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.

Yingxiang Acupoint Embedding Improves Mucosal Barrier Function in Rats with Local Allergic Rhinitis.

INTRODUCTION: Epithelial barrier disruption is the initial cause of various diseases. We previously reported that acupoint catgut embedding (AE) improves tight junction proteins (TJs) in rats with allergic rhinitis. However, whether AE improves the epithelial barrier in local allergic rhinitis (LAR) remains unknown. METHODS: A total of 36 Sprague Dawley (SD) male rats aged 5-7 weeks were divided into 6 groups with 6 rats each: control group, LAR model group, false acupoint embedding + LAR group, acupoint embedding + LAR group, capsaicin + LAR group, and tunicamycin + acupoint embedding + LAR group. Behavioral observation, ELISA to detect inflammatory factors in nasal lavage fluid and serum IgE, nasal mucosal permeability test, hematoxylin-eosin staining, PCR to detect Substance P (SP), Western blot, and immunofluorescence to detect endoplasmic reticulum stress (ERS) index and TJs were used to investigate the mechanism of AE in LAR. RESULTS: AE improved the symptoms and pathological features of nasal mucosa of LAR rats, reduced the inflammatory factors (IL4, IL5, IL13) of nasal lavage fluid, and showed no significant change in serum IgE levels in all groups. In addition, AE decreased the expression of SP in nasal mucosa of LAR rats, inhibited ERS, increased the expression of tight junction protein, reduced the permeability of nasal mucosa, and improved the function of nasal mucosal barrier. CONCLUSION: This study confirms that AE can improve the nasal mucosal barrier function of LAR by reducing the expression of SP, inhibiting ERS and increasing the expression of TJs, thus enhancing the nasal mucosal barrier function.

Local Allergic Rhinitis: Lights and Shadows of a Mysterious Entity.

Local allergic rhinitis (LAR) is, to date, a debated and complex entity, still orphan of global consideration and a multicentric approach. LAR does not seem to find a proper positioning in the classic classifications and phenotypes of chronic rhinitis, and its pathophysiology relies specifically on the presence of local IgE. These patients in fact have a suggestive clinical history of allergic rhinitis in the presence of negative skin prick tests and serum IgE tests for the suspect allergen. Nasal allergen challenge, assessment of local IgE, basophil activation test (BAT), and nasal cytology are, at the moment, the most used tests in the diagnostic approach to the disease, despite their limitations. Considering that the correct interpretation of diagnostic tests and their clinical relevance is fundamental in the assessment of the right diagnosis and the subsequent therapy, we propose a new diagnostic approach that encompasses all of these methodologies and suggest that several pragmatic randomized control trials as well as prospective, multicentric studies directed at the long-term follow-up of LAR be carried out to further investigate this debated entity.

Challenges in Local Allergic Rhinitis Diagnosis, Management, and Research: Current Concepts and Future Perspectives.

Local allergic rhinitis (LAR) is diagnosed based on the presence of clinical symptoms such as rhinorrhea, sneezing, and nasal itching using negative skin prick testing and serum IgE assessment. Several novel studies have shown that it is possible to use the assessment of nasal sIgE (specific immunoglobulin E) secretion as an additional diagnostic criterion for local allergic rhinitis. Additionally, allergen immunotherapy is a promising-albeit still not fully assessed and evaluated-future method of managing patients with LAR. In this review, the historical background, epidemiology, and main pathophysiological mechanisms of LAR shall be presented. Additionally, we address the current state of knowledge based on selected articles regarding the assessment of the local mucosal IgE presence in response to exposure to such allergens as mites, pollen, molds, and others. The impact of LAR on quality of life as well as the possible options of management (including allergen immunotherapy (AIT), which showed promising results) will then be presented.

The aspects of local allergic rhinitis in Polish children and adolescents.

Introduction: Local allergic rhinitis (LAR) is one of the endotypes of rhinitis which occurs commonly in different age groups. Aim: To present the occurrence and characteristics of LAR in Polish children and adolescents. Material and methods: In the study protocol, three hundred sixty-one patients aged 5-17 with chronic rhinitis were included from 8 centres in Poland. Medical history and diagnostic procedures were performed with aeroallergens: skin prick tests, allergen-specific serum IgE and nasal provocation tests. In addition to LAR, allergic rhinitis (AR), dual allergic rhinitis (DUAL) and non-allergic rhinitis (NAR) were explored and compared. Results: LAR was confirmed in 21% of patients, systemic allergic rhinitis (SAR) in 43.9%, DUAL in 9.4% and NAR in 33.9% of patients. Based on nasal provocation test (NPT), allergy to HDM prevailed in the LAR group (68%), grass in the SAR group (58%), and grass and HDM in the DUAL group (32% and 64%). Girls were prevalent in the LAR group, and severe rhinitis and asthma were more common than other endotypes (p < 0.05). Conclusions: LAR is a common disease in children and adolescents and is often associated with severe rhinitis and frequently coexists with asthma.

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.

Nasal lavage fluid sIgE levels in differential diagnostics of allergic rhinitis.

Differential diagnosis plays a key role in diagnosing specific types of allergic rhinitis. The method involving allergen-specific immunoglobulin E (sIgE) detection in nasal lavage fluid, which has continually been the object of standardization efforts, is characterized by high specificity/sensitivity and plays a special role in diagnosing local allergic rhinitis. This article is a systematic review of the literature on the methodology, standardization, and use of sIgE detection in nasal lavage fluid in patients undergoing diagnostic tests for allergic rhinitis.

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.

New concepts in pediatric rhinitis.

Rhinitis-and especially allergic rhinitis (AR)-remains the most frequent hypersensitivity condition, affecting up to a quarter of the population and impacting the quality of life of individual patients and the health economy. Data, especially with respect to underlying pathophysiologic mechanisms, mainly derive from studies on adults and are subsequently extrapolated to the pediatric population. Therapeutic algorithms for children with rhinitis are long based on the same principles as in adults. We explore and describe novel aspects of rhinitis, ranging from mechanisms to disease classification, phenotypes, diagnostic and monitoring tools, and the use of treatments, with a focus on the traits of pediatric age groups.

Rhinitis 2020: A practice parameter update.

This comprehensive practice parameter for allergic rhinitis (AR) and nonallergic rhinitis (NAR) provides updated guidance on diagnosis, assessment, selection of monotherapy and combination pharmacologic options, and allergen immunotherapy for AR. Newer information about local AR is reviewed. Cough is emphasized as a common symptom in both AR and NAR. Food allergy testing is not recommended in the routine evaluation of rhinitis. Intranasal corticosteroids (INCS) remain the preferred monotherapy for persistent AR, but additional studies support the additive benefit of combination treatment with INCS and intranasal antihistamines in both AR and NAR. Either intranasal antihistamines or INCS may be offered as first-line monotherapy for NAR. Montelukast should only be used for AR if there has been an inadequate response or intolerance to alternative therapies. Depot parenteral corticosteroids are not recommended for treatment of AR due to potential risks. While intranasal decongestants generally should be limited to short-term use to prevent rebound congestion, in limited circumstances, patients receiving regimens that include an INCS may be offered, in addition, an intranasal decongestant for up to 4 weeks. Neither acupuncture nor herbal products have adequate studies to support their use for AR. Oral decongestants should be avoided during the first trimester of pregnancy. Recommendations for use of subcutaneous and sublingual tablet allergen immunotherapy in AR are provided. Algorithms based on a combination of evidence and expert opinion are provided to guide in the selection of pharmacologic options for intermittent and persistent AR and NAR.

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.

Local Allergic Rhinitis Revisited.

PURPOSE OF REVIEW: Local allergic rhinitis (LAR) represents a diagnostic and therapeutic challenge for clinicians. Even though it affects a considerable number of chronic rhinitis patients and a significant number of articles regarding prevalence, evolution, diagnosis, and treatment have been published, the condition remains still largely unrecognized and therefore misdiagnosed and mistreated. RECENT FINDINGS: LAR is a unique form of chronic rhinitis; it is neither classical allergic rhinitis (AR) nor non-allergic rhinitis (NAR). The symptoms, duration, severity, and complications of LAR are similar to those of AR and can affect adults and children. Thus, a portion of patients diagnosed with NAR or chronic rhinitis of unknown etiology may have LAR. The relationship between LAR inflammation and systemic allergic inflammation is unclear. Patients are frequently misdiagnosed with idiopathic NAR, and distinguishing between both entities is difficult without specific diagnostic tests. Underdiagnosis of LAR has implications on the management of these patients, as they are deprived of allergen immunotherapy (AIT) that has been demonstrated to modulate the immune mechanisms underlying allergic diseases. This review aims to comprehensively summarize the current knowledge on LAR and address unmet needs in the areas of disease diagnosis and treatment.

Allergen Immunotherapy for Local Respiratory Allergy.

PURPOSE OF REVIESW: Local respiratory allergy (LRA) is an eosinophilic phenotype of chronic airway disease. Three entities have been described within the LRA spectrum: local allergic rhinitis (LAR) and local allergic asthma (LAA) in non-atopic patients, and dual allergic rhinitis (DAR) in atopic patients (coexistence of LAR and allergic rhinitis). In this article, we aim to review the current evidence on the therapeutic options for LRA. RECENT FINDINGS: No controlled study has assessed the effect of standard therapy (oral antihistamines, intranasal or inhaled corticosteroids, bronchodilators) in LRA subjects. Three randomized clinical trials and one observational study demonstrated that allergen immunotherapy (AIT) is able to control nasal and ocular symptoms, decrease the need for rescue medication, and improve quality of life in LAR individuals. Nasal or inhaled steroids can be expected to improve eosinophilic inflammation in LRA patients but cannot change the natural course of the disease. Moreover, the long-term and disease-modifying effects of AIT in LRA subjects need to be investigated.

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.

Nasal and ocular challenges.

Nasal and ocular challenges facilitate the evaluation of subjective and objective responses to defined allergen or irritant exposure. Nasal and ocular allergen challenges are the gold standard to diagnose allergic rhinitis and conjunctivitis, respectively, and aid in the evaluation of novel therapies in clinical trials. Additionally, nasal and ocular allergen challenges might help identify medically relevant allergens in clinical practice. Nonspecific or irritant challenges evaluate mucosal hyperreactivity. Direct mucosal challenges, which can be performed in an office or research setting, expose the participant to higher allergen doses than common in the natural environment. Park studies and environmental chambers, which are most practical in clinical trials, more closely simulate natural allergen exposure. International consensus guidelines for nasal and ocular challenges do not exist. Therefore the positivity criteria, methodologies, and extract or allergen preparations used in challenges vary in the literature. Regardless of these limitations, nasal and ocular challenges are helpful clinical and research tools for nasal and ocular diseases.

Recent developments and highlights in rhinitis and allergen immunotherapy.

This review paper aims to provide an overview of recent developments in the field of allergic and non-allergic rhinitis, as well as allergen immunotherapy. Recent advances in phenotyping and endotyping various forms of rhinitis have brought us one step closer towards tailoring treatment more appropriately for a given patient. Updates on local allergic rhinitis are also covered. Allergen immunotherapy (AIT) is an area of significant interest, with multiple original papers and recent position papers and guidelines published. Evidence related to the application of AIT in seasonal and perennial allergic rhinitis (AR), local allergic rhinitis and novel and expanded applications is discussed in the publication.

Local allergic rhinitis is an independent rhinitis phenotype: The results of a 10-year follow-up study.

BACKGROUND: The knowledge about the natural history of local allergic rhinitis (LAR) is limited. One unmet question is to demonstrate whether LAR should be considered the first step in the development of allergic rhinitis (AR) or an independent phenotype. The aim of this study was to prospectively evaluate the natural history of a population with LAR, the potential conversion to AR with systemic atopy and the development of asthma during 10 years. METHODS: This is the second phase of a 10-year follow-up study of a cohort of 176 patients with LAR of recent onset and 115 age- and sex-matched healthy controls prospectively evaluated from 2005 to 2016. Clinical-demographic questionnaire, spirometry, skin prick test and specific IgE were evaluated yearly. Nasal allergen provocation tests (NAPT) with Dermatophagoides pteronyssinus, Alternaria alternata, Olea europaea and grass pollen were performed at baseline, and after 5 and 10 years. RESULTS: After 10-year LAR, patients experienced a significant and clinically relevant worsening of the rhinitis, with increase in emergency assistance, development of asthma, loss of allergen tolerance and impairment of the quality of life. This worsening became significant after 5 years and progressed throughout 10 years. A similar rate of development of AR with systemic atopy was detected in patients and controls (9.7% vs 7.8%, log-rank P=.623). In 5 patients, conversion to systemic atopy occurred >10 years (3%). CONCLUSIONS: LAR is a well-differentiated clinical entity with a low rate of development of systemic atopy, a natural evolution towards worsening and a risk factor for suffering asthma.

Specific immunotherapy in local allergic rhinitis: A randomized, double-blind placebo-controlled trial with Phleum pratense subcutaneous allergen immunotherapy.

BACKGROUND: Allergen immunotherapy has been shown to be an effective treatment for local allergic rhinitis (LAR) to house dust mites. Studies with pollen allergen immunotherapy are limited to observational studies. The aim of this study was to evaluate the clinical efficacy and safety of Phleum pratense subcutaneous immunotherapy (Phl-SCIT) in LAR. METHODS: In a randomized double-blind placebo-controlled study, 56 patients with moderate-severe LAR to grass pollen received Phl-SCIT with a depigmented polymerized pollen vaccine or placebo for the first year, and Phl-SCIT the second one. The blind was maintained throughout the study. Primary outcome was combined symptom medication score (CSMS) during grass pollen season (GPS). Secondary clinical outcomes included organ-specific symptoms, medication-free days, rhinitis severity and asthma control. Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), nasal allergen provocation test (NAPT), skin testing, serum levels of specific IgG4 and specific IgE and safety were also evaluated. RESULTS: Subcutaneous immunotherapy (SCIT) had a short-term and sustained effect with significant improvements of all primary and secondary clinical outcomes and RQLQ score. SCIT significantly increased serum sIgG4 levels and allergen tolerance, from the 6th to 24th months of treatment. At the end of the study, 83% of patients treated with ≥6 months of SCIT tolerated a concentration of P. pratense over 50 times higher than baseline, and 56% gave a negative NAPT. SCIT was well tolerated; six mild local reactions occurred, and there were no serious adverse events related to the study medication. CONCLUSIONS: Subcutaneous immunotherapy with depigmented polymerized allergen extracts is a safe and clinically effective treatment for LAR to P. pratense.