A pediatric randomized, controlled trial of German cockroach subcutaneous immunotherapy.

BACKGROUND: Cockroach allergy contributes to morbidity among urban children with asthma. Few trials address the effect of subcutaneous immunotherapy (SCIT) with cockroach allergen among these at-risk children. OBJECTIVES: We sought to determine whether nasal allergen challenge (NAC) responses to cockroach allergen would improve following 1 year of SCIT. METHODS: Urban children with asthma, who were cockroach-sensitized and reactive on NAC, participated in a year-long randomized double-blind placebo-controlled SCIT trial using German cockroach extract. The primary endpoint was the change in mean Total Nasal Symptom Score (TNSS) during NAC after 12 months of SCIT. Changes in nasal transcriptomic responses during NAC, skin prick test wheal size, serum allergen-specific antibody production, and T-cell responses to cockroach allergen were assessed. RESULTS: Changes in mean NAC TNSS did not differ between SCIT-assigned (n = 28) versus placebo-assigned (n = 29) participants (P = .63). Nasal transcriptomic responses correlated with TNSS, but a treatment effect was not observed. Cockroach serum-specific IgE decreased to a similar extent in both groups, while decreased cockroach skin prick test wheal size was greater among SCIT participants (P = .04). A 200-fold increase in cockroach serum-specific IgG4 was observed among subjects receiving SCIT (P < .001) but was unchanged in the placebo group. T-cell IL-4 responses following cockroach allergen stimulation decreased to a greater extent among SCIT versus placebo (P = .002), while no effect was observed for IL-10 or IFN-γ. CONCLUSIONS: A year of SCIT failed to alter NAC TNSS and nasal transcriptome responses to cockroach allergen challenge despite systemic effects on allergen-specific skin tests, induction of serum-specific IgG4 serum production and down-modulation of allergen-stimulated T-cell responses.

Utility of silver birch and house dust mite extracts derived from licensed sublingual tablets for nasal allergen challenge.

BACKGROUND: Nasal allergen challenge (NAC) is used to investigate the effects of allergen exposure and assess treatment efficacy in allergic rhinitis (AR). This study aims to establish dose-responses to NAC using licensed silver birch (SB) pollen and house dust mite (HDM) sublingual tablets as sources of the allergen extracts in participants with AR. METHODS: Sixteen volunteers with HDM-induced perennial AR and 15 volunteers with SB pollen-induced seasonal rhinitis underwent a graded up-dosing NAC with extracts derived from HDM allergen (Acarizax®) and SB (Itulazax®) tablets, respectively. Total nasal symptom score (TNSS, range 0-12) and peak nasal inspiratory flow (PNIF) were recorded before, at 10 min and at the end of the NAC. The dose of each allergen that provoked a TNSS of at least 7 ("provoking dose 7") in most allergic participants was identified. NACs using the "provoking dose 7" were performed on 5 non-allergic individuals to test for irritant effects. The "provoking dose 7" of HDM extract was used in a subgroup of two SB allergic, non-HDM allergic, volunteers, and vice versa for SB extract, to test for allergen specificity of the responses. RESULTS: Most patients experienced a TNSS of at least 7/12 at a median concentration of 1500 AU/mL for both SB pollen and HDM. The average decline in PNIF at this dose was 63.15% for SB and 63.99% for HDM. NACs using the 1500 AU/mL concentrations were performed on 5 non-allergic individuals with no symptomatic or PNIF response. 1500 AU/mL of HDM extract produced no symptoms in SB allergics nor 1500 AU/mL SB extract in HDM allergics. CONCLUSION: For both SB and HDM extracts, the optimal allergen dose for NAC to cause a moderate-severity response ("provoking dose 7/12") was 1500 AU/mL. Licensed sublingual allergen tablets provide a readily available and inexpensive source of SB and HDM extracts for use in future interventional studies in AR.

Local Allergic Rhinitis.

Local allergic rhinitis (LAR) is defined by a clinical history suggestive of allergic rhinitis (AR), negativity of systemic IgE measurement and positive response to nasal allergen challenge (NAC). The term local respiratory allergy includes LAR, local allergic asthma (positive response in bronchial allergen challenge) and dual allergic rhinitis defined by the coexistence of AR and LAR. LAR worsens in severity and presence of comorbidities over time, and it is an independent entity from AR. Prevalence is higher in Mediterranean countries. LAR onset occurs during childhood in 36% of cases. Physiopathological features of LAR are: increased nasal eosinophilic inflammation, tryptase and eosinophil cationic protein, and presence of nasal specific IgE in secretions of 20-40% of subjects. A recent study demonstrated increase in sequential class switch recombination to IgE markers in mucosa of LAR with accumulation of IgE+ CD38+ plasmablasts. Moreover, there is increased expression in B cells of mucosal homing receptors CXCR3+ and CXCR4 in peripheral blood, with accumulation of Th9 and Th2 cells. NAC is the gold standard in the diagnosis of LAR. The measurement of specific IgE in nasal secretions basophil activation test or are still not suitable for diagnosis. There is ample evidence of the usefulness of allergen immunotherapy in the treatment in LAR after 4 DBPCRT in 152 patients. In conclusion, knowledge about LAR is continuously increasing, with detailed definition of physiopathological mechanisms and new phenotypes. More awareness of the disease should be promoted among different specialists, and NAC must be considered an essential diagnostic tool in any age group, including children.

Local allergic rhinitis in children: identification and characterization in a specialty outpatient clinic.

Summary: Background. Local Allergic Rhinitis (LAR) is a phenotype defined by rhinitis symptoms with negative responses to systemic sensitization tests but with an exclusively nasal allergic inflammatory response. Data on the pediatric age group is scarce, and no Latin American data has been published so far. Methods. Nasal Allergen Challenge (NAC) was performed with Dermatophagoides pteronyssinus and Blomia tropicalis in six- to 18-year-old patients diagnosed with rhinitis and no systemic sensitization. NAC was monitored using subjective parameters and acoustic rhinometry. The study aimed to identify LAR in child and adolescent subjects previously diagnosed with non-allergic rhinitis (NAR) in a Brazilian specialty outpatient clinic (Allergy and Immunology). Results. During the study period, we analyzed 758 skin prick tests (SPT). Of those, 517 (68.2%) were diagnosed with rhinitis. Among those, 18.4% (95/517) had a negative SPT, meeting the criteria for inclusion in the study. Twenty-five patients underwent NAC, and 40% (10/25) of them, previously considered to have NAR, had a positive test and were reclassified as having LAR. Based on the analyzed characteristics, clinically differentiating LAR from NAR was impossible. Conclusions. This study represents the first investigation of LAR in child and adolescent subjects in Latin America, contributing significantly to the understanding of its prevalence and characteristics in this geographic area. Among a subgroup of patients lacking systemic sensitization submitted to NAC, 40% (10/25) demonstrated a positive NAC with Dermatophagoides pteronyssinus and Blomia tropicalis, warranting their reclassification to LAR. NAC with multiple allergens has been proven safe and viable in pediatric populations, affirming its critical role in the accurate diagnosis of LAR.

Evaluation of the reproducibility of responses to nasal allergen challenge and effects of inhaled nasal corticosteroids.

BACKGROUND: Similar immune responses in the nasal and bronchial mucosa implies that nasal allergen challenge (NAC) is a suitable early phase experimental model for drug development targeting allergic rhinitis (AR) and asthma. We assessed NAC reproducibility and the effects of intranasal corticosteroids (INCS) on symptoms, physiology, and inflammatory mediators. METHODS: 20 participants with mild atopic asthma and AR underwent three single blinded nasal challenges each separated by three weeks (NCT03431961). Cohort A (n = 10) underwent a control saline challenge, followed by two allergen challenges. Cohort B (n = 10) underwent a NAC with no treatment intervention, followed by NAC with 14 days pre-treatment with saline nasal spray (placebo), then NAC with 14 days pre-treatment with INCS (220 µg triamcinolone acetonide twice daily). Nasosorption, nasal lavage, blood samples, forced expiratory volume 1 (FEV1), total nasal symptom score (TNSS), peak nasal inspiratory flow (PNIF) were collected up to 24 h after NAC. Total and active tryptase were measured as early-phase allergy biomarkers (≤30 min) and IL-13 and eosinophil cell counts as late-phase allergy biomarkers (3-7 h) in serum and nasal samples. Period-period reproducibility was assessed by intraclass correlation coefficients (ICC), and sample size estimates were performed using effect sizes measured after INCS. RESULTS: NAC significantly induced acute increases in nasosorption tryptase and TNSS and reduced PNIF, and induced late increases in nasosorption IL-13 with sustained reductions in PNIF. Reproducibility across NACs varied for symptoms and biomarkers, with total tryptase 5 min post NAC having the highest reproducibility (ICC = 0.91). Treatment with INCS inhibited NAC-induced IL-13 while blunting changes in TNSS and PNIF. For a similar crossover study, 7 participants per treatment arm are needed to detect treatment effects comparable to INCS for TNSS. CONCLUSION: NAC-induced biomarkers and symptoms are reproducible and responsive to INCS. NAC is suitable for assessing pharmacodynamic activity and proof of mechanism for drugs targeting allergic inflammation.

Nasal IL-13 production identifies patients with late-phase allergic responses.

BACKGROUND: There is limited knowledge on how local cytokine secretion patterns after nasal allergen challenge correlate with clinical symptoms especially with regard to the "late allergic response," which occurs in approximately 40% to 50% of patients with allergy. OBJECTIVE: We sought to characterize the immunologic and clinical nasal responses to birch pollen allergen challenge with a special focus on the late allergic response. METHODS: In this randomized, double-blind, placebo-controlled trial, birch pollen-allergic participants were challenged with birch pollen extract (n = 20) or placebo (n = 10) on 3 consecutive days. On days 1 and 3, nasal secretions were collected at selected time points over a 24-hour time course for the measurement of 33 inflammatory mediators. Clinical responses were determined through subjective symptom scores and objective nasal airflow measurements. RESULTS: Provoked participants had significantly greater clinical responses and showed significant increases in tryptase and the soluble IL-33 receptor serum stimulation 2 (sST2) in nasal secretions within minutes compared with the placebo group. Eight of 20 provoked participants displayed high IL-13 levels 2 to 8 hours after allergen provocation. This group also showed significant changes in clinical parameters, with a secondary drop in nasal airflow measured by peak nasal inspiratory flow and increased symptoms of nasal obstruction, which significantly differed from IL-13 nonresponders after 6 hours. CONCLUSIONS: IL-13 response status correlates with clinical responses and type 2 cytokine responses in the late phase after allergen provocation.

Birch-induced allergic rhinitis: Results of exposure during nasal allergen challenge, environmental chamber, and pollen season.

Background: Pollen variation can affect field study data quality. Nasal allergen challenge (NAC) is considered the gold standard for evaluating allergic rhinitis, while environmental exposure chambers (EECs) are mainly used in phase 2 drug development studies. We aimed to study birch-induced allergic rhinitis under 3 different conditions. Methods: This study included 30 participants allergic to birch pollen, based on birch skin prick test, specific immunoglobulin E (IgE), and positive NAC. Participants were exposed to placebo twice, followed by 2 consecutive 4-h birch airborne exposures, repeated on 2 occasions to evaluate reproducibility and priming effect. Nasal response was defined as total corrected nasal symptom score (ΔTNSS) ≥ 5 during NAC and EEC. The primary end-point was to measure TNSS during the last 2 h of first allergen exposure. TNSS was also analyzed during natural exposure. Results: The dose most commonly yielding positive TNSS during NAC was 175.2 ng/200 µL. Eighteen participants experienced ΔTNSS ≥5 during the last 2 h of the first exposure, whereas 21 had positive responses at all 4 exposures. Mean ΔTNSS was 1 with placebo versus 6 with birch. Exposures were reproducible, with no observed priming effect. Airborne Bet v 1 was 25 ng/m3, while the pollen measurement was 279/m3 during pollen season. TNSS reached 5 in 67.9% of participants during peak pollen season. Conclusion: EEC outcomes were similar to those obtained with NAC and natural exposure, suggesting the usefulness of EEC in allergic rhinitis studies. The primary end-point was reached, as 60% of participants experienced nasal responses.

Organ-specific allergen challenges in airway allergy: Current utilities and future directions.

Atopy has been long used as the screening method for airway allergy. Nevertheless, aeroallergens can trigger respiratory symptoms not only in atopic patients (atopic respiratory allergy, ARA), but also in non-atopic subjects (local respiratory allergy, LRA). Moreover, ARA and LRA can coexist in the same patient, and this clinical scenario has been called dual respiratory allergy (DRA). When the clinical history cannot determine the relevance of sensitizations in ARA patients, nasal, conjunctival or bronchial allergen challenges (NAC, CAC, and BAC, respectively) should be conducted. Moreover, these tests are required to identify patients with LRA and DRA. The clarification of the allergic triggers of airway diseases has a profound impact on the management strategies the patients can be offered. Importantly, allergen immunotherapy (AIT) remains as the only disease-modifying intervention for ARA. Recent data indicate that AIT might have a similar effect on LRA patients. Nevertheless, AIT success relies largely on the correct phenotyping of allergic individuals, and NAC, CAC, and BAC are very helpful tools in this regard. In this review, we will summarize the main indications and methodology of CAC, NAC, and BAC. Importantly, the clinical implementation of these tests might translate into precision medicine approaches and better health outcomes for patients with airway allergy.

Cupressus arizonica: an emerging aeroallergen for East Mediterranean children.

Background/aim: Cupressus sempervirens is a tree native to the Mediterranean region. We aimed to investigate the frequency of sensitization/allergy to Cupressus arizonica pollen, which is not native to Anatolia. Materials and methods: Patients aged 5-18 years who underwent respiratory allergy screening in Türkiye's largest referral center over a 1-year period were reviewed retrospectively for a diagnostic study of Cupressus allergy. Results: Of 246 patients, 207 (67.6% male) with a median age of 11.7 (IQR 9.2-15) years were found to be aeroallergen-sensitive and C. arizonica (32%) was the second most common sensitivity after grass pollen (83.6%). In the C. arizonica-sensitive subgroup, only 3% (2/67) were monosensitive, and grass (77.6%), cat (38.8%), and weeds (38.8%) were the most common co-sensitivities. Cup a 1 specific IgE (sIgE) was measured in 26 patients with C. arizonica sensitivity and all were found to be positive. A nasal allergen challenge (NAC) was performed for 44 of 67 patients with C. arizonica sensitivity, and 13 of 44 patients had a positive outcome (NAC+) at the highest two extract concentrations. The Cupressus wheal sizes and Cup a 1 sIgE levels of the NAC+ subgroup were higher than those of the NAC- subgroup but reached significance only for wheal size [6 (5-7.5) vs. 4.5 (4-6), p=0.004]. The NAC+ subgroup reported more frequent nasal discharge, congestion, and eye symptoms than the NAC- subgroup during the relevant pollen season. Conclusion: C. arizonica sensitivity has increased in the East Mediterranean region, similarly to North Mediterranean data, and this is associated with the presence of allergy both clinically and in laboratory findings. C. arizonica should be included in the aeroallergen screening panels of children from the East Mediterranean.

Study of Cat Allergy Using Controlled Methodology-A Review of the Literature and a Call to Action.

The prevalence of cat allergen-induced AR is increasing worldwide, prompting its study using controlled methodology. Three general categories of allergen exposure models currently exist for the study of cat allergen-induced AR: natural exposure cat rooms, allergen exposure chambers (AEC), and nasal allergen challenges (NAC). We evaluated existing literature surrounding the use of these models to study cat allergen induced AR using online research databases, including OVID Medline, Embase, and Web of Science. We report that natural exposure cat rooms have been important in establishing the foundation for our understanding of cat allergen-induced AR. Major limitations, including variable allergen ranges and differing study designs highlight the need for a more standardized protocol. In comparison, AECs are an exceptional model to mimic real-world allergen exposure and study long-term implications of AR with large sample sizes. Existing AECs are limited by heterogeneous facility designs, differing methods of cat allergen distribution, and issues surrounding cost and accessibility. Conversely, NACs allow for smaller participant cohorts for easier biological sampling and are ideal for phase I, phase 2 or proof-of-concept studies. NACs generally have a standardized protocol and are less expensive compared to AECs. Nevertheless, NACs solely capture acute allergen exposure and have the further limitation of using allergen extracts rather than natural allergen. As the use of combined controlled methodologies is sparse, we recommend concurrent use of AECs and NACs to study short- and long-term effects of AR, thereby providing a more holistic representation of cat allergen-induced AR.

Nasal administration of a probiotic assemblage in allergic rhinitis: A randomised placebo-controlled crossover trial.

BACKGROUND: Topical probiotics have been suggested as a treatment option for allergic rhinitis, as they may skew the immune response towards a beneficial type-1 non-allergic profile. So far observations in man have exclusively involved oral intake. The aim of this study was to examine whether a topical/nasal administration of a probiotic assemblage (PA) affects quality of life, symptoms and signs of allergic rhinitis in a nasal allergen challenge (NAC) model. METHODS: In a placebo-controlled and crossover design, 24 patients with seasonal allergic rhinitis were randomised to topical/nasal administration with a PA of Lactobacillus rhamnosus SP1, Lactobacillus paracasei 101/37 and Lactococcus lactis L1A or placebo for 3 weeks. Participants and investigators were blind to treatment allocation. The last week of each treatment period was combined with a NAC series. Efficacy variables were "Mini-Rhinoconjunctivitis Quality of Life Questionnaire" (Mini-RQLQ), "Total Nasal Symptom Score" (TNSS), "Peak Nasal Inspiratory Flow" (PNIF) and "Fractional Exhaled Nitric Oxide" (FeNO). In addition, to assess whether or not the PA produced any pro-inflammatory effect per se, soluble analytes were monitored in nasal lavage fluids. Finally, bacterial cultures, sampled using swabs from the middle nasal meatus, were assessed for the presence of the PA by MALDI-TOF analysis. RESULTS: Administration of the PA did not produce any nasal symptoms (cf. placebo). An innate immune response was discerned within the PA run (cf. baseline), but no change in nasal lavage fluid levels of cytokines/mediators was observed cf. placebo except for IL-17/IL-17A (a minor increase in the PA run). Administration of the PA did neither affect Mini-RQLQ, TNSS, PNIF nor FeNO. No evidence of persistent colonization was observed. CONCLUSIONS: Topical/nasal administration of a PA comprising Lactobacillus rhamnosus SP1, Lactobacillus paracasei 101/37 and Lactococcus lactis L1A, while likely evoking a minor innate immune response yet being safe, does not affect quality of life, symptoms or signs of allergic rhinitis. TRIAL REGISTRATION: not registered.

Usefulness of the Nasal Allergen Provocation Test in the Diagnosis of Shellfish Allergy.

BACKGROUND AND OBJECTIVES: Shellfish allergy is a major cause of food allergy and anaphylaxis worldwide. Several allergenic proteins have been described in the last few years, but the only diagnostic tool that still enables discrimination between allergic and nonallergic sensitized persons is the oral food challenge (OFC). The aim of this study was to evaluate the usefulness of the nasal allergen provocation test (NAPT) as a diagnostic tool in shellfish allergy. METHODS: Forty-five patients with confirmed sensitization to shrimp by a positive skin prick test (SPT) result with a commercial shrimp extract were recruited and classified as sensitized-allergic or sensitized-nonallergic based on current tolerance to shrimp intake, the result of an OFC with a freeze-dried cooked shrimp mixture extract, or a recent history of anaphylaxis induced by shrimp ingestion. These patients and 10 controls not sensitized to shrimp underwent NAPT with a freeze-dried cooked shrimp mixture extract. The response was evaluated using acoustic rhinometry and a visual analog scale. RESULTS: Significant differences (P=.001) were found between the sensitized-allergic group (18/20 positive NAPT, 90%) and both the sensitized-nonallergic group (2/18 positive NAPT, 11.1%) and controls (0/10 positive NAPT). NAPT enables differentiation between allergic and nonallergic persons with a sensitivity of 90%, specificity of 89%, positive predictive value of 90%, and negative predictive value of 89%. CONCLUSIONS: Our results indicate that NAPT makes it possible to differentiate between sensitized symptomatic patients and sensitized tolerant patients and could be a valuable diagnostic tool when assessing shrimp allergy.

Usefulness of the Nasal Allergen Provocation Test in the Diagnosis of Shellfish Allergy

Background: Shellfish allergy is a major cause of food allergy and anaphylaxis worldwide. Several allergenic proteins have been described in the last few years, but the only diagnostic tool that still enables discrimination between allergic and nonallergic sensitized persons is the oral food challenge (OFC). Objective: The aim of this study was to evaluate the usefulness of the nasal allergen provocation test (NAPT) as a diagnostic tool in shellfish allergy. Methods: Forty-five patients with confirmed sensitization to shrimp by a positive skin prick test (SPT) result with a commercial shrimp extract were recruited and classified as sensitized-allergic or sensitized-nonallergic based on current tolerance to shrimp intake, the result of an OFC with a freeze-dried cooked shrimp mixture extract, or a recent history of anaphylaxis induced by shrimp ingestion. These patients and 10 controls not sensitized to shrimp underwent NAPT with a freeze-dried cooked shrimp mixture extract. The response was evaluated using acoustic rhinometry and a visual analog scale. Results: Significant differences (P=.001) were found between the sensitized-allergic group (18/20 positive NAPT, 90%) and both the sensitized-nonallergic group (2/18 positive NAPT, 11.1%) and controls (0/10 positive NAPT). NAPT enables differentiation between allergic and nonallergic persons with a sensitivity of 90%, specificity of 89%, positive predictive value of 90%, and negative predictive value of 89%. Conclusions: Our results indicate that NAPT makes it possible to differentiate between sensitized symptomatic patients and sensitized tolerant patients and could be a valuable diagnostic tool when assessing shrimp allergy (AU)

High Histamine Control Concentration Leads to False Negative Allergy Skin Testing.

BACKGROUND: Allergy skin test reliability depends on the reagents and controls selected. Histamine is used at 1 mg/ml and 6 mg/ml concentration but few studies address the rationale for selecting one versus the other and how this may impact diagnostic accuracy. OBJECTIVE: To determine the rate of false negative allergen skin tests responses between UniTest PC (using the 1 mg/mL histamine) and Quintip devices (using 6 mg/mL) for 4 common aeroallergens. METHODS: Subjects aged 18-65 with symptoms of allergy to cat and/or ragweed received skin testing with 4 aeroallergens (dust mite mix, timothy grass, ragweed, cat), histamine and control diluent. Those individuals who tested positive to cat or ragweed with one skin prick test (SPT) device but not the other then proceeded to nasal allergen challenge (NAC). The primary outcomes were the aeroallergen false negative rates and sensitivities of the skin test devices followed by nasal allergen (NAC). RESULTS: Twenty-five individuals were recruited and underwent a total of 300 SPTs. SPT to allergens (ragweed, dust mite, cat, and timothy grass) resulted in a statistically significant difference in wheal size among the two skin testing devices (p value <0.0001, 0.0001, 0.0006, and 0.0053 respectively). Six NAC procedures were performed to cat/ragweed and 5 of 6 (83% were positive). The overall allergen sensitivity rate for UniTest and Quintip were 97% and 78% respectively with most false negatives due to the use of 6 mg/ml histamine control reagent. CONCLUSION: Our study shows that 6 mg/ml concentration of histamine control reagent may contribute to a false interpretation of aeroallergen skin prick test results.

The use of nasal allergen vs allergen exposure chambers to evaluate allergen immunotherapy.

INTRODUCTION: Allergen-specific immunotherapy (AIT) is the only disease-modifying treatment option for allergic rhinitis (AR) patients with persistent moderate-severe AR for whom traditional pharmacotherapies are ineffective. The nasal allergen challenge (NAC) and allergen exposure chamber (AEC) are two translational models of AR that can be used to investigate the properties, safety, and efficacy of AIT. AREAS COVERED: Peer-reviewed, human-centered articles utilizing AEC or NAC models to investigate AIT between 2010 and 2020 were curated from PubMed, EMBASE, and OVID Medline databases. AECs have been used to evaluate traditional subcutaneous and sublingual administrations of AIT, including cross-protective effects and different dosing regimens. More recently, the effectiveness of novel AIT formulations has been evaluated. NACs are another model used to study AIT, including using novel intralymphatic routes of administration. It is an especially powerful and versatile tool to determine if basic science and animal model findings are clinically translatable. EXPERT OPINION: The AEC and NAC models both produce clinically relevant and reproducible results. AECs are more effective for studying many participants but are limited because they require a specialized facility. As more AIT therapies and new formulations are developed over time, the versatility of the NAC will be especially useful.

Systematic evaluation of allergic phenotypes of rhinitis in children and adolescents.

BACKGROUND: Three allergic phenotypes of rhinitis have been described in adults: allergic rhinitis (AR), local allergic rhinitis (LAR), and dual allergic rhinitis (DAR, coexistence of AR and LAR). Nevertheless, most centers follow a diagnostic approach only based on skin prick test and serum allergen-specific IgE (collectively called atopy tests, AT). This approach prevents the recognition of LAR and DAR, the diagnosis of which requires a nasal allergen challenge (NAC). Here, we investigate the existence of LAR and DAR phenotypes in children and adolescents, and the misdiagnosis rate associated with a work-up exclusively based on AT. METHODS: Clinical data were obtained during physician-conducted interviews, and AT and NAC were systematically performed in 5- to 18-year-old patients with chronic rhinitis. The misdiagnosis rate was defined as the proportion of cases where AT and NAC results were discordant. RESULTS: A total of 173 patients (mean age 15.1 years, 39.9% male) completed the study. AR (positive AT and NAC), LAR (negative AT and positive NAC), DAR (positive AT and NAC for some allergens and negative AT and positive NAC for other allergens), and non-allergic rhinitis (negative NAC) were diagnosed in 45.7%, 24.9%, 11.6%, and 17.9% of individuals, respectively. The clinical profile was comparable among allergic phenotypes, but allergic patients had a significantly earlier rhinitis onset, higher conjunctivitis prevalence, and more severe disease than NAR individuals. A diagnostic work-up exclusively based on AT misclassified 37.6% of patients. CONCLUSIONS: LAR and DAR represent relevant differential diagnosis in pediatric rhinitis. NAC increases the diagnostic accuracy of clinical algorithms for rhinitis in children and adolescents.

Development of nasal allergen challenge with cockroach in children with asthma.

BACKGROUND: Nasal allergen challenge (NAC) could be a means to assess indication and/or an outcome of allergen-specific therapies, particularly for perennial allergens. NACs are not commonly conducted in children with asthma, and cockroach NACs are not well established. This study's objective was to identify a range of German cockroach extract doses that induce nasal symptoms and to assess the safety of cockroach NAC in children with asthma. METHODS: Ten adults (18-37 years) followed by 25 children (8-14 years) with well-controlled, persistent asthma and cockroach sensitization underwent NAC with diluent followed by up to 8 escalating doses of cockroach extract (0.00381-11.9 µg/mL Bla g 1). NAC outcome was determined by Total Nasal Symptom Score (TNSS) and/or sneeze score. Cockroach allergen-induced T-cell activation and IL-5 production were measured in peripheral blood mononuclear cells. RESULTS: 67% (6/9) of adults and 68% (17/25) of children had a positive NAC at a median response dose of 0.120 µg/mL [IQR 0.0380-0.379 µg/mL] of Bla g 1. Additionally, three children responded to diluent alone and did not receive any cockroach extract. Overall, 32% (11/34) were positive with sneezes alone, 15% (5/34) with TNSS alone, and 21% (7/34) with both criteria. At baseline, NAC responders had higher cockroach-specific IgE (P = .03), lower cockroach-specific IgG/IgE ratios (children, P = .002), and increased cockroach-specific IL-5-producing T lymphocytes (P = .045). The NAC was well tolerated. CONCLUSION: We report the methodology of NAC development for children with persistent asthma and cockroach sensitization. This NAC could be considered a tool to confirm clinically relevant sensitization and to assess responses in therapeutic studies.

Nasal allergen challenge and environmental exposure chamber challenge: A randomized trial comparing clinical and biological responses to cat allergen.

BACKGROUND: The direct-instillation nasal allergen challenge (NAC) and the environmental exposure chamber (EEC) are 2 methods of conducting controlled allergen provocations. The clinical and biological comparability of these methods has not been thoroughly investigated. OBJECTIVE: We sought to compare clinical and immunologic responses to cat allergen in NAC versus EEC. METHODS: Twenty-four participants were randomized to receive either NAC followed by a 2-day challenge in an EEC or a 2-day challenge in an EEC followed by NAC. Challenges were separated by 28-day washout periods. We measured total nasal symptom scores, peak nasal inspiratory flow, nasal (0-8 hours) and serum cytokines, serum antibodies, peripheral blood antigen-specific T lymphocytes, and gene expression in nasal scrapings. The primary outcome was the total nasal symptom score area under the curve for the first 3 hours after allergen exposure in NAC or after initiation of exposure in EEC. RESULTS: Both challenges increased IL-5 and IL-13 in nasal fluids and serum and resulted in altered nasal cell expression of gene modules related to mucosal biology and transcriptional regulation. Changes in gene modules, more so than cytokine measurements, showed significant associations with total nasal symptom score and peak nasal inspiratory flow. Overall, EEC exposure generated larger responses and more early terminations compared with NAC. Although the 2 challenges did not correlate in symptom magnitude or temporality, striking correlations were observed in cytokine levels. CONCLUSIONS: Although clinical outcomes of NAC and EEC were temporally different and nonequivalent in magnitude, immunologic responses were similar. Selection of a particular allergen challenge method should depend on considerations of study objectives and cost.