BACKGROUND: Mepolizumab inhibits IL-5 activity and reduces exacerbation frequency and maintenance oral cortico-steroid (OCS) dosage in patients with severe eosinophilic asthma (SEA). Some patients remain dependent on OCS despite anti -IL-5 treatment, suggesting residual corticosteroid-responsive mechanisms. OBJECTIVE: To determine the clinical and anti-inflammatory effects of OCS in patients with SEA on mepolizumab. METHODS: We conducted a randomized, triple-blind, placebo -controlled crossover trial of prednisolone (0.5 mg/kg/d, maximum 40 mg/d, for 14 - 2 days) in adults with SEA after 12 or more weeks of mepolizumab. We compared change in asthma symptoms, quality of life, lung function measured by spirometry and airwave oscillometry, fractional exhaled nitric oxide, and blood and sputum eosinophil cell count after prednisolone and placebo treatment. RESULTS: A total of 27 patients completed the study. Prednisolone did not improve 5-item Asthma Control Ques-tionnaire (mean difference in change for prednisolone vs placebo, -0.23; 95% CI, -0.58 to 0.11), mini-Asthma Quality of Life Questionnaire (0.03; 95% CI, -0.26 to 0.42), St. George's Respiratory Questionnaire (0.24; 95% CI, -3.20 to 3.69), or Visual Analogue Scale scores for overall asthma symptoms (0.11; 95% CI, -0.58 to 0.80). The mean difference for FEV1 in favor of prednisolone was 105 mL (95% CI, -4 to 213 mL); forced expiratory flow at 25% and 75% 484 mL/s (95% CI, 151 to 816 mL/s); fractional exhaled nitric oxide reduction 41% (95% CI, 25% to 54%); blood eosinophil count reduction 49% (95% CI, 31% to 62%); and percentage of sputum eosinophil reduction 71% (95% CI, 26% to 89%). CONCLUSIONS: OCS improved small-airway obstruction and reduced biomarkers of type 2 inflammation but had no signifi- cant effect on symptoms or quality of life in patients with SEA receiving treatment with mepolizumab. Crown Copyright (c) 2022 Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). (J Allergy Clin Immunol Pract 2022;10:2925-34)

Introduction: In the first wave of the COVID-19 pandemic, total A&E attendances and hospital admissions reduced in the UK. We investigated whether asthma related mortality in Scotland during this period increased when hospital admissions reduced and if gender had any effect on COVID-19 plus asthma deaths. Methods: Five-year hospital admission data [Jan 2015 - June 2020] from Public Health Scotland's Scottish Morbidity Records and medical certificate of death (MCCD) data from National Records of Scotland were analysed using statistical process control charts. Results: In April 2020, asthma admissions reduced (Figure 1A) [218 vs previous 5-year mean of 418] and 7958 deaths occurred; an excess of 2731 from previous 5-year mean, with 2442 deaths directly attributed to COVID-19. In the same month asthma was recorded on the MCCD as either the underlying or the contributory cause in 130 deaths, compared to previous 5-year mean of 27.5 (Figure 1B), and as the underlying cause of death in 7 cases, comparable to previous 5-year mean of 9.2 deaths (Figure 1C). Of the remaining 123 patients with asthma recorded as a contributory cause, 81 had COVID-19 recorded as the underlying cause of death. Of these 48(60%) were female, compared with 1130(48%) deaths in those without contributory asthma (p=0.044). Conclusions: Reduced acute healthcare utilisation during the pandemic did not result in increased mortality with asthma as the underlying cause of death.

Introduction: Stress, depression and anxiety can affect asthma control and quality of life, but access to clinical psychology is limited. Mindfulness based cognitive therapy (MBCT), a group-based course to reduce stress, has reported benefit in chronic disease. We assessed asthma patients’ attendance at a 10-week MBCT course and its effect on asthma control. Methods: Patients with uncontrolled physician diagnosed asthma (asthma control questionnaire [ACQ-6] score ≥1.5 despite optimised medication) were offered referral to MBCT. ACQ-6, asthma quality of life questionnaire (AQLQ), hospital anxiety and depression scale (HADS-A/HADS-D), perceived stress scale (PSS), spirometry, FeNO and blood eosinophils, were recorded before and after the MBCT course and at 3- and 6-months post completion. Results: Sixty patients were considered for MBCT, 5 successfully completed (figure 1). In those who completed MBCT; median scores for PSS (21 to 13), HADS-A (11 to 6) and HADS-D (12 to 6) reduced by course end, and this was sustained at 6 months. An improvement in median ACQ-6 was seen at 3 months (2.3 from 3.3 [MCID 0.5]) and sustained at 6 months (2.8). An improvement in median AQLQ was seen at 3 months (4.8 from 3.3 [MCID 0.5]) but was not sustained. Conclusion: Successful completion of MBCT was low. In those who did complete, a reduction in stress, anxiety and depression was seen, with improvement in asthma control.

Background: Mepolizumab and prednisolone have overlapping anti-inflammatory effects so the clinical effects of prednisolone might be absent in stable patients on treatment with mepolizumab. Methods: We tested this hypothesis in a randomized, double-blind, placebo-controlled, crossover trial of prednisolone (0.5mg/kg/day for 2 weeks) after ≥12 weeks of mepolizumab. Results: Blood and sputum eosinophil count decreased post-prednisolone (-0.02x109/L, p=0.003; -10.5x109/L, p=0.004); differences compared to placebo were -0.02x109/L (p<0.001) and -6.5x109/L (p=0.002), respectively. Sputum eosinophil % of total reduced by 2.0% post-prednisolone (p=0.004). Compared to placebo, FeNO reduced by 13ppb post-prednisolone (p=0.001). A small between group difference was measured in FEV1 and FEF25-75 (0.1L, p=0.019; 0.2L, p=0.006). ACQ-5, VAS, mini-AQLQ and SGRQ did not change post-prednisolone. Conclusions: In patients with SEA treated with mepolizumab, prednisolone has no significant effects on symptoms or QoL but improves FEV1 and small airway function and reduces FeNO, potentially reflecting suppression of persisting IL-4/IL-13 pathways.

The United Kingdom National Review of Asthma Deaths (NRAD) recommends that patients who require ≥3 courses of oral corticosteroids (OCS) for exacerbations in the past year or those on British Thoracic Society (BTS) Step 4/5 treatment must be referred to a specialist asthma service. The aim of the study was to identify the proportion of asthma patients in primary care that fulfil NRAD criteria for specialist referral and factors associated with frequent exacerbations. A total of 2639 adult asthma patients from 10 primary care practices in Glasgow, UK were retrospectively studied between 2014 and 2015. Frequent exacerbators and short-acting β 2 -agonist (SABA) over-users were identified if they received ≥2 confirmed OCS courses for asthma and ≥13 SABA inhalers in the past year, respectively. Community dispensing data were used to assess treatment adherence defined as taking ≥75% of prescribed inhaled corticosteroid (ICS) dose. The study population included 185 (7%) frequent exacerbators, 137 (5%) SABA over-users, and 319 (12%) patients on BTS Step 4/5 treatment. Among frequent exacerbators, 41% required BTS Step 4/5 treatment, 46% had suboptimal ICS adherence, 42% had not attended an asthma review in the past year and 42% had no previous input from a specialist asthma service. Older age, female gender, BTS Step 4/5, SABA over-use and co-existing COPD diagnosis increased the risk of frequent exacerbations independently. Fourteen per 100 asthma patients would fulfil the NRAD criteria for specialist referral. Better collaboration between primary and secondary care asthma services is needed to improve chronic asthma care.

Objectives: Bronchial thermoplasty (BT) is a technology that reduces airway smooth muscle mass and airway hyper-reactivity; studies have demonstrated a durable reduction in asthma exacerbations after BT treatment compared to standard of care. This analysis aimed to assess the projected cost–effectiveness of BT for asthma in Scotland. Methods: A Markov model was adapted comparing BT to standard care among poorly controlled, severe persistent asthma patients. Costs of BT, healthcare utilization, quality of life and maintenance medications were estimated from country- and clinic-specific pricing. Clinical efficacy and health utilities were estimated from the double-blind AIR2 trial and adjusted with clinic-data. The models assessed patients for 5 years; incremental cost-effectiveness ratios (ICERs) are reported. Results: We project the QALY improvement with BT was 0.1830. Incremental costs of BT were £4,460, driven primary by savings produced from averted future asthma exacerbations. Incremental cost-effectiveness ratios for BT compared to standard of care were £24,426/QALY 95% CI :(BT Dominant – £76,450/QALY). Sensitivity Analysis suggests a 58.3% likelihood of the ICER being less than £30,000/QALY. Results were most sensitive to utilities and time horizon. Conclusions: Our findings are suggestive of projected cost-effectiveness of bronchial thermoplasty in severe, poorly-controlled asthma in Scotland. Real-world evidence of long term outcomes would help validate these results and further demonstrate cost-effectiveness.

Background: Exacerbations are an important cause of morbidity in asthma, particularly in severe disease. Previous studies have identified variables associated with exacerbations, although little is known about risk factors in real-life populations of severe asthma. Methods: We determined the influence of demographics, disease characteristics and biomarkers of inflammation on the frequency of severe exacerbations in 872 adults with refractory asthma recruited to the British Thoracic Society Severe Asthma Registry. Results: 717 (82%) of subjects gave a history of ≥2 severe exacerbations in the last year and almost two-thirds had ≥4. Frequent exacerbations were significantly associated with younger age, higher BMI, higher ACQ score, worse asthma quality-of-life score, higher anxiety and depression score, history of GORD, increased unscheduled GP/emergency visits and hospital admissions in the last year and higher exhaled nitric oxide (FeNO). Preliminary analyses revealed independent variables associated with an increased risk of exacerbations were ACQ score, unscheduled GP/emergency visits in the last year, number of hospital admissions in the last year and FeNO in the total population and blood eosinophils in those not on maintenance oral steroids. Conclusion: Over 80% of a real-life population of adults with severe refractory asthma gave a history of frequent (≥2) severe exacerbations in the last year. Clinical outcomes and inflammatory variables were independent risk factors for severe exacerbations in this population. Further analysis will examine whether combining the independent risk factors in a scoring system can identify those at greatest risk of severe exacerbations.

BACKGROUND:Asthma in the elderly as well as asthma of adult-onset has been associated with increased morbidity, but little is known specifically about the effects of age on clinical and inflammatory outcomes in severe refractory asthma. The aims of the study were to examine the effects of age [<65 versus ≥65 years] and age of onset of asthma [childhood-onset, <18 versus adult-onset, ≥18 years] on clinical and inflammatory variables in patients with severe asthma. METHODS:In 1042 subjects with refractory asthma recruited to the British Thoracic Society Severe Asthma Registry, we compared patient demographics, disease characteristics and biomarkers of inflammation in patients aged <65 years (n = 896) versus ≥65 years (n = 146) and onset at age <18 years (n = 430) versus ≥18 years (n = 526). RESULTS:Severe asthma patients aged ≥65 years had improved symptom control, better asthma quality of life and in the last year, less emergency visits and rescue oral steroid courses [3 (1-6) versus 5 (2-7), p < 0.001] than severe asthmatics aged <65 years. Blood eosinophils were lower in the elderly group. Patients with severe adult-onset asthma had similar symptom control, lung function and health-care utilization compared to severe childhood-onset asthma. Adult-onset asthmatics had higher blood eosinophils and were less atopic. CONCLUSIONS:Patients with severe refractory asthma aged ≥65 years exhibit better clinical and health care outcomes and have lower blood eosinophils compared to those aged <65 years. Severe refractory adult-onset asthma is associated with similar levels of asthma control, higher blood eosinophils and less atopy than severe refractory childhood-onset asthma.

Published information on the effectiveness of bronchial thermoplasty (BT) for severe asthma in ‘real life’ patients is limited. We compared safety and efficacy outcomes 12 months post procedure in 10 clinic patients and 15 patients recruited to clinical trials of BT at the same centre. Baseline asthma severity was greater in the clinic group. Adverse events were similar. Clinical improvements occurred in 50% of the clinic patients compared with 73% of the research patients.

Arachidonic acid metabolites are implicated in the pathogenesis of asthma although only limited information is available on the impact of current smoking history on these metabolites. The aim of the study was to examine the effect of smoking status on urinary, sputum, and plasma eicosanoid concentrations and relevant enzyme transcripts in asthma.

Introduction Endothelin-1 is implicated in airway contraction and remodelling in asthma and exacerbations in asthma and COPD We examined the endothelin system via the sputum transcriptome of subjects with severe stable asthma and COPD Methods Normalised sputum cell RNA U133+2 transcripts from the Glasgow COPD and Asthma Biomarker cohort were analysed by Kruskal Wallis and Mann Whitney testing Results EDN1 was elevated in COPD and non-smokers with asthma (p=0.034 & 0.062), ECE1 in COPD and smokers with asthma (p=0.001) and CPA3 in smokers (all groups)(p=0.002) and non-smokers with asthma compared to non smokers (p Conclusion The endothelin pathway appears to be activated in both asthma and COPD. Endothelin receptor blockade may provide additional benefits to current therapies in asthma and COPD.

BACKGROUND Severe refractory asthma affects all age-groups including the elderly. We examined the effect of age on clinical and inflammatory outcomes in patients recruited to the British Thoracic Society [BTS] Severe Asthma Registry. METHODS All subjects with refractory asthma [ATS criteria] ≥18 years old from the BTS Severe Asthma Registry were included in the analysis. RESULTS 754 subjects with refractory asthma were studied. Age was normally distributed (mean of 49.4 yrs [SD 13.6], range 18-82 yrs). Age correlated with a lower number of unscheduled emergency visits [-0.137; p=0.000], hospital admissions [r = -0.147; p=0.000], ITU admissions [r = -0.095; p=0.010], but asthma control was not affected [ACQ or ACT scores]. FEV 1 % predicted was lower with increasing age. Comparison of clinical and inflammatory outcomes in patients aged <65 years with those aged ≥65 years is shown in the table. Age < 65 years, n=655 Age ≥ 65 years, n=99 p value Smoking status %: current, former, never 10.3% , 25.3%, 64.2% 3.1%, 47.9%, 48.9% <0.001 Asthma control questionnaire score 3.4 (2.3, 4.1) 3.1 (2.5, 4.1) 0.446 Total asthma quality of life score 3.4 (2.5, 4.3) 3.5 (2.7, 4.5) 0.284 Unscheduled emergency visits in past yr 4 (2, 6.5) 3 (2, 6) 0.047 Rescue steroid courses past yr 5 (2, 7) 3 (2, 5.7) 0.001 Post BD FEV1 % predicted 78 (58, 94) 69 (54, 82) 0.023 Sputum neutrophil count % 50 (22, 75) 41 (22, 76) 0.628 Sputum eosinophil count % 2.9 (0.6, 10.1) 1.8 (0.4, 10.6) 0.617 Median [IQR] CONCLUSION Elderly patients with refractory asthma have poor symptom control and asthma quality of life, at levels similar to younger patients with refractory asthma. However, the number of severe exacerbations and unscheduled emergency visits is slightly less in the elderly group.

Parturition is associated with myometrial and cervical inflammation. The causes and consequences of this inflammatory response are not clear. Mast cells (MCs) are important inducers of allergic and non‐allergic inflammation, and their secreted products can induce myometrial contractions. Thus, mast cell activation has been hypothesized to have a role in initiating labor and/or driving labor‐associated inflammation. We report that small numbers of MCs expressing chymase and tryptase are present in the myometrium and cervix of pregnant women. Labor did not lead to any change in mast cell abundance in these tissues, but was associated with reduced expression of the mast‐cell regulator FcεR1A, indicative of a change in mast cell properties. This coincided with contraction‐dependent myocyte production of interleukin‐10 (IL‐10), a known suppressor of FcεR1A expression. MCs were also found in the uterine horn and cervical region of pregnant C57BL/6 mice, increasing in number in the cervix, but not the myometrium, with labor. As expected, these cells were absent from mast‐cell‐deficient Kit W−sh mice. Nonetheless, pregnant Kit W−sh mice showed no defects in the timing of labor induction or in the upregulation of leukocyte markers during labor. Thus, MCs are present in the uterus and cervix of humans and mice, and our mouse studies suggest that they do not have a vital role in the induction of labor, or in the promotion of labor‐associated inflammation.

Background: Matrix metalloproteinase (MMP)-12 has been implicated in the pathogenesis of both chronic obstructive pulmonary disease (COPD) and asthma. The influence of disease severity on sputum MMP-12 concentrations and activity is not known.Objectives: We sought to examine the relationship between disease severity assessed by means of lung function and computed tomography (CT) and induced sputum MMP-12 concentrations and activity in patients with asthma and COPD. Methods: In 208 subjects (109 asthmatic patients, smokers and never smokers, mild, moderate, and severe; 53 patients with COPD, smokers and exsmokers, mild, moderate, and severe; and 46 healthy control subjects, smokers and never smokers), we measured induced sputum MMP-12 concentrations (ELISA) and enzyme activity (fluorescence resonance energy transfer), sputum cell MMP12 mRNA expression (quantitative PCR [qPCR]), diffusing capacity for carbon monoxide (DLCO), and CT assessment of emphysema (percentage of low-attenuation areas at less 2950 Hounsfield units).Results: Sputum MMP-12 concentrations are greater in patients with COPD and smokers with asthma than in healthy nonsmokers (P = .003 and P = .035, respectively) but similar to those seen in healthy smokers. In patients with COPD, disease severity, when measured by means of CT-assessed emphysema, but not by means of spirometry or DLCO values, is directly associated with sputum MMP-12 concentrations and activity. In the asthma groups there is no significant association between disease severity and sputum MMP-12 concentrations or activity.Conclusions: Sputum MMP-12 concentrations and activity in patients with COPD are directly associated with the extent of emphysema measured by means of CT. This finding supports a role for MMP-12 in the pathogenesis of COPD and might suggest that blocking MMP-12 activity in patients with COPD could prevent the further development of emphysema. (J Allergy Clin Immunol 2012; 129: 655-63.)

BACKGROUND:Mast cells (MCs) are the classical mediators of allergy, however, their importance in the development of innate and adaptive immune responses is increasingly being recognized. Herein, the present MC literature is summarized, with particular focus on studies of MCs in the endometrium and myometrium, and their involvement in fertility, implantation, pregnancy and labour. METHODS:Recent developments in MC biology were identified by systematic searches of PubMed, Medline and Google Scholar from 2000 to November 2009. To specifically examine the role of MCs in fertility and pregnancy, we then performed a systematic review of English literature cited in the PubMed, Medline and Google Scholar databases, but extended the search period, from 1980 to January 2010 RESULTS:MCs can respond to immunoglobulin E-independent innate immune stimuli and are present within the endometrium, with activation and release of mediators occurring prior to menstruation and in association with endometriosis. With respect to pregnancy, MCs are redundant during blastocyst implantation and although their mediators can induce myometrial contractility, there is no epidemiological link of preterm birth with allergy, suggesting a non-essential role or robust regulation. In males, MCs are present in the testes and are increased in oligo- and azoospermia, with MC mediators directly suppressing sperm motility in a potentially reversible manner. CONCLUSIONS:MCs are prevalent in the female and male reproductive tract. However, whether MCs are absolutely required for a successful pregnancy or are fundamental to reproductive pathology, and thereby a therapeutic target, remains to be determined.