EAACI guidelines on environmental science for allergy and asthma: The impact of short-term exposure to outdoor air pollutants on asthma-related outcomes and recommendations for mitigation measures.

The EAACI Guidelines on the impact of short-term exposure to outdoor pollutants on asthma-related outcomes provide recommendations for prevention, patient care and mitigation in a framework supporting rational decisions for healthcare professionals and patients to individualize and improve asthma management and for policymakers and regulators as an evidence-informed reference to help setting legally binding standards and goals for outdoor air quality at international, national and local levels. The Guideline was developed using the GRADE approach and evaluated outdoor pollutants referenced in the current Air Quality Guideline of the World Health Organization as single or mixed pollutants and outdoor pesticides. Short-term exposure to all pollutants evaluated increases the risk of asthma-related adverse outcomes, especially hospital admissions and emergency department visits (moderate certainty of evidence at specific lag days). There is limited evidence for the impact of traffic-related air pollution and outdoor pesticides exposure as well as for the interventions to reduce emissions. Due to the quality of evidence, conditional recommendations were formulated for all pollutants and for the interventions reducing outdoor air pollution. Asthma management counselled by the current EAACI guidelines can improve asthma-related outcomes but global measures for clean air are needed to achieve significant impact.

The impact of outdoor pollution and extreme temperatures on asthma-related outcomes: A systematic review for the EAACI guidelines on environmental science for allergic diseases and asthma.

Air pollution is one of the biggest environmental threats for asthma. Its impact is augmented by climate change. To inform the recommendations of the EAACI Guidelines on the environmental science for allergic diseases and asthma, a systematic review (SR) evaluated the impact on asthma-related outcomes of short-term exposure to outdoor air pollutants (PM2.5, PM10, NO2, SO2, O3, and CO), heavy traffic, outdoor pesticides, and extreme temperatures. Additionally, the SR evaluated the impact of the efficacy of interventions reducing outdoor pollutants. The risk of bias was assessed using ROBINS-E tools and the certainty of the evidence by using GRADE. Short-term exposure to PM2.5, PM10, and NO2 probably increases the risk of asthma-related hospital admissions (HA) and emergency department (ED) visits (moderate certainty evidence). Exposure to heavy traffic may increase HA and deteriorate asthma control (low certainty evidence). Interventions reducing outdoor pollutants may reduce asthma exacerbations (low to very low certainty evidence). Exposure to fumigants may increase the risk of new-onset asthma in agricultural workers, while exposure to 1,3-dichloropropene may increase the risk of asthma-related ED visits (low certainty evidence). Heatwaves and cold spells may increase the risk of asthma-related ED visits and HA and asthma mortality (low certainty evidence).

The impact of exposure to tobacco smoke and e-cigarettes on asthma-related outcomes: Systematic review informing the EAACI guidelines on environmental science for allergic diseases and asthma.

To inform the clinical practice guidelines' recommendations developed by the European Academy of Allergy and Clinical Immunology systematic reviews (SR) assessed using GRADE on the impact of environmental tobacco smoke (ETS) and active smoking on the risk of new-onset asthma/recurrent wheezing (RW)/low lung function (LF), and on asthma-related outcomes. Only longitudinal studies were included, almost all on combustion cigarettes, only one assessing e-cigarettes and LF. According to the first SR (67 studies), prenatal ETS increases the risk of RW (moderate certainty evidence) and may increase the risk of new-onset asthma and of low LF (low certainty evidence). Postnatal ETS increases the risk of new-onset asthma and of RW (moderate certainty evidence) and may impact LF (low certainty evidence). Combined in utero and postnatal ETS may increase the risk of new-onset asthma (low certainty evidence) and increases the risk of RW (moderate certainty evidence). According to the second SR (24 studies), ETS increases the risk of severe asthma exacerbations and impairs asthma control and LF (moderate certainty evidence). According to the third SR (25 studies), active smoking increases the risk of severe asthma exacerbations and of suboptimal asthma control (moderate certainty evidence) and may impact asthma-related quality-of-life and LF (low certainty evidence).

The impact of indoor pollution on asthma-related outcomes: A systematic review for the EAACI guidelines on environmental science for allergic diseases and asthma.

Systematic review using GRADE of the impact of exposure to volatile organic compounds (VOCs), cleaning agents, mould/damp, pesticides on the risk of (i) new-onset asthma (incidence) and (ii) adverse asthma-related outcomes (impact). MEDLINE, EMBASE and Web of Science were searched for indoor pollutant exposure studies reporting on new-onset asthma and critical and important asthma-related outcomes. Ninety four studies were included: 11 for VOCs (7 for incidenceand 4 for impact), 25 for cleaning agents (7 for incidenceand 8 for impact), 48 for damp/mould (26 for incidence and 22 for impact) and 10 for pesticides (8 for incidence and 2 for impact). Exposure to damp/mould increases the risk of new-onset wheeze (moderate certainty evidence). Exposure to cleaning agents may be associated with a higher risk of new-onset asthma and with asthma severity (low level of certainty). Exposure to pesticides and VOCs may increase the risk of new-onset asthma (very low certainty evidence). The impact on asthma-related outcomes of all major indoor pollutants is uncertain. As the level of certainty is low or very low for most of the available evidence on the impact of indoor pollutants on asthma-related outcomes more rigorous research in the field is warranted.

Admixture mapping of severe asthma exacerbations in Hispanic/Latino children and youth.

BACKGROUND: In the USA, genetically admixed populations have the highest asthma prevalence and severe asthma exacerbations rates. This could be explained not only by environmental factors but also by genetic variants that exert ethnic-specific effects. However, no admixture mapping has been performed for severe asthma exacerbations. OBJECTIVE: We sought to identify genetic variants associated with severe asthma exacerbations in Hispanic/Latino subgroups by means of admixture mapping analyses and fine mapping, and to assess their transferability to other populations and potential functional roles. METHODS: We performed an admixture mapping in 1124 Puerto Rican and 625 Mexican American children with asthma. Fine-mapping of the significant peaks was performed via allelic testing of common and rare variants. We performed replication across Hispanic/Latino subgroups, and the transferability to non-Hispanic/Latino populations was assessed in 1001 African Americans, 1250 Singaporeans and 941 Europeans with asthma. The effects of the variants on gene expression and DNA methylation from whole blood were also evaluated in participants with asthma and in silico with data obtained through public databases. RESULTS: Genomewide significant associations of Indigenous American ancestry with severe asthma exacerbations were found at 5q32 in Mexican Americans as well as at 13q13-q13.2 and 3p13 in Puerto Ricans. The single nucleotide polymorphism (SNP) rs1144986 (C5orf46) showed consistent effects for severe asthma exacerbations across Hispanic/Latino subgroups, but it was not validated in non-Hispanics/Latinos. This SNP was associated with DPYSL3 DNA methylation and SCGB3A2 gene expression levels. CONCLUSIONS: Admixture mapping study of asthma exacerbations revealed a novel locus that exhibited Hispanic/Latino-specific effects and regulated DPYSL3 and SCGB3A2.

Is exposure to pollen a risk factor for moderate and severe asthma exacerbations?

Limited number of studies have focused on the impact of pollen exposure on asthma. As a part of the EAACI Guidelines on Environment Science, this first systematic review on the relationship of pollen exposure to asthma exacerbations aimed to bridge this knowledge gap in view of implementing recommendations of prevention. We searched electronic iPubMed, Embase, and Web of Science databases using a set of MeSH terms and related synonyms and identified 73 eligible studies that were included for systemic review. When possible, meta-analyses were conducted. Overall meta-analysis suggests that outdoor pollen exposure may have an effect on asthma exacerbation, but caution is needed due to the low number of studies and their heterogeneity. The strongest associations were found between asthma attacks, asthma-related ED admissions or hospitalizations, and an increase in grass pollen concentration in the previous 2-day overall in children aged less than 18 years of age. Tree pollen may increase asthma-related ED visits or admissions lagged up to 7-day overall in individuals younger than 18 years. Rare data show that among subjects under 18 years of age, an exposure to grass pollen lagged up to 3 days may lower lung function. Further research considering effect modifiers of pollen sensitization, hay fever, asthma, air pollution, green spaces, and pre-existing medications is urgently warranted to better evaluate the impacts of pollen on asthma exacerbation. Preventive measures in relation to pollen exposure should be integrated in asthma control as pollen increase continues due to climate change.

Pathogenesis, immunology, and immune-targeted management of the multisystem inflammatory syndrome in children (MIS-C) or pediatric inflammatory multisystem syndrome (PIMS): EAACI Position Paper.

Multisystem inflammatory syndrome in children (MIS-C) is a rare, but severe complication of coronavirus disease 2019 (COVID-19). It develops approximately 4 weeks after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and involves hyperinflammation with multisystem injury, commonly progressing to shock. The exact pathomechanism of MIS-C is not known, but immunological dysregulation leading to cytokine storm plays a central role. In response to the emergence of MIS-C, the European Academy of Allergy and Clinical Immunology (EAACI) established a task force (TF) within the Immunology Section in May 2021. With the use of an online Delphi process, TF formulated clinical statements regarding immunological background of MIS-C, diagnosis, treatment, follow-up, and the role of COVID-19 vaccinations. MIS-C case definition is broad, and diagnosis is made based on clinical presentation. The immunological mechanism leading to MIS-C is unclear and depends on activating multiple pathways leading to hyperinflammation. Current management of MIS-C relies on supportive care in combination with immunosuppressive and/or immunomodulatory agents. The most frequently used agents are systemic steroids and intravenous immunoglobulin. Despite good overall short-term outcome, MIS-C patients should be followed-up at regular intervals after discharge, focusing on cardiac disease, organ damage, and inflammatory activity. COVID-19 vaccination is a safe and effective measure to prevent MIS-C. In anticipation of further research, we propose a convenient and clinically practical algorithm for managing MIS-C developed by the Immunology Section of the EAACI.

Obese Asthma Phenotype Is Associated with hsa-miR-26a-1-3p and hsa-miR-376a-3p Modulating the IGF Axis.

Clarifying inflammatory processes and categorising asthma into phenotypes and endotypes improves asthma management. Obesity worsens severe asthma and reduces quality of life, although its specific molecular impact remains unclear. We previously demonstrated that hsa-miR-26a-1-3p and hsa-miR-376a-3p, biomarkers related to an inflammatory profile, discriminate eosinophilic from non-eosinophilic asthmatics. We aimed to study hsa-miR-26a-1-3p, hsa-miR-376a-3p, and their target genes in asthmatic subjects with or without obesity to find biomarkers and comprehend obese asthma mechanisms. Lung tissue samples were obtained from asthmatic patients (n = 16) and healthy subjects (n = 20). We measured miRNA expression using RT-qPCR and protein levels (IGF axis) by ELISA in confirmation samples from eosinophilic (n = 38) and non-eosinophilic (n = 39) obese (n = 26) and non-obese (n = 51) asthma patients. Asthmatic lungs showed higher hsa-miR-26a-1-3p and hsa-miR-376a-3p expression than healthy lungs. A study of seven genes regulated by these miRNAs revealed differential expression of IGFBP3 between asthma patients and healthy individuals. In obese asthma patients, we found higher hsa-miR-26a-1-3p and IGF-1R values and lower values for hsa-miR-376a-3p and IGFBP-3. Hsa-miR-26a-1-3p and IGFBP-3 were directly and inversely correlated with body mass index, respectively. Hsa-miR-26a-1-3p and hsa-miR-376a-3p could be used as biomarkers to phenotype patients with eosinophilic and non-eosinophilic asthma in relation to comorbid obesity.

Analysis of Differentially Expressed MicroRNAs in Serum and Lung Tissues from Individuals with Severe Asthma Treated with Oral Glucocorticoids.

Nowadays, microRNAs (miRNAs) are increasingly used as biomarkers due to their potential contribution to the diagnosis and targeted treatment of a range of diseases. The aim of the study was to analyze the miRNA expression profiles in serum and lung tissue from patients with severe asthma treated with oral corticosteroids (OCS) and those without OCS treatment. For this purpose, serum and lung tissue miRNAs of OCS and non-OCS asthmatic individuals were evaluated by miRNAs-Seq, and subsequently miRNA validation was performed using RT-qPCR. Additionally, pathway enrichment analysis of deregulated miRNAs was conducted. We observed altered expression by the next-generation sequencing (NGS) of 11 miRNAs in serum, of which five (hsa-miR-148b-3p, hsa-miR-221-5p, hsa-miR-618, hsa-miR-941, and hsa-miR-769-5p) were validated by RT-qPCR, and three miRNAs in lung tissue (hsa-miR-144-3p, hsa-miR-144-5p, and hsa-miR-451a). The best multivariate logistic regression model to differentiate individuals with severe asthma, treated and untreated with OCS, was to combine the serum miRNAs hsa-miR-221-5p and hsa-miR-769-5p. Expression of hsa-miR-148b-3p and hsa-miR-221-5p correlated with FEV1/FVC (%) and these altered miRNAs act in key signaling pathways for asthma disease and the regulated expression of some genes (FOXO3, PTEN, and MAPK3) involved in these pathways. In conclusion, there are miRNA profiles differentially expressed in OCS-treated individuals with asthma and could be used as biomarkers of OCS treatment.

Role of miR-185-5p as modulator of periostin synthesis and smooth muscle contraction in asthma.

Asthma is a chronic respiratory disease produced by an aberrant immune response that originates with breathing difficulties and cough, through airway remodeling. The above pathophysiological events of asthma emerge the regulators of effectors, like epigenetics, which include microRNAs (miRNAs) who perform post-transcriptional regulation, controlling diverse pathways in respiratory diseases. The objective of the study was to determine how miR-185-5p regulates the secretion of periostin by airway structural cells, and smooth muscle cells contraction, both related to airway remodeling in asthma. We used miR-185-5p mimic and inhibitors in bronchial smooth muscle cells (BSMCs) and small airway epithelial cells (SAECs) from healthy subjects. Gene expression and protein levels of periostin (POSTN), CDC42, and RHOA were analyzed by RT-PCR and ELISA/Western blot, respectively. BSMC contractility was analyzed using cell-embedded collagen gels and measurement of intracellular calcium was performed using Fura-2. Additionally, miR-185-5p and periostin expression were evaluated in sputum from healthy and asthmatics. From these experiments, we observed that miR-185-5p modulation regulates periostin mRNA and protein in BSMCs and SAECs. A tendency for diminished miR-185-5p expression and higher periostin levels was seen in sputum cells from asthmatics compared to healthy, with an inverse correlation observed between POSTN and miR-185-5p. Inhibition of miR-185-5p produced higher BSMCs contraction induced by histamine. Calcium mobilization was not modified by miR-185-5p, showing that miR-185-5p role in BSMC contractility is performed by regulating CDC42 and RhoA pro-contractile factors instead. In conclusion, miR-185-5p is a modulator of periostin secretion by airway structural cells and of smooth muscle contraction, which can be related to asthma pathophysiology, and thus, might be a promising therapeutic target.

EAACI position paper on the clinical use of the bronchial allergen challenge: Unmet needs and research priorities.

Allergic asthma (AA) is a common asthma phenotype, and its diagnosis requires both the demonstration of IgE-sensitization to aeroallergens and the causative role of this sensitization as a major driver of asthma symptoms. Therefore, a bronchial allergen challenge (BAC) would be occasionally required to identify AA patients among atopic asthmatics. Nevertheless, BAC is usually considered a research tool only, with existing protocols being tailored to mild asthmatics and research needs (eg long washout period for inhaled corticosteroids). Consequently, existing BAC protocols are not designed to be performed in moderate-to-severe asthmatics or in clinical practice. The correct diagnosis of AA might help select patients for immunomodulatory therapies. Allergen sublingual immunotherapy is now registered and recommended for controlled or partially controlled patients with house dust mite-driven AA and with FEV1 ≥ 70%. Allergen avoidance is costly and difficult to implement for the management of AA, so the proper selection of patients is also beneficial. In this position paper, the EAACI Task Force proposes a methodology for clinical BAC that would need to be validated in future studies. The clinical implementation of BAC could ultimately translate into a better phenotyping of asthmatics in real life, and into a more accurate selection of patients for long-term and costly management pathways.

The impact of type 2 immunity and allergic diseases in atherosclerosis.

Allergic diseases are allergen-induced immunological disorders characterized by the development of type 2 immunity and IgE responses. The prevalence of allergic diseases has been on the rise alike cardiovascular disease (CVD), which affects arteries of different organs such as the heart, the kidney and the brain. The underlying cause of CVD is often atherosclerosis, a disease distinguished by endothelial dysfunction, fibrofatty material accumulation in the intima of the artery wall, smooth muscle cell proliferation, and Th1 inflammation. The opposed T-cell identity of allergy and atherosclerosis implies an atheroprotective role for Th2 cells by counteracting Th1 responses. Yet, the clinical association between allergic disease and CVD argues against it. Within, we review different phases of allergic pathology, basic immunological mechanisms of atherosclerosis and the clinical association between allergic diseases (particularly asthma, atopic dermatitis, allergic rhinitis and food allergy) and CVD. Then, we discuss putative atherogenic mechanisms of type 2 immunity and allergic inflammation including acute allergic reactions (IgE, IgG1, mast cells, macrophages and allergic mediators such as vasoactive components, growth factors and those derived from the complement, contact and coagulation systems) and late phase inflammation (Th2 cells, eosinophils, type 2 innate-like lymphoid cells, alarmins, IL-4, IL-5, IL-9, IL-13 and IL-17).

Molecular allergology and its impact in specific allergy diagnosis and therapy.

Progressive knowledge of allergenic structures resulted in a broad availability of allergenic molecules for diagnosis. Component-resolved diagnosis allowed a better understanding of patient sensitization patterns, facilitating allergen immunotherapy decisions. In parallel to the discovery of allergenic molecules, there was a progressive development of a regulation framework that affected both in vitro diagnostics and Allergen Immunotherapy products. With a progressive understanding of underlying mechanisms associated to Allergen immunotherapy and an increasing experience of application of molecular diagnosis in daily life, we focus in analyzing the evidences of the value provided by molecular allergology in daily clinical practice, with a focus on Allergen Immunotherapy decisions.

EAACI Biologicals Guidelines-Recommendations for severe asthma.

Severe asthma imposes a significant burden on patients, families and healthcare systems. Management is difficult, due to disease heterogeneity, co-morbidities, complexity in care pathways and differences between national or regional healthcare systems. Better understanding of the mechanisms has enabled a stratified approach to the management of severe asthma, supporting the use of targeted treatments with biologicals. However, there are still many issues that require further clarification. These include selection of a certain biological (as they all target overlapping disease phenotypes), the definition of response, strategies to enhance the responder rate, the duration of treatment and its regimen (in the clinic or home-based) and its cost-effectiveness. The EAACI Guidelines on the use of biologicals in severe asthma follow the GRADE approach in formulating recommendations for each biological and each outcome. In addition, a management algorithm for the use of biologicals in the clinic is proposed, together with future approaches and research priorities.

Food allergy as an asthma comorbidity in children and adolescents: a practical approach through a real-world study.

INTRODUCTION: Several studies have shown interactions between food allergy (FA) and asthma, but the influence of FA in asthma traits has been scarcely studied. METHODS: A real-world retrospective observational study was conducted among patients between 3 and 18 years old referred to our Asthma Clinic from November 2014 to November 2017. Data were obtained from daily clinical practice. Only patients properly diagnosed with asthma and FA were included. RESULTS: 815 patients were included: 483 asthmatics and 332 non-asthmatics and 180 FA and 635 no FA. Food allergy was statistically more prevalent among asthma patients (p = 0.014). In a high pollen exposure area, Madrid, among subjects with asthma (121 FA, 362 no-FA), sensitization to lipid transfer protein (LTP) (p = 0.016, OR: 3.064, RR: 2.512) and pollen (p = 0.016, OR: 3.064, RR: 2.512) are risk factors to have a concomitant FA diagnosis, whereas sensitization to profilin is not. Peripheral blood eosinophils were higher in subjects with asthma and FA (≥450 eos/µL) than in asthmatics without FA (≤300 eos/µL) (p = 0.031). Blood eosinophilia, using a cut-off >300 eos/µL, was only present in the FA group. Therefore, this trait should be considered when phenotyping a patient as eosinophilic asthma. Sex had an impact on several variables: height, weight, BMI, blood eosinophils count, sensitization profile, and early-onset asthma. CONCLUSIONS: Asthma and FA are closely related and the presence of FA should be investigated in every asthma patient. This study shows an association between asthma with concomitant FA and sensitization to pollen and LTP, blood eosinophilia, and growth alterations. Differences between boys and girls were also described, so a sex-specific approach is recommended.

Changes in Serum MicroRNAs after Anti-IL-5 Biological Treatment of Severe Asthma.

There is currently enough evidence to think that miRNAs play a role in several key points in asthma, including diagnosis, severity of the disease, and response to treatment. Cells release different types of lipid double-membrane vesicles into the extracellular microenvironment, including exosomes, which function as very important elements in intercellular communication. They are capable of distributing genetic material, mRNA, mitochondrial DNA, and microRNAs (miRNAs). Serum miRNA screening was performed in order to analyze possible changes in serum miRNAs in 10 patients treated with reslizumab and 6 patients with mepolizumab after 8 weeks of treatment. The expression of miR-338-3p was altered after treatment (p < 0.05), although no significant differences between reslizumab and mepolizumab were found. Bioinformatic analysis showed that miR-338-3p regulates important pathways in asthma, such as the MAPK and TGF-ß signaling pathways and the biosynthesis/degradation of glucans (p < 0.05). However, it did not correlate with an improvement in lung function. MiRNA-338-3p could be used as a biomarker of early response to reslizumab and mepolizumab in severe eosinophilic asthmatic patients. In fact, this miRNA could be involved in airway remodeling, targeting genes related to MAPK and TGF-ß signaling pathways.

Efficacy and safety of treatment with dupilumab for severe asthma: A systematic review of the EAACI guidelines-Recommendations on the use of biologicals in severe asthma.

Dupilumab, a fully human monoclonal antibody against interleukin-4 receptor α, is approved as add-on maintenance treatment for inadequately controlled type 2 severe asthma. This systematic review evaluated the efficacy, safety and economic impact of dupilumab compared to standard of care for uncontrolled severe asthma. PubMed, EMBASE and Cochrane Library were searched for RCTs and health economic evaluations. Critical and important asthma-related outcomes were evaluated. The risk of bias and the certainty of the evidence were assessed using GRADE. Three RCTs including 2735 subjects >12 years old and 24-52 weeks of follow-up were included. Dupilumab reduced with high certainty severe asthma exacerbations (Incidence rate ratio 0.51; 95% CI 0.45-0.59) and the percentage use of oral corticosteroid use (mean difference (MD) -28.2 mg/d; 95% CI -40.7 to -15.7). Asthma control (ACQ-5), quality of life (AQLQ) and rescue medication use [puffs/d] improved, without reaching the minimal important clinical difference: ACQ-5 MD -0.28 (95% CI -0.39 to -0.17); AQLQ MD +0.28 (95% CI 0.20-0.37); and rescue medication MD -0.35 (95% CI -0.73 to +0.02). FEV1 increased (MD +0.15; 95% CI +0.11 to +0.18) (moderate certainty). There was an increased rate of dupilumab-related adverse events (AEs) (moderate certainty) and of drug-related serious AEs (low certainty). The incremental cost-effectiveness ratio of dupilumab versus standard therapy was 464 000$/QALY (moderate certainty). More data on long-term safety are needed both for children and for adults, together with more efficacy data in the paediatric population.

Efficacy and safety of treatment with biologicals (benralizumab, dupilumab, mepolizumab, omalizumab and reslizumab) for severe eosinophilic asthma. A systematic review for the EAACI Guidelines - recommendations on the use of biologicals in severe asthma.

Five biologicals have been approved for severe eosinophilic asthma, a well-recognized phenotype. Systematic reviews (SR) evaluated the efficacy and safety of benralizumab, dupilumab, mepolizumab, omalizumab and reslizumab (alphabetical order) compared to standard of care for severe eosinophilic asthma. PubMed, Embase and Cochrane Library were searched to identify RCTs and health economic evaluations, published in English. Critical and important asthma-related outcomes were evaluated for each of the biologicals. The risk of bias and the certainty of the evidence were assessed using GRADE. 19 RCTs (three RCTs for benralizumab, three RCTs for dupilumab, three RCTs for mepolizumab, five RCTs for omalizumab and five RCTs for reslizumab), including subjects 12 to 75 years old (except for omalizumab including also subjects 6-11 years old), ranging from 12 to 56 weeks were evaluated. All biologicals reduce exacerbation rates with high certainty of evidence: benralizumab incidence rate ratio (IRR) 0.53 (95% CI 0.39 to 0.72), dupilumab (IRR) 0.43 (95% CI 0.32 to 0.59), mepolizumab IRR 0.49 (95% CI 0.38 to 0.66), omalizumab (IRR) 0.56 (95% CI 0.40 to 0.77) and reslizumab (IRR) 0.46 (95% CI 0.37 to 0.58). Benralizumab, dupilumab and mepolizumab reduce the daily dose of oral corticosteroids (OCS) with high certainty of evidence. All evaluated biologicals probably improve asthma control, QoL and FEV1 , without reaching the minimal important difference (moderate certainty). Benralizumab, mepolizumab and reslizumab slightly increase drug-related adverse events (AE) and drug-related serious AE (low to very low certainty of evidence). The incremental cost-effectiveness ratio per quality-adjusted life year value is above the willingness to pay threshold for all biologicals (moderate certainty). Potential savings are driven by decrease in hospitalizations, emergency and primary care visits. There is high certainty that all approved biologicals reduce the rate of severe asthma exacerbations and for benralizumab, dupilumab and mepolizumab for reducing OCS. There is moderate certainty for improving asthma control, QoL, FEV1 . More data on long-term safety are needed together with more efficacy data in the paediatric population.

Efficacy and safety of treatment with biologicals (benralizumab, dupilumab and omalizumab) for severe allergic asthma: A systematic review for the EAACI Guidelines - recommendations on the use of biologicals in severe asthma.

Allergic asthma is a frequent asthma phenotype. Both IgE and type 2 cytokines are increased, with some degree of overlap with other phenotypes. Systematic reviews assessed the efficacy and safety of benralizumab, dupilumab and omalizumab (alphabetical order) vs standard of care for patients with uncontrolled severe allergic asthma. PubMed, Embase and Cochrane Library were searched to identify RCTs and health economic evaluations, published in English. Critical and important asthma-related outcomes were evaluated. The risk of bias and the certainty of the evidence were assessed using GRADE. All three biologicals reduced with high certainty the annualized asthma exacerbation rate: benralizumab incidence rate ratios (IRR) 0.63 (95% CI 0.50 - 0.81); dupilumab IRR 0.58 (95%CI 0.47 - 0.73); and omalizumab IRR 0.56 (95%CI 0.42 - 0.73). Benralizumab and dupilumab improved asthma control with high certainty and omalizumab with moderate certainty; however, none reached the minimal important difference (MID). Both benralizumab and omalizumab improved QoL with high certainty, but only omalizumab reached the MID. Omalizumab enabled ICS dose reduction with high certainty. Benralizumab and omalizumab showed an increase in drug-related adverse events (AEs) with low to moderate certainty. All three biologicals had moderate certainty for an ICER/QALY value above the willingness to pay threshold. There was high certainty that in children 6-12 years old omalizumab decreased the annualized exacerbation rate [IRR 0.57 (95%CI 0.45-0.72)], improved QoL [relative risk 1.43 (95%CI 1.12 -1.83)], reduced ICS [mean difference (MD) -0.45 (95% CI -0.58 to -0.32)] and rescue medication use [ MD -0.41 (95%CI -0.66 to -0.15)].