Seasonal Local Allergic Rhinitis in Areas With High Concentrations of Grass Pollen.

BACKGROUND: Local allergic rhinitis (LAR) is a phenotype of allergic rhinitis characterized by the presence of a localized immune response in the nasal mucosa of patients with negative skin prick test (SPT) results and undetectable serum specific IgE (sIgE). It unknown whether LAR is limited to areas with low or moderate aeroallergen exposure. OBJECTIVE: To explore the presence of LAR and the clinical and immunological characteristics of this entity in geographic areas with high grass pollen loads. METHODS: A cross-sectional observational study was carried out in 2 hospitals in central Spain (Madrid and Ciudad Real). Sixty-one patients with seasonal rhinitis and negative SPT results and undetectable serum sIgE were evaluated using a clinical questionnaire, determination of serum total IgE, and a nasal allergen provocation test (NAPT) with Phleum species. The response to NAPT was monitored using assessment of nasal symptoms, acoustic rhinometry, and determination of sIgE, tryptase, and eosinophil cationic protein in the nasal cavity. RESULTS: Seasonal LAR was detected in 37 patients (61%) using the techniques described above. Eleven percent of patients with LAR were adolescents or children, and 14% reported onset of rhinitis in childhood. Most patients reported persistent-moderate seasonal nasal symptoms, and 41% reported worsening of the disease during the last 2 years. Conjunctivitis was the most common comorbidity, affecting 95% of cases. CONCLUSIONS: LAR to grass pollen is relevant in patients with seasonal symptoms indicative of allergic rhinitis but with a negative skin test result who live in areas with high allergenic pollen loads. This entity should be included the differential diagnosis of rhinitis.

Optimisation of grass pollen nasal allergen challenge for assessment of clinical and immunological outcomes.

Nasal allergen challenge can be used to assess the clinical and immunological aspects of rhinitis due to inhalant allergens. We aimed to develop a reproducible technique for grass pollen nasal allergen challenge and to study biomarkers within nasal secretions. 20 Grass pollen allergic individuals underwent nasal challenges with purified Timothy grass allergen. An initial dose-titration challenge was used to determine dose-response characteristics. Subsequently, volunteers underwent 3 further challenges using individualised threshold doses. Symptom scores, visual analogue scores, and peak nasal inspiratory flow (PNIF) were recorded at baseline and up to 6h after challenge. Nasal secretions were collected at each time point using synthetic filter papers or absorptive polyurethane sponges and analysed for IL-4, -5, -10, -13, IFN-γ, Tryptase and Eosinophil Cationic Protein (ECP). Challenges gave reproducible symptom scores and decreased PNIF. Tryptase levels in nasal fluid peaked at 5 min after challenge and returned to baseline levels at 1h. ECP, IL-5, IL-13 and IL-4 levels were increased from 2-3 h and showed progressive increases to 5-6 h. Sponges proved the superior nasal fluid sampling technique. We have developed a reproducible nasal allergen challenge technique. This may be used as a surrogate clinical endpoint in trials assessing the efficacy of treatments for allergic rhinitis. Tryptase in local nasal secretions is a potential biomarker of the early phase response; ECP and the Th2 cytokines IL-5, -13 and -4 markers of late phase allergic responses. Our model allows correlation between clinical responses and local biomarkers following nasal allergen challenge.

Nasal nitric oxide measurements in the assessment of nasal allergen challenge.

BACKGROUND: Several objective methods are used to assess the result of nasal allergen challenge. OBJECTIVE: The aim of this study was to compare the diagnostic value of nasal nitric oxide (nNO) measurements with that of peak nasal inspiratory flow (PNIF), nasal lavage fluid beta-tryptase levels, and changes in cell count after nasal challenge with grass pollen. METHODS: The study population comprised 24 patients allergic to grass pollen and 24 healthy controls. All participants underwent grass allergen challenge preceded by administration of placebo. A visual analog scale was administered. nNO and PNIF were determined, and nasal lavage fluid was collected before and 30 minutes after administration of placebo and allergen. The study was performed outside the pollen season. RESULTS: Significant changes in nNO, PNIF, nasal lavage fluid beta-tryptase level, and cell count were observed only in allergic patients after administration of the allergen. Receiver operating characteristic (ROC) curves were drawn for each determination. A change in nNO levels of -11.987% was indicated as the best cutoff point for differentiating between allergic patients and healthy participants with a sensitivity of 60.9%, specificity of 100%, negative predictive value of 71%, and positive predictive value of 100%. Comparison of the area under the ROC curve did not show significant differences between the diagnostic value of changes in nNO levels and other objective methods of assessing the outcome of the challenge. CONCLUSION: Changes in nNO levels do not differ significantly from other methods used to objectively assess the outcome of nasal challenge. Given their insufficient sensitivity, nNO measurements have limited value as the sole diagnostic tool when assessing the outcome of nasal challenge.

Baseline serum tryptase levels and adverse reactions to injection specific immunotherapy with airborne allergens: is there a relationship?

BACKGROUND: Elevated baseline serum tryptase levels are associated with severe systemic reactions following hymenoptera stings or venom immunotherapy. Little is known about baseline tryptase levels in patients with respiratory allergy and whether a relationship exists with systemic reactions induced by injection specific immunotherapy (SIT) with airborne allergens. The objective of this study was to measure tryptase levels in subjects with respiratory allergy and analyze the results in the light of tolerance/intolerance to injection SIT. METHODS: Baseline serum tryptase levels were measured in 106 adults allergic to different airborne allergens and in 40 normal controls. Thirty-one patients underwent injection SIT, and 15 of these 31 experienced at least one SIT-induced systemic reaction. RESULTS: Patients and normal controls showed similar median tryptase levels (2.98 vs. 3.13 ng/ml, respectively), although these were elevated in 6 patients (6%) versus 0 of 40 controls (0%). Tryptase levels did not differ between those patients with or without a history of systemic reactions (median 3.7 vs. 5.91 ng/ml, not significant). Three of 4 patients showing elevated tryptase levels belonged to the SIT-tolerant group. Elevated tryptase levels were not associated with specific allergens nor with distance from the specific pollen season. A bone marrow aspirate performed in the only patient with a history of systemic reactions following injection SIT and tryptase >11.4 ng/ml showed a normal morphology and phenotype. CONCLUSIONS: Unlike patients with hymenoptera venom allergy, in patients with respiratory allergy, elevated serum tryptase levels do not represent a risk factor for adverse reactions to SIT.

TSG-6 protein, a negative regulator of inflammatory arthritis, forms a ternary complex with murine mast cell tryptases and heparin.

TSG-6 (TNF-α-stimulated gene/protein 6), a hyaluronan (HA)-binding protein, has been implicated in the negative regulation of inflammatory tissue destruction. However, little is known about the tissue/cell-specific expression of TSG-6 in inflammatory processes, due to the lack of appropriate reagents for the detection of this protein in vivo. Here, we report on the development of a highly sensitive detection system and its use in cartilage proteoglycan (aggrecan)-induced arthritis, an autoimmune murine model of rheumatoid arthritis. We found significant correlation between serum concentrations of TSG-6 and arthritis severity throughout the disease process, making TSG-6 a better biomarker of inflammation than any of the other arthritis-related cytokines measured in this study. TSG-6 was present in arthritic joint tissue extracts together with the heavy chains of inter-α-inhibitor (IαI). Whereas TSG-6 was broadly detectable in arthritic synovial tissue, the highest level of TSG-6 was co-localized with tryptases in the heparin-containing secretory granules of mast cells. In vitro, TSG-6 formed complexes with the tryptases murine mast cell protease-6 and -7 via either heparin or HA. In vivo TSG-6-tryptase association could also be detected in arthritic joint extracts by co-immunoprecipitation. TSG-6 has been reported to suppress inflammatory tissue destruction by enhancing the serine protease-inhibitory activity of IαI against plasmin. TSG-6 achieves this by transferring heavy chains from IαI to HA, thus liberating the active bikunin subunit of IαI. Because bikunin is also present in mast cell granules, we propose that TSG-6 can promote inhibition of tryptase activity via a mechanism similar to inhibition of plasmin.

Nasal inflammatory mediators and specific IgE production after nasal challenge with grass pollen in local allergic rhinitis.

BACKGROUND: Evidence exists of a new form of local allergic rhinitis (LAR) with local production of specific IgE (sIgE) and a positive response to nasal allergen provocation test (NAPT) in patients previously diagnosed with idiopathic rhinitis. However, the immunologic mechanisms involved are still poorly understood. OBJECTIVE: We explored the involvement of nasal sIgE, eosinophil, and mast cell activation in the response to NAPT with grass pollen (NAPT-grass) in a group of patients already classified with LAR. METHODS: Out-of-spring NAPT-grass was performed in 30 patients with LAR and 30 healthy controls. Nasal symptoms, acoustic rhinometry, and nasal lavage were performed at baseline and 15 minutes and 1, 6, and 24 hours post-NAPT. Tryptase, eosinophilic cationic protein (ECP), and total and sIgE to grass pollen were measured in nasal lavage by immunoassays. RESULTS: NAPT-grass was positive in all patients with LAR. We detected significant increases of tryptase and ECP in 40% and 43%, respectively, at 15 minutes and 1, 6, and 24 hours post-NAPT compared with baseline (P < .05). sIgE was increased in 30%, with significant increases at 1 and 6 hours (P < .05) and 24 hours (P = .002) post-NAPT. The maximum release of tryptase was detected 15 minutes after NAPT, whereas the maximum release of ECP and sIgE was detected 24 hours after challenge. NAPT-grass was negative in all healthy controls, with no increase in tryptase, ECP, total IgE, or sIgE. CONCLUSION: These results demonstrate that patients with LAR had local production of sIgE and mast cell/eosinophil activation induced by nasal exposure to grass pollen.