Airborne fungi are potent inducers of respiratory disease and cause the debilitating conditions severe asthma with fungal sensitisation (SAFS) and allergic bronchopulmonary aspergillosis (ABPA). However, the immune cell types and the inflammatory airway environment that defines SAFS and ABPA patients is not extensively characterised. To address this, we recruited SAFS and ABPA patients, asthmatics without evidence of fungal sensitisation and healthy controls (n = 20 individuals per group). Immune cells were isolated from collected sputum and peripheral blood samples and immunophenotyping was performed via flow cytometry. By applying a machine learning approach to our dataset, we identify a critical association between CD4+ T cells, type 2 conventional dendritic cells, eosinophils, proinflammatory factors and severe respiratory disease. These complex immune signatures should be investigated further to improve the diagnostics and treatment of SAFS and ABPA.

Omalizumab is recommended as an add-on therapy in patients aged ≥6 years with inadequately controlled, moderate-to-severe persistent allergic asthma. The efficacy and safety of omalizumab treatment in allergic asthma clinical trials and its effectiveness in the real world have been reported in numerous studies. In this review, we examine clinical evidence in pediatric and adult patients with allergic asthma who received omalizumab treatment for at least 2 years, to assess its effectiveness, durability, and trajectory of response over time as well as safety. We performed a literature search from inception until March 2022 in PubMed using the keywords "omalizumab" and "allergic asthma" to retrieve articles examining the effects of omalizumab in patients with allergic asthma, aged ≥6 years. Only articles that evaluated the effectiveness of omalizumab for at least 2 years were included. Data from case reports were excluded. Our review confirmed the long-term effectiveness and safety of omalizumab, demonstrating reduced rate of exacerbations, improved lung function, asthma control, and quality of life, decreased health care resource utilization, and use of corticosteroids (oral/inhaled) with a favorable safety and tolerability profile for up to 9 years in adult patients with moderate-to-severe allergic asthma. Similar results were also observed in the pediatric population with up to 7.5 years of omalizumab treatment. This review highlights and confirms the sustained clinical benefits of omalizumab over long periods of treatment in pediatric and adult populations with allergic asthma.

Background: COVID-19 is a highly heterogenic disease. We aimed to investigate which clinical admission parameters predict disease-related mortality in COVID-19 patients. Method: Admission clinical parameters in patients admitted between 10/03/20-09/04/20, with confirmed COVID-19 infection were recorded. Data was extracted from clinical records and 30-day mortality calculated. Results: A total of 286 patients were identified: 63.3% male, 86.0% Caucasian, mean (SD) age: 68.1 (16.1) years, 60.5% were overweight, 38.5% had hypertension, 15.7% asthma, 11.2% chronic obstructive pulmonary disease, 19.2% diabetes and 13.6% ischaemic heart disease. The 30-day mortality rate was 24.5% and 16.8% required intensive care admission. Patients who died within 30 days post-admission had higher oxygen requirement (p<0.001), higher respiratory rate (p=0.008), higher CRP (p=0.023) and lower lymphocyte counts (p=0.049) on admission compared with those alive. Patients who died within 30 days were also older (p<0.001) and were more likely to have diabetes and COPD (p=0.047 and 0.030 respectively). Age (Odds ratio (OR): 1.05, p<0.001), oxygen requirement (OR: 1.03, p<0.001) and respiratory rate (OR:1.06, p=0.003) on admission were significantly associated with 30-day mortality in univariate logistic regression. An age ≥ 70 years (OR:3.4, 95%CI [1.9-6.1], p<0.001) and oxygen requirement on admission of ≥ 35% (OR:3.3, 95%CI [1.7-6.1], p<0.001) were independent predictors for 30-day mortality; 51.9% of patients who met both criteria died at 30 days. Conclusion: COVID-19 poses high inpatient mortality, using clinical admission parameters to predict outcome may aid risk stratification and resource allocation.

Methods BT10+ was an international, multicentre, follow-up study of participants who were previously enrolled in the AIR, RISA, and AIR2 trials and who had 10 or more years of follow-up since bronchial thermoplasty treatment. Data on patient demographics, quality of life, lung function, CT scans (AIR2 participants only), severe exacerbations, and health-care use during the previous year were collected at the BT10+ 10-year outcomes study visit. The primary effectiveness endpoint was durability of the thermoplasty treatment effect, determined by comparing the proportion of participants who had severe exacerbations during the first and fifth years after bronchial thermoplasty treatment with the proportion of participants who had severe exacerbations during the 12-month period before the BT10+ visit. The primary safety endpoint was the absence of clinically significant post-treatment respiratory image changes after bronchial thermoplasty, defined as bronchiectasis or bronchial stenosis as confirmed by pulmonary volumetric highresolution CT scan at the BT10+ visit (AIR2 participants only). All analyses were done on an intention-to-treat basis. The trial is registered with ClinicalTrials.gov, NCT03243292. The last patient was enrolled on Dec 11, 2018. The last patient completed follow-up on Jan 10, 2019. Findings The BT10+ study enrolled 192 (45%) of the 429 participants who were enrolled in the AIR, RISA, and AIR2 trials. The BT10+ participants comprised 136 who received bronchial thermoplasty (52% of the 260 participants who received bronchial thermoplasty in the original trials), and 56 sham or control participants (33% of 169 from the original trials). 18 (32%) sham or control participants received bronchial thermoplasty after the previous trials concluded. The participants included in BT10+ were followed for 10?8?15?6 years (median 12?1 years) post-treatment. Baseline characteristics were similar between participants enrolled in BT10+ and those not enrolled. Participants treated with bronchial thermoplasty had similar proportions of severe exacerbations at the BT10+ visit (34 [25%] of 136 participants) compared with 1 year (33 [24%] of 135 participants; difference 0?6%, 95% CI ?9?7 to 10?8) and 5 years (28 [22%] of 130 participants; difference 3?5%, ?6?7% to 13?6) after treatment. Quality of life measurements and spirometry were similar between year 1, year 5, and the BT10+ visit. At the BT10+ study visit, pulmonary high-resolution CT scans from AIR2 participants treated with bronchial thermoplasty showed that 13 (13%) of 97 participants had bronchiectasis. When compared with baseline high-resolution CT scans, six (7%) of 89 participants treated with bronchial thermoplasty who did not have bronchiectasis at baseline had developed bronchiectasis after treatment (5 classified as mild, 1 classified as moderate). Participants treated with bronchial thermoplasty after the original study and participants in the sham or control group also had reductions in severe exacerbations at the BT10+ visit compared with baseline. Summary Background Bronchial thermoplasty is an endoscopic treatment for uncontrolled asthma. Previous randomised clinical trials have shown that bronchial thermoplasty reduces severe exacerbations in people with asthma. However, the long-term efficacy and safety of bronchial thermoplasty beyond 5 years is unknown. The BT10+ study aimed to investigate the efficacy and safety of bronchial thermoplasty after 10 or more years of follow-up. Methods BT10+ was an international, multicentre, follow-up study of participants who were previously enrolled in the AIR, RISA, and AIR2 trials and who had 10 or more years of follow-up since bronchial thermoplasty treatment. Data on patient demographics, quality of life, lung function, CT scans (AIR2 participants only), severe exacerbations, and health-care use during the previous year were collected at the BT10+ 10-year outcomes study visit. The primary effectiveness endpoint was durability of the thermoplasty treatment effect, determined by comparing the proportion of participants who had severe exacerbations during the first and fifth years after bronchial thermoplasty treatment with the proportion of participants who had severe exacerbations during the 12-month period before the BT10+ visit. The primary safety endpoint was the absence of clinically significant post-treatment respiratory image changes after bronchial thermoplasty, defined as bronchiectasis or bronchial stenosis as confirmed by pulmonary volumetric high resolution CT scan at the BT10+ visit (AIR2 participants only). All analyses were done on an intention-to-treat basis. The trial is registered with ClinicalTrials.gov, NCT03243292. The last patient was enrolled on Dec 11, 2018. The last patient completed follow-up on Jan 10, 2019. Findings The BT10+ study enrolled 192 (45%) of the 429 participants who were enrolled in the AIR, RISA, and AIR2 trials. The BT10+ participants comprised 136 who received bronchial thermoplasty (52% of the 260 participants who received bronchial thermoplasty in the original trials), and 56 sham or control participants (33% of 169 from the original trials). 18 (32%) sham or control participants received bronchial thermoplasty after the previous trials concluded. The participants included in BT10+ were followed for 10middot8-15middot6 years (median 12middot1 years) post-treatment. Baseline characteristics were similar between participants enrolled in BT10+ and those not enrolled. Participants treated with bronchial thermoplasty had similar proportions of severe exacerbations at the BT10+ visit (34 [25%] of 136 participants) compared with 1 year (33 [24%] of 135 participants; difference 0middot6%, 95% CI -9middot7 to 10middot8) and 5 years (28 [22%] of 130 participants; difference 3middot5%, -6middot7% to 13middot6) after treatment. Quality of life measurements and spirometry were similar between year 1, year 5, and the BT10+ visit. At the BT10+ study visit, pulmonary high-resolution CT scans from AIR2 participants treated with bronchial thermoplasty showed that 13 (13%) of 97 participants had bronchiectasis. When compared with baseline high-resolution CT scans, six (7%) of 89 participants treated with bronchial thermoplasty who did not have bronchiectasis at baseline had developed bronchiectasis after treatment (5 classified as mild, 1 classified as moderate). Participants treated with bronchial thermoplasty after the original study and participants in the sham or control group also had reductions in severe exacerbations at the BT10+ visit compared with baseline. Interpretation Our findings suggest that efficacy of bronchial thermoplasty is sustained for 10 years or more, with an acceptable safety profile. Therefore, bronchial thermoplasty is a long-acting therapeutic option for patients with asthma that remains uncontrolled despite optimised medical treatment. Funding Boston Scientific. Copyright (c) 2021 Elsevier Ltd. All rights reserved.

Why do some patients with severe asthma not follow healthcare provider (HCP) advice to adjust treatment? We explored possible barriers when adjusting asthma treatment in a secondary analysis of data from a randomised, controlled, single-blind (study participant), multi-centre, parallel group 48-week clinical study comparing biomarker directed treatment adjustment to standard care in severe asthma. The main outcome measure was patient choice not to follow HCP advice to adjust asthma treatment. Of 1572 treatment advisories (301 subjects) instructions were followed in 1,377 cases (87.6%). Patients were more likely to follow advice to remain on current treatment (96.7%) than to either reduce (70.3%) or increase (67.1%) their treatment, with 64% of patients following all treatment advice. Multivariate analysis showed belonging to an ethnic minority group (OR: 3.10; 95% CI: 1.68, 5.73) and prior study medication change (≥2 OR: 2.77, 95% CI: 1.51, 5.10) were associated with failure to follow treatment advice. Emergency room attendance (<1yr) (OR: 0.54, 95% CI: 0.32, 0.92) was associated with following treatment advice. The largest effect was seen with transition onto or off oral corticosteroids (OR: 29.28; 95% CI: 16.07, 53.36) vs. those requested to maintain treatment. Study centre was also an important determinant. Factors such as minority ethnic group and different patient behaviour in specialist clinical centres will require further focussed studies to explore the underlying mechanisms. These findings have implications for generalisability for models of care in severe asthma.

Introduction: Benralizumab and mepolizumab are subcutaneous monoclonal antibodies licensed for the treatment of severe eosinophilic asthma Benralizumab acts by blocking the anti-IL5 a receptor whilst mepolizumab binds to IL-5 inhibiting it binding to eosinophils There is currently an absence of head-to-head data but trial outcomes have found a similar reduction in exacerbation frequency Aim: To compare clinical outcomes of patients receiving benralizumab or mepolizumab at 6 and 12 months of treatment Method: A retrospective review of 50 mepolizumab and 50 benralizumab patients was carried out The mepolizumab group reviewed had started treatment immediately prior to introduction of benralizumab to ensure a similar patient population Measurements at baseline, 6 months and 12 months of treatment were compared for the following: daily oral cortico-steroid dose (OCS);asthma control scores;blood and sputum eosinophils;FeNO We also examined adherence to inhaled corticosteroid (ICS) at baseline Results: Statistically significant differences were seen in FeNO, ACQ scores, blood and sputum eosinophils at 6 and 12 months (table) Blood eosinophils were undetectable in 75% (n=33) of patients on benralizumab and 2% (n=1) on mepolizumab at 6 months, and at 12 months 77% (n=10) and 8% (n=2) respectively Likewise sputum eosinophils were (Table presented) undetectable at 12 months in 83% (n=5) on benralizumab and 16% (n=2) in mepolizumab Mean (SD) adherence to ICS in patients initiating benralizumab was 88 (11)% versus 80 (3)% in mepolizumab (p<0 001) Lung function and FeNO measurements were not available at 12 months due to COVID-19 restrictions Conclusion: There was a higher proportion of patients on benralizumab achieving complete suppression of blood and sputum eosinophils at six and 12 months compared to those on mepolizumab Asthma control scores after treatment were also superior with benralizumab compared to mepolizumab Despite higher levels of adherence in the benralizumab group these patients had a higher FeNO after treatment

Severe asthma imposes a significant burden on individuals, families and the healthcare system. Treatment is complex, due to disease heterogeneity, comorbidities and complexity in care pathways. New approaches and treatments improve health outcomes for people with severe asthma. However, emerging multidimensional and targeted treatment strategies require a reorganisation of asthma care. Consensus is required on how reorganisation should occur and what areas require further research. The Centre of Excellence in Severe Asthma convened three forums between 2015 and 2018, hosting experts from Australia, New Zealand and the UK. The forums were complemented by a survey of clinicians involved in the management of people with severe asthma. We sought to: (i) identify areas of consensus among experts; (ii) define activities and resources required for the implementation of findings into practice; and (iii) identify specific priority areas for future research. Discussions identified areas of unmet need including assessment and diagnosis of severe asthma, models of care and treatment pathways, add-on treatment approaches and patient perspectives. We recommend development of education and training activities, clinical resources and standards of care documents, increased stakeholder engagement and public awareness campaigns and improved access to infrastructure and funding. Further, we propose specific future research to inform clinical decision-making and develop novel therapies. A concerted effort is required from all stakeholders (including patients, healthcare professionals and organisations and government) to integrate new evidence-based practices into clinical care and to advance research to resolve questions relevant to improving outcomes for people with severe asthma.

Background Asthma treatment guidelines recommend increasing corticosteroid dose to control symptoms and reduce exacerbations. This approach is potentially flawed because symptomatic asthma can occur without corticosteroid responsive type-2 (T2)-driven eosinophilic inflammation, and inappropriately high-dose corticosteroid treatment might have little therapeutic benefit with increased risk of side-effects. We compared a biomarker strategy to adjust corticosteroid dose using a composite score of T2 biomarkers (fractional exhaled nitric oxide [FENO], blood eosinophils, and serum periostin) with a standardised symptom-risk-based algorithm (control). Methods We did a single-blind, parallel group, randomised controlled trial in adults (18-80 years of age) with severe asthma (at treatment steps 4 and 5 of the Global Initiative for Asthma) and FENO of less than 45 parts per billion at 12 specialist severe asthma centres across England, Scotland, and Northern Ireland. Patients were randomly assigned (4:1) to either the biomarker strategy group or the control group by an online electronic case-report form, in blocks of ten, stratified by asthma control and use of rescue systemic steroids in the previous year. Patients were masked to study group allocation throughout the entirety of the study. Patients attended clinic every 8 weeks, with treatment adjustment following automated treatment-group-specific algorithms: those in the biomarker strategy group received a default advisory to maintain treatment and those in the control group had their treatment adjusted according to the steps indicated by the trial algorithm. The primary outcome was the proportion of patients with corticosteroid dose reduction at week 48, in the intention-to-treat (ITT) population. Secondary outcomes were inhaled corticosteroid (ICS) dose at the end of the study; cumulative dose of ICS during the study; proportion of patients on maintenance oral corticosteroids (OCS) at study end; rate of protocol-defined severe exacerbations per patient year; time to first severe exacerbation; number of hospital admissions for asthma; changes in lung function, Asthma Control Questionnaire-7 score, Asthma Quality of Life Questionnaire score, and T2 biomarkers from baseline to week 48; and whether patients declined to progress to OCS. A secondary aim of our study was to establish the proportion of patients with severe asthma in whom T2 biomarkers remained low when corticosteroid therapy was decreased to a minimum ICS dose. This study is registered with ClinicalTrials.gov, NCT02717689 and has been completed. Findings Patients were recruited from Jan 8, 2016, to July 12, 2018. Of 549 patients assessed, 301 patients were included in the ITT population and were randomly assigned to the biomarker strategy group (n=240) or to the control group (n=61). 28.4% of patients in the biomarker strategy group were on a lower corticosteroid dose at week 48 compared with 18.5% of patients in the control group (adjusted odds ratio [aOR] 1.71 [95% CI 0.80-3.63]; p=0.17). In the per-protocol (PP) population (n=121), a significantly greater proportion of patients were on a lower corticosteroid dose at week 48 in the biomarker strategy group (30.7% of patients) compared with the control group (5.0% of patients; aOR 11.48 [95% CI 1.35-97.83]; p=0.026). Patient choice to not follow treatment advice was the principle reason for loss to PP analysis. There was no difference in secondary outcomes between study groups and no loss of asthma control among patients in the biomarker strategy group who reduced their corticosteroid dose. Interpretation Biomarker-based corticosteroid adjustment did not result in a greater proportion of patients reducing corticosteroid dose versus control. Understanding the reasons for patients not following treatment advice in both treatment strategies is an important area for future research. The prevalence of T2 biomarker-low severe asthma was low.

BACKGROUND: Daily inhaled corticosteroids (ICSs) are fundamental to asthma management, but adherence is low. OBJECTIVES: To investigate (1) whether LC-MS/MS could be used to detect ICSs in serum and (2) whether serum levels related to markers of disease severity. METHODS: We collected blood samples over an 8-hour period from patients with severe asthma prescribed at least 1000 mu g daily of beclomethasone dipropionate equivalent. Following baseline sampling, patients were observed taking their usual morning dose. Subsequent blood samples were obtained 1, 2, 4, and 8 hours postinhalation and analyzed by LC-MS/MS. Correlations between serum ICS levels and severity markers were investigated. RESULTS: A total of 60 patients were recruited (41 females; 39 prescribed maintenance prednisolone; mean age, 49 +/- 12 years; FENT1, 63 +/- 20 %predicted). Eight hours postinhalation, all patients using budesonide (n = 10) and beclomethasone dipropionate (15), and all but 1 using fluticasone propionate (28), had detectable serum drug levels. Fluticasone furorate was detected in 2 patients (of 4), ciclesonide in none (of 7). Low adherence by repeat prescription records (<80%) was identified in 43%. Blood ICS levels correlated negatively with exacerbation rate, and (for fluticasone propionate only) positively with FEV1 %predicted. CONCLUSIONS: Commonly used ICSs can be reliably detected in the blood at least 8 hours after dosing, and could therefore be used as a measure of adherence in severe asthma. Higher exacerbation rates and poorer lung function (for fluticasone propionate) were associated with lower blood levels. (C) 2021 American Academy of Allergy, Asthma & Immunology

Objectives Bronchial thermoplasty (BT) is a device-based treatment for subjects ≥18 years with severe asthma not well controlled with inhaled corticosteroids and long-acting beta-agonists. The Bronchial Thermoplasty Global Registry (BTGR) collected real-world data on subjects undergoing this procedure. Design The BTGR is an all-comer, prospective, open-label, multicentre study enrolling adult subjects indicated for and treated with BT. Setting Eighteen centres in Spain, Italy, Germany, the UK, the Netherlands, the Czech Republic, South Africa and Australia Participants One hundred fifty-seven subjects aged 18 years and older who were scheduled to undergo BT treatment for asthma. Subjects diagnosed with other medical conditions which, in the investigator’s opinion, made them inappropriate for BT treatment were excluded. Primary and secondary outcome measures Baseline characteristics collected included demographics, Asthma Quality of Life Questionnaire (AQLQ), Asthma Control Test (ACT), medication usage, forced expiratory volume in one second and forced vital capacity, medical history, comorbidities and 12-month baseline recall data (severe exacerbations (SE) and healthcare utilisation). SE incidence and healthcare utilisation were summarised at 1 and 2 years post-BT. Results Subjects’ baseline characteristics were representative of persons with severe asthma. A comparison of the proportion of subjects experiencing events during the 12 months prior to BT to the 2-year follow-up showed a reduction in SE (90.3% vs 56.1%, p<0.0001), emergency room visits (53.8% vs 25.5%, p<0.0001) and hospitalisations (42.9% vs 23.5 %, p=0.0019). Reductions in asthma maintenance medication dosage were also observed. AQLQ and ACT scores improved from 3.26 and 11.18 at baseline to 4.39 and 15.54 at 2 years, respectively (p<0.0001 for both AQLQ and ACT). Conclusions The BTGR demonstrates sustained improvement in clinical outcomes and reduction in asthma medication usage 2 years after BT in a real-world population. This is consistent with results from other BT randomised controlled trials and registries and further supports improvement in asthma control after BT. Trial registration number NCT02104856 .

Background Anti-IL-5 monoclonal antibodies reduce systemic corticosteroid use, exacerbation rate, and airway inflammation in severe asthma. Different effectors of the eosinophil IL-5 pathway are targeted, but algorithms to choose the most appropriate biologic for each patient are still being refined. Our team regularly monitors severe asthma patients' airway inflammation using sputum eosinophils. Aims To investigate clinical outcomes of patients that switched to benralizumab after non-response to mepolizumab associated with persistent sputum eosinophilia. Methods We prospectively monitored sputum cell counts of patients starting MDT-approved benralizumab after: failing to respond to mepolizumab, and whose positive sputum eosinophils remained above the threshold of 3%. Additional clinical parameters were recorded including corticosteroid dose, ACQ, AQLQ, and blood eosinophils. Lung function testing was severely impacted by the COVID pandemic. Results Fifty-one of 183 (27.9%) mepolizumab patients to date have been identified as candidates for a switch of therapy with residual positive sputum eosinophils, of which 44 have received their first doses of benralizumab and 16 have completed 6 months of treatment with available sputum eosinophil results. After 6 months on benralizumab therapy, clinically and statistically significant improvements in ACQ and mAQLQ were observed compared to baseline. All but two patients had negative sputum eosinophils (< 3%) compared to levels on mepolizumab (Table). Both also had elevated blood eosinophils: one patient was sampled during an exacerbation, the other is being investigated for parasitic infestation due to frequent foreign travels. At baseline 81% of patients were taking maintenance oral corticosteroids compared to 44% at 6 months (NS). Conclusions More than a quarter of patients failed to respond to mepolizumab and displayed persistent airway eosinophilia. Of these, 88% achieved negative airway inflammation on benralizumab with significant clinical improvement (ACQ, AQLQ) and clinically (though not statistically on this small sample size) significant fall of OCS. Benralizumab appears to prove effective at reducing inflammation at tissue level in patients previously unable to achieve this on a different anti-IL-5 therapy. As more patients progress through their treatment, repeat monitoring at 12 months will establish if this benefit is maintained and is associated with long term steroid dose reduction, and exacerbation rate.

BACKGROUND: Frequent exacerbations are an important cause of morbidity in patients with severe asthma. OBJECTIVE: Our aim was to identify factors associated with frequent exacerbations in a large well-characterized severe asthma population and determine whether factors differed inpatients treated with and without maintenance oral corticosteroids (OCS). METHODS: Adults with severe asthma from specialized asthma centers across the United Kingdom were recruited to the UK Severe Asthma Registry. Demography, comorbidities andphysiological measurements were collected. We conducted univariable and multivariable logistic regression analyses to identify factors associated with frequent exacerbations, defined as 3 or more exacerbations treated with high-dose systemic corticosteroids in the past year. RESULTS: Of 1,592 patients with severe asthma from the UK Severe Asthma Registry, 1,137 (71%) were frequent exacerbators and 833 (52%) were on maintenance OCS. The frequent exacerbators were more likely to be ex-smokers, have gastroesophageal reflux disease, higher Asthma Control Questionnaire 6 (ACQ-6) score, and higher blood eosinophilia. Multivariable regression analyses showed ACQ-6 score greater than 1.5 (odds ratio [OR] 4.25; P < .001), past smoking history (OR 1.55; P = .024), and fractional exhaled nitric oxide greater than 50ppb (OR 1.54; P = .044) were independently associated with frequent exacerbations. Past smoking history correlated with frequent exacerbations only in patients on maintenance OCS (OR 2.25; P = .004), whereas ACQ-6 score greater than 1.5 was independently associated with frequent exacerbations in those treated with and without maintenance OCS (OR 2.74; P = .017 and OR 6.42; P < .001, respectively). CONCLUSIONS: Several factors were associated with frequent exacerbations in a large UK severe asthma registry population. High ACQ-6 score had the strongest association with frequent exacerbations irrespective of maintenance OCS status.(c) 2021 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/). (J Allergy Clin Immunol Pract 2021;9:2691-701)

Introduction and Objectives Severe asthma patients are often treated with long-term high-dose inhaled and systemic corticosteroids which puts them at significant risk of developing adrenal insufficiency. We aimed to collate and review all relevant studies of adult severe asthma patients prescribed inhaled, oral and/or intramuscular corticosteroids and report: 1. the prevalence of adrenal insufficiency; and 2. the methods used to diagnose it. Methods A systematic review was undertaken using PubMed and Cochrane Library Database on 27th April 2020, using appropriate search terms (1970 to present). Articles were included or excluded by two independent reviewers. Adrenal suppression prevalence, measurement methods, previous corticosteroid dosage, length of corticosteroid therapy and other relevant data were extracted. The critical appraisal skills programme (CASP) checklist was used to assess the quality of each article. Results The search generated 755 articles, 10 were accepted, figure 1. This included randomised control trials, case-control and cohort studies. No articles were rejected based on CASP score. Prevalence of adrenal suppression and baseline adrenal suppression of patient cohorts as indicated by blood cortisol <500 nmol/l was reported in all 10 studies. Adrenal suppression prevalence in patients taking high-dose long-term inhaled corticosteroids only was 0–25%. Prevalence in patients prescribed high-dose, long-term inhaled and oral corticosteroid therapy was 68–100%. No studies reported findings in patients prescribed intramuscular corticosteroids. All articles discussed morning serum/plasma cortisol as a measurement of adrenal suppression. Of those 10 studies, only six stated the reference range used for blood cortisol. One article used 10-hour overnight urinary cortisol with overnight urinary cortisol:creatinine ratio and three used 24-hour urinary cortisol. Additionally, eight reported using the standard 250µg Synacthen test, one of which used both the standard and low-dose (1µg) Synacthen test. Conclusion Adrenal suppression is common in severe asthma patients taking long-term high-dose inhaled and oral corticosteroids, and present even in some patients taking only long-term high-dose inhaled corticosteroids. Standardisation is needed for methods and reference ranges for diagnostic tests of adrenal suppression in clinical and research practice.

The COVID-19 pandemic has put unprecedented strain on the healthcare systems, particularly intensive care and extracorporeal membrane oxygenation (ECMO) resources. We aimed to investigate the lengths of hospital stay of COVID-19 patients in a tertiary respiratory centre. Clinical data of all patients admitted between 10/03/2020 and 9/04/2020, with confirmed COVID-19 infection was extracted. For comparison, data from patients admitted with bacterial pneumonia during the same time in the previous year was recorded. Out of a total of 286 patients with COVID-19 (63% male, mean (SD) age of 68 (16) years), 25% died within 30 days of admission. Fewer patients (n=166) were admitted during the same time last year with pneumonia, with a lower 30-day mortality rate (14.5%, p=0.012). The total inpatient lengths of stay (LoS) in COVID-19 patients were significantly higher than patients with pneumonia (median (IQR): 7 (3-13) days and 5 (2-10) days, respectively; p=0.003). Fifty (18%) COVID patients required admission to intensive care unit (ICU) (32% in hospital mortality), with the median (IQR) duration of ICU stay of 17 (10-48) days. For those who required ICU admission, the total in-hospital LoS was prolonged (24 (16-45) days), with a minority (8%) of patients required continuous inpatient care beyond 80 days. Six (12%) COVID-19 patients required ECMO support (median (IQR) duration: 13 (10-18) days) compared to none during the same time last year for pneumonia. For those who required ECMO support, the median (IQR) in-hospital stay was 44 (36-73) days. COVID-19 exerts a substantial burden to hospital resources therefore necessitating careful resource allocation.

Introduction Severe asthma affects an estimated 3%–5% of people with asthma and is associated with frequent exacerbations, poor symptom control and significant morbidity from the disease itself, as well as high dose of inhaled and systemic steroids used to treat it. The introduction of specialist asthma services across the UK has attempted to improve quality of care and ensure that patients undergo a full systematic assessment prior to initiation of advanced biological therapies. However, improvements are required in the patient pathway to minimise avoidable harm. Objectives To define standards of care in areas where the evidence base is lacking through patient and healthcare professional (HCP) consensus. Methods The precision UK National Working Group of asthma experts identified 42 statements formed from 7 key themes. An online four-point Likert scale questionnaire was sent to HCPs working in asthma throughout the UK to assess agreement (consensus) with these statements; a subset of the statements formed a patient questionnaire. Consensus was defined as high if ≥75% and very high if ≥90% of respondents agreed with a statement. Results A total of 117/197 responses (59.3% response rate) were received from severe asthma patients (n=15) and HCPs (n=102) including respiratory physicians, respiratory nurse specialists, respiratory pharmacists, specialist physiotherapists and general practitioners. Consensus was very high in 25 (60%) statements, high in 12 (29%) statements and was not achieved in 5 (12%) statements. Based on the consensus scores, the precision UK National Working Group derived 10 key recommendations. These focus on referrals from primary and secondary care, accessing specialist asthma services, homecare provision for severe asthma patients and outcome measures. Conclusions Implementation of these 10 recommendations across the severe asthma pathway in the UK has the potential to improve outcomes for patients by reducing delays to assessment and initiation of advanced phenotype-specific therapies.

BACKGROUND:Severe asthma is a complex heterogeneous disease typically requiring advanced therapies. Underlying the treatment of all asthma, however, is the consistent recommendation across international guidelines to ensure that adherence to therapy is adequate. Currently, there is no consensus on an objective marker of adherence.METHODS:We performed a prospective observational study of 17 participants taking oral prednisolone using serum prednisolone levels as a marker of adherence, and sputum eosinophilia as a marker of control of type 2 airway inflammation. Based on these biomarkers, we classified participants into a non-adherent and an adherent cohort, and further stratified by the presence of ongoing sputum eosinophilia.RESULTS:We identified 3 non-adherent participants and 14 who were adherent, based on their serum prednisolone levels. Stratification using sputum eosinophil counts identified one participant as having ongoing sputum eosinophilia in the setting of non-adherence, while six were identified as steroid resistant with ongoing sputum eosinophilia despite adherence to oral prednisolone therapy.CONCLUSION:Serum prednisolone can be used an objective marker of adherence in those patients with severe asthma taking daily oral prednisolone. In combination with sputum eosinophil counts, a steroid resistant cohort can be distinguished from one with ongoing inflammation in the setting of non-adherence. This information can then be used by clinicians to differentiate the optimal next steps for treatment in these specific populations.TRIAL REGISTRATION:Participants were recruited as part of the Markers of Inflammation in the Management of Severe Asthma (MIMOSA) study, trial registration ACTRN12616001015437 , 02 August 2016.

Fractional exhaled nitric oxide (FENO) demonstrates marked same-day variation in patients with severe asthma, which may impact on clinical decisions. The same-day variability must be carefully considered when interpreting FENO as a single-breath test.https://bit.ly/38M1eJV

BACKGROUND:Asthma is a complex disease with multiple phenotypes that may differ in disease pathobiology and treatment response. IL33 single nucleotide polymorphisms (SNPs) have been reproducibly associated with asthma. IL33 levels are elevated in sputum and bronchial biopsies of patients with asthma. The functional consequences of IL33 asthma SNPs remain unknown. OBJECTIVE:This study sought to determine whether IL33 SNPs associate with asthma-related phenotypes and with IL33 expression in lung or bronchial epithelium. This study investigated the effect of increased IL33 expression on human bronchial epithelial cell (HBEC) function. METHODS:Association between IL33 SNPs (Chr9: 5,815,786-6,657,983) and asthma phenotypes (Lifelines/DAG [Dutch Asthma GWAS]/GASP [Genetics of Asthma Severity & Phenotypes] cohorts) and between SNPs and expression (lung tissue, bronchial brushes, HBECs) was done using regression modeling. Lentiviral overexpression was used to study IL33 effects on HBECs. RESULTS:We found that 161 SNPs spanning the IL33 region associated with 1 or more asthma phenotypes after correction for multiple testing. We report a main independent signal tagged by rs992969 associating with blood eosinophil levels, asthma, and eosinophilic asthma. A second, independent signal tagged by rs4008366 presented modest association with eosinophilic asthma. Neither signal associated with FEV1, FEV1/forced vital capacity, atopy, and age of asthma onset. The 2 IL33 signals are expression quantitative loci in bronchial brushes and cultured HBECs, but not in lung tissue. IL33 overexpression in vitro resulted in reduced viability and reactive oxygen species-capturing of HBECs, without influencing epithelial cell count, metabolic activity, or barrier function. CONCLUSIONS:We identify IL33 as an epithelial susceptibility gene for eosinophilia and asthma, provide mechanistic insight, and implicate targeting of the IL33 pathway specifically in eosinophilic asthma.

The IL1RL1 (ST2) gene locus is robustly associated with asthma; however, the contribution of single nucleotide polymorphisms (SNPs) in this locus to specific asthma subtypes and the functional mechanisms underlying these associations remain to be defined. We tested for association between IL1RL1 region SNPs and characteristics of asthma as defined by clinical and immunological measures and addressed functional effects of these genetic variants in lung tissue and airway epithelium. Utilizing 4 independent cohorts (Lifelines, Dutch Asthma GWAS [DAG], Genetics of Asthma Severity and Phenotypes [GASP], and Manchester Asthma and Allergy Study [MAAS]) and resequencing data, we identified 3 key signals associated with asthma features. Investigations in lung tissue and primary bronchial epithelial cells identified context-dependent relationships between the signals and IL1RL1 mRNA and soluble protein expression. This was also observed for asthma-associated IL1RL1 nonsynonymous coding TIR domain SNPs. Bronchial epithelial cell cultures from asthma patients, exposed to exacerbation-relevant stimulations, revealed modulatory effects for all 4 signals on IL1RL1 mRNA and/or protein expression, suggesting SNP-environment interactions. The IL1RL1 TIR signaling domain haplotype affected IL-33–driven NF-κB signaling, while not interfering with TLR signaling. In summary, we identify that IL1RL1 genetic signals potentially contribute to severe and eosinophilic phenotypes in asthma, as well as provide initial mechanistic insight, including genetic regulation of IL1RL1 isoform expression and receptor signaling.

Background: Manchester Asthma and Airways Service Team (MAAST) routinely use sputum eosinophils (SpEo) differential cell count (DCC) to monitor and guide clinical practice. With the growing demand for SpEo monitoring due to the advent of biologics therapies, DCC training and quality control procedures are of paramount importance. Aim: To evaluate if the difference in DCCs between operators would affect clinical decision. Methods: One hundred and twenty six consecutive cytospins were counted in parallel by a DCC experienced sputologist and a trainee. MAAST uses a threshold of 3% SpEo for escalation of treatment. Results: Of the 126 cytospins, 6 were ruled out due to poor quality by both operators, whilst the trainee dismissed a further 13 slides. Blant-Altman analysis showed a sensible level of agreement between the sputologist and trainee counts, whilst the intraclass correlation coefficient was 0.951 (95%CI: 0.928-0.967). Conclusions: Experienced sputologist and trainee9s DCC agreed in 90% cases. Whilst performing with similar ICC of existing published studies, the trainee underestimated SpEo. This would have changed the treatment decision in 10% of cases. These results illustrate the need for extensive training and quality control in SpEo DCC, which might be a contributing factor in the perceived difficulty in establishing sputum monitoring services. It also highlights the need for the development of alternative and automated DCC technologies.