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    Inflammatory phenotypes in patients with severe asthma are associated with distinct airway microbiology. Taylor Steven L,Leong Lex E X,Choo Jocelyn M,Wesselingh Steve,Yang Ian A,Upham John W,Reynolds Paul N,Hodge Sandra,James Alan L,Jenkins Christine,Peters Matthew J,Baraket Melissa,Marks Guy B,Gibson Peter G,Simpson Jodie L,Rogers Geraint B The Journal of allergy and clinical immunology BACKGROUND:Asthma pathophysiology and treatment responsiveness are predicted by inflammatory phenotype. However, the relationship between airway microbiology and asthma phenotype is poorly understood. OBJECTIVE:We aimed to characterize the airway microbiota in patients with symptomatic stable asthma and relate composition to airway inflammatory phenotype and other phenotypic characteristics. METHODS:The microbial composition of induced sputum specimens collected from adult patients screened for a multicenter randomized controlled trial was determined by using 16S rRNA gene sequencing. Inflammatory phenotypes were defined by sputum neutrophil and eosinophil cell proportions. Microbiota were defined by using α- and β-diversity measures, and interphenotype differences were identified by using similarity of percentages, network analysis, and taxon fold change. Phenotypic predictors of airway microbiology were identified by using multivariate linear regression. RESULTS:Microbiota composition was determined in 167 participants and classified as eosinophilic (n = 84), neutrophilic (n = 14), paucigranulocytic (n = 60), or mixed neutrophilic-eosinophilic (n = 9) asthma phenotypes. Airway microbiology was significantly less diverse (P = .022) and more dissimilar (P = .005) in neutrophilic compared with eosinophilic participants. Sputum neutrophil proportions, but not eosinophil proportions, correlated significantly with these diversity measures (α-diversity: Spearman r = -0.374, P < .001; β-diversity: r = 0.238, P = .002). Interphenotype differences were characterized by a greater frequency of pathogenic taxa at high relative abundance and reduced Streptococcus, Gemella, and Porphyromonas taxa relative abundance in patients with neutrophilic asthma. Multivariate regression confirmed that sputum neutrophil proportion was the strongest predictor of microbiota composition. CONCLUSIONS:Neutrophilic asthma is associated with airway microbiology that is significantly different from that seen in patients with other inflammatory phenotypes, particularly eosinophilic asthma. Differences in microbiota composition might influence the response to antimicrobial and steroid therapies and the risk of lung infection. 10.1016/j.jaci.2017.03.044
    Sputum transcriptomics reveal upregulation of IL-1 receptor family members in patients with severe asthma. Rossios Christos,Pavlidis Stelios,Hoda Uruj,Kuo Chih-Hsi,Wiegman Coen,Russell Kirsty,Sun Kai,Loza Matthew J,Baribaud Frederic,Durham Andrew L,Ojo Oluwaseun,Lutter Rene,Rowe Anthony,Bansal Aruna,Auffray Charles,Sousa Ana,Corfield Julie,Djukanovic Ratko,Guo Yike,Sterk Peter J,Chung Kian Fan,Adcock Ian M, The Journal of allergy and clinical immunology BACKGROUND:Sputum analysis in asthmatic patients is used to define airway inflammatory processes and might guide therapy. OBJECTIVE:We sought to determine differential gene and protein expression in sputum samples from patients with severe asthma (SA) compared with nonsmoking patients with mild/moderate asthma. METHODS:Induced sputum was obtained from nonsmoking patients with SA, smokers/ex-smokers with severe asthma, nonsmoking patients with mild/moderate asthma (MMAs), and healthy nonsmoking control subjects. Differential cell counts, microarray analysis of cell pellets, and SOMAscan analysis of sputum analytes were performed. CRID3 was used to inhibit the inflammasome in a mouse model of SA. RESULTS:Eosinophilic and mixed neutrophilic/eosinophilic inflammation were more prevalent in patients with SA compared with MMAs. Forty-two genes probes were upregulated (>2-fold) in nonsmoking patients with severe asthma compared with MMAs, including IL-1 receptor (IL-1R) family and nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 (NRLP3) inflammasome members (false discovery rate < 0.05). The inflammasome proteins nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 1 (NLRP1), NLRP3, and nucleotide-binding oligomerization domain (NOD)-like receptor C4 (NLRC4) were associated with neutrophilic asthma and with sputum IL-1β protein levels, whereas eosinophilic asthma was associated with an IL-13-induced T2 signature and IL-1 receptor-like 1 (IL1RL1) mRNA expression. These differences were sputum specific because no activation of NLRP3 or enrichment of IL-1R family genes in bronchial brushings or biopsy specimens in patients with SA was observed. Expression of NLRP3 and of the IL-1R family genes was validated in the Airway Disease Endotyping for Personalized Therapeutics cohort. Inflammasome inhibition using CRID3 prevented airway hyperresponsiveness and airway inflammation (both neutrophilia and eosinophilia) in a mouse model of severe allergic asthma. CONCLUSION:IL1RL1 gene expression is associated with eosinophilic SA, whereas NLRP3 inflammasome expression is highest in patients with neutrophilic SA. T2-driven eosinophilic inflammation and neutrophil-associated inflammasome activation might represent interacting pathways in patients with SA. 10.1016/j.jaci.2017.02.045
    Stratification of asthma phenotypes by airway proteomic signatures. Schofield James P R,Burg Dominic,Nicholas Ben,Strazzeri Fabio,Brandsma Joost,Staykova Doroteya,Folisi Caterina,Bansal Aruna T,Xian Yang,Guo Yike,Rowe Anthony,Corfield Julie,Wilson Susan,Ward Jonathan,Lutter Rene,Shaw Dominick E,Bakke Per S,Caruso Massimo,Dahlen Sven-Erik,Fowler Stephen J,Horváth Ildikó,Howarth Peter,Krug Norbert,Montuschi Paolo,Sanak Marek,Sandström Thomas,Sun Kai,Pandis Ioannis,Riley John,Auffray Charles,De Meulder Bertrand,Lefaudeux Diane,Sousa Ana R,Adcock Ian M,Chung Kian Fan,Sterk Peter J,Skipp Paul J,Djukanović Ratko, The Journal of allergy and clinical immunology BACKGROUND:Stratification by eosinophil and neutrophil counts increases our understanding of asthma and helps target therapy, but there is room for improvement in our accuracy in prediction of treatment responses and a need for better understanding of the underlying mechanisms. OBJECTIVE:We sought to identify molecular subphenotypes of asthma defined by proteomic signatures for improved stratification. METHODS:Unbiased label-free quantitative mass spectrometry and topological data analysis were used to analyze the proteomes of sputum supernatants from 246 participants (206 asthmatic patients) as a novel means of asthma stratification. Microarray analysis of sputum cells provided transcriptomics data additionally to inform on underlying mechanisms. RESULTS:Analysis of the sputum proteome resulted in 10 clusters (ie, proteotypes) based on similarity in proteomic features, representing discrete molecular subphenotypes of asthma. Overlaying granulocyte counts onto the 10 clusters as metadata further defined 3 of these as highly eosinophilic, 3 as highly neutrophilic, and 2 as highly atopic with relatively low granulocytic inflammation. For each of these 3 phenotypes, logistic regression analysis identified candidate protein biomarkers, and matched transcriptomic data pointed to differentially activated underlying mechanisms. CONCLUSION:This study provides further stratification of asthma currently classified based on quantification of granulocytic inflammation and provided additional insight into their underlying mechanisms, which could become targets for novel therapies. 10.1016/j.jaci.2019.03.013
    Exhaled Volatile Organic Compounds Are Able to Discriminate between Neutrophilic and Eosinophilic Asthma. Schleich Florence N,Zanella Delphine,Stefanuto Pierre-Hugues,Bessonov Kirill,Smolinska Agnieska,Dallinga Jan W,Henket Monique,Paulus Virginie,Guissard Françoise,Graff Sophie,Moermans Catherine,Wouters Emiel F M,Van Steen Kristel,van Schooten Frederik-Jan,Focant Jean-François,Louis Renaud American journal of respiratory and critical care medicine Analysis of exhaled breath for asthma phenotyping using endogenously generated volatile organic compounds (VOCs) offers the possibility of noninvasive diagnosis and therapeutic monitoring. Induced sputum is indeed not widely available and markers of neutrophilic asthma are still lacking. To determine whether analysis of exhaled breath using endogenously generated VOCs can be a surrogate marker for recognition of sputum inflammatory phenotypes. We conducted a prospective study on 521 patients with asthma recruited from the University Asthma Clinic of Liege. Patients underwent VOC measurement, fraction of exhaled nitric oxide (Fe) spirometry, sputum induction, and gave a blood sample. Subjects with asthma were classified in three inflammatory phenotypes according to their sputum granulocytic cell count. In the discovery study, seven potential biomarkers were highlighted by gas chromatography-mass spectrometry in a training cohort of 276 patients with asthma. In the replication study ( = 245), we confirmed four VOCs of interest to discriminate among asthma inflammatory phenotypes using comprehensive two-dimensional gas chromatography coupled to high-resolution time-of-flight mass spectrometry. Hexane and 2-hexanone were identified as compounds with the highest classification performance in eosinophilic asthma with accuracy comparable to that of blood eosinophils and Fe. Moreover, the combination of Fe, blood eosinophils, and VOCs gave a very good prediction of eosinophilic asthma (area under the receiver operating characteristic curve, 0.9). For neutrophilic asthma, the combination of nonanal, 1-propanol, and hexane had a classification performance similar to Fe or blood eosinophils in eosinophilic asthma. Those compounds were found in higher levels in neutrophilic asthma. Our study is the first attempt to characterize VOCs according to sputum granulocytic profile in a large population of patients with asthma and provide surrogate markers for neutrophilic asthma. 10.1164/rccm.201811-2210OC
    Elevated serum IgE, oral corticosteroid dependence and IL-17/22 expression in highly neutrophilic asthma. Bullone Michela,Carriero Vitina,Bertolini Francesca,Folino Anna,Mannelli Alessandro,Di Stefano Antonino,Gnemmi Isabella,Torchio Roberto,Ricciardolo Fabio L M The European respiratory journal Information on the clinical traits associated with bronchial neutrophilia in asthma is scant, preventing its recognition and adequate treatment. We aimed to assess the clinical, functional and biological features of neutrophilic asthma and identify possible predictors of bronchial neutrophilia.The inflammatory phenotype of 70 mild-to-severe asthma patients was studied cross-sectionally based on the eosinophilic/neutrophilic counts in their bronchial lamina propria. Patients were classified as neutrophilic or non-neutrophilic. Neutrophilic asthma patients (neutrophil count cut-off: 47.17 neutrophils·mm; range: 47.17-198.11 neutrophils·mm; median: 94.34 neutrophils·mm) were further classified as high (≥94.34 neutrophils·mm) or intermediate (47.17- <94.34 neutrophils·mm). The effect of smoking ≥10 pack-years was also assessed.Neutrophilic asthma patients (n=38; 36 mixed eosinophilic/neutrophilic) had greater disease severity, functional residual capacity, inhaled corticosteroid (ICS) dose and exacerbations, and lower forced vital capacity (FVC) % pred and forced expiratory volume in 1 s (FEV) reversibility than non-neutrophilic asthma patients (n=32; 28 eosinophilic and four paucigranulocytic). Neutrophilic asthma patients had similar eosinophil counts, increased bronchial CD8, interleukin (IL)-17-F and IL-22 cells, and decreased mast cells compared with non-neutrophilic asthma patients. FEV and FVC reversibility were independent predictors of bronchial neutrophilia in our cohort. High neutrophilic patients (n=21) had increased serum IgE levels, sensitivity to perennial allergens, exacerbation rate, oral corticosteroid dependence, and CD4 and IL-17F cells in their bronchial mucosa. Excluding smokers revealed increased IL-17A and IL-22 cells in highly neutrophilic patients.We provide new evidence linking the presence of high bronchial neutrophilia in asthma to an adaptive immune response associated with allergy (IgE) and IL-17/22 cytokine expression. High bronchial neutrophilia may discriminate a new endotype of asthma. Further research is warranted on the relationship between bronchoreversibility and bronchial neutrophilia. 10.1183/13993003.00068-2019
    Mixed Sputum Granulocyte Longitudinal Impact on Lung Function in the Severe Asthma Research Program. Hastie Annette T,Mauger David T,Denlinger Loren C,Coverstone Andrea,Castro Mario,Erzurum Serpil,Jarjour Nizar,Levy Bruce D,Meyers Deborah A,Moore Wendy C,Phillips Brenda R,Wenzel Sally E,Fahy John V,Israel Elliot,Bleecker Eugene R American journal of respiratory and critical care medicine Some reports indicate longitudinal variability in sputum differential cell counts, whereas others describe stability. Highly variable sputum eosinophil percentages are associated with greater lung function loss than persistently elevated eosinophil percentages, but elevated neutrophils are linked to more severe asthma. To examine sputum granulocyte stability or variability longitudinally and associations with important clinical characteristics. The SARP III (Severe Asthma Research Program III) cohort underwent comprehensive phenotype characterization at baseline and annually over 3 years. Adult subjects with acceptable sputum levels were assigned to one of three longitudinal sputum groups: eosinophils predominantly <2%, eosinophils predominantly ≥2%, or highly variable eosinophil percentages (>2 SDs determined from independent, repeated baseline eosinophil percentages). Subjects were similarly assigned to one of three longitudinal neutrophil groups with a 50% cut point. The group with predominantly <2% sputum eosinophils had the highest lung function (prebronchodilator FEV% predicted,  < 0.01; FEV/FVC ratio,  < 0.001) at baseline and throughout 3 years compared with other eosinophil groups. Healthcare use did not differ, although the highly variable eosinophil group reported more asthma exacerbations at Year 3. Longitudinal neutrophil groups showed few differences. However, a combination of predominantly ≥2% eosinophil and ≥50% neutrophil groups resulted in the lowest prebronchodilator FEV% predicted ( = 0.049) compared with the combination with predominantly <2% eosinophils and<50% neutrophils. Subjects with predominantly ≥2% sputum eosinophils in combination with predominantly ≥50% neutrophils showed greater loss of lung function, whereas those with highly variable sputum eosinophils had greater healthcare use. 10.1164/rccm.202009-3713OC
    Mapping atopic dermatitis and anti-IL-22 response signatures to type 2-low severe neutrophilic asthma. Badi Yusef Eamon,Pavel Ana B,Pavlidis Stelios,Riley John H,Bates Stewart,Kermani Nazanin Zounemat,Knowles Richard,Kolmert Johan,Wheelock Craig E,Worsley Sally,Uddin Mohib,Alving Kjell,Bakke Per S,Behndig Annelie,Caruso Massimo,Chanez Pascal,Fleming Louise J,Fowler Stephen J,Frey Urs,Howarth Peter,Horváth Ildikó,Krug Norbert,Maitland-van der Zee Anke H,Montuschi Paolo,Roberts Graham,Sanak Marek,Shaw Dominick E,Singer Florian,Sterk Peter J,Djukanovic Ratko,Dahlen Sven-Eric,Guo Yi-Ke,Chung Kian Fan,Guttman-Yassky Emma,Adcock Ian M, The Journal of allergy and clinical immunology 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, T2, and T17/T22 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 T22/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. 10.1016/j.jaci.2021.04.010
    The inflammatory profile of exacerbations in patients with severe refractory eosinophilic asthma receiving mepolizumab (the MEX study): a prospective observational study. McDowell P Jane,Diver Sarah,Yang Freda,Borg Catherine,Busby John,Brown Vanessa,Shrimanker Rahul,Cox Ciara,Brightling Christopher E,Chaudhuri Rekha,Pavord Ian D,Heaney Liam G, The Lancet. Respiratory medicine BACKGROUND:Clinical trials with mepolizumab, a humanised monoclonal antibody against interleukin-5, show a 50% reduction in severe asthma exacerbations in people with severe eosinophilic asthma. Exacerbations in patients treated with mepolizumab seem to be different to exacerbations in those given placebo, as patients treated with mepolizumab report fewer symptoms, have a lower sputum eosinophil count, and smaller fall in peak expiratory flow. We aimed to investigate the inflammatory phenotype and physiological characteristics of exacerbation events in patients with severe eosinophilic asthma who were treated with mepolizumab. METHODS:This multicentre, prospective, observational cohort study was carried out at four UK specialist severe asthma centres. Participants were aged 18-80 years, with severe eosinophilic asthma (Global Initiative for Asthma steps 4 and 5), and were eligible for mepolizumab therapy. All participants received mepolizumab 100 mg subcutaneously every 4 weeks, had a scheduled study visit when stable on mepolizumab (≥3 months on treatment), and measured daily peak flow and completed symptoms diaries throughout the course of the study. Participants attended their study centre for unscheduled exacerbation assessment when symptoms worsened outside of their normal daily variation and before commencing rescue treatment. If a participant was unable to attend their study centre for exacerbation or had initiated rescue treatment before the study visit, clinical details of the missed exacerbation were collected by clinical staff. In this exploratory study, the endpoint was 100 clinical assessments at exacerbation completed across all sites for participants on mepolizumab before initiation of rescue treatment. Characteristics of those who had exacerbations on mepolizumab were compared with those who did not, peak flow and symptoms diaries were compared for assessed versus missed exacerbations, and exacerbation phenotypes defined by sputum eosinophil cell count were compared. The utility of fractional exhaled nitric oxide (FeNO) and C-reactive protein in determining exacerbation phenotype on mepolizumab treatment were also assessed. This study is registered with ClinicalTrials.gov, NCT03324230. FINDINGS:Between Nov 30, 2017, and May 29, 2019, 145 participants were enrolled and treated with mepolizumab, five were excluded from the analysis. 172 exacerbations occurred, with 96 (56%) assessed before commencing rescue treatment. Compared with patients who did not exacerbate, patients who exacerbated had a higher exacerbation rate and more emergency department attendances in the year before commencing mepolizumab. The change in peak expiratory flow at nadir in the assessed exacerbation group was mean -40·5 L/min (SD 76·3) versus mean -37·0 L/min (93·0; p=0·84) in the missed exacerbation group, and there was no difference in reported symptom burden. When comparing exacerbations with a high sputum eosinophil count (≥2%; SE) with exacerbations with a low sputum eosinophil count (<2%; SE), the SE exacerbations were FeNO high (median difference 33 parts per billion [ppb; 95% CI 8 to 87]; p=0·0004), with lower FEV percent predicted (mean difference -15·9% [-27·0 to -4·8]; p=0·0075), lower FEV to forced vital capacity ratio (mean difference -10·3 [-17·0 to -3·6]; p=0·0043), and higher blood eosinophil counts (median difference 40 cells per μL [20 to 70]; p=0·0009). By contrast, SE exacerbations had higher C-reactive protein concentrations (median difference 12·7 mg/L [3·5 to 18·5]; p<0·0001), higher sputum neutrophil counts (median difference 52·7% [34·5 to 59·2]; p<0·0001), and were more likely to be treated with antibiotics (p=0·031). FeNO (≤20 or ≥50 ppb) was the most useful discriminator of inflammatory phenotype at exacerbation. The most common adverse event was hospital admission due to asthma exacerbation (17 [50%] of 34 events), none of the adverse events were study procedure related. INTERPRETATION:Exacerbations on mepolizumab are two distinct entities, which can largely be differentiated using FeNO: non-eosinophilic events are driven by infection with a low FeNO and high C-reactive protein concentration, whereas eosinophilic exacerbations are FeNO high. The results of the MEX study challenge the routine use of oral corticosteroids for the treatment of all asthma exacerbation events on mepolizumab, as well as the switching of biological therapies for treatment failure without profiling the inflammatory phenotype of ongoing asthma exacerbations. The results highlight clinically available tools to enable profiling of these residual exacerbations in patients treated with mepolizumab. FUNDING:UK Medical Research council. 10.1016/S2213-2600(21)00004-7
    Effect of tezepelumab on airway inflammatory cells, remodelling, and hyperresponsiveness in patients with moderate-to-severe uncontrolled asthma (CASCADE): a double-blind, randomised, placebo-controlled, phase 2 trial. Diver Sarah,Khalfaoui Latifa,Emson Claire,Wenzel Sally E,Menzies-Gow Andrew,Wechsler Michael E,Johnston James,Molfino Nestor,Parnes Jane R,Megally Ayman,Colice Gene,Brightling Christopher E, The Lancet. Respiratory medicine BACKGROUND:Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin (TSLP), an epithelial cell-derived cytokine. In phase 2b and 3 studies, tezepelumab significantly reduced exacerbations versus placebo in patients with severe uncontrolled asthma, irrespective of baseline levels of type 2 inflammatory biomarkers. We investigated the mechanism of action of tezepelumab by assessing its effects on airway inflammatory cells, airway remodelling, and airway hyperresponsiveness. METHODS:CASCADE was an exploratory, double-blind, randomised, placebo-controlled, parallel-group, phase 2 study done in 27 medical centres in Canada, Denmark, Germany, the UK, and the USA. Adults aged 18-75 years with uncontrolled, moderate-to-severe asthma were randomly assigned (1:1) to receive tezepelumab 210 mg or placebo administered subcutaneously every 4 weeks for a planned 28 weeks, extended to up to 52 weeks if COVID-19-related disruption delayed participants' end-of-treatment assessments. Randomisation was balanced and stratified by blood eosinophil count. The primary endpoint was the change from baseline to the end of treatment in the number of airway submucosal inflammatory cells in bronchoscopic biopsy samples. Eosinophils, neutrophils, CD3 T cells, CD4 T cells, tryptase mast cells, and chymase mast cells were evaluated separately. This endpoint was also assessed in subgroups according to baseline type 2 inflammatory biomarker levels, including blood eosinophil count. Airway remodelling was assessed via the secondary endpoints of change from baseline in reticular basement membrane thickness and epithelial integrity (proportions of denuded, damaged, and intact epithelium). Exploratory outcomes included airway hyperresponsiveness to mannitol. All participants who completed at least 20 weeks of study treatment, had an end-of-treatment visit up to 8 weeks after the last dose of study drug, and had evaluable baseline and end-of-treatment bronchoscopies were included in the primary efficacy analysis. All participants who received at least one dose of study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, NCT03688074. FINDINGS:Between Nov 2, 2018, and Nov 16, 2020, 250 patients were enrolled, 116 of whom were randomly assigned (59 to tezepelumab, 57 to placebo). 48 in the tezepelumab group and 51 in the placebo group completed the study and were assessed for the primary endpoint. Treatment with tezepelumab resulted in a nominally significantly greater reduction from baseline to the end of treatment in airway submucosal eosinophils versus placebo (ratio of geometric least-squares means 0·15 [95% CI 0·05-0·41]; nominal p<0·0010), with the difference seen across all baseline biomarker subgroups. There were no significant differences between treatment groups in the other cell types evaluated (ratio of geometric least-squares means: neutrophils 1·36 [95% CI 0·94-1·97]; CD3 T cells 1·12 [0·86-1·46]; CD4 T cells 1·18 [0·90-1·55]; tryptase mast cells 0·83 [0·61-1·15]; chymase mast cells 1·19 [0·67-2·10]; all p>0·10). In assessment of secondary endpoints, there were no significant differences between treatment groups in reticular basement membrane thickness and epithelial integrity. In an exploratory analysis, the reduction in airway hyperresponsiveness to mannitol was significantly greater with tezepelumab versus placebo (least-squares mean change from baseline in interpolated or extrapolated provoking dose of mannitol required to induce ≥15% reduction in FEV from baseline: tezepelumab 197·4 mg [95% CI 107·9 to 286·9]; placebo 58·6 mg [-30·1 to 147·33]; difference 138·8 [14·2 to 263·3], nominal p=0·030). Adverse events were reported in 53 (90%) patients in the tezepelumab group and 51 (90%) patients in the placebo group, and there were no safety findings of concern. INTERPRETATION:The improvements in asthma clinical outcomes observed in previous studies with tezepelumab are probably driven, at least in part, by reductions in eosinophilic airway inflammation, as shown here by reduced airway eosinophil counts regardless of baseline blood eosinophil count. Tezepelumab also reduced airway hyperresponsiveness to mannitol, indicating that TSLP blockade might have additional benefits in asthma beyond reducing type 2 airway inflammation. FUNDING:AstraZeneca and Amgen. 10.1016/S2213-2600(21)00226-5
    Allergen immunotherapy effectively reduces the risk of exacerbations and lower respiratory tract infections in both seasonal and perennial allergic asthma: a nationwide epidemiological study. The European respiratory journal BACKGROUND:Allergic asthma is associated with increased risk of respiratory tract infections and exacerbations. It remains unclear whether this susceptibility is conditioned by seasonal or by perennial allergy. AIM:To investigate perennial allergy compared with seasonal allergy as a risk factor for lower respiratory tract infections and exacerbations in asthma and whether this risk can be reduced by allergen immunotherapy (AIT). METHODOLOGY:This is a prospective register-based nationwide study of 18-44-year-olds treated with AIT during1995-2014. Based on the type of AIT and use of anti-asthmatic drugs, patients were subdivided into two groups: perennial allergic asthma (PAA) seasonal allergic asthma (SAA). Data on antibiotics against lower respiratory tract infections (LRTI) and oral corticosteroids for exacerbations were analyzed before starting AIT (baseline) and three years after completing AIT (follow-up). RESULTS:We identified 2688 patients with asthma treated with AIT, among whom, 1249 had PAA and 1439 had SAA. At baseline, patients with SAA had more exacerbations, 23.8%, respectively, 16.5% p=<0.001 but there were no differences in LRTI. During the three-year follow-up, we observed a highly significant reduction of exacerbations with an average decrease of 57% in PAA and 74% in SAA. We also observed a significant reduction of LRTI in both PAA and SAA: 17% and 20% decrease, respectively. CONCLUSION:AIT effectively reduced the risk of exacerbations and lower respiratory tract infections in both seasonal- and perennial allergic asthma. Perennial allergy is seemingly not a stronger risk factor for respiratory infections and exacerbations than is seasonal allergy. 10.1183/13993003.00446-2022
    Endotyping pediatric obesity-related asthma: Contribution of anthropometrics, metabolism, nutrients, and CD4 lymphocytes to pulmonary function. The Journal of allergy and clinical immunology BACKGROUND:Obesity-related complications including visceral fat, metabolic abnormalities, nutrient deficiencies, and immune perturbations are interdependent but have been individually associated with childhood asthma. OBJECTIVE:We sought to endotype childhood obesity-related asthma by quantifying contributions of obesity-related complications to symptoms and pulmonary function. METHODS:Multiomics analysis using Similarity Network Fusion followed by mediation analysis were performed to quantify prediction of obese asthma phenotype by different combinations of anthropometric, metabolic, nutrient, and T-cell transcriptome and DNA methylome data sets. RESULTS:Two clusters (n = 28 and 26) distinct in their anthropometric (neck and midarm circumference, waist to hip ratio [WHR], and body mass index [BMI] z score), metabolic, nutrient, and T-cell transcriptome and DNA methylome footprint predicted 5 or more pulmonary function indices across 7 different data set combinations. Metabolic measures attenuated the association of neck, WHR, and BMI z score with FEV/forced vital capacity (FVC) ratio and expiratory reserve volume (ERV), of neck, midarm, and BMI z score with functional residual capacity, but only of WHR with inspiratory capacity. Nutrient levels attenuated the association of neck, midarm circumference, and BMI z score with functional residual capacity, and of WHR with FEV/FVC ratio, ERV, and inspiratory capacity. T-cell transcriptome attenuated the association of all 4 anthropometric measures with FEV/FVC ratio, but only of WHR with ERV and inspiratory capacity. The DNA methylome attenuated the association of all 4 anthropometric measures with FEV/FVC ratio and ERV, but only of WHR with inspiratory capacity. CONCLUSIONS:Anthropometric, metabolic, nutrient, and immune perturbations have individual but interdependent contributions to obese asthma phenotype, with the most consistent effect of WHR, highlighting the role of truncal adiposity in endotyping childhood obesity-related asthma. 10.1016/j.jaci.2022.04.033
    In Black and Latinx patients, as-needed inhaled glucocorticoids reduced asthma exacerbations at 15 mo. Annals of internal medicine SOURCE CITATION:Israel E, Cardet JC, Carroll JK, et al. N Engl J Med. 2022;386:1505-18. 35213105. 10.7326/J22-0040
    Evolution of Eczema, Wheeze and Rhinitis from Infancy to Early Adulthood: Four Birth Cohort Studies. American journal of respiratory and critical care medicine BACKGROUND:The relationship between eczema, wheeze/asthma and rhinitis is complex, and epidemiology and mechanisms of their comorbidities is unclear. OBJECTIVE:To investigate within-individual patterns of morbidity of eczema, wheeze and rhinitis from birth to adolescence/early adulthood. METHODS:We investigated onset/progression/resolution of eczema, wheeze and rhinitis using descriptive statistics, sequence mining and Latent Markov modelling (LMM) in four population-based birth cohorts. We used logistic regression to ascertain if early-life eczema or wheeze, or genetic factors (filaggrin mutations and 17q21 variants), increase the risk of multimorbidity. RESULTS:Single conditions, although the most prevalent, were observed significantly less frequently than by chance. There was considerable variation in the timing of onset/remission/persistence/intermittence. Multimorbidity of eczema+wheeze+rhinitis was rare, but significantly over-represented (3-6 times more often than by chance). Although infantile eczema was associated with subsequent multimorbidity, most children with eczema (75.4%) did not progress to any multimorbidity pattern. FLG mutations and rs7216389 were not associated with persistence of eczema/wheeze as single conditions, but both increased the risk of multimorbidity (FLG by 2-3-fold, rs7216389 risk variant by 1.4-1.7-fold). LMM revealed 5 latent states (No disease/low risk; Mainly eczema; Mainly Wheeze; Mainly rhinitis; Multimorbidity). The most likely transition to Multimorbidity was from Eczema state (0.21). However, although this was one of the highest transition probabilities, only 1/5 of those with eczema transitioned to multimorbidity. CONCLUSIONS:Atopic diseases fit a multimorbidity framework, with no evidence for sequential "atopic march" progression. The highest transition to multimorbidity was from eczema, but most children with eczema (>three quarters) had no comorbidities. 10.1164/rccm.202110-2418OC
    The Impact of Insulin Resistance on Loss of Lung Function and Response to Treatment in Asthma. American journal of respiratory and critical care medicine RATIONALE:The role of obesity-associated insulin resistance (IR) in airflow limitation in asthma is uncertain. OBJECTIVES:Using data in the Severe Asthma Research Program 3 (SARP-3), we evaluated relationships between homeostatic measure of IR (HOMA-IR), lung function (cross sectional and longitudinal analyses) and treatment responses to bronchodilators and corticosteroids. METHODS:HOMA-IR values was categorized as without (< 3.0), moderate (3.0-5.0), or severe (>5.0). Lung function included forced expired volume in one second (FEV1) and forced vital capacity (FVC) measured before and after treatment with inhaled albuterol and intramuscular triamcinolone acetonide (TA) and yearly for 5 years. MEASUREMENTS AND MAIN RESULTS:Among 307 participants in SARP-3, 170 (55%) were obese and 140 (46%) had IR. Compared to patients without IR, those with IR had significantly lower values for forced expired volume in one second (FEV1) and forced vital capacity (FVC), and these lower values were not attributable to obesity effects. Compared to patients without IR, those with IR had lower FEV1 responses to beta adrenergic agonists and systemic corticosteroids. The annualized decline in FEV1 was significantly greater in patients with moderate IR (-41 mLs/year) and severe IR (-32 mLs/year,) than in patients without IR (-13mLs/year, p< 0.001 for both comparisons). CONCLUSION:IR is common in asthma and is associated with lower lung function, accelerated loss of lung function, and suboptimal lung function responses to bronchodilator and corticosteroid treatments. Clinical trials in patients with asthma and IR are needed to determine if improving IR might also improve lung function. 10.1164/rccm.202112-2745OC