Nasal allergen challenge (NAC): Practical aspects and applications from an EU/US perspective-a Work Group Report of the AAAAI Rhinitis, Rhinosinusitis and Ocular Allergy Committee.

Nasal allergen challenge (NAC) is applied in a variety of settings (research centers, specialty clinics, and hospitals) as a useful diagnostic and research tool. NAC is indicated for diagnosis of seasonal and perennial allergic rhinitis, local allergic rhinitis, and occupational rhinitis; to design the composition of allergen immunotherapy in patients who are polysensitized; and to investigate the physio-pathological mechanisms of nasal diseases. NAC is currently a safe and reproducible technique, although it is time- and resource-consuming. NAC can be performed by a variety of methods, but the lack of a uniform technique for performing and recording the outcomes represents a challenge for those considering NAC as a clinical tool in the office. The availability of standardized allergens for NAC is also different in each country. The objective of this workgroup report is to review the current information about NAC, focusing on the practical aspects and application for diagnosis of difficult rhinitis phenotypes (eg, local allergic rhinitis, occupational rhinitis), taking into account the particular context of practice in the United States and the European Union.

[Importance of aspirin challenges in patients with NSAID-exacerbated respiratory disease]. / Stellenwert von ASS-Provokationen beim Analgetika-Intoleranz-Syndrom.

BACKGROUND: Nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD) is often characterized by a severe course of chronic rhinosinusitis with nasal polyps (CRSwNP), comorbid asthma, and NSAID hypersensitivity. The gold standard for N-ERD diagnosis is challenge with acetylsalicylic acid (ASA). In expert recommendations, the diagnosis of N-ERD is established based on a plausible positive history of NSAID hypersensitivity and CRSwNP with asthma. OBJECTIVE: The following review describes the performance of ASA challenges and their sensitivity and specificity. It also examines the extent to which a positive history of NSAID hypersensitivity correlates with ASA challenge results in clinical trials and when ASA challenges should be performed. RESULTS AND CONCLUSION: ASA challenges have high sensitivity and specificity. In clinical ASA challenge studies, there is a high concordance between a positive history of NSAID hypersensitivity obtained by rhinologists and the measured data of ASA challenge in patients with CRSwNP and comorbid asthma. Therefore, ASA challenge is primarily indicated in patients with an unclear history of NSAID hypersensitivity.

Local allergic rhinitis in children.

Local allergic rhinitis (LAR) is one of the endotypes of rhinitis. Despite much data about epidemiology diagnosis and treatment in adult patients with LAR, there is little information on children. Many studies indicate the need for such an assessment of the phenomenon in children, which results in one meta-analysis based on young patients selected from cohorts of patients of different ages.

Local allergic rhinitis in children: A systematic review.

BACKGROUND: Local allergic rhinitis (LAR) is a well-defined and reported phenotype in adults, but data is scarce for children and adolescents, and it is probably an undiagnosed and highly underestimated condition in childhood. OBJECTIVES: The objectives of this systematic review were to identify original observational studies published on LAR in children and adolescents and to describe the prevalence and characteristics of this phenotype in the pediatric age group. METHODS: A systematic search was performed in PubMed and EMBASE databases. The search was limited to publications on humans, written in English, published between January 1, 2000 and September 20, 2021. Participants had to be under 18 years old and with a diagnosis of LAR confirmed by nasal allergen provocation test (NAPT). RESULTS: Ten articles were identified. Despite the wide variability of protocols, prevalence rates ranged from 3.7 to 83.3% among children previously diagnosed as having nonallergic rhinitis, being markedly lower in Eastern countries (3.7-16.6%) when compared to Western countries (22.3-83.3%). To date, no relevant clinical characteristics capable of differentiating LAR patients from other childhood rhinitis phenotypes have been identified. CONCLUSIONS: LAR is an allergic rhinitis phenotype also found in children. Population and regional differences and differences in NAPT protocols may explain the heterogeneity in LAR prevalence rates observed in different parts of the world. In addition to clarifying this large discrepancy, longitudinal studies are also needed to assess the clinical characteristics of the LAR phenotype in the pediatric age group, and its stability into adulthood must be confirmed.

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.

Comparison of bronchial and nasal allergen provocation in children and adolescents with bronchial asthma and house dust mite sensitization.

BACKGROUND: Bronchial allergen provocation (BAP) is an established tool for the diagnosis of allergy in patients with asthma, but its use is limited by the potential risk of severe asthmatic reactions. Nasal provocation testing (NPT) may be an alternative safe method and does not require sophisticated equipment. OBJECTIVE: The aim of this prospective study was to evaluate the concordance of both methods in patients with asthma and house dust mite (HDM) sensitization. METHODS: A total of 112 patients with HDM sensitization underwent BAP and had the following parameters analysed: decrease in FEV1, exhaled NO, and total and specific IgE. Within 12 weeks, NPT with HDM was performed in 74 patients with a median age of 9 years (range, 5-16 years). The results were evaluated using the Lebel score which quantifies major symptoms like rhinorrhea, nasal obstruction, sneezes and minor symptoms, such as pruritus, conjunctivitis and pharyngitis. RESULTS: Fifty-seven of 74 patients had an early asthmatic reaction, of which 41 were identified using the Lebel score. The Lebel score had a sensitivity of 71.9% and a positive predictive value (PPV) of 89.1%. In addition, an eNO ≥ 10 ppb (AUC 0.78), a specific IgE Dermatophagoïdes pteronyssinus ≥ 25.6 kU/L (AUC 0.76) and a specific IgE Dermatophagoïdes farinae ≥ 6.6 kU/L (AUC 0.78) were good predictors of an early asthmatic reaction. CONCLUSION: A sequential use of NPT prior to BAP is justified to establish the relevance of HDM allergy. In patients with a negative NPT, BAP is still recommended to rule out a HDM-induced asthmatic reaction.

Statement of the Spanish Society of Allergology and Clinical Immunology on Provocation Tests With Aspirin/Nonsteroidal Anti-inflammatory Drugs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used throughout the world. They are frequently involved in hypersensitivity reactions, which range from local or mild reactions to systemic and severe reactions. Consequently, it is necessary to perform an exhaustive study of patients in order to make an accurate diagnosis, search for safe procedures in the case of severe reactions, and identify alternative treatment options. Various guidelines and protocols address the management of hypersensitivity to NSAIDs, although these vary widely from country to country. The Committees of Asthma, Rhinoconjunctivitis, and Drug Allergy of the Spanish Society of Allergy and Clinical Immunology (SEAIC) propose the present position statement on available options for provocation testing with aspirin/NSAIDs. This document is the fruit of an exhaustive review of current evidence and is based on recent publications addressing the diagnosis of patients with hypersensitivity to NSAIDs and on a consensus-oriented discussion among a group of experts from the SEAIC. The main objective was to draft an easy-toread, practical guideline for health care professionals in specialist areas who assess and manage patients with suspected hypersensitivity to NSAIDs. Furthermore, indications, contraindications, and procedures for oral, bronchial, and nasal provocation tests with aspirin/NSAIDs have been updated.

Safety and reproducibility of nasal allergen challenge.

BACKGROUND: The nasal allergen challenge (NAC) is a useful tool for the diagnosis of allergic rhinitis (AR) and local allergic rhinitis (LAR) and might serve to design and monitor allergen immunotherapy. Nevertheless, data about its safety and reproducibility are scarce. OBJECTIVE: To investigate the safety and reproducibility of NAC in pediatric and adult rhinitis patients with/without asthmatic symptoms, and in healthy controls. METHODS: A retrospective evaluation of the NACs conducted in our Unit for 2005-2017 and monitored by acoustic rhinometry and nasal-ocular symptoms was performed to analyze the safety of two methods for allergen application (metered spray & micropipette) and NAC protocols (NAC with single or multiple allergens/session [NAC-S & NAC-M]). The adverse events (AEs), spirometry values, and rescue medication required for AE were recorded. The reproducibility was examined by a prospective analysis of three repeated NAC-S performed at 1-2-month interval in AR, LAR and nonallergic rhinitis patients, and in healthy controls. RESULTS: A total of 11 499 NACs were performed in 518 children and 5830 adults. Only four local AE occurred, and 99.97% of NACs were well tolerated. The reproducibility and positive and negative predictive values of three consecutive NAC-S performed in 710 subjects were 97.32%, 100%, and 92.91%, respectively. There were no false-positive results in the 710 analyzed subjects. Safety and reproducibility were comparable between the methods of allergen application and the rhinitis phenotypes. CONCLUSION: The NAC is a safe and highly reproducible diagnostic test ready to be used in the clinical practice in both children and adults with or without asthma.

Detection of local allergic rhinitis in children with chronic, difficult-to-treat, non-allergic rhinitis using multiple nasal provocation tests.

BACKGROUND: There is little evidence on the incidence and characteristics of local allergic rhinitis (LAR) in children. Most studies have included subjects with perennial rhinitis only, and results are based on the investigation of no more than three allergens per study. Our aim was to determine the proportion of children with LAR amongst children with chronic, difficult-to-treat, perennial or seasonal, rhinitis but no evidence of sensitization to aeroallergens, or other alternative diagnosis. METHODS: We performed multiple nasal provocation tests (M-NPTs) with four locally relevant aeroallergens (Phleum pratense, Olea europea, Alternaria alternata, and Dermatophagoides pteronyssinus) in children with absence of aeroallergen sensitization, seen during a calendar year in a specialized rhinitis clinic. We additionally performed single NPT to children with allergic rhinitis (AR; positive control group). The result of the NPT was based on symptoms and acoustic rhinometry. Identification of nasal hyper-reactivity (NHR) triggers was through a questionnaire. RESULTS: Local allergic rhinitis was confirmed in 29.2% (7/24) of the negative SPT/blood testing population. All but one of the children reacted to one allergen and one to two. All AR children had positive single NPT with results similar to the LAR. There were no differences in age at examination and rhinitis onset, gender distribution, family atopy, and past or current environment of residency, while the prevalence of reported NHR triggers was comparable amongst the three groups. CONCLUSION: This is the first pediatric study where the seasonal or perennial rhinitis population was thoroughly tested for LAR against four aeroallergens. LAR is present in a considerable proportion of children with chronic, difficult-to-treat rhinitis and no sensitization to aeroallergens, and therefore, the performance of NPT should be strongly considered in these cases. There were no distinct clinical characteristics between LAR, AR, and non-allergic rhinitis in children.

Cold dry air provocation is a reliable diagnostic tool in nonallergic rhinitis.

BACKGROUND: No diagnostic criteria have been available for nonallergic rhinitis (NAR) to this point in time. Nonspecific nasal hyperresponsiveness (NHR), which could be efficiently assessed by cold dry air (CDA) provocation, is an essential feature of NAR. Thus, this study's purpose was to assess the diagnostic value of CDA provocation in discriminating patients with NAR from healthy individuals. METHODS: CDA provocation was performed among 13 healthy volunteers and 15 NAR patients. Nasal symptom scores, total nasal volume (TNV), total nasal resistance (TNR) and minimal cross-sectional area (MCA) were checked before and after the provocation. Non-paramedic tests and receiver operating characteristic (ROC) curves were used in data evaluation. RESULTS: Subjects in the NAR group showed significantly larger changes after CDA provocation in total nasal symptom score (TNSS) and nasal congestion score compared with healthy volunteers, while the change for rhinorrhea score was comparable. Similarly, significant differences in the change of MCA and TNV were witnessed between both groups. We built a predictive model for NAR, Y = minus 3.285 plus 2.520 times the difference of TNR (%) plus 1.027 times the difference of TNSS minus 6.542 times the difference of TNV (%), whose area under curve was 0.93. According to the Youden index, the criterion was set to be Y greater than -0.52, when its sensitivity and specificity were 93.3% and 84.6%, respectively. CONCLUSIONS: With superior patient-friendliness, safety and efficacy, we successfully performed the first NAR predictive model in the Chinese population, based on a short protocol of CDA provocation, by means of both subjective scores and objective tests (acoustic rhinometry and rhinomanometry).

EAACI Position paper on the standardization of nasal allergen challenges.

Nasal allergen challenge (NAC) is an important tool to diagnose allergic rhinitis. In daily clinical routine, experimentally, or when measuring therapeutic success clinically, nasal allergen challenge is fundamental. It is further one of the key diagnostic tools when initiating specific allergen immunotherapy. So far, national recommendations offered guidance on its execution; however, international divergence left many questions unanswered. These differences in the literature caused EAACI to initiate a task force to answer unmet needs and find a consensus in executing nasal allergen challenge. On the basis of a systematic review containing nasal allergen challenges of the past years, task force members reviewed evidence, discussed open issues, and studied variations of several subjective and objective assessment parameters to propose a standardized way of a nasal allergen challenge procedure in clinical practice. Besides an update on indications, contraindications, and preparations for the test procedure, main recommendations are a bilaterally challenge with standardized allergens, with a spray device offering 0.1 mL per nostril. A systematic catalogue for positivity criteria is given for the variety of established subjective and objective assessment methods as well as a schedule for the challenge procedure. The task force recommends a unified protocol for NAC for daily clinical practice, aiming at eliminating the previous difficulty of comparing NAC results due to unmet needs.

Role of nasal challenge and local eosinophilia in indirect exposure to cat in allergic rhinitis patients.

Summary: Introduction. Sensitization to cat allergens is common worldwide. Currently, there is a trend towards costly and often unavailable diagnostic analysis. Objectives. The aim is to assess the reliability of skin prick test (SPT) and serum specific IgE (ssIgE) to cat sensitization, by performing nasal challenge test (NCT) in a community with low cat ownership but common presence of stray cats. Patients and methods. Forty-one pa-tients with perennial allergic rhinitis (AR) who were mono or polysensitized (including cat) were included. We had 31 cat non-owners and 10 present cat owners. SPT (> 5 mm / diameter), ssIgE (≥ 0.70 IU/ml), nasal smear for eosinophil (Eo) and NCT were compared between groups. Outcomes included nasal challenge score, nasal Eo positivity, peak inspiratory and expiratory flow (PIF and PEF) 2 and 8 hours after the NCT, and were compared to baseline. Results. Baseline SPT wheal size and ssIgE level were similar in both groups. NCT positivity was more frequent in cat owners. The strongest nasal reaction was on the top concentration in both groups. Nasal Eo positivity in cat owners was higher before and 2 hours after NCT, but similar to non-owners at last measurement. NCT positive cat non-owners had bigger SPT wheal size than NCT negative non-owners, but smaller than NCT positive cat owners. In contrast to PEF, a significant fall in PIF was noticed in both groups. Mono and polysensitised patients showed similar NCT positivity. Conclusion. Stray cats may pose a relevant risk of developing perennial AR. Regardless of cat ownership status, SPT and ssIgE should be the first diagnostic tool. Nasal Eo and NCT seem to be good diagnostic tools in cat non-owners if diagnosis is elusive.

Nasal Ketorolac Challenge Using Acoustic Rhinometry in Patients With Aspirin-Exacerbated Respiratory Disease.

BACKGROUND AND OBJECTIVE: Safer and less time-consuming alternatives to single-blind placebo-controlled oral challenge (SBPCOC) have been sought for the diagnosis of aspirin-exacerbated respiratory disease (AERD). Nasal challenges with various nonsteroidal anti-inflammatory drugs and assessment methods have been developed. Objective: Our objective was to evaluate the utility and safety of nasal ketorolac challenge (NKC) using acoustic rhinometry in patients with suspected AERD. METHODS: The study population comprised 36 patients with suspected AERD. NKC was performed with placebo (saline) and 13 mg of ketorolac sprayed as aerosol into both nostrils. A positive challenge result was defined as an increase of ≥30% in nasal symptoms (recorded using a visual analog scale) and a 30% drop in the sum of the volumes of both nasal cavities at 2-8 cm. Patients with a negative NKC result underwent SBPCOC with aspirin (cumulative dose of 750 mg). RESULTS: A naso-ocular reaction during NKC was detected in 21 patients. Four patients also developed mild asthma exacerbations (although only 1 experienced a decrease in FEV1 >15%). No other significant adverse events occurred. The remaining 15 patients with a negative NKC result had a negative response during aspirin SBPCOC. CONCLUSIONS: NKC assessed using acoustic rhinometry is a reliable method for the study of patients with AERD. We suggest that NKC assessed with acoustic rhinometry was useful and safe for selection of candidates for safe oral aspirin challenge.

Local allergic rhinitis: A critical reappraisal from a paediatric perspective.

The so-called local allergic rhinitis (LAR) has been proposed as a phenotype of rhinitis with Th2-driven prominent local allergic inflammation, nasal synthesis of specific IgE and a positive response to a nasal allergen provocation test, in the absence of 'systemic' atopy (negative skin prick test and serum allergen-specific IgE antibodies). To date, available data on LAR are mostly focused on adults. The purpose of this 'Rostrum' was to critically discuss data and implications of the 'LAR concept' in paediatrics. In the natural history of rhinitis due to IgE-mediated reactions triggered by exposure to allergens, a 'LAR' can be either the initial, transient stage of classical allergic rhinitis or a stable phenotype never evolving to 'systemic' IgE sensitization. Given the present difficulties in performing routinely nasal allergen provocation test in children, the development of sensitive and specific tests to detect IgE in the child's nasal secretions is a research priority. We suggest also the hypothetical role of allergen immunoprophylaxis or immunotherapy in LAR. Last, the term 'local allergic rhinitis' may be inappropriate, as rhinitis is always 'local', while IgE sensitization can be either 'local' or 'systemic'.

Local and systemic effects of cat allergen nasal provocation.

BACKGROUND: Cat allergen is widely distributed in homes and schools; allergic sensitization is common. OBJECTIVE: To develop a model of cat allergen nasal challenge to establish dose-response and time-course characteristics and investigate local and systemic biomarkers of allergic inflammation. METHODS: Nineteen cat-allergic individuals underwent titrated nasal challenge, range 0.243 to 14.6 µg/mL Fel d1, and matched diluent-only provocation. Clinical response to 8 h was assessed by symptom scores and peak nasal inspiratory flow (PNIF). Nasal fluid was collected using polyurethane sponges and analysed by ImmunoCAP and multiplex assays. Whole blood flow cytometry for basophil surface CD63, CD107a, and CD203c was carried out at baseline and 6 h post-challenge. RESULTS: A dose-response to allergen was seen in symptom scores and PNIF, maximal at 10 000 BU/mL (4.87 µg/mL Fel d1), P < 0.0001 vs. diluent. Nasal fluid tryptase was elevated at 5 min after challenge (P < 0.05 vs. diluent); eotaxin, IL-4, -5, -9, and -13 were increased at 8 h (P < 0.05 to P < 0.0001 vs. diluent); TSLP was undetectable; IL-10, IL-17A, and IL-33 were unchanged compared to diluent challenge. Nasal fluid IL-5 and IL-13 correlated inversely with PNIF after challenge (IL-5, r = -0.79, P < 0.0001; IL-13, r = -0.60, P = 0.006). Surface expression of CD63 and CD107a was greater at 6 h than at baseline, both in the presence (both P < 0.05) and absence (CD63, P < 0.01; CD107a, P < 0.05) of in vitro allergen stimulation; no changes were seen on diluent challenge day. CONCLUSIONS: Cat allergen nasal challenge produces local and systemic Th2-driven inflammatory responses and has potential as a surrogate outcome measure in clinical trials.

In vivo diagnosis of allergic diseases--allergen provocation tests.

The allergen challenge test has been the mainstay of diagnosis of allergic diseases for a long time since it offers a direct proof of the clinical relevance of a particular allergen for the allergic disease symptoms and severity. Standardisation and availability for daily practice (including safety issues) are still to be refined but most of the challenge tests have safely crossed the border from research tools to diagnostic tests available for daily practice for a well trained clinical staff.

Local allergic nasal reactions convert to classic systemic allergic reactions: a long-term follow-up.

BACKGROUND: There is poor knowledge about the evolution of the negative skin test in local allergy over time. Does the negative skin test of patients with local allergies remain negative permanently or does it become positive? METHODS: We describe our long-term observation concerning the evolution of the negative skin test over time. This is a retrospective, follow-up study using data from the medical records of a group of patients with local allergy. A total of 42 patients aged between 3 and 70 years (median age: 31.5 years) were studied. The duration of follow-up varied from 1 to 27 years. Skin tests were performed using the skin-prick test and intracutaneous techniques for pollen, molds, mites, feathers (goose and duck) and animal danders. Nasal provocation tests were conducted with the same allergens. Additionally, specific IgE in 17 patients was measured by enzyme allergosorbent test. RESULTS: During the period of observation, the negative skin test reactions converted into positive reactions in 17 patients (40%). In addition to the negative skin reactions, 55% of the patients also presented positive skin reactions. The conversion rate was higher in children and adolescents than in adults. In 4 patients, conversions occurred >7 years after the initial examination. Specific IgE was negative in all but 2 patients, in whom the conversion in the skin test was accompanied by a switch from negative to positive specific IgE. CONCLUSION: Conversions from local to classic systemic respiratory allergic reactions appear to be a common phenomenon.

A new, faster, and safe nasal provocation test method for diagnosing mite allergic rhinitis.

BACKGROUND: Diagnosing house dust mite (HDM) allergic rhinitis is difficult. The nasal provocation test (NPT) has been shown to be the most pertinent, but several methods are available. According to guidelines, the NPT requires a skin end-point titration and an objective measurement of nasal patency. Hence, NPT is time consuming and its use is limited. OBJECTIVE: To evaluate the sensitivity, specificity, and safety of a new, more rapid, and simple alternative NPT (NPT-R) to HDM. METHODS: Eighty-eight patients with from rhinitis (49 allergic to HDM and 39 controls with and without atopy) were included. Allergic rhinitis to HDM was confirmed by a "classic" NPT based on the Lebel score and rhinomanometry. After a period of 4 weeks, NPT-R was performed and only the clinical score was measured. RESULTS: The study population was young (mean ± SD, 27.7 ± 8.5 years old), composed mostly of women (61 vs 27 men), and 24% reported asthma. The sensitivity and specificity of NPT-R were 83.7% and 100%, respectively. The correlation between the NPTs was statistically significant (0.833, P < .0001, n = 88) and the 2 NPTs were completely safe. Performing NPT-R was more rapid (mean ± SD, 22 ± 8 minutes) than the classic NPT (97 ± 20 minutes). CONCLUSION: The NPT-R is safe and easier and faster than the classic NPT. This new method appears to be a very useful tool in the diagnosis of HDM allergic rhinitis when the diagnosis is uncertain or before initiating immunotherapy. TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT01485523.