Application of Precision Medicine to the Treatment of Anaphylaxis

Marina Labella; Marlene Garcia-Neuer; Mariana Castells

Disclosures

Curr Opin Allergy Clin Immunol. 2018;18(3):190-197. 

In This Article

Definition and Diagnosis; Pathways of Anaphylaxis; Phenotypes, Endotypes and Biomarkers

In 1901, the term anaphylaxis was coined from ana = absence, phylaxis = protection in Greek. A universal definition has not been established for anaphylaxis; however, it is universally accepted that anaphylaxis is rapid in onset and may cause death. Ambiguity around the definition of anaphylaxis may lead to the underrecognition, underdiagnosis and undertreatment.

The description of phenotypes, endotypes and biomarkers has improved the understanding of HSR and anaphylaxis.[1–3] As we can see in Figure 1, a majority of Type I reactions[4,5] are mediated by IgE, which requires previous exposure to the culprit agent. Other non-IgE-mediated Type I pathways in animal models have been described and involve IgG and stimulating platelet activating factor (PAF).[6–8] The endotype for Type I reactions are mediated by mast cell and basophils which release tryptase, histamine, leukotrienes, prostaglandins and PAF causing flushing, pruritus, urticaria, throat tightness, shortness of breath, back pain, nausea, vomiting, diarrhea and cardiovascular collapse.[9] The common triggers for these reactions include foods, drugs, environmental allergens, immunocomplex and Hymenoptera venom. CRR endotype is mediated by T cells, monocytes and macrophages. These reactions can occur at first lifetime exposure but have also been described after several exposures and are typical with mAbs. The major mediators are TNF-α, IL-6 and IL-1β which are responsible for fever, chills, rigors, nausea, pain, headache, oxygen desaturation and hypotension. Mixed reactions (Type 1 and CRR) have been reported after chemotherapy and mAb therapy; however, the mechanism is difficult to differentiate. Complement/bradykinine-like reactions can induce flushing, hives, hipoxia, vasodilation and hypotension due to the direct activation of mast cells generating anaphylotoxins such as C3a and C5a, as well as the activation of the intrinsic coagulation pathway.[10,11] This mechanism has been seen in contrast dye, dialysis membranes, oversulfated chondroitin sulfates and drugs infusions suspended in certain lipid vehicles, such as Cremophor EL (BASF Corporation, Florham Park, New Jersey, USA), polysorbate 80 and polyethylene glycol infusion.[5] Mast-cell activation syndrome endophenotype can be triggered by stress, drugs, foods, alcohol, surgery, vaccines, Hymenoptera venom and exercise due to an inappropriate release of mediators commonly caused by the KIT D816V mutation.[12–14]

Figure 1.

Pathways of anaphylaxis. Phenotypes of anaphylaxis include Type 1 reactions, cytokine release reactions, mixed reactions, complement-like reactions and mast cells activation syndromes. Phenotypes are defined by endotypes and underlying biomarkers such as prostaglandins, leukotrienes, platelet activating factor, histamine, tryptase, TNF-α, IL-6 and IL-1β. The first line of treatment is epinephrine and desensitization is indicated is selected cases. Reproduced with permission [2].

Measurement of biomarkers during or shortly after anaphylaxis, such as tryptase or IL-6,[15,16] can help elucidate mechanisms behind the reaction. Tryptase levels can be detected a few minutes after the onset of the reaction and return to normal levels within 24–48 h. Increases above 11.4 ng/nl are indicative of acute mast-cell/basophil activation. An increase in tryptase levels at least 2 ng/ml + 1.2 × baseline value is also considered clinically meaningful. Familial tryptasemia is a disease recently described in which several members of a family, without mastocytosis, present elevated baseline tryptase levels due a greater number α-tryptase genes.[14] Levels of other inflammatory mediators such as TNF-α, IL-6 and IL-1β may identify a CRR but have not yet been validated.[17]

Skin testing is a useful tool to identify the involvement of IgE-mediated mechanisms. The specificity of skin testing has been defined in Type I-mediated reactions; however, skin testing has not been validated in CRR reactions.

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