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BackgroundPatients with severe asthma may present with characteristics representing overlapping phenotypes, making them eligible for more than one class of biologic. Our aim was to describe the profile of adult patients with severe asthma eligible for both anti-IgE and anti-IL5/5R and to compare the effectiveness of both classes of treatment in real life.MethodsThis was a prospective cohort study that included adult patients with severe asthma from 22 countries enrolled into the International Severe Asthma registry (ISAR) who were eligible for both anti-IgE and anti-IL5/5R. The effectiveness of anti-IgE and anti-IL5/5R was compared in a 1:1 matched cohort. Exacerbation rate was the primary effectiveness endpoint. Secondary endpoints included long-term-oral corticosteroid (LTOCS) use, asthma-related emergency room (ER) attendance, and hospital admissions.ResultsIn the matched analysis (n = 350/group), the mean annualized exacerbation rate decreased by 47.1% in the anti-IL5/5R group and 38.7% in the anti-IgE group. Patients treated with anti-IL5/5R were less likely to experience a future exacerbation (adjusted IRR 0.76; 95% CI 0.64, 0.89; p ConclusionsIn real life, both anti-IgE and anti-IL5/5R improve asthma outcomes in patients eligible for both biologic classes; however, anti-IL5/5R was superior in terms of reducing asthma exacerbations and LTOCS use. Background: Patients with severe asthma may present with characteristics representing overlapping phenotypes, making them eligible for more than one class of biologic. Our aim was to describe the profile of adult patients with severe asthma eligible for both anti-IgE and anti-IL5/5R and to compare the effectiveness of both classes of treatment in real life. Methods: This was a prospective cohort study that included adult patients with severe asthma from 22 countries enrolled into the International Severe Asthma registry (ISAR) who were eligible for both anti-IgE and anti-IL5/5R. The effectiveness of anti-IgE and anti-IL5/5R was compared in a 1:1 matched cohort. Exacerbation rate was the primary effectiveness endpoint. Secondary endpoints included long-term-oral corticosteroid (LTOCS) use, asthma-related emergency room (ER) attendance, and hospital admissions. Results: In the matched analysis (n = 350/group), the mean annualized exacerbation rate decreased by 47.1% in the anti-IL5/5R group and 38.7% in the anti-IgE group. Patients treated with anti-IL5/5R were less likely to experience a future exacerbation (adjusted IRR 0.76; 95% CI 0.64, 0.89; p < 0.001) and experienced a greater reduction in mean LTOCS dose than those treated with anti-IgE (37.44% vs. 20.55% reduction; p = 0.023). There was some evidence to suggest that patients treated with anti-IL5/5R experienced fewer asthma-related hospitalizations (IRR 0.64; 95% CI 0.38, 1.08), but not ER visits (IRR 0.94, 95% CI 0.61, 1.43). Conclusions: In real life, both anti-IgE and anti-IL5/5R improve asthma outcomes in patients eligible for both biologic classes; however, anti-IL5/5R was superior in terms of reducing asthma exacerbations and LTOCS use.

Inflammation, structural, and functional abnormalities within the airways are key features of asthma. Although these processes are well documented, their expression varies across the heterogeneous spectrum of asthma. Type 2 inflammatory responses are characterized by increased levels of eosinophils, FeNO, and type 2 cytokines in blood and/or airways. Presently, type 2 asthma is the best-defined endotype, typically found in patients with allergic asthma, but surprisingly also in nonallergic patients with (severe) asthma. The etiology of asthma with non-type 2 inflammation is less clear. During the past decade, targeted therapies, including biologicals and small molecules, have been increasingly integrated into treatment strategies of severe asthma. These treatments block specific inflammatory pathways or single mediators. Single or composite biomarkers help to identify patients who will benefit from these treatments. So far, only a few inflammatory biomarkers have been validated for clinical application. The European Academy of Allergy & Clinical Immunology Task Force on Biomarkers in Asthma was initiated to review different biomarker sampling methods and to investigate clinical applicability of new and existing inflammatory biomarkers (point-of-care) to support diagnosis, targeted treatment, and monitoring of severe asthma. Subsequently, we discuss existing and novel targeted therapies for asthma as well as applicable biomarkers.

ispartof: ALLERGY vol:74 issue:4 pages:837-840 ispartof: location:Denmark status: published

BACKGROUND: Impaired antiviral interferon expression may be involved in asthma exacerbations commonly caused by rhinovirus infections. Allergy is a known risk factor for viral-induced asthma exacerbation, but little is known whether allergens may affect interferon responses.OBJECTIVE: Our hypothesis is that house dust mite (HDM) impairs viral stimulus-induced antiviral signalling.METHODS: Experimental asthma exacerbations were produced in vitro in human bronchial epithelial cells (HBECs) and in mice by using sequential challenges with HDM and a viral infection mimic, Poly(I:C). We examined rhinovirus pattern recognition receptors (PRRs) signalling pathways and potential mechanisms of impaired interferon response.RESULTS: HBECs and mice exposed to HDM prior to Poly(I:C) exhibited a reduced antiviral response compared to Poly(I:C) alone, including reduced IFN-β, IFN-lambda, TLR3, RIG-I, MDA5, IRF-3 and IRF-7. Heat-inactivation of HDM partially restored the TLR3-induced interferon response in vitro and in vivo. Our HBEC-data further showed that HDM directly affects TLR3 signalling by targeting the receptor glycosylation level.CONCLUSIONS: Direct effects of allergens such as HDM on PRRs can present as potential mechanism for defective antiviral airway responses. Accordingly, therapeutic measures targeting inhibitory effects of allergens on antiviral PRRs may find use as a strategy to boost antiviral response and ameliorate exacerbations in asthmatic patients. This article is protected by copyright. All rights reserved. (Less)

Novel therapies such as type 2 targeting biologics are emerging treatment options for patients with chronic inflammatory respiratory diseases, fulfilling the needs of severely uncontrolled patients. The majority of patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and over half of patients with asthma show a type 2 inflammatory signature in sinonasal mucosa and/or lungs. Importantly, both chronic respiratory diseases are frequent comorbidities, ensuring alleviation of both upper and lower airway pathology by systemic biological therapy. Type 2-targeting biologics such as anti-IgE, anti-IL4Rα, anti-IL5, and anti-IL5Rα have entered the market for selected pheno/endotypes of asthma patients and may soon also become available for CRSwNP patients. Given the high prevalence of chronic respiratory diseases and the high cost associated with biologics, patient selection is crucial in order to implement such therapies into chronic respiratory disease care pathways. The European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) organized a multidisciplinary Expert Board Meeting to discuss the positioning of biologics into the care pathways for CRSwNP patients with and without comorbid asthma. ispartof: ALLERGY vol:74 issue:12 pages:2312-2319 ispartof: location:Denmark status: published

Introduction: Increased exhaled nitric oxide (NO) levels in asthma are suggested to be through inducible NO synthase (iNOS). The aim of this study was to investigate the expression of iNOS in bronchoalveolar lavage (BAL) cells and tissue from central and peripheral airways and compare it with the exhaled bronchial and alveolar NO levels in patients with asthma vs a control group. Methods: Thirty-two patients with asthma (defined as controlled or uncontrolled according to Asthma Control Test score cut-off: 20) and eight healthy controls were included. Exhaled NO was measured, and alveolar concentration and bronchial flux were calculated. iNOS was measured in central and peripheral lung biopsies, as well as BAL cells. Bronchoalveolar lavage macrophages were stimulated in vitro, and iNOS expression and NO production were investigated. Results: Expression of iNOS was increased in central airway tissue and the alveolar compartment in uncontrolled as compared to controlled asthmatics and healthy controls. There were no differences, however, in iNOS mRNA levels in total BAL cells in uncontrolled as compared to controlled asthma. Bronchoalveolar lavage cell mRNA levels of iNOS or iNOS expression in central and alveolar tissue did not relate to alveolar NO, nor to bronchial flux of NO. In vitro stimulation with leukotriene D4 increased iNOS mRNA levels and NO production in cultured BAL macrophages. Conclusion: The levels of both bronchial and alveolar iNOS are increased in uncontrolled as compared to controlled asthma. However, levels of iNOS in BAL macrophages were not reflected by alveolar NO. Both central and distal iNOS levels may reflect responsiveness to steroid treatment. (Less)

Background: In atopic asthma, chronic Th2-biased inflammation is associated with an increased risk of pneumococcal infection. The anionic phosphoglycoprotein osteopontin (OPN) is highly expressed in asthma and has been ascribed several roles during inflammation. This study aimed to investigate whether OPN affects inflammation and vulnerability to pneumococcal infection in atopic asthma. Methods: House dust mite (HDM) extract was used to induce allergic airway inflammation in both wild-type (Spp1+/+) and OPN knockout (Spp1−/−) C57BL/6J mice, and the airway was then infected with Streptococcus pneumoniae. Parameters reflecting inflammation, tissue injury, and bacterial burden were measured. In addition, samples from humans with allergic asthma were analyzed. Results: Both allergen challenge in individuals with allergic asthma and the intranasal instillation of HDM in mice resulted in increased OPN levels in bronchoalveolar lavage fluid (BALF). More immune cells (including alveolar macrophages, neutrophils, eosinophils, and lymphocytes) and higher levels of proinflammatory cytokines were found in Spp1−/− mice than in Spp1+/+ mice. Moreover, OPN-deficient mice exhibited increased levels of markers reflecting tissue injury. Upon infection with S. pneumoniae, Spp1+/+ mice with allergic airway inflammation had a significantly lower bacterial burden in both BALF and lung tissue than did Spp1−/− mice. Furthermore, Spp1−/− mice had higher levels of cytokines and immune cells in BALF than did Spp1+/+ mice. Conclusion: OPN reduces inflammation, decreases tissue injury, and reduces bacterial loads during concurrent pneumococcal infection and allergic airway inflammation in a murine model. These findings suggest that OPN significantly affects vulnerability to pneumococcal infection in atopic asthma. (Less)

Background This placebo-controlled study assessed the effects of the once-daily inhaled corticosteroid (ICS) fluticasone furoate (FF) and long-acting beta2-agonist (LABA) vilanterol (VI) on early and late asthmatic responses (EAR/LAR) and airway hyper-responsiveness (AHR). Methods Patients (n = 27) were randomized to FF (100 μg), VI (25 μg), FF/VI (100/25 μg), and placebo for 21 days (four periods). Allergen challenge was performed 1 h post-dose on day 21. AHR was assessed on day 22 using methacholine. Results Allergen challenge caused an early change (0–2 h) in minimum forced expiratory volume in 1 s (FEV1) of −1.091 l (95% CI: −1.344; −0.837) following placebo therapy; changes were −0.955 l (−1.209; −0.702), −0.826 l (−1.070; −0.581), and −0.614 l (−0.858; −0.370) following VI, FF, or FF/VI therapy, respectively. Treatment differences were significant for all comparisons between therapies. Mean changes in 0–2 h %FEV1 were as follows: −28.05 (placebo), −23.10 (VI), −22.33 (FF), and −16.10 (FF/VI). Following placebo, the late change (4–10 h) in weighted mean FEV1 was −0.466 l (−0.589; −0.343) and −0.298 l (−0.415; −0.181) after VI, and was +0.018 l with both FF/VI (−0.089; 0.124) and FF (−0.089; 0.125). Treatment differences were significant for all comparisons between therapies except FF/VI vs FF. Mean changes in 4–10 h %FEV1 were as follows: −21.08 (placebo), −14.30 (VI), −5.02 (FF), and −5.83 (FF/VI). AHR 24 h after allergen challenge was significantly reduced with FF/VI and FF vs placebo, and FF/VI was superior to either component. Conclusion Combined treatment with FF/VI provides additive protection from the EAR relative to its components, significant protection over VI alone from the LAR, and confers sustained protection from hyper-responsiveness 24 h post-dose.

Background: A unique feature of alveolar mast cells is their low high-affinity IgE receptor (FceRI) expression. Recent discoveries in uncontrolled asthma suggest that the appearance of FceRI-expressing alveolar mast cells may be a novel disease-specific feature of allergic asthma. This study investigates whether increased FceRI-expressing alveolar mast cells are present in patients with mild allergic asthma or even in non-asthmatic allergic rhinitis patients (AR) who have developed bronchial hyperactivity (BHR). Methods: Bronchial and alveolar tissues were obtained from healthy controls, AR patients with or without BHR, and AR patients with concurrent asthma. Samples were processed for immunohistochemical identification of MC(T) and MC(TC) and expression of FceRI and surface-bound IgE. Results: Bronchial mast cell expression of FceRI was high in all groups. In contrast, in the alveolar tissue, the expression of FceRI on mast cells was low in healthy controls and in the AR patient groups, whereas a high expression was present in AR patients with concurrent asthma (P = 0.006 compared to controls). The asthmatics had a 29-fold increase in numbers (P = 0.006) and a 19-fold increase in proportion (P = 0.007) of alveolar mast cells that expressed surface-bound IgE. Conclusions: The present data show that alveolar mast cells in patients with mild atopic asthma, but not atopic patients with AR, have turned into a highly FceRI- and IgE-expressing phenotype. These data support the hypothesis that increased FceRI expression on alveolar mast cells is a novel disease-specific feature of allergic asthma that is important for understanding asthma phenotypes and designing new therapeutic strategies. (Less)

A methacholine or a histamine test is often used to quantitate bronchial responsiveness, in studies investigating the influence of various inhaled stimuli on the responsiveness and composition of bronchoalveolar lavage (BAL) fluid. Histamine has been shown to evoke an inflammatory cell response in BAL fluid. In order to test the influence of the methacholine test on the cellular composition of BAL fluid, we investigated 14 healthy, nonsmoking volunteers with a methacholine test 24 h before performing a BAL. The results showed no significant changes in the cellular composition of BAL fluid, as compared with control BAL in the same persons.

To examine the influence of the histamine chloride challenge test on the bronchoalveolar lavage cell population, lavage fluid from 15 subjects was collected 24 h after the histamine test, and was compared with the lavage fluid from a reference group of 25 subjects. Inhaled histamine is commonly used to quantitate non-specific bronchial responsiveness. Increase in airway responsiveness after exposure to ozone or allergen is associated with airway inflammation. Bronchoalveolar lavage, has therefore become a valuable tool in the study of bronchoalveolar cells and mediators in subjects with asthma and bronchial hyperresponsiveness. The total cell number and differential cell counts in bronchoalveolar lavage fluid 24 h after inhalation challenge test with histamine-chloride were studied. There was a significant increase in lymphocytes, mast cells and neutrophils after histamine test. The conclusion was that inhaled histamine-chloride can induce an inflammatory cell response in the lung. Thus the histamine-chloride test should not be performed before bronchoalveolar lavage.