Birch-naive, oak-allergic subjects' response to birch pollen in an environmental chamber.

Background: Oak and birch pollens are strongly cross-reactive. It is unknown how robust this cross-reactivity is in patients without natural exposure to pollen of both trees. We assessed the symptom response to birch pollen in subjects with skin-prick test (SPT) results positive to oak and birch but only naturally exposed to oak by using an allergen challenge chamber. Methods: The subjects with SPT results positive to oak and birch had their serum-specific immunoglobulin E (ssIgE) to oak and birch antigens measured. Residential historical data were obtained. The subjects were exposed to birch pollen (3500 ± 700 grains/m³) in two consecutive 3-hour challenges. Symptoms were recorded at baseline and 30-minute intervals. Results: Twenty-four subjects, 12 men; ages 20-58 years, completed the study. Sixteen subjects (66.7%) responded with high Total Symptom Scores (TSS) ≥10 of a maximum 21. Twelve subjects (50%) had ssIgE values ≥0.70 kU/L to oak, 10 of whom had ssIgE values ≥0.70 kU/L to birch. These 10 subjects had a significantly higher maximum TSS than the rest. Also, 15 subjects without a previous natural exposure to birch pollen responded with TSS equivalent to the 9 subjects with previous exposure. Conclusion: Virginia live oak ssIgE levels of patients allergic to oak and birch correlated with the symptom response to birch pollen exposure, even without previous natural exposure to birch. The subjects naive to birch pollen responded to birch pollen exposure with symptoms comparable with both those with previous sustained exposure and also those who resided in endemic areas, as reported by other researchers.

Technical standards in allergen exposure chambers worldwide - an EAACI Task Force Report.

Allergen exposure chambers (AECs) can be used for controlled exposure to allergenic and non-allergenic airborne particles in an enclosed environment, in order to (i) characterize the pathological features of respiratory diseases and (ii) contribute to and accelerate the clinical development of pharmacological treatments and allergen immunotherapy for allergic disease of the respiratory tract (such as allergic rhinitis, allergic rhinoconjunctivitis, and allergic asthma). In the guidelines of the European Medicines Agency for the clinical development of products for allergen immunotherapy (AIT), the role of AECs in determining primary endpoints in dose-finding Phase II trials is emphasized. Although methodologically insulated from the variability of natural pollen exposure, chamber models remain confined to supporting secondary, rather than primary, endpoints in Phase III registration trials. The need for further validation in comparison with field exposure is clearly mandated. On this basis, the European Academy of Allergy and Clinical Immunology (EAACI) initiated a Task Force in 2015 charged to gain a better understanding of how AECs can generate knowledge about respiratory allergies and can contribute to the clinical development of treatments. Researchers working with AECs worldwide were asked to provide technical information in eight sections: (i) dimensions and structure of the AEC, (ii) AEC staff, (iii) airflow, air processing, and operating conditions, (iv) particle dispersal, (v) pollen/particle counting, (vi) safety and non-contamination measures, (vii) procedures for symptom assessments, (viii) tested allergens/substances and validation procedures. On this basis, a minimal set of technical requirements for AECs applied to the field of allergology is proposed.

Clinical standardization of two controlled allergen challenge facilities: The Environmental Exposure Unit and the Biogenics Research Chamber.

BACKGROUND: Controlled allergen challenge facilities (CACF), in disparate geographic regions with dissimilar engineering and base populations, have historically functioned as single, independent sites in clinical allergy trials. We aimed to demonstrate "between-unit reproducibility" to allow controlled challenge trials of participants using 2 CACFs. OBJECTIVE: To compare and standardize 2 CACFs located in Kingston, Ontario, Canada, and San Antonio, Texas, by examining participant-reported symptom severity during qualifying and treatment visits and evaluating response to treatment, while using the same allergen. METHODS: At 2 different CACFs, participants were enrolled in a double-blind, placebo-controlled, crossover intervention trial with cetirizine 10 mg. Different distribution devices delivered common short ragweed pollen via laminar air flow and maintained an airborne concentration of 3500 ± 700 grains/m3 in both facilities. A 1-hour "sham" run with no pollen release preceded a priming exposure of 3 hours and was followed 3 days later by a qualifying/treatment 5-hour exposure. At least 14 days later, another priming exposure was followed by the crossover exposure and treatment. RESULTS: Forty-eight and 43 subjects completed the study at Kingston and San Antonio, respectively. Demographics were similar. Fewer than 10% exhibited symptoms with sham exposure. No significant differences were found between the 2 facilities in maximal total rhinoconjunctivitis symptom score, total nasal symptom score, and total ocular symptom score, nor in areas under the curve. In both facilities, no significant effects of cetirizine 10 mg over placebo were detected. CONCLUSION: The results were equivalent, demonstrating that the 2 CACFs can be used together in dual-center clinical trials and show the possibility of multicenter trials involving multiple CACFs.

Cockroach sensitization mitigates allergic rhinoconjunctivitis symptom severity in patients allergic to house dust mites and pollen.

BACKGROUND: Modifiers of symptom severity in patients with allergic rhinoconjunctivitis (AR) are imprecisely characterized. The hygiene hypothesis implicates childhood microbial exposure as a protective factor. Cockroach sensitization (C+) might be a proxy for microbial exposure. OBJECTIVE: We sought to determine whether C+ assayed by means of skin prick tests influenced AR symptom severity in controlled and natural settings. METHODS: Total symptom scores (TSSs) were recorded by 21 participants with house dust mite allergy (M+) in the natural setting and during repeated exposures of 3 hours per day to house dust mite allergen in an allergen challenge chamber (ACC). In M+ participants the peripheral blood and nasal cells were assayed for T-cell activation and transcriptomic profiles (by using RNA sequencing), respectively. Participants allergic to mountain cedar (n = 21), oak (n = 34), and ragweed (n = 23) recorded TSSs during separate out-of-season exposures to these pollens (any pollen sensitization [P+]) in the ACC; a subset recorded TSSs in the pollination seasons. RESULTS: The hierarchy of TSSs (highest to lowest) among M+ participants tracked the following skin prick test sensitization statuses: M+P+C- > M+P+C+ > M+P-C- > M+P-C+. In nasal cells and peripheral blood the immune/inflammatory responses were rapidly resolved in M+P+C+ compared with M+P+C- participants. Among those allergic to pollen, C+ was associated with a lower TSS during pollen challenges and the pollination season. After aggregated analysis of all 4 ACC studies, C+ status was associated with a 2.8-fold greater likelihood of a lower TSS compared with C- status (odds ratio, 2.78; 95% CI, 1.18-6.67; P = .02). CONCLUSIONS: C+ status is associated with mitigation of AR symptom severity in adults with AR.

Responsiveness to timothy grass pollen in individuals without known natural exposure in an allergen challenge chamber.

BACKGROUND: The responsiveness to a nonendemic grass species is unknown and cannot be research without an allergen challenge chamber. OBJECTIVE: To determine the clinical responsiveness to timothy grass pollen (TGP) in participants without known natural exposure in an allergen challenge chamber (ACC). METHODS: Of the 26 screened participants, 22 met screening criteria and completed the 2 chamber exposures. The study consisted of an initial screening visit that included a blood draw for serum specific IgE (ssIGE) to Bermuda grass pollen and TGP followed by a 4½-day run-in phase and two 3-hour ACC exposure visits. This study was performed early in the first week of December 2013, when no seasonal pollens were detected in San Antonio, Texas. Symptom scores were recorded at baseline and every 30 minutes. RESULTS: Of the 26 screened participants, 22 met the screening criteria and completed the 2 chamber exposures. Thirteen participants had always lived in South Texas without natural exposure, and 9 had previously lived in areas with TGP exposure. All participants tested positive to TGP and Bermuda grass pollen. Twelve and 13 of 22 had positive ssIgE test results to Timothy and Bermuda allergens, respectively, with 11 having positive results for both allergens. There were strong correlations among skin prick test size, a positive ssIgE test result, and high symptoms from TGP exposure. There was little difference in symptoms between those who had lived their entire lives in South Texas and those who had lived elsewhere. CONCLUSION: In Texas, where exposure to TGP is minimal, strongly positive SPT and ssIgE test results were predictors of high symptoms to TGP exposure. Never exposed participants in South Texas reacted to TGP similar to those who had previous natural exposure, suggesting that in vivo cross-reactivity may be higher than predicted by prior in vitro data and may allow the use in clinical trials of allergens not endemic to the locale of an ACC.

Effect of confounding cofactors on responses to pollens during natural season versus pollen challenge chamber exposure.

BACKGROUND: The severity of allergic rhinoconjunctivitis (AR) symptomatology elicited after exposure to pollen in the absence versus the presence of confounding cofactors, such as in a pollen challenge chamber (PCC) and the natural pollinating season, respectively, might differ. OBJECTIVE: We sought to determine the correlation of AR severity in the natural season versus out-of-season PCC exposures. METHODS: Twenty-four Virginia live oak (VLO)-positive, 14 VLO-negative, 16 mountain cedar (MC)-positive, 8 MC-negative, and 26 ragweed-positive participants recorded AR symptoms (total symptom score [TSS]) during the VLO, MC, and ragweed pollinating seasons and during 2 consecutive PCC exposures of 3 hours each to these pollens separately. RESULTS: The TSSs recorded before the natural season were higher than the pre-PCC values. This prepriming was greater among VLO(+) than MC(+) participants, and it blunted further increases in TSSs during the VLO natural season. Nonatopic participants were nonreactive in the PCC. There was wide variation in the level of AR symptomatology after exposure to VLO, MC, or ragweed pollen in the PCC. Prepriming formed the basis for higher AR responses observed in the natural season than in the PCC, resulting in the identification of distinct PCC/natural season endophenotypes and a partial correlation between the TSSs recorded in the natural season versus those recorded in the PCC (r = 0.34, 0.54, and 0.65 for VLO(+), MC(+), and ragweed-positive participants, respectively). CONCLUSIONS: Prepriming in the natural pollinating season might obscure the true correlation between AR severity in the natural season versus the PCC. By mitigating confounding cofactors, PCC exposures have utility for evaluation of novel AR therapeutics.

The mountain cedar model in clinical trials of seasonal allergic rhinoconjunctivitis.

BACKGROUND: Clinical trials of seasonal allergic rhinoconjunctivitis use the mountain cedar (Juniperus ashei) season as the predominate model. OBJECTIVE: To evaluate clinical trials of rhinoconjunctivitis using mountain cedar, to present analysis of pollen counts during 18 seasons, and to discuss the model. METHODS: The medical literature was searched for clinical trials performed using mountain cedar either in or out of season. Pollen counts were recorded and analyzed for the duration of 18 seasons. RESULTS: Thirty-eight trials were identified. Of these, 1 evaluated onset of allergy, 8 were immunotherapy trials, 28 were pharmaceutical clinical trials, and 1 studied symptoms elicited in a pollen challenge chamber trial. Many generic equivalency trials are unreported. In the 18 years of counts in the Texas Hill Country, a dependable and intense pollen density was present in every season. The combination of dependable seasons without confounding pollens, the large number of allergic patients, and the ability to concentrate resources in one geographic area has made mountain cedar allergy a mainstay for therapeutic trials for allergic rhinoconjunctivitis. CONCLUSION: Mountain cedar allergy presents a dependable and durable model of allergic rhinoconjunctivitis.

Responses to ragweed pollen in a pollen challenge chamber versus seasonal exposure identify allergic rhinoconjunctivitis endotypes.

BACKGROUND: The level of concordance between allergic symptoms induced on exposure to pollen in a pollen challenge chamber (PCC) versus the natural season is unknown. OBJECTIVE: We sought to test the hypothesis that the symptom levels of allergic rhinoconjunctivitis elicited after out-of-season exposure to short ragweed in a PCC and during the natural season for giant ragweed pollen are highly correlated. METHODS: Thirty-one ragweed-sensitive participants recorded symptoms for 15 days during the natural giant ragweed season in San Antonio, Texas. Twenty-six of these participants were challenged to short ragweed pollen in a PCC for 3 hours per day for up to 4 days. RESULTS: In the PCC participants were dichotomized into those in whom low versus high levels of symptoms developed slowly or rapidly (ie, slow/low vs rapid/high). Each successive exposure visit associated with a progressive increase in symptom levels that approximated those experienced during the natural season. Hierarchic clustering identified 3 endotypes: endotypes I and II reflected concordantly low (n= 7) versus high (n = 14) total symptom scores (TSSs) in both the natural season and the PCC, respectively. Accordingly, the correlation between the TSSs recorded in the natural season and in the PCC for these 21 participants was very high. Although participants with endotype III (n = 5) had greater TSSs in the natural season than in the PCC, the degree of correlation between the TSSs remained high. CONCLUSIONS: Our findings affirm our hypothesis, underscore the high cross-reactivity between distinct pollens, and highlight the utility of the PCC to identify novel allergy endotypes that might have contrasting mechanistic underpinnings and potentially therapeutic responses.

Validation of the biogenics research chamber for Juniperus ashei (mountain cedar) pollen.

BACKGROUND: Pollen challenge chambers have been used to evaluate medication in allergic rhinoconjunctivitis under controlled conditions. OBJECTIVE: To validate a facility for the study of subjects' responses to inhalational challenges with Juniperus ashei (mountain cedar) pollen. METHODS: Two chambers, 307 m(3) and 188 m(3), seating 50 and 25 individuals, respectively, were constructed with clean room materials. The computer-controlled air handler used powered diffusers and exhausts to maintain a laminar flow. Pollen was delivered by a feeder into a vortex created by an eductor through a series of stainless steel tubes. Nonprimed mountain cedar sensitive and healthy control subjects were exposed to a masked sham air run and increasing increments of pollen during a 5-hour period outside the natural season. These individuals were then exposed for 2-hour periods for up to 4 sequential days at fixed pollen counts to demonstrate effects of priming. RESULTS: Airflow from diffusers and exhausts maintained 12 exchange cycles per hour. Pollen counts ranged from 1,300 to 12,000 grains/m(3). None of the subjects responded during the masked sham run. Healthy controls did not respond. Nonprimed subjects had an inadequate response. Primed subjects responded symptomatically within a period adequate for entry into studies. There were no serious adverse responses. CONCLUSIONS: The chambers functioned within the parameters for which they were designed. Subjects did not respond to a sham run. Priming runs were required to stimulate symptoms at levels in a timeframe sufficient for pharmacologic studies. Pollen counts 3 to 4 times the average seasonal counts were required to elicit significant symptoms.