Idiopathic anaphylaxis yardstick

Ann Allergy Asthma Immunol xxx (2019) 1e12

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Yardstick

Idiopathic anaphylaxis yardstick Practical recommendations for clinical practice Melody C. Carter, MD *; Cem Akin, MD y; Mariana C. Castells, MD, PhD z; Erin P. Scott, PhD x; Phil Lieberman, MD { * National

Institutes of Health, Bethesda, Maryland Department of Medicine, University of Michigan, Ann Arbor, Michigan z Department of Medicine, Division of Rheumatology, Immunology, and Allergy, Mastocytosis Center, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts x Scott Medical Communications, LLC, Tyler, Texas { Departments of Medicine and Pediatrics, Divisions of Allergy and Immunology, University of Tennessee, Memphis, Tennessee y

A R T I C L E

I N F O

Article history: Received for publication June 10, 2019. Received in revised form August 20, 2019. Accepted for publication August 27, 2019.

A B S T R A C T Anaphylaxis is considered idiopathic when there is no known trigger. The signs and symptoms of idiopathic anaphylaxis (IA) are identical to those of anaphylaxis because of a known cause and can include cutaneous, circulatory, respiratory, gastrointestinal, and neurologic symptoms. Idiopathic anaphylaxis can be a frustrating disease for patients and health care providers. Episodes are unpredictable, and differential diagnosis is challenging. Current anaphylaxis guidelines have little specific guidance regarding differential diagnosis and long-term management of IA. Therefore, the objective of the Idiopathic Anaphylaxis Yardstick is to use published data and the authors’ combined clinical experience to provide practical recommendations for the diagnosis and management of patients with IA. Copyright Ó 2019 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Introduction Idiopathic anaphylaxis (IA) is by definition an exclusionary diagnosis. Many known triggers of anaphylaxis exist, including food, medications, hormones (ie, progesterone), insect venom, and physical factors such as exercise.1-3 When there is no known trigger, the anaphylaxis is considered idiopathic. The signs and symptoms of IA are identical to those of anaphylaxis caused by a known trigger and can include cutaneous, circulatory, respiratory, gastrointestinal, and neurologic symptoms (Table 1).4-6 The National Institute of Allergy and Infectious Disease (NIAID) and Food Allergy and Anaphylaxis Network (FAAN) states that a diagnosis of anaphylaxis is likely, even when the allergic status of the patient and the potential cause of the reaction is unknown, when the onset of illness is acute (minutes to several hours), with involvement of the skin,

Reprints: Phil Lieberman, MD, 6104 Poplar Boulevard, Memphis, TN 38119; E-mail: [email protected]. Disclosures: Dr. Carter has nothing to disclose. Dr. Akin has consultancy agreements with Novartis and Blueprint Medicines and received research support from Blueprint Medicines. Dr. Castells receives research support from Blueprint Medicines and editorial support from ACAAI. Dr. Scott has provided contract medical writing and editorial support for ALK and ACAAI. Dr. Lieberman is a consultant for Kaleo Pharma. Funding Sources: American College of Allergy, Asthma and Immunology, including editorial support and an honorarium for each author.

mucosa, or both, and is accompanied by respiratory compromise or reduced blood pressure or associated symptoms of end-organ dysfunction.7 As acknowledged by the NIAID/FAAN report, no diagnostic criteria for anaphylaxis is 100% sensitive and specific, and some patients with IA, although rare, will fall outside the proposed definition.7 As with anaphylaxis caused by known triggers, IA may be lifethreatening and, although rare, fatalities have been reported.8,9 Although risk factors specifically for IA have not been formally statistically assessed, the rate of IA is substantially higher in women than in men.10,11 A history of atopy or intermittent urticaria or angioedema also appears to increase the risk of IA.10,11 Mastocytosis is an important risk factor for IA, and in patients with IA a clonal mast cell disease should be considered in the differential diagnosis.12,13 Mast cells, along with basophils, are the effector cells in human anaphylaxis, and the symptoms are caused by release of vasoactive mediators and cytokines from activated mast cells and basophils. Idiopathic anaphylaxis is therefore classified under idiopathic mast cell activation syndromes in a recent classification of mast cell disorders.14 The prevalence of IA is difficult to estimate, especially because new causes of anaphylaxis that were previously categorized as idiopathic have been identified in recent years. In a review of 601 anaphylaxis cases from a single center in the United States spanning 1978 to 2003, 59% of the cases were categorized as

https://doi.org/10.1016/j.anai.2019.08.024 1081-1206/Copyright Ó 2019 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

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idiopathic.11 In a follow-up review of the same clinic spanning the years 2006 to 2016, 35% of cases were categorized as idiopathic.15 The decrease in frequency was attributed to the discovery of anaphylaxis caused by serum immunoglobulin E (IgE) to galactosea-1,3-galactose (alpha-gal), which was first described in 2008 and 2009.16,17 In the follow-up review, 33% of anaphylaxis events with a definitive cause were attributable to alpha-gal.15 However, the prevalence of alpha-gal is related to the distribution of ectoparasitic ticks (see later discussion) and may differ from region to region. The decrease in IA cases was also attributed to better recognition and diagnosis of mast cell-related disorders (ie, systemic mastocytosis), which were responsible for 6% of the reviewed anaphylaxis events in the follow-up study.15 A large retrospective review of 730 patients with anaphylaxis in the United States in the years 2002 to 2013 found that 13.7% of cases were attributed to IA,18 and in a review of 40 pediatric anaphylaxis cases treated in an emergency department (ED) in the United States in the year 2014, 17.5% of cases were classified as IA.19 Various studies in Asian and Middle Eastern countries reported IA as the cause of anaphylaxis in 11.8% to 15% of cases.20-23 Various theories have been investigated to explain the pathogenesis of IA. A “hidden” allergen in food is an obvious potential culprit and is discussed further later. Another theory is that patients with IA have hypersensitive mast cells that are prone to degranulation because of the presence of extracellular Th2 cytokines. In support of this theory, peripheral blood mononuclear cells from patients with IA, regardless of atopic status, were found to release increased levels of the Th2 cytokines interleukin (IL)-4, IL-5, and IL13 after stimulation compared with cells from atopic and nonatopic controls.24 Patients also exhibit elevated total serum tryptase and urine N-methylhistamine during an IA episode; elevated total serum tryptase is specific for mast cell activation.25 However, in a prospective study of patients with IA, ex vivo studies of cultured mast cells indicated no evidence of a hyperreponsive mast cell phenotype.12 Another theory of IA pathogenesis involves activated lymphocytes. Patient with IA have been shown to have a higher percentage of activated T-cells (CD3þ HLA-DRþ) in peripheral blood during acute episodes compared with patients in remission.26 In addition, patients with IA were shown to have a higher percentage of activated B-cells (CD19 þ CD23þ) both in remission and during an acute episode compared with healthy controls.26 Whether the increase in activated lymphocytes is part of the underlying pathogenesis of IA or is a secondary effect of an IA event is unclear. Other theories posited to explain the mast cell activation indicative of IA include an effect of female hormones on mast cells or basophils or the presence of IgE autoantibodies.27 Attempts to modulate female hormones to control IA have been inconclusive, and neither progesterone nor estradiol has any effect on basophil histamine release.28,29 Idiopathic anaphylaxis can be a frustrating disease for patients and health care providers. Episodes are unpredictable, and differential diagnosis is challenging. Current anaphylaxis guidelines have little specific guidance regarding differential diagnosis and longterm management of IA.2,7,30-32 Therefore, the objective of this Yardstick is to provide practical recommendations for the diagnosis and management of patients with IA. Patient Profile The typical patient experiences acute-onset bronchospasm, hypotension, syncope, or gastrointestinal symptoms or urticaria or angioedema with upper airway obstruction. Urticaria and angioedema may be absent in some forms of IA. After detailed history, physical examination, and diagnostic testing (including extensive food and drug skin prick and serum-specific IgE testing), no known anaphylaxis triggers can be identified. Serum tryptase may be

elevated during the event (ideally measured within the first 4 hours), based on the formula of 20% þ 2 ng/mL over the baseline value. The patient’s baseline serum tryptase (bST) value also may be elevated and may not increase if the trigger is an unidentified food allergen.33 Differential Diagnoses Several diseases and disorders have symptoms that mimic IgEmediated anaphylaxis, and some causes of anaphylaxis have been discovered or better recognized in recent years (ie, alpha-gal). Thus, many differential diagnoses need to be considered to categorize an event as IA. Patient History A detailed patient history is the first step toward diagnosis when a patient presents with suspected anaphylaxis (Table 2).34 The history should include information as to events that occurred shortly before the event, such as ingestion of food or drugs, activities (ie, exercise), exposure to heat or cold, or insect stings. The time, location, and duration of the event should be considered, as well as the exact nature of the symptoms, state of wellness, and what, if any, treatment was received. Cyclical anaphylaxis is seen in progestogen hypersensitivity syndrome.1 Flushing Syndromes Patients with recurrent flushing are often investigated for allergic origins. Flushing may be a sign of anaphylaxis if accompanied by other signs and symptoms as listed in Table 1. Isolated flushing alone is rarely attributable to an allergic cause or systemic mast cell activation. Differential diagnosis of flushing is broad and includes hormonal (eg, carcinoid, pheochromocytoma, medullary thyroid cancer, perimenopausal, testosterone deficiency), pharmacologic (eg, vasodilator drugs, niacin), cutaneous (eg, rosacea), neurologic (eg, dysautonomia), psychologic (emotions), physiologic (eg, heat, exercise), food intake (eg, spicy food, scombroid food poisoning), and mast cell activation, including anaphylaxis. Mast Cell Activation Syndromes and Mastocytosis Flushing is a common symptom in patients with mastocytosis. Flushing associated with mastocytosis typically lasts 15 to 30 minutes (as opposed to brief episodes seen in perimenopausal flushing) and may be associated with other findings such as tachycardia, abdominal cramps, lightheadedness, presyncope, or syncope. Mastocytosis is a clonal disorder of the hematopoietic system associated with activating KIT mutations (most commonly D816V). Patients with mastocytosis have a lifetime risk of anaphylaxis of approximately 30%,35,36 which is more commonly seen in adults with systemic mastocytosis as compared with children who have cutaneous disease alone.36 Triggers for anaphylaxis in mastocytosis include Hymenoptera stings, exercise, medications, and other IgE-mediated causes, although many of the episodes do not have an identifiable trigger.36 Therefore, mastocytosis is considered in the differential diagnosis of patients with recurrent unexplained anaphylaxis. Diagnosis of systemic mastocytosis requires a tissue biopsy (most often bone marrow) and demonstration of World Health Organization criteria (Table 3).37,38 Most (but not all) patients with mastocytosis have elevated bST levels, which further increase after anaphylactic episodes.36 Some patients with a low burden of clonal mast cells may have a normal bST and only display 1 or 2 clonal markers (KIT mutation or CD25 positivity on mast cells) in bone marrow. These patients are termed to have monoclonal mast cell activation syndrome (MMAS).39 The first study examining a group of patients who were previously diagnosed with IA found that 5 of 12 patients had clonal mast cell disease (mastocytosis or MMAS) when bone marrow biopsy

M.C. Carter et al. / Ann Allergy Asthma Immunol xxx (2019) 1e12 Table 1 Signs and Symptoms of Idiopathic Anaphylaxis (IA)a Respiratory Upper airway obstruction Dyspnea Wheezing Bronchospasm Circulatory Hypotension Loss of consciousness Cardiac arrhythmia/tachycardia Cutaneous Pruritus Urticaria Angioedema Flushing Gastrointestinal Diarrhea Abdominal pain Vomiting Neurologic Syncope/pre-syncope Seizure a Diagnosis of IA requires an acute onset of symptoms involving skin, mucosal tissue, or both AND respiratory compromise AND/OR reduced blood pressure or associated symptoms of end-organ dysfunction.7

specimens were carefully examined.40 These patients were more likely to present with flushing and syncopal or presyncopal events caused by hypotension, and were less likely to have urticaria and angioedema compared with patients with true IA (ie, without mastocytosis or MMAS). Therefore, a scoring system based on symptoms, tryptase levels, and sex was devised to predict patients with anaphylaxis who are more likely to have mastocytosis (REMA score).41 Mast cell activation syndrome (MCAS) is a rare clinical entity with heterogeneous causes. It is diagnosed in patients who present with typical signs of episodic mast cell activation, an increase in a validated marker of mast cell activation during an episode, and a positive response to mast cell targeting drugs, such as antihistamines, anti-leukotrienes, epinephrine, or omalizumab.42 The causes of mast cell activation can be clonal, in which mast cells carry D816V or another activating KIT mutation (eg, episodes associated with mastocytosis or MMAS) or nonclonal (IgE or noneIgE-mediated “secondary” mast cell activation, or idiopathic). Because mast cells are the main cells implicated in pathogenesis of anaphylaxis, all patients with IA also have an MCAS, although not all patients with MCAS have IA. Tryptase is the most specific and the best validated marker for mast cell activation. As mentioned previously, a formula of 20% of baseline þ 2 ng/mL has been proposed and validated as a reliable marker of mast cell activation.43,44 Serum or plasma tryptase should be obtained within 4 hours of the episode and compared with bST.42 Other markers such as urinary histamine metabolites (N-methylhistamine or methylimidazole acetic acid),

prostaglandin D2, and leukotriene C4 or their metabolites also increase in urine during allergic reactions; however, their cutoff levels, specificity, and sensitivities are not well established. Whether a chronic form of mast cell activation presenting with daily symptoms such as itching, abdominal pain, and fatigue, rather than well-defined episodes, exists is not known. Drug-/Alcohol-Induced Flushing Flushing can be an adverse effect of many medications, including calcium channel blockers, nitroglycerin, niacin, phosphodiesterase-5 inhibitors, 5-alpha reductase inhibitors, leuprolide, alpha- and beta-adrenergic blockers, glucocorticoids, opioids, cyclosporine, and vancomycin.45 Most of these drugs act directly on vascular smooth muscle, although mast cellemediated flushing can occur through noneIgE-mediated mechanisms (vancomycin) as well. Flushing associated with medication use is suspected on the basis of history and should be eliminated when the suspected drug is discontinued. Drug-induced flushing is usually not associated with hives or other signs of anaphylaxis. Alcohol may cause flushing in susceptible individuals. People with a deficiency of aldehyde dehydrogenase (more common in Asian heritage) may have severe flushing after ingestion of alcohol because of the buildup of acetaldehyde.46 Tumor-Related Flushing A number of neuroendocrine tumors can induce chronic flushing and other symptoms similar to anaphylaxis. Flushing episodes can be caused by carcinoid syndrome associated with neuroendocrine tumors, vasointestinal-polypeptideeproducing tumors (generally in the pancreas), medullary thyroid tumors, and pheochromocytoma (catecholamine-secreting tumors of the adrenal medulla). Urticaria and angioedema can be observed but are not common with these conditions. Hereditary Alpha Tryptasemia Syndrome (HATS) Elevated bST is estimated to occur in 4% to 6% of the general population.47,48 Germline duplications and triplications in the TPSAB1 gene encoding for a-tryptase segregate with inherited increases in bST, resulting in hereditary alpha tryptasemia syndrome (HATS).49,50 A duplication of both alleles or triplication of 1 allele is associated with significantly higher bST levels. In a study examining 35 families, these genetic changes were demonstrated in an autosomal dominant inheritance pattern with similar symptom complexes such as irritable bowel syndrome, cutaneous complaints, connective tissue abnormalities, and dysautonomia.50 Although the mean total bST was 15.9 ng/mL and 21.6 ng/mL in 2 studies,49,50 duplications of TPSAB1 have been demonstrated in patients with serum tryptase values of greater than 8 ng/mL.50 This is important to note, because tryptase values are considered normal when less than 11.4 ng/mL. A commercial test is now available to identify patients with multiple TPSAB1 genes.51

Table 2 Essential Features of the History in the Evaluation of a Patient Who Has Experienced an Episode of Anaphylaxisa A. Detailed history of ingestants (foods/drugs) taken within 6 hours before the event, including nonprescription medications (ie, nonsteroidal anti-inflammatory drugs) B. Activity in which the patient was engaged at the time of the event C. Location of the event (home, school, work, indoors, or outdoors) D. Exposure to heat or cold E. Any related sting or bite F. Time of day or night G. Duration of the event H. Recurrence of symptoms after initial resolution I. The exact nature of the symptoms (eg, if cutaneous, determine whether flush, pruritus, urticaria, angioedema) J. Assessing for physical factors or triggers K. In a female, the relationship between the event and menstrual cycle L. Was medical care given and what treatments were administered a

Reproduced and adapted with permission from Lieberman et al, 2013.34

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Table 3 Systemic Mastocytosis (SM) Criteria.a,37,38 Major SM criterion

Minor SM criterion

Multifocal dense infiltrates of MCs (15 MCs in aggregates) in BM biopsies or in sections of other extracutaneous organ(s) a. >25% of all MCs are atypical cells (type I or type II) on BM smears or are spindle-shaped in MC infiltrates detected on sections of visceral organs b. KIT point mutation at codon 816 in the BM or another extracutaneous organ or by blood PCR test c. MCs in BM or blood or another extracutaneous organ exhibit CD2 or CD25 d. Baseline serum tryptase level >20 ng/mL (in case of an unrelated myeloid neoplasm, item d is not valid as an SM criterion)

Table 4 Symptoms and Laboratory Findings Associated with Sensitization to Galactose-a-1, 3-Galactose in Relation to Red Meat Allergy Symptoms Cutaneous Gastrointestinal

Cardiovascular

Urticaria, erythematous palms, angioedema, pruritus Abdominal cramping, indigestion, nausea, diarrhea,  vomiting Hypotension, tachycardia, syncope

Atopy

Abbreviations: BM, bone marrow; MC, mast cells. a If at least 1 major and 1 minor or 3 minor SM criteria are fulfilled, the diagnosis of SM can be established. Reproduced with permission from Valent et al, 2017.38 Other

Symptoms that have been associated with HATS affect several organ systems and include cutaneous, connective tissue, atopy, and gastrointestinal and neuropsychiatric symptoms. Phenotypic characteristics are episodic flushing, pruritus, urticaria, and gastrointestinal symptoms, including eosinophilic esophagitis, hypermobile connective tissue disorder, and chronic musculoskeletal pain.49 Although an association with venom allergy and anaphylaxis may be present, these are not common in children. In a study of tryptase values in more than 15,000 patients, 900 patients had bST levels of 11.4 ng/mL or more.48 Anaphylaxis occurred in 21% of the patients with elevated bST, and the main triggers were food, insect stings, and drugs. Children represented 5.6% of the patients with an elevated bST. Symptoms in this patient population were similar to those of patients diagnosed with HATS and an increased frequency and severity of symptoms correlated with bST values, but the genetic status was unknown.

Laboratory findings

þSPT/intradermal to beef, lamb, and pork (small wheals, 2-4 mm diameter) Specific IgE-a-gal Specific IgE-cat epithelium, beef, lamb, pork Non-B blood type

Abbreviation: SPT, skin prick test.

pork and cat, evidence exists for specific IgE to pork and cat albumin, which cross-reacts with IgE to alpha-gal.58 Patients with cat allergy have IgE antibodies that bind to a carbohydrate epitope on cat IgA; this epitope has been identified as alpha-gal.59,60 However, most patients with alpha-gal sensitization are negative for specific IgE to Fel d 1.61 Patients also can have delayed reactions to foods containing gelatins made from mammals because of alpha-gal cross-reactivity.62 Cross-reactivity from the in vitro alpha-gal assay can occur with Bos d (beef) as a result of bovine thyroglobulin.63 Although evidence exists for cross-reactivity with milk proteins, patients can generally tolerate low-fat milk and milkbased products.

IgE to a-gal

Somatoform Conditions

Sensitization to galactose-a-1, 3-galactose (alpha-gal) has been associated with an immediate hypersensitivity reaction to cetuximab and delayed (3-6 hours) anaphylaxis to red meat.16,17 Although allergic sensitization is usually associated with a protein, this carbohydrate moiety has been responsible for severe adverse reactions16 and the hyperacute rejection of pigeprimate xenotransplantation.52 Symptoms of red meat allergy as a result of alpha-gal sensitization are similar to those of other IgE-mediated hyperreactions but are delayed several hours (Table 4). Reactions to pork kidney may be more immediate.53 Because of the delayed nature of the reaction, alpha-gal sensitization may not have been included in the differential diagnosis of some patients previously diagnosed with IA. The delayed response is thought to be associated with the digestive process needed to expose the carbohydrate epitope.54 Factors such as exercise, alcohol, or aspirin may lower the threshold of responsiveness to alpha-gal.53 The structure of alpha-gal is similar to that of the B blood group55 and is found in multiple tissues of nonprimate mammals.56 The development of this IgE-specific antibody to alpha-gal is linked to bites from ectoparasitic ticks worldwide and specifically to the Amblyomma americanum in the southeast region of the United States.57 The history of a seed tick bite or activities that allow for exposure to seed ticks in certain geographic areas is a good historical point for considering the diagnosis along with symptoms that occur hours after a meal. Currently, the areas of concern are mainly in the southeastern United States but are now advancing west and northward (Fig 1). Repeated tick exposure is associated with continued sensitivity. Patients also may test positive for specific IgE to beef, lamb, pork, and cat without clinical symptoms (Table 4). In the case of

Prostaglandins are released during mast cell activation in IA and can induce neurologic symptoms (described as the organic brain syndrome), including “brain fog,” confusion, anxiety, and short memory span. Such neurologic symptoms also can be associated with mastocytosis64 and can be a presenting sign during anaphylaxis. Posttraumatic stress disorder can be a consequence of IA and is an underrecognized and underdiagnosed condition associated with traumatic experiences after chemotherapy or monoclonal antibody-induced anaphylaxis,65,66 as well as after food-induced anaphylaxis in children and adolescents.67 Panic attacks, vocal cord dysfunction, and Munchausen stridor can mimic the IA symptom of throat tightening. A group of patients presenting with symptoms mimicking anaphylaxis without objective findings, who also meet the criteria for undifferentiated somatoform disorder, have been described and termed to have undifferentiated somatoform IA.68 Hidden Allergen In our experience, hidden allergens are not common causes of IA, but they should be considered in every patient. A comprehensive list of important hidden allergens and their sources are shown in Table 5. If a hidden food allergen is suspected in an event of anaphylaxis, ingredients from the recent meal should be reviewed, and if known allergens are identified, the patient should be counseled to avoid the food.69 If the ingredient list does not identify a known allergen, contamination or cross-contact with the allergen should be considered, and if identified, avoidance should be emphasized.69 Anaphylaxis after ingestion of food made with wheat flour contaminated with house dust mite is an example of a

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Figure 1. Distribution of the lone star tick (Amblyomma americanum) in the United States. Reproduced from the Centers for Disease Control and Prevention. https://www.cdc. gov/ticks/maps/lone_star_tick.html

“hidden” food allergen.70,71 A low-histamine diet (ie, avoidance of fermented dairy products and fermented vegetables) is sometimes advised, but no evidence to support this practice for IA has been reported.72 Although considered as potential allergens in the past, that artificial food coloring, dyes, or preservatives induce anaphylaxis is unlikely. Attempts to reproduce symptoms on oral challenge with such food additives as metabisulfite and monosodium glutamate have generally been negative.73,74 Pediatric Considerations The global lifetime prevalence of anaphylaxis is estimated to be 0.05% to 2.0%.75 Studies reporting the incidence in pediatric populations from the United States, Canada, Sweden, Spain, and Australia are estimated to be 0.2%,76 0.2%,77 0.03%,78 0.05%,79 and 0.1%,80 respectively. Underdiagnosis of anaphylaxis in children may be because symptoms are not as overt, especially in infants, where the symptoms of anaphylaxis may be subtle and often noncardiovascular.80-82 Underreporting is also a problem, which is compounded by different reporting statistics measures.83 In a retrospective analysis of children aged 0 to 18 years presenting to the emergency room (ER) with a food-related acute allergic reaction, the percentage of patients with a discharge diagnosis of anaphylaxis ranged from 6% to 25%, with the lowest rate in infants (6%).84 Cutaneous symptoms are common in both adults and children; however, adults tend to experience more cardiovascular symptoms as opposed to respiratory and gastrointestinal symptoms in children.84-89 In addition, infants may have fewer gastrointestinal symptoms than older children and may have more subtle symptoms such as drooling and pruritus.81 Hypotension, as 1 of the diagnostic criteria, can be missed in children because blood pressure measurements are not consistently obtained in the ER.81,84 Previous studies have noted blood pressure measurements in only 16.6% of infants and 12.5% of children younger than age 3 compared with 90% of children older than 3 years.76 A few studies in pediatric anaphylaxis demonstrate asthma and atopic dermatitis

as risk factors,85,88-91 and patients with a clonal mast cell (MC) disorder, such as mastocytosis, are reported to be at increased risk for severe or fatal outcomes.36,92,93 The differential diagnosis for IA in children is broad and includes many organ systems (Table 6). Obtaining a complete history and performing a comprehensive physical examination are imperative. The most common associated entities are undiagnosed atopic disease, gastrointestinal disorders, neurologic/central nervous system disorders, and skin diseases. Food-/spice-induced anaphylaxis can be overlooked, especially when a meal is eaten at a restaurant. Natural food dyes derived from proteins such as carmine and annatto also can also be associated with IgE-mediated reactions, unlike artificial food dyes.94-96 The history of the sequence of events is helpful to delineate an IgE-mediated event but is often not as helpful to identify the allergen. Concurrent illness and exercise may lower the threshold for reaction. Gastrointestinal symptoms such as vomiting and diarrhea are symptoms associated with anaphylaxis but also with other diseases in children. When symptoms are severe, dehydration can affect the state of consciousness and the hemodynamic state that could mimic symptoms of anaphylaxis. Anaphylaxis has been diagnosed as a seizure disorder because of the altered state of consciousness.97 Patients are inadvertently placed on anti-seizure medication, which can be difficult to discontinue because providers are hesitant to stop medications to obtain definitive data. Anxiety or depression tends to occur as a comorbid presentation of IA but can be disabling and lead to exaggeration of symptoms. Because cutaneous reactions occur in more than 80% of patients with anaphylaxis, angioedema, and urticaria in isolation may be assigned a diagnosis of anaphylaxis. Thus, adherence to diagnostic criteria is important, along with supportive objective measurements of mast cell and basophilmediated events. Cardiovascular causes are not common as a trigger for anaphylaxis in children. Kounis syndrome has been diagnosed in the pediatric population and is associated with allergic symptoms in the presence of electrocardiographic changes.98,99 Postural orthostatic tachycardia syndrome (POTS), with symptoms that are typically cardiovascular, neurologic, and gastrointestinal, should also be

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Table 5 Important Hidden Food Allergens and Their Associated Sourcesa Culprit food allergen þ associated allergens

Sources

Pectin þ cashew, pistachio

Thickening agent in foods (ie, candy, jellies, smoothies) Medications (ie, barium suspensions) Pink peppercorns Dry powder inhalers DTaP, Tdap, oral polio vaccine Medications (ie, intravenous methylprednisolone sodium succinate, lactulose) Cosmetics and personal care products (ie, lotions, bath products, make-up, gingival gel) Yellow fever, influenza, MMR, and rabies vaccines Beer Cosmetics (ie, hair care products, bath products, makeup) Cosmetics Whole-grain cereals, laxatives Baked goods or pasta, often listed as gluten-free and most frequently in Europe Mammalian meats, dairy Medications (ie, cetuximab, heparin, porcine/bovine valves, gelatin) Influenza, MMR, Varicella spp, Varicella zoster, rabies, typhoid, and yellow fever vaccines Medications (ie, hemostatic agents, capsules, suppositories, erythropoietin, plasma volume expanders, sulfur colloid injection) Candy, gelatin desserts Foods and beverages Topical and oral products (ie, dental products, personal care products, cosmetics, perfume/cologne, air fresheners, scented candles, household cleaners) Foods and beverages Medications Cosmetics (ie, eyeliner, eye shadow) Textiles Foods and beverages Food additive in baked goods, dressings, beverages Herbal supplements and medications Food: occurs naturally in many plants including artichoke, chicory, etc, and added to processed food including candy, yogurt, ice cream, butter, margarine, cereal, chocolate, etc. Inutest (intravenous test of renal function)

Pink peppercorns þ cashew, pistachio, mango Cow’s milk

Egg Wheat (hydrolyzed wheat protein) Oat Psyllium Lupine þ peanut Alpha-gal Gelatin: can be derived from meat or fish, raising concern for cross-contamination with beef, pork, fish, and alpha-gal

Spices þ cross-reactive fruits and vegetables including celery-mugwort-birch syndrome

Carmine (ie, E120)

Annatto75 Guar gum (ie, guarana) Inulin þ oligofructose (hydrolysate of inulin)

Abbreviations: Alpha-gal, galactose-a-1,3-galactose; DTaP, Diphtheria tetanus acellular pertussis; MMR, measles, mumps, rubella; Tdap, Tetanus diphtheria acellular pertussis. Modified and reproduced with permission from Baker et al.69

a

ruled out. Although POTS has been diagnosed in patients as young as 6 years old, most patients are adolescents.100 One study has demonstrated a significant difference in heart rate variability in children with vasovagal syncope when compared with POTS, which may be helpful to differentiate between the 2.101 Other less common differential diagnoses for anaphylaxis are endocrine or infectious and vaccine responses. The history and physical signs are

Table 6 Differential Diagnosis for Idiopathic Anaphylaxis in Children Organ system

Differential diagnosis

Atopic disease

Undiagnosed allergic disease, eg, food, spice Kounis syndrome, POTS Adrenal, neuroendocrine tumor IBD, celiac disease, food intolerance Acute viral illness, sepsis Seizures, psychosomatic CIU, HAE Systemic mastocytosis Vaccine responses SCLS, VCD, alpha-gal, HATS, EIA

Cardiovascular Endocrine Gastrointestinal Infectious diseases Neurologic/CNS Skin diseases Hematologic Drug-induced side effects Miscellaneous

Abbreviations: CIU, chronic idiopathic urticaria; EIA, exercise-induced anaphylaxis; HAE, hereditary angioedema; HATS, hereditary alpha tryptasemia syndrome; IBD, irritable bowel disease; POTS, postural orthostatic tachycardia syndrome; SCLS, systemic capillary leak syndrome; VCD, vocal cord dysfunction.

paramount to ruling out these disorders. Anaphylaxis is not a common presentation of undiagnosed clonal mast cell disease in children. Systemic mastocytosis is rare to see in a child without typical cutaneous lesions and a history of organomegaly.102 Both HATS and alpha-gal syndrome, discussed earlier, are seen in the pediatric population.101 In children diagnosed with systemic capillary leak syndrome (SCLS), hypotension, vomiting, lethargy, and abdominal pain are common.103 As seen in adults, the key distinguishing feature between anaphylaxis and SCLS is hemoconcentration and frequent association with an antecedent viral illness.103 In 2 studies, severe anaphylaxis in children was shown to be associated with an elevated bST value compared with children with mild and moderate anaphylaxis.43,104 In 1 study of children with food allergy, the highest values were seen in children with food allergy and anaphylaxis.104 The cutoff bST values of 5.7 and 14.5 ng/ mL were associated with 50% and 90% predicted probabilities of moderate and severe anaphylaxis, respectively. There is a paucity of data regarding IA in the pediatric age group, the incidence is assumed to be lower than in adults. In a series of 335 patients seen in an ER with the diagnosis of IA, only 9.6% of the patients were pediatric.105 In 2 retrospective studies of children with anaphylaxis, the cause was unknown in approximately 7% of children in both studies.106,107 In summary, establishing the diagnosis of anaphylaxis with objective measurements to support the diagnosis is an important step in establishing the cause of a precipitating event. Children also can experience somatoform reactions that can imitate anaphylaxis

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Table 7 Laboratory Parameters and Outcomes for Probable Mast Cell Activation or Exclusionary Diagnoses Laboratory parameter

Laboratory outcome

Probable indicator

Serum tryptase Urine histamine metabolites Urine 11bPGF2a Urine prostaglandin D2 KIT D816V mutation Skin test/serum IgE levels Alpha-gal Serum serotonin 24-hour urinary 5-HIAA Serum chromogranin A Vasoactive intestinal peptide Serum calcitonin 24-hour urinary fractioned catecholamines

Change from baseline 20% þ 2.0 ng/mL44 Elevated from baseline42 Elevated from baseline42 Elevated from baseline44 Positive42 Positive Positive >400 ng/mL121 >15 mg per 24 hours121 >36.4 ng/mL122 >200 pg/mL116 >8 pg/mL in women and >16 pg/mL in mena,121 Norepinephrine >1005 nmol/d123 Epinephrine >191 nmol/d Dopamine >4571 nmol/d 1.3 mg/24 h123 Metanephrine 0.5 nmol/L124 Normetanephrine 0.9 nmol/L

Mast cell activation Mast cell activation Mast cell activation Possible mastocytosis, acetylsalicylic acid sensitivity Mastocytosis Allergen sensitivity Alpha-gal sensitivity Carcinoid syndrome117 Carcinoid syndrome117 Neuroendocrine tumor Vasoactive intestinal peptide tumor117 Medullary carcinoma of the thyroid117 Pheochromocytoma117

24-hour urine metanephrines Plasma fractionated metanephrines

Pheochromocytoma117 Pheochromocytoma117

Abbreviations: HIAA, hydroxyindolacetic acid; PGF2a, prostaglandin F2a. a Using the Nichols Advantage calcitonin immunoassay.

or be a victim of Munchausen syndrome. Because food is the main trigger for anaphylaxis in children, an extensive search for an unknown allergen is essential.

Recommended Laboratory Tests A number of laboratory tests can help determine whether an event is anaphylaxis or can help to rule out anaphylaxis (Table 7). Along with patient history, the laboratory results can be used to determine potential triggers of anaphylaxis or identify differential diagnoses (Fig 2). Several of the tests can be ordered at the same time to reduce complexity in tracking results. An extensive panel of food testing may be useful in IA to identify anaphylaxis caused by uncommon foods. In a retrospective analysis of 102 patients with IA, patients were tested for a panel of 79 random food allergens known or suspected of inducing anaphylaxis, and a positive clinical correlation was made for 7 patients.108 Fresh food testing may be useful to identify sensitivities that are undetected by commercial extracts.109,110 Serum-specific IgE to foods can serve as an alternative or supplement to skin prick testing. Serum tryptase may be a tool to indicate anaphylaxis and mast cell activation. Evidence suggests that changes in tryptase levels have better diagnostic capability for anaphylaxis than peak tryptase levels.111,112 Several investigators have made attempts to discern what level of increase over baseline is significant to make anaphylaxis likely. As part of a venom immunotherapy trial, serum tryptase was measured at baseline, 15 minutes, and 60 minutes after sting challenge.112 A change in tryptase of 2.0 ng/mL or more from baseline was determined to be the most sensitive and specific indicator of anaphylaxis.112 In another study of venom hypersensitivity, at least a 135% change in serum tryptase from baseline was considered the best indicator of anaphylaxis.111 However, in a realworld analysis of patients treated in an ED, changes in tryptase of 2.0 ng/mL or more or 135% were not considered sufficiently sensitive or specific enough to distinguish anaphylaxis from nonanaphylactic critical illnesses.113 In that particular study, the most sensitive characteristic was a combined peak tryptase greater than 11.4 ng/mL and/or change of 2.0 ng/mL or more, although specificity was poor.113 As mentioned previously, an increase in serum tryptase of 20% or more þ 2 ng/mL also has been proposed as establishing a diagnosis of mast cell activation.44 Data obtained in children with anaphylaxis presenting to an ED confirm the utility of employing this criteria.43

Since the discovery of individuals with HATS, a condition in which patients can have symptoms of MCAS,49 an elevated bST can prompt a test for this disorder. Several laboratory evaluations can help differentiate mastocytosis from IA. In a retrospective analysis of 25 patients with MCAS (nonclonal), 24-hour urinary 11aPGF2a was elevated in 17 patients.114 Prostaglandin D2 is another marker of mast cell activation, although it is also a nonspecific mediator produced by eosinophils, dendritic cells, and other immune and nonimmune system cells. Levels of prostaglandin D2 correlate with flushing episodes and are significantly elevated in mastocytosis. However, prostaglandins also can be elevated in anaphylaxis, so baseline measurements are the most helpful with regard to the differentiation between the 2 conditions. The clinical utility of recognizing mastocytosis by KIT D816V mutation analysis from peripheral blood has been demonstrated in a study of 113 adults seen in the ER for anaphylaxis.115 In that study, the method used had a very high diagnostic sensitivity and specificity and was quick, simple to perform, inexpensive (reagents <$50), and readily available.115 Therefore, KIT D816V mutation analysis should be strongly considered in patients with anaphylaxis suspected of having mastocytosis. In the United States, testing for KIT D816V mutation is not readily available in the ER and may need to be ordered by the primary or specialty health care provider. The laboratory tests chromogranin A and 24-hour urinary 5hydroxyindolacetic acid (HIAA) can be used to screen for neuroendocrine tumors that lead to chronic flushing. Chromogranin A is a useful circulating marker for carcinoid tumors and is elevated in 90% of patients with neuroendocrine tumors.116,117 Chromagranin A is not elevated in mastocytosis.118 The sensitivity of chromogranin A is low because it is altered by many diseases and medications (ie, H2 receptor antagonists and proton pump inhibitors), which is a limitation of this marker.119 Patients should be drug-free for 24 hours from H2 receptor antagonists and for 7 days from acid suppressors before testing.119 5-HIAA is a metabolite of serotonin that is overproduced in carcinoid tumors and is the best test to confirm carcinoid syndrome.120 Care needs to be taken with the 5-HIAA test, because several foods, including bananas, tomatoes, pecans, avocados, kiwi, eggplant, plums, pineapple, and nuts (pecans, walnuts, and hickory), are serotonin-rich and can affect 5-HIAA levels.120 Medications, including cough medicine, containing guaifenesin, salicylates, acetaminophen, and L-dopa also need to be avoided before 5-HIAA testing.120 Serum serotonin is available but is not recommended by most expert societies; plasma serotonin may be available soon.

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Figure 2. Diagnostic algorithm for idiopathic anaphylaxis. ASA, acetylsalicylic acid; HATS, hereditary alpha tryptasemia; HIAA, hydroxyindolacetic acid; NET, neuroendocrine tumor; PGF2a, prostaglandin F2a. *Diagnosis according to accepted criteria (eg, Sampson et al, 20067). yBecause challenges can have safety risks, a challenge should not be conducted if history is conclusive or serum-specific IgE is >15 kU/L and should be conducted with caution in patients with serum-specific IgE from 0.35 to 15 kU/L, in consideration with concurrent atopic diagnoses. zPeripheral blood.

Useful biomarkers for vasointestinal-polypeptideeproducing tumors, medullary thyroid tumors, and pheochromocytoma are vasointestinal-polypeptid, serum calcitonin, and catecholamines/ metanephrines, respectively.

Treatment of Idiopathic Anaphylaxis Avoid Drugs That May Worsen or Complicate Events A thorough medical history including scheduled and as-needed medication use should be obtained. Any temporal relationship of symptoms to starting new medications should be noted, and the patient should be considered for switching to an equally effective alternative if one exists. If feasible, drugs that can potentially cause flushing may be held or switched to an alternative to assess the response. Systemic glucocorticoids often administered in high doses in treatment of anaphylaxis may themselves cause flushing, which may be confused with symptoms of anaphylaxis. Nonsteroidal anti-inflammatory drugs can trigger or potentiate urticaria and angioedema, and, therefore, their use should be limited. Controversy exists in the use of beta-blockers in patients with recurrent anaphylaxis because of the concern about potential blockage of epinephrine action if needed to treat an anaphylactic reaction. However, the data supporting this potential concern are limited, and their use may be necessary in patients with concurrent cardiovascular disease if no suitable alternatives exist. In patients with recurrent angioedema who are on angiotensin-converting enzyme inhibitors, considering an alternative medication such as an angiotensin receptor blocker is reasonable. Role of Epinephrine No controlled studies are available, but delayed or non-use of epinephrine has been associated with hospitalizations, complications, and death during anaphylaxis.33,121-123 Per anaphylaxis

treatment guidelines, all anaphylaxis events should be treated with epinephrine.2 Evidence suggests that treatment of systemic reactions with epinephrine prevents progression to more severe symptoms.2

Drugs Used to Prevent or Lessen Severity A number of drugs have been shown to prevent or lessen the severity of IA (Table 8).

Corticosteroids No evidence suggests a role for systemic corticosteroids in the treatment of acute anaphylactic reactions; however, they are often administered in acute care settings to prevent delayed or biphasic reactions.124 No randomized, controlled clinical trials validate the efficacy of this practice.125 Chronic long-term use of corticosteroids may be necessary in some patients with recurrent IA.126,127 Typical regimens for adults start from 40 to 60 mg prednisone daily and taper the dose by 5 to 10 mg every 2 weeks.27 In these patients, the lowest dose of steroid capable of preventing anaphylaxis should be used. Steroid-sparing alternatives, including omalizumab, should be considered in those with recurrent episodes when steroids are tapered.

Table 8 Drugs That May Prevent or Lessen the Severity of IA Prednisone128 H1 and H2 receptor antagonists128 Albuterol Ketotifen129, 130 Leukotriene receptor antagonists Omalizumab131-134 Rituximab135

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H1 or H2 Receptor Antagonists Patients with recurrent frequent IA require daily management with H1 receptor antagonists.126 Nonsedating antihistamines may be used up to 4 times per day, similar to the treatment guidelines for chronic urticaria.128 Supplemental use of shorter-acting antihistamines such as diphenhydramine or hydroxyzine still may be required. Twice-daily use of H2 receptor antagonists can be useful adjunctive medication to H1 receptor antagonists, especially in patients on glucocorticoids (to prevent gastrointestinal complications), or because of their complementary effects on histamine blockade in skin and blood vessels. Sympathomimetic Drugs (eg, Albuterol) Inhaled bronchodilators should be available to treat acute IA episodes presenting with bronchoconstriction. Little evidence supports use of oral albuterol in maintenance therapy of IA. Ketotifen Ketotifen is not readily available in the United States. Little evidence has been published using ketotifen in IA,129,130 but its mast cellestabilizing properties have been demonstrated in mastocytosis.131,132 Ketotifen for IA may be more effective when used in combination with H1 or H2 receptor antagonists.133 Doxepin is an alternative mast cell stabilizer but is not recommended for most patients because of its sedating effects and other potential side effects. Leukotriene Receptor Antagonists Little evidence and no controlled studies support the use of leukotriene receptor antagonists to prevent IA, but anecdotal evidence suggests that montelukast can control urticaria,134 and when combined with antihistamines, prevent food-dependent exerciseinduced anaphylaxis.135 Omalizumab Several case reports support the benefit of omalizumab for the prevention of IA,136-139 as well as the prevention of anaphylaxis associated with Hymenoptera allergy immunotherapy, mastocytosis, and MCAS.140-145 Omalizumab also has been shown in randomized double-blind placebo-controlled and open-label trials to be efficacious in decreasing anaphylaxis associated with oral immunotherapy to food allergens.146-149 Rituximab Based on the observation of elevated B-cells in patients with IA,26 ritixumab was given as an exploratory treatment to a woman with frequent refractory IA.150 Ritixumab was successful in inducing remission in this patient.150 In our opinion, ritixumab should be considered only after failure of more benign treatments. Tyrosine Kinase Inhibitors for Recurrent Episodes Tyrosine kinase inhibitors clearly have been shown to lessen severity and prevent the manifestations caused by mast cell mediator release. However, their major role is as a cytoreductive agent to prevent nonemast celleinduced symptoms, and there are potential side effects from their use. In addition, their use, in most instances, should be co-managed with a hematologist/oncologist. Tyrosine kinase inhibitors (midostaurin and imatinib) in the treatment of mastocytosis have been reported in 1 individual case and in an open-label phase 2 trial.151,152 No clinical trials of tyrosine kinase inhibitors have been conducted for the potential prevention of anaphylaxis. Difficult Patients: What to Do When They Do Not Respond Patients who do not respond to targeted therapy based on the diagnosis usually have a disease entity that has not been identified or have additional confounding issues that are not responsive to

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current therapy. There are steps that may be helpful to pin down a diagnosis. 1. Revisit the history and physical examination for information that the patient forgot to report a. Patient logs for more precise documentation of timing and severity b. Late-night reactions such as those associated with alpha-gal c. Potentiating factors such as alcohol, exercise, menses, illness d. Psychological issues such as anxiety or depression e. Overlooked skin lesions (urticaria pigmentosa can be mistaken for freckles); timing of development is important f. Direct observation of symptoms when possible, with supporting vitals g. Prescription to obtain serum tryptase level for reactions that require an ER visit and obtaining a baseline tryptase after the event 2. Maximize therapeutic doses a. Anti-mediator therapy b. Consider a short trial of corticosteroids c. Consider a trial of omalizumab 3. Referral for food challenges, if appropriate

Pediatric Considerations Avoidance of known triggers to prevent anaphylaxis applies to children and adults. Epinephrine administration and other measures (eg, oxygen administration) for acute IA episodes in children should be followed according to treatment guidelines.2 For prevention of IA symptoms in children, nonsedating H1 and H2 receptor antagonists are recommended. A combination of both H1 and H2 receptor antagonists tends to have better efficacy for symptom control. Systemic dosing of corticosteroids is not recommended for mild or moderate symptoms. Children requiring chronic therapy will demonstrate efficacy but with undesirable side effects. Thus, systemic corticosteroids are not recommended for long-term therapy in children. Based on an older study in children with mastocytosis and a retrospective study in patients with chronic urticaria, ketotifen may have a suppressive effect on symptoms.153,154 Alternatively, doxepin may be helpful for older children at night. Leukotriene receptor antagonists are more effective in children with asthma who exhibit respiratory symptoms with their IA episodes, but there is little efficacy for flushing. Oral cromolyn sodium is most effective in children with gastrointestinal manifestations of their symptoms because it is not typically absorbed into the bloodstream. However, patients also report a positive benefit on flushing. A local cream of cromolyn sodium compounded by a pharmacist is helpful for children with cutaneous symptoms such as pruritus and blistering. Efficacy of omalizumab for the prevention of IA episodes in children has been published in case reports.136,139 Dosing for omalizumab should be based on the packet insert, or for patients with low IgE values, using the dosing schedule recommended for chronic idiopathic urticaria. Cytoreductive therapy is in general not recommended in the pediatric population. Targeted therapy for mast cells is reserved for children with mastocytosis and organ dysfunction. Discussion Advances in diagnostics have led to the discovery of disorders that were the likely cause of IA for many patients in the past (ie, alpha-gal, clonal mast cell disease, HATS). Differential diagnosis of IA can be challenging because a number of other diseases and disorders also can cause anaphylaxis or manifest with symptoms associated with anaphylaxis. A detailed patient history is key to a differential diagnosis. In addition, a number of laboratory tests, in

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particular markers of mast cell activation (eg, serum tryptase), are essential diagnostic tools. We recommend a diagnostic algorithm that begins with patient history and mast cell activation markers and expands to laboratory tests to rule out clonal mast cell diseases, allergen sensitivities, and tumor-related flushing episodes. Treatment of acute episodes of IA is the same as that for anaphylaxis with known triggers, with epinephrine administration being of utmost importance. Evidence for the successful prevention of IA episodes is mainly anecdotal case reports for most of the treatment options. For patients with frequent IA episodes, we recommend H1 and H2 receptor antagonists, alone or in combination, as first-line treatment. In summary, IA can be frustrating for patients and health care providers because diagnosis and treatment can be challenging. Seeking a cause for the IA should be actively pursued, as well as other causes of mast cell activation. Current anaphylaxis guidelines have little specific guidance regarding IA. Therefore, this Yardstick provides practical recommendations for the diagnosis and management of patients with IA, using published literature and our collective clinical experience. References 1. Foer D, Buchheit KM, Gargiulo AR, et al. Progestogen hypersensitivity in 24 cases: diagnosis, management, and proposed renaming and classification. J Allergy Clin Immunol Pract. 2016;4:723e729. 2. Lieberman P, Nicklas RA, Randolph C, et al. Anaphylaxis: a practice parameter update 2015. Ann Allergy Asthma Immunol. 2015;115:341e384. 3. Castells M. Diagnosis and management of anaphylaxis in precision medicine. J Allergy Clin Immunol. 2017;140:321e333. 4. Sale SR, Greenberger PA, Patterson R. Idiopathic anaphylactoid reactions: a clinical summary. JAMA. 1981;246:2336e2339. 5. Boxer M, Greenberger PA, Patterson R. Clinical summary and course of idiopathic anaphylaxis in 73 patients. Arch Intern Med. 1987;147:269e272. 6. Wiggins CA, Dykewicz MS, Patterson R. Idiopathic anaphylaxis: classification, evaluation, and treatment of 123 patients. J Allergy Clin Immunol. 1988;82: 849e855. 7. Sampson HA, Munoz-Furlong A, Campbell RL, et al. Second symposium on the definition and management of anaphylaxis: summary reportdSecond National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol. 2006;117:391e397. 8. Patterson R, Clayton DE, Booth BH, et al. Fatal and near fatal idiopathic anaphylaxis. Allergy Proc. 1995;16:103e108. 9. Krasnick J, Patterson R, Meyers GL. A fatality from idiopathic anaphylaxis. Ann Allergy Asthma Immunol. 1996;76, 376-278. 10. Orfan NA, Stoloff RS, Harris KE, Patterson R. Idiopathic anaphylaxis: total experience with 225 patients. Allergy Proc. 1992;13:35e43. 11. Webb LM, Lieberman P. Anaphylaxis: a review of 601 cases. Ann Allergy Asthma Immunol. 2006;97:39e43. 12. Carter MC, Desai A, Komarow HD, et al. A distinct biomolecular profile identifies monoclonal mast cell disorders in patients with idiopathic anaphylaxis. J Allergy Clin Immunol. 2018;141:180e188. 13. Akin C. Anaphylaxis and mast cell disease: what is the risk? Curr Allergy Asthma Rep. 2010;10:34e38. 14. Akin C. Mast cell activation syndromes. J Allergy Clin Immunol. 2017;140: 349e355. 15. Pattanaik D, Lieberman P, Lieberman J, Pongdee T, Keene AT. The changing face of anaphylaxis in adults and adolescents. Ann Allergy Asthma Immunol. 2018;121:594e597. 16. Chung CH, Mirakhur B, Chan E, et al. Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. N Engl J Med. 2008;358: 1109e1117. 17. Commins SP, Satinover SM, Hosen J, et al. Delayed anaphylaxis, angioedema, or urticaria after consumption of red meat in patients with IgE antibodies specific for galactose-a-1,3-galactose. J Allergy Clin Immunol. 2009;123: 426e433. 18. Gonzalez-Estrada A, Silvers SK, Klein A, et al. Epidemiology of anaphylaxis at a tertiary care center: a report of 730 cases. Ann Allergy Asthma Immunol. 2017; 118:80e85. 19. Wright CD, Longjohn M, Lieberman PL, Lieberman JA. An analysis of anaphylaxis cases at a single pediatric emergency department during a 1-year period. Ann Allergy Asthma Immunol. 2017;118:461e464. 20. de Silva NR, Dasanayake W, Karunatilake C, et al. Aetiology of anaphylaxis in patients referred to an immunology clinic in Colombo, Sri Lanka. Allergy Asthma Clin Immunol. 2018;14:81. 21. Goh SH, Soh JY, Loh W, et al. Cause and clinical presentation of anaphylaxis in Singapore: from infancy to old age. Int Arch Allergy Immunol. 2018;175:91e98.

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Dermatologic adverse reactions to 7 common food additives in patients with allergic diseases: a double-blind, placebo-controlled study. J Allergy Clin Immunol. 2008;121:1059e1061. 75. Lieberman P, Camargo Jr CA, Bohlke K, et al. Epidemiology of anaphylaxis: findings of the American College of Allergy, Asthma and Immunology Epidemiology of Anaphylaxis Working Group. Ann Allergy Asthma Immunol. 2006;97:596e602. 76. Huang F, Chawla K, Jarvinen KM, Nowak-Wegrzyn A. Anaphylaxis in a New York City pediatric emergency department: triggers, treatments, and outcomes. J Allergy Clin Immunol. 2012;129:162e168. 77. Ben-Shoshan M, La Vieille S, Eisman H, et al. Anaphylaxis treated in a Canadian pediatric hospital: incidence, clinical characteristics, triggers, and management. J Allergy Clin Immunol. 2013;132:739e741. 78. Vetander M, Helander D, Flodstrom C, et al. Anaphylaxis and reactions to foods in children: a population-based case study of emergency department visits. 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