Nasal allergen-neutralizing antibodies correlate closely with tolerated intranasal allergen challenge dose following grass pollen subcutaneous immunotherapy in patients with local allergic rhinitis.

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.

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.

Diagnosis of immediate reactions to amoxicillin: Comparison of basophil activation markers CD63 and CD203c in a prospective study.

BACKGROUND: Amoxicillin (AX) combined or not with clavulanic acid (CLV) is frequently involved in IgE-mediated reactions. Drug provocation test (DPT) is considered as the gold standard for diagnosis, although contraindicated in high-risk patients. Basophil activation test (BAT) can help diagnose immediate reactions to beta-lactams, although controversy exists regarding the best activation marker. We have performed a real-life study in a prospective cohort to analyze the real value of BAT as diagnostic tool and the best activation marker, CD63 and CD203c, for the evaluation of immediate reactions to these drugs. METHODS: We prospectively evaluated patients with a clinical suspicion of immediate reactions after AX or AX-CLV administration during a 6-year period. The allergological work-up was done following the EAACI recommendations. BAT was performed in all patients using CD63 and CD203c as activation markers. RESULTS: In AX-allergic patients, both activation markers, CD63 and CD203c, showed similar SE values (48.6% and 46.7%, respectively); however, specificity was of 81.1% and 94.6%, respectively, with CD203c showing good positive predictive value and like-hood ratio. In CLV-allergic patients, CD203c showed higher SE (50%) than CD63 (42.9%), maintaining the same value of SP (80%). Combining the results of both markers can slightly increase the sensitivity (51.4% for AX and 54.8% for CLV), although decreasing the specificity (79.7% and 73%, respectively). Interestingly, all patients with an anaphylactic shock showed a positive BAT to CLV using CD203c. CONCLUSIONS: BAT using CD203c showed a good confirmatory power, especially for AX allergy. Placing BAT as a first step in the diagnostic procedure can help reduce the need of performing a complete allergological work-up in 46.6% of patients, diminishing the risk of reinducing allergic reactions.

Sequential class switch recombination to IgE and allergen-induced accumulation of IgE+ plasmablasts occur in the nasal mucosa of local allergic rhinitis patients.

BACKGROUND: The involvement of allergen-specific (s)IgE in local allergic rhinitis (LAR) has been debated. Here, we investigate the effect of nasal allergen challenge with Dermatophagoides pteronyssinus (NAC-DP) in mucosal and peripheral B-cell subpopulations in LAR patients. METHODS: Nine LAR, 5 allergic rhinitis (AR), and 5 non-atopic healthy control (HC) individuals were subjected to a 3-day NAC-DP protocol, and nasal biopsies and blood samples were collected before and after provocation. Nasal biopsies were used for immunohistochemistry and gene expression studies, whereas the frequency of lymphocyte subsets and basophil activation test (BAT) were analyzed in blood samples by flow cytometry. sIgG was measured in sera. RESULTS: NAC-DP induced an increase in IgE+ CD38+ plasmablasts in the nasal mucosa of LAR patients, but not in AR or HC individuals. Markers of sequential recombination to IgE (εCSR) (from IgG) were observed in 33% of LAR, 20% of AR, and 0% of HC subjects. NAC-DP increased the proportion of peripheral CD19+ CD20+ CD38+ plasmablasts in AR and LAR patients, but not in HC. Expression of the mucosal homing receptor CXCR3 in peripheral CD19+ CD20+ CD38+ plasmablasts from LAR, AR, and HC individuals was 7%, 5%, and 0.5%, respectively. In vitro DP stimulation increased proliferating CD19+ CD20+ CD38+ plasmablasts in LAR and AR patients, but not in HC. Serum DP-sIgG was higher in LAR and AR patients as compared to HC. BAT was positive in 33%, 100%, and 0% of LAR, AR, and HC subjects, respectively. CONCLUSION: These results suggest that allergen exposure induces the sequential εCSR of IgG+ CD19+ CD20+ CD38+ plasmablasts in the nasal mucosa of LAR patients.

EAACI position paper on the clinical use of the bronchial allergen challenge: Unmet needs and research priorities.

Allergic asthma (AA) is a common asthma phenotype, and its diagnosis requires both the demonstration of IgE-sensitization to aeroallergens and the causative role of this sensitization as a major driver of asthma symptoms. Therefore, a bronchial allergen challenge (BAC) would be occasionally required to identify AA patients among atopic asthmatics. Nevertheless, BAC is usually considered a research tool only, with existing protocols being tailored to mild asthmatics and research needs (eg long washout period for inhaled corticosteroids). Consequently, existing BAC protocols are not designed to be performed in moderate-to-severe asthmatics or in clinical practice. The correct diagnosis of AA might help select patients for immunomodulatory therapies. Allergen sublingual immunotherapy is now registered and recommended for controlled or partially controlled patients with house dust mite-driven AA and with FEV1 ≥ 70%. Allergen avoidance is costly and difficult to implement for the management of AA, so the proper selection of patients is also beneficial. In this position paper, the EAACI Task Force proposes a methodology for clinical BAC that would need to be validated in future studies. The clinical implementation of BAC could ultimately translate into a better phenotyping of asthmatics in real life, and into a more accurate selection of patients for long-term and costly management pathways.

Management of patients with chronic rhinosinusitis during the COVID-19 pandemic-An EAACI position paper.

BACKGROUND: Chronic rhinosinusitis is regarded as a chronic airway disease. According to WHO recommendations, it may be a risk factor for COVID-19 patients. In most CRSwNP cases, the inflammatory changes affecting the nasal and paranasal mucous membranes are type-2 (T2) inflammation endotypes. METHODS: The current knowledge on COVID-19 and on treatment options for CRS was analyzed by a literature search in Medline, Pubmed, international guidelines, the Cochrane Library and the Internet. RESULTS: Based on international literature, on current recommendations by WHO and other international organizations as well as on previous experience, a panel of experts from EAACI and ARIA provided recommendations for the treatment of CRS during the COVID-19 pandemic. CONCLUSION: Intranasal corticosteroids remain the standard treatment for CRS in patients with SARS-CoV-2 infection. Surgical treatments should be reduced to a minimum and surgery preserved for patients with local complications and for those with no other treatment options. Systemic corticosteroids should be avoided. Treatment with biologics can be continued with careful monitoring in noninfected patients and should be temporarily interrupted during the course of the COVID-19 infection.

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.

Coexistence of nasal reactivity to allergens with and without IgE sensitization in patients with allergic rhinitis.

BACKGROUND: Allergic rhinitis (AR) and local allergic rhinitis (LAR) are defined by nasal reactivity to aeroallergens with and without positive skin prick test (SPT), respectively. In this study, we aimed to investigate whether both types of allergen-specific reactivity can coexist in the same individual. METHODS: Forty-eight patients with perennial rhinitis symptoms and positive SPT with seasonal allergens only (discrepant group) were subjected to consecutive nasal allergen challenges (NAC) with seasonal (NAC-S) and perennial allergens (NAC-P). A nasal lavage was collected before and after the NACs to measure eosinophil cationic protein (ECP). A basophil activation test (BAT) with seasonal and/or perennial allergens was performed in ten patients from the discrepant group and in six seasonal allergic rhinitis (SAR), eight perennial local allergic rhinitis (LAR), six nonallergic rhinitis (NAR), and six healthy control (HC) individuals. RESULTS: All patients in the discrepant group tested positive in the NAC-S, and 41 of them (85.4%), also in the NAC-P (group A). Conversely, seven patients tested negative in the NAC-P (group B). ECP in the nasal lavage increased after the NAC-P in the group A (P = .004), but not in the group B. The BAT with seasonal allergens was positive in 100% of SAR and group A cases, whereas the BAT with perennial allergens was positive in 37.5% and 60% of LAR and group A cases, respectively. All NAR and HC subjects tested negative for the BAT. CONCLUSION: This study shows that nasal reactivity to aeroallergens with and without positive SPT can coexist in the same patient. We propose the term dual allergic rhinitis for this rhinitis phenotype.

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.

Management of ocular allergy.

The treatment and management of ocular allergy (OA) remain a major concern for different specialties, including allergists, ophthalmologists, primary care physicians, rhinologists, pediatricians, dermatologists, clinical immunologists, and pharmacists. We performed a systematic review of all relevant publications in MEDLINE, Scopus, and Web Science including systematic reviews and meta-analysis. Publications were considered relevant if they addressed treatments, or management strategies of OA. A further wider systematic literature search was performed if no evidence or good quality evidence was found. There are effective drugs for the treatment of OA; however, there is a lack an optimal treatment for the perennial and severe forms. Topical antihistamines, mast cell stabilizers, or double-action drugs are the first choice of treatment. All of them are effective in reducing signs and symptoms of OA. The safety and optimal dosing regimen of the most effective topical anti-inflammatory drugs, corticosteroids, are still a major concern. Topical calcineurin inhibitors may be used in steroid-dependent/resistant cases of severe allergic keratoconjunctivitis. Allergen-specific immunotherapy may be considered in cases of failure of first-line treatments or to modify the natural course of OA disease. Based on the current wealth of publications and on the collective experience, recommendations on management of OA have been proposed.

Bronchial asthma triggered by house dust mites in patients with local allergic rhinitis.

BACKGROUND: Over 30% of local allergic rhinitis (LAR) patients self-report bronchial symptoms suggestive of asthma, but the relationship between the allergen exposure and the bronchial symptoms has not been studied. OBJECTIVE: To investigate whether a bronchial counterpart of LAR exists. METHODS: Patients were classified by clinical history, skin prick test/serum specific IgE (sIgE), and nasal allergen provocation test (NAPT) into the LAR, allergic rhinitis (AR), and nonallergic rhinitis (NAR) phenotypes. Twenty-eight LAR, 18 AR, and 19 NAR patients self-reporting bronchial symptoms suggestive of asthma and 8 healthy controls (HC) were subjected to a methacholine test (MT) before (Visit 1) and 24 hours after (Visit 3) a bronchial provocation test with Dermatophagoides pteronyssinus (BPT-DP) (Visit 2). Induced sputum and peripheral blood obtained after each MT were analyzed for immune cell populations, tryptase, ECP, and sIgE. RESULTS: A positive MT was found in 50% of LAR, 83.3% of AR, 57.89% of NAR, and 0% of HC individuals (P = 0.022 AR vs LAR) at V1. BPT-DP was positive in 8 LAR and 15 AR patients (28% vs 83.3%, P < 0.001), with no positive responses in NAR and HC. All BPT-DP+ patients experienced a significant decrease of PC20 at V3 vs V1 (P = 0.016 LAR, P ≤ 0.001 AR). BPT-DP+ patients also showed a significant increase of eosinophils, monocytes, and ECP in induced sputum at V3 compared with V1. CONCLUSION: The results suggest the existence of a new asthma phenotype (local allergic asthma) defined by absence of systemic atopy and positivity to BPT with allergen.

IgE Test in Secretions of Patients with Respiratory Allergy.

PURPOSE OF REVIEW: IgE is a key player in multiple inflammatory airway diseases. Ample literature demonstrates its presence in mucosa of patients with allergic rhinitis (AR), local allergic rhinitis (LAR), asthma, or chronic rhinosinusitis with nasal polyposis (CRSwNP). RECENT FINDINGS: Current evidence shows that high-affinity IgE in blood stream of allergic individuals derives mainly from the mucosae. Also, mucosal synthesis of IgE can occur in the absence of systemic atopy, and may be relevant in atopic and non-atopic phenotypes of rhinitis as demonstrated in LAR. Specific IgE (sIgE) detection varies depending on technique used for sample collection and its measurement. sIgE detection is highly specific for diagnosis of LAR. Moreover, measurement of sIgE in secretions could be useful in monitoring response to allergen-specific immunotherapy in both AR and LAR phenotypes. This review will focus on recent developments in the role of IgE in respiratory diseases, and the clinical implications of its measurement in secretions.

Follow-up study in local allergic rhinitis shows a consistent entity not evolving to systemic allergic rhinitis.

BACKGROUND: Local allergic rhinitis (LAR) is a common disease that affects 25.7% of the rhinitis population and more than 47% of patients previously diagnosed with nonallergic rhinitis. Whether LAR is the first step in the natural history of allergic rhinitis (AR) with systemic atopy or a consistent entity is unknown. OBJECTIVE: The aim was to evaluate the natural history of a population with LAR of recent onset and the development of AR and asthma. METHODS: A prospective 10-year follow-up study with initial cohorts of 194 patients with LAR of recent onset and 130 healthy controls is being undertaken. A clinical-demographic questionnaire, spirometry, skin prick test, and specific IgE to aeroallergens were done yearly. Nasal allergen provocation tests with Dermatophagoides pteronyssinus, Alternaria alternata, Olea europea, and a mix of grass pollen were performed at baseline and after 5 years. RESULTS: At disease onset, most of the patients with LAR had moderate-to-severe persistent-perennial rhinitis; conjunctivitis and asthma were the main comorbidities (51.1% and 18.8%, respectively), and D pteronyssinus was the most relevant aeroallergen (51.1%). After 5 years of follow-up, a worsening of rhinitis was detected in 26.2%, with an increase in symptom persistence and severity, and new associations with conjunctivitis and asthma. Atopy was detected by skin prick test and/or serum specific-IgE in patients with LAR (6.81%) and in controls (4.5%). CONCLUSIONS: This study shows a similar rate of development of systemic atopy in LAR and controls, which suggests that LAR is an entity well differentiated from AR. To determine the natural course of LAR more precisely, this study is in progress to complete 10 years of follow-up.

Local allergic rhinitis: concept, pathophysiology, and management.

Local allergic rhinitis (LAR) is a localized nasal allergic response in the absence of systemic atopy characterized by local production of specific IgE (sIgE) antibodies, a T(H)2 pattern of mucosal cell infiltration during natural exposure to aeroallergens, and a positive nasal allergen provocation test response with release of inflammatory mediators (tryptase and eosinophil cationic protein). Although the prevalence remains to be established, a number of patients previously given a diagnosis of nonallergic rhinitis or idiopathic rhinitis are now being classified as having LAR. Culprit allergens responsible include house dust mite, grass and olive pollens, and many others. For the diagnosis of LAR, neither skin prick testing nor determination of the presence of serum sIgE antibodies is useful, and a nasal allergen provocation test is needed to identify the culprit allergen or allergens. In a certain proportion of cases, local sIgE can be detected, and conjunctivitis, asthma, or both can be associated. Whether patients with LAR will have systemic atopy in the future is a matter of debate. Further studies are needed for examine the prevalence of this phenomenon in different areas, to improve the diagnostic methods to better identify these patients, and to develop therapeutic approaches, including the use of immunotherapy.

Vernal keratoconjunctivitis: Current immunological and clinical evidence and the potential role of omalizumab.

Vernal keratoconjunctivitis (VKC) is a severe ocular allergic disease characterized by chronic inflammation of the cornea and conjunctiva that may lead to loss of visual acuity and blindness. The disease occurs primarily in children and is more common in geographical regions characterized by warm temperatures and high humidity. The clinical manifestations of VKC, when inadequately treated, may lead to severe complications and corneal damage. The prevalence of allergen sensitization, specific serum immunoglobulin E (IgE), and specific tear IgE was reported in approximately 55%-60% of patients with VKC, confirming the involvement of IgE-mediated and non-IgE-mediated mechanisms in the pathophysiology of the condition. This article explores current knowledge on the immunological pathways of VKC and the role of the monoclonal anti-IgE antibody, omalizumab, in its management. The review evaluated the effects of omalizumab beyond the direct IgE-mediated reactions and discusses its potential as a therapeutic target for VKC. Multiple retrospective analyses, case series, and case reports have reported the effectiveness of omalizumab in the management of VKC. A summary of the clinical data from these studies revealed that in children with VKC omalizumab treatment was well tolerated with improvement or resolution of ocular symptoms, reduction in steroid use, and enhancement of quality of life. Omalizumab may serve as a promising treatment option for VKC due to its ability to target both IgE-mediated and non-IgE-mediated pathophysiological pathways. Larger, controlled clinical trials are needed to support these findings.

Allergen exposure boosts peripheral Th9 responses in patients with local allergic rhinitis.

KEY POINTS: Intranasal allergen exposure increases peripheral total Th2 and Th9 cells in patients with local allergic rhinitis (LAR). Peripheral T-cell response seems dominated by Th9 cells in patients with LAR, whereas Th2 responses prevail in patients with allergic rhinitis. Our results identify Th9 cells as potential therapeutic targets for patients with LAR.

Nasal allergen provocation test with multiple aeroallergens detects polysensitization in local allergic rhinitis.

BACKGROUND: Patients previously given a diagnosis of nonallergic rhinitis (NAR) might have a new form of local allergic rhinitis (LAR) with local production of specific IgE antibodies and a positive response to a nasal allergen provocation test (NAPT). OBJECTIVE: We evaluated an NAPT protocol using multiple aeroallergens (NAPT-M) for the detection of polysensitization to several aeroallergens in patients with LAR. METHODS: NAPT-Ms with 2 different panels of aeroallergens for patients with perennial and seasonal rhinitis were performed in 25 patients with LAR and 25 patients with NAR whose disease was diagnosed by means of NAPTs 1 year earlier. The response to nasal challenge was evaluated based on subjective (nasal-ocular symptoms) and objective (acoustic rhinometry) parameters. Nasal levels of tryptase and eosinophil cationic protein were determined by means of immunoassay at baseline, 15 minutes, and 1, 2, and 24 hours after challenge. RESULTS: NAPT-Ms showed 100% concordance with the gold standard of NAPTs with a single aeroallergen. No false-positive or false-negative responses were detected. The use of NAPT-Ms achieved 75% reduction in the total number of visits required for final diagnosis in the NAR group (from 168 to 42 visits) and a 55% reduction in the LAR group (from 144 to 65 visits) compared with NAPTs with a single aeroallergen. CONCLUSIONS: These results demonstrate that clinically relevant polysensitization to aeroallergens in patients with LAR occurred and that the NAPT-M is a useful, specific, sensitive, reproducible, and less time-consuming in vivo diagnostic test for the screening of patients with LAR.