Clinical validation of controlled exposure to birch pollen in the Environmental Exposure Unit (EEU)

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Abstract

Background

The Environmental Exposure Unit (EEU) in Kingston, Ontario, Canada is a controlled allergen challenge facility (CACF) that has been previously clinically validated for the use of ragweed and grass pollen in clinical studies. In this study we aim to validate the use of birch pollen to challenge allergic participants.

Methods

A total of 59 volunteers were screened and 38 birch allergic participants and ten non-allergics completed the study, outside of tree pollen season. Participants had to have a minimum of 2-year history of allergic rhinoconjunctivitis during the typical tree pollen season and have a positive skin prick test to birch allergen ≥5 mm from the control. Qualified participants were exposed to birch ( Betula pendula) pollen for 4 h in the EEU and recorded their symptoms of sneezing, rhinorrhea, nasal congestion, nasal itch which comprised the total nasal symptom score (TNSS), as well as itchy/watery eyes, red/burning eyes and itching of ears/palate/throat which along with the TNSS comprised the total rhinoconjunctival symptom score (TRSS) along with Peak Nasal Inspiratory Flow (PNIF) at baseline and at 30 min intervals for the duration of exposure, then hourly for up to 12 h from the start of exposure.

Results

Allergic participants reported a gradual rise in TNSS and TRSS, reaching a mean and standard error of the mean of 7.08 ± 0.45 and 11.58 ± 0.93 respectively by 180 min from the start of exposure. Symptoms gradually declined to near baseline values following departing from the unit, reaching 1.9 and 2.7 by 450 min. Allergic participants reported significantly higher TNSS than non-allergics starting from 30 min (p < 0.01, two-way ANOVA with Bonferroni corrections), maintaining maximum significance from 60 to 300 min (p < 0.0001) and losing significance by 420 min. TRSS and PNIF followed similar trends as those seen with TNSS. Participants were phenotyped using previously published definitions using the TNSS into Early Phase Responders (EPR, 57.8 %), protracted EPR (pEPR, 39.5 %), and Dual Phase Responders (DPR, 2.7 %).

Conclusions

The EEU can competently challenge birch allergic participants and achieve statistically significant changes in symptoms and nasal airflow, while such changes are not reported in non-allergic controls.

Trial registration NCT02351830 clinicaltrials.gov

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Most cited references 24

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Optimisation of grass pollen nasal allergen challenge for assessment of clinical and immunological outcomes.

Guy Scadding, Moises A. Calderon, Virginia Bellido … (2012)

Nasal allergen challenge can be used to assess the clinical and immunological aspects of rhinitis due to inhalant allergens. We aimed to develop a reproducible technique for grass pollen nasal allergen challenge and to study biomarkers within nasal secretions. 20 Grass pollen allergic individuals underwent nasal challenges with purified Timothy grass allergen. An initial dose-titration challenge was used to determine dose-response characteristics. Subsequently, volunteers underwent 3 further challenges using individualised threshold doses. Symptom scores, visual analogue scores, and peak nasal inspiratory flow (PNIF) were recorded at baseline and up to 6h after challenge. Nasal secretions were collected at each time point using synthetic filter papers or absorptive polyurethane sponges and analysed for IL-4, -5, -10, -13, IFN-γ, Tryptase and Eosinophil Cationic Protein (ECP). Challenges gave reproducible symptom scores and decreased PNIF. Tryptase levels in nasal fluid peaked at 5 min after challenge and returned to baseline levels at 1h. ECP, IL-5, IL-13 and IL-4 levels were increased from 2-3 h and showed progressive increases to 5-6 h. Sponges proved the superior nasal fluid sampling technique. We have developed a reproducible nasal allergen challenge technique. This may be used as a surrogate clinical endpoint in trials assessing the efficacy of treatments for allergic rhinitis. Tryptase in local nasal secretions is a potential biomarker of the early phase response; ECP and the Th2 cytokines IL-5, -13 and -4 markers of late phase allergic responses. Our model allows correlation between clinical responses and local biomarkers following nasal allergen challenge. Copyright © 2012 Elsevier B.V. All rights reserved.

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

Anne K Ellis, Mena Soliman, Lisa Steacy … (2015)

Background The 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. Methods 20 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. Results In 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. Conclusions Participants 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.

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Amoxicillin rash in patients with infectious mononucleosis: evidence of true drug sensitization

Katinka Ónodi-Nagy, Ágnes Kinyó, Angéla Meszes … (2015)

Background It hasn’t been clearly understood yet whether sensitization to antibiotics, the virus itself or transient loss of drug tolerance due to the virus, is responsible for the development of maculopapular exanthems following amoxicillin intake in patients with infectious mononucleosis. We aimed to examine whether sensitization to penicillin developed among patients with skin rash following amoxicillin treatment within infectious mononucleosis. Methods Ten patients were investigated for drug sensitization by lymphocyte transformation test and six patients were further tested by prick-, intradermal and patch tests employing the penicillin’s main antigens. Results Lymphocyte transformation test showed negative results with amoxicillin, while one patient had positive reaction to cefixime. Six patients with suspected sensitization to amoxicillin were then investigated by in vivo tests. Prick tests were negative in all six patients, but the intradermal tests showed positive reactions in four patients. Conclusions Our data demonstrate that in vitro testing is not sensitive enough in determining drug sensitization to penicillin. In vivo tests should be performed to detect sensitization and indeed with skin tests our results confirmed that sensitization to aminopenicillin may develop within infectious mononucleosis.

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Author and article information

Contributors

Anne K. Ellis: (613) 548-2336 , ellisa@kgh.kari.net

Mena Soliman: soliman.m@queensu.ca

Lisa M. Steacy: steacyl@kgh.kari.net

Daniel E. Adams: adamsd@kgh.kari.net

Barnaby Hobsbawn: hobsbawb@kgh.kari.net

Terry J. B. Walker: walkert1@kgh.kari.net

Journal

Journal ID (nlm-ta): Allergy Asthma Clin Immunol

Journal ID (iso-abbrev): Allergy Asthma Clin Immunol

Title: Allergy, Asthma, and Clinical Immunology : Official Journal of the Canadian Society of Allergy and Clinical Immunology

Publisher: BioMed Central (London )

ISSN (Print): 1710-1484

ISSN (Electronic): 1710-1492

Publication date (Electronic): 19 October 2016

Publication date PMC-release: 19 October 2016

Publication date Collection: 2016

Volume: 12

Electronic Location Identifier: 53

Affiliations

[1 ]Division of Allergy & Immunology, Department of Medicine, Queen’s University, Kingston, ON Canada

[2 ]Allergy Research Unit, Kingston General Hospital, 76 Stuart Street, Kingston, ON K7L 2V7 Canada

Article

Publisher ID: 156

DOI: 10.1186/s13223-016-0156-7

PMC ID: 5069953

PubMed ID: 27777594

SO-VID: 8b77e4a2-3f61-4c8f-8d17-6acaafc6544e

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 1 June 2016

Date accepted : 28 September 2016

Custom metadata

ScienceOpen disciplines: Immunology

Keywords: allergic rhinitis,environmental exposure unit,eeu,environmental exposure chamber,controlled allergen challenge facility,cacf,birch pollen,total nasal symptom score (tnss),peak nasal inspiratory flow (pnif)

Data availability:

ScienceOpen disciplines: Immunology

Keywords: allergic rhinitis, environmental exposure unit, eeu, environmental exposure chamber, controlled allergen challenge facility, cacf, birch pollen, total nasal symptom score (tnss), peak nasal inspiratory flow (pnif)

Clinical validation of controlled exposure to birch pollen in the Environmental Exposure Unit (EEU)

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Most cited references 24

Optimisation of grass pollen nasal allergen challenge for assessment of clinical and immunological outcomes.

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

Amoxicillin rash in patients with infectious mononucleosis: evidence of true drug sensitization

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