The Drug Lymphocyte Stimulation Test (DLST) predominantly serves the purpose of discerning drugs responsible for delayed-type hypersensitivity reactions. Effectively employing DLST necessitates the meticulous determination of the cut-off Stimulation Index (SI). For diagnosing drug-induced liver injury, an optimized cut-off SI of 195% has been established, rendering DLST a reported utility[11, 12]. Notably, in the context of sulfonamide allergy, DLST demonstrated usefulness by identifying 25 out of 34 cases when the cut-off SI was set at 220%[13]. Similarly, in patients with mesalazine allergy, DLST proved valuable for definitive diagnosis, utilizing an SI > 180% as the cut-off value[14]. However, the utility of DLST diminishes without the optimization of the cut-off SI. In patients experiencing adverse side effects from anti-tuberculosis drugs, DLST exhibited low sensitivity (less than 20%) at a cut-off SI of 180%, indicating its lack of usefulness[15, 16], while specificity was reported to be high but with low sensitivity for the same purpose[17]. The significance of DLST in cases of favipiravir-induced drug fever remains unclear when the cut-off SI is set at 220% [18]. Moreover, DLST has proven useful in diagnosing drug-induced interstitial lung disease[19], with cut-off SI values of 180% or 200% being conventionally employed[20]. However, for local anesthetics, the utilization of 180% or 200% as a cut-off SI without optimization has likely contributed to the perceived inefficacy of DLST in this context. In our clinic, local anesthetics eliciting an SI > 180% are generally deemed a contraindication for the patient, yet this may only be a partially adequate judgment.
A remarkable escalation in the Stimulation Index (SI) is infrequent but documented in patients experiencing allergic reactions across various contexts. Notably, individuals manifesting Stevens-Johnson syndrome or systemic papular erythema displayed SI values of 2180% and 430%, respectively[5]. In cases of generalized exanthematous pustulosis, SI surged over 400% in response to tosufloxacin [21] and clopidogrel [22]. Patients with drug eruptions induced by ranitidine hydrochloride, entecavir, or esomeprazole exhibited SI values of 1586%[9], 400% [6], and 1100% [8], respectively. In instances of DLST conducted for patients with drug-induced linear IgA bullous dermatosis caused by antimicrobial agents, the SI for the implicated agent approached 500% [23]. Among dental patients experiencing palpitation, dysphoria, and facial edema immediately following the injection of local anesthetics with an adrenaline formula, the SI for the adrenaline formula surpassed 500% [24]. Pichler et al. posited that determining relevance based on SI values between 200% and 300% is challenging without supplementary support, emphasizing that an SI > 300% strongly suggests positivity, particularly when the test yields positive results at multiple concentrations [3]. In our findings, SI > 300% was observed in a total of 7 cases. Within our cohort, these cases are deemed to harbor potential hypersensitivity to dental local anesthetics.
In this investigation, the primary triggers for allergy testing encompass both hives and swelling following the injection of local anesthetics, indicating potential allergic reactions to these substances. Conversely, manifestations such as dyspnea, drowsiness, and tachycardia appear to be associated with hyperventilation syndrome, vagal reflex, and reactions to adrenaline, respectively. Although the distribution of cases with Stimulation Index (SI) > 180% did not exhibit significant variations based on the primary reasons in this study, the proportion of SI > 180% was notably higher in patients experiencing hives or swelling compared to those with dyspnea, drowsiness, and discomfort. This implies a potential correlation between these symptoms post-injection of dental local anesthetics and the corresponding SI values. Despite DLST traditionally being regarded as a test for delayed hypersensitivity, it has been reported to detect anaphylaxis [2] when drug-specific memory T cells are activated [1, 3]. Additionally, a distinct elevation in SI has been documented in patients presenting allergic symptoms immediately after the injection of local anesthetics [24]. Therefore, DLST is likely to be a safe screening tool for allergic reaction to local anesthesia if an appropriate cut-off SI is determined. In our case diagnosed with allergy for lidocaine by a dermatologist, SI for lidocaine was 184%, suggesting a possibility that SI > 180 has clinical significance. Since there is no clinical research demonstrating a relationship among clinical allergic symptoms after the injection of local anesthetics, a high SI for them, and a positive result in skin tests or challenge tests, the cut-off SI for local anesthetics remains unclear. To validate it, skin tests followed by challenge tests should have been performed in patients with SI > 180% in this study.
Our study represents the inaugural research delineating the distribution of Stimulation Index (SI) in Drug Lymphocyte Stimulation Tests (DLST) for local anesthetics. Upon examining histograms of SI for formulations of lidocaine, prilocaine, and mepivacaine, their distributions exhibited a long-tailed pattern, deviating from a normal distribution, a confirmation substantiated by the Quantile-Quantile (Q-Q) plot for each anesthetic. According to our findings, an SI > 300% is deemed rare, with an SI > 400% considered extremely high in response to local anesthetics, as none of the 500 patients with a history of adverse reactions to local anesthesia displayed an SI > 400. In our clinical practice, patients with an SI > 180% were deemed positive for allergic reactions to local anesthetics based on information from clinical laboratories, and advanced tests, including skin tests, were avoided for safety. However, to establish the significance of DLST, skin tests followed by challenge tests should have been administered to these patients, contingent on their consent. SI from formulations of prilocaine and mepivacaine demonstrated a significant correlation with that of the lidocaine formula in this study. These findings align with previous reports recommending skin tests for various local anesthetics [25].
In conclusion, while the DLST shows promise as a potentially valuable tool for discerning the causative factors behind adverse reactions to dental local anesthetics, the current body of evidence falls short in definitively substantiating its efficacy. To elucidate the intricate relationship among clinical symptoms, SI derived from DLST, and skin tests, a comprehensive examination is imperative. Notably, patients exhibiting an SI > 300% emerge as pivotal in the endeavor to validate the efficacy of DLST.