In Vitro Diagnosis of Immediate Drug Hypersensitivity Anno 2017: Potentials and Limitations

Abstract

Background: For most physicians, quantification of drug-specific immunoglobulin E (drug-sIgE) antibodies constitutes the primary in vitro measure to document immediate drug hypersensitivity reactions (IDHR). Unfortunately, this is often insufficient to correctly identify patients with IgE-mediated IDHR and impossible for non-IgE-mediated IDHR that result from alternative routes of basophil and mast cell activation. In these difficult cases, diagnosis might benefit from cellular tests such as basophil activation tests (BAT).

Aim: The aim was to review the potential and limitations of quantification of sIgE and BAT in diagnosing IDHR. The utility of quantification of serum tryptase is discussed.

Methods: A literature search was conducted using the key words allergy, basophil activation, CD63, CD203c, diagnosis, drugs, hypersensitivity, flow cytometry, specific IgE antibodies; this was complemented by the authors' own experience.

Results: The drugs that have been most studied with both techniques are β-lactam antibiotics and curarizing neuromuscular blocking agents (NMBA). For sIgE morphine, data are available on the value of this test as a biomarker for sensitization to substituted ammonium structures that constitute the major epitope of NMBA, especially rocuronium and suxamethonium. For the BAT, there are also data on non-steroidal anti-inflammatory drugs (NSAIDs) and iodinated radiocontrast media. For β-lactam antibiotics, sensitivity and specificity of sIgE varies between 0 and 85% and 52 and 100%, respectively. For NMBA, sensitivity and specificity varies between 38.5 and 92% and 85.7 and 100%, respectively. Specific IgE to morphine should not be used in isolation to diagnose IDHR to NMBA nor opiates. For the BAT, sensitivity generally varies between 50 and 60%, whereas specificity attains 80%, except for quinolones and NSAIDs.

Conclusions: Although drug-sIgE assays and BAT can provide useful information in the diagnosis of IDHR, their predictive value is not absolute. Large-scale collaborative studies are mandatory to harmonize and optimize test protocols and to establish drug-specific decision thresholds.

Fig. 1

HistaFlow plots in a cefazolin-reactive patient showing clear anaphylactic degranulation of basophils in response to cefazolin (100 µg/mL). a–c Resting cells stimulated with buffer; d–f display the responses to positive control stimulation with anti-IgE; and g–i THE response upon stimulation with the antibiotic. Note that only CD203c++/CD63+ cells release histamine (decrease of DAO, c, f, i). See [110]. DAO diamine oxidase, HisRel histamine release, IgE immunoglobulin E

Fig. 2

Representative plot of CD63 appearance and histamine release in response to buffer, anti-IgE as a positive control, pholcodine 10 µg/mL, and the structurally almost similar opiates codeine (100 mg/mL) and morphine (100 µg/mL) in a patient with pholcodine allergy and a negative challenge for codeine and morphine [82]. DAO diamine oxidase, IgE immunoglobulin E, pos.ctrl positive control