Anaphylaxis in the 21st century: phenotypes, endotypes, and biomarkers

Abstract

Anaphylaxis is the most serious of all allergic reactions and can be fatal. The diagnosis is frequently delayed, and misdiagnosis often occurs with asthma or urticaria. Biomarkers such as tryptase are not routinely checked, and appropriate treatment with epinephrine is not administered in a majority of cases, increasing the risk of poor outcomes. The objective of this review is to provide a better understanding of the pathophysiology of anaphylaxis with a description of phenotypes, endotypes, and biomarkers available in both the clinical and research settings. Expanding knowledge with regard to the presentation, causes, and triggers for anaphylaxis among health care providers will improve its diagnosis and management, increase patient safety, and decrease morbidity and mortality.

Serum Baseline Tryptase Level as a Marker for the Severity of Anaphylaxis

“…Although systemic mastocytosis was unlikely after bone marrow biopsy showing no abnormalities in mast cells, we could not exclude a mast cell activation syndrome (MCAS) as the underlying cause of symptoms in this patient. According to WHO criteria, additional findings including mast cells expressing CD2 and/or CD25 and presence of the KIT D816V mutation would help in the diagnosis of clonal MCAS [7, 28]. Nonclonal MCAS could also be suspected; however, we could not find common features of this condition in our patient, including IgE-mediated allergy, inflammatory and autoimmune diseases, neoplasms, Ehlers-Danlos syndrome, postural orthostatic tachycardia syndrome, bone abnormalities, or osteomuscular and central nervous symptoms, as described [7].…”

“…Currently, anaphylaxis phenotypes have been defined as type-I-like reactions, when classical allergic symptoms due to the release of inflammatory mediators from mast cells and basophils are present, including flushing, pruritus, urticaria, angioedema, dyspnea, wheezing, nausea, vomiting, diarrhea, hypotension, and cardiovascular collapse; cytokine storm-like reactions and mixed reactions, which are frequently provoked by chemotherapy or monoclonal antibodies and induce atypical symptoms such as chills, fever, or pain, in addition to classical symptoms, and reactions mediated by complement, which can be caused by contrast dyes or dialysis membranes, and often induce hypotension and oxygen desaturation [1, 7, 8]. Endotypes underlying these clinical presentations include IgE and non-IgE-mediated mechanisms, cytokine release, direct mast cell and basophil activation, complement activation with generation of anaphylatoxins C3a and C5a, contact system activation with bradykinin release, IgG-mediated cell activation which is still debat able in humans, and mixed reactions [1, 7, 8].…”

“…Endotypes underlying these clinical presentations include IgE and non-IgE-mediated mechanisms, cytokine release, direct mast cell and basophil activation, complement activation with generation of anaphylatoxins C3a and C5a, contact system activation with bradykinin release, IgG-mediated cell activation which is still debat able in humans, and mixed reactions [1, 7, 8]. …”

“…In keeping with precision medicine concepts, biomarkers in anaphylaxis would be very useful to improve diagnosis, particularly if point-of-care diagnostic biomarkers could be developed, to allow endotyping of patients, to propose new therapies based on the stratification of severity, and to predict risk [7, 8]. To date, serum tryptase levels are the best-characterized biomarker of anaphylaxis and have been included as part of institutional protocols [9-15].…”

“…In patients with low baseline tryptase levels, levels may increase during anaphylaxis but still remain in the normal range; therefore, levels of 2 ng/mL plus 1.2 times baseline have been considered significantly increased [1]. Measurements of the histamine metabolite methylhistamine; prostaglandin D 2 and its metabolite 9α-11β prostaglandin F 2 ; and leukotrienes E 4 and C 4 have also been investigated; however, difficulties in obtaining 24-h urine samples in the scenario of anaphylaxis may hamper their practical use [7, 8]. Elevated IL-6 levels have been proposed as a marker of cytokine storm-type anaphylaxis [1].…”