Cofactors in food anaphylaxis in adults.

Around 25% to 50% of food-induced allergic reactions in adults cause anaphylaxis, and epidemiologic evidence suggests that food is the most common cause of anaphylaxis. Reaction severity is unpredictable, and patients will often experience reactions of variable severity, even to an identical exposure (both dose and allergen). A common explanation for this phenomenon has been the impact of "cofactors"-factors that might contribute to reaction severity independent of the allergen exposure. Cofactors can influence reaction severity in 2 ways: either by reducing the reaction threshold (ie, the dose needed to trigger any symptoms) so that patients have no symptoms in the absence of the cofactor and only react with the cofactor present, or by increasing reaction severity such that individuals have only mild symptoms in the absence of the cofactor, but a more severe reaction when the cofactor is present. Indeed, the same patient may have reactions with different cofactors or even need more than one cofactor to develop a severe reaction. Cofactors reportedly play a role in approximately 30% of anaphylaxis reactions in adults. Exercise, nonsteroidal, anti-inflammatory drugs, alcohol, and sleep deprivation are the most frequent cofactors reported. Routine evaluation of the possible involvement of cofactors is essential in managing patients with food anaphylaxis: in patients with a suggestive history but a negative oral food challenge, cofactors should be taken into account to provide appropriate advice to reduce the risk of future anaphylaxis.

Proposal of 0.5 mg of protein/100 g of processed food as threshold for voluntary declaration of food allergen traces in processed food-A first step in an initiative to better inform patients and avoid fatal allergic reactions: A GA²LEN position paper.

BACKGROUND: Food anaphylaxis is commonly elicited by unintentional ingestion of foods containing the allergen above the tolerance threshold level of the individual. While labeling the 14 main allergens used as ingredients in food products is mandatory in the EU, there is no legal definition of declaring potential contaminants. Precautionary allergen labeling such as "may contain traces of" is often used. However, this is unsatisfactory for consumers as they get no information if the contamination is below their personal threshold. In discussions with the food industry and technologists, it was suggested to use a voluntary declaration indicating that all declared contaminants are below a threshold of 0.5 mg protein per 100 g of food. This concentration is known to be below the threshold of most patients, and it can be technically guaranteed in most food production. However, it was also important to assess that in case of accidental ingestion of contaminants below this threshold by highly allergic patients, no fatal anaphylactic reaction could occur. Therefore, we performed a systematic review to assess whether a fatal reaction to 5mg of protein or less has been reported, assuming that a maximum portion size of 1kg of a processed food exceeds any meal and thus gives a sufficient safety margin. METHODS: MEDLINE and EMBASE were searched until 24 January 2021 for provocation studies and case reports in which one of the 14 major food allergens was reported to elicit fatal or life-threatening anaphylactic reactions and assessed if these occurred below the ingestion of 5mg of protein. A Delphi process was performed to obtain an expert consensus on the results. RESULTS: In the 210 studies included, in our search, no reports of fatal anaphylactic reactions reported below 5 mg protein ingested were identified. However, in provocation studies and case reports, severe reactions below 5 mg were reported for the following allergens: eggs, fish, lupin, milk, nuts, peanuts, soy, and sesame seeds. CONCLUSION: Based on the literature studied for this review, it can be stated that cross-contamination of the 14 major food allergens below 0.5 mg/100 g is likely not to endanger most food allergic patients when a standard portion of food is consumed. We propose to use the statement "this product contains the named allergens in the list of ingredients, it may contain traces of other contaminations (to be named, e.g. nut) at concentrations less than 0.5 mg per 100 g of this product" for a voluntary declaration on processed food packages. This level of avoidance of cross-contaminations can be achieved technically for most processed foods, and the statement would be a clear and helpful message to the consumers. However, it is clearly acknowledged that a voluntary declaration is only a first step to a legally binding solution. For this, further research on threshold levels is encouraged.

Detection of Wheat Lipid Transfer Protein (Tri a 14) Sensitization: Comparison between Currently Available Diagnostic Tools.

BACKGROUND: Wheat lipid transfer protein (LTP; Tri a 14) and ω5-gliadin have been described as major allergens in wheat allergy (WA) and relevant in wheat-induced anaphylaxis, frequently associated with cofactors. OBJECTIVE: The objective of this study was to compare tools currently available in routine diagnosis to detect Tri a 14 sensitization, its clinical relevance, and cosensitization to ω5-gliadin and other LTPs. METHODS: One hundred eighteen adults sensitized to rTri a 14 by ImmunoCAP® (cutoff ≥0.1 kUA/L) identified among 210 LTP allergic patients were included. We evaluated (1) wheat skin prick test (SPT), (2) specific IgE (sIgE) to wheat, rTri a 14, rTri a 19, peach, apple, walnut, hazelnut, and peanut LTPs using ImmunoCAP® and microarray ImmunoCAP®ISAC (cutoff ≥0.3I SU), and (3) wheat-related symptoms. RESULTS: Wheat SPT and sIgE were positive in 31% and 85% of subjects, respectively. rTri a 14 by microarray was detected in 25%. Eight percent showed cosensitization to ω5-gliadin. Thirty percent referred symptoms (gastrointestinal [13%], urticaria [11%], and anaphylaxis [8%]). Cofactors (45%) were significantly associated with systemic reactions. CONCLUSION: WA due to Tri a 14 is frequently related with systemic reactions and because are frequently related to cofactors, the culprit may not be suspected. Together with the poor performance to identify Tri a 14 sensitization of the current routine diagnostic tools based on the analysis of whole wheat extract, such as wheat SPT or sIgE, there is a high risk that WA may be overlooked. Thus, when WA is suspected, sIgE Tri a 14 assessment is recommended, together with wheat and ω5-gliadin, preferably in the singleplex format, and carefully evaluated considering ≥0.1 kUA/L as a cutoff.

Validation of a commercial allergen microarray platform for specific immunoglobulin E detection of respiratory and plant food allergens.

BACKGROUND: As the use of multiplex-specific immunoglobulin E (sIgE) detection methods becomes increasingly widespread, proper comparative validation assessments of emerging new platforms are vital. OBJECTIVE: To evaluate the clinical and technical performance of a newly introduced microarray platform, Allergy Explorer (ALEX) (MacroArray Diagnostics), in the diagnosis of pollen (cypress, grass, olive), dust mite (Dermatophagoides pteronyssinus), mold (Alternaria alternata), fruit (apple, peach), and nut (walnut, hazelnut and peanut) allergies and to compare it with those of the ImmunoCAP Immuno Solid-phase Allergen Chip (ISAC) 112 microarray and the ImmunoCAP singleplex method (ThermoFisher Scientific). METHODS: We enrolled 153 patients with allergy and 16 controls without atopy. The sIgE assays were conducted using ISAC112, ALEX version 2 (ALEX2), and ImmunoCAP for whole extracts and major components. Technical validation of ALEX2 was performed by measuring repeatability and interassay, interbatch, and interlaboratory reproducibility. RESULTS: When measured globally (detection by 1 or more allergen components), ALEX2 had adequate sensitivity and specificity for most of the allergens studied, comparable in general with that of ISAC112 (except for olive pollen and walnut) and similar to that of ImmunoCAP whole extract measurements. Component-by-component analysis revealed comparable results for all techniques, except for Ole e 1 and Jug r 3, in both ISAC112 and ImmunoCAP comparisons, and Alt a 1, when compared with ISAC112. Continuous sIgE levels correlate with sIgE by ImmunoCAP. Good reproducibility and repeatability were observed for ALEX2. CONCLUSION: ALEX2 has sound technical performance and adequate diagnostic capacity, comparable in general with that of ISAC112 and ImmunoCAP.

Evaluation of desensitization protocols to betalactam antibiotics.

WHAT IS KNOWN AND OBJECTIVE: Betalactam antibiotics are the most frequent cause of hypersensitivity reactions. Rapid drug desensitization (RDD) is a technique that induces temporary tolerance to a drug allowing a patient to receive the optimal agent. The increased use of RDD and the lack of standardization among available protocols in terms of formulation, starting dose, number of steps and dosing frequency make it essential to determine the safety and appropriate management of these protocols, especially regarding reconstitution, diluents, stability and drug administration in order to guarantee reproducibility. We reviewed betalactam desensitization protocols in a tertiary hospital, in accordance with currently published practices and evaluated its use on patients over a period of three years. METHODS: (a) We performed a literature search in PubMed, MEDLINE and Google Scholar databases for case reports and/or systematic reviews describing desensitization protocols for betalactam antibiotics. Pharmacokinetic parameters and physicochemical stability were checked for each antibiotic. (b) We retrospectively reviewed inpatients undergoing our antibiotic desensitization protocols from February 2018 to January 2021. Data and outcomes of desensitization procedures were analysed. RESULTS: We developed nine RDD protocols: meropenem, ceftriaxone, ceftazidime, ampicillin, ceftolozane/tazobactam, cloxacillin, piperacillin/tazobactam, amoxicillin/clavulanate and penicillin G sodium. Five antibiotics have RDD protocols for two different doses, adjusted to patients with impaired renal function. Detailed data (diluent, total dose, volume, concentrations, duration and stability) of the protocol of each antibiotic used are provided. 28 desensitizations were performed in 17 patients, three of them with confirmed allergies by skin test. 26 out of 28 (92.9%) of them were successfully completed, including those three with positive skin results. The pathogens most frequently involved were E. faecalis and P. aeruginosa; both frequently associated with bacterial resistance. Meropenem, ceftriaxone and ceftazidime were the antibiotics most desensitized. 25 out of 26 (96.1%) procedures were successful in resolving the infection. WHAT IS NEW AND CONCLUSIONS: Detailed information about compounding, dilution and stability is crucial to ensure safe and successful desensitization processes, as well as good coordination between the Allergy and Pharmacy departments. The increase in bacterial resistance to many of the commercially available antibiotics limits the therapeutic options for treating multidrug-resistant infections; in those situations, antibiotic desensitization may be a key therapeutic option. Although there is a broad consensus in limiting the use of RDD to patients with confirmed allergy, in usual clinical practice its application in those strongly suspected of having type I hypersensitivity is still observed. Our betalactam desensitization protocols have shown themselves to be safe and effective, as evidenced by data from the 17 patients on whom they have been tested.

Use of multiple epinephrine doses in anaphylaxis: A systematic review and meta-analysis.

BACKGROUND: Regulatory bodies recommend that all patients at risk of anaphylaxis be prescribed 2 epinephrine autoinjectors, which they should carry at all times. This is in contrast to some guidelines. The proportion of anaphylaxis reactions that are treated with multiple doses of epinephrine has not been systematically evaluated. OBJECTIVE: Our aim was to undertake a systematic review and meta-analysis of published studies reporting epinephrine treatment for anaphylaxis in which data relating to the number of doses administered were available. METHODS: We searched the Medline, Embase, and Cochrane databases for relevant studies reporting at least 10 anaphylaxis events (due to food or venom) from 1946 until January 2020. Data were extracted in duplicate for the meta-analysis, and the risk of bias was assessed. The study was registered under the PROSPERO identifier CRD42017069109. RESULTS: A total of 86 studies (36,557 anaphylaxis events) met the inclusion criteria (20 of the studies [23%] were prospective studies; 64 [74%] reported reactions in the community, and 22 [26%] included food challenge data). Risk of bias was assessed as low in 50 studies. Overall, 7.7% of anaphylaxis events from any cause (95% CI = 6.4-9.1) were treated with multiple doses of epinephrine. When only epinephrine-treated reactions for which subsequent doses were administered by a health care professional were considered, 11.1% of food-induced reactions (95% CI = 9.4-13.2) and 17.1% of venom-induced reactions (95% CI = 11.3-25.0) were treated with more than 1 epinephrine dose. Heterogeneity was moderate to high in the meta-analyses, but at sensitivity analysis this estimate was not affected by study design or anaphylaxis definition. CONCLUSION: Around 1 in 10 anaphylaxis reactions are treated with more than 1 dose of epinephrine.

Cardiovascular changes during peanut-induced allergic reactions in human subjects.

BACKGROUND: Food allergy is the most common cause of anaphylaxis. Changes in posture during acute reactions can trigger fatal outcomes, but the impact of allergic reactions on the cardiovascular system in nonfatal reactions remains poorly understood. OBJECTIVE: Our aim was to systematically evaluate changes in cardiovascular function during acute allergic reactions to peanut. METHODS: Participants underwent double-blind placebo-controlled food challenge to peanut as part of a clinical trial. Changes in hemodynamic parameters (heart rate, stroke volume, blood pressure, and peripheral blood flow) and electrocardiogram findings during food challenges were assessed using noninvasive continuous monitoring. RESULTS: A total of 57 adults (median age 24 years [interquartile range = 20-29]), 53% of whom were female, participated; 22 (39%) had anaphylaxis. Acute reactions were associated with significant changes in stroke volume (mean decrease of 4.2% [95% CI = 0.8-7.6; P = .03]), heart rate (mean increase 11.6% [95% CI = 8.4-14.8; P < .0001]), and peripheral blood flow (mean increase 19.7% [95% CI = 10.8-28.6; P < .0001]), irrespective of reaction severity. These changes were reproduced at a subsequent repeat peanut challenge in 26 participants, and could be reversed with administration of intravenous fluids which resulted in faster resolution of abdominal symptoms. CONCLUSIONS: In this first detailed human study of cardiovascular changes during food-induced allergic reactions, we found evidence for significant fluid redistribution, independent of reaction severity. This provides a sound rationale for optimizing venous return during significant allergic reactions to food. Finally, these data provide a new paradigm for understanding severity in anaphylaxis, in which poor outcomes may occur as a result of a failure in compensatory mechanisms.

Basophil Activation Test Utility as a Diagnostic Tool in LTP Allergy.

Plant-food allergy is an increasing problem, with nonspecific lipid transfer proteins (nsLTPs) triggering mild/severe reactions. Pru p 3 is the major sensitizer in LTP food allergy (FA). However, in vivo and in vitro diagnosis is hampered by the need for differentiating between asymptomatic sensitization and allergy with clinical relevance. The basophil activation test (BAT) is an ex vivo method able to identify specific IgE related to the allergic response. Thus, we aimed to establish the value of BAT in a precise diagnosis of LTP-allergic patients. Ninety-two individuals with peach allergy sensitized to LTP, Pru p 3, were finally included, and 40.2% of them had symptoms to peanut (n = 37). In addition, 16 healthy subjects were recruited. BAT was performed with Pru p 3 and Ara h 9 (peanut LTP) at seven ten-fold concentrations, and was evaluated by flow cytometry, measuring the percentage of CD63 (%CD63+) and CD203c (%CD203chigh) cells, basophil allergen threshold sensitivity (CD-Sens), and area under the dose−response curve (AUC). Significant changes in BAT parameters (%CD63+ and %CD203chigh) were found between the controls and patients. However, comparisons for %CD63+, %CD203chigh, AUC, and CD-Sens showed similar levels among patients with different symptoms. An optimal cut-off was established from ROC curves, showing a significant positive percentage of BAT in patients compared to controls and great values of sensitivity (>87.5%) and specificity (>85%). In addition, BAT showed differences in LTP-allergic patients tolerant to peanut using its corresponding LTP, Ara h 9. BAT can be used as a potential diagnostic tool for identifying LTP allergy and for differentiating peanut tolerance, although neither reactivity nor sensitivity can distinguish the severity of the clinical symptoms.

Food-dependent NSAID-induced hypersensitivity (FDNIH) reactions: Unraveling the clinical features and risk factors.

BACKGROUND: In up to 70%-80% of patients with a suspected non-steroidal anti-inflammatory drug hypersensitivity (NSAIDH), challenge tests with the culprit drug yield negative results. On the other hand, there could be a NSAIDH overdiagnosis when anaphylaxis is the clinical manifestation. We hypothesize that some negative NSAID challenge tests and an overdiagnosis of NSAIDH occur in patients with food-dependent NSAID-induced hypersensitivity (FDNIH). METHODS: We studied 328 patients with a suspected acute NSAIDH. FDNIH was diagnosed in patients meeting all the following: (1) tolerance to the food ingested more temporally closed before the reaction, later the episode, (2) respiratory or cutaneous symptoms or anaphylaxis related to NSAID, (3) positive skin prick test to foods and/or specific IgE to food allergens (Pru p 3, Tri a 19, Pen a 1) involved in the reaction, and (4) negative oral provocation test to the culprit NSAID. RESULTS: 199 patients (60%) were diagnosed with NSAIDH and 52 (16%) with FDNIH. Pru p 3 was involved in 44 cases (84.6%) and Tri a 19 in 6 cases (11%). FDNIH subjects were younger (p < .001), with a higher prevalence of rhinitis (p < .001) and previous food allergy (p < .001), together with a higher proportion of subjects sensitized to pollens (p < .001) and foods (p < .001). Using just four variables (Pru p 3 sensitization, Tri a 19 sensitization, anaphylaxis, and any NSAID different from pyrazolones), 95.3% of cases were correctly classified, with a sensitivity of 92% and specificity of 96%. CONCLUSION: Evaluation of FDNIH should be included in the diagnostic workup of NSAIDH.

The diagnosis and management of allergic reactions in patients sensitized to non-specific lipid transfer proteins.

Sensitization to one or more non-specific lipid transfer proteins (nsLTPs), initially thought to exist mainly in southern Europe, is becoming accepted as a cause of allergic reactions to plant foods across Europe and beyond. The peach nsLTP allergen Pru p 3 is a dominant sensitizing allergen and peaches a common food trigger, although multiple foods can be involved. A frequent feature of reactions is the requirement for a cofactor (exercise, alcohol, non-steroidal anti-inflammatory drugs, Cannabis sativa) to be present for a food to elicit a reaction. The variability in the food and cofactor triggers makes it essential to include an allergy-focused diet and clinical history in the diagnostic workup. Testing on suspected food triggers should also establish whether sensitization to nsLTP is present, using purified or recombinant nsLTP allergens such as Pru p 3. The avoidance of known trigger foods and advice on cofactors is currently the main management for this condition. Studies on immunotherapy are promising, but it is unknown whether such treatments will be useful in populations where Pru p 3 is not the primary sensitizing allergen. Future research should focus on the mechanisms of cofactors, improving diagnostic accuracy and establishing the efficacy of immunotherapy.

Oral immunotherapy in severe cow's milk allergic patients treated with omalizumab: Real life survey from a Spanish registry.

BACKGROUND: Oral immunotherapy is a frequent treatment for the management of food allergies, but adverse events (AE) are common. This study assessed the outcome of cow's milk oral immunotherapy (MOIT) in severe cow`s milk-allergic patients treated with omalizumab in a real-life setting. METHODS: OmaBASE was a national, multicenter, open, and observational registry that collected clinical, immunologic, and treatment from patients with food allergy receiving omalizumab. RESULTS: Data derived from 58 patients aged 10.3 years (IQR 6.3-13.2) and median milk-specific IgE 100 kUA /L at the start of omalizumab treatment. Most had experienced anaphylaxis by accidental exposures (70.7%) and had asthma (81.0%). Omalizumab in monotherapy induced tolerance to ≥6000 mg of cow's milk protein (CMP) to 34.8% of patients tested by oral food challenge. Omalizumab combined with MOIT conferred desensitization to ≥6000 mg of CMP to 83.0% of patients. Omalizumab withdrawal triggered more AE (P = .013) and anaphylaxis (P = .001) than no discontinuation. Anaphylaxis was observed in 36.4% of patients who discontinued omalizumab, and more in those with sudden (50.0%) rather than progressive (12.5%) discontinuation. At database closure, 40.5% of patients who had completed follow-up tolerated CMP without omalizumab (7.2% 1500-4500 mg; 33.3% ≥6000 mg). CONCLUSION: Milk oral immunotherapy initiated under omalizumab allows the desensitization of subjects with severe cow's milk allergy even after omalizumab discontinuation. However, discontinuation of omalizumab can lead to severe AE and should be carefully monitored.

Phenotyping peach-allergic patients sensitized to lipid transfer protein and analysing severity biomarkers.

BACKGROUND: Patients with peach allergy due to nsLTP sensitization constitute a heterogeneous group in terms of sensitization profile and severity. This could be due to the presence of additional allergies to pollens. The aim of this study was to analyse the clinical characteristics, sensitization profile and severity of reactions in peach-allergic patients sensitized to nsLTP from two Mediterranean areas with different pollen exposure. METHODS: Patients with diagnosis of LTP allergy from the Allergy Unit of Hospital Regional Universitario de Malaga (HRUM) and Hospital Clinic de Barcelona (HCB) were prospectively included and classified into two groups; (a) LTP-monoallergic: those that presented reaction only with peach and (b) LTP-Allergy: those that presented reaction with peach and at least another plant-food containing LTP. RESULTS: A total of 252 patients were included, 235 (93.2%) had LTP-syndrome and 17 (6.8%) were LTP-monoallergic. We found a higher percentage of anaphylaxis and delayed onset of symptoms in the LTP-monoallergic group (P = .02 and P = .04, respectively). Moreover, anaphylaxis was less frequent in patients with profilin sensitization (P = .03). The comparison of patients' data from HRUM with data from HCB showed differences in sensitization to olive tree pollen and profilin (P = .01 and P = .001, respectively). CONCLUSION: This study was undertaken to characterize two large group of subjects from to two regions with differing exposures to pollen. We found that more than 90% of peach-allergic patients in both populations evolved to LTP-Allergy and showed an early onset. Profilin sensitization could be more useful as a severity biomarker than the number of nsLTP, aeroallergen sensitizations or sIgE levels. This could provide clues regarding sensitization and severity patterns that might be relevant in other geographical areas.

Progress in understanding hypersensitivity reactions to nonsteroidal anti-inflammatory drugs.

Nonsteroidal anti-inflammatory drugs (NSAIDs), the medications most commonly used for treating pain and inflammation, are the main triggers of drug hypersensitivity reactions. The latest classification of NSAIDs hypersensitivity by the European Academy of Allergy and Clinical Immunology (EAACI) differentiates between cross-hypersensitivity reactions (CRs), associated with COX-1 inhibition, and selective reactions, associated with immunological mechanisms. Three phenotypes fill into the first group: NSAIDs-exacerbated respiratory disease, NSAIDs-exacerbated cutaneous disease and NSAIDs-induced urticaria/angioedema. Two phenotypes fill into the second one: single-NSAID-induced urticaria/angioedema/anaphylaxis and single-NSAID-induced delayed reactions. Diagnosis of NSAIDs hypersensitivity is hampered by different factors, including the lack of validated in vitro biomarkers and the uselessness of skin tests. The advances achieved over recent years recommend a re-evaluation of the EAACI classification, as it does not consider other phenotypes such as blended reactions (coexistence of cutaneous and respiratory symptoms) or food-dependent NSAID-induced anaphylaxis. In addition, it does not regard the natural evolution of phenotypes and their potential interconversion, the development of tolerance over time or the role of atopy. Here, we address these topics. A state of the art on the underlying mechanisms and on the approaches for biomarkers discovery is also provided, including genetic studies and available information on transcriptomics and metabolomics.

Performance of basophil activation test and specific IgG4 as diagnostic tools in nonspecific lipid transfer protein allergy: Antwerp-Barcelona comparison.

BACKGROUND: Recent studies show that nsLTP sensitization is not limited to the Mediterranean basin and can present diverse clinical phenotypes. It remains challenging to predict clinical outcome when specific IgE antibodies (sIgE) to nsLTPs are present. This study compares both clinical and in vitro allergy characteristics but also diagnostic performance of a basophil activation test (BAT) and sIgG4 in nsLTP-sensitized patients from Antwerp (ANT, Belgium) and Barcelona (BCN, Spain). METHODS: Adult subjects with positive sIgE rPru p 3 and/or rMal d 3 ≥ 0.10 kUA /L (n = 182) and healthy controls (n = 37) were included. NsLTP-sensitized individuals were stratified according to clinical symptoms with peach/apple, respectively. BAT rPru p 3 and rMal d 3 were performed and sIgG4 antibodies to both components quantified. RESULTS: In BCN, only ratios of sIgG4/sIgE rMal d 3 and BAT rMal d 3 (0.001 µg/mL) can identify clinically relevant Mal d 3 sensitization (sensitivity of 60%-63% and a specificity of 75%-67%, respectively). In ANT, only the sIgE/total IgE rPru p 3 ratio shows added value (sensitivity 60% and specificity 83%). Finally, it appears that symptomatic patients in BCN are more sensitive to lower allergen concentrations compared to ANT. In addition, it was shown that ANT patients were more often sensitized to pollen and that specific pollen sources differed between regions. CONCLUSIONS: NsLTP-related allergy profiles and diagnostic performance differ significantly between regions and are component-specific, which makes extrapolation of data difficult to do. In addition, it seems that basophil sensitivity might show geographical differences. Additional research is needed to confirm these findings.

Polymorphisms in CEP68 gene associated with risk of immediate selective reactions to non-steroidal anti-inflammatory drugs.

Non-steroidal anti-inflammatory drugs (NSAIDs) are the main triggers of drug hypersensitivity reactions. Such reactions can be pharmacologically or immunologically mediated, but in both cases individual susceptibility can be influenced by genetic factors. Polymorphisms in centrosomal protein of 68 kDa (CEP68) have been associated with pharmacologically mediated NSAIDs reactions. Here, we evaluated this gene in immunologically mediated single-NSAID-induced urticaria/angioedema or anaphylaxis (SNIUAA) by analyzing 52 single nucleotide polymorphisms in CEP68 in 176 patients and 363 NSAIDs-tolerant controls. Two intronic variants (rs2241160 and rs2241161) were significantly associated with an increased risk of SNIUAA, suggesting CEP68 to be a key player in both types of NSAIDs hypersensitivity. However, we found no overlap with genetic variants previously associated with pharmacologically mediated hypersensitivity, pointing to a complex role for this gene and its potential use in the development of biomarkers of clinical utility to diagnose patients at risk of these reactions and to differentiate entities.

Eicosanoid mediator profiles in different phenotypes of nonsteroidal anti-inflammatory drug-induced urticaria.

BACKGROUND: The role of arachidonic acid metabolites in NSAID-induced hypersensitivity has been studied in depth for NSAID-exacerbated respiratory disease (NERD) and NSAID-exacerbated cutaneous disease (NECD). However, no information is available for NSAID-induced urticarial/angioedema (NIUA), despite it being the most frequent clinical entity induced by NSAID hypersensitivity. We evaluated changes in leukotriene and prostaglandin metabolites for NIUA patients, using patients with NECD and single-NSAID-induced urticaria/angioedema or anaphylaxis (SNIUAA) for comparison. METHODS: Urine samples were taken from patients with confirmed NSAID-induced urticaria and healthy controls, at baseline and at various time intervals after ASA administration. Eicosanoid measurement was performed using high-performance liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry. RESULTS: No differences were found between groups at baseline. Following ASA administration, LTE4 and 9α,11ß-PGF2 levels were increased in both NIUA and NECD patients compared to baseline, rising initially, before decreasing toward initial levels. In addition, the levels of these metabolites were higher in NIUA and NECD when compared with the SNIUAA and control groups after ASA administration. No changes were found with respect to baseline values for SNIUAA and control groups. CONCLUSIONS: We present for the first time data regarding the role of COX-1 inhibition in NIUA. Patients with this entity show a similar pattern eicosanoid levels following ASA challenge to those with NECD. Further studies will help ascertain the cell populations involved and the underlying molecular mechanisms.

Psychometric properties of the Spanish version of the once-daily Urticaria Activity Score (UAS) in patients with chronic spontaneous urticaria managed in clinical practice (the EVALUAS study).

BACKGROUND: The daily diary Urticaria Activity Score (UAS) and its weekly score (UAS7) are widely used to assess signs and symptoms in patients with chronic spontaneous urticaria (CSU). The objective of this study was to assess the psychometric properties of a Spanish version of the once-daily UAS. METHODS: Observational study in patients ≥18 years old receiving usual care for CSU (daily or almost daily occurrence of generalized hives or angioedema for ≥6 weeks). Patients were included consecutively and completed the UAS, EQ-5D, and the Chronic Urticaria Quality of Life scale (CU-Q2oL) at two study visits 6 weeks apart. On each occasion, the UAS was completed once-daily for 7 consecutive days to be able to calculate the UAS7 score. Psychometric properties of reliability, construct validity, and responsiveness were assessed. The Minimal Important Difference (MID) was estimated for the UAS7 using anchor- and distribution-based approaches. RESULTS: Data from 166 patients was available for analysis (mean age 49 years, 65.7% female). Floor (5.4% of patients with the lowest possible score) and ceiling (1.2%) effects were low; 15% of patients had missing values. Internal consistency and test-retest reliability were good (Cronbach's alpha of 0.83 and an ICC of 0.84, respectively). Convergent validity was demonstrated through the pattern of correlations with the EQ-5D and CU-Q2oL and known groups' validity was demonstrated by the instrument's ability to discriminate between patients with different overall levels of urticaria severity, with between-group effect-sizes (ES) ranging from 0.36 to 1.19. The UAS7 proved responsive to change with effect sizes ranging from 0.3 to 1.52 in patients reporting improvement or deterioration in overall urticaria status. The MID for the UAS7 score was estimated at 7-8 points, on a scale of 0-42. CONCLUSIONS: The Spanish version of the UAS score has demonstrated a robust psychometric performance in patients with CSU managed in conditions of usual care. It can therefore be considered a suitable instrument to assess disease activity in clinical practice in Spanish-speaking patients. The Spanish version's reliability and validity are similar to those reported for other language versions of the once- and twice-daily variants of the UAS.

Follow-up of patients with uncontrolled asthma: clinical features of asthma patients according to the level of control achieved (the COAS study).

Our aim was to study the asthma control achieved in patients with uncontrolled asthma who had received appropriate treatment according to the Global Initiative for Asthma (GINA) 2010 (valid at the time the study was designed), and to analyse the factors associated with a lack of asthma control.This was a multicentre study in routine clinical practice performed in patients with uncontrolled asthma according to GINA 2010. At visit 1, we recorded demographics, asthma characteristics and spirometry. We assessed asthma control using GINA 2010 criteria and the Asthma Control Test (ACT). Treatment was optimised according to GINA 2010. At visit 2, 3 months later, we reassessed spirometry, asthma control and factors associated with failure to achieve control.We recruited 1299 patients with uncontrolled asthma (mean age 46.5±17.3 years, 60.7% women, 25.8% obese). The mean percentage of predicted forced expiratory volume in 1 s was 76.4±12.8% and the mean post-bronchodilator increase was 14.9±6.8%. We observed poor agreement between ACT and GINA 2010 when evaluating asthma control (kappa = -0.151). At visit 2, asthma in 71.2% of patients was still not fully controlled. Patients whose asthma remained uncontrolled were older, had a higher body mass index, greater disease severity, longer disease evolution and worse lung function.After treatment optimisation, most patients did not achieve optimal control according to GINA 2010. Risk factors for failure to achieve asthma control were time of disease evolution, severity, age, weight and lung function impairment (excluded in the GINA 2014).