Lisa M. Steacy

Environmental exposure unit: a sensitive, specific, and reproducible methodology for allergen challenge

INSTRUCTIONS Credit can now be obtained, free for a limited time, by reading the review article in this issue and completing all activity components. Please note the instructions listed below: Review the target audience, learning objectives and all disclosures. Complete the pre-test online at http://www.annallergy.org (click on the CME heading). Follow the online instructions to read the full version of the article; reflect on all content as to how itmay be applicable to your practice. Complete the post-test/evaluation and claim credit earned; at this time, you will have earned up to 1.0 AMA PRA Category 1 CreditTM. Please note that the minimum passing score on the post-test is 70%. Release Date: November 1, 2013 Expiration Date: October 31, 2015 Estimated Time to Complete: 60 minutes Target Audience: Physicians involved in providing patient care in the field of allergy/asthma/immunology Learning Objectives: At the conclusion of this activity, participants should be able to: Describe the Environmental Exposure Unit (EEU) methodology for controlled allergen challenge Discuss the technical aspects, study designs, and controlled variables in EEU studies that allow for the effective determination of onset of action and clinical efficacy of new anti-allergic treatments 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 amaximumof 1 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Planning Committee Members: Anne K. Ellis, MD, MSc, FRCPC (Sr Author) Michael S. Tankersley, MD (CME Series Editor) Gailen D. Marshall, Jr, MD, PhD (Editor-in-Chief) Disclosure of Relevant Financial Relationships: A.K. Ellis has served as principal investigator for Circassia, Ltd., M.L. North, T. Walker, L.M. Steacy, M.S. Tankersley and G.D. Marshall have nothing to disclose. Reviewers and Education/Editorial staff have no relevant financial relationships to disclose. Astemizole has been withdrawn and is no longer available in the United States. Recognition of Commercial Support: This activity has not received external commercial support. Copyright Statement: 2013-2015 ACAAI. All rights reserved. CME Inquiries: Contact the American College of Allergy, Asthma & Immunology at education@acaai.org or 847-427-1200.

Controlled Allergen Challenge Facilities and Their Unique Contributions to Allergic Rhinitis Research

The aim of this study is to review advances in basic and clinical allergic rhinitis (AR) research over the past decade that have been conducted using controlled allergen challenge facility (CACF) models of allergen challenge. Databases, including PubMed, Medline, and Web of Science were searched for articles employing an ambient pollen exposure in a controlled facility to study AR, published between 2004 and the present date, using the terms as follows: CACF, Environmental Exposure Unit (EEU), Vienna Challenge Chamber (VCC), Fraunhofer Institute Environmental Challenge Chamber, Atlanta Allergen Exposure Unit, Biogenics Research Chamber, Allergen BioCube, Chiba and Osaka Environmental Challenge Chamber, exposure unit, challenge chamber, or environmental exposure chamber. Articles were then selected for relevance to the goals of the present review, including important contributions toward clinical and/or basic science allergy research. CACFs offer sensitive, specific, and reproducible methodology for allergen challenge. They have been employed since the 1980s and offer distinct advantages over traditional in-season multicentre trials when evaluating new treatments for AR. They have provided clinically applicable efficacy and pharmacologic information about important allergy medications, including antihistamines, decongestants, antileukotrienes, immunotherapies, and nasal steroids. CACF models have also contributed to basic science and novel/experimental therapy research. To date, no direct studies have been conducted comparing outcomes from one CACF to another. Over the past decade, CACF models have played an essential role in investigating the pathophysiology of AR and evaluating new therapies. The future opportunities for this model continue to expand.

Treatment with grass allergen peptides improves symptoms of grass pollen–induced allergic rhinoconjunctivitis

Background Synthetic peptide immunoregulatory epitopes are a new class of immunotherapy to treat allergic rhinoconjunctivitis (ARC). Grass allergen peptides, comprising 7 synthetic T‐cell epitopes derived from Cyn d 1, Lol p 5, Dac g 5, Hol l 5, and Phl p 5, is investigated for treatment of grass pollen–induced ARC. Objective We sought to evaluate the efficacy, safety, and tolerability of intradermally administered grass allergen peptides. Methods A multicenter, randomized, double‐blind, placebo‐controlled study evaluated 3 regimens of grass allergen peptides versus placebo in patients with grass pollen–induced allergy (18‐65 years). After a 4‐day baseline challenge to rye grass in the environmental exposure unit (EEU), subjects were randomized to receive grass allergen peptides at 6 nmol at 2‐week intervals for a total of 8 doses (8x6Q2W), grass allergen peptides at 12 nmol at 4‐week intervals for a total of 4 doses (4x12Q4W), or grass allergen peptides at 12 nmol at 2‐week intervals for a total of 8 doses (8x12Q2W) or placebo and treated before the grass pollen season. The primary efficacy end point was change from baseline in total rhinoconjunctivitis symptom score across days 2 to 4 of a 4‐day posttreatment challenge (PTC) in the EEU after the grass pollen season. Secondary efficacy end points and safety were also assessed. Results Two hundred eighty‐two subjects were randomized. Significantly greater improvement (reduction of total rhinoconjunctivitis symptom score from baseline to PTC) occurred across days 2 to 4 with grass allergen peptide 8x6Q2W versus placebo (−5.4 vs −3.8, respectively; P = .0346). Greater improvement at PTC also occurred for grass allergen peptide 8x6Q2W versus placebo (P = .0403) in patients with more symptomatic ARC. No safety signals were detected. Conclusion Grass allergen peptide 8x6Q2W significantly improved ARC symptoms after rye grass allergen challenge in an EEU with an acceptable safety profile.

Nasal allergen challenge studies of allergic rhinitis: a guide for the practicing clinician

INSTRUCTIONSCredit can now be obtained, free for a limited time, by reading the review article in this issue and completing all activity components.Please note the instructions listed below: Review the target audience, learning objectives and all disclosures. Complete the pre-test online at http://www.annallergy.org (click on the CME heading). Followtheonlineinstructionstoreadthefullversionofthearticle;reflectonallcontentastohowitmaybeapplicabletoyourpractice. Complete the post-test/evaluation and claim credit earned; at this time, you will have earned up to 1.0 AMA PRA Category 1 Credit

The Allergic Rhinitis - Clinical Investigator Collaborative (AR-CIC): nasal allergen challenge protocol optimization for studying AR pathophysiology and evaluating novel therapies

BackgroundThe Nasal Allergen Challenge (NAC) model allows the study of Allergic Rhinitis (AR) pathophysiology and the proof of concept of novel therapies. The Allergic Rhinitis – Clinical Investigator Collaborative (AR-CIC) aims to optimize the protocol, ensuring reliability and repeatability of symptoms to better evaluate the therapies under investigation.Methods20 AR participants were challenged, with 4-fold increments of their respective allergens every 15 minutes, to determine the qualifying allergen concentration (QAC) at which the Total Nasal Symptom Score (TNSS) of ≥10/12 OR a Peak Nasal Inspiratory Flow (PNIF) reduction of ≥50% from baseline was achieved. At the NAC visit, the QAC was used in a single challenge and TNSS and PNIF were recorded at baseline, 15 minutes, 30 minutes, 1 hour, and hourly up to 12 hours. 10 additional ragweed allergic participants were qualified at TNSS of ≥8/12 AND ≥50% PNIF reduction; the Cumulative Allergen Challenge (CAC) of all incremental doses was used during the NAC visit. 4 non-allergic participants were challenged with the highest allergen concentration.ResultsIn the QAC study, a group qualified by only meeting PNIF criteria achieved lower TNSS than those achieving either TNSS criteria or PNIIF+TNSS (p<0.01). During the NAC visit, participants in both studies reached their peak symptoms at 15minutes followed by a gradual decline, significantly different from non-allergic participants. The “PNIF only” group experienced significantly lower TNSS than the other groups during NAC visit. QAC and CAC participants did not reach the same peak TNSS during NAC that was achieved at screening. QAC participants qualifying based on TNSS or TNSS+PNIF managed to maintain PNIF scores.ConclusionsParticipants experienced reliable symptoms of AR in both studies, using both TNSS and PNIF reduction as part of the qualifying criteria proved better for qualifying participants at screening. Phenotyping based on pattern of symptoms experienced is possible and allows the study of AR pathophysiology and can be applied in evaluation of efficacy of a novel medication. The AR-CIC aims to continue to improve the model and employ it in phase 2 and 3 clinical trials.

Double blind randomized crossover trial of PF-03654764+fexofenadine in the environmental exposure unit (EEU)

Background Oral histamine receptor–1 antagonists, such as fexofenadine, offer suboptimal relief of allergic rhinitis-associated nasal congestion. Combinations with oral sympathomimetics, such as pseudoephedrine, relieve congestion but produce side effects. Histamine receptor-3 antagonists, such as PF-03654764, reduce congestion in animals and have been proposed as novel therapeutics. Previous nasal allergen challenge studies of similar H1+H3 receptor antagonist combinations demonstrated reduced congestion. Herein we employ the Environmental Exposure Unit (EEU) to conduct the first randomized controlled trial of PF-03654764 in allergic rhinitis. The primary objective was to compare the effect of PF-03654764+fexofenadine to pseudoephedrine+fexofenadine on the subjective measures of congestion and Total Nasal Symptom Score (TNSS). The objective of post-hoc analyses were to compare all treatments to placebo and determine the onset of action (OA).

Blood and nasal epigenetics correlate with allergic rhinitis symptom development in the environmental exposure unit

Epigenetic alterations may represent new therapeutic targets and/or biomarkers of allergic rhinitis (AR). Our aim was to examine genome‐wide epigenetic changes induced by controlled pollen exposure in the environmental exposure unit (EEU).

A post-hoc qualitative analysis of real time heads-up pollen counting versus traditional microscopy counting in the environmental exposure unit (EEU)

Background A custom digital imagery method for real time identification and counting of pollen was qualitatively evaluated in the Environmental Exposure Unit (EEU). Methods Airborne grass pollen was collected in the EEU via a Rotorod ® impact sampler. The pollen grains on each sampling rod were counted using both traditional and headsup microscopy. The heads-up technique incorporated a microscope camera to create an on-screen image of the sampling rod. Firstly, unique images were created by manually advancing the stage, without duplicating previously captured pollen grains. Well-defined, sharp images were obtained by fine focus and zoom combinations to enhance certainty and recognition speed. Secondly, using a custom application, each pollen grain was identified and counted on-screen by “point and click” or “screen touch”, simultaneously counting and permanently anchoring opaque dots to the pollen grain locations. Counts were stored in real time on a central database. Results Increased clarity of the polle ng rains resulted in higher counting accuracy. Duplicate counting of pollen grains was eliminated by digitally labelling counted grains. Additional need for manual counting devices, commonly associated with mechanical and human errors, was eliminated. Error free counts can be obtained with increased speed, therefore, improving the overall efficiency of the process and the EEU system as a whole. Conclusions This validated heads-up counting technique will allow for an increased response time to changes in the EEU pollen levels. This advancement could also enhance pollen counting processes followed by others using direct microscopy pollen counting techniques.

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.

Repeatability of nasal allergen challenge results – further validation of the allergic rhinitis clinical investigator collaborative (AR-CIC) protocols

BACKGROUND Nasal allergen challenge (NAC) models have been used to study allergic rhinitis and new therapies. Symptoms and biological samples can be evaluated at time points after allergen exposure. OBJECTIVE To verify protocol repeatability and adequate interval between allergen exposures. METHODS Ten ragweed allergic participants were exposed to incrementally increasing dosages of ragweed allergen intranasally until they achieved a total nasal symptom score (TNSS) of 8 of 12 and a peak nasal inspiratory flow (PNIF) of 50% reduction or more from baseline. Three weeks later, participants were challenged with a cumulative dose equal to the sum of all the allergen doses received at screening. TNSS and PNIF were recorded at regular intervals, including a 24-hour assessment. A subsequent visit was conducted after a further 3 weeks. Nasal secretion samples were collected for cytokine and eosinophil quantification. RESULTS Nine participants completed all visits. TNSS and PNIF responses followed previous patterns, with an initial peak at 30 minutes followed by a gradual decline. Most participants reported similar patterns at both NAC visits, although some did not demonstrate the same phenotype at both visits. Some experienced a secondary symptom increase 24 hours after NAC. Eosinophil and cytokine sections followed a similar pattern at both NAC visits. CONCLUSION NAC is an adequate method for modeling AR in humans, demonstrating appropriate repeatability of symptoms, nasal mucosal eosinophil, and cytokines. The 24-hour time point, previously not studied in our model, may be beneficial in evaluation of long-acting medications. This three-week interval NAC model will be beneficial for studies in which before and after treatment comparisons are desired.