Mark W. Tenn

Update in Pediatric Allergy

The past few years has noted a number of new development relevant to the practice of pediatric allergy. This chapter aims to hit the highlights of areas of clinical practice where there are either significant changes to recommendations, and/or areas of clear clinical importance where the pediatrician should ensure they are following best practices. Specifically, we have highlighted new developments in food allergy, atopic dermatitis, allergic rhinitis, and anaphylaxis.

Lack of effect of Grastek® on birch pollen-induced allergic rhinoconjunctivitis in the Environmental Exposure Unit

BACKGROUND Timothy grass pollen allergen extract tablets (Grastek) are standardized sublingual immunotherapy tablets (SLIT-T) approved for the treatment of grass pollen-induced allergic rhinitis (AR) and conjunctivitis. Many grass allergic patients are also cosensitized to birch pollen. Whether Timothy grass SLIT-T can confer symptomatic benefits for birch pollen-induced AR symptoms is unknown. OBJECTIVE To evaluate the treatment effect of Timothy grass SLIT-T for birch pollen-induced AR in participants sensitized to both grass and birch pollen using an environmental exposure unit (EEU). METHODS This study was a phase 4, randomized, double-blind, placebo-controlled, parallel-group study that enrolled participants aged 18 to 65 years allergic to both timothy grass and birch pollen. After a baseline EEU birch pollen challenge, in which a minimum total nasal symptom score (TNSS) of 6 of 12 was required for enrollment, participants were randomized to receive Timothy grass SLIT-T or placebo taken once daily for 4 months. No confirmatory grass pollen challenge was performed. The primary end point was the change in TNSS averaged from assessments from hours 2 to 5 during the posttreatment birch pollen challenge compared with baseline. The secondary and exploratory end points included temporally identical changes in total ocular symptom score (TOSS), total rhinoconjunctivitis symptom score (TRSS), and individual symptom scores. RESULTS The difference in TNSS reduction after 4 months of therapy between the Timothy grass SLIT-T and placebo group was not significant (P = .83). Reductions in TOSS (P = .19) and TRSS (P = .67) were also comparable between groups. Findings between groups for individual symptom scores were similar (all P > .40), except for watery eyes, in which symptom reduction was slightly better in the placebo arm (P = .01). Timothy grass SLIT-T was well tolerated, and no serious adverse effects occurred. CONCLUSION A bystander effect of grass SLIT-T on birch pollen-induced AR symptoms was not detected. Symptomatic benefits of grass SLIT-T are likely allergen specific. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02394600.

Peripheral group 2 innate lymphoid cells are decreased following nasal allergen challenge in allergic rhinitis

To the Editor, Allergic rhinitis (AR) is an upper airway inflammatory disorder involving IgE‐mediated inflammation of the nasal mucosa. Inflammatory responses are triggered following inhalation of sensitized aeroallergens and are characterized by Th2 inflammation and the rapid migration of eosinophils into the nasal cavity. Group 2 innate lymphoid cells (ILC2s) represent an alternative source of Th2 cytokines, potentially augmenting pre‐existing Th2‐driven inflammation seen in AR. Lacking a specific antigen receptor and lineage surface markers for B and T cells, ILC2s are activated by IL‐25, IL‐33, and TSLP and can drive Th2 inflammation via production of IL‐5, IL‐13, and modest amounts of IL‐4. In AR patients, elevated levels of peripheral blood ILC2s were reported during the grass pollen season and following a nasal allergen challenge (NAC) with cat allergen extract. This suggests a possible role for these cells in driving allergic symptoms. However, participants from these studies may have been primed (reversible increase in reactivity of the nasal tissue) due to repeated low‐dose allergenic stimulation during pollen season or at home (ie, owning a cat). Sensitized individuals who are also primed can experience more severe allergic symptoms and changes in systemic immunity after allergen exposure. To date, few studies have assessed the effects of acute allergen exposure on circulating ILC2s in non‐primed AR individuals. Thus, the aim of the current study was to evaluate the frequency of peripheral blood ILC2s in AR individuals after a NAC performed outside of the local birch pollen season. We also evaluated ILC2 frequencies in nasal lavage (NL) samples collected pre‐ and post‐challenge. Eleven individuals with birch pollen–induced AR and eight non‐ allergics were recruited into the study (Table S1). The study was reviewed and granted ethical clearance by the Queens University and Affiliated Teaching Hospitals Research Ethics Board, and all participants provided written informed consent. All participants underwent a NAC with a pre‐titrated dose of birch pollen extract (ALK‐Abello) (Figure S1A). Total nasal symptom score (TNSS; sum of rhinorrhea, nasal congestion, sneezing, and nasal itching) and peak nasal inspiratory flow (PNIF) were recorded during the challenge. Peripheral blood and NL samples were collected at baseline and 4 hours post‐challenge. Peripheral blood mononuclear cells (PBMCs) were isolated by density gradient centrifugation and cryopreserved. The 4‐hour time point was selected to remain consistent with the cat‐NAC study. Details of the NAC methodology can be found in the Methods S1 section. Thawed PBMCs and freshly obtained NL samples were stained with a fixable viability dye (PBMCs only, eBioscience), a lineage cocktail (CD3, CD14, CD16, CD19, CD20, CD56; BD Biosciences), and antibodies to CD4, CD11b, CD235a, FcεRI, CD45, CRTH2, and CD127 (all from eBioscience). ILC2s were identified as CD45 lymphocytes that were also lineage negative and expressed CRTH2 and CD127 (Figure 1A). Compared to non‐allergics, birch‐allergic participants experienced a significantly higher TNSS at 15 minutes (P < 0.0001) through 8 hours (P = 0.0048) and a larger PNIF reduction at 15 (P = 0.0016) and 30 minutes (P = 0.0004) post‐allergen challenge (Figure S1B,C). The mean frequency of peripheral blood CD45 cells remained unchanged after allergen challenge in both groups (Figure 1B). The mean frequency (±SEM) of peripheral blood ILC2s at baseline (0.019 ± 0.003% vs 0.018 ± 0.006%, P = 0.60) and post‐challenge (0.014 ± 0.002% vs 0.015 ± 0.004%, P = 0.90) was comparable between birch‐allergic and non‐allergic participants. Contrasting previous studies, peripheral blood ILC2s were significantly decreased following allergen challenge in birch‐allergic participants (P = 0.0344) (Figure 1C). This was not detected in non‐allergic participants (P = 0.25). A reduction in ILC2s was noted in this group; however, it was likely driven by one non‐allergic participant. In birch‐allergic participants, percentage changes in peripheral blood ILC2s after challenge significantly correlated with TNSS at 4 hours (r = 0.73, P = 0.01) (Figure 1D). This was not observed for 4‐ hour percentage PNIF reduction (r = −0.28, P = 0.41) (Figure 1E). In contrast, peripheral ILC2s at 4 hours alone did not correlate with 4‐ hour TNSS (r = −0.16, P = 0.63) and 4‐hour percentage PNIF reduction (r = −0.13, P = 0.70) (Figure 1F,G). A borderline correlation was observed between percentage changes in peripheral ILC2s and percentage PNIF reduction at 8 hours (late‐phase response, r = 0.61, P = 0.0491) (Table S2). Finally, correlations were not observed for 15‐minute (peak symptom severity) symptom scores (Table S2). These findings suggest that in pollen‐sensitized asymptomatic individuals, the change in peripheral ILC2s after a high‐dose pollen challenge may better reflect symptom severity compared to post‐challenge measurements alone, as observed in symptomatic individuals during pollen season. To investigate local ILC2 responses following allergen challenge, a similar gating strategy was used. We were unable to detect nasal ILC2s in NL samples collected pre‐ and post‐NAC (Figure 2A). Only a very small proportion of NL cells expressed CD45 (median frequency, 3.2%‐6.5% of all cells), which remained unchanged after allergen challenge (Figure 2B). The nasal lymphocyte population was also less defined, with 15/19 participants having less than 100 DOI: 10.1111/all.13614

Advances in rhinitis—models and mechanisms

OBJECTIVE To summarize studies highlighting recent advances in rhinitis-related research in the past 2 years. DATA SOURCES Original research articles were procured and examined from the Rhinitis and Upper Airway Disease section of the 2015 to 2017 Annals of Allergy, Asthma & Immunology issues. Additional original research articles were identified from PubMed and Google Scholar using the following search terms: allergic rhinitis, rhinitis, chronic rhinosinusitis, environmental exposure unit, and nasal allergen challenge. Only research articles published in the past 2 years were procured. STUDY SELECTIONS Articles conducting research in allergic rhinitis (AR) or chronic rhinosinusitis or using controlled allergen challenge facilities or the nasal allergen challenge model were selected. RESULTS Studies in the past 2 years have focused on using skin prick tests and early-life phenotyping to predict AR development in children. They also have elucidated the role of a subset of CD4+ T cells, basophils, and mast cells in non-eosinophilic chronic rhinosinusitis with nasal polyps, a relatively new chronic rhinosinusitis subtype in the Asian population. Several advances have been made in understanding the role of several cytokines and peripheral cell mitochondrial function in AR using controlled allergen challenge facilities and direct nasal allergen challenges. CONCLUSION Findings from the recent literature highlight the utility of early-life predictors of AR in possibly targeting high-risk groups for prophylactic interventions. Studies also emphasize the use of controlled allergen challenge facilities and the nasal allergen challenge model as robust experimental models to study AR pathogenesis.

The clinical relevance of filaggrin mutations: Effect on allergic disease

INSTRUCTIONS Credit can now be obtained, free for a limited time, by reading the review article and completing all activity components. Please note the instructions listed below: Review the target audience, learning objectives and all disclosures. Complete the pre-test. Read the article and reflect on all content as to how it may be applicable to your practice. Complete the post-test/evaluation and claim credit earned. At this time, physicians will have earned up to 1.0 AMA PRA Category 1 CreditTM. Minimum passing score on the post-test is 70%. Overall Purpose Participants will be able to demonstrate increased knowledge of the clinical treatment of allergy/asthma/immunology and how new information can be applied to their own practices. Learning Objectives At the conclusion of this activity, participants should be able to: Describe the role of filaggrin in the maintenance of skin barrier function Discuss how filaggrin null mutations can augment the risk of developing allergic diseases Release Date: November 1, 2016 Expiration Date: October 31, 2018 Target Audience Physicians involved in providing patient care in the field of allergy/asthma/immunology Accreditation The American College of Allergy, Asthma & Immunology (ACAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Designation The American College of Allergy, Asthma & Immunology (ACAAI) designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Planning Committee Members Mark W. Tenn, MD, BHSc (Author) Anne K. Ellis, MD, MSc, FRCPC (Author) Jonathan A. Bernstein, MD (CME Subcommittee) Guha Krishnaswamy, MD (CME Subcommittee) Mitchell H. Grayson, MD (CME Series Editor, Deputy Editor) Gailen D. Marshall, Jr, MD, PhD (Editor-in-Chief)