Assessment of Patients With Beta-Lactams Positive Provocation Tests by Biomarkers of IgG-Related Neutrophil Activation

Abstract

Background: Beta-lactams (BLs) are the predominant cause of immediate allergic reactions to drugs. Immediate hypersensitivity reactions (IHR) with positive provocation tests and negative skin and in vitro tests have undetermined mechanisms. We evaluated whether biomarkers of IgG-dependent neutrophil activation could help to assess this subgroup of BL IHRs.

Methods: We evaluated biomarkers of neutrophil activation and neutrophil extracellular traps (NETs) in the serum of 26 BL IHR patients presenting with a positive provocation test, negative skin and serum specific IgE, and positive specific sIgG, and 8 perioperative BL IHR cases with positive skin tests and negative sIgE compared to 19 non-allergic matched controls.

Results: We observed increased levels of DNase activity, neutrophil elastase (NE), myeloperoxidase (MPO)-DNA, IL8 and decreased IL4 and IL13 in patients, compared to matched controls, in the first 15 min of IHRs. DNAse activity, NE and MPO-DNA were maintained at high levels 2 h later (T0 + 2), while cell-free DNA and CXCR2 decreased significantly. IgG-related activation of neutrophils was suggested by significant correlations between NE, IL8 and CXCR2 axis and a single cluster associating BL sIgG antibodies and NE at T0 + 2, in principal factor analysis of all biomarkers.

Conclusion: Biomarkers of neutrophil activation and NETs were increased in BL IHRs with negative skin tests, positive sIgG and negative serum sIgE, and positive provocation test. We propose DNAse activity and NE as biomarkers for the biological assessment of BL IHRs and provocation tests and to consider IgG-related neutrophil activation as one of the mechanisms involved in BL IHRs with undetermined cause.

Keywords: beta‐lactam allergy; immediate hypersensitivity reactions; myeloperoxidase; neutrophil elastase; neutrophil extracellular traps (NETs); neutrophils.