Immune Response to Snake Envenoming and Treatment with Antivenom; Complement Activation, Cytokine Production and Mast Cell Degranulation

Abstract

BackgroundSnake bite is one of the most neglected public health issues in poor rural communities worldwide. In addition to the clinical effects of envenoming, treatment with antivenom frequently causes serious adverse reactions, including hypersensitivity reactions (including anaphylaxis) and pyrogenic reactions. We aimed to investigate the immune responses to Sri Lankan snake envenoming (predominantly by Russell's viper) and antivenom treatment.Methodology/Principal FindingsPlasma concentrations of Interleukin (IL)-6, IL-10, tumor necrosis factor α (TNFα), soluble TNF receptor I (sTNFRI), anaphylatoxins (C3a, C4a, C5a; markers of complement activation), mast cell tryptase (MCT), and histamine were measured in 120 Sri Lankan snakebite victims, both before and after treatment with antivenom. Immune mediator concentrations were correlated with envenoming features and the severity of antivenom-induced reactions including anaphylaxis. Envenoming was associated with complement activation and increased cytokine concentrations prior to antivenom administration, which correlated with non-specific systemic symptoms of envenoming but not with coagulopathy or neurotoxicity. Typical hypersensitivity reactions to antivenom occurred in 77/120 patients (64%), satisfying criteria for a diagnosis of anaphylaxis in 57/120 (48%). Pyrogenic reactions were observed in 32/120 patients (27%). All patients had further elevations in cytokine concentrations, but not complement activation, after the administration of antivenom, whether a reaction was noted to occur or not. Patients with anaphylaxis had significantly elevated concentrations of MCT and histamine.Conclusions/SignificanceWe have demonstrated that Sri Lankan snake envenoming is characterized by significant complement activation and release of inflammatory mediators. Antivenom treatment further enhances the release of inflammatory mediators in all patients, with anaphylactic reactions characterised by high levels of mast cell degranulation but not further complement activation. Anaphylaxis is probably triggered by non allergen-specific activation of mast cells and may be related to the quality of available antivenom preparations, as well as a priming effect from the immune response to the venom itself.

Workgroup Report by the Joint Task Force Involving American Academy of Allergy, Asthma & Immunology (AAAAI); Food Allergy, Anaphylaxis, Dermatology and Drug Allergy (FADDA) (Adverse Reactions to Foods Committee and Adverse Reactions to Drugs, Biologicals, and Latex Committee); and the Centers for Disease Control and Prevention Botulism Clinical Treatment Guidelines Workgroup—Allergic Reactions to Botulinum Antitoxin: A Systematic Review

“…Because snake venom itself can cause complement activation and anaphylaxis, it is not possible to differentiate anaphylaxis caused by venom and that caused by antitoxin among treated patients [31]. Intradermal ST to snake and scorpion antivenoms have shown PPV averaging 32%, indicating that hypersensitivity ST is ineffective in predicting immediate-type hypersensitivity manifestations among patients given snake and scorpion antivenom [32].…”

Snake bite mortality in children: beyond bite to needle time

“…This reaction is mediated by inflammatory cytokines. Snake envenoming has been found to be characterised by significant complement activation and release of inflammatory mediators, which was found to be unrelated to administration of ASV, even though it further enhanced release of these inflammatory mediators 15. It is likely that the intense inflammatory response following a poisonous snake bite is the cause of this leucocyte response.…”

Snakebite Envenoming – A Combined Density Equalizing Mapping and Scientometric Analysis of the Publication History

“…PLOS Neglected Tropical Diseases has published in the past years numerous studies related to the field of snakebites [37,38]. They range, for example, from neurotoxicological aspects [39], immune responses [37], phylogeny, venom composition of diverse species [38], the analysis of geographical information [40] to basic science issues [41–43] and public health [44].…”