Allergic Adverse Drug Events After Alert Overrides in Hospitalized Patients.

OBJECTIVES: This study aimed to assess how often overridden drug allergy alerts (ODAAs) lead to allergic adverse drug events (All-ADEs) and to evaluate the frequency with which drug allergy alerts (DAAs) were overridden and the reasons, as well as appropriateness of these overrides. METHODS: A retrospective observational study of DAA generated between 2014 and 2016 was conducted. The corresponding DAA records were reviewed to determine the frequency of alert overrides. A chart review was performed on a subset of 194 ODAA (the first of every 3 chronologically ordered ODAA) to identify All-ADEs and to evaluate the override reasons and the appropriateness of these overrides. RESULTS: A total of 2044 DAAs were overridden (override rate of 44.8%). Most were triggered by a nonexact match (93.81%), when ordering nervous system (21.1%) and cardiovascular system (19.6%) drugs and were generated by physicians (72.7%). The main override reason was that the patient was already taking the drug or had previously tolerated the drug. Only 9.28% of ODAAs were inappropriately overridden. Six All-ADEs (3.09%) were identified and were due to anti-infective (1), antineoplastic (1), and iodinated-contrast (4) drug administration. Most All-ADEs were cutaneous and were mild. None was life-threatening or fatal. The All-ADEs rate was higher among inappropriately ODAA (15.79%, P = 0.013). CONCLUSIONS: Alert overrides are not exempt from clinical consequences, although few are associated with All-ADEs. It is necessary to identify the drugs involved in those reactions and to update allergy lists to generate only specific and important DAA and to avoid the negative consequences of overrides.

A systematic review of drug allergy alert systems.

BACKGROUND AND OBJECTIVE: Drug allergy alert systems (DAAS), have been considered an effective strategy to reduce preventable adverse drug events (ADEs), improving patient's safety. To date, no review has been conducted analyzing characteristics of DAAS in the hospital setting. Therefore, the aim of this study is to identify, describe and summarize the DAAS used in hospitals. The secondary objectives are to analyse drug allergy alerts (DAA) characteristics, the override rate (OvR) and the clinical consequences of alert overrides. METHODS: Searches were conducted in Medline and Cochrane Library to identify studies describing DAAS. Systems characteristics, generated alerts, DAA, OvR, and its clinical consequences were extracted and analyzed. RESULTS: Twenty-eight articles were included in the review. Seventeen different electronic DAAS were identified, of which 53% were commercially available. Systems differed in drug allergy information and rules for generating alerts. DAA were generally interruptive, triggered by non-exact match at drug prescribing and when ignored, an override reason was mandatory. The OvR ranged from 43.7% to 97%. The main override reason given by providers was that 'patient had previously tolerated or had taken the drug without allergic reaction'. Clinical consequences of overriding DAA were only analyzed in four studies, with an ADE incidence between 0% and 6%. CONCLUSIONS: Different DAAS are used in hospitals with some degree of heterogeneity. Accurate and updated drug allergy information is important to generate only high value alerts. A regular review of DAAS and a standardization of alert rules, alert information and override reasons are necessary to optimize systems. Future studies should evaluate the impact of the DAAS aspects on preventing ADEs.

SARS-CoV-2 vaccine excipients polyethylene glycol and trometamol do not induce mast cell degranulation, in an in vitro model for non-IgE-mediated hypersensitivity.

The development of vaccines against SARS-CoV2 brought about several challenges, including the management of hypersensitivity reactions to these formulations. The search for underlying mechanisms involved in these adverse events initially focused on excipients which may trigger mast cell activation responses via non-IgE pathways: polyethylene glycol and trometamol. We sought to determine whether these components, in their pure form, were capable of stimulating mast cells directly. To test this hypothesis, we used an in vitro model for non-IgE-mediated activation that has previously shown degranulation responses induced via MRGPRX2 with known drug agonists of the receptor. Human LAD2 mast cells were incubated with different concentrations (1, 10, 50 mg/ml) of trometamol and of purified polyethylene glycol/Macrogol (molecular weights: 2,000, 3,350, 4,000, and 6,000). Mast cell degranulation was assessed using a beta-hexosaminidase read-out. Interestingly, degranulation responses for all reagents tested showed no significant differences from those obtained from the negative control (basal degranulation). Receptor-silencing assays were therefore not conducted. In summary, purified PEG and trometamol did not induce mast cell degranulation in this in vitro model for the study of non-IgE mechanisms of drug hypersensitivity, previously shown to be useful in the investigation of MRGPRX2 ligands. Studies using complete vaccine formulations, lipid conjugates, and receptor gene variants are needed to further clarify mechanisms of vaccine hypersensitivity.

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.

Validation of novel recipes for masking peanuts in double-blind, placebo-controlled food challenges.

BACKGROUND: Double-blind, placebo-controlled oral food challenges are the gold standard in food allergy diagnosis. Nevertheless, proper masking of peanuts is particularly complex owing to their intense flavor and odor. Thus, it is important to use validated recipes to ensure their adequate masking during oral food challenges. OBJECTIVE: To design and validate recipes containing masked peanuts for double-blind, placebo-controlled oral food challenges. METHODS: Two types of products (cookies and a custard­type dessert) containing the masked peanuts and other ingredients with low allergenic potential were designed and validated. For this purpose, of the 24 initial cookie recipes and 12 initial custard recipes developed, those that did not exhibit significant differences in their texture were selected for sensory validation. RESULTS: Similarity triangle tests were performed using a panel of 36 selected tasters, enabling the validation of 1 pair of cookie recipes and 1 pair of custard-type dessert recipe, both with low allergenic potential and suitable for those with celiac disease and for vegans. CONCLUSION: The validated recipes are of clinical and research interest because they allow to confirm a peanut allergy and detect a wide range of tolerated threshold doses, which makes it possible to provide specific indications for each patient.

MYO1F Regulates IgE and MRGPRX2-Dependent Mast Cell Exocytosis.

The activation and degranulation of mast cells is critical in the pathogenesis of allergic inflammation and modulation of inflammation. Recently, we demonstrated that the unconventional long-tailed myosin, MYO1F, localizes with cortical F-actin and mediates adhesion and migration of mast cells. In this study, we show that knockdown of MYO1F by short hairpin RNA reduces human mast cell degranulation induced by both IgE crosslinking and by stimulation of the Mas-related G protein-coupled receptor X2 (MRGPRX2), which has been associated with allergic and pseudoallergic drug reactions, respectively. Defective degranulation was accompanied by a reduced reassembly of the cortical actin ring after activation but reversed by inhibition of actin polymerization. Our data show that MYO1F is required for full Cdc42 GTPase activation, a critical step in exocytosis. Furthermore, MYO1F knockdown resulted in less granule localization in the cell membrane and fewer fissioned mitochondria along with deficient mitochondria translocation to exocytic sites. Consistent with that, AKT and DRP1 phosphorylation are diminished in MYO1F knockdown cells. Altogether, our data point to MYO1F as an important regulator of mast cell degranulation by contributing to the dynamics of the cortical actin ring and the distribution of both the secretory granules and mitochondria.

The Multifaceted Mas-Related G Protein-Coupled Receptor Member X2 in Allergic Diseases and Beyond.

Recent research on mast cell biology has turned its focus on MRGPRX2, a new member of the Mas-related G protein-coupled subfamily of receptors (Mrgprs), originally described in nociceptive neurons of the dorsal root ganglia. MRGPRX2, a member of this group, is present not only in neurons but also in mast cells (MCs), specifically, and potentially in other cells of the immune system, such as basophils and eosinophils. As emerging new functions for this receptor are studied, a variety of both natural and pharmacologic ligands are being uncovered, linked to the ability to induce receptor-mediated MC activation and degranulation. The diversity of these ligands, characterized in their human, mice, or rat homologues, seems to match that of the receptor's interactions. Natural ligands include host defense peptides, basic molecules, and key neuropeptides such as substance P and vasointestinal peptide (known for their role in the transmission of pain and itch) as well as eosinophil granule-derived proteins. Exogenous ligands include MC secretagogues such as compound 48/80 and mastoparan, a component of bee wasp venom, and several peptidergic drugs, among which are members of the quinolone family, neuromuscular blocking agents, morphine, and vancomycin. These discoveries shed light on its capacity as a multifaceted participant in naturally occurring responses within immunity and neural stimulus perception, as in responses at the center of immune pathology. In host defense, the mice Mrgprb2 has been proven to aid mast cells in the detection of peptidic molecules from bacteria and in the release of peptides with antimicrobial activities and other immune mediators. There are several potential actions described for it in tissue homeostasis and repair. In the realm of pathologic response, there is evidence to suggest that this receptor is also involved in chronic inflammation. Furthermore, MRGPRX2 has been linked to the pathophysiology of non-IgE-mediated immediate hypersensitivity drug reactions. Different studies have shown its possible role in other allergic diseases as well, such as asthma, atopic dermatitis, contact dermatitis, and chronic spontaneous urticaria. In this review, we sought to cover its function in physiologic processes and responses, as well as in allergic and nonallergic immune disease.

Quality of Life in Patients with Allergic Reactions to Medications: Influence of a Drug Allergy Evaluation.

BACKGROUND: Suspicion of allergic drug reaction can cause important disturbances in the patient's life. OBJECTIVE: We evaluated in a prospective multicenter study the quality of life of patients who suffered a possible allergic drug reaction, and analyzed the effect of a drug allergy evaluation. METHODS: Patients (>18 years old) answered the specific questionnaire twice: before the drug allergy evaluation, and 1 month after it was completed. Statistics were performed using STATA. RESULTS: A total of 360 patients (240, 66.6% female; mean age, 45.4 years; standard deviation [SD], 15.6 years) completed the first questionnaire. After the evaluation, 150 of 346 patients (43.4%) were diagnosed as allergic to the drug (115 of 150 immediate; 35 of 150 delayed) and 196 of 346 patients (56.6%) as nonallergic. The mean value of the first questionnaire was 32.14 (SD, 11.84); patients with anaphylaxis, nonanaphylactic immediate reaction, with more than 1 drug reaction, or a chronic osteoarticular disease, had a statistically significant higher score in Q0 (worse quality of life). After the allergy study, the mean of the second questionnaire was 27.27 (SD, 9.96), showing a global improvement (P < .001). No statistically significant difference was found between drug allergic and non-drug allergic patients (P = .340); however, being >40 years old (P = .030), having a chronic osteoarticular disease (P = .003) and having more than 1 reaction to drugs (P < .001) were associated with a statistically significant worse quality of life after the evaluation. CONCLUSIONS: Having suffered anaphylaxis, more than 1 reported drug allergy or presenting a musculoskeletal disease are factors that worsen the quality of life. Quality of life improved significantly after completing a drug allergy evaluation.

Efficacy and Safety of Omalizumab (Xolair) for Cholinergic Urticaria in Patients Unresponsive to a Double Dose of Antihistamines: A Randomized Mixed Double-Blind and Open-Label Placebo-Controlled Clinical Trial.

BACKGROUND: Cholinergic urticaria (UCOL) is a highly disabling inducible urticaria triggered by an increase in core body temperature. OBJECTIVE: To explore the safety and efficacy of omalizumab in controlling UCOL. METHODS: We conducted a multicenter randomized mixed double-blind and open-label (first 4 months blinded followed by 8 months open-label) placebo-controlled clinical trial in 22 patients suffering from UCOL who were unresponsive to a double dose of antihistamines. We performed an exercise challenge test during each visit as our main outcome variable. RESULTS: The overall rate of exercise challenge test negative at week 48 was 31.3%, with an average increase in exercise challenge test negative rate of 2.9% points (95% CI, 1.5-4.2) per visit. Statistically significant differences in the negative exercise challenge test rate between the placebo and active intervention groups were not observed during the blinded period (first 4 months of the study). However, from the fourth dose, a progressive improvement was observed. When comparing before and after treatment, statistically significant improvements in all secondary outcome measures were noted after 4 doses (UCOL score: P = .0015; visual analog scale score: P = .0108; days with symptoms: P = .0125) and after 8 doses (UCOL score: P = .0005; chronic urticaria quality of life questionnaire: P = .0105; visual analog scale score: P = .0008; and days with symptoms: P = .0144). In the follow-up visit after the cessation of treatment, the symptoms reappeared, with positive exercise challenge test result and significant increases in all variables. Only 4 of 22 patients remained asymptomatic after 3 months of no treatment. No adverse effects were reported. CONCLUSIONS: This randomized mixed double-blind and open-label placebo-controlled trial showed evidence of the safety and potential efficacy of omalizumab in patients with UCOL.

MRGPRX2-mediated mast cell response to drugs used in perioperative procedures and anaesthesia.

The study of anaphylactoid reactions during perioperative procedures and anaesthesia represents a diagnostic challenge for allergists, as many drugs are administered simultaneously, and approximately half of them trigger allergic reactions without a verifiable IgE-mediated mechanism. Recently, mast cell receptor MRGPRX2 has been identified as a cause of pseudo-allergic drug reactions. In this study, we analyse the ability of certain drugs used during perioperative procedures and anaesthesia to induce MRGPRX2-dependent degranulation in human mast cells and sera from patients who experienced an anaphylactoid reaction during the perioperative procedure. Using a ß-hexosaminidase release assay, several drugs were seen to cause mast cell degranulation in vitro in comparison with unstimulated cells, but only morphine, vancomycin and cisatracurium specifically triggered this receptor, as assessed by the release of ß-hexosaminidase in the control versus the MRGPRX2-silenced cells. The same outcome was seen when measuring degranulation based on the percentage of CD63 expression at identical doses. Unlike that of the healthy controls, the sera of patients who had experienced an anaphylactoid reaction induced mast-cell degranulation. The degranulation ability of these sera decreased when MRGPRX2 was silenced. In conclusion, MRGPRX2 is a candidate for consideration in non-IgE-mediated allergic reactions to some perioperative drugs, reinforcing its role in mast cell responses and their pathophysiology.

Improvement of the Elevated Tryptase Criterion to Discriminate IgE- From Non-IgE-Mediated Allergic Reactions.

BACKGROUND: Differentiating between immunoglobulin E (IgE)-dependent and IgE-independent hypersensitivity reactions may improve the etiologic orientation and clinical management of patients with allergic reactions in the anesthesia setting. Serum tryptase levels may be useful to discriminate the immune mechanism of allergic reactions, but the diagnostic accuracy and optimal cutpoint remain unclear.We aimed to compare the diagnostic accuracy of tryptase during reaction (TDR) alone and the TDR/basal tryptase (TDR/BT) ratio for discriminating IgE- from non-IgE-mediated allergic reactions, and to estimate the best cut point for these indicators. METHODS: We included 111 patients (45% men; aged 3-99 years) who had experienced an allergic reaction, even though the allergic reaction could be nonanaphylactic. Allergy tests were performed to classify the reaction as an IgE- or non-IgE-mediated one. The area under the curve (AUC) of the receiver operating characteristic analysis was performed to estimate the discriminative ability of TDR and TDR/BT ratio. RESULTS: An IgE-mediated reaction was diagnosed in 49.5% of patients, and 56% of patients met anaphylaxis criteria. The median (quartiles) TDR for the IgE-mediated reactions was 8.0 (4.9-19.6) and 5.1 (3.5-8.1) for the non-IgE-mediated (P = .022). The median (quartiles) TDR/BT ratio was 2.7 (1.7-4.5) in IgE-mediated and 1.1 (1.0-1.6) in non-IgE-mediated reactions (P < .001). The TDR/BT ratio showed the greatest ability to discriminate IgE- from non-IgE-mediated reactions compared to TDR (AUC TDR/BT = 0.79 [95% confidence interval (CI), 0.70-0.88] and AUC TDR = 0.66 [95% CI, 0.56-0.76]; P = .001). The optimal cut point for TDR/BT (maximization of the sum of the sensitivity and specificity) was 1.66 (95% CI, 1.1-2.2). CONCLUSIONS: The TDR/BT ratio showed a significantly better discriminative ability than TDR to discriminate IgE- from non-IgE-mediated allergic reactions. An optimal TDR/BT ratio threshold of approximately 1.66 may be useful in clinical practice to classify allergic reactions as IgE- or non-IgE-mediated.

Medical Device for Automated Prick Test Reading.

Allergy tests are routinely performed in most hospitals everyday. However, measuring the outcomes of these tests is still a very laborious manual task. Current methods and systems lack of precision and repeatability. This paper presents a novel mechatronic system that is able to scan a patient's entire arm and provide allergists with precise measures of wheals for diagnosis. The device is based on 3-D laser technology and specific algorithms have been developed to process the information gathered. This system aims to automate the reading of skin prick tests and make gains in speed, accuracy, and reliability. Several experiments have been performed to evaluate the performance of the system.

Oral immunotherapy using polymeric nanoparticles loaded with peanut proteins in a murine model of fatal anaphylaxis.

BACKGROUND: Peanut allergy is the most common cause of anaphylaxis and food-related death. However, there is currently no approved immunotherapy treatment. Hence, this warrants the need for relevant and convenient animal models to test for adequate immunotherapies. MATERIALS & METHODS: In this study, we compared three mouse strains: CD1, BALB/c and C57, to select a model of peanut allergy. After that, we conducted then a therapeutic study using an immunogenic peanut extract encapsulated in nanoparticles made with polymer Gantrez® following the solvent displacement method. RESULTS & CONCLUSION: After implementing a dosing schedule with oral commercial peanut butter, the antibody responses, cytokine profiles and, above all, the anaphylaxis induced after a challenge with peanut proteins, showed that the outbred CD1 strain was the most susceptible to peanut sensitization. CD1 sensitized mice were orally immunized with three doses of the nanoparticle formulation capable of protecting them against the severe anaphylactic symptoms induced by the peanut challenge.

Omalizumab efficacy in cases of chronic spontaneous urticaria is not explained by the inhibition of sera activity in effector cells.

Omalizumab (OmAb) is a humanized anti-IgE antibody approved for the treatment of chronic spontaneous urticaria (CSU). OmAb's mechanism of action is known to include actions on free IgE and on pre-bound IgE. However, OmAb is equally and rapidly effective against autoimmune and non-autoimmune urticaria where IgE involvement is not clear, suggesting the involvement of additional mechanisms of action. In this study, we sought to investigate the ability of OmAb to inhibit mast cell and basophil degranulation induced by sera from CSU patients. For this purpose, we performed a comparison between the in vitro incubation of sera from CSU patients treated with OmAb and the in vivo administration of OmAb in a clinical trial. We found that OmAb added in vitro to sera from CSU patients did not modify the ability of the sera to induce cell degranulation. Similarly, the sera from patients treated with OmAb in the context of the clinical trial who had a good clinical outcome maintained the capacity to activate mast cells and basophils. Thus, we conclude that the beneficial activity of OmAb does not correlate with the ability of patient sera to induce cell degranulation.

Adjuvants for allergy immunotherapeutics.

Allergic diseases are reaching epidemic proportions in developed countries. In particular, food allergy is increasing in prevalence and severity, thus becoming an important socioeconomic burden. Numerous cell types and cell populations, which form an intricate and balanced network, are involved in an immune response. This balance is occasionally disturbed, leading to the onset of different diseases, such as allergic diseases. Antihistamines and corticosteroids provide some degree of relief from the symptoms of allergic conditions. However, the only treatment that can revert the disease is immunotherapy. Nevertheless, specific immunotherapy has at least 2 major drawbacks: it is time-consuming, and it can produce local and even systemic allergic side effects. Immunotherapy's potential goes beyond our current knowledge of the immune response; nevertheless, we can still design strategies to reach a safer immune modulation for treating allergies. This review deals with the use of adjuvants to reduce the undesirable side effects associated with specific allergen immunotherapy. For example, nanoparticles used as immunoadjuvants are offering promising results in preclinical assays.

Lipid Transfer Protein Syndrome in a Non-Mediterranean Area.

BACKGROUND: Plant food allergies associated with lipid transfer protein (LTP) have been widely described in the Mediterranean Basin. OBJECTIVE: The aim of this work was to describe the clinical profile and pollen sensitization of plant food- allergic patients sensitized to LTP in a non-Mediterranean area. METHODS: Patients with clear IgE-mediated symptoms associated with plant foods and a positive skin prick test (SPT) to Pru p 3 were included in a prospective study in the north of Spain. Reported symptoms were analyzed together with a battery of food and pollen SPTs and specific IgE components by ISAC microarray. Cross-inhibition studies were performed by ImmunoCAP with plane tree, mugwort and rPru p 3. RESULTS: Among the 72 patients included, the most frequent food allergy reported was to peaches (69%) followed by nuts (walnuts 55%, peanuts 54% and hazelnuts 43%). Most patients suffered from symptoms with multiple plant foods (a median of 6 foods per patient). Regarding the patients' pollen sensitization, 36% were sensitized to mugwort pollen (72% showing sIgE to Art v 3), 33% to grass pollen and 24% to plane tree pollen (94% with sIgE to Pla a 3). Inhibition studies showed that specific IgEs against mugwort and plane tree pollen are inhibited by Pru p 3 in a strong manner, whereas Pru p 3 was less inhibited by pollen extracts. CONCLUSIONS: LTP syndrome occurs in a non-Mediterranean area and is related to multiple sensitizations to foods and pollens such as plane tree and mugwort. In these pollen sensitizations, Pru p 3 seems to be the primary sensitizer.