Mast Cell Activation Profile and TFH13 Detection Discriminate Food Anaphylaxis Versus Sensitization.

BACKGROUND AND OBJECTIVE: The prevalence of food allergy (FA) has increased significantly, and the risk of developing anaphylaxis is unpredictable. Thus, discriminating between sensitized patients and those at risk of having a severe reaction is of utmost interest. To explore mast cell activation pattern and T follicular helper (TFH) 13 presence in sensitized and food anaphylaxis patients. METHODS: Patients sensitized to Lipid transfer protein (LTP) were classified as anaphylaxis or sensitized depending on the symptoms elicited by LTP-containing food. CD34+-derived MCs from patients and controls were obtained, sensitized with pooled sera, and challenged with Pru p 3 (peach LTP). Degranulation, PGD2, and cytokine/chemokine release were measured. The TFH13 population was examined by flow cytometry in the peripheral blood of all groups. In parallel, LAD2 cells were activated similarly to patients' MCs. RESULTS: A distinguishable pattern of mast cell activation was found in anaphylaxis compared to sensitized patients. Robust degranulation, PGD2, and IL-8 and GM-CSF secretion were higher in anaphylaxis, whereas TFG- and CCL2 secretion increased in sensitized patients. Concomitantly, anaphylaxis patients had a larger TFH13 population. MC activation profile was dependent on the sera rather than the MC source. In agreement with that, LAD2 cells reproduce the same pattern as MCs from anaphylactic and sensitized patients. CONCLUSION: The distinct profile of mast cell activation allows to discriminate between anaphylaxis and sensitized patients. Pooled sera may determine mast cell activation independently of mast cell origin. Besides, the presence of TFH13 cells in anaphylaxis patients points to an essential role of IgE affinity.

Differential healthcare direct costs of asthma and chronic rhinosinusitis with nasal polyps in Catalonia (Spain).

INTRODUCTION: This study compares the direct healthcare costs associated with asthma and chronic rhinosinusitis with nasal polyps (CRSwNP) from 2013 to 2017 in Catalonia (Spain) with a population control group without these conditions. METHODS: A population administrative database containing healthcare information was used. The database contained information on primary care, hospitalisations, and emergency care from 2013 to 2017 in Catalonia. The unit cost of each healthcare procedure was imputed using a complete list of public prices for primary care services, hospital, and speciality services. Differential costs were estimated using a finite mixture model. RESULTS: Individuals diagnosed with asthma or CRSwNP showed a higher incidence of comorbidities than the control group. Mean annual direct costs per patient were €1,102 for asthma, €1,612 for CRSwNP and €2,197 for those with both conditions. According to our estimations, differential costs were €162 - €274 for patients with asthma and €481 - €1,257 for patients with CRSwNP compared to the reference population. These costs were significantly higher when asthma and CRSwNP coexist and especially in their severe condition. CONCLUSION: This population-based study revealed that asthma and CRSwN are associated with great economic burdens for healthcare systems. These costs were significantly higher when comorbidity was present (asthma and CRSwNP) and especially in their severe condition (€4,441).

Prevalence of Atopic Dermatitis in the adult population of Catalonia (Spain): a retrospective, large-scale population-based study.

BACKGROUND AND OBJECTIVES: Studies on the prevalence of Atopic Dermatitis (AD) for the adult cohort in general-based populations are scarce worldwide. We performed a retrospective population-based observational cohort study of 537,098 adult patients diagnosed with AD in Catalonia (Spain), a larger population than in previous studies. To study the prevalence of AD generally by age, gender, disease severity, multi-morbidities, and serum total Immunoglobin E (tIgE) and undergo appropriate medical treatment (AMT) for the Catalan population. METHODS: Adult individuals (≥18 years old) diagnosed with AD by medical records at different health care levels (primary, hospital, emergency) from the Catalan Health System (CHS) were included. Statistical analyses were conducted to evaluate socio-demographic characteristics, prevalence, multi-morbidities, serum tIgE and AMT. RESULTS: The overall diagnosed AD prevalence in the adult Catalan population was 8.7%, being higher for the non-severe (8.5%) than for the severe (0.2%) populations and females (10.1%) than males (7.3%). Topical corticosteroids were the most prescribed drug (66.5%), and the use of all prescribed treatments was higher in severe AD patients, especially systemic corticosteroids (63.8%) and immunosuppressant agents (60.7%). More than half (52.2%) of severe AD patients reported serum tIgE ≥ 100 KU/L, and higher values were observed for those with multi-morbidities. Acute bronchitis (13.7%), allergic rhinitis (12.1%), and asthma (8.6%) were the most frequent comorbid respiratory diseases. CONCLUSIONS: Our study provides new and robust evidence of AD´s prevalence and related characteristics in adults using a large-scale population-based study and a more significant cohort of individuals.

Prevalence of asthma in Catalonia (Spain): a retrospective, large-scale population-based study.

BACKGROUND AND OBJECTIVE: Asthma epidemiology reports an estimated global prevalence of about 4.3-8.6% in adults, with last differences among geographical regions. This study analyses a more significant population of asthma patients (473,737 individuals).To study the prevalence of medical diagnosis of asthma, overall and by age, gender, and disease severity, as well as comorbidities and type 2 biomarkers, and undergo medical treatments of a retrospective population-based asthma cohort from Catalonia (Spain). METHODS: Individuals with a diagnosis of asthma established by medical records at different healthcare levels (primary, hospital, and emergency) from the Catalan Health System (CHS) were included. Socio-demographic characteristics, prevalence, overall and by age and gender, disease severity, comorbidities, and biomarkers of type-2 inflammation were evaluated, together with appropriate medical treatment. RESULTS: The overall diagnosed asthma prevalence in the population of Catalonia was 6.3%, where patients mainly had mild asthma (5.3%) and were significantly higher in females (6.8%) than males (5.7%). By age groups, asthma was more prevalent in boys and young men adults; however, being more prevalent in females above the age of 30y. The prevalence of severe asthma was 0.4%, 42.6% had uncontrolled asthma, and a high proportion (84.2%) were under systemic corticosteroid prescription. As expected, SABAs were the most prescribed drug (62.6%), followed by systemic corticosteroids (43.3%). More than half (53.8%) of patients showed type 2 inflammation. CONCLUSION: Asthma prevalence in Catalonia is similar to other areas studied in Spain, with a high prevalence in women and of T2 asthma.

Risk Factors in Severe Anaphylaxis: Which Matters the Most, Food or Cofactors?

BACKGROUND AND OBJECTIVE: The prevalence of anaphylactic shock, the most severe manifestation of anaphylaxis, remains unknown. Risk factors and biomarkers have not been fully identified. Objective: To identify risk factors in patients who experience anaphylactic shock. METHODS: Using lipid transfer protein (LTP) allergy as a model, we compared the characteristics of patients who developed anaphylaxis and anaphylactic shock. We recorded demographics, pollen sensitization, foods ingested up to 2 hours before onset of the reaction, and the presence of cofactors. Culprit foods were identified through a compatible clinical history and positive allergology work-up (skin prick test and/or sIgE). RESULTS: We evaluated 150 reactions in 55 patients with anaphylaxis (134 reactions) and 12 with anaphylactic shock (16 reactions). Patients in the anaphylaxis group experienced twice as many reactions (mean [SD], 2.4 [2.5] for anaphylaxis vs 1.3 [1.5] for anaphylactic shock; P<.02). No relationship was found between any food group and severity of the reaction. The most frequent food involved in both groups of patients was the combination of several plant-derived foods (plant food mix), followed by peach and nuts. Indeed, in the reactions caused by plant food mix, the presence of a cofactor was observed more often than in other food groups. On the other hand, cofactors were not present in peach- and nut-related reactions. Exercise was the most frequent cofactor in all groups. CONCLUSION: In our series, the severity of the reactions was not determined by the kind of food or presence of a cofactor. Anaphylactic shock seems to be an infrequent presentation that may be associated with other individual-related factors requiring further evaluation.

Major Allergen Content in Allergen Immunotherapy Products: The Limited Value of Numbers.

The prevalence of allergic disorders has increased drastically over the last 50 years to the extent that they can be considered epidemic. At present, allergen-specific immunotherapy (AIT) is the only therapy that targets the underlying cause of allergic disorders, and evidence of its superiority is based on data accumulated from clinical trials and observational studies demonstrating efficacy and safety. However, several aspects remain unresolved, such as harmonization and standardization of manufacturing and quantification procedures across manufacturers, homogeneous reporting of strength, and the establishment of international reference standards for many allergens. This article discusses issues related to the measurement of major allergen content in AIT extracts, raising the question of whether comparison of products from different manufacturers is an appropriate basis for selecting a specific AIT product. Allergen standardization in immunotherapy products is critical for ensuring quality and, thereby, safety and efficacy. However, lack of harmonization in manufacturing processes, allergen quantification (methodologies and references), national regulatory differences, clinical practice, and labeling shows that the comparison of AIT products based solely on major allergen amounts is not rational and, in fact, impossible. Moreover, when rating the information given for a specific product, it is necessary to take into account further inherent characteristics of products and their application in clinical practice, such as the state of extract modification, addition of adjuvant or adjuvant system, route of administration (sublingual/ subcutaneous), and cumulative dose as per posology (including the volume per administration). Finally, only convincing clinical data can serve as the basis for product-specific evaluation and cross-product comparability of individual products.

Prevalence of Chronic Rhinosinusitis with Nasal Polyps in Catalonia (Spain): a retrospective, large-scale population-based study.

BACKGROUND: Studies on the prevalence of chronic rhinosinusitis (CRS) with nasal polyps (NP) in general-based populations are scarce in Europe and worldwide. We performed a retrospective population-based observational cohort study of 30,189 adult patients diagnosed with NP in Catalonia (Spain). METHODOLOGY: Adult individuals (≤18 years old) with a diagnosis of NP established by medical records at different health care levels (primary, hospital, and emergency) from the Catalan Health System (CHS) were included. Socio-demographic characteristics, prevalence, overall and by age and gender, disease severity, multi-morbidities, and biomarkers of type-2 inflammation were evaluated, together with appropriate medical treatment (AMT) and Endoscopic Sinus Surgery (ESS). RESULTS: In general population and severity sub-populations, the overall diagnosed NP prevalence was 0.49% and higher for males than females (0.60% vs 0.39%, p less than 0.0016). The prevalence for the severe NP population was 0.12%. The NP prevalence increased with age, the highest being at ≤60 years old for both gender and severity groups. Asthma (40.1%), acute rhinosinusitis (41.1%), and allergic rhinitis (32.1%) were among the most frequent comorbid respiratory diseases. ESS was performed in 15.4% of NP patients. Type 2 inflammation was present in 83.8% of the NP population and was more frequent in severe than non-severe (87.1% vs 82.7%, p less than 0.0001) patients and in those with respiratory multi-morbidities (91%). CONCLUSIONS: This is the first large-scale population-based NP epidemiology study conducted in Spain, including severity based on undergoing medical and surgical treatment and type 2 inflammation. Although the prevalence data are lower than in previous European studies, the large NP cohort studied represents an essential strength of the results.

Polymorphisms in eicosanoid-related biosynthesis enzymes associated with acute urticaria/angioedema induced by nonsteroidal anti-inflammatory drug hypersensitivity.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are the main triggers of drug hypersensitivity, with NSAID-induced acute urticaria/angioedema (NIUA) the most frequent phenotype. NSAID hypersensitivity is caused by cyclooxygenase 1 inhibition, which leads to an imbalance in prostaglandin (PG) and cysteinyl leukotriene (CysLT) synthesis. As only susceptible individuals develop NSAID hypersensitivity, genetic factors are believed to be involved; however, no study has assessed the overall genetic variability of key enzymes in PG and CysLT synthesis in NSAID hypersensitivity. OBJECTIVES: To evaluate simultaneously variants in the main genes involved in PG and CysLT biosynthesis in NIUA. METHODS: Two independent cohorts of patients were recruited in Spain, alongside NSAID-tolerant controls. The discovery cohort included only patients with NIUA; the replication cohort included patients with NSAID-exacerbated respiratory disease (NERD). A set of tagging single-nucleotide polymorphisms (tagSNPs) in PTGS1, PTGS2, ALOX5 and LTC4S was genotyped using mass spectrometry coupled with endpoint polymerase chain reaction. RESULTS: The study included 1272 individuals. Thirty-five tagSNPs were successfully genotyped in the discovery cohort, with three being significantly associated after Bonferroni correction (rs10306194 and rs1330344 in PTGS1; rs28395868 in ALOX5). These polymorphisms were genotyped in the replication cohort: rs10306194 and rs28395868 remained associated with NIUA, and rs28395868 was marginally associated with NERD. Odds ratios (ORs) in the combined analysis (discovery and replication NIUA populations) were 1·7 for rs10306194 [95% confidence interval (CI) 1·34-2·14; Pcorrected = 2·83 × 10-4 ) and 2·19 for rs28395868 (95% CI 1·43-3·36; Pcorrected = 0·002). CONCLUSIONS: Variants of PTGS1 and ALOX5 may play a role in NIUA and NERD, supporting the proposed mechanisms of NSAID-hypersensitivity and shedding light on their genetic basis.

Hypersensitivity Reactions to Cancer Chemotherapy: Practical Recommendations of ARADyAL for Diagnosis and Desensitization.

Rapid drug desensitization has enabled first-line therapies in patients with drug hypersensitivity reactions to chemotherapeutic drugs including monoclonal antibodies. Desensitization is a safe and highly effective procedure, not only for IgE-mediated reactions, but also for those mediated by non-IgE mechanisms. The likelihood of breakthrough reactions during desensitization is low, and most are mild; in fact, moderate-to-severe reactions are infrequent. In this document, 16 allergy departments belonging to the Spanish research network ARADyAL present a review of the available scientific evidence and provide general guidelines for the diagnosis and management of drug hypersensitivity reactions to chemotherapeutic drugs and monoclonal antibodies. Emphasis is placed on the desensitization procedure.

Impact Of "eHealth" in Allergic Diseases and Allergic Patients.

The emergence of new technology enables allergists and patients to compile data and receive feedback regarding key symptoms, risk behavior, and/or management. The term "eHealth" refers to a diverse group of tools that use computerized technologies to improve both the efficacy and the efficiency of the health care industry. eHealth comprises a variety of technologies, as follows: mobile devices (mHealth) in medical care, including electronic diaries, wearable sensors, and adherence monitoring; health informatics (eg, electronic health records, computerized physician order entry, clinical decision support); telemedicine, which is the use of information and communication technologies for the management of diseases and medical education; social media platforms, and the analysis of information acquired through these platforms using "big data" technologies. In this review, we summarize the latest findings on the use of eHealth technology and the relevance of eHealth to allergic conditions.

Effects of Rupatadine on Platelet- Activating Factor-Induced Human Mast Cell Degranulation Compared With Desloratadine and Levocetirizine (The MASPAF Study).

BACKGROUND AND OBJECTIVE: Platelet-activating factor (PAF) is a lipid mediator involved in the pathophysiology of several allergic diseases, for example, in the amplification of mast cell (MC) activation in anaphylaxis. Rupatadine is an antihistamine with a demonstrated anti-PAF effect, although its capacity to inhibit PAF-induced MC degranulation has not been fully evaluated. Objectives: To compare the ability of rupatadine to inhibit PAF-induced MC degranulation with that of desloratadine and levocetirizine and to confirm the dual anti-H1 and anti-PAF activity of rupatadine. METHODS: The human MC line LAD2 and primary MCs (human lung tissue MCs [hLMCs]) were used. MC mediator release was evaluated using the b-hexosaminidase and histamine release assay. The effects of rupatadine (H1 antagonist + PAF receptor antagonist), desloratadine, and levocetirizine (H1 antagonists) on LAD2 and hLMCs were compared. The PAF receptor antagonists WEB2086, BN52021, and CV6209 were also tested. PAF receptor protein expression was evaluated in both LAD2 and hLMCs. RESULTS: CV6209 and rupatadine inhibited PAF-induced MC degranulation in both LAD2 and hLMCs. In LAD2, rupatadine (5 and 10 µM) and levocetirizine (5 µM), but not desloratadine, inhibited PAF-induced b-hexosaminidase release. Rupatadine (1-10 µM), levocetirizine (1-10 µM), and desloratadine (10 µM) inhibited PAF-induced histamine release. Rupatadine at 10 µM had an inhibitory effect on hLMC degranulation, but levocetirizine and desloratadine did not. CONCLUSIONS: This study shows that rupatadine and, to a lesser extent, levocetirizine, but not desloratadine, inhibit PAF-induced degranulation in both LAD2 and hLMCs. These findings support the dual antihistamine and anti-PAF effect of rupatadine in allergic disorders.

Nonsteroidal anti-inflammatory drugs enhance IgE-mediated activation of human basophils in patients with food anaphylaxis dependent on and independent of nonsteroidal anti-inflammatory drugs.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) act as cofactors worsening the allergic reactions induced by food allergens. AIM: The aim of this study was to evaluate the effect of both lysine acetylsalicylate (L-ASA) (non-selective cyclooxygenase (COX) inhibitor) and valdecoxib (selective COX-2 inhibitor) in basophils activated by peach lipid transfer protein (Pru p 3) in patients with food-dependent NSAID-induced anaphylaxis (FDNIA). METHODS: Twenty Pru p 3-allergic patients with FDNIA group, eleven peach anaphylaxis not exacerbated by NSAIDs (no-NSAID group) and 5 healthy volunteers were recruited. Basophil activation (BA) was measured as expression of CD63 (Flow(2) CAST(™) ; Bühlmann(®) ), after stimulation with Pru p 3, both alone and in combination with L-ASA (1.13, 3.38 and 6.78 mm) or valdecoxib (0.87, 7.8 and 31.25 µm). RESULTS: Basophils from no-NSAID group were significantly more reactive and sensitive to Pru p 3 than those from the FDNIA group. In both groups, an increase in BA was observed when basophils were exposed to Pru p 3 and L-ASA. In the FDNIA group, valdecoxib partially terminates the BA induced by Pru p 3, whereas in the no-NSAID group, a dual effect was observed depending on the concentration tested. CONCLUSIONS: This study indicates that subjects with food-induced anaphylaxis differ from FDNIA subjects in the higher reactivity and sensitivity of their basophils to allergen challenge. We have shown a direct effect of NSAIDs on basophils using a human model of FDNIA. Our results also suggest that selective COX2 inhibitors might be a safe alternative. BA test may be a useful tool in the study of the pathogenic mechanism of the cofactor phenomenon.

Mechanisms of Anaphylaxis Beyond IgE.

Anaphylaxis is an acute, life-threatening, multisystem syndrome resulting from the sudden release of mediators derived from mast cells and basophils. Food allergens are the main triggers of anaphylaxis, accounting for 33%-56% of all cases and up to 81% of cases of anaphylaxis in children. Human anaphylaxis is generally thought to be mediated by IgE, with mast cells and basophils as key players, although alternative mechanisms have been proposed. Neutrophils and macrophages have also been implicated in anaphylactic reactions, as have IgG-dependent, complement, and contact system activation. Not all allergic reactions are anaphylactic, and the presence of the so-called accompanying factors (cofactors or augmenting factors) may explain why some conditions lead to anaphylaxis, while in other cases the allergen elicits a milder reaction or is even tolerated. In the presence of these factors, allergic reactions may be induced at lower doses of allergen or become more severe. Cofactors are reported to be relevant in up to 30% of anaphylactic episodes. Nonsteroidal anti-inflammatory drugs and exercise are the best-documented cofactors, although estrogens, angiotensin-converting enzyme inhibitors, ß-blockers, lipid-lowering drugs, and alcohol have also been involved. The mechanisms underlying anaphylaxis are complex and involve several interrelated pathways. Some of these pathways may be key to the development of anaphylaxis, while others may only modulate the severity of the reaction. An understanding of predisposing and augmenting factors could lead to the development of new prophylactic and therapeutic approaches.

Specialist-based treatment reduces the severity of allergic rhinitis.

BACKGROUND: Although the treatment of allergic rhinitis (AR) is now well established, its impact on severity has not yet been evaluated. OBJECTIVE: The aim was to analyse specialist-based treatment on AR severity, nasal symptoms and quality of life. METHODS: A longitudinal observational, prospective, multi-centre study with 4 weeks of follow-up was carried out by 141 allergologists and ENT specialists in Spain. Selection criteria were adult patients with AR, clinically diagnosed at least 2 years before, with a total nasal symptom score (TNSS) ≥5, not receiving either antihistamines within the previous week or nasal corticosteroids during the 2 previous weeks. Disease severity using both original Allergic Rhinitis and its Impact on Asthma (o-ARIA) and modified (m-ARIA) classifications, nasal symptoms, and Quality of Life (ESPRINT-15), were measured at baseline and after 4 weeks of treatment. RESULTS: Among the recruited AR patients (n = 707, 58% women), 39.3% were intermittent and 60.7% persistent, 40.2% had asthma and 61.4% conjunctivitis. Most patients were treated with second generation antihistamines in monotherapy (63.2%) or in combination with intranasal corticosteroids (31.5%). While using o-ARIA, 96.9% of patients had 'moderate/severe' AR, the m-ARIA discriminated between 'moderate' (55.4%) and severe (41.5%) AR, at baseline. After 4 weeks of treatment, improvement was found on disease severity (P < 0.0001), TNSS (8.2 ± 1.8 vs. 3.5 ± 2.3, P < 0.0001) and Quality of Life (ESPRINT-15 global score: 3.0 ± 1.2 vs. 1.1 ± 1.0, P < 0.0001). CONCLUSIONS: Specialist-based treatment reduces AR severity, evaluated using the m-ARIA classification for the first time, in addition to the improvement of nasal symptoms and quality of life. CLINICAL RELEVANCE: Specialist-based treatment improves AR severity, in addition to nasal symptoms and quality of life. However, no matter the treatment option some AR patients remain severe and need further follow-up.

Acoustic rhinometry and aspirin nasal challenge in the diagnosis of aspirin-intolerant asthma: clinical finding and safety aspects.

BACKGROUND: The safety and utility of nasal provocation tests with lysine-aspirin (L-ASA) in the diagnosis of aspirin-intolerant asthma (AIA) have previously been described in a short series of patients. OBJECTIVES: To describe the clinical features and safety of an L-ASA challenge test in patients with AIA. METHODS: We evaluated 72 patients (79% women), with a mean ± SD age of 47.9 ± 14.5 years. All patients were submitted to an L-ASA nasal provocation test (29 mg in each nostril) under acoustic rhinometry (AcR) control. Symptom score (0-3), visual analogical scale and nitric oxide determinations were performed at baseline and at 15, 30, 60 and 90 min. A decrease in nasal volume of at least 25% was considered a positive test. Nasal nitric oxide (nNO) and forced expiratory volume in 1 s were measured. RESULTS: Nasal congestion and rhinorrhea represented 51 and 32%, respectively, of total symptoms. According to AcR data, the L-ASA challenge test was positive in 20% of patients at 15 min, an additional 36% were positive at 30 min, 18% at 60 min, and the remaining 26% at 90 min. nNO nasal values decreased but did not reach statistical significance. No pulmonary or systemic reactions were observed. CONCLUSIONS: Symptoms of nasal congestion associated with the reduction in nasal volume measured by AcR are the most useful parameters for establishing the diagnosis of AIA using the L-ASA nasal challenge. The method is very well tolerated and can be safely used even in patients with severe asthma.