Cause Of Hypersensitivity Reactions Research Articles

The Role of the Allergist in the Management of Chemotherapy-Induced Hypersensitivity Reactions

Chemotherapy-Induced Hypersensitivity Reactions are one of the main problems for oncology physicians and chemotherapy patients. The hypersensitivity reaction can either cause the cessation of the first-line treatment and it may impair the final result and impede or decrease the chances for successful treatment. Chemotherapy drugs are foreign substances that are capable to inducing the various hypersensitivity reactions from mild cutaneous symptoms to severe respiratory distress and cardiovascular collapse. The original Gell and Coomb’s classification categorizes hypersensitivity reactions into four types according to the type of immune response and the effector mechanism responsible for cell and tissue injury. The most common reactions are caused by platinum compounds, taxanes, epipodophyllotoxins, and asparaginase. The use of biologicals is increasing now, and these drugs are frequent causes of hypersensitivity reactions too. Skin testing is a method of diagnosing drug hypersensitivity, but it has not been developed enough in the field of medical oncology where a variety of the antineoplastic agents may be caused hypersensitivity reactions. Drug desensitization is the benefitial therapy in patients with chemotherapyinduced hypersensitivity reactions to chemotherapeutic drugs. This is useful for chemotherapy patients with malignancies and hematological diseases when no comparable alternative is available.

A Comprehensive Review of Sulfonamide Hypersensitivity: Implications for Clinical Practice.

Sulfonamides, which are drugs commonly prescribed in hospital and outpatient settings, have historically been associated with a high incidence of hypersensitivity reactions. It is believed that there is an increased risk of cross-reactions with other drugs that contain this functional group in their structure. However, it has not been conclusively established that the sulfonamide group is the sole cause of hypersensitivity reactions, as non-antibiotic sulfonamides do not share the same accessory groups with antibiotic sulfonamides. Therefore, cross-reactivity between different types of sulfonamides and sulfonamide-type antibiotics is not clearly demonstrated, and allergic reactions may involve other mechanisms. Misinformation about this topic can lead to inappropriate use of alternative antibiotics with lower efficacy or higher adverse effects, contributing to antibiotic resistance. It is crucial to individualize and monitor patients with a history of allergies to sulfonamide-type antibiotics when introducing a new drug containing sulfa and manage any adverse reactions promptly. Desensitization protocols may be a viable option for patients who specifically benefit from these antibiotics, particularly those who are immunosuppressed. This article provides a descriptive bibliographic review to update information on sulfa allergy, its prevalence, management, and recommendations to prevent such reactions and optimize pharmacotherapy, without underusing these drugs.

Association between House Dust Mite Sensitization and IL4/IL13 and IL4RA Genetic Variants in Nonsteroidal Anti-inflammatory Drug-induced Acute Urticaria/angioedema

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the main cause of hypersensitivity reactions to drugs, with NSAID-induced urticaria/angioedema (NIUA) being the most frequent clinical entity. NIUA has long been associated with Dermatophagoides pteronyssinus (DP) sensitization by different authors; however, further studies explaining such association are needed. As both NSAID-hypersensitivity and atopic diseases are modelled by genetic factors, and taking into account the role of IL4/IL13 and their receptors in atopy, we have carried out a genetic association study in NIUA focusing on these genes.

Evaluation of desensitization protocols to betalactam antibiotics.

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. (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. 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. 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.

Re-evaluating expanding intravenous catheters in medical practice.

BackgroundIntravenous catheters are common and essential devices within medical practice. Their placement can be difficult, leading to application of several technologies to improve success. Functionally expanding catheters were once an exciting technology, derailed clinically by hypersensitivity reactions. The exact cause of reactions, attributed to Aquavene catheter materials, remains unknown.AimsTo reinvestigate functionally expanding intravenous catheters.Materials and MethodsThe history of the functionally expanding intravenous catheter is presented here along with its utility in current medical practice, potential for further investigation, and possible redesign of these once promising devices.ResultsThis review demonstrates clinical utility and a lack of definitive cause for failure of the previous functionally expanding intravenous catheter design. As Aquavene materials themselves are commonly considered the cause of hypersensitivity reactions which removed expanding intravenous catheters from the market, this review found several possible substitutes for this material for use in any redesign.Discussion and ConclusionThe functionally expanding intravenous catheter failed due to hypersensitivity reactions in patients. Alternative materials exist for a possible redesign on this once promising clinical product.

Assessing taxane-associated adverse events using the FDA adverse event reporting system database.

Background:Taxanes are an essential class of antineoplastic agents used to treat various cancers and are a fundamental cause of hypersensitivity reactions. In addition, other adverse events, such as bone marrow toxicity and peripheral neuropathy, can lead to chemotherapy discontinuation. This study aimed to evaluate the safety of taxanes in the real world.Methods:Taxane-associated adverse events were identified by the Medical Dictionary for Regulatory Activities Preferred Terms and analyzed and compared by mining the US Food and Drug Administration Adverse Event Reporting System pharmacovigilance database from January 2004 to December 2019. Reported adverse events, such as hypersensitivity reaction, bone marrow toxicity, and peripheral neuropathy, were analyzed with the following signal detection algorithms: reporting odds ratio (ROR), proportional reporting ratio (PRR), multi-item gamma Poisson shrinker (MGPS), Bayesian confidence propagation neural network (BCPNN), and logistic regression methods. Adverse outcome events and death outcome rates were compared between different taxane groups using Pearson's χ2 test, whereas significance was determined at P < 0.05 with a 95% confidence interval (CI).Results:A total of 966 reports of hypersensitivity reactions, 1109 reports of bone marrow toxicity, and 1374 reports of peripheral neuropathy were analyzed. Compared with paclitaxel and docetaxel, bone marrow toxicity following the use of nab-paclitaxel had the highest ROR of 6.45 (95% two-sided CI, 6.05–6.88), PRR of 5.66, (χ2 = 4342.98), information component of 2.50 (95% one-sided CI = 2.34), and empirical Bayes geometric mean of 5.64 (95% one-sided CI = 5.34). Peripheral neuropathy following the use of nab-paclitaxel showed a higher ROR of 12.78 (95% two-sided CI, 11.55–14.14), PRR of 12.16 (χ2 = 4060.88), information component of 3.59 (95% one-sided CI = 3.25), and empirical Bayes geometric mean of 12.07 (95% one-sided CI = 11.09).Conclusions:The results showed that bone marrow toxicity and peripheral neuropathy were the major adverse events induced by taxanes. Nab-paclitaxel exhibited the highest potential for taxane-associated adverse events. Further research in the future is warranted to explain taxane-associated adverse effects in real-world circumstances.

Allergy to penicillin and betalactam antibiotics.

ABSTRACTBetalactams are the most frequent cause of hypersensitivity reactions to drugs mediated by a specific immune mechanism. Immediate reactions occur within 1 to 6 hours after betalactam administration, and are generally IgE-mediated. They clinically translate into urticaria, angioedema and anaphylaxis. Non-immediate or delayed reactions occur after 1 hour of administration. These are the most common reactions and are usually mediated by T cells. The most frequent type is the maculopapular or morbilliform exanthematous eruption. Most individuals who report allergies to penicillin and betalactams can tolerate this group of antibiotics. To make diagnosis, a detailed medical history is essential to verify whether it was an immediate or non-immediate reaction. Thereafter, in vivo and/or in vitro tests for investigation may be performed. The challenging test is considered the gold standard method for diagnosis of betalactam hypersensitivity. The first approach when suspecting a reaction to betalactam is to discontinue exposure to the drug, and the only specific treatment is desensitization, which has very precise indications. The misdiagnosis of penicillin allergy affects the health system, since the “penicillin allergy” label is associated with increased bacterial resistance, higher rate of therapeutic failure, prolonged hospitalizations, readmissions, and increased costs. Thus, it is essential to develop strategies to assist the prescription of antibiotics in patients identified with a label of “betalactam allergy” at hospitals, and to enhance education of patients and their caregivers, as well as of non-specialist physicians.

Influence of lysosomal protease sensitivity in the immunogenicity of the antitumor biopharmaceutical asparaginase

L-asparaginase (ASNase) from Escherichia coli (EcAII) is used in the treatment of acute lymphoblastic leukaemia (ALL). EcAII activity in vivo has been described to be influenced by the human lysosomal proteases asparaginyl endopeptidase (AEP) and cathepsin B (CTSB); these hydrolases cleave and could expose epitopes associated with the immune response against EcAII. In this work, we show that ASNase resistance to CTSB and/or AEP influences the formation of anti-ASNase antibodies, one of the main causes of hypersensitivity reactions in patients. Error-prone polymerase chain reaction was used to produce variants of EcAII more resistant to proteolytic cleavage by AEP and CTSB. The variants with enzymatic activity and cytotoxicity levels equivalent to or better than EcAII WT were submitted to in vivo assays. Only one of the mutants presented increased serum half-life, so resistance to these proteases is not the only feature involved in EcAII stability in vivo. Our results showed alteration of the phenotypic profile of B cells isolated after animal treatment with different protease-resistant proteoforms. Furthermore, mice that were exposed to the protease-resistant proteoforms presented lower anti-asparaginase antibodies production in vivo. Our data suggest that modulating resistance to lysosomal proteases can result in less immunogenic protein drugs.

Clinical Characterization and Diagnostic Approaches for Patients Reporting Hypersensitivity Reactions to Quinolones

Quinolones are the second most frequent cause of hypersensitivity reactions (HSRs) to antibiotics. A marked increase in the number of patients with HSRs to quinolones has been detected. To describe the clinical characteristics of patients with HSRs to quinolones and present methods for their diagnosis. Patients attending the allergy unit due to reactions suggestive of HSRs to quinolones were prospectively evaluated between 2005 and 2018. Diagnosis was achieved using clinical history, skin tests (STs), basophil activation tests (BATs), and drug provocation tests (DPTs) if ST and BAT results were negative. We included 128 subjects confirmed as having HSRs to quinolones and 42 found to be tolerant. Anaphylaxis was the most frequent entity in immediate HSRs and was most commonly induced by moxifloxacin. Patients were evaluated a median of 150 days (interquartile range, 60-365 days) after the reaction. Of patients who underwent ST and BAT, 40.7% and 70%, respectively, were positive. DPT with a quinolone was performed in 48 cases, giving results depending on the culprit drug: when moxifloxacin was involved, 62.5% of patients gave a positive DPT result to ciprofloxacin, whereas none reacted to levofloxacin. The risk of HSR was 96 times higher in subjects who reported moxifloxacin-induced anaphylaxis and 18 times higher in those reporting immediate reactions compared with clinical entities induced by quinolones other than moxifloxacin and nonimmediate reactions. The diagnosis of HSR to quinolones is complex. The use of clinical history is essential as a first step. BAT shows higher sensitivity than STs. DPTs can be useful for finding safe alternative quinolones.

Mechanistic Insights of an Immunological Adverse Event Induced by an Anti-KIT Antibody Drug Conjugate and Mitigation Strategies.

Purpose: Hypersensitivity reactions (HSRs) were observed in three patients dosed in a phase I clinical trial treated with LOP628, a KIT targeted antibody drug conjugate. Mast cell degranulation was implicated as the root cause for the HSR. Underlying mechanism of this reported HSR was investigated with an aim to identifying potential mitigation strategies.Experimental Design: Biomarkers for mast cell degranulation were evaluated in patient samples and in human peripheral blood cell-derived mast cell (PBC-MC) cultures treated with LOP628. Mitigation strategies interrogated include pretreatment of mast cells with small molecule inhibitors that target KIT or signaling pathways downstream of FcεR1, FcγR, and treatment with Fc silencing antibody formats.Results: Transient elevation of serum tryptase was observed in patients 1-hour posttreatment of LOP628. In agreement with the clinical observation, LOP628 and its parental antibody LMJ729 induced degranulation of human PBC-MCs. Unexpectedly, KIT small molecule inhibitors did not abrogate mast cell degranulation. By contrast, small molecule inhibitors that targeted pathways downstream of Fc receptors blunted degranulation. Furthermore, interference of the KIT antibody to engage Fc receptors by pre-incubation with IgG or using engineered Fc silencing mutations reduced or prevented degranulation. Characterization of Fcγ receptors revealed human PBC-MCs expressed both FcγRII and low levels of FcγRI. Interestingly, increasing the level of FcγRI upon addition of IFNγ, significantly enhanced LOP628-mediated mast cell degranulation.Conclusions: Our data suggest LOP628-mediated mast cell degranulation is the likely cause of HSR observed in the clinic due to co-engagement of the FcγR and KIT, resulting in mast cell activation. Clin Cancer Res; 24(14); 3465-74. ©2018 AACR.

Hypersensitivity Reactions to Non-Steroidal Anti-Inflammatory Drugs.

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the leading causes of hypersensitivity reactions to drugs, and they are classified in two groups: those induced by nonspecific immunological mechanisms (non-allergic or cross-intolerance (CI) reactions), or by specific immunological mechanisms (allergic or selective reactions (SR)). The pathogenesis of CI is associated with their pharmacological activity (COX-1 inhibition), with symptoms due to an imbalance in the arachidonic acid pathway, independently of their chemical structure. SRs are mediated by specific IgE- or by a T-cell response and can be induced by a single NSAID or a class of chemically related NSAIDs, with patients tolerating chemically unrelated compounds. NSAIDs hypersensitivity reactions have been classified in five main groups: i) NSAIDs-exacerbated respiratory disease (NERD); ii) NSAIDs-exacerbated cutaneous disease (NECD); iii) NSAIDs-induced urticaria/angioedema (NIUA); iv) Single NSAID-induced urticaria/angioedema or anaphylaxis (SNIUAA); v) Single NSAID-induced delayed reactions (SNIDRs). Although this classification described above is widely accepted by most authors some phenotypes such as blended reactions do not fit. Therefore more research is needed in this topic.

P012 Successful IV desensitization to racemic leucovorin, an underappreciated cause of hypersensitivity reactions from cancer chemotherapy

P012 Successful IV desensitization to racemic leucovorin, an underappreciated cause of hypersensitivity reactions from cancer chemotherapy

Pyrazolones metabolites are relevant for identifying selective anaphylaxis to metamizole.

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most common cause of hypersensitivity reactions, with pyrazolones the most frequent drugs inducing selective reactions. Immediate selective hypersensitivity to pyrazolones is thought to be mediated by specific-IgE. Sensitivity of in vitro diagnostic tests is low and this may be due to the incomplete characterization of the structures involved. Here we investigated whether main metabolites of metamizole (dipyrone) in human could be involved in the immune response using the basophil activation test (BAT). We studied subjects with confirmed selective immediate hypersensitivity to metamizole and performed BAT with metamizole and its metabolites: 4-methylamino-antipyrine (MAA), 4-aminoantipyrine (AA), 4-acetylamino-antipyrine (AAA) and 4-formylamino-antipyrine (FAA). BAT results showed an increase of positive results from 37.5% to 62.5% using metamizole plus metabolites as compared with the BAT carried out only with the parent drug, demonstrating that metamizole metabolites have a role in the reaction and can induce specific basophil activation in patients with immediate hypersensitivity to this drug. Our findings indicate that pyrazolone metabolites are useful for improving the in vitro diagnosis of allergic reactions to metamizole.

Cross-Reactivity among Beta-Lactams.

Penicillins and cephalosporins are the major classes of beta-lactam (BL) antibiotics in use today and one of the most frequent causes of hypersensitivity reactions to drugs. Monobactams, carbapenems, oxacephems, and beta-lactamase inhibitors constitute the four minor classes of BLs. This review takes into account mainly the prospective studies which evaluated cross-reactivity among BLs in subjects with a well-demonstrated hypersensitivity to a certain class of BLs by performing allergy tests with alternative BLs and, in case of negative results, administering them. In subjects with either IgE-mediated or T-cell-mediated hypersensitivity, cross-reactivity among BLs, particularly among penicillins and among cephalosporins, as well as between penicillins and cephalosporins, seems to be mainly related to structural similarities among their side-chain determinants. Specifically, in penicillin-allergic subjects, cross-reactivity between penicillins and cephalosporins may exceed 30% when they are administered cephalosporins with identical side chains to those of responsible penicillins. In these subjects, a few prospective studies have demonstrated a rate of cross-reactivity between penicillins and both carbapenems and aztreonam lower than 1%. With regard to subjects with an IgE-mediated hypersensitivity to cephalosporins, in a single study, about 25% of the 98 subjects with such hypersensitivity had positive results to penicillins, 3% to aztreonam, 2% to imipenem/cilastatin, and 1% to meropenem. The cross-reactivity related to the selective recognition of the BL ring by IgE or T lymphocytes, which entails positive responses to all BLs tested, appears to be exceptional. Some studies concerning cross-reactivity among BLs have found patterns of allergy-test positivity which cannot be explained by either the common BL ring or by similar or identical side chains, thus indicating the possibility of coexisting sensitivities to different BLs because of prior exposures to them.

Patients Taking Amoxicillin-Clavulanic Can Become Simultaneously Sensitized to Both Drugs

Betalactam antibiotics are the most frequent cause of hypersensitivity reactions to drugs mediated by a specific immune mechanism. Amoxicillin (AX) is the most often elicitor, which was originally prescribed alone, and is now often prescribed alongside clavulanic acid (CLV). After the administration of AX-CLV, there are subjects who develop AX allergy whilst tolerating CLV, whilst for others the opposite occurs. To our knowledge, there are no clinical reports of patients with IgE-mediated allergy to both AX and CLV. Skin testing was performed by skin prick test and if negative followed by intradermal test. Serum specific IgE determination was performed by ImmunoCAP and basophil activation test (BAT) was performed by flow cytometry. Single blind placebo controlled drug provocation test was performed to assess tolerance to other penicillins. Case 1: 48 year-old woman who developed urticaria and angioedema 45 min after the oral administration of AX-CLV. Case 2: 43 year-old woman who developed systemic pruritus with generalised urticaria and facial and tongue angioedema 15 min after the oral administration of AX-CLV. The allergological work-up indicated that the two patients were allergic to both AX and CLV with good tolerance to BP and penicillin V. Both patients gave positive skin test results to AX and CLV, showed specific anti-AX IgE and gave positive BAT results to AX and CLV. Our study provides evidence that sensitization to both AX and CLV can appear in the same patient. To our knowledge this is the first study showing this sensitization pattern.

Ibuprofen induced Stevens-Johnson syndrome - toxic epidermal necrolysis in Nepal

Despite the fact that any drug can be an impending cause of hypersensitivity reactions, Ibuprofen, an over-the-counter drug used extensively as an analgesic and antipyretic in Asia, is considered to be relatively safe. But herein we report a rare extremely 'rapid onset' occurrence of a severe case of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in a 22-year-old male, induced by 3 doses of 400 mg of Ibuprofen taken at 8-hour interval for eye pain, probably the first case report of rapid onset of TEN by nonsteroidal antiinflammatory drugs in Nepal. SJS and TEN are idiosyncratic, delayed hypersensitivity inflammatory adverse drug reactions that are severe adverse cutaneous drug reactions which predominantly involve the skin and mucous membranes and are linked with high morbidity and mortality. Nevertheless, removal of ibuprofen and its metabolites with plasma exchange and treatment with antibiotics and intravenous corticosteroids along with supportive therapy improved the course of the disorder. This rare case report addresses the fact that severe hypersensitivity reactions can occur with Ibuprofen, which can be potentially dangerous and life threatening. It is thus important for the clinicians to be alert to such severe hypersensitivity reactions even with drugs which are deemed to be probably safe.

Evaluation of hypersensitivity reactions to nonsteroidal anti-inflammatory drugs according to the latest classification.

The consensus document for hypersensitivity reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) proposed by the European Network for Drug Allergy (ENDA) interest group (2011) was revised in 2013. We aimed to evaluate the usability of the latest NSAID hypersensitivity classification of ENDA. A total of 370 patients with a history of hypersensitivity reactions to NSAIDs among the 1250 outpatients referred for suspected drug allergy between July 2013 and June 2014 were evaluated, and 308 patients who were confirmed as having NSAID hypersensitivity were included in this study. After confirming the diagnosis, a single-blind placebo-controlled drug provocation test was performed with aspirin or diclofenac to categorize the patients according to the ENDA classification. The reactions not meeting the ENDA classification criteria were grouped as blended reactions. Among the 308 patients (224 female, mean age 42.12 ± 13.24), the leading cause of hypersensitivity reactions was metamizol (30.5%) followed by aspirin (30.2%). The most common NSAID hypersensitivity subgroup was SNIUAA (46.4%) and the least common type was SNIDR (1.6%). Cross-reactivity was identified in 50.3% of the patients. In five patients (1.6%), the hypersensitivity reactions to NSAIDs did not meet the ENDA classification: Three patients experienced anaphylaxis with different NSAIDs, one patient encountered anaphylaxis with one NSAID and urticaria with other NSAIDs, and the last patient had angioedema with different NSAIDs. The latest ENDA classification for NSAID hypersensitivity is generally a practical and useful instrument for clinicians. We only point out that anaphylaxis with different NSAIDs can be seen in a small group of patients.

NSAIDs Hypersensitivity: When and How to Desensitize?

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly used drugs and are among the major causes of hypersensitivity reactions. NSAIDs can evoke different types of both immunological and non-immunologically mediated hypersensitivity reactions, and management of these reactions depends on type of hypersensitivity reaction. As NSAIDs are comprised of several drugs with different chemical structures which can inhibit both cyclooxygenases or selectively cyclooxygenase type 2 (COX-2), in most of the cases, it is possible to find a safe non-cross-reactive drug for a patient. However, in certain situations, especially when patients require anti-platelet treatment, patients can be desensitized to aspirin.

Comprehensive Allergy Evaluation Is Useful in the Subsequent Care of Patients with Drug Hypersensitivity Reactions During Anesthesia

For patients with a history of drug hypersensitivity reaction (HSR) during anesthesia, strategies to minimize risk with subsequent anesthesia are unclear. Identification of the cause of HSR during anesthesia remains challenging. To determine the success of a comprehensive allergy evaluation and management plan for patients with HSR during anesthesia, including identification of the causative agent and review of outcomes during subsequent anesthesia exposure. We performed chart reviews of patients referred for the evaluation of HSR during anesthesia between 2003 and 2012. Data collection included patient characteristics, signs/symptoms of HSR during anesthesia, and subsequent outcomes. Patients underwent comprehensive allergy evaluation including skin testing for identifying potential culprit agents, and the results were used to provide recommendations for any subsequent anesthesia. Over the 10-year study period, 73 patients with HSR during anesthesia were referred for further evaluation. Thirteen patients (18%) had positive skin test results to a drug received during anesthesia. One patient with a positive skin test result was diagnosed with mastocytosis. The causative agents identified in these 13 patients included latex, β-lactam antibiotics, neuromuscular blockers, tetracaine, odansetron, and fentanyl. On follow-up, 47 of the 73 patients (64%) subsequently underwent procedures requiring anesthesia. Using our recommendations from evaluation and testing, 45 of these 47 patients (96%) successfully tolerated subsequent anesthesia. The 2 patients who developed recurrent HSR during anesthesia were later diagnosed with mast cell disorders. Our comprehensive evaluation and management plan minimizes risk with subsequent anesthesia even when the cause of HSR could not be identified. Baseline tryptase levels may be helpful in this patient population to diagnose mast cell disorders.

Mass spectrometric characterization of circulating covalent protein adducts derived from a drug acyl glucuronide metabolite: multiple albumin adductions in diclofenac patients.

Covalent protein modifications by electrophilic acyl glucuronide (AG) metabolites are hypothetical causes of hypersensitivity reactions associated with certain carboxylate drugs. The complex rearrangements and reactivities of drug AG have been defined in great detail, and protein adducts of carboxylate drugs, such as diclofenac, have been found in liver and plasma of experimental animals and humans. However, in the absence of definitive molecular characterization, and specifically, identification of signature glycation conjugates retaining the glucuronyl and carboxyl residues, it cannot be assumed any of these adducts is derived uniquely or even fractionally from AG metabolites. We have therefore undertaken targeted mass spectrometric analyses of human serum albumin (HSA) isolated from diclofenac patients to characterize drug-: derived structures and, thereby, for the first time, have deconstructed conclusively the pathways of adduct formation from a drug AG and its isomeric rearrangement products in vivo. These analyses were informed by a thorough understanding of the reactions of HSA with diclofenac AG in vitro. HSA from six patients without drug-: related hypersensitivities had either a single drug-: derived adduct or one of five combinations of 2-8 adducts from among seven diclofenac N-acylations and three AG glycations on seven of the protein's 59 lysines. Only acylations were found in every patient. We present evidence that HSA modifications by diclofenac in vivo are complicated and variable, that at least a fraction of these modifications are derived from the drug's AG metabolite, and that albumin adduction is not inevitably a causation of hypersensitivity to carboxylate drugs or a coincidental association.