Recent update on the management of anaphylaxis

Food-induced anaphylaxis

Food-induced anaphylaxis (FIA) is a serious allergic reaction following the ingestion of food allergens, and the incidence of FIA and other types of food allergy continues to rise [7]. The most common causative foods in children and adolescents are eggs, cow’s milk, peanuts, wheat, and soybeans [7,27]. Meanwhile, seafood (fish and shellfish) and wheat are the major causes in adults [28]. Allergic response and anaphylaxis to cow’s milk have been reported to be 2.0% to 13.0% in children who are able to synthesize IgE antibodies against intruded cow’s milk [29]. Egg allergy triggers severe anaphylaxis in infants and children [30]. In addition, peanuts and tree nuts are major causes of anaphylaxis in European children and adolescents, which is related to the presence of asthma comorbidity and increased rate of biphasic reactions [31]. Wheat allergy affects 0.5% to 1.0% of the pediatric population; chronic wheat consumption could lead to anaphylaxis, especially wheat-dependent exercise-induced anaphylaxis.

Risk factors for fatal FIA include comorbidity with asthma, previous history of food allergy, exposure to hidden allergens, and cofactors (exercise, alcohol, and NSAIDs). It is reported that cofactors play a role in 25.6% to 39.0% of anaphylactic reactions in adults and 14.0% to 18.3% in children [32]. Among them, exercise is the major cofactor for FIA, which is called food-dependent exercise-induced anaphylaxis (FDEIA). FDEIA is not very common, but reported up to half of the patients with exercise-induced anaphylaxis (5.0% to 15.0% of all anaphylaxis cases) [33]. Shrimp, wheat, soybean, and rice are frequently reported to induce FDEIA, in which shrimp and wheat are most common [34-36]. In some cases of FDEIA, NSAIDs are a cofactor for enhancing anaphylaxis symptoms, especially in patients with wheat-induced FDEIA or plant foods (nuts, seeds, vegetables, and peanut)-derived lipid transfer proteins-induced FDEIA in the Mediterranean area [37,38]. In addition, anaphylactic events can be enhanced by other cofactors, such as temperature change, ingestion of vegetable or meat, food contaminated with aeroallergens (house dust mite and mold), and others (snail, taro, red bean, and mushroom).

Drug-induced anaphylaxis

Drug-induced anaphylaxis is well known as a severe immediate hypersensitivity reaction; however, some drugs are emerging with delayed anaphylactic reactions through other mechanisms. It is caused by numerous drugs, among which antibiotics, NSAIDs, local anesthetics, H₂ blockers, and RCM are common causative drugs, which may be attributed to higher prescription rates. Antibiotics, radiocontrast agents, and intraoperative agents are the common cause associated with mortality [39]. Among antibiotics, cefaclor is most common (account for 50.0%) in Korean adults, followed by NSAIDs, H₂ blockers, and RCM, while anesthetics and chemotherapeutic agents are less commonly reported [7]. Penicillins have been reported as the most prevalent cause in patients with antibiotic-induced anaphylaxis in the US and Vietnam [17,40]. Analgesics, including NSAIDs, are the third most common drug in the US (13.0 per 10,000), followed by opiates (9.8 per 10,000), and local anesthetics (1.4 per 10,000) [40]. The prevalence of hypersensitivity and anaphylaxis to RCM differs according to the structures of RCM. RCM is categorized into ionic versus nonionic forms which are further classified into monomer (high osmolality) versus dimeric (low osmolality) forms [41]. Hypersensitivity reaction and anaphylaxis are more common in monomeric ionic forms (3.8% to 12.7% and 0.02% to 0.04% respectively) than in nonionic forms (0.7% to 3.0% for hypersensitivity reactions) [41]. Factors for predisposing RCM-induced hypersensitivity reactions include the previous history of RCM hypersensitivity reactions, atopy status, comorbidity with asthma, and severe cardiovascular disease [42]. In another study, RCM-induced anaphylaxis is more common in older patients and with exposure to RCM and iopromide [43]. In addition, perioperative hypersensitivity and anaphylaxis are immediate and potentially life-threatening systemic reactions occurring during the perioperative period. Cardiovascular, respiratory, and integumentary systems are primarily affected by perioperative drugs (which can develop without of skin reactions) [44]. Major causative drugs are neuromuscular blocking agents, antibiotics, NSAIDs, anesthetic agents, natural rubber latex, blue dyes, chlorhexidine, and sugammadex (an antidote to aminosteroid muscle relaxants) [45,46].

Venom-induced anaphylaxis

Venom-induced anaphylaxis (VIA) is observed in 1.2% to 3.5% of the general population and is more frequently associated with cardiovascular symptoms [47]. The sensitization and causative venoms can be identified via skin testing or measurement of serum-specific IgE levels to each venom [47]. Approximately 5.0% of patients with VIA exhibit systemic mastocytosis (clonal disorders with an increase in the number of abnormal mast cells in the tissue) that is associated with poor prognosis [48]. Honeybee and vespid venoms are common ones inducing VIA in South Korea [49].

Vaccine-induced anaphylaxis

Vaccine-induced anaphylaxis is extremely rare. Hypersensitivity can occur because of either vaccine components, such as active agents (inactive or attenuated live vaccine virus and toxoid), additives (antibiotics, preservatives such as gelatin, stabilizers, and adjuvants), or contamination of latex or culture media (ovalbumin from egg white) [50]. Lipid components, such as polyethylene glycols (PEG) and polysorbate 80/20 are added to medications as well as vaccines (including coronavirus disease 2019 [COVID-19] vaccine) for improving drug delivery and extending half-life, which could induce anaphylaxis [50]. PEG-induced anaphylaxis mostly occurs from injectable medications with higher molecular weight products such as PEG3350 and PEG4000 [50]. In addition, patients with immediate hypersensitivity to PEG3350-containing medications have been reported to exhibit immunological cross-reactivity with polysorbate 80-containing drugs [51]. The risk of anaphylaxis after vaccination has been estimated to be 1.31 (95% confidence interval, 0.90 to 1.84) per million vaccine doses [52]. There are many precautions in patients with severe egg allergy for administering injectable influenza vaccines that contain small amounts of egg protein, and influenza vaccines most frequently induce anaphylaxis [53,54]. Anaphylaxis events are more commonly found in patients with allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, and food/drug allergy, while 41.0% had no history of allergic disease [53]. A recent report demonstrated a higher prevalence of COVID-19 vaccine-associated anaphylaxis (11.1 cases of anaphylaxis per million doses) after a first dose of the Pfizer-BioN-Tech COVID-19 vaccine regarding the report of the Vaccine Adverse Event Reporting System, among which 71.0% of them occurred within 15 minutes after vaccination [55]. Current mRNA vaccines (Pfizer-BioNTech and Moderna COVID-19 vaccines) contain PEG components such as 2(PEG2000)-N,N-ditetradecylacetamide and PEG2000 dimyristoyl glycerol, respectively, which have been reported as the causes of COVID-19–induced anaphylaxis. Meanwhile, Johnson & Johnson/Janssen COVID-19 vaccine, AstraZeneca severe acute respiratory syndrome coronavirus 2 adenovirus carrier vaccine, and several influenza vaccines (Fluarix quad and Flulaval Quad) contain polysorbate 80 [56,57]. Although anaphylaxis after vaccination is rare in all age groups, this immediate-onset and life-threatening condition require adequate medical professionals and supplies to treat potential anaphylactic reactions during vaccination procedures.

Classification

Anaphylaxis is a severe form of hypersensitivity reactions, which are unpredictable and related to immunological (allergic) and non-allergic reactions. Clinically, hypersensitivity reactions are classified into two types: immediate (arising within 1 hour after exposure) and nonimmediate (delayed reactions arising more than 1 hour after exposure). Immediate reactions can be caused by either mast cells or basophil activation through type I IgE (allergy)/non-IgE (pseudo-allergy) mechanisms or direct complement activation, leading to the release of mediators (histamine and tryptase) to induce variable manifestations, ranging from pruritus to edema, urticaria, and anaphylactic shock. Meanwhile, T cell induced reactions (type IV) and rare events induced by antibodies (type II and III), such as hemolysis, thrombocytopenia, damaged vascular walls, and glomeruli, have been reported related to delayed reactions [24].

Severity grading

Although grading systems for the severity of anaphylaxis have several limitations, Table 2 [19,47,58-60] summarizes recent studies which have investigated demographic, clinical characteristics, and biomarkers for the severity of anaphylaxis according to each causative agent. Six significant risk factors for severe anaphylaxis in Hymenoptera venom allergy include short interval from sting to reaction, absence of urticaria or angioedema during anaphylaxis, older age, male sex, elevation in baseline serum tryptase level, and diagnosis of systemic mastocytosis [47,58]. In addition, hereditary α-tryptasemia (excess copies of α-tryptase at TPSAB1) is associated with increased serum tryptase levels and severe anaphylaxis in patients with systemic mastocytosis, VIA, and idiopathic anaphylaxis, in which patients with hereditary α-tryptasemia show 500-fold higher serum tryptase level than the general population [60,61]. Moreover, risk factors for severe anaphylaxis have been reported to be advanced age, severe cardiovascular disease, bronchial asthma, systemic mastocytosis, and use of certain drugs, such as NSAIDs, which promote mast cell activation or leukotriene secretion [19]. A multicenter prospective observational study showed that asthma history, symptom onset within 5 minutes after allergen exposure, unhealthy appearance, tachycardia, and hypotension are independent risk factors for severe anaphylaxis in children [59].

Table 2.

Severity-related factors for anaphylaxis

Clinical features and predisposing factors

Clinical manifestations at the time of presentation are helpful in the diagnosis of anaphylaxis [2]. Diagnostic criteria based on the guideline suggested by WAO in 2020 are 1) sudden onset of an illness (minutes to several hours) with simultaneous involvement of the skin, mucosal tissue, or both (generalized hives, pruritus or flushing, and swollen lips-tongue-uvula) plus at least one of the following: respiratory compromise (dyspnea, wheeze-bronchospasm, stridor, reduced peak expiratory flow, and hypoxemia) reduced blood pressure or symptoms of end-organ dysfunction; and 2) acute onset of hypotension or bronchospasm, or laryngeal involvement after exposure to a known or probable allergen (minutes to several hours), even in the absence of typical skin involvement (urticarial rash/erythema/flushing, and angioedema) [2]. Moreover, laboratory tests can help physicians evaluate anaphylaxis phenotypes and find causative agents. As shown in Table 3 [25,26,62-66], inflammatory mediators (histamine, tryptase, chymase, carboxypeptidase A3, and platelet-activating factor) are measured during the acute phase and/or stable condition (at least 24 hours after all signs and symptoms have been resolved) to confirm the diagnosis of anaphylaxis [67]. Meanwhile, the basophil activation test, serum-specific IgE measurement, and skin tests as well as component-resolved diagnostics are used to find causative agents.

Table 3.

Biomarkers for anaphylaxis

Potential biomarkers

Histamine and tryptase are the most common inflammatory mediators derived from activated mast cells/basophils. Although histamine exhibits important biological reactivities, such as vasodilation and smooth muscle contraction, its half-life in plasma or serum is too short to be measured in the ED after anaphylaxis occurs. Therefore, levels of histamine and its metabolite methyl-histamine are more frequently detected in urine than in plasma or serum, particularly urine collected for over 24 hours which supports the diagnosis of mast cell activation syndromes, including systemic mastocytosis and secondary disorders with Ig-E-mediated disorders, anaphylaxis, and autoimmune disorders [68]. Tryptase is the major enzyme stored within human mast cells. Tryptase levels are measured by the immunoCAP system in serum samples. It is more useful to measure at 2-time points; acute (sampled between 30 minutes and 2 hours after symptom initiation) and baseline tryptase levels (sampled before the event or at least 24 hours after all signs and symptoms have resolved) [67]. Baseline tryptase levels are considered low if they are lower than 11.4 ng/mL. Mast cell degradation during anaphylactic events is considered if acute levels increase higher than 2 ng/mL plus 1.2 times from baseline [67]. To date, serum tryptase has been documented to be the most useful biomarker for the diagnosis of anaphylaxis, although there have been some reported cases of anaphylaxis showing normal serum tryptase levels [69]. Other mediators of inflammation, such as arachidonic acid-derivated proinflammatory mediators (prostaglandin D₂ and cysteinyl leukotriene E₄), tumour necrosis factor α, interleukin 6, and interleukin 1β levels, are derived from T cells, neutrophils, eosinophils, and endothelial cells through non-IgE mechanisms, which can be increased in serum samples in patients with anaphylaxis, albeit they are not useful in clinical practice [70].

Identification of causative and exacerbating factors

Culprit allergens can be identified by a careful history. Skin tests, allergen-specific IgE measurement, and component-resolved diagnostics can be used to find causative agents and severity. Skin tests are considered safe for patients with a history of anaphylaxis and applied to identify sensitization to numerous allergens, including airborne, food allergens, drugs (β-lactam, general anesthetics), and Hymenoptera venom triggers. They have some limitations to the diagnosis of patients with anaphylaxis induced by cross-reactivity or hidden allergens. Component-resolved diagnostics may overcome these limitations through their ability to identifying some molecules present in allergenic extracts [71,72]. Additionally, ex vivo, basophil activation tests are used to diagnose IgE or non-mediated reactions using sensitized basophils from each patient. It is useful for evaluating immediate reactions to β-lactam antibiotics and muscle relaxants as well as FIA [73,74]. It is ideal to perform these tests 4 weeks after the acute episode [2]. Allergists and immunologists should educate patients about causative agents and related cross-reactivities for active avoidance [2]. In addition, exposure to other risk cofactors should be avoided to reduce recurrence.

Epinephrine

Epinephrine regulates cardiovascular and respiratory systems via improving vasoconstriction, peripheral vascular resistance, bronchoconstriction, and mucosal edema [19,25]. Epinephrine treatment should be immediately given after removing triggers and assessing current patient conditions according to emergency protocols [2,19]. According to the WAO guideline, the recommended injection dose is between 0.01 mg/kg of body weight and up to a maximum total dose of 0.5 mg (equivalent to 0.5 and 1 mg/mL [1:1,000], respectively). For instance, infants weighing under 10 kg are given a dose of 0.01 mg/kg of 1 mg/mL (1:1,000) epinephrine, children aged 1 to 5 years 0.15 mg, children aged 6 to 12 years 0.3 mg, and teenagers/adults 0.5 mg [2]. Intramuscular administration to the vastus lateralis of the quadriceps, instead of subcutaneous or intravenous administration, is recommended because of its effective and rapid absorption [2,77]. Additionally, the requirement of more than 1 dose of epinephrine every 5 to 15 minutes should be considered in patients who present with 1) poor response to a first dose, 2) history of more than 1 dose administrations of epinephrine due to anaphylaxis or biphasic anaphylaxis, refractoriness to treatment, food allergy, severe asthma, or current medications such as β-blockers [19]. After the initial management, patients should lie down with their lower limbs elevated or in their most comfortable position. Patients with anaphylaxis should be immediately transported to the hospital. Comprehensive care and quick assessment of patients is necessary even in the ambulance. After arriving at hospital, vital signs, such as electrocardiogram, pulse, and blood pressure should be monitored in order to evaluate degree of severity, shock, and the risk of biphasic reactions [19,78]. High-flow oxygen (100.0%) should also be given to all patients with cardiovascular or pulmonary reactions [25].

Antihistamines

Antihistamines are beneficial for relieving cutaneous manifestations and rhinoconjunctivitis [19,79]. First-generation H₁-antagonists (dimetindene and clemastine) could relieve cutaneous symptoms, and be available for intravenous injection, but are limited by their side effects such as sedation, confusion, antimuscarinic effects (tachycardia, mouth dryness, etc.), and hypotension [79,80]. As second-generation H₁-antagonists have no parenteral forms, they cannot be used in the acute management of anphlaxis [2,76].

Glucocorticosteroids

Glucocorticosteroids are well-known as secondary drugs for preventing biphasic reactions [2,19]. However, recent Cochrane reviews evaluated the benefits and harms of glucocorticoid treatment in acute management, and found no clear evidence for the use of glucocorticoids in anaphylaxis treatment in the ED or for biphasic reaction prevention [81,82]. High doses of glucocorticoids (500–1,000 mg in adults) can be prescribed for patients with generalized urticaria, concomitant asthma, airway edema, or stridor after being stabilized [19,83]. In cases of children, prednisolone in the form of suppositories or enemas (a dose of 2 mg/kg) as well as in an injectable form is suitable for administration.

Glucagon and inhaled β-2 adrenergic agonists

Parenteral treatments of glucagon have supportive effects in patients with poor response to epinephrine or in those using β-blockers [84]. Inhaled β-2 adrenergic agonists are given in patients with bronchoconstriction [2].

Special issues in the acute management

Clinicians should be careful to administer epinephrine in some patients. First, unavoidable adverse effects- and overdose-caused symptoms, including transient anxiety, headache, dizziness, palpitations, etc., are noted [18,76]. Secondly, if patients do not respond to intramuscular epinephrine injections, they can receive an intravenous infusion of epinephrine by trained health care professionals under intensive monitoring instead of the third dose of epinephrine [76,85-87]. Thirdly, patients with a history of cardiovascular diseases should be carefully managed because epinephrine has arrhythmogenic effects and increases cardiac output [88].

Infants need to be carefully monitored [76]. There are some difficulties in evaluating this age group because 1) they are unable to describe their symptoms; 2) there are no specific criteria for this population; and 3) overdose epinephrine treatment which may induce life-threatening symptoms (pulmonary edema) could be masked by anaphylaxis symptoms [76,89]. Recent studies have shown higher frequencies of initial antihistamine treatment (more than 80%), followed by intravenous fluid and systemic steroid treatment instead of initial intravascular epinephrine treatment in the ED in South Korea [7,90,91]. However, the benefits of these drugs in the infant population have not yet been evaluated in large-scale and randomized controlled studies.

EAI

The prescription rate is relatively low, although it has been increasing from 2.4% in 2010 to 6.9% in 2014 [7]. Commercial EAIs containing 4 doses (0.1, 0.15, 0.3, and 0.5 mg) [2]. A dose of 0.15 mg is recommended for patients weighing 15 to 30 kg, whereas a dose of 0.3 mg is recommended for patients weighing 30 kg or more [92]. EAIs with 0.1 mg (suitable for patients weighing less than 15 kg) and 0.5 mg (suitable for patients weighing more than 50 kg) are not commercially available in the majority of countries, including Korea [7]. There are some issues regarding the depth of drug delivery in children. A recent study using ultrasound evaluated needle length and propulsive force from skin to bone in 100 children weighing less than 15 kg with food allergies. A dose of 0.15 mg was reported to have the risk of injection into the bone in such subjects [93]. In patients with a bodyweight of more than 40 kg who receive an EAI at a dose of 0.3 mg, the needle may ne too short to correctly deliver epinephrine to the appropriate intramuscular structures when evaluated by ultrasound [92], with only 77.0% of the dose absorbed [93]. In these patients, use of 0.5 mg EAI should be considered.

The prescription of EAI (at least 1 dose) is recommended by the European Academy of Allergy and Clinical Immunology in patients with history of food, latex, and aeroallergen-induced anaphylaxis, exercise-induced anaphylaxis, idiopathic anaphylaxis, uncontrolled severe asthma with food allergy, systemic cutaneous reactions with venom allergy in adults and children, and mast cell disorders [83]. In some countries where EAIs are not available, prefilled epinephrine syringes can be used. However, there is insufficient evidence to prove that this prefilled syringe (1 mg/mL epinephrine) is stable and sterile [94].

Allergen immunotherapy and drug desensitization

Immunomodulatory approaches should be considered in venom immunotherapy and drug desensitization [83]. Indeed, patients with VIA show the best response to subcutaneous venom immunotherapy for preventing anaphylaxis in both children and adults [78,83]. For drug desensitization, administration of drugs (with increasing doses) can achieve a tolerant state to targeted drug doses [83]. Desensitizations can be successful for patients with anaphylaxis induced by chemotherapy, biologics, NSAIDs, and antibiotics [26].

Omalizumab

Omalizumab, an anti-IgE antibody, down-regulates the expressions of high-affinity IgE receptor andFcεRI on the surfaces of basophils, mast cells, and dendritic cells, suppressing the IgE-dependent cascade [75]. Omalizumab has been applied to manage patients with moderate to severe asthma and/or those with chronic inducible and spontaneous urticaria [95]. Recently, it has been applied to manage severe food allergy, eosinophil-related gastroenteritis, acute reactions after rush immunotherapy, and mast cell disorders even in idiopathic anaphylaxis, although further randomized and controlled trials are needed [96-99].