Allergic fungal rhinosinusitis (AFRS) is a subtype of chronic rhinosinusitis, characterized by excessive immune responses to environmental molds or fungi. The diagnosis and classification of AFRS into systemic and local types remain clinically challenging due to overlapping characteristics. This study investigated the prevalence of AFRS, its manifestation and associated factors in systemic and local AFRS. A total of 200 patients diagnosed with fungal rhinosinusitis underwent both skin provocation tests (SPT) and nasal provocation tests (NPT) to confirm AFRS and classify systemic and local types. Patients were considered to have AFRS if either the SPT or NPT was positive. Among these, patients with systemic AFRS were those who had a SPT positive. Local AFRS was when patients had a negative SPT and a positive NPT. Medical history, serum total IgE level, nasal endoscopy examinations, and CT scans were also recorded. Most patients were female (65.8%), with a mean age of 55.6 years (SD = 14.4). Based on the SPT and NPT results, 31% of patients (n = 62) were diagnosed with AFRS. Among these, 54.8% (n = 34) had systemic AFRS, while 45.2% (n = 28) had local AFRS. Patients with AFRS exhibited significantly higher levels of total IgE, eosinophils, and more pronounced signs and symptoms compared to those without AFRS. However, no statistically significant differences were observed between patients with systemic AFRS and those with local AFRS. AFRS was prevalent in our study. Among patients with AFRS, both systemic AFRS and local AFRS were also prevalent. While allergic indicators and clinical presentations can aid in AFRS diagnosis, minimal distinctions were observed between systemic and local AFRS. A comprehensive assessment incorporating both local and systemic allergic responses through provocation tests, such as a combination of skin and nasal tests, is imperative for optimizing AFRS diagnosis and management.

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.

BACKGROUND: The fluctuation in concentrations of airborne allergens frequently presents a challenge to assessing the efficacy of allergen immunotherapy (AIT) in \'field\' studies. Allergen exposure chambers (AECs) are specialized medical installations developed to expose individuals to allergens at defined and consistent concentrations under a controlled environment. The aim of the study was to validate the provocation test with timothy grass pollen as well as to assess its safety in the AEC in patients with allergic rhinitis.
METHODS: In the ALLEC® AEC, varying concentrations of timothy grass pollen were dispersed. Allergic symptoms were measured by total nasal symptom score (TNSS), acoustic rhinometry, peak nasal inspiratory flow (PNIF) and nasal discharge volume. Lung function, assessed through peak expiratory flow rate (PEFR) and forced expiratory volume in the first second (FEV1), was used to evaluate safety.
RESULTS: The consistency of the test was proved by the stability of environmental conditions, including temperature, humidity and CO2 levels, as well as constant concentrations of grass pollen at predetermined levels ranging from 1000 to 10,000 particles per cubic meter (p/m3). Allergic individuals developed symptoms at concentrations of 3000 p/m3 and above, across all measured endpoints. Lung function was not affected throughout all the challenges. The reproducibility of symptoms was confirmed throughout the tests. The concentration of 8000 p/m3 together with a challenge duration of 120 min was found to be optimal.
CONCLUSIONS: The study demonstrates that the ALLEC® grass pollen exposure chamber provides a reliable and safe method for inducing repeatable symptoms in patients with allergic rhinitis. This approach can be effectively applied for allergy diagnostics and clinical endpoint determination during AIT.

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.
CONCLUSIONS: 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.
UNASSIGNED: HINTERGRUND: Das Analgetika-Intoleranz-Syndrom (AIS) ist häufig durch schwere Verläufe der chronischen Rhinosinusitis mit nasaler Polyposis (CRSwNP) mit komorbidem Asthma und einer Acetylsalicylsäure(ASS)-Intoleranz gekennzeichnet. Bei Intoleranzreaktionen stellen ASS-Provokationen den Goldstandard der Diagnostik dar. Expertenempfehlungen zufolge liegt ein AIS bei plausibler positiver Anamnese von Intoleranz gegenüber nichtsteroidalen Antirheumatika (NSAR) und einer CRSwNP mit Asthma vor.
UNASSIGNED: Im vorliegenden Review wird die Durchführung von ASS-Provokationen sowie deren Sensitivität und Spezifität dargestellt. Des Weiteren wird untersucht, inwieweit eine positive NSAR-Intoleranz-Anamnese mit Ergebnissen von ASS-Provokationen in klinischen Studien übereinstimmt und wann ASS-Provokationen erfolgen sollten.
UNASSIGNED: ASS-Provokationen weisen eine hohe Sensitivität und Spezifität auf. In klinischen ASS-Provokationsstudien zeigt sich eine hohe Übereinstimmung zwischen einer von Rhinologen erhobenen positiven NSAR-Intoleranz-Anamnese und den Messdaten von ASS-Provokationen bei Patienten mit einer CRSwNP und einem komorbiden Asthma. Somit sind ASS-Provokationen vorrangig bei unklarer NSAR-Intoleranz-Anamnese indiziert.

BACKGROUND: Local allergic rhinitis (LAR) is defined by chronic nasal symptoms, absence of atopy, positive nasal allergen challenge (NAC) and a good response to subcutaneous allergen immunotherapy (SCIT). We sought to investigate SCIT capacity to induce local and systemic blocking antibodies in LAR patients.
METHODS: A RDBPC study of grass SCIT was performed, with participants receiving either SCIT (Group A; n = 10) or placebo (Group B; n = 14) in the first 6 months. Both groups subsequently received SCIT for 12 months at Year 2. Nasal and serum antibodies (IgG4, IgA1 and IgA2) and their inhibitory capacity were measured at multiple timepoints.
RESULTS: The allergen concentration tolerated increased significantly at 6 months (Group A; p = .047) and 24 months (Group B; p = .049) compared with baseline and persisted until the end of the study. Induction of serum sIgA1 to Phl p was seen in Groups A and B, albeit the former being induced earlier (1.71-fold, p = .027). A significant induction in sIgG4 to Phl p 1 and 5 was observed in serum of Group A (p = .047 and p = .0039) and sIgA2 to Phl p in Group B (p = .032 and p = .0098) at 18 and 24 months, respectively. Both local and systemic blocking antibodies can inhibit allergen-IgE complexes binding to CD23 on B cells, and this correlated with level of allergen tolerated intra-nasally in Group A (serum; 𝜌 = -.47, p = .0006, nasal; 𝜌 = -.38, p = .0294).
CONCLUSIONS: Grass pollen SCIT induced functional systemic blocking antibodies that correlate with the concentration of allergen tolerated following NAC, highlighting their potential as a biomarker of SCIT in LAR.

BACKGROUND: Nasal hyperreactivity (NHR) is prevalent in all chronic upper airway inflammatory phenotypes, including allergic rhinitis (AR) and chronic rhinosinusitis with nasal polyps (CRSwNP). Although NHR in patients with non-allergic rhinitis is mediated by neuronal pathways, AR and CRSwNP are mainly characterized by type 2 inflammation.
METHODS: Eighteen healthy controls and 45 patients with symptomatic AR/CRSwNP underwent a cold, dry air (CDA) provocation test for objective diagnosis of NHR. Before and after, questionnaires were filled out and nasal secretions and biopsies were collected. Markers for neurogenic inflammation (substance P, calcitonin gene-related peptide, neurokinin A), epithelial activation (IL-33), and histamine were measured in secretions by ELISA; and expression of neuronal markers PGP9.5, TRPV1, and TRPM8 was studied in biopsies by RT-q-PCR. Effects of histamine on TRPV1/A1 were studied with Ca2+-imaging using murine trigeminal neurons.
RESULTS: CDA-provocation reduced peak nasal inspiratory flow (PNIF) of patients with subjective NHR but not of non-NHR controls/patients CDA-provocation reduced peak nasal inspiratory flow (PNIF) of patients with subjective NHR but not of non-NHR controls/patients. Subjective (subjectively reported effect of CDA) and objective (decrease in PNIF) effects of CDA were significantly correlated. Levels of neuropeptides and histamine in nasal secretions and mRNA expression of PGP9.5, TRPV1, and TRPM8 correlated with CDA-induced PNIF-reduction. CDA-provocation induced an increase in IL-33-levels. Both TRPV1 and TRPA1 expressed on afferent neurons were sensitized by exposure to histamine.
CONCLUSIONS: NHR is not an on/off phenomenon but spans a continuous spectrum of reactivity. A neurogenic inflammatory background and increased histamine-levels are risk factors for NHR in AR/CRSwNP.

BACKGROUND: Dust mites are the leading cause of respiratory allergic diseases worldwide. Allergy to storage mites (SMs) has mostly been related to occupational exposures. However, recent studies have shown that sensitisation to SM, such as Lepidoglyphus destructor (Lep d), is of considerable importance also in urban populations, with high prevalence in dust samples of domestic environments. Co-sensitisation between house dust mites (HDMs) and SM is now regarded as very frequent in some regions, and cross-reactivity between them seems to be narrow. Therefore, SM allergenic capacity is increasingly a subject of study. The nasal provocation test (NPT), as an in vivo technique, could be considered the gold standard for the clinical relevance assessment of an allergen, in polysensitised rhinitis patients.
OBJECTIVE: The objective of this study was to analyse the clinical relevance of the SM Lep d, by assessing the relationship between in vivo sensitisation and expression of allergic respiratory disease in an urban setting.
METHODS: In our study, we enrolled a total of 32 allergic patients with rhinitis (with or without asthma) with proven sensitisation by skin prick test (SPT) and specific IgE (sIgE) to HDMs and/or SM. Patients underwent NPT with Lep d using subjective (Lebel Symptom Score Scale) and objective measurements (peak nasal inspiratory flow [PNIF]) for assessment of nasal response.
RESULTS: Most of the patients with positive SPT and sIgE to Lep d had a positive NPT (24/27; 89%). True Lep d allergy, assessed by a positive NPT, could be predicted by a SPT wheal size >9.7 mm and a sIgE >0.42 kUA/L, with 100%/95.7% sensitivity and 75.0%/83.3% specificity, respectively. Co-sensitisation between Lep d and Der p was high, 75.0%. Asthma was more frequent in the positive Lep d NPT group (54 vs. 12%, p < 0.05). Significantly more patients from this group reported physical exercise, nonspecific irritants, and respiratory infections as relevant triggers of respiratory symptoms (p < 0.01-p < 0.05).
CONCLUSIONS: To our knowledge, this is the first study to show that sensitisation to Lep d may have clinical relevance in a non-occupational setting. In this group, there seems to be a relationship between allergy to Lep d and severity of respiratory disease, with more bronchial inflammation, when comparing with mite-allergic patients sensitised only to HDM. Therefore, the authors consider that sensitisation to Lep d should be considered when assessing and treating allergic respiratory disease in urban environments.

Thanks to their valuable assessment possibilities (subjective complaints and changes in nasal patency during the examination), nasal provocation tests may serve as an alternative tool for oral food challenges in the future. However, this test requires successive attempts to regulate its methodology in order to develop a standardized lyophilisate form and determine the threshold dose for a positive result. The study objective was to present the methodological foundation for nasal food allergen provocation tests induced by freeze-dried powdered chicken egg whites. A control group of 25 individuals with no history of allergy to chicken eggs or any other allergy was included in the study. Optical rhinometry and visual analog scales were used to assess the response of nasal mucosa to local allergen challenges. Minor variations in nasal flows, as measured by optical rhinometry, were observed in the provocation tests. The mean optical density measurements (as measured regardless of the allergen dose used) varied from positive to negative values and vice versa, e.g., amounting to 0.018 OD (standard deviation 0.095) at 15 min and -0.011 OD (standard deviation 0.090) at 30 min. No significant differences were observed concerning the perceived nasal discomfort using the visual analog scale. Due to the absence of nasal mucosal reactivity, nasal challenge is an excellent methodological tool for implementing food allergen tests.

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.
We sought to characterize the immunologic and clinical nasal responses to birch pollen allergen challenge with a special focus on the late allergic response.
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.
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.
IL-13 response status correlates with clinical responses and type 2 cytokine responses in the late phase after allergen provocation.

BACKGROUND: Local allergic rhinitis (LAR) is a condition involving a localized nasal allergic response in absence of systemic atopy. Most studies on LAR have been performed in adults. We aimed to describe clinical characteristics of LAR pediatric patients, its clinical evolution over a 7-year follow-up period and to study the role of basophil activation test (BAT), for its diagnosis.
METHODS: Forty-four children with non-allergic rhinitis (NAR) were included (24 males, 20 females, aged under 15 years). Nasal allergen provocation test (NAPT) and BAT were performed with Dermatophagoides pteronyssinus and Phleum pratense.
RESULTS: Seven patients (16%) were diagnosed of LAR. Six reacted to D pteronyssinus and one to P pratense. All LAR and 86% of NAR patients presented perennial symptoms. Fifty-seven percent of NAR and LAR patients referred persistent symptoms. Around half of NAR and LAR patients reported mild-moderate clinical manifestations. Three LAR patients associated conjunctival symptoms, proportionally more than NAR patients (19%, 7 out of 37). NAR patients presented bronchial asthma (n = 10) more frequently than LAR children (n = 1). More than half of LAR and NAR patients presented family history of atopy. BAT was negative in all LAR patients. On follow-up, 3 LAR patients and 10 of the 25 NAR patients who agreed to be retested, presented systemic sensitization. Dust mites were the most frequent allergen involved.
CONCLUSIONS: LAR should be ruled out in children with NAR. Almost half of children with LAR develop systemic sensitization over time. BAT shows low sensitivity for the diagnosis of LAR in children.