International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis.

BACKGROUND: Critical examination of the quality and validity of available allergic rhinitis (AR) literature is necessary to improve understanding and to appropriately translate this knowledge to clinical care of the AR patient. To evaluate the existing AR literature, international multidisciplinary experts with an interest in AR have produced the International Consensus statement on Allergy and Rhinology: Allergic Rhinitis (ICAR:AR). METHODS: Using previously described methodology, specific topics were developed relating to AR. Each topic was assigned a literature review, evidence-based review (EBR), or evidence-based review with recommendations (EBRR) format as dictated by available evidence and purpose within the ICAR:AR document. Following iterative reviews of each topic, the ICAR:AR document was synthesized and reviewed by all authors for consensus. RESULTS: The ICAR:AR document addresses over 100 individual topics related to AR, including diagnosis, pathophysiology, epidemiology, disease burden, risk factors for the development of AR, allergy testing modalities, treatment, and other conditions/comorbidities associated with AR. CONCLUSION: This critical review of the AR literature has identified several strengths; providers can be confident that treatment decisions are supported by rigorous studies. However, there are also substantial gaps in the AR literature. These knowledge gaps should be viewed as opportunities for improvement, as often the things that we teach and the medicine that we practice are not based on the best quality evidence. This document aims to highlight the strengths and weaknesses of the AR literature to identify areas for future AR research and improved understanding

Allergic Sensitization in Rhinitis and Asthma

Allergic rhinitis (AR) is usually defined as an inflammatory disease of the nasal mucosa induced by an interaction of environmental allergens and IgE in sensitized patients. Its symptoms are sneezing, nasal itching, rhinorrhoea and nasal obstruction. Allergic rhinitis affects approximately 20- 30% of the population worldwide and its prevalence is increasing. Isolated AR is rare and it actually has to be considered as a systemic allergic disease, associated to comorbidities, such as conjunctivitis, chronic middle ear effusions, irregular sleep, sinusitis, lymphoid hypertrophy with obstructive sleep apnoea. The most relevant comorbidity is asthma, a heterogeneous disease, usually characterized by chronic airway inflammation in which many cells and cellular elements play an important role. Bronchial asthma is characterized by bronchial hyper-reactivity and symptoms may be triggered or worsened by factors such as viral infections, allergens, tobacco smoke, exercise and stress. A state of "minimal persistent inflammation" is permanently maintained in the lower respiratory tract of asthmatic individuals. The diagnosis of asthma is based on evidence of variable airflow limitation tested with spirometry and a positive bronchodilation reversibility test. Skin prick tests (SPTs) are widely used to demonstrate an immediate IgE-mediated allergic reaction. They represent a major diagnostic tool in the field of allergy. Skin prick tests have a high specificity and sensitivity for the diagnosis of inhalant allergens. Immunotherapy (AIT) for allergic diseases has entered in a new age characterized by the development of a few innovative therapeutic classes of standardized allergen formulations registered. Clinical randomized trials have demonstrated the efficacy of AIT in allergic rhinitis in children and in adults, expressed in terms of reduction of symptom score and use of rescue medication. The efficacy is confirmed both for subcutaneous (SCIT) and sublingual (SLIT) immunotherapy in adults and in pediatric patients. The long lasting effect of AIT after its discontinuation is an important added value of this therapy. Controlled studies are available, where the carry-over effect of AIT is demonstrated for two years after discontinuance. The capacity to prevent new sensitizations, and to modify the evolution of the disease from the rhinitis to asthma are two important features of AIT. Allergen immunotherapy showed preventive capacity and also a carryover effect once treatment is discontinued

International consensus statement on allergy and rhinology: Allergic rhinitis – 2023

Background: In the 5 years that have passed since the publication of the 2018 International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis (ICAR-Allergic Rhinitis 2018), the literature has expanded substantially. The ICAR-Allergic Rhinitis 2023 update presents 144 individual topics on allergic rhinitis (AR), expanded by over 40 topics from the 2018 document. Originally presented topics from 2018 have also been reviewed and updated. The executive summary highlights key evidence-based findings and recommendation from the full document. Methods: ICAR-Allergic Rhinitis 2023 employed established evidence-based review with recommendation (EBRR) methodology to individually evaluate each topic. Stepwise iterative peer review and consensus was performed for each topic. The final document was then collated and includes the results of this work. Results: ICAR-Allergic Rhinitis 2023 includes 10 major content areas and 144 individual topics related to AR. For a substantial proportion of topics included, an aggregate grade of evidence is presented, which is determined by collating the levels of evidence for each available study identified in the literature. For topics in which a diagnostic or therapeutic intervention is considered, a recommendation summary is presented, which considers the aggregate grade of evidence, benefit, harm, and cost. Conclusion: The ICAR-Allergic Rhinitis 2023 update provides a comprehensive evaluation of AR and the currently available evidence. It is this evidence that contributes to our current knowledge base and recommendations for patient evaluation and treatment

International consensus statement on allergy and rhinology: Allergic rhinitis – 2023

Background In the 5 years that have passed since the publication of the 2018 International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis (ICAR-Allergic Rhinitis 2018), the literature has expanded substantially. The ICAR-Allergic Rhinitis 2023 update presents 144 individual topics on allergic rhinitis (AR), expanded by over 40 topics from the 2018 document. Originally presented topics from 2018 have also been reviewed and updated. The executive summary highlights key evidence-based findings and recommendation from the full document. Methods ICAR-Allergic Rhinitis 2023 employed established evidence-based review with recommendation (EBRR) methodology to individually evaluate each topic. Stepwise iterative peer review and consensus was performed for each topic. The final document was then collated and includes the results of this work. Results ICAR-Allergic Rhinitis 2023 includes 10 major content areas and 144 individual topics related to AR. For a substantial proportion of topics included, an aggregate grade of evidence is presented, which is determined by collating the levels of evidence for each available study identified in the literature. For topics in which a diagnostic or therapeutic intervention is considered, a recommendation summary is presented, which considers the aggregate grade of evidence, benefit, harm, and cost. Conclusion The ICAR-Allergic Rhinitis 2023 update provides a comprehensive evaluation of AR and the currently available evidence. It is this evidence that contributes to our current knowledge base and recommendations for patient evaluation and treatment

Investigating problematic severe asthma in children : a translational approach

Children with problematic severe asthma (PA) have persistent symptoms and/or severe exacerbations despite treatment with high doses of currently available asthma medications. The term PA includes children who are difficult to treat due to unidentified exacerbating factors (e.g. allergens or environmental hazards, comorbidities, psychological and social issues, and/or poor adherence) and those lacking identifiable aggravating factors but, nonetheless, do not respond well to asthma therapy. Children with PA are a heterogeneous group of patients with varying clinical presentations, pulmonary function and patterns of inflammation. This thesis is based on the results of a Swedish nationwide cross-sectional study in which school aged children with PA (n=57) were compared to age matched peers with persistent, but controlled asthma (CA), (n=39). The major objectives were to identify distinguishing features of children suffering from PA, to differentiate between children who were difficult to treat and those who were severely resistant to therapy and to investigate novel and potentially clinical relevant biomarkers of PA. PA was defined by insufficient asthma control despite high doses of inhaled corticosteroids. The protocol included a detailed characterization of: history and clinical presentation; pulmonary function; bronchial hyperresponsiveness; inflammatory biomarkers in blood (including white blood cells, interleukin-5 and chitinases (chitotriosidase and the chitinase-like protein YKL-40)), urine (EPX) and exhaled air (FeNO); allergy (IgE antibodies, component resolved allergy diagnostics, basophil allergen threshold sensitivity (CD-sens)); morphology (computerized tomography of sinuses and lungs (in the PA group only)). The major distinguishing features of children with PA involve familial background (heredity, socioeconomic status), clinical presentation (comorbidities and triggering factors) and pathophysiological differences including degree of airway obstruction, bronchial hyperresponsiveness and inflammatory profile (IL-5, number of eosinophilic and neutrophilic cells in blood). Sixty percent of children with PA had therapy-resistant asthma, with the remainder being difficult to treat due to identified aggravating factors. Individual IgE-responses were similar between children with PA and CA. Children with PA were more often multi-sensitized to > 3 single lipocalin (nMus m 1, rEqu c 1, Fel d 4, rCan f 1, 2), kallikrein (rCan f 5) and secretoglobin (rFel d 1) allergens compared to children with CA. Cat-allergic children with PA had higher allergen sensitivity, as measured by CDsens, compared to cat-allergic peers with CA. Furthermore, CD-sens correlated with clinical markers of asthmatic disease, including asthma control and biomarkers of eosinophilic inflammation. YKL-40 levels and chitotriosidase activity were increased in the serum of children with PA, and YKL-40 specifically correlated with airway remodelling (as assessed by computerized tomography) and blood neutrophils in children severely resistant to asthma therapy. By employing a comprehensive and standardized clinical assessment we have discerned specific features of children with PA and identified children who are severely resistant to therapy. We have applied two novel methods of allergy diagnostics (Component resolved diagnostics and CD-sens) and found that these two methods provide relevant information when investigating children with PA. Finally, our findings confirm that YKL-40 is a potential biomarker of asthma severity and airway remodeling. A translational research approach is necessary when investigating associations between disease mechanisms and clinical presentation in complex diseases

Diagnosis of dog allergy in children : molecular assessment and refined characterization

Dog allergy is a common cause of rhinitis and asthma in children, yet the diagnosis is a clinical challenge. Allergic sensitization, i.e. the presence of serum IgE antibodies, to dog dander affect up to 30 % of all children and adolescents, but not all sensitized children display symptoms. The most important diagnostic tool, the detection of IgE antibodies to dog dander extracts in serum does not reveal which allergen molecule in the extract that gives rise to the allergic sensitization and symptoms. Through molecular allergy diagnostics it is now possible to detect allergic sensitization to specific allergen molecules from dog, but the clinical relevance of sensitization to the different dog allergen molecules is not yet clear. When our investigations were initiated in 2014, there were six recognized dog allergen molecules, Can f 1- Can f 6, of whom Can f 1, Can f 2, Can f 4 and Can f 6 belong to the lipocalin protein family. Can f 3 is the dog serum albumin, and Can f 5 is the male dog allergen prostatic kallikrein. The overall aim of this doctoral thesis was to improve diagnostics of dog allergy by identifying patterns of sensitization to dog allergen molecules associated with rhinitis and asthma in dog dander sensitized children and by exploring novel biomarkers and complementary diagnostic tests for dog allergy. In paper I, we found that a positive nasal provocation test with dog dander extract was associated with an increasing number of positive sensitizations to dog allergen molecules and with sensitization to allergens from the lipocalin protein family. When investigating the impact of the different allergens, we found that sensitization to Can f 3, Can f 4 and Can f 6 conferred an increased risk for a positive vs a negative nasal challenge. On the contrary, monosensitization to Can f 5 was associated with a negative nasal provocation test. In paper II, we showed that the basophil activation tests to allergen molecules, evaluated by the basophil allergen threshold sensitivity (CD-sens), were positive in a majority of the sensitized children with a positive, as well as in those with a negative nasal provocation test. However, the levels of CD-sens to dog dander and to Can f 1 were higher in children with a positive nasal provocation. The levels of IgG or IgG4 to the investigated allergens did not differ between sensitized children with a positive and a negative nasal provocation test, while sensitized children with a dog at home had higher levels of IgG4 to Can f 1 and Can f 5 and lower CD-sens to all investigated allergen molecules. In paper III, we performed nasal transcriptomic analysis in dog dander sensitized children and healthy controls. The most over-expressed gene in dog dander sensitized children was CST1, coding for Cystatin 1. CST1 expression was enhanced in a cluster of children with lower FEV1, increased bronchial hyperreactivity, pronounced eosinophilia and higher CD-sens to dog compared with other dog dander sensitized children. Finally, in paper IV, we showed that asthma in dog dander sensitized children was associated with multisensitization to furry animal allergen molecules and to lipocalins. Children with severe asthma had higher IgE levels to the dog lipocalins Can f 2, Can f 4 and Can f 6 than other dog dander sensitized children. Moreover, severe asthma was associated with symptoms of dog allergy evaluated by nasal provocation testing. In conclusion, we demonstrate that a detailed assessment using molecular allergy diagnostics may help clinicians to assess the impact of allergic sensitization on dog allergy and asthma morbidity. We found that multisensitization to dog allergens and sensitization to lipocalins is associated with dog allergy and that the analysis of CD sens, IgG4 antibodies and nasal gene expression may provide further information in the diagnosis of this common disease

Daily allergy burden and heart rate characteristics in adults with allergic rhinitis based on a wearable telemonitoring system

Background: Allergic rhinitis includes a certain degree of autonomic imbalance. However, no information is available on how daily changes in allergy burden affect autonomic imbalance. We aimed to estimate associations between daily allergy burden (allergy symptoms and mood) and daily heart rate characteristics (resting heart rate and sample entropy, both biomarkers of autonomic balance) of adults with allergic rhinitis, based on real-world measurements with a wearable telemonitoring system. Methods: Adults with a tree pollen allergy used a smartphone application to self-report daily allergy symptoms (score 0–44) and mood (score 0–4), and a Mio Alpha 2 wristwatch to collect heart rate characteristics during two pollen seasons of hazel, alder and birch in Belgium. Associations between daily allergy burden and heart rate characteristics were estimated using linear mixed effects distributed lag models with a random intercept for individuals and adjusted for potential confounders. Results: Analyses included 2497 participant-days of 72 participants. A one-point increase in allergy symptom score was associated with an increase in next-day resting heart rate of 0.08 (95% CI: 0.02–0.15) beats per minute. A one-point increase in mood score was associated with an increase in same-day sample entropy of 0.80 (95% CI: 0.34–1.26) × 10−2. No associations were found between allergy symptoms and heart rate sample entropy, nor between mood and resting heart rate. Conclusion: Daily repeated measurements with a wearable telemonitoring system revealed that the daily allergy burden of adults with allergic rhinitis has systemic effects beyond merely the respiratory system.</p

International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis

Background: Critical examination of the quality and validity of available allergic rhinitis (AR) literature is necessary to improve understanding and to appropriately translate this knowledge to clinical care of the AR patient. To evaluate the existing AR literature, international multidisciplinary experts with an interest in AR have produced the International Consensus statement on Allergy and Rhinology: Allergic Rhinitis (ICAR:AR).Methods: Using previously described methodology, specific topics were developed relating to AR. Each topic was assigned a literature review, evidence-based review (EBR), or evidence-based review with recommendations (EBRR) format as dictated by available evidence and purpose within the ICAR:AR document. Following iterative reviews of each topic, the ICAR:AR document was synthesized and reviewed by all authors for consensus.Results: The ICAR:AR document addresses over 100 individual topics related to AR, including diagnosis, pathophysiology, epidemiology, disease burden, risk factors for the development of AR, allergy testing modalities, treatment, and other conditions/comorbidities associated with AR.Conclusion: This critical review of the AR literature has identified several strengths; providers can be confident that treatment decisions are supported by rigorous studies. However, there are also substantial gaps in the AR literature. These knowledge gaps should be viewed as opportunities for improvement, as often the things that we teach and the medicine that we practice are not based on the best quality evidence. This document aims to highlight the strengths and weaknesses of the AR literature to identify areas for future AR research and improved understanding. </p