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Background: Although estimates of suboptimal adherence to oral corticosteroids in asthma range from 30% to 50%, no ideal method for measurement exists; the impact of poor adherence in severe asthma is likely to be particularly high. Research Questions: What is the prevalence of suboptimal adherence detected by self-reporting and direct measures? Is suboptimal adherence associated with disease activity? Study Design and Methods: Data were included from individuals with severe asthma taking part in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes) study and prescribed daily oral corticosteroids. Participants completed the Medication Adherence Report Scale, a five-item questionnaire used to grade adherence on a scale from 1 to 5, and provided a urine sample for analysis of prednisolone and metabolites by liquid chromatography-mass spectrometry. Results: Data from 166 participants were included in this study: mean (SD) age, 54.2 (± 11.9) years; FEV 1, 65.1% (± 20.5%) predicted; female, 58%; 37% completing the Medication Adherence Report Scale reported suboptimal adherence; and 43% with urinary corticosteroid data did not have detectable prednisolone or metabolites in their urine. Good adherence by both methods was detected in 49 of the 142 (35%) of participants in whom both methods were performed; adherence detection did not match between methods in 53%. Self-reported high adherers had better asthma control and quality of life, whereas directly measured high adherers had lower blood eosinophil levels. Interpretation: Low adherence is a common problem in severe asthma, whether measured directly or self-reported. We report poor agreement between the two methods, suggesting some disassociation between self-assessment of medication adherence and regular oral corticosteroid use, which suggests that each approach may provide complementary information in clinical practice.

Fungal sensitization is associated with poor asthma control. We aimed to determine the prevalence and factors associated with fungal asthma among Ugandan adults. Individuals aged ≥18 years with a new diagnosis of asthma in the last 12 months participating in the African Severe Asthma Program constituted the study population. Skin prick test results, clinical and demographic data were retrieved from the database, and serum Aspergillus fumigatus specific antibodies and total IgE were measured in stored blood. We enrolled 374 patients, median (IQR) age 34 (25–45) years, 286 (76.5%) females and 286 (76.5%) with severe asthma. Prevalence of Aspergillus fumigatus sensitization was 42.0% (95% CI: 37.1–47.0%), allergic bronchopulmonary aspergillosis (ABPA) 3.2% (1.8–5.5%), severe asthma with fungal sensitization (SAFS) 16% (12.7–20.1%) and allergic bronchopulmonary mycosis (ABPM) 2.9% (1.7–5.2%). Older age (55–64 years) (crude odds ratio (cOR) = 2.6), sensitization to at least one allergen (cOR = 9.38) and hypertension (cOR = 1.99) were significantly associated with Aspergillus sensitization, whereas tertiary education level (cOR = 0.29), severe depression (cOR = 0.15) and strong emotions (cOR = 0.47) were not. High occupational exposure to Aspergillus (cOR = 4.26) and contact with moulds (cOR = 14.28) were significantly associated with ABPA. Palpitations (cOR = 5.54), uncontrolled asthma (cOR = 3.54), eczema/dermatitis (cOR = 3.07), poor lung function (cOR = 2.11) and frequent exacerbations (cOR = 1.01) were significantly associated with SAFS. Eczema/dermatitis (cOR = 1.55) was significantly associated with ABPM, but cold weather trigger (cOR = 0.24) was not. Fungal asthma is a significant problem among Ugandans with asthma and should be particularly considered in individuals who remain uncontrolled despite optimal standard of care for asthma, as it is responsive to available and affordable oral antifungal therapy. Lay Summary This study showed that fungal asthma is a significant problem among Ugandans with asthma with a high prevalence. Fungal asthma should be considered in patients with uncontrolled asthma despite receiving optimal standard of care. This is the first modern attempt to define these endotypes of asthma in Africa.

Asthma is the most common chronic respiratory disease in the UK; however, the misdiagnosis rate is substantial. The lack of consistency in national guidelines and the paucity of data on the performance of diagnostic algorithms compound the challenges in asthma diagnosis. Asthma is a highly rhythmic disease, characterised by diurnal variability in clinical symptoms and pathogenesis. Asthma also varies day to day, seasonally and from year to year. As much as it is a hallmark for asthma, this variability also poses significant challenges to asthma diagnosis. Almost all established asthma diagnostic tools demonstrate diurnal variation, yet few are performed with standardised timing of measurements. The dichotomous interpretation of diagnostic outcomes using fixed cut-off values may further limit the accuracy of the tests, particularly when diurnal variability straddles cut-off values within a day, and careful interpretation beyond the ‘positive’ and ‘negative’ outcome is needed. The day-to-day and more long-term variations are less predictable and it is unclear whether performing asthma diagnostic tests during asymptomatic periods may influence diagnostic sensitivities. With the evolution of asthma diagnostic tools, home monitoring and digital apps, novel strategies are needed to bridge these gaps in knowledge, and circadian variability should be considered during the standardisation process. This review summarises the biological mechanisms of circadian rhythms in asthma and highlights novel data on the significance of time (the fourth dimension) in asthma diagnosis.

BACKGROUND: Electronic noses (eNoses) are emerging point-of-care tools that may help in the subphenotyping of chronic respiratory diseases such as asthma.OBJECTIVE: We aimed to investigate whether eNoses can classify atopy in pediatric and adult patients with asthma.METHODS: Participants with asthma and/or wheezing from 4 independent cohorts were included; BreathCloud participants (n = 429), Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes adults (n = 96), Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes pediatric participants (n = 100), and Pharmacogenetics of Asthma Medication in Children: Medication with Anti-Inflammatory Effects 2 participants (n = 30). Atopy was defined as a positive skin prick test result (≥3 mm) and/or a positive specific IgE level (≥0.35 kU/L) for common allergens. Exhaled breath profiles were measured by using either an integrated eNose platform or the SpiroNose. Data were divided into 2 training and 2 validation sets according to the technology used. Supervised data analysis involved the use of 3 different machine learning algorithms to classify patients with atopic versus nonatopic asthma with reporting of areas under the receiver operating characteristic curves as a measure of model performance. In addition, an unsupervised approach was performed by using a bayesian network to reveal data-driven relationships between eNose volatile organic compound profiles and asthma characteristics.RESULTS: Breath profiles of 655 participants (n = 601 adults and school-aged children with asthma and 54 preschool children with wheezing [68.2% of whom were atopic]) were included in this study. Machine learning models utilizing volatile organic compound profiles discriminated between atopic and nonatopic participants with areas under the receiver operating characteristic curves of at least 0.84 and 0.72 in the training and validation sets, respectively. The unsupervised approach revealed that breath profiles classifying atopy are not confounded by other patient characteristics.CONCLUSION: eNoses accurately detect atopy in individuals with asthma and wheezing in cohorts with different age groups and could be used in asthma phenotyping.

IntroductionAsthma is a heterogeneous disease with poorly defined phenotypes. Patients with severe asthma often receive multiple treatments including oral corticosteroids (OCS). Treatment may modify the observed metabotype, rendering it challenging to investigate underlying disease mechanisms. Here, we aimed to identify dysregulated metabolic processes in relation to asthma severity and medication.MethodsBaseline urine was collected prospectively from healthy participants (n=100), patients with mild-to-moderate asthma (n=87) and patients with severe asthma (n=418) in the cross-sectional U-BIOPRED cohort; 12–18-month longitudinal samples were collected from patients with severe asthma (n=305). Metabolomics data were acquired using high-resolution mass spectrometry and analysed using univariate and multivariate methods.ResultsA total of 90 metabolites were identified, with 40 significantly altered (p−20), OCS-treated asthmatic patients differed significantly from non-treated patients (p=9.5×10−4), and longitudinal metabotypes demonstrated temporal stability. Carnitine levels evidenced the strongest OCS-independent decrease in severe asthma. Reduced carnitine levels were associated with mitochondrial dysfunction via decreases in pathway enrichment scores of fatty acid metabolism and reduced expression of the carnitine transporter SLC22A5 in sputum and bronchial brushings.ConclusionsThis is the first large-scale study to delineate disease- and OCS-associated metabolic differences in asthma. The widespread associations with different therapies upon the observed metabotypes demonstrate the need to evaluate potential modulating effects on a treatment- and metabolite-specific basis. Altered carnitine metabolism is a potentially actionable therapeutic target that is independent of OCS treatment, highlighting the role of mitochondrial dysfunction in severe asthma.

Patients suspected of ventilator-associated lower respiratory tract infections (VA-LRTIs) commonly receive broad-spectrum antimicrobial therapy unnecessarily. We tested whether exhaled breath analysis can discriminate between patients suspected of VA-LRTI with confirmed infection, from patients with negative cultures. Breath from 108 patients suspected of VA-LRTI was analysed by gas chromatography-mass spectrometry. The breath test had a sensitivity of 98% at a specificity of 49%, confirmed with a second analytical method. The breath test had a negative predictive value of 96% and excluded pneumonia in half of the patients with negative cultures. Trial registration number: UKCRN ID number 19086, registered May 2015.

Summary Background BNT162b2 mRNA and ChAdOx1 nCOV-19 adenoviral vector vaccines have been rapidly rolled out in the UK from December, 2020. We aimed to determine the factors associated with vaccine coverage for both vaccines and documented the vaccine effectiveness of the BNT162b2 mRNA vaccine in a cohort of health-care workers undergoing regular asymptomatic testing. Methods The SIREN study is a prospective cohort study among staff (aged ≥18 years) working in publicly-funded hospitals in the UK. Participants were assigned into either the positive cohort (antibody positive or history of infection [indicated by previous positivity of antibody or PCR tests]) or the negative cohort (antibody negative with no previous positive test) at the beginning of the follow-up period. Baseline risk factors were collected at enrolment, symptom status was collected every 2 weeks, and vaccination status was collected through linkage to the National Immunisations Management System and questionnaires. Participants had fortnightly asymptomatic SARS-CoV-2 PCR testing and monthly antibody testing, and all tests (including symptomatic testing) outside SIREN were captured. Data cutoff for this analysis was Feb 5, 2021. The follow-up period was Dec 7, 2020, to Feb 5, 2021. The primary outcomes were vaccinated participants (binary ever vacinated variable; indicated by at least one vaccine dose recorded by at least one of the two vaccination data sources) for the vaccine coverage analysis and SARS-CoV-2 infection confirmed by a PCR test for the vaccine effectiveness analysis. We did a mixed-effect logistic regression analysis to identify factors associated with vaccine coverage. We used a piecewise exponential hazard mixed-effects model (shared frailty-type model) using a Poisson distribution to calculate hazard ratios to compare time-to-infection in unvaccinated and vaccinated participants and estimate the impact of the BNT162b2 vaccine on all PCR-positive infections (asymptomatic and symptomatic). This study is registered with ISRCTN, number ISRCTN11041050, and is ongoing. Findings 23 324 participants from 104 sites (all in England) met the inclusion criteria for this analysis and were enrolled. Included participants had a median age of 46·1 years (IQR 36·0–54·1) and 19 692 (84%) were female; 8203 (35%) were assigned to the positive cohort at the start of the analysis period, and 15 121 (65%) assigned to the negative cohort. Total follow-up time was 2 calendar months and 1 106 905 person-days (396 318 vaccinated and 710 587 unvaccinated). Vaccine coverage was 89% on Feb 5, 2021, 94% of whom had BNT162b2 vaccine. Significantly lower coverage was associated with previous infection, gender, age, ethnicity, job role, and Index of Multiple Deprivation score. During follow-up, there were 977 new infections in the unvaccinated cohort, an incidence density of 14 infections per 10 000 person-days; the vaccinated cohort had 71 new infections 21 days or more after their first dose (incidence density of eight infections per 10 000 person-days) and nine infections 7 days after the second dose (incidence density four infections per 10 000 person-days). In the unvaccinated cohort, 543 (56%) participants had typical COVID-19 symptoms and 140 (14%) were asymptomatic on or 14 days before their PCR positive test date, compared with 29 (36%) with typical COVID-19 symptoms and 15 (19%) asymptomatic in the vaccinated cohort. A single dose of BNT162b2 vaccine showed vaccine effectiveness of 70% (95% CI 55–85) 21 days after first dose and 85% (74–96) 7 days after two doses in the study population. Interpretation Our findings show that the BNT162b2 vaccine can prevent both symptomatic and asymptomatic infection in working-age adults. This cohort was vaccinated when the dominant variant in circulation was B1.1.7 and shows effectiveness against this variant. Funding Public Health England, UK Department of Health and Social Care, and the National Institute for Health Research.

Inflammation is strongly implicated in both injury and repair processes occurring after stroke. In this exploratory study we assessed the feasibility of repeated sampling of exhaled volatile organic compounds and performed an untargeted metabolomic analysis of plasma collected at multiple time periods after stroke. Metabolic profiles were compared with the time course of the inflammatory markers C-reactive protein (CRP) and interleukin-6 (IL-6). Serial breath sampling was well-tolerated by all patients and the measurement appears feasible in this group. We found that exhaled decanal tracks CRP and IL-6 levels post-stroke and correlates with several metabolic pathways associated with a post-stroke inflammatory response. This suggests that measurement of breath and blood metabolites could facilitate development of novel therapeutic and diagnostic strategies. Results are discussed in relation to the utility of breath analysis in stroke care, such as in monitoring recovery and complications including stroke associated infection.

Asthma, the most common chronic respiratory disease, is frequently misdiagnosed, and accounts for a significant proportion of healthcare expenditure. This has driven the National Institute for Health and Care Excellence (NICE) in the United Kingdom (UK) to produce recent guidance; in places, this contrasts to that of the British Thoracic Society/Scottish Intercollegiate Guideline Network (BTS/SIGN), which have been producing their own guidance since 2003. Here we review the history of asthma diagnostic guidelines, and compare and review the evidence behind them, in adults and in children. We discuss the definitions of asthma and how these drive the concepts behind diagnostic strategies. We anticipate future directions in asthma diagnosis which will take into account the concepts of personalised medicine and disease endotypes. We also consider the utility of tests in use now and in the future, in particular novel tests relating to small airway inflammation and obstruction.

BackgroundThe sensitivity of patient-reported outcomes (PROs) to detect the effects of treatment change depends on the match between the change in items of the PRO and the change that takes place in a sample of people. The aim of this study is to compare the sensitivity of different PROs in detecting changes following the initiation of biologic treatment in asthma. Methods: Patients starting a biologic treatment as part of clinical care completed the Asthma Control Questionnaire (ACQ-6), the Severe Asthma Questionnaire (SAQ and SAQ-global scores) and the EQ5D (EQ-5D-5L and EQ5D-VAS) at baseline. They completed the ACQ-6, SAQ, SAQ-global and a retrospective global rating of change (GRoC) scale at weeks 4, 8 and 16 and completed the EQ-5D-5L and EQ5D-VAS at week 16. The SAQ-global and EQ5D-VAS differ but both are single item 100-point questions. Sensitivity was measured by Cohen’s D effect size at each of the three time points. Results: 110 patients were recruited. Depending on the time of assessment, effect size varied between 0.45 and 0.64 for the SAQ, between 0.50 and 0.77 for the SAQ-global; between 0.45 and 0.69 for ACQ-6; between 0.91 and 1.22 for GRoC; 0.32 for EQ-5D-5L and 0.49 for EQ5D-VAS. Conclusion: The sensitivity to change of a questionnaire varies with the time of measurement. The three asthma-specific prospective measures (SAQ, SAQ-global and ACQ-6) have similar sensitivity to change. The single-item EQ5D-VAS was less sensitive than the asthma specific measures and less sensitive than the single-item SAQ-global. The EQ-5D-5L was least sensitive.

Background: understanding why patients with severe asthma do not follow healthcare provider (HCP) advice to adjust treatment is critical to achieving personalised disease management.Methods: we reviewed patient choice to follow HCP advice to adjust asthma treatment in 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.Results: of 1572 treatment advisories (301 participants), instructions were followed in 1377 cases (87.6%). Patients were more likely to follow advice to remain on 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 associated belonging to an ethnic minority group (OR: 3.10; 95% CI: 1.68, 5.73) and prior study medication changes (≥2 OR: 2.77, 95% CI: 1.51, 5.10) with failure to follow treatment advice. In contrast, emergency room attendance in the prior year (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) when compared to those requested to maintain treatment. Centre was also an important determinant regarding the likelihood of patients to follow treatment advice.Conclusions: belonging to an ethnic minority group and multiple prior treatment adjustments were associated with not following HCP treatment advice. Patients also responded differently to HCP advice across UK specialist centres. These findings have implications for generalisability for models of care in severe asthma and require further focussed studies.

Background Clinicians are increasingly recognizing severe asthma patients in whom biologics and other add-on therapies lead to dramatic improvement. Currently, there is no agreed-upon super-responder (SR) definition. Objective To survey severe asthma experts using a modified Delphi process, to develop an international consensus-based definition of a severe asthma SR. Methods The Delphi panel was composed of 81 participants (94% specialist pulmonologists or allergists) from 24 countries and consisted of three iterative online voting rounds. Consensus on individual items, whether acceptance or rejection, required at least 70% agreement by panel members. Results Consensus was achieved that the SR definition should be based on improvement across three or more domains assessed over 12 months. Major SR criteria included exacerbation elimination, a large improvement in asthma control (two or more times the minimal clinically important difference), and cessation of maintenance of oral steroids (or weaning to adrenal insufficiency). Minor SR criteria were composed of a 75% exacerbation reduction, having well-controlled asthma, and 500 mL or greater improvement in FEV1. The SR definition requires improvement in at least two major criteria. In the future, the SR definition should be expanded to incorporate quality of life measures, although current tools can be difficult to implement in a clinical setting and further research is needed. Conclusions This international consensus-based definition of severe asthma SRs is an important prerequisite for better understanding SR prevalence, predictive factors, and the mechanisms involved. Further research is needed to understand the patient's perspective and to measure quality of life more precisely in SRs.

Background Diagnosis of fungal allergies in asthma remains problematic in low-and middle-income countries due to non-availability of point-of-care testing. In this study, we aimed to evaluate the performance of an Aspergillus immunochromatographic technology (ICT) IgG/M lateral flow device (LFD) for the serological diagnosis of allergic bronchopulmonary aspergillosis (ABPA) and severe asthma with fungal sensitisation (SAFS) among Ugandan adult asthmatics. Methods 374 adult (aged ≥18years) asthmatics in the African Severe Asthma Program study, Ugandan site constituted the study population. ABPA and SAFS were diagnosed according to standard criteria. Asthmatics who did not meet the above criteria constituted a control group. The LFD tests were performed and read according to manufacturer’s instructions. Results ABPA was found in 12/374 (3.2%) and SAFS in 60/374 (16%) participants. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for the Aspergillus ICT for the diagnosis of ABPA were 0.0%, 96.4%, 0.0% and 96.7% respectively, and for SAFS 6.7%, 97.1%, 30.8% and 84.5% respectively. False positive and negative rates were 3.5% and 3.2% for ABPA and 2.4% and 14.9% for SAFS, respectively. Patients with a positive LFD significantly had higher median Aspergillus fumigatus-specific IgE levels compared to those with negative LFD (median: 0.06 kUA/l VS 0.03 kUA/L, P = 0.011). Conclusion The Aspergillus ICT IgG/M LFD had a poor diagnostic performance for the diagnosis of both ABPA and SAFS. Its greatest value may be in distinguishing chronic and allergic aspergillosis in Africa.

Respiratory viral infections are a significant cause of morbidity in asthma [1]. Patients with severe asthma were assumed to be at greater risk from novel coronavirus-2 (COVID-19) infection. In the global response to the COVID-19 pandemic, multiple countries enacted social containment policies. In the UK a countrywide lockdown occurred in March 2020, with stringent self-isolation (“shielding”) advice for high-risk patients, including people with 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 α 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 corticosteroid 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 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 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.

Objective: Asthma diagnostic guidelines from NICE mandate up to five tests in a sequential algorithm, three of which are aerosol generating procedures (AGPs) [spirometry, reversibility (BDR), bronchial challenge testing (BCT)] The SARS-CoV-2 pandemic has resulted in significant restrictions to AGPs, highlighting the urgent need for an alternative diagnostic model We aimed to develop a 'rule-in' diagnostic model using non AGPs [chest auscultation, exhaled nitric oxide (FeNO), two week-peak flow variability (PEFv) and serum eosinophils (eos)] which would enable GPs to confidently diagnose asthma in a subgroup of patients and reduce the need for AGPs and onward referral Methods: Symptomatic but untreated patients with physician-suspected asthma were referred into the RADicA (Rapid Access Diagnostics in Asthma) study Patients underwent clinical consultation followed by tests including FeNO, spirometry, BDR, PEFv, BCT, and eos Asthma diagnosis was made on the basis of all available information (including response to eight weeks inhaled corticosteroid treatment) by a panel of respiratory physicians Data from patients coded as 'definite asthma' or 'not asthma' were evaluated, individually and in combination in order to investigate which non-AGP tests could predict asthma PEFv was classified as a non-AGP because it is not performed in the clinical setting Results: Of 61 symptomatic adults [median (IQR) age 32(26-44)yrs, 62% female] 61% had 'definite asthma' by expert panel decision Each of the four non-AGP tests were able to predict asthma with low sensitivity and high specificity (figure 1) Using established cut-offs (PEFv>20%, FeNO≥40ppb, eos>0 4 × 109/L), an algorithm which simply required the presence of two or more positive tests was able to 'rule-in' asthma with a specificity (95% CI) of 100(78-100)%, sensitivity 20(8-39)% In comparison using all available tests required for the NICE algorithm resulted in a sensitivity of 53(34-72)%, specificity 100(79-100)% Conclusion: Four simple non-AGPs could be used in primary care to accurately diagnose asthma The majority of patients (Figure presented) with negative tests would still require further investigation, and so it is clear that AGPs, or novel alternatives, are still required for the diagnosis of asthma in most patients

Background Differences in response to adrenergic b2 (ADRb2) agonists in severe asthma can be attributed to genetic variation, with 49 different single-nucleotide polymorphisms (SNPs) in one exon on chromosome 5q31–33 of the ADRb2 receptor gene. The Arg16Gly/Gln27Glu polymorphisms enforces differential agonist-stimulated receptor down-regulation in airway smooth muscle cells. The Thr164Ile polymorphism reduces receptor-binding affinity. In this systematic review we aimed to determine which of these polymorphisms of the ADRb2 gene are associated with severe adult asthma. Methods Two independent reviewers carried out the systematic search on PubMed and Cochrane Library databases using appropriate MESH key words on 1st July 2020. Asthma severity was determined following GINA and ATS/ERS 2019 guidelines and the critical appraisal skills programme (CASP) quality assessment tool was used to assess quality of articles. Relevant data including the ADRb2 polymorphisms and location, clinical effect and patient demographics were recorded. Results From an initial 245 articles, 25 were selected for this systematic review (figure 1): twelve were population-wide studies looking at association of single nucleotide polymorphisms (SNPs) with severe asthma phenotype; and thirteen were pharmacogenetics studies. The most common SNP associated with severe asthma was Arg16Gly, Gln27Glu. Allele frequency varied between Caucasians Gly16 (0.61)/Gln27 (0.57) versus Asians, Gly16 (0.40)/Gln27 (0.80) with asthma. The rare variants Thr164Ile and −376 In-Del were observed in Hispanics/African- Americans. SNPs with clinical implications in severe asthma: Arg16Gly, Gln27Glu: associated with down–regulation and uncoupling of β 2–adrenoreceptors, bronchial hyper responsiveness and decreased bronchodilator response. Gly16: associated with bronchodilator desensitisation and found in increased frequency in severe (70%) versus mild asthma (59%) and non–asthmatic controls (60%) (two studies). Gly16, Gln27, Ile164 were not risk factors for fatal/near–fatal asthma in Caucasians. Thr164Ile: Salbutamol refractoriness in Indians & African Americans (two studies). Increases likelihood of severe asthma exacerbation requiring hospitalisation in Caucasians −376 In–Del rare variant: poor symptom control/increased exacerbations requiring hospitalisation in African Americans. Conclusions ADRb2 polymorphisms have been associated with varied adverse disease characteristics in severe asthma, but replication of findings is needed, as is investigation of clinical impact for example in guiding therapeutic strategies.

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 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.

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 (Table presented) 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 The defining feature of asthma is variability in symptoms and airflow obstruction over time. Historical variation in forced expiratory volume in 1 second (FEV1) is a diagnostic indicator in asthma. We aimed to investigate the variability of spirometry measurements between diagnostic visits in untreated patients with a high clinical suspicion of asthma. Method Patients with symptoms consistent with asthma, but diagnosis- and treatment-naive, were prospectively recruited from primary care. Clinical history and examination were carried out, then spirometry and fractional exhaled nitric oxide (FeNO) measured on two visits. An asthma diagnosis was confirmed or refuted using full diagnostic testing and assessment of response to inhaled corticosteroids. Results Of 116 patients, 81% completed spirometry measurements on both clinical visits [58.5% adults, 43.6% male, mean (SD) age: 23.5 (15.6) years]. The median (IQR) duration between clinics was 21 (15–28) days. Of these, 59.6% had definite asthma, 30.9% did not have asthma, and 9.5% could not be classified. The change in FEV1:FVC and% change in FEV1 (difference between-visits/the lower measurement) was higher in asthmatics [median (IQR): 2.9 (1.3–5.3)% and 6.9 (2.6–11.3)%, respectively] compared to non-asthmatics [1.6 (0.6–3.7)% and 4.3 (1.8–6.5)% respectively, p=0.02]. The% change in FEV1 correlated with% change in FENO between visits in adults (r=0.45, p=0.001). Seventeen (18%) patients had ≥12% change in FEV1 between visits, of which 76.5% were asthmatics (accounting for 23% of all asthma patients) and 11.8% were non-astmatics. Seven (of which 6 asthmatics) patients had FEV1:FVC straddling the fixed diagnostic cutoff (70%) between clinic visits. Conclusion Clinically meaningful variability in spirometry was observed in one-fifth of patients with confirmed but untreated asthma between clinical visits, and so may be useful in asthma diagnosis for a minority. This variability in airflow correlated with that in inflammation (FeNO). Validation of novel tests more sensitive to change in both parameters, and/or more targetted test-timing (e.g. morning/evening) may increase the utility of this diagnostic strategy.

Introduction Severe asthma patients were assumed to be at greater risk of morbidity from infection with the novel severe acute respiratory syndrome coronavirus (COVID-19), hence, in the UK, were advised to shield. Community data on COVID-19 infection in severe asthmatics is lacking. We assessed the burden of shielding, the impact of COVID-19 and the effect of asthma medication on the UK severe asthma population. Methods Adults previously consented to inclusion in the UK Severe Asthma Registry (UKSAR) across 14 centres were contacted in June 2020 to collect data on potential COVID-19 infection, asthma control and shielding. Electronic records, where available, were reviewed for confirmation. Data was combined with clinical data from the UKSAR. Univariate and multivariate logistic regression analyses were performed to identify risk factors for COVID-19 infection. Results 1365 patients were included. 1268 (93%) were advised to shield, 1131 (89%) patients who received shielding advice followed it. Men (OR 0.4, p=0.045) and those in non-shielding households (OR 0.27, p=0.001) were less likely to follow shielding advice. 544 (47%) of patients advised to shield reported worsening of mental health; females (OR 1.59, p=0.001) and those with history of anxiety or depression (OR 2.12 p=0.001) were at greater risk. 97 (7.1%) patients had suspected/confirmed COVID-19 infection, 19 (1.39%) PCR/serology confirmed infection, 13(0.95%) were hospitalised and 2 patients (0.15%) died (table 1). 918 (67%) were on biologic therapy, 515 (37%) maintenance oral corticosteroid (mOCS). Multivariate analysis showed neither biologic therapy (OR 0.73, p=0.165) nor mOCS (OR 1.18, p=0.427) increased the risk of COVID-19 infection. Patients on biologics were less likely to require an acute course of corticosteroids for asthma symptoms (OR 0.6, p=0.002) while patients on mOCS were more likely (OR 1.96 p≤0.001). Inhaled corticosteroids (ICS) were not associated with COVID-19 infection, including high dose (2000 mcg BDP equivalent) (OR 0.64, p=0.234). Hospitalised patients were on lower median doses of ICS vs non-hospitalised patients (1000 vs 2000 mcg BDP equivalent, p=0.002). Conclusion Hospitalisation and death occurred in small numbers in our severe asthma population. From this observational data, biologic agents for asthma were not associated with increased risk of COVID-19 infection or hospitalisation.

Background Asthma diagnostic guidelines require procedures with aerosol-generating potential (aerosol-generating procedures [AGPs]) to guide decision making. Restricted access to AGPs poses significant challenges in primary care and resource-poor countries, further amplified during the coronavirus disease 2019 pandemic. Objective To establish an approach to asthma diagnosis that does not require AGPs. Method Symptomatic yet untreated (beyond as-required bronchodilator use) adults with clinician-suspected asthma and maximum 10 pack year smoking history were recruited. Clinical history, physical examination, spirometry with bronchodilator reversibility, home peak flow monitoring, and bronchial challenges were performed, and fractional exhaled nitric oxide and serum eosinophils measured. Tests were then repeated following treatment with inhaled corticosteroids before an asthma diagnosis was confirmed or refuted by an expert panel. Results A total of 65 adults (mean age, 34.8 ± 12.2 years) were recruited. Five were excluded as “unclassifiable,” because of borderline results or missing data. Of the remainder, 36 were diagnosed with asthma and 24 were not. Using data from non-AGPs only (wheeze on auscultation and blood eosinophilia) and home peak flow variability, a “rule-in” diagnostic model provided comparable discriminative ability to the application of established guidelines. Clinical suspicion of asthma together with at least 1 positive non-AGP test result provided a sensitivity of 55%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 60%. Application of this model reduced the need for spirometry-based tests by one-third. Conclusions The proposed diagnostic algorithm may be clinically useful in “ruling-in” asthma in adults when access to AGPs is limited. This algorithm is not suitable for those with low clinical probability, with a significant smoking history, or where alternative diagnoses are more likely. This pragmatic approach to asthma diagnosis merits prospective validation.

Introduction. Sarcoidosis is a chronic granulomatous disease of unknown aetiology with a variable clinical course and prognosis. There is an urgent need to identify new and novel biomarkers to help differentiate between clinical phenotypes and guide clinical decisions with respect to commencing and monitoring treatment. Across the spectrum of respiratory disease there has been a growing interest in the role of breath-based biomarkers given their non-invasive nature and ability to repeat sampling with ease for serial monitoring. Soluble interleukin-2 receptor (sIL2R) in bronchoalveolar lavage and serum correlates with disease activity in sarcoidosis; however, no previous study has evaluated sIL2R in exhaled breath. Objectives. The main aim of this cross-sectional case-controlled pilot study was to determine the concentration of sIL2R in exhaled breath condensate (EBC) from patients with recently diagnosed sarcoidosis compared to healthy volunteers and to establish, if present, if this correlated with markers of disease activity, pulmonary function tests and serological markers used in current clinical practice. Methods. Paired serum and EBC samples were collected from twelve treatment naïve patients with histologically proven sarcoidosis diagnosed during the previous six months and compared to twelve healthy volunteers matched for age and gender. Results. Mean concentration of serum sIL2R was significantly elevated in participants with sarcoidosis compared to healthy controls (1584.3 ± 489.1 versus 874.2 ± 235.7 pg mL−1; p = 0.001). Soluble interleukin-2 receptor in EBC was detectable in only five subjects including three participants with sarcoidosis. The range of sIL2R across all five samples was 148.0–288.2 pg mL−1 with the two highest concentrations observed in two participants with sarcoidosis. There was no significant difference observed in EBC sIL2R between sarcoidosis and healthy controls (p = 0.71). No apparent correlations were observed between EBC sIL2R and radiological stage, pulmonary function tests or serological markers. Conclusion. Soluble interleukin-2 receptor is detectable in EBC; however, the findings from our study do not support its role as a diagnostic marker in sarcoidosis. Further research is required to evaluate its prognostic utility.

Prior to the COVID‐19 pandemic, laryngoscopy was the mandatory gold standard for the accurate assessment and diagnosis of inducible laryngeal obstruction. However, upper airway endoscopy is considered an aerosol‐generating procedure in professional guidelines, meaning routine procedures are highly challenging and the availability of laryngoscopy is reduced. In response, we have convened a multidisciplinary panel with broad experience in managing this disease and agreed a recommended strategy for presumptive diagnosis in patients who cannot have laryngoscopy performed due to pandemic restrictions. To maintain clinical standards whilst ensuring patient safety, we discuss the importance of triage, information gathering, symptom assessment and early review of response to treatment. The consensus recommendations will also be potentially relevant to other future situations where access to laryngoscopy is restricted, although we emphasize that this investigation remains the gold standard.

Background: The burden of living with severe asthma is under-appreciated by clinicians due to a past lack of health related quality of life (HRQoL) measures designed for these patients. The Severe Asthma Questionnaire (SAQ) is a new valid HRQoL disease-specific severe asthma scale. The EQ5D is a generic HRQol scale. Methods: We collected cross-sectional data in patients (≥ 18 years old) from 6 UK severe asthma centres. The SAQ and EQ-5D-5L were compared as a function of exacerbations and systemic steroid burden in the preceding 12 months. Results: 395 patients completed the SAQ and 309 the EQ5D. Patients with ≥4 exacerbations compared with 0.70, p Conclusions: This study quantifies the increased HRQoL deficit of patients living with severe asthma who have higher compared to lower exacerbations and have higher compared to lower cumulative steroid burden at clinically relevant cut-off points. The difference in deficit is demonstrated for both disease specific and generic HRQol scales.

Introduction: Mepolizumab is an anti-IL-5 monoclonal antibody indicated for the treatment of severe asthma. We have evaluated patient outcomes over the first 18-months of treatment, and investigated comorbidities in non-responders. Method: Data from 120 patients were analysed. Patients stopping within 12 months underwent further clinical assessment. Results: 86(72%) of patients responded, achieving a 50% reduction in daily prednisolone dose and/or annual exacerbation rate. 20 stopped due to non-response, five due to side effects and eight due to patient choice. In responders, 12-month improvements in prednisolone use, exacerbation rate, asthma quality of life questionnaire(AQLQ) and asthma control questionnaire(ACQ) were maintained at 18-months(table1). Non-responders had lower median (IQR) baseline blood eosinophils than responders [0.07(0.02-0.24)vs 0.17(0.05-0.32),p = 0.048], and a 12-month rise in mean (SD) FeNO [35(33)to50(20)ppb,p = 0.012]. Significant comorbidity was present in 62%(n=28) of patients stopping treatment [tracheomalacia(31%), bronchiectasis(21%), inducible laryngeal obstruction(13%), breathing pattern disorder(27%), combination(21%)]. Conclusion: 12-month benefit from mepolizumab is maintained at 18 months. Treatment-failures may have a phenotype driven more by the IL4/IL13 pathway. Over half of the patients who failed to respond or stopped treatment had significant respiratory comorbidity.

Introduction: Increasing corticosteroids (CS) to control asthma symptoms and exacerbations has potential for inappropriately high and difficult to down-titrate CS doses. Aims and Objectives: We tested whether a T2 biomarker-based strategy (BS) to guide CS reduction (factoring fractional exhaled nitric oxide (FeNO), blood eosinophils, serum periostin) vs. a symptom-based control would see fewer exacerbations and better asthma control and lung function. Methods: In this randomised (4:1/BS:control), single-blind parallel group trial, patients (pts) with severe asthma and FeNO Results: In the intention-to-treat population (240 BS vs. 61 control pts), the proportion of BS pts on lower CS dose at Wk48 was 28.4% vs. 18.5% in the controls (adjusted OR: 1.71; 95%CI 0.80, 3.63; p=0.165). In the per protocol (PP) population (n=121), significantly more pts had lower CS doses at Wk48 in the BS vs. the control group (30.7% vs. 5.0% (OR: 11.48; 95%CI 1.35, 97.83; p=0.026). Failure to follow treatment advice was the main reason for ITT and PP population differences. There was no difference in secondary outcomes between study arms. Conclusion: Biomarker based CS adjustment did not result in a greater proportion of pts reducing CS vs. control, probably because many pts did not follow treatment advice. The biomarker strategy seemed beneficial in pts where symptoms and T2 biomarker profile were discordant.

Introduction: Adherence to maintenance inhaled therapy and correct inhaler technique are essential for good asthma control. In our adult severe asthma new patient multidisciplinary assessment a pharmacy-led medication review confirms adherence to preventer inhalers and prednisolone courses using prescribing records. This enables an accurate assessment of the severity of the patient’s asthma and suitability for biologic therapies. Aim: To evaluate disparity between patient-reported and confirmed adherence to inhaled therapy and prednisolone courses over a 12 month period. Method: Data from 50 consecutive new patient assessments were collected and analysed. Results: 42 (84%) patients reported good adherence and 93% of these (n = 39) had good adherence confirmed by prescription pickup rates over 80%. 12% of patients made one critical error in inhaler technique, and 52% made two or more. Combined good adherence with good technique was only seen in 30% of cases. Patients reported median (IQR) 3.58 (1.00-5.00) prednisolone courses in the previous year; 2.96 (1.00-4.25) were confirmed (Wilcoxon’s p=0.005 for difference). This reduction in confirmed exacerbation rate led to ineligibility for a biologic in 4 cases (8%). Conclusion: Patient reported adherence to inhalers was similar to pharmacy confirmed adherence in our severe asthma cohort. Optimising adherence and technique with specialist pharmacist support plays a vital role in optimising asthma control, and is likely to be needed for the majority of patients. Patients may over report prednisolone courses which can lead to unnecessary changes to asthma treatment and unnecessary biologic therapy.

Background: Fractional exhaled nitric oxide (FeNO) is a common biomarker used in the diagnosis and monitoring of asthma in children. Little is known about the variability of FeNO beyond one week in healthy or asthmatic children. We investigated the medium-term variability of FeNO in children with and without asthma. Methods: Children from the Manchester Asthma and Allergy Study attended follow-up at the age of 11 years on two occasions. Skin prick testing was completed. FeNO and spirometry were measured on each visit. Clinically significant FeNO variability (∆FeNO) was defined according to ATS 2011 recommendations. Results: Of the 425 children who had FeNO measured on two occasions [median (IQR) 20 (9-47) days apart], 11% had current asthma and 33% were atopic. Mean (SD) FeNO in children with current asthma [37.5 (31.6) ppb] or atopy [34.6 (32.2) ppb] was higher than those without [16.7 (21.0) ppb and 10.9 (9.4) ppb, respectively, p Conclusion: Increased medium-term variability of FeNO were observed in children with current wheeze and atopy compared to those without. History of hayfever, asthma medication use and atopy were independent confounding factors for clinically significant variability in FeNO.

Background: The American Food and Drug Administration (FDA) guidelines require a scale measuring quality of life (QOL) to comprise QOL items but not symptoms items. The mini-Asthma Quality of Life Questionnaire (miniAQLQ) was developed before those guidelines were published and the authors identified 5/15 items as symptom items (items 1, 4, 6, 8, 10), items similar to those of a commonly used measure of asthma symptoms, the Asthma Control Questionnaire (ACQ). The aim was to examine the correlations between the ACQ, the miniAQLQ, the five miniAQLQ symptoms, the remaining 10 QOL items of the miniAQLQ and the Severe Asthma Questionnaire (SAQ), a QOL scale consistent with the FDA guidelines. Methods: In a cross-sectional survey, 395 patients with severe asthma from 6 UK specialist asthma centres completed the SAQ, ACQ and the miniAQLQ. Results: The miniAQLQ symptom and miniAQLQ QOL item correlations with the ACQ are significantly different, p Conclusion: Correlations and sample sizes are shown in Table 1. The symptom items of the miniAQLQ are highly correlated with the ACQ because the symptom items of the miniAQLQ are very similar with items in the ACQ. The use of ACQ and miniAQLQ together is likely to be of limited value. Symptoms contribute to QOL but are separate from it both statistically and conceptually.

Fractional exhaled nitric oxide (FeNO) is a single-breath test used in asthma diagnosis and management. Whilst a number of studies in mild to moderate asthma have demonstrated excellent repeatability of FeNO by assessing intra-device reproducibility from consecutive blows [1–3], the between-session and diurnal variability have been inconsistent [4–9]. Asthma is a highly variable disease. The excessive diurnal variability in airflow obstruction is a marker for disease severity, poor control and mortality. Diurnal variability of FeNO is also a predictor for poor asthma control [8]. We have demonstrated that FeNO has a significant time-of-the-day difference with a median of 12 parts per billion (ppb) between peak and trough readings within a 24-hour cycle in stable mild/moderate asthma [10]; whether this same-day variation is clinically significant in the diagnosis and management of asthma remains unclear. FeNO has been readily used in the monitoring of severe asthma, but its same-day reproducibility as a single-breath test is unknown in this group. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Wang has nothing to disclose. Conflict of interest: Dr. Alahmadi has nothing to disclose. Conflict of interest: Dr. Niven has nothing to disclose. Conflict of interest: Stephen J Fowler has no conflict of interest

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 μg 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; FEV 1, 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 (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.

Mepolizumab was the first anti-interleukin-5 (anti-IL-5) monoclonal antibody licensed for the treatment of severe asthma, recommended as add-on treatment in patients with frequent exacerbations or requiring maintenance oral corticosteroids (OCS) despite optimal inhaled therapy [1, 2]. In clinical trials it reduced exacerbation rates and OCS use, and improved lung function, asthma control and health-related quality of life over the first year of treatment [3–6]. Current guidance states that anti-IL-5 biologics should be continued long term if benefit is demonstrated over the first year, yet little is known about whether initial responses are sustained, or whether they can be predicted by clinical characteristics., This study found that 30% of patients stopped mepolizumab in the second year of treatment. Those with a sustained response had lower blood eosinophils and better asthma control questionnaire scores prior to starting mepolizumab. https://bit.ly/3ChWN63

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) originated from Wuhan, China, at the end of 2019 and has rapidly spread to cause a global pandemic associated with substantial morbidity and mortality.1 By mid-April 2020, nearly two million confirmed cases of COVID-19 had been reported from 210 countries, resulting in over 100 000 deaths. Similar to previous novel coronavirus diseases (severe acute respiratory syndrome and Middle East respiratory syndrome), COVID-19 often leads to severe respiratory failure, and it might be assumed that patients with chronic respiratory diseases such as asthma would be at higher risk of developing severe illness. It is perhaps surprising then that, thus far, no clear association has been found2–5; asthma was reported in less than 1% of patients with COVID-19 from Wuhan,2 3 and chronic airway diseases, including asthma, in 10%–13% of nearly 2400 patients hospitalised in New York City.4 5 Although Williamson et al reported a modest increase in risk of COVID-19-related hospital deaths in asthma, this was mainly in patients recently receiving oral corticosteroids.6 It seems unlikely that respiratory comorbidities would be under-reported, so what other explanations may be offered? Shielding and self-isolation may be helping to reduce acquisition of SARS-CoV-2, but there is no reason to think this …

Background: Although the efficacy of corticosteroid treatment in controlling asthma is widely accepted, its effectiveness is undermined by poor adherence. However, the optimal method for measuring adherence to asthma therapy remains unclear. Objective: To perform a review of the literature reporting biological, objective methods for assessing adherence to inhaled or oral corticosteroids in asthma; we included studies reporting direct measurement of exogenous corticosteroids in blood, or the effect of adherence on exhaled nitric oxide. Design: We searched three databases MEDLINE (using both PubMed and Ovid), the Cumulative Index of Nursing and Allied Health Literature (CINAHL) and Web of Science for articles published between January 1975 and July 2020. Quality of the studies was assessed using the National Institute of Health checklist. Results: From 2850 screened articles, 26 fulfilled the inclusion criteria. Measurement of blood prednisolone with or without cortisol was used in eight studies as a measure of oral corticosteroid adherence, and fractional exhaled nitric oxide (FeNO) in 17 studies for inhaled corticosteroid adherence. Inhaled corticosteroids were measured directly in the blood in one study. By direct measurement of drug levels in the blood, adherence rates to oral corticosteroids ranged from 47% to 92%, although the performance and timing of the test were often not known, making interpretation of findings and serum prednisolone concentrations difficult. FeNO is generally lower in adherent than non-adherent patients, but no absolute cut-off can be proposed based on the available data. However, a fall in FeNO following supervised inhaled corticosteroid dosing could indicate previous poor adherence. Conclusions and Clinical Relevance: Despite prednisolone and cortisol levels commonly being used as adherence markers in clinical practice, further work is required to assess the influence of the dose and timing on blood levels. The promising findings of FeNO suppression testing should be explored in further prospective studies.