The role of aspirin desensitization followed by oral aspirin therapy in managing patients with aspirin-exacerbated respiratory disease: A Work Group Report from the Rhinitis, Rhinosinusitis and Ocular Allergy Committee of the American Academy of Allergy, Asthma & Immunology.

Aspirin-exacerbated respiratory disease (AERD) is characterized by the clinical triad of chronic rhinosinusitis with nasal polyps, asthma, and an intolerance to medications that inhibit the cycloxgenase-1 enzyme. Patients with AERD on average have more severe respiratory disease compared with patients with chronic rhinosinusitis with nasal polyps and/or asthma alone. Although patients with AERD traditionally develop significant upper and lower respiratory tract symptoms on ingestion of cycloxgenase-1 inhibitors, most of these same patients report clinical benefit when desensitized to aspirin and maintained on daily aspirin therapy. This Work Group Report provides a comprehensive review of aspirin challenges, aspirin desensitizations, and maintenance aspirin therapy in patients with AERD. Identification of appropriate candidates, indications and contraindications, medical and surgical optimization strategies, protocols, medical management during the desensitization, and recommendations for maintenance aspirin therapy following desensitization are reviewed. Also included is a summary of studies evaluating the clinical efficacy of aspirin therapy after desensitization as well as a discussion on the possible cellular and molecular mechanisms explaining how this therapy provides unique benefit to patients with AERD.

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.

Asthma and allergic rhinitis associate with the rs2229542 variant that induces a p.Lys90Glu mutation and compromises AKR1B1 protein levels.

Asthma and rhinitis are two of the main clinical manifestations of allergy, in which increased reactive oxygen or electrophilic species can play a pathogenic role. Aldose reductase (AKR1B1) is involved in aldehyde detoxification and redox balance. Recent evidence from animal models points to a role of AKR1B1 in asthma and rhinitis, but its involvement in human allergy has not been addressed. Here, the putative association of allergic rhinitis and asthma with AKR1B1 variants has been explored by analysis of single-strand variants on the AKR1B1 gene sequence in 526 healthy subjects and 515 patients with allergic rhinitis, 366 of whom also had asthma. We found that the rs2229542 variant, introducing the p.Lys90Glu mutation, was significantly more frequent in allergic patients than in healthy subjects. Additionally, in cells transfected with expression vectors carrying the wild-type or the p.Lys90Glu variant of AKR1B1, the mutant consistently attained lower protein levels than the wild-type and showed a compromised thermal stability. Taken together, our results show that the rs2229542 variant associates with asthma and rhinitis, and hampers AKR1B1 protein levels and stability. This unveils a connection between the genetic variability of aldose reductase and allergic processes.

Alcohol hyper-responsiveness in chronic rhinosinusitis with nasal polyps.

BACKGROUND: An important percentage of subjects diagnosed with chronic upper airway disease report alcohol-induced worsening of their symptoms. The prevalence and characteristics of respiratory reactions provoked by alcohol-containing drinks have not been fully investigated yet. OBJECTIVE: The aim of this study was to estimate the prevalence and characteristics of alcohol hyper-responsiveness in patients with chronic airway disease and healthy controls. Furthermore, nasal inflammation was evaluated in nasal polyp patients with and without hyper-responsiveness. METHODS: We evaluated the prevalence and characteristics of alcohol-induced respiratory complaints in 1281 subjects. Chronic rhinosinusitis with nasal polyps (CRSwNP) patients with and without NSAID exacerbated respiratory disease (NERD), chronic rhinosinusitis patients without nasal polyps (CRSsNP), allergic rhinitis (AR) patients and healthy controls were approached by means of a questionnaire. Inflammatory markers (eosinophilic cationic protein (ECP), IL-5, IgE, SAE-specific IgE, IL-17, TNFα and IFNγ) in tissue were then compared between alcohol hyper-responsive and non-hyper-responsive CRSwNP patients. RESULTS: The highest prevalence of nasal and bronchial alcohol hyper-responsiveness was observed in patients with NERD, followed by CRSwNP, and less frequent in CRSsNP, AR and healthy controls. Alcohol hyper-responsiveness is significantly more prevalent in CRSwNP patients suffering from recurrent disease and in patients with severe symptomatology. In nasal tissue of the hyper-responsive CRSwNP group, we observed significantly higher nasal levels of the eosinophilic biomarker ECP. CONCLUSION AND CLINICAL RELEVANCE: Nasal hyper-responsiveness to alcohol is significantly more prevalent in severe eosinophilic upper airway disease.

Association study of genetic variants in PLA2G4A, PLCG1, LAT, SYK, and TNFRS11A genes in NSAIDs-induced urticaria and/or angioedema patients.

NSAIDs-induced urticaria and/or angioedema (NIUA) is the most frequent entity of hypersensitivity reactions to NSAIDs. The underlying cause is considered to be because of a nonspecific immunological mechanism in which mast cells are key players. We studied the association of nine single nucleotide polymorphisms in five genes involved in mast cell activation (SYK, LAT1, PLCG1, PLA2G4A, and TNFRSF11A) in 450 NIUA patients and 500 controls. We identified several statistically significant associations when stratifying patients by symptoms: PLA2G4A rs12746200 (urticaria vs. controls, Pc=0.005). PLCG1 rs2228246 (angioedema vs. controls; Pc=0.044), and TNFRS11A rs1805034 (urticaria+angioedema vs. controls; Pc=0.041). The frequency of haplotype PLCG1 rs753381-rs2228246 (C-G) in angioedema-NIUA patients was lower than that in controls (Pc=0.040). In addition, the haplotype frequency of TNFRS11A rs1805034-rs35211496 (C-T) was higher among urticaria-NIUA and urticaria+angioedema-NIUA patients than the controls (Pc=0.045 and 0.046). Our results shed light on the involvement of variants in genes related to non-immunological mast cell activation in NIUA.

Differential Plasma-cell evolution is linked with Dermatophagoides pteronyssinus immunotherapy response.

Allergic rhinitis is highly prevalent worldwide. Immunotherapy has been shown to control its symptoms, however, up to 30% of patients may not respond. Previous studies of the immunological mechanisms involved in allergen-immunotherapy (AIT) have focused on the humoral and T-cell response and several studies have evaluated some B-cell subpopulations during AIT and their role in immunological tolerance. However, although B and plasma-cell subpopulations are two of the most important cellular subtypes involved in allergic reactions, their relation with AIT efficacy remains unelucidated. The objective was to analyze the effects of immunotherapy on different B and plasma-cell subpopulations and whether these changes correlate with the clinical response to the treatment. Although no changes are found in B-cell subpopulations, responder patients show increased levels of memory B-cells even before the beginning of treatment. Changes in plasma-cell subpopulations are found, mainly in circulating inflammatory plasma-cells that could affect the response to the allergen. Moreover, an early increase of specific-IgG4 and IgG4 secreting-cells was found. All these suggest that the determination of the memory B-cells before the initiation of the treatment, and the quantification of IgG4 and IgG4-secreting-cells in the first months of immunotherapy, could serve as markers for the clinical response to treatment.

Genome-wide association study in NSAID-induced acute urticaria/angioedema in Spanish and Han Chinese populations.

AIM: Acute urticaria/angioedema (AUA) induced by cross-intolerance to NSAIDs is the most frequent clinical entity in hypersensitivity reactions to drugs. In this work, we conducted a genome-wide association study in Spanish and Han Chinese patients suffering from NSAID-induced AUA. MATERIALS & METHODS: A whole-genome scan was performed on a total of 232 cases (112 Spanish and 120 Han Chinese) with NSAID-induced AUA and 225 unrelated controls (124 Spanish and 101 Han Chinese). RESULTS: Although no polymorphism reached genome-wide significance, we obtained suggestive associations for three clusters in the Spanish group (RIMS1, BICC1 and RAD51L 1) and one region in the Han Chinese population (ABI3BP). Five regions showed suggestive associations after meta-analysis: HLF, RAD51L1, COL24A1, GalNAc-T13 and FBXL7. A majority of these genes are related to Ca(2+), cAMP and/or P53 signaling pathways. CONCLUSION: The associations described were different from those related to the metabolism of arachidonic acid and could provide new mechanisms underlying NSAID-induced AUA.

Induction of accelerated reactions to amoxicillin by T-cell effector mechanisms.

BACKGROUND: Although allergic drug reactions have been considered to be immediate (IgE mediated) or delayed (T-cell effector mechanisms), accelerated reactions have also been defined; however, they have not been sufficiently studied. OBJECTIVE: To study the mechanisms involved in accelerated reactions to amoxicillin. METHODS: We monitored the response in 3 patients who had an accelerated reaction to amoxicillin. A T-cell effector response was searched after a Drug Provocation Test. Symptoms were recorded after initiation of the reaction, and sequential samples were taken at different intervals after challenge. Skin biopsy specimens were also taken, and a lymphocyte transformation test (LTT) was performed. RESULTS: After the drug provocation test, all 3 patients had a positive response within 2 to 6 hours of drug administration, with full expression at 6 hours, requiring corticoids and antihistamine treatment. They had generalized erythema with facial angioedema but no cardiovascular or respiratory symptoms. Monitoring of the response revealed the presence in the skin of CD4 and CD8 lymphocytes with increased expression of homing and cell activation markers. Immunohistochemistry revealed a perivascular mononuclear cell infiltrate with activated CD4 and CD8 cells expressing perforin and granzyme B. No tryptase release was detected in either the affected tissue or the peripheral blood. The LTT result was positive in all 3 patients. CONCLUSION: We found that accelerated reactions to ß-lactams are mediated by effector T cells. The increase in different T-cell markers and a positive LTT result to amoxicillin, in parallel with the occurrence of symptoms after challenge, support this mechanism.

La rinitis alérgica local es una entidad prevalente inducida por alérgenos inhalados estacionales y perennes / Local allergic rhinitis is a prevalent entity induced by seasonal and perennial inhalant allergens

La rinitis alérgica local (RAL) es un nuevo fenotipo de rinitis con producción nasal de anticuerpos IgE específicos en ausencia de atopia sistémica que puede afectar a sujetos previamente diagnosticados de rinitis no alérgica y rinitis idiopática. Esta nueva entidad se caracteriza por la existencia de síntomas clínicos sugestivos de rinitis alérgica, producción local de IgE específica y presencia de un patrón inflamatorio Th2 en la mucosa nasal durante la exposición natural, así como tras la prueba de provocación nasal con alérgenos con producción local de IgE específica, triptasa y proteína catiónica de eosinófilos (ECP). La existencia de esta nueva entidad hace necesaria la realización de un diagnóstico alergológico preciso en pacientes con síntomas sugestivos de rinitis alérgicas cuando el prick test y la determinación de IgE específica sérica sean negativos. La detección local de anticuerpos IgE específicos en las secreciones nasales durante la exposición natural a aeroalérgenos y la respuesta positiva a la prueba de provocación nasal con aeroalérgenos con producción local de triptasa, ECP e IgE específica han demostrado ser una aproximación adecuada para detectar pacientes con RAL.

Influence of dog ownership and high endotoxin on wheezing and atopy during infancy.

BACKGROUND: Increased exposure to microbial products early in life may protect from development of atopic disorders in childhood. Few studies have examined the relationship of endotoxin exposure and pet ownership on atopy and wheezing during infancy. OBJECTIVE: Evaluate relationships among high endotoxin exposure, pet ownership, atopy, and wheezing in high-risk infants. METHODS: Infants (n = 532; mean age, 12.5 +/- 0.8 months) with at least 1 parent with confirmed atopy were recruited. A complete medical history and skin prick testing to foods and aeroallergens were performed at age 1 year. House dust samples were analyzed for endotoxin. RESULTS: Prevalences of wheezing were not independently associated with dog or cat ownership or endotoxin levels. Percutaneous reactivity to at least 1 allergen was observed in 28.6% of infants. Univariate analyses showed significant associations of any wheezing, recurrent wheezing, and recurrent wheezing with an event with daycare attendance, number of siblings, respiratory infections, maternal smoking, and history of parental asthma. Logistic regression adjusting for the latter variables showed that recurrent wheezing (odds ratio, 0.4; 95% CI, 0.1-0.9) as well as 2 other wheeze outcomes were significantly reduced in homes with high endotoxin exposure in the presence of 2 or more dogs. CONCLUSION: Pet ownership or endotoxin did not independently modify aeroallergen sensitization or wheezing during infancy. However, high endotoxin exposure in the presence of multiple dogs was associated with reduced wheezing in infants. CLINICAL IMPLICATIONS: A home environment with many dogs and high levels of endotoxin may be conducive to reduced wheezing in infancy.