Anxiety in adults with allergic rhinitis during the coronavirus disease 2019 pandemic: A Canadian perspective.

BACKGROUND: Despite the symptom overlap between allergic rhinitis (AR) and coronavirus disease 2019 (COVID-19), pandemic-time anxiety in people with AR remains an area of limited study. OBJECTIVE: To assess the AR-anxiety relationship in the unique context of the COVID-19 pandemic from a Canadian perspective. METHODS: The COVID-19 Associated Anxiety in patients with Asthma and AR Experiencing Symptoms survey was distributed on the "Qualtrics XM" platform, with 835 adult participants responding to the first iteration from April to August 2020. Anxiety was assessed on the Generalized Anxiety Disorder Assessment-7 (GAD-7), and AR burden of disease was assessed on the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ). All analyses were conducted using IBM SPSS Statistics 27. RESULTS: High levels of anxiety were found, with 28.0% of the AR group and 27.5% of the control group meeting the diagnostic criteria for generalized anxiety disorder. After controlling for covariates, AR status had no significant predictive effect on GAD-7 in a hierarchal multiple regression model (ΔR2 = .00, P = .69). In the AR subgroup, there were significant positive correlations between anxiety and burden of disease for the total RQLQ score and all 7 domain scores (P < .001 for all), with the non-nose or eye symptom domain having the strongest correlation (r = .63). After controlling for covariates, total RQLQ score had a predictive effect on GAD-7 in a hierarchal multiple regression model (ΔR2 = .049, P < .001). CONCLUSION: High levels of anxiety exist during the COVID-19 pandemic regardless of AR status, indicating the importance of early anxiety screening in all patients. This study also highlights the importance of non-nose or eye symptoms in AR management.

Comparative nasal airflow with loratadine-pseudoephedrine and fluticasone nasal spray for allergic rhinitis.

BACKGROUND: Although it is known that oral antihistamine-pseudoephedrine combination tablets have a faster onset than intranasal corticosteroid sprays in the treatment of allergic rhinitis after the first dose, the magnitude of change has not been measured in a comparative manner. Furthermore, the sensation of sprayed liquid in the nose may lead patients to mistakenly believe that intranasal steroid sprays work instantly. OBJECTIVE: To evaluate, numerically, nasal airflow changes provided by a single dose of loratadine-pseudoephedrine tablet (LP) and fluticasone propionate nasal spray (FP) in participants experiencing allergic rhinitis symptoms, including nasal congestion. METHODS: This single-center, double-blinded, placebo-controlled, crossover study evaluated objective nasal airflow changes in patients with a documented sensitivity to ragweed pollen. Participants were randomized to receive 1 of 4 treatment sequences, and their peak nasal inspiratory flow (PNIF) was measured in a span of 4 hours after pollen exposure in an environmental exposure unit. RESULTS: Average change in PNIF was 31% with LP in the course of the study, significantly greater than with placebo and FP (12% and 15%, respectively; P < .001). Nevertheless, FP did not produce a significant change compared with its placebo. At hour one post-dose, LP had a clinically significant 31% increase in PNIF, whereas FP only yielded an 8.6% increase (P < .001). Measurable nasal airflow improvements are associated with the opening of nasal passages, allowing congested patients to breathe more freely. CONCLUSION: A single dose of LP quickly and significantly (P < .001) improved nasal airflow after ragweed pollen challenge in an environmental exposure unit. Comparatively, FP did not display this same benefit. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03443843.

Clinical symptoms and biomarkers of Bermuda grass-induced allergic rhinitis using the nasal allergen challenge model.

BACKGROUND: Bermuda grass is a prevalent allergen that flourishes in tropical climates. Its exposure is traditionally believed to be low in Ontario due to the colder environment. However, high sensitization rates have been observed in Kingston, Ontario. OBJECTIVE: We sought to investigate whether its allergens can provoke allergic rhinitis (AR) symptoms in sensitized participants from south-eastern Ontario and determine if nasal allergen challenge (NAC) model is appropriate to study Bermuda grass-induced AR. METHODS: Twenty-one participants sensitized to Bermuda grass and 12 nonallergic participants completed a titrated NAC with increasing allergen concentrations at a screening visit. Total nasal symptom score (TNSS) and peak nasal inspiratory flow were collected before allergen exposure and 10 minutes after delivery of each concentration. Twelve participants with a Bermuda grass allergy who met the qualifying criteria (TNSS ≥ 8 and peak nasal inspiratory flow fall ≥ 50%) and 11 nonallergic controls returned for single-dose NAC visit. RESULTS: At titrated NAC, 19 of 21 sensitized participants met the criteria of positive allergic response when challenged. During single-dose NAC, participants with allergy had significantly greater TNSS between 15 minutes and 3 hours after NAC than controls. Likewise, allergic participants had a significantly increased number of nasal lavage eosinophils at both 1 and 6 hours after NAC. Bermuda grass-specific immunoglobulin E was significantly increased in Bermuda grass allergic participants at NAC than screening visit. CONCLUSION: Although Bermuda grass is a non-native allergen in Ontario, it can induce AR symptoms in sensitized participants, and the NAC model is appropriate to study Bermuda grass-induced AR.

Utility of Environmental Exposure Unit Challenge Protocols for the Study of Allergic Rhinitis Therapies.

PURPOSE OF REVIEW: This paper explores how the Environmental Exposure Unit (EEU) experimental model can be used to further our understanding of pharmacotherapies and immunotherapies for the treatment of allergic rhinitis (AR). RECENT FINDINGS: EEUs are used increasingly for the study of combination therapies, immunotherapies, and novel AR treatments. A combined antihistamine/corticosteroid nasal spray formulation was seen to have a faster onset of action relative to the therapies individually in the Environmental Exposure Chamber. House dust mite sublingual immunotherapy tablets are both safe and efficacious as evaluated by the Vienna Challenge Chamber. The Kingston EEU found that a novel peptide-based immunotherapy approach to be effective in reducing grass pollen-induced AR. Lastly, nasal filters were determined to reduce seasonal AR symptoms, given out-of-season in the Denmark Environmental Exposure Unit. EEUs are controlled, replicable models that provide valuable insight into the efficacy, onset and duration of action, and dose-related impacts of AR therapeutics, with direct clinical relevance.

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.

Investigating Immune Gene Signatures in Peripheral Blood from Subjects with Allergic Rhinitis Undergoing Nasal Allergen Challenge.

Nasal allergen challenge (NAC) is a human model of allergic rhinitis (AR) that delivers standardized allergens locally to the nasal mucosa allowing clinical symptoms and biospecimens such as peripheral blood to be collected. Although many studies have focused on local inflammatory sites, peripheral blood, an important mediator and a component of the systemic immune response, has not been well studied in the setting of AR. We sought to investigate immune gene signatures in peripheral blood collected after NAC under the setting of AR. Clinical symptoms and peripheral blood samples from AR subjects were collected during NAC. Fuzzy c-means clustering method was used to identify immune gene expression patterns in blood over time points (before NAC and 1, 2, and 6 h after NAC). We identified and validated seven clusters of differentially expressed immune genes after NAC onset. Clusters 2, 3, and 4 were associated with neutrophil and lymphocyte frequencies and neutrophil/lymphocyte ratio after the allergen challenge. The patterns of the clusters and immune cell frequencies were associated with the clinical symptoms of the AR subjects and were significantly different from healthy nonallergic subjects who had also undergone NAC. Our approach identified dynamic signatures of immune gene expression in blood as a systemic immune response associated with clinical symptoms after NAC. The immune gene signatures may allow cross-sectional investigation of the pathophysiology of AR and may also be useful as a potential objective measurement for diagnosis and treatment of AR combined with the NAC model.

Repeatability of nasal allergen challenge results: Further validation of the allergic rhinitis clinical investigator collaborative 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.

Lack of effect of Timothy grass pollen sublingual immunotherapy tablet on birch pollen-induced allergic rhinoconjunctivitis in an 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.

The Kingston Allergy Birth Cohort: Exploring parentally reported respiratory outcomes through the lens of the exposome.

BACKGROUND: The Kingston Allergy Birth Cohort (KABC) is a prenatally recruited cohort initiated to study the developmental origins of allergic disease. Kingston General Hospital was chosen for recruitment because it serves a population with notable diversity in environmental exposures relevant to the emerging concept of the exposome. OBJECTIVE: To establish a profile of the KABC using the exposome framework and examine parentally reported respiratory symptoms to 2 years of age. METHODS: Data on phase 1 of the cohort (n = 560 deliveries) were compiled, and multivariate Cox proportional hazards regression models were used to determine associations with respiratory symptoms. RESULTS: The KABC exhibits diversity within the 3 exposome domains of general external (socioeconomic status, rural or urban residence), specific external (cigarette smoke, breastfeeding, mold or dampness), and internal (respiratory health, gestational age), as well as significant associations between exposures from different domains. Significant associations emerged between parental reports of wheeze or cough without a cold and prenatal cigarette smoke exposure, mold or dampness in the home, and the use of air fresheners in the early-life home environment. Breastfeeding, older siblings, and increased gestational age were associated with decreased respiratory symptoms. CONCLUSION: The KABC is a unique cohort with diversity that can be leveraged for exposomics-based studies. This study found that all 3 domains of the exposome had effects on the respiratory health of KABC children. Ongoing studies using phase 1 of the KABC continue to explore the internal exposome through allergy skin testing and epigenetic analyses and the specific external domain through in-home environmental analyses, air pollution modeling, and ultimately potential convergences within and among domains.

Efficacy of the novel nasal steroid S0597 tested in an environmental exposure unit.

BACKGROUND: S0597 is a novel glucocorticosteroid that was formulated as an intranasal spray to treat seasonal allergic rhinitis (SAR). In a previous phase 2 study, doses of 100 to 400 µg twice daily were well tolerated and more effective than placebo for improving nasal symptoms induced by grass pollen. OBJECTIVE: To assess the clinical efficacy and safety of a once-daily S0597 nasal spray for treatment of SAR induced by ragweed pollen in an environmental exposure unit (EEU). METHODS: A single-center, phase 2, randomized, double-blind study in 222 adults with SAR and a positive skin prick test result to short ragweed. Participants underwent ragweed pollen challenge in the EEU at the screening or priming visit and on days 1, 7, and 14 and received 50, 200, or 400 µg of S0597 or placebo in the evening for 13 days. The primary efficacy end point was change in total nasal symptom score (TNSS) from baseline to day 14. RESULTS: Improvement in TNSS from baseline to day 14 was statistically significant in all S0597 groups compared with placebo. Least-squares mean differences in change from baseline between active treatment and placebo were 1.18, 1.84, and 1.17 for the 50-, 200-, and 400-µg/d S0597 groups, respectively (P < .05). The 200-µg group demonstrated statistically significant improvements in all TNSS subscales (rhinorrhea, nasal congestion, sneezing, nasal itching) compared with placebo at days 7 and 14. CONCLUSION: Treatment with 50 to 400 µg of S0597 once daily was well tolerated and significantly more effective than placebo in relieving nasal symptoms of SAR associated with ragweed pollen. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01940146.

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.

Anxiety in adults with asthma during the coronavirus disease 2019 pandemic: a Canadian perspective.

BACKGROUND: Asthma is a chronic airway inflammatory disease that affects millions of Canadians and often contributes to higher levels of anxiety among patients. Since the coronavirus disease 2019 (COVID-19) pandemic was a time of increased anxiety and fear among the Canadian population, it was thought that those with asthma may experience heightened anxiety levels due to uncertain access to care, the potential to misinterpret asthma symptoms for symptoms of COVID-19 (or vice versa), and the concern about being treated differently by those around them when experiencing asthma symptoms. Therefore, this study sought to perform a cross-sectional analysis of the asthma-anxiety relationship in adults with and without asthma in the unique context of the COVID-19 pandemic from a Canadian perspective. METHODS: This study employed the COVID-19 Associated Anxiety in Allergic Rhinitis and Asthma patients Experiencing Symptoms (CAAARES) survey, consisting of COVID-19-specific questions, the Generalized Anxiety Disorder Assessment-7 (GAD-7) and the Asthma Control Questionnaire-6 (ACQ-6). Data collection occurred through the Qualtrics XM platform and data analyses were conducted with the IBM SPSS Statistics 28 software. RESULTS: A total of 741 valid responses were collected (asthma group, n = 244; control group, n = 497). 31.6% and 26.2% of respondents in the asthma and control groups, respectively, met the diagnostic criteria for GAD. There was no significant difference (p = .067) in mean GAD-7 scores between the two groups. A Hierarchal Multiple Regression (HMR) model was developed, and neither asthma status nor ACQ-6 score had a significant predictive effect on the GAD-7 score. There was a statistically significant (p < .001) weak positive correlation (r = .22) between GAD-7 and ACQ-6 scores. In a simple mediation (SMM) model, perceived COVID-19 stress of others was not identified as a significant mediator of the relationship between ACQ-6 and GAD-7 (indirect effect ß = 0.014). CONCLUSION: Our study of a Canadian cohort demonstrates elevated levels of anxiety overall, amongst both asthma and control groups. While AR status was significantly greater in the asthma group, it was not a significant predictive variable of GAD-7 score. Our data suggests that COVID-19-specific factors appear to have a greater contribution to anxiety than asthma status or control.

Onset of action for loratadine tablets for the symptomatic control of seasonal allergic rhinitis in adults challenged with ragweed pollen in the Environmental Exposure Unit: a post hoc analysis of total symptom score.

BACKGROUND: Loratadine is a second-generation, non-sedating antihistamine used for the relief of allergic rhinitis symptoms. Previous studies reported that when loratadine was encapsulated, the onset of action for symptom relief was 180 min. However, unmodified loratadine tablets were not evaluated at that time. Using data from a previously published Environmental Exposure Unit (EEU) study comparing azelastine nasal spray with loratadine tablets, cetirizine tablets, and placebo, this post hoc analysis determines the onset of action of loratadine tablets (i.e. unmodified) by analyzing the total symptom score for the relief of nasal and ocular seasonal allergic rhinitis (SAR) symptoms. METHODS: A Phase IV, randomized, single-center, double-blind, placebo-controlled, double-dummy, four-way crossover study was conducted in the EEU. Seventy participants were randomized sequentially into one of the four treatments during ragweed pollen exposure. Nasal and ocular symptom scores were self-reported by the participants and recorded. The original study analysis was carried out by evaluating the nasal symptom scores only. For this post hoc analysis, both nasal and ocular data from the loratadine and placebo treatment arms were analyzed. The primary endpoint for this analysis was the onset of action of loratadine as measured by the change in total symptom score (TSS) from baseline in comparison to placebo. The onset of ocular symptom relief using the total ocular symptom score (TOSS) was also reported. RESULTS: Loratadine tablets demonstrated a significant and durable improvement in both TSS (P = .005) and TOSS (P = .013) at 75 min post-treatment administration compared to placebo. The mean proportion of participants reporting none or mild for all component symptoms of TSS and TOSS at 75 min and thereafter was significantly higher in the loratadine (TSS, P = .0005; TOSS, P ≤ .0001) vs. placebo treatment arm. CONCLUSIONS: The onset of action of loratadine tablets was 75 min for the relief of nasal and ocular symptoms in adults with SAR. These results suggest a faster onset of action for loratadine tablets (75 min) compared to previously reported studies which were conducted with modified (i.e. gelatin-encapsulated) loratadine tablets (180 min).Trial registration Clinicaltrials.gov identifier NCT00561717.

The Allergic Rhinitis Clinical Investigator Collaborative (AR-CIC): verification of nasal allergen challenge procedures in a study utilizing an investigational immunotherapy for cat allergy.

BACKGROUND: The Allergic Rhinitis Clinical Investigator Collaborative (AR-CIC) is a network of experienced Allergic Rhinitis (AR) researchers developing better research tools based on the nasal allergen challenge (NAC). A key objective of such is the ability to detect efficacy in a small population. AR-CIC sought to test its NAC protocol as a secondary objective in two small mechanistic research trials of a novel form of immunotherapy [Cat Peptide Antigen Desensitisation (Cat-PAD)] for which efficacy had previously been demonstrated. The primary objective (not presented here) was to identify potential biomarkers of efficacy for peptide immunotherapy, and this provided an ideal opportunity to corroborate the NAC protocol. We aim to clinically validate the AR-CIC NAC methodology in a pooled analysis of secondary endpoints measured in two open label mechanistic studies of cat allergic participants treated with Cat-PAD. METHODS: Cat allergic AR sufferers with ongoing cat exposure were included. Participants had to demonstrate a total nasal symptom score (TNSS) of at least 8 (max 12) and/or achieve a reduction in peak nasal inspiratory flow (PNIF) of ≥ 50% during a screening titrated NAC. Eligible participants then underwent a baseline NAC visit with the allergen dose that produced a positive challenge at screening, followed by four monthly injections of 6 nmol Cat-PAD. A follow up NAC visit documented changes in nasal response 1 month following the completion of treatment. RESULTS: Nineteen subjects completed the study protocol in the two studies combined. Four injections of Cat-PAD resulted in a significant reduction in TNSS responses generated via NAC following allergen challenge (15 min p < 0.05, 30 min p < 0.05, 1 h p < 0.01, 2 h p < 0.05). There was modest correlation between symptom scores and PNIF measurements. CONCLUSIONS: This study supports the validity of the AR-CIC's optimised NAC protocol for conducting research of the potential efficacy of novel therapeutics in multi-centre studies.Trial registration Both studies reported herein were registered clinicaltrials.gov (NCT01383590 and NCT01383603).