Advances in Medical Sciences 63 (2018) 265–277 Contents lists available at ScienceDirect Advances in Medical Sciences journal homepage: www.elsevier.com/locate/advms Review article Markers of anaphylaxis – a systematic review a a a Maria Magdalena Tomasiak-Łozowska , Maciej Klimek , Agnieszka Lis , a,b a, Marcin Moniuszko , Anna Bodzenta-Łukaszyk * a Department of Allergology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland b Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, Bialystok, Poland A R T I C L E I N F O A B S T R A C T Article history: fi Received 3 September 2017 Anaphylaxis is de ned as severe, life-threatening, systemic or general, immediate reaction of Accepted 17 December 2017 hypersensitivity, with repeatable symptoms caused by the dose of stimulus which is well tolerated Available online 20 March 2018 by healthy persons. The proper diagnosis, immediate treatment and differential diagnosis are crucial for saving patient's life. However, anaphylaxis is relatively frequently misdiagnosed or confused with other Keywords: clinical entities. Thus, there is a continuous need for identifying detectable markers improving the proper Anaphylaxis diagnosis of anaphylaxis. Here we presented currently known markers of anaphylaxis and discussed in Mast cell more detail the most clinically valuable ones: tryptase, platelet activacting factor (PAF), PAF- Tryptase acethylhydrolase, histamine and its metabolites. Histamine © 2017 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved. Platelet activating factor Contents 1. Introduction . 265 2. Material and methods . 266 3. Results and Discussion . 267 3.1. Anaphylaxis – definition, clinical manifestations, differential diagnosis . 267 3.1.1. Role of mast cells in anaphylaxis . 267 3.2. Tryptase . 269 3.3. Histamine . 271 3.3.1. Histamine and myocardial dysfunction . 272 3.4. Platelet-activating factor (PAF) . 273 3.5. Genetic markers of anaphylaxis . 274 4. Conclusion . 274 Conflict of interest . 275 Financial disclosure . 275 References . 275 1. Introduction healthy persons [1]. Mast cells are the most important cells, involved in anaphylactic reactions. The mediators of these cells are: Anaphylaxis is defined as severe, life-threatening, systemic or histamine, tryptase, serotonin, proteoglycans, proteases, chemotac- general, immediate reaction of hypersensitivity, with repeatable tic factors and de novo synthetized lipid mediators: prostaglandin symptoms caused by the dose of stimulus which is well tolerated by D2 (PGD2), leukotriene B4 (LTB4), platelet activacting factor (PAF), cysteinyl leukotrienes (LTC4, LTD4, LTE4,), cytokines (TNF-alpha, IL- 4, IL-5, IL-6, IL-8) [1–4]. Therefore, the proper diagnosis, immediate treatment and also differential diagnosis are crucial for saving * Corresponding author at: Department of Allergology and Internal Diseases, patient’s life. The measurements of potential markers of anaphy- Medical University of Bialystok, M. Sklodowskiej-Curie 24A, 15-276 Bialystok, laxis could be helpful in this situation. Inpresent, the measurements Poland. Tel.: +48 85 831 8373. of tryptase levels are used in clinical practice [1–4]. Scientific E-mail address: [email protected] (A. Bodzenta-Łukaszyk). reports revealed, that the activity of this enzyme, which is https://doi.org/10.1016/j.advms.2017.12.003 1896-1126/© 2017 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved. 266 M.M. Tomasiak-Łozowska et al. / Advances in Medical Sciences 63 (2018) 265–277 characteristic for mast cell granules, correlates well with the PAF was discovered). In January 2017, when we started the severity of anaphylactic reactions [1–4]. The measurements of manuscript preparation, full-text articles were assessed for eligibili- levels of platelet activating factor (which causes the increase in ty. In order to select the data available in the literature, we performed vascular permeability) and PAF-acethylhydrolase, as well as the searching of the data using the following strategy: anaphylaxis À histamine and its metabolites, could be also the valuable tool in 990; anaphylaxis AND clinicaltrialÀ 405; anaphylaxis AND review À cases of anaphylaxis. 2263; anaphylaxis AND case report À 2304; anaphylaxis AND Here we presented currently known markers of anaphylaxis guidelines À 551; mast cell À 19803; mast cell AND anaphylaxis À and discussed in more detail the most clinically valuable ones: 1347; histamine À 21096; histamine AND review À 3610; histamine tryptase, platelet activacting factor (PAF), PAF-acethylhydrolase, AND anaphylaxis À 990; histamine AND clinical trial À 2157; histamine and its metabolites. histamine AND anaphylaxis AND clinical trial À 30; histamine AND anaphylaxis AND case report À 157; histamine receptor À 8551; 2. Material and methods histamine receptor AND anaphylaxis À 202; tryptase À 3132; tryptase AND review À 460; tryptase AND anaphylaxis À 464; A search was started on 01.04.2015. using the MEDLINE/PubMed tryptase AND mast cell À 2570; tryptase AND clinical trial À 128; database (United States National Library of Medicine National tryptase AND case report À 287; PAF À 4046; PAF and review À 347; Institutes of Health). The key words, used in the process of searching PAF AND anaphylaxis À 68; PAF AND clinical trial À 297; PAF AND data; were as follows: anaphylaxis; mast cells; histamine; histamine clinical trial AND anaphylaxis À 0; PAF AND case report AND receptors; tryptase; PAF. In order to select the data available in the anaphylaxis À 0. Filters: published in last 17 years; full text. literature, we performed the searching of the data using the From those full-text articles, 285 were selected for further following strategy: anaphylaxis À 19786; anaphylaxis AND clinical analysis. In the final version of the manuscript, 168 articles were trial À 693; anaphylaxis AND review À 3012; anaphylaxis AND case cited (5 clinical papers, 37 papers on mast cells and their functions report À 4764; anaphylaxis AND guidelinesÀ 576;mast cellÀ 35164; in anaphylaxis, and papers on tryptase, histamine and PAF (n = 31, mast cell AND anaphylaxis À 2418; histamine À 67318; histamine n = 34, n = 61, respectively)). AND review À 8456; histamine AND anaphylaxis À 3474; histamine The search was mainly limited to studies written in English. 166 AND clinical trial À 6330; histamine AND anaphylaxis AND clinical from 168 citations were found in MEDLINE. In the part of the trial À 96; histamine AND anaphylaxis AND case report À 351; manuscript, concerning clinical signs and symptoms, two Polish histamine receptor À 21173; histamine receptor AND anaphylaxis À authors of chapters in textbooks were cited (Refs. [2,55]). Three 535; tryptase À 3990; tryptase AND review À 569; tryptase AND citations, concerning tryptase in diagnostics of allergic diseases, anaphylaxis À 518; tryptase AND mast cell À 3342; tryptase AND anaphylactic reactions to low-molecular weight chemicals, and clinicaltrialÀ 198; tryptaseANDcase reportÀ 366;PAFÀ 10460;PAF idiopathic anaphylaxis, were written in Polish in original versions and review À 830; PAFAND anaphylaxis À 280; PAF AND clinical trial (Refs. [14,17,163], respectively). À 297; PAF AND clinical trial AND anaphylaxis À 0; PAF AND case The process of searching for data is presented graphically report AND anaphylaxis À 0. Filters: published since 1972 (in 1972 according to PRISMA 2009 flow diagram in Fig. 1. Fig. 1. PRISMA 2009 flow diagram [5]. M.M. Tomasiak-Łozowska et al. / Advances in Medical Sciences 63 (2018) 265–277 267 Table 1 3. Results and Discussion Frequency of occurrence of clinical features of anaphylaxis [3,4, modified]. – fi 3.1. Anaphylaxis de nition, clinical manifestations, differential Skin/mucosa Urticarial eruption diagnosis 80–90% Angioedema -oropharyngeal -laryngeal The European Academy of Allergy and Clinical Immunology -intestinal (EAACI) describes anaphylaxis as a severe, life-threatening, Flushing systemic or generalized, immediate hypersensitivity reaction. It Pruritus (palms/soles/oral/genitalia) Bronchopulmonary Laryngeal edema is, in other words, a manifestation of objective, repeatable 60–70% Wheeze/Cough symptoms caused by an exposure to a stimulus of a strength that Rhinitis would be well tolerated by healthy individuals [1]. Cardiac Hypotension/shock fi Anaphylaxis is not usually treated as a speci c disease, but as a 40–50% Reduced cardiac output set of symptoms characterizing a specific reaction of people who Myocardial ischemia Hypotension/shock are hypersensitive to various factors [2]. In the International Reduced cardiac output Statistical Classification of Diseases and Related Health Problems Myocardial ischemia ICD-10, it most closely matches an anaphylactic shock (T78.2). Arrhytmia Clinical manifestations of anaphylaxis depend on the organs or Cardiac arrest Substernal pain systems affected. The clinical symptoms of hypersensitivity Kounis syndrome reactions, defined as anaphylaxis, can have a mild course and be Gastrointestinal Nausea of a local nature (hives, swelling) or give severe reactions with 40–50% Vomiting symptoms of shock (ie. a significant decrease in blood pressure, Diarrhea symptoms of airway obstruction) [2]. Intestinal edema Neurological Dizziness If one of the following criteria is fulfilled, the characteristic <15% Confusion symptoms are very likely to be described as anaphylaxis [3]: Headache Feeling of impending doom 1 Respiratory reactions (shortness of breath, wheezing, stridor,