Immediate local anesthetic reactions and diagnostic test results in pediatric patients.

BACKGROUND/OBJECTIVES: Adverse reactions to local anesthetics are relatively common, but proven IgE-mediated allergy is extremely rare. We aimed to determine the frequency of local anesthetic allergy in pediatric patients. PATIENTS AND METHODS: The medical records of 73 patients who presented to our clinic with a history of suspected allergic reaction to local anesthetics and underwent diagnostic testing between 2012 and 2020 were retrospectively analyzed. Diagnoses were based on case histories, skin tests, and subcutaneous challenge tests. RESULTS: A total of 75 test series were carried out on the 73 patients (43 boys; median [IQR] age 9.25 [7.26-14.25] years, range 3-17.8 years). The most commonly tested drugs were lidocaine (n = 38; 50.6%) and prilocaine (n = 15; 20%). Local anesthetic allergy was confirmed in one (1.3%) of the 73 patients by positive subcutaneous challenge test with mepivacaine. CONCLUSION: There are limited data in the current literature regarding local anesthetic allergies and diagnosis test results in pediatric patients. Proven local anesthetic allergy is less common than expected by society and physicians, and therefore diagnostic tests are needed for patients with no contra-indications such as severe or life-threatening reactions.

Local anesthetics allergy: who should be tested?

Summary: Objective. To document the test results of patients referred to our clinic for testing with local anesthetics (LAs) in real life conditions and provide data related to the necessity of these tests. Methods. All consecutive subjects who were referred to be evaluated for LA allergy during a two-year follow up were included in the analysis. All subjects underwent skin prick / intradermal tests followed by a subcutaneous provocation test with the LAs tested. Results. A total of 228 subjects were included. The main referral reason was the presence of a history of drug hypersensitivity reaction (DHR) to drugs other than LAs (n = 128; 56%), whereas a history of LA allergy constituted the second most common referral reason (n = 64, 28.1%). In the majority of cases (n = 39; 60.9%), the culprit LA was not known by the patients. Asthma was the third most common referral reason, presented in 49 cases (21.5%). Ten cases had positivity to the tested LA in skin testing / challenges. Nine out of 10 patients had a history of DHR to drugs other than LA, whereas 5 of them had also a history of DHR to LA. Six of the 10 patients had a history of multiple DHR. None of the asthma patients without any DHR history were positive in the LA tests. Eight out of 10 cases who underwent skin testing / challenge with an alternative LA, tolerated the alternative LA. Conclusion. The most common referral reason for testing with LA was a history of DHR to drugs other than LAs, whereas asthma was the third most common referral reason. Patients with a history of multiple DHR may be considered for testing with LAs. Asthmatics and those with other allergic diseases without a history of drug / LA allergy do not need to be tested with LA.

Cross-reactivity among amide-type local anesthetics in a case of allergy to mepivacaine.

Among the various adverse reactions to local anesthetics, IgE-mediated reactions, particularly to the more commonly used amide group, are extremely rare. We report the case of a 39-year-old man who suffered itching and generalized urticaria with facial angioedema 15 minutes after administration of mepivacaine. Skin tests revealed a strong positive reaction to mepivacaine, lidocaine, and ropivacaine, but negative reactions to bupivacaine and levobupivacaine. Furthermore, double-blind placebo-controlled subcutaneous challenge with bupivacaine and levobupivacaine was well tolerated. We conclude that an extensive allergologic study must be carried out in rare cases of true allergic reaction to amide-type local anesthetics in order to rule out cross reactivity.

Recognition of local anesthetics by alphabeta+ T cells.

Patients with drug allergy show a specific immune response to drugs. Chemically nonreactive drugs like, for example, local anesthetics are directly recognized by alphabeta+ T cells in an HLA-DR restricted way, as neither drug metabolism nor protein processing is required for T cell stimulation. In this study we identified some of the structural requirements that determine cross-reactivity of T cells to local anesthetics, with the aim to improve the molecular basis for the selection of alternatives in individuals sensitized to a certain local anesthetic and to better understand presentation and T cell recognition of these drugs. Fifty-five clones (52 lidocaine specific, three mepivacaine specific from two allergic donors) were analyzed. Stimulatory compounds induced a down-regulation of the T cell receptor, demonstrating that these non-peptide antigens are recognized by the T cell receptor itself. A consistent cross-reactivity between lidocaine and mepivacaine was found, as all except one lidocaine specific clone proliferated to both drugs tested. Sixteen chemically related local anesthetics (including ester local anesthetics, OH- and desalkylated metabolites) were used to identify structural requirements for T cell recognition. Each of the four clones examined in detail was uniquely sensitive to changes in the structures of the local anesthetic: clone SFT24, i.e., did not recognize any of the tested OH- or desalkylated metabolites, while the clone OFB2 proliferated to all OH-metabolites and other differently modified molecules. The broadly reactive clone OFB2 allowed us to propose a model, suggesting that the structure of the amine side chain of local anesthetics is essential for recognition by the T cell receptor.

HLA-restricted, processing- and metabolism-independent pathway of drug recognition by human alpha beta T lymphocytes.

T cell recognition of drugs is explained by the hapten-carrier model, implying covalent binding of chemically reactive drugs to carrier proteins. However, most drugs are nonreactive and their recognition by T cells is unclear. We generated T cell clones from allergic individuals specific to sulfamethoxazole, lidocaine (nonreactive drugs), and cef-triaxone (per se reactive beta-lactam antibiotic) and compared the increase of intracellular free calcium concentration ([Ca2+]i) and the kinetics of T cell receptor (TCR) downregulation of these clones by drug-specific stimulations. All drugs tested induced an MHC-restricted, dose- and antigen-presenting cell (APC)-dependent TCR downregulation on specific CD4(+) and CD8(+) T cell clones. Chemically nonreactive drugs elicited an immediate and sustained [Ca2+]i increase and a rapid TCR downregulation, but only when these drugs were added in solution to APC and clone. In contrast, the chemically reactive hapten ceftriaxone added in solution needed > 6 h to induce TCR downregulation. When APC were preincubated with ceftriaxone, a rapid downregulation of the TCR and cytokine secretion was observed, suggesting a stable presentation of a covalently modified peptide. Our data demonstrate two distinct pathways of drug presentation to activated specific T cells. The per se reactive ceftriaxone is presented after covalent binding to carrier peptides. Nonreactive drugs can be recognized by specific alphabeta+ T cells via a nonconventional presentation pathway based on a labile binding of the drug to MHC-peptide complexes.

Characterization of lidocaine-specific T cells.

To investigate the cellular immune response to the drug lidocaine, we generated T cell lines and clones from the peripheral blood of four patients with proven allergy to lidocaine. The patients had contact dermatitis after topical application of lidocaine, and local swelling or generalized erythema exudativum multiforme after submucosal/subcutaneous injection of lidocaine. Two of three lidocaine-specific T cell lines were oligoclonal and one even became monoclonal, while the simultaneously analyzed immune response to tetanus toxoid was polyclonal. The lidocaine-specific T cell lines cross-reacted to mepivacaine, but not to other local anesthetics (bupivacaine, procaine, oxybuprocaine, and tetracaine). The majority of reactive T cells belonged to the CD4 cell lineage and were MHC class II restricted, but cloning also revealed some MHC class I-restricted CD8+ clones. A total of 2 of 56 lidocaine-specific T cell clones were CD4-CD8- and expressed TCR-gammadelta. The majority of 13 analyzed CD4 clones produced a rather polarized cytokine pattern, with a dominance of Th2-like cytokines showing a high IL-5 production. In addition, three CD4+ and all CD8+ (n = 7) clones secreted high IFN-gamma and low levels of IL-5/IL-4 (Th1-like). The data illustrate that a drug that sensitizes via the skin elicits a heterogeneous T cell response. The high IL-5 production and the participation of specific CD4+CD8+ and even gammadelta+ T cells appear to be distinguishing features of this hapten-specific immune response.