Asthma.

Asthma is one of the most common chronic non-communicable diseases worldwide and is characterised by variable airflow obstruction, causing dyspnoea and wheezing. Highly effective therapies are available; asthma morbidity and mortality have vastly improved in the past 15 years, and most patients can attain good asthma control. However, undertreatment is still common, and improving patient and health-care provider understanding of when and how to adjust treatment is crucial. Asthma management consists of a cycle of assessment of asthma control and risk factors and adjustment of medications accordingly. With the introduction of biological therapies, management of severe asthma has entered the precision medicine era-a shift that is driving clinical ambitions towards disease remission. Patients with severe asthma often have co-existing conditions contributing to their symptoms, mandating a multidimensional management approach. In this Seminar, we provide a clinically focused overview of asthma; epidemiology, pathophysiology, diagnosis, and management in children and adults.

Diagnosis of cystic lung diseases: a position statement from the UK Cystic Lung Disease Rare Disease Collaborative Network.

BACKGROUND: Rare cystic lung diseases are increasingly recognised due the wider application of CT scanning making cystic lung disease management a growing part of respiratory care. Cystic lung diseases tend to have extrapulmonary features that can both be diagnostic but also require surveillance and treatment in their own right. As some of these diseases now have specific treatments, making a precise diagnosis is crucial. While Langerhans cell histiocytosis, Birt-Hogg-Dubé syndrome, lymphoid interstitial pneumonia and lymphangioleiomyomatosis are becoming relatively well-known diseases to respiratory physicians, a targeted and thorough workup improves diagnostic accuracy and may suggest other ultrarare diseases such as light chain deposition disease, cystic pulmonary amyloidosis, low-grade metastatic neoplasms or infections. In many cases, diagnostic information is overlooked leaving uncertainty over the disease course and treatments. AIMS: This position statement from the Rare Disease Collaborative Network for cystic lung diseases will review how clinical, radiological and physiological features can be used to differentiate between these diseases. NARRATIVE: We highlight that in many cases a multidisciplinary diagnosis can be made without the need for lung biopsy and discuss where tissue sampling is necessary when non-invasive methods leave diagnostic doubt. We suggest an initial workup focusing on points in the history which identify key disease features, underlying systemic and familial diseases and a clinical examination to search for connective tissue disease and features of genetic causes of lung cysts. All patients should have a CT of the thorax and abdomen to characterise the pattern and burden of lung cysts and extrapulmonary features and also spirometry, gas transfer and a 6 min walk test. Discussion with a rare cystic lung disease centre is suggested before a surgical biopsy is undertaken. CONCLUSIONS: We suggest that this focused workup should be performed in all people with multiple lung cysts and would streamline referral pathways, help guide early treatment, management decisions, improve patient experience and reduce overall care costs. It could also potentially catalyse a national research database to describe these less well-understood and unidentified diseases, categorise disease phenotypes and outcomes, potentially leading to better prognostic data and generating a stronger platform to understand specific disease biology.

Radiomultiomics: quantitative CT clusters of severe asthma associated with multi-omics.

RATIONALE: Lung quantitative computed tomographic (qCT) severe asthma clusters have been reported, but their replication and underlying disease mechanisms are unknown. We identified and replicated qCT clusters of severe asthma in two independent asthma cohorts and determined their association with molecular pathways. METHODS: We used consensus clustering on qCT measurements of airway and lung CT scans, performed in 105 severe asthmatic adults from the U-BIOPRED cohort. The same qCT measurements were used to replicate qCT clusters in a subsample of the ATLANTIS asthma cohort (n=97). We performed integrated enrichment analysis using blood, sputum, bronchial biopsies, bronchial brushings and nasal brushings transcriptomics and blood and sputum proteomics to characterize radiomultiomic-associated clusters (RACs). RESULTS: qCT clusters and clinical features in U-BIOPRED were replicated in the matched ATLANTIS cohort. In the U-BIOPRED cohort, RAC1 (n=30) was predominantly female with elevated BMI, mild airflow limitation, normal qCT parameters and upregulation of the complement pathway. RAC2 (n=34) subjects had a lower degree of airflow limitation, airway wall thickness and dilatation, with upregulation of proliferative pathways, including neurotrophic receptor tyrosine kinase 2/tyrosine kinase receptor B (NTRK2/TRKB), and down-regulation of semaphorin pathways. RAC3 (n=41) showed increased lung attenuation area and air trapping, severe airflow limitation, hyperinflation, and upregulation of cytokine signaling and signaling by interleukin pathways, and matrix metallopeptidase 1, 2 and 9. CONCLUSIONS: U-BIOPRED severe asthma qCT clusters were replicated in a matched independent asthmatic cohort and associated with specific molecular pathways. Radiomultiomics might represent anovel strategy to identify new molecular pathways in asthma pathobiology.

The cost-effectiveness of procalcitonin for guiding antibiotic prescribing in individuals hospitalized with COVID-19: part of the PEACH study.

BACKGROUND: Many hospitals introduced procalcitonin (PCT) testing to help diagnose bacterial coinfection in individuals with COVID-19, and guide antibiotic decision-making during the COVID-19 pandemic in the UK. OBJECTIVES: Evaluating cost-effectiveness of using PCT to guide antibiotic decisions in individuals hospitalized with COVID-19, as part of a wider research programme. METHODS: Retrospective individual-level data on patients hospitalized with COVID-19 were collected from 11 NHS acute hospital Trusts and Health Boards from England and Wales, which varied in their use of baseline PCT testing during the first COVID-19 pandemic wave. A matched analysis (part of a wider analysis reported elsewhere) created groups of patients whose PCT was/was not tested at baseline. A model was created with combined decision tree/Markov phases, parameterized with quality-of-life/unit cost estimates from the literature, and used to estimate costs and quality-adjusted life years (QALYs). Cost-effectiveness was judged at a £20 000/QALY threshold. Uncertainty was characterized using bootstrapping. RESULTS: People who had baseline PCT testing had shorter general ward/ICU stays and spent less time on antibiotics, though with overlap between the groups' 95% CIs. Those with baseline PCT testing accrued more QALYs (8.76 versus 8.62) and lower costs (£9830 versus £10 700). The point estimate was baseline PCT testing being dominant over no baseline testing, though with uncertainty: the probability of cost-effectiveness was 0.579 with a 1 year horizon and 0.872 with a lifetime horizon. CONCLUSIONS: Using PCT to guide antibiotic therapy in individuals hospitalized with COVID-19 is more likely to be cost-effective than not, albeit with uncertainty.

A retrospective propensity-score-matched cohort study of the impact of procalcitonin testing on antibiotic use in hospitalized patients during the first wave of COVID-19.

BACKGROUND: Procalcitonin (PCT) is a blood marker used to help diagnose bacterial infections and guide antibiotic treatment. PCT testing was widely used/adopted during the COVID-19 pandemic in the UK. OBJECTIVES: Primary: to measure the difference in length of early (during first 7 days) antibiotic prescribing between patients with COVID-19 who did/did not have baseline PCT testing during the first wave of the pandemic. Secondary: to measure differences in length of hospital/ICU stay, mortality, total days of antibiotic prescribing and resistant bacterial infections between these groups. METHODS: Multi-centre, retrospective, observational, cohort study using patient-level clinical data from acute hospital Trusts/Health Boards in England/Wales. Inclusion: patients ≥16 years, admitted to participating Trusts/Health Boards and with a confirmed positive COVID-19 test between 1 February 2020 and 30 June 2020. RESULTS: Data from 5960 patients were analysed: 1548 (26.0%) had a baseline PCT test and 4412 (74.0%) did not. Using propensity-score matching, baseline PCT testing was associated with an average reduction in early antibiotic prescribing of 0.43 days [95% confidence interval (CI): 0.22-0.64 days, P < 0.001) and of 0.72 days (95% CI: 0.06-1.38 days, P = 0.03] in total antibiotic prescribing. Baseline PCT testing was not associated with increased mortality or hospital/ICU length of stay or with the rate of antimicrobial-resistant secondary bacterial infections. CONCLUSIONS: Baseline PCT testing appears to have been an effective antimicrobial stewardship tool early in the pandemic: it reduced antibiotic prescribing without evidence of harm. Our study highlights the need for embedded, rapid evaluations of infection diagnostics in the National Health Service so that even in challenging circumstances, introduction into clinical practice is supported by evidence for clinical utility. STUDY REGISTRATION NUMBER: ISRCTN66682918.

Epithelial Interleukin-1 Receptor-Like-1 Activation Is Contingent on Interleukin-33 Isoforms and Asthma-Related Receptor Variation.

INTRODUCTION: The interleukin-33/interleukin-1 receptor-like-1 (IL-33/IL1RL1) signalling pathway is implicated in asthma pathogenesis, with IL1RL1 nonsynonymous genetic polymorphisms associated with disease risk. We aimed to determine these variants' effect on IL1RL1 signalling induced by different IL33 isoforms thought to be elevated in the asthmatic airway. METHOD: In a project funded by GSK plc, which has developed an IL-33 receptor inhibitor for asthma treatment, human embryonic kidney 293 (HEK293) cells expressing secreted embryonic alkaline phosphatase (SEAP) driven by a nuclear factor kappa-beta (NF-κB) promoter, were transiently transfected with IL1RL1, containing one of four extracellular and Toll/interleukin 1 receptor (TIR) domain haplotypes. Cells were stimulated with seven different splice and proteolytic-generated IL-33 isoforms (0.001-50 ng/mL) for 24 h. Supernatant SEAP activity and interleukin-8 (IL-8) levels were determined. Primary human bronchial epithelial cells (HBECs) representing different genotype carriers were stimulated with IL-33112-270 (50 ng/mL) and induced IL-8 mRNA expression measured. RESULTS: HEK293 cells carrying both asthma extracellular and TIR domain IL1RL1 risk haplotypes presented maximal IL33-driven signalling, with minimal signalling after IL-33 activation in other protective haplotypes. All IL-33 isoforms activated IL1RL1 but with differing magnitudes. Proteolytically cleaved IL3395-270 and IL33106-270 had the greatest effect and the IL33113-270, and Exon 3,4 deletion isoform exhibited the lowest. The effect of extracellular and TIR domain genetic variants on receptor signalling was replicated in primary HBECs. Maximal IL1RL1 signalling was observed in cells carrying both extracellular and TIR signalling domain risk haplotypes. CONCLUSIONS: Overall, our study suggests asthma patients carrying the extracellular and TIR domain risk haplotype and have a lung microenvironment that promotes elevated levels of cleaved IL33, particularly where IL3395-270 and IL33106-270 may be more amenable to IL33/IL1RL1 targeting.

Interleukin-5 as a pleiotropic cytokine orchestrating airway type 2 inflammation: Effects on and beyond eosinophils.

Interleukin (IL)-5 is the key cytokine in the maturation, activation, proliferation, migration and survival of eosinophils, which are key effector cells in many upper and lower airway diseases. Through its effects on eosinophils, IL-5 indirectly contributes to various pathophysiological processes including tissue damage, repair and remodelling. Understanding the importance of IL-5 in eosinophil-associated diseases led to the development of anti-IL-5 therapies, which provide clinical benefits across a range of conditions. However, recent evidence suggests that eosinophil-depletion alone may not account for all of the therapeutic effects of anti-IL-5 therapy and that IL-5 may also contribute to disease independently of its effects on eosinophils. Indeed, evidence from ex vivo studies and targeted therapy in vivo demonstrates that IL-5 and its inhibition affects a much broader range of cells beyond eosinophils, including epithelial cells, plasma cells, mast cells, basophils, neutrophils, type 2 innate lymphoid cells, T regulatory cells and fibroblasts. This review will provide an update on the evidence supporting the breadth of IL-5 biology relevant to disease pathogenesis beyond eosinophil-associated inflammation, where there is a need for additional insight, and the clinical implications of a more central role of IL-5 in type 2 inflammation.

Oropharyngeal Microbiota Clusters in Children with Asthma or Wheeze Associate with Allergy, Blood Transcriptomic Immune Pathways, and Exacerbation Risk.

Rationale: Children with preschool wheezing or school-age asthma are reported to have airway microbial imbalances. Objectives: To identify clusters in children with asthma or wheezing using oropharyngeal microbiota profiles. Methods: Oropharyngeal swabs from the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes) pediatric asthma or wheezing cohort were characterized using 16S ribosomal RNA gene sequencing, and unsupervised hierarchical clustering was performed on the Bray-Curtis ß-diversity. Enrichment scores of the Molecular Signatures Database hallmark gene sets were computed from the blood transcriptome using gene set variation analysis. Children with severe asthma or severe wheezing were followed up for 12-18 months, with assessment of the frequency of exacerbations. Measurements and Main Results: Oropharyngeal samples from 241 children (age range, 1-17 years; 40% female) revealed four taxa-driven clusters dominated by Streptococcus, Veillonella, Rothia, and Haemophilus. The clusters showed significant differences in atopic dermatitis, grass pollen sensitization, FEV1% predicted after salbutamol, and annual asthma exacerbation frequency during follow-up. The Veillonella cluster was the most allergic and included the highest percentage of children with two or more exacerbations per year during follow-up. The oropharyngeal clusters were different in the enrichment scores of TGF-ß (transforming growth factor-ß) (highest in the Veillonella cluster) and Wnt/ß-catenin signaling (highest in the Haemophilus cluster) transcriptomic pathways in blood (all q values <0.05). Conclusions: Analysis of the oropharyngeal microbiota of children with asthma or wheezing identified four clusters with distinct clinical characteristics (phenotypes) that associate with risk for exacerbation and transcriptomic pathways involved in airway remodeling. This suggests that further exploration of the oropharyngeal microbiota may lead to novel pathophysiologic insights and potentially new treatment approaches.

Stratification of asthma by lipidomic profiling of induced sputum supernatant.

BACKGROUND: Asthma is a chronic respiratory disease with significant heterogeneity in its clinical presentation and pathobiology. There is need for improved understanding of respiratory lipid metabolism in asthma patients and its relation to observable clinical features. OBJECTIVE: We performed a comprehensive, prospective, cross-sectional analysis of the lipid composition of induced sputum supernatant obtained from asthma patients with a range of disease severities, as well as from healthy controls. METHODS: Induced sputum supernatant was collected from 211 adults with asthma and 41 healthy individuals enrolled onto the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes) study. Sputum lipidomes were characterized by semiquantitative shotgun mass spectrometry and clustered using topologic data analysis to identify lipid phenotypes. RESULTS: Shotgun lipidomics of induced sputum supernatant revealed a spectrum of 9 molecular phenotypes, highlighting not just significant differences between the sputum lipidomes of asthma patients and healthy controls, but also within the asthma patient population. Matching clinical, pathobiologic, proteomic, and transcriptomic data helped inform the underlying disease processes. Sputum lipid phenotypes with higher levels of nonendogenous, cell-derived lipids were associated with significantly worse asthma severity, worse lung function, and elevated granulocyte counts. CONCLUSION: We propose a novel mechanism of increased lipid loading in the epithelial lining fluid of asthma patients resulting from the secretion of extracellular vesicles by granulocytic inflammatory cells, which could reduce the ability of pulmonary surfactant to lower surface tension in asthmatic small airways, as well as compromise its role as an immune regulator.

The role of inflammation in anxiety and depression in the European U-BIOPRED asthma cohorts.

BACKGROUND: Growing evidence indicates high comorbid anxiety and depression in patients with asthma. However, the mechanisms underlying this comorbid condition remain unclear. The aim of this study was to investigate the role of inflammation in comorbid anxiety and depression in three asthma patient cohorts of the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) project. METHODS: U-BIOPRED was conducted by a European Union consortium of 16 academic institutions in 11 European countries. A subset dataset from subjects with valid anxiety and depression measures and a large blood biomarker dataset were analysed, including 198 non-smoking patients with severe asthma (SAn), 65 smoking patients with severe asthma (SAs), 61 non-smoking patients with mild-to-moderate asthma (MMA), and 20 healthy non-smokers (HC). The Hospital Anxiety and Depression Scale was used to measure anxiety and depression and a series of inflammatory markers were analysed by the SomaScan v3 platform (SomaLogic, Boulder, Colo). ANOVA and the Kruskal-Wallis test were used for multiple-group comparisons as appropriate. RESULTS: There were significant group effects on anxiety and depression among the four cohort groups (p < 0.05). Anxiety and depression of SAn and SAs groups were significantly higher than that of MMA and HC groups (p < 0.05. There were significant differences in serum IL6, MCP1, CCL18, CCL17, IL8, and Eotaxin among the four groups (p < 0.05). Depression was significantly associated with IL6, MCP1, CCL18 level, and CCL17; whereas anxiety was associated with CCL17 only (p < 0.05). CONCLUSIONS: The current study suggests that severe asthma patients are associated with higher levels of anxiety and depression, and inflammatory responses may underlie this comorbid condition.

Asthma and COPD: A Focus on ß-Agonists - Past, Present and Future.

Asthma has been recognised as a respiratory disorder for millennia and the focus of targeted drug development for the last 120 years. Asthma is one of the most common chronic non-communicable diseases worldwide. Chronic obstructive pulmonary disease (COPD), a leading cause of morbidity and mortality worldwide, is caused by exposure to tobacco smoke and other noxious particles and exerts a substantial economic and social burden. This chapter reviews the development of the treatments of asthma and COPD particularly focussing on the ß-agonists, from the isolation of adrenaline, through the development of generations of short- and long-acting ß-agonists. It reviews asthma death epidemics, considers the intrinsic efficacy of clinical compounds, and charts the improvement in selectivity and duration of action that has led to our current medications. Important ß2-agonist compounds no longer used are considered, including some with additional properties, and how the different pharmacological properties of current ß2-agonists underpin their different places in treatment guidelines. Finally, it concludes with a look forward to future developments that could improve the ß-agonists still further, including extending their availability to areas of the world with less readily accessible healthcare.

Inverse association between blood pressure and pulse oximetry accuracy: an observational study in patients with suspected or confirmed COVID-19 infection.

BACKGROUND: Pulse oximeters are a standard non-invasive tool to measure blood oxygen levels, and are used in multiple healthcare settings. It is important to understand the factors affecting their accuracy to be able to use them optimally and safely. This analysis aimed to explore the association of the measurement error of pulse oximeters with systolic BP, diastolic BP and heart rate (HR) within ranges of values commonly observed in clinical practice. METHODS: The study design was a retrospective observational study of all patients admitted to a large teaching hospital with suspected or confirmed COVID-19 infection from February 2020 to December 2021. Data on systolic and diastolic BPs and HR levels were available from the same time period as the pulse oximetry measurements. RESULTS: Data were available for 3420 patients with 5927 observations of blood oxygen saturations as measured by pulse oximetry and ABG sampling within 30 min. The difference in oxygen saturation using the paired pulse oximetry and arterial oxygen saturation difference measurements was inversely associated with systolic BP, increasing by 0.02% with each mm Hg decrease in systolic BP (95% CI 0.00% to 0.03%) over a range of 80-180 mm Hg. Inverse associations were also observed between the error for oxygen saturation as measured by pulse oximetry and with both diastolic BP (+0.03%; 95% CI 0.00% to 0.05%) and HR (+0.04%; 95% CI 0.02% to 0.06% for each unit decrease in the HR). CONCLUSIONS: Care needs to be taken in interpreting pulse oximetry measurements in patients with lower systolic and diastolic BPs, and HRs, as oxygen saturation is overestimated as BP and HR decrease. Confirmation of the oxygen saturation with an ABG may be appropriate in some clinical scenarios.

Mapping atopic dermatitis and anti-IL-22 response signatures to type 2-low severe neutrophilic asthma.

BACKGROUND: Transcriptomic changes in patients who respond clinically to biological therapies may identify responses in other tissues or diseases. OBJECTIVE: We sought to determine whether a disease signature identified in atopic dermatitis (AD) is seen in adults with severe asthma and whether a transcriptomic signature for patients with AD who respond clinically to anti-IL-22 (fezakinumab [FZ]) is enriched in severe asthma. METHODS: An AD disease signature was obtained from analysis of differentially expressed genes between AD lesional and nonlesional skin biopsies. Differentially expressed genes from lesional skin from therapeutic superresponders before and after 12 weeks of FZ treatment defined the FZ-response signature. Gene set variation analysis was used to produce enrichment scores of AD and FZ-response signatures in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes asthma cohort. RESULTS: The AD disease signature (112 upregulated genes) encompassing inflammatory, T-cell, TH2, and TH17/TH22 pathways was enriched in the blood and sputum of patients with asthma with increasing severity. Patients with asthma with sputum neutrophilia and mixed granulocyte phenotypes were the most enriched (P < .05). The FZ-response signature (296 downregulated genes) was enriched in asthmatic blood (P < .05) and particularly in neutrophilic and mixed granulocytic sputum (P < .05). These data were confirmed in sputum of the Airway Disease Endotyping for Personalized Therapeutics cohort. IL-22 mRNA across tissues did not correlate with FZ-response enrichment scores, but this response signature correlated with TH22/IL-22 pathways. CONCLUSIONS: The FZ-response signature in AD identifies severe neutrophilic asthmatic patients as potential responders to FZ therapy. This approach will help identify patients for future asthma clinical trials of drugs used successfully in other chronic diseases.

Lysyl oxidase like 2 is increased in asthma and contributes to asthmatic airway remodelling.

BACKGROUND: Airway smooth muscle (ASM) cells are fundamental to asthma pathogenesis, influencing bronchoconstriction, airway hyperresponsiveness and airway remodelling. The extracellular matrix (ECM) can influence tissue remodelling pathways; however, to date no study has investigated the effect of ASM ECM stiffness and cross-linking on the development of asthmatic airway remodelling. We hypothesised that transforming growth factor-ß (TGF-ß) activation by ASM cells is influenced by ECM in asthma and sought to investigate the mechanisms involved. METHODS: This study combines in vitro and in vivo approaches: human ASM cells were used in vitro to investigate basal TGF-ß activation and expression of ECM cross-linking enzymes. Human bronchial biopsies from asthmatic and nonasthmatic donors were used to confirm lysyl oxidase like 2 (LOXL2) expression in ASM. A chronic ovalbumin (OVA) model of asthma was used to study the effect of LOXL2 inhibition on airway remodelling. RESULTS: We found that asthmatic ASM cells activated more TGF-ß basally than nonasthmatic controls and that diseased cell-derived ECM influences levels of TGF-ß activated. Our data demonstrate that the ECM cross-linking enzyme LOXL2 is increased in asthmatic ASM cells and in bronchial biopsies. Crucially, we show that LOXL2 inhibition reduces ECM stiffness and TGF-ß activation in vitro, and can reduce subepithelial collagen deposition and ASM thickness, two features of airway remodelling, in an OVA mouse model of asthma. CONCLUSION: These data are the first to highlight a role for LOXL2 in the development of asthmatic airway remodelling and suggest that LOXL2 inhibition warrants further investigation as a potential therapy to reduce remodelling of the airways in severe asthma.

Urinary metabotype of severe asthma evidences decreased carnitine metabolism independent of oral corticosteroid treatment in the U-BIOPRED study.

INTRODUCTION: Asthma 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. METHODS: Baseline 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. RESULTS: A total of 90 metabolites were identified, with 40 significantly altered (p<0.05, false discovery rate <0.05) in severe asthma and 23 by OCS use. Multivariate modelling showed that observed metabotypes in healthy participants and patients with mild-to-moderate asthma differed significantly from those in patients with severe asthma (p=2.6×10-20), 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. CONCLUSIONS: This 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.

Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation.

RATIONALE: Asthma phenotyping requires novel biomarker discovery. OBJECTIVES: To identify plasma biomarkers associated with asthma phenotypes by application of a new proteomic panel to samples from two well-characterised cohorts of severe (SA) and mild-to-moderate (MMA) asthmatics, COPD subjects and healthy controls (HCs). METHODS: An antibody-based array targeting 177 proteins predominantly involved in pathways relevant to inflammation, lipid metabolism, signal transduction and extracellular matrix was applied to plasma from 525 asthmatics and HCs in the U-BIOPRED cohort, and 142 subjects with asthma and COPD from the validation cohort BIOAIR. Effects of oral corticosteroids (OCS) were determined by a 2-week, placebo-controlled OCS trial in BIOAIR, and confirmed by relation to objective OCS measures in U-BIOPRED. RESULTS: In U-BIOPRED, 110 proteins were significantly different, mostly elevated, in SA compared to MMA and HCs. 10 proteins were elevated in SA versus MMA in both U-BIOPRED and BIOAIR (alpha-1-antichymotrypsin, apolipoprotein-E, complement component 9, complement factor I, macrophage inflammatory protein-3, interleukin-6, sphingomyelin phosphodiesterase 3, TNF receptor superfamily member 11a, transforming growth factor-ß and glutathione S-transferase). OCS treatment decreased most proteins, yet differences between SA and MMA remained following correction for OCS use. Consensus clustering of U-BIOPRED protein data yielded six clusters associated with asthma control, quality of life, blood neutrophils, high-sensitivity C-reactive protein and body mass index, but not Type-2 inflammatory biomarkers. The mast cell specific enzyme carboxypeptidase A3 was one major contributor to cluster differentiation. CONCLUSIONS: The plasma proteomic panel revealed previously unexplored yet potentially useful Type-2-independent biomarkers and validated several proteins with established involvement in the pathophysiology of SA.

Impact of introducing procalcitonin testing on antibiotic usage in acute NHS hospitals during the first wave of COVID-19 in the UK: a controlled interrupted time series analysis of organization-level data.

BACKGROUND: Blood biomarkers have the potential to help identify COVID-19 patients with bacterial coinfection in whom antibiotics are indicated. During the COVID-19 pandemic, procalcitonin testing was widely introduced at hospitals in the UK to guide antibiotic prescribing. We have determined the impact of this on hospital-level antibiotic consumption. METHODS: We conducted a retrospective, controlled interrupted time series analysis of organization-level data describing antibiotic dispensing, hospital activity and procalcitonin testing for acute hospitals/hospital trusts in England and Wales during the first wave of COVID-19 (24 February to 5 July 2020). RESULTS: In the main analysis of 105 hospitals in England, introduction of procalcitonin testing in emergency departments/acute medical admission units was associated with a statistically significant decrease in total antibiotic use of -1.08 (95% CI: -1.81 to -0.36) DDDs of antibiotic per admission per week per trust. This effect was then lost at a rate of 0.05 (95% CI: 0.02-0.08) DDDs per admission per week. Similar results were found specifically for first-line antibiotics for community-acquired pneumonia and for COVID-19 admissions rather than all admissions. Introduction of procalcitonin in the ICU setting was not associated with any significant change in antibiotic use. CONCLUSIONS: At hospitals where procalcitonin testing was introduced in emergency departments/acute medical units this was associated with an initial, but unsustained, reduction in antibiotic use. Further research should establish the patient-level impact of procalcitonin testing in this population and understand its potential for clinical effectiveness.

Dynamic early warning scores for predicting clinical deterioration in patients with respiratory disease.

BACKGROUND: The National Early Warning Score-2 (NEWS-2) is used to detect patient deterioration in UK hospitals but fails to take account of the detailed granularity or temporal trends in clinical observations. We used data-driven methods to develop dynamic early warning scores (DEWS) to address these deficiencies, and tested their accuracy in patients with respiratory disease for predicting (1) death or intensive care unit admission, occurring within 24 h (D/ICU), and (2) clinically significant deterioration requiring urgent intervention, occurring within 4 h (CSD). METHODS: Clinical observations data were extracted from electronic records for 31,590 respiratory in-patient episodes from April 2015 to December 2020 at a large acute NHS Trust. The timing of D/ICU was extracted for all episodes. 1100 in-patient episodes were annotated manually to record the timing of CSD, defined as a specific event requiring a change in treatment. Time series features were entered into logistic regression models to derive DEWS for each of the clinical outcomes. Area under the receiver operating characteristic curve (AUROC) was the primary measure of model accuracy. RESULTS: AUROC (95% confidence interval) for predicting D/ICU was 0.857 (0.852-0.862) for NEWS-2 and 0.906 (0.899-0.914) for DEWS in the validation data. AUROC for predicting CSD was 0.829 (0.817-0.842) for NEWS-2 and 0.877 (0.862-0.892) for DEWS. NEWS-2 ≥ 5 had sensitivity of 88.2% and specificity of 54.2% for predicting CSD, while DEWS ≥ 0.021 had higher sensitivity of 93.6% and approximately the same specificity of 54.3% for the same outcome. Using these cut-offs, 315 out of 347 (90.8%) CSD events were detected by both NEWS-2 and DEWS, at the time of the event or within the previous 4 h; 12 (3.5%) were detected by DEWS but not by NEWS-2, while 4 (1.2%) were detected by NEWS-2 but not by DEWS; 16 (4.6%) were not detected by either scoring system. CONCLUSION: We have developed DEWS that display greater accuracy than NEWS-2 for predicting clinical deterioration events in patients with respiratory disease. Prospective validation studies are required to assess whether DEWS can be used to reduce missed deteriorations and false alarms in real-life clinical settings.

Urinary Leukotriene E4 and Prostaglandin D2 Metabolites Increase in Adult and Childhood Severe Asthma Characterized by Type 2 Inflammation. A Clinical Observational Study.

Rationale: New approaches are needed to guide personalized treatment of asthma.Objectives: To test if urinary eicosanoid metabolites can direct asthma phenotyping.Methods: Urinary metabolites of prostaglandins (PGs), cysteinyl leukotrienes (CysLTs), and isoprostanes were quantified in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes) study including 86 adults with mild-to-moderate asthma (MMA), 411 with severe asthma (SA), and 100 healthy control participants. Validation was performed internally in 302 participants with SA followed up after 12-18 months and externally in 95 adolescents with asthma.Measurement and Main Results: Metabolite concentrations in healthy control participants were unrelated to age, body mass index, and sex, except for the PGE2 pathway. Eicosanoid concentrations were generally greater in participants with MMA relative to healthy control participants, with further elevations in participants with SA. However, PGE2 metabolite concentrations were either the same or lower in male nonsmokers with asthma than in healthy control participants. Metabolite concentrations were unchanged in those with asthma who adhered to oral corticosteroid treatment as documented by urinary prednisolone detection, whereas those with SA treated with omalizumab had lower concentrations of LTE4 and the PGD2 metabolite 2,3-dinor-11ß-PGF2α. High concentrations of LTE4 and PGD2 metabolites were associated with lower lung function and increased amounts of exhaled nitric oxide and eosinophil markers in blood, sputum, and urine in U-BIOPRED participants and in adolescents with asthma. These type 2 (T2) asthma associations were reproduced in the follow-up visit of the U-BIOPRED study and were found to be as sensitive to detect T2 inflammation as the established biomarkers.Conclusions: Monitoring of urinary eicosanoids can identify T2 asthma and introduces a new noninvasive approach for molecular phenotyping of adult and adolescent asthma.Clinical trial registered with www.clinicaltrials.gov (NCT01976767).

Phenotypic and functional translation of IL33 genetics in asthma.

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.