Large-scale provocation studies identify maladaptive responses to ubiquitous aeroallergens as a correlate of severe allergic rhinoconjunctivitis and asthma.

BACKGROUND: Allergic asthma (AA) and allergic rhinoconjunctivitis (ARC) are common comorbid environmentally triggered diseases. We hypothesized that severe AA/ARC reflects a maladaptive or unrestrained response to ubiquitous aeroallergens. METHODS: We performed provocation studies wherein six separate cohorts of persons (total n = 217) with ARC, with or without AA, were challenged once or more with fixed concentrations of seasonal or perennial aeroallergens in an aeroallergen challenge chamber (ACC). RESULTS: Aeroallergen challenges elicited fully or partially restrained vs. unrestrained evoked symptom responsiveness, corresponding to the resilient and adaptive vs. maladaptive AA/ARC phenotypes, respectively. The maladaptive phenotype was evoked more commonly during challenge with a non-endemic versus endemic seasonal aeroallergen. In an AA cohort, symptom responses evoked after house dust mite (HDM) challenges vs. recorded in the natural environment were more accurate and precise predictors of asthma severity and control, lung function (FEV1), and mechanistic correlates of maladaptation. Correlates included elevated levels of peripheral blood CD4+ and CD8+ T-cells, eosinophils, and T-cell activation, as well as gene expression proxies for ineffectual epithelial injury/repair responses. Evoked symptom severity after HDM challenge appeared to be more closely related to levels of CD4+ and CD8+ T-cells than eosinophils, neutrophils, or HDM-specific IgE. CONCLUSIONS: Provocation studies support the concept that resilience, adaptation, and maladaptation to environmental disease triggers calibrate AA/ARC severity. Despite the ubiquity of aeroallergens, in response to these disease triggers in controlled settings (ie, ACC), most atopic persons manifest the resilient or adaptive phenotype. Thus, ARC/AA disease progression may reflect the failure to preserve the resilient or adaptive phenotype. The triangulation of CD8+ T-cell activation, airway epithelial injury/repair processes and maladaptation in mediating AA disease severity needs more investigation.

Repetitive aeroallergen challenges elucidate maladaptive epithelial and inflammatory traits that underpin allergic airway diseases.

BACKGROUND: Signifying the 2-compartments/1-disease paradigm, allergic rhinoconjunctivitis (ARC) and asthma (AA) are prevalent, comorbid conditions triggered by environmental factors (eg, house dust mites [HDMs]). However, despite the ubiquity of triggers, progression to severe ARC/AA is infrequent, suggesting either resilience or adaptation. OBJECTIVE: We sought to determine whether ARC/AA severity relates to maladaptive responses to disease triggers. METHODS: Adults with HDM-associated ARC were challenged repetitively with HDMs in an aeroallergen challenge chamber. Mechanistic traits associated with disease severity were identified. RESULTS: HDM challenges evoked maladaptive (persistently higher ARC symptoms), adaptive (progressive symptom reduction), and resilient (resistance to symptom induction) phenotypes. Symptom severity in the natural environment was an imprecise correlate of the phenotypes. Nasal airway traits, defined by low inflammation-effectual epithelial integrity, moderate inflammation-effectual epithelial integrity, and higher inflammation-ineffectual epithelial integrity, were hallmarks of the resilient, adaptive, and maladaptive evoked phenotypes, respectively. Highlighting a crosstalk mechanism, peripheral blood inflammatory tone calibrated these traits: ineffectual epithelial integrity associated with CD8+ T cells, whereas airway inflammation associated with both CD8+ T cells and eosinophils. Hallmark peripheral blood maladaptive traits were increased natural killer and CD8+ T cells, lower CD4+ mucosal-associated invariant T cells, and deficiencies along the TLR-IRF-IFN antiviral pathway. Maladaptive traits tracking HDM-associated ARC also contributed to AA risk and severity models. CONCLUSIONS: Repetitive challenges with HDMs revealed that maladaptation to disease triggers may underpin ARC/AA disease severity. A combinatorial therapeutic approach may involve reversal of loss-of-beneficial-function traits (ineffectual epithelial integrity, TLR-IRF-IFN deficiencies), mitigation of gain-of-adverse-function traits (inflammation), and blocking of a detrimental crosstalk between the peripheral blood and airway compartments.

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.

Preservation of epithelial cell barrier function and muted inflammation in resistance to allergic rhinoconjunctivitis from house dust mite challenge.

BACKGROUND: An emerging paradigm holds that resistance to the development of allergic diseases, including allergic rhinoconjunctivitis, relates to an intact epithelial/epidermal barrier during early childhood. Conceivably, the immunologic and genomic footprint of this resistance is preserved in nonatopic, nonallergic adults and is unmasked during exposure to an aeroallergen. OBJECTIVE: The aim of this study was to obtain direct support of the epithelial/epidermal barrier model for allergic rhinoconjunctivitis. METHODS: Twenty-three adults allergic to house dust mites (HDMs) (M+) and 15 nonsensitive, nonallergic (M-) participants completed 3-hour exposures to aerosolized HDM (Dermatophagoides pteronyssinus) powder on 4 consecutive days in an allergen challenge chamber. We analyzed: (1) peripheral blood leukocyte levels and immune responses; and (2) RNA sequencing-derived expression profiles of nasal cells, before and after HDM exposure. RESULTS: On HDM challenge: (1) only M+ persons developed allergic rhinoconjunctivitis symptoms; and (2) peripheral blood leukocyte levels/responses and gene expression patterns in nasal cells were largely concordant between M+ and M- participants; gross differences in these parameters were not observed at baseline (pre-exposure). Two key differences were observed. First, peripheral blood CD4+ and CD8+ T-cell activation levels initially decreased in M- participants versus increased in M+ participants. Second, in M- compared with M+ participants, genes that promoted epidermal/epithelial barrier function (eg, filament-aggregating protein [filaggrin]) versus inflammation (eg, chemokines) and innate immunity (interferon) were upregulated versus muted, respectively. CONCLUSION: An imprint of resistance to HDM challenge in nonatopic, nonallergic adults was muted T-cell activation in the peripheral blood and inflammatory response in the nasal compartment, coupled with upregulation of genes that promote epidermal/epithelial cell barrier function.

Redness response phenotypes of allergic conjunctivitis in an allergen challenge chamber.

BACKGROUND: There are few direct data concerning symptom dynamics of allergic conjunctivitis (AC) in an allergen challenge chamber (ACC). OBJECTIVE: To determine the AC dynamics on subsequent exposures to ragweed pollen (RW) in individuals with allergic rhinitis in an ACC. To determine whether consecutive exposures in an ACC have any persistent detrimental ocular physical effects. METHODS: Participants underwent 3 exposures to RW in an ACC. Ocular symptoms of itching and tearing were self-assessed. Ocular redness and lid swelling were assessed by trained ophthalmic technicians. Complete ophthalmic examinations (COEs) were performed by an ophthalmologist. RESULTS: A total of 188 of 201 participants (93%) developed an ocular redness score of 2 or more in each eye in ACC exposure 1. Reproducibility of redness occurred in approximately 70% of individuals completing ACC exposures 1 through 3. There were no significant changes between baseline COE and end of study COE. Phenotypes were identified by redness responses during and after exposure. Baseline total ocular symptom scores, at 24 hours after a priming exposure, were identified as late-phase reactions rather than enhanced sensitivity. CONCLUSION: When assessed by trained professionals, AC was present with a very high frequency in selected individuals allergic to RW monitored in an ACC. Intrasubject reproducibility of redness was consistent across 3 ACC allergen exposures. Phenotypes were identified as early-phase responses, protracted early-phase responses, dual responses, and late-phase responses. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02079649.

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.

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.

Reversal of SSRI-associated apathy syndrome by discontinuation of therapy.

OBJECTIVE: To report 6 cases of selective serotonin reuptake inhibitor (SSRI)-associated apathy syndrome. CASE SUMMARIES: In all 6 cases, the patient reported loss of motivation while being treated with an SSRI. Loss of motivation was of new onset and temporally associated with the use of the SSRI. A trial of discontinuation of the SSRI was performed in all 6 patients and 2 were started on bupropion while cross-tapering from the SSRI. During the treatment trials, depression and apathy were monitored in all patients. Each case was assessed using the Apathy Evaluation Scale, Clinician version (AES-C), and by evaluating how the patient responded to discontinuation of the SSRI. DISCUSSION: Scores on the AES-C improved significantly in all 6 cases after the SSRI was discontinued. Improvement was also seen in the motivation, novelty, and persistence subdomain scores of the AES-C. A pretreatment AES-C score was available only in the first case. Based on the Naranjo probability scale, there was a probable cause of apathy syndrome with SSRI therapy in the first case and a possible association in the rest of the cases. CONCLUSIONS: In some patients SSRIs may cause an apathy syndrome that can be reversed through discontinuation of the agent. When evaluating patients being treated with an SSRI, clinicians should have a high degree of suspicion and specifically inquire for this iatrogenic form of apathy syndrome.

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.

Food hypersensitivity by inhalation.

Though not widely recognized, food hypersensitivity by inhalation can cause major morbidity in affected individuals. The exposure is usually more obvious and often substantial in occupational environments but frequently occurs in non-occupational settings, such as homes, schools, restaurants, grocery stores, and commercial flights. The exposure can be trivial, as in mere smelling or being in the vicinity of the food. The clinical manifestations can vary from a benign respiratory or cutaneous reaction to a systemic one that can be life-threatening. In addition to strict avoidance, such highly-sensitive subjects should carry self-injectable epinephrine and wear MedicAlert(R) identification. Asthma is a strong predisposing factor and should be well-controlled. It is of great significance that food inhalation can cause de novo sensitization.