.0% (95%CI: 2.7, 3.4)-OR 7.3 (95%CI: 5.3, 10.1). ICU admission was the dominant outcome predictor-OR 12.4 (95%CI: 7.7, 20.1). COVID-19 mortality in the last third of 2020 improved-OR 0.64 (95%CI: 0.47, 0.86). Hospital LOS and resource utilization were increased. CONCLUSION: A diagnosis of COVID-19 was associated with significantly increased mortality and LOS but represented only 3.5% of admissions and did not attenuate the established temporal decline in overall in-hospital mortality.

Sleep medicine and coronavirus disease 2019.

PURPOSE OF REVIEW: To evaluate the impact of the COVID-19 pandemic on the care of people with sleep disorders, to explore relationships between OSA and COVID-19, and to describe current knowledge of the effect of the pandemic on sleep globally. RECENT FINDINGS: COVID-19 has led to significant changes in the practice of sleep medicine, including the care of patients with OSA. An OSA diagnosis may portend a worse prognosis with COVID-19, whilst prior COVID-19 may have an impact on sleep breathing. SUMMARY: The pandemic has caused marked difficulties with access to diagnostic sleep studies and reduced capacity for CPAP initiation. Conversely, adherence to CPAP therapy may have improved, and use of remote consultations and telemonitoring has increased. An OSA diagnosis may be associated with increased risk of severe COVID-19, although any apparent relationship may be attributable to confounding factors, such as obesity and metabolic disease. Small studies have reported some increase in CPAP requirements in OSA patients following COVID-19 infection. More generally, the pandemic has been associated with a deterioration in subjective sleep quality across the population; much of this appears because of increased anxiety and stress. Finally, studies assessing putative links between COVID-19 and REM sleep issues are ongoing.

Real-World Effectiveness of Anti-IL-5/5R Therapy in Severe Atopic Eosinophilic Asthma with Fungal Sensitization.

BACKGROUND: Severe asthma with fungal sensitization (SAFS) is a complex clinical phenotype associated with poorly controlled type 2 inflammation and significant morbidity from both the disease itself and a high steroid burden. OBJECTIVE: To assess the effectiveness of biologic therapies targeting eosinophilic inflammation in SAFS. METHODS: We assessed the effectiveness of treatment with mepolizumab or benralizumab in patients with SAFS, and compared outcomes with patients with severe atopic asthma without fungal sensitization and patients with severe nonatopic asthma. Baseline clinical characteristics and clinical outcomes at 48 weeks were evaluated. A subgroup analysis was performed of patients who met the criteria for allergic bronchopulmonary aspergillosis (ABPA) rather than SAFS. RESULTS: A total of 193 patients treated with mepolizumab (n = 63) or benralizumab (n = 130) were included. Patients with SAFS had higher baseline IgE level compared with patients with severe atopic asthma without fungal sensitization and severe nonatopic asthma (733 ± 837 IU/mL vs 338 ± 494 and 142 ± 171, respectively; both P < .001). There were no other significant baseline differences in clinical characteristics between groups. At 48 weeks, there were significant improvements in 6-item asthma control questionnaire score and exacerbation frequency, and reduction in maintenance oral corticosteroid dose across all groups (all P < .05). No significant between-group differences in outcomes were observed at 48 weeks. Patients with ABPA (n = 9) had a significant reduction in exacerbation frequency (P = .013) with treatment. CONCLUSIONS: Treatment with eosinophil-targeting biologics led to improvements in exacerbation frequency, oral corticosteroid requirements, and patient-reported outcomes in patients with SAFS, with a reduction in exacerbations in the subgroup of patients with ABPA. These data highlight the potential clinical utility of targeting eosinophilic inflammation in SAFS and ABPA.

Real-World Effectiveness of Benralizumab in Severe Eosinophilic Asthma.

BACKGROUND: Benralizumab is an IL5-receptor monoclonal antibody licensed for the treatment of severe eosinophilic asthma (SEA). It has demonstrated efficacy in clinical trials in reducing asthma exacerbation rates and maintenance oral corticosteroids (mOCSs). RESEARCH QUESTION: What is the real-world effectiveness of benralizumab and what baseline characteristics are associated with response to therapy? STUDY DESIGN AND METHODS: We assessed outcomes in all SEA patients who began benralizumab treatment at our specialist center. At each dosing visit, exacerbation history, mOCS dose, spirometry, and Asthma Control Questionnaire (ACQ6) and Mini-Asthma Quality of Life Questionnaire (mAQLQ) scores were recorded. Response to treatment was defined as a reduction of ≥ 50% in annualized exacerbation rate (AER) or in mOCS dose after 48 weeks of treatment. Super response was defined as zero exacerbations and no mOCSs for asthma. RESULTS: One hundred thirty patients were included in the analysis. At 48 weeks, a 72.8% reduction in AER was noted, from 4.92 ± 3.35 per year in the year preceding biologic treatment to 1.34 ± 1.71 per year (P < .001), including 57 patients (43.8%) who were exacerbation-free with benralizumab. In those receiving mOCSs (n = 74 [56.9%]), the median daily prednisolone dose fell from 10 mg (interquartile range, 5-20 mg) to 0 mg (interquartile range, 0-5 mg; P < .001), and 38 of 74 patients (51.4%) were able to discontinue mOCS therapy. Clinically and statistically significant improvements were found in ACQ6 scores, mAQLQ scores, and FEV1. Overall, 51 patients (39%) met the super responder definition and 112 patients (86%) met the responder definition. The optimal regression model of super responders vs other responders included baseline characteristics associated with a strongly eosinophilic phenotype and less severe disease. Eighteen patients (13.8%) were nonresponders to benralizumab. Evidence of chronic airway infection was observed in 6 of 18 patients, and an increase in the blood eosinophil count consistent with the development of anti-drug antibodies was observed in 5 of 18 patients. INTERPRETATION: In a large real-world SEA cohort, benralizumab led to significant improvements in all clinical outcome measures. A lack of response was seen in a minority of patients and should be a focus for future investigation.