Penicillin causes non-allergic anaphylaxis by activating the contact system

Abstract

Immediate hypersensitivity reaction (IHR) can be divided into allergic- and non-allergic-mediated, while “anaphylaxis” is reserved for severe IHR. Clinically, true penicillin allergy is rare and most reported penicillin allergy is “spurious”. Penicillin-initiated anaphylaxis is possible to occur in skin test- and specific IgE-negative patients. The contact system is a plasma protease cascade initiated by activation of factor XII (FXII). Many agents with negative ion surface can activate FXII to drive contact system. Our data showed that penicillin significantly induced hypothermia in propranolol- or pertussis toxin-pretreated mice. It also caused a rapid and reversible drop in rat blood pressure, which did not overlap with IgE-mediated hypotension. These effects could be countered by a bradykinin-B2 receptor antagonist icatibant, and consistently, penicillin indeed increased rat plasma bradykinin. Moreover, penicillin not only directly activated contact system FXII-dependently, but also promoted bradykinin release in plasma incubated-human umbilical vein endothelial cells. In fact, besides penicillin, other beta-lactams also activated the contact system in vitro. Since the autoactivation of FXII can be affected by multiple-factors, plasma from different healthy individuals showed vastly different amidolytic activity in response to penicillin, suggesting the necessity of determining the potency of penicillin to induce individual plasma FXII activation. These results clarify that penicillin-initiated non-allergic anaphylaxis is attributed to contact system activation, which might bring more effective diagnosis options for predicting penicillin-induced fatal risk and avoiding costly and inappropriate treatment clinically.

Mechanisms of human drug-induced anaphylaxis

“…Recent human clinical data proposed even further possible mechanisms in addition to MRGPRX2, exemplified by the role of the contact system via factor XII activation and bradykinin release in some penicillin-induced anaphylaxis, 90 or after heparin injection and severe hypotension due to oversulfated chondroitin sulfate contamination. 91 Explorations outside of basophil activation, that is, neutrophil, platelet, and monocyte activation, and of antidrug IgE, that is, presence of antidrug IgG, 40,41,92 should increase in clinical research to improve our understanding of anaphylaxis and define markers for its endotypes.…”

Use and Interpretation of Acute and Baseline Tryptase in Perioperative Hypersensitivity and Anaphylaxis

“…Acute hypotensive reactions have been documented in dialysis patients when receiving over-sulfated chondroitin sulfate, a contaminant of heparin that activated the contact pathway, factor XII, leading to activation of plasma kallikrein and generation of bradykinin [44][45] . Various drugs, including penicillin G, when administered at suprapharmacologic concentrations, can activate the contact pathway in mice and rats and in human plasma 46 , which does not occur at pharmacologic doses. Acute reactions to iodinated radiocontrast media have been reported to occur by complement activation 47 , and more recently acute elevations in serum tryptase suggest that some cases involve mast cell activation 48 .…”

Practical guide for evaluation and management of beta-lactam allergy: position statement from the Canadian Society of Allergy and Clinical Immunology

“…Several mechanisms leading to the immune response have been proposed, including the hapten model, pharmacologic interaction model and altered peptide repertoire model [(reviewed in [ 10 ]]. Non-immune mediated or “pseudoallergic” reactions has been attributed to plasma contact system activation [ 11 ].…”

“…The public health implications of erroneous labelling of beta-lactam allergy are well established, including an increased length and cost of hospital stay, decreased infection resolution rates, increased risk of infection recurrence, increased risk of adverse events from use of second-line antibiotics including C-difficile infections, and even increased mortality [ 10 , 11 , 24 – 26 ]. The over-labelling of beta-lactam allergy is associated with increased costs and antimicrobial resistance; testing for beta-lactam allergy would be 9.5 times less expensive than treating an in-patient population with an alternative antimicrobial [ 5 ].…”