Diagnosis of Anaphylaxis: A Comprehensive Guide for Healthcare Professionals

Introduction to Anaphylaxis: Recognizing the Life-Threatening Emergency

Anaphylaxis is a severe, potentially fatal systemic hypersensitivity reaction with rapid onset. It’s characterized as a generalized, rapidly evolving, and multi-systemic allergic response that demands immediate recognition and treatment. Historically, anaphylaxis was categorized into IgE-mediated (anaphylactic) and non-IgE-mediated (anaphylactoid) reactions. However, current medical consensus consolidates these under the single term “anaphylaxis” due to the similarity in clinical presentation and management. Regardless of the underlying mechanism, prompt and accurate Diagnosis Of Anaphylaxis is crucial because of its potential for rapid progression to respiratory failure and cardiovascular collapse if left untreated. This article provides an in-depth review of the diagnosis, evaluation, and management of anaphylaxis for healthcare professionals.

Understanding the Causes and Triggers of Anaphylaxis

Anaphylaxis can be triggered by a wide array of substances. Common culprits include medications, certain foods, and insect stings. Immunotherapy injections, intended to modulate allergic responses, can paradoxically induce anaphylaxis in some individuals. Latex hypersensitivity is also an increasingly recognized trigger. In some instances, the specific trigger remains unidentified, leading to a diagnosis of idiopathic anaphylaxis.

Frequently identified causes of anaphylaxis encompass:

• Insect stings: Particularly from bees, wasps, hornets, and fire ants.
• Latex: Found in various medical devices and products.
• Foods: A range of foods are known allergens, including peanuts, tree nuts, fish, shellfish, milk, eggs, wheat, soy, sesame, and even red meat.
• Alpha-gal anaphylaxis: A specific type triggered by an IgE antibody response to galactose-alpha-1,3-galactose, a carbohydrate found in mammalian meat.

Epidemiology of Anaphylaxis: Who is at Risk?

Anaphylaxis is a global health concern, with an estimated lifetime prevalence ranging from 1% to 3% of the world’s population, and alarmingly, its prevalence is on the rise. While anaphylactic reactions can occur across all age groups, they are more frequently observed in younger individuals and in developed nations. A significant challenge in addressing anaphylaxis is its underdiagnosis and misdiagnosis. This diagnostic gap leads to delayed or missed treatment, contributing to increased morbidity and mortality associated with this condition. Early and accurate diagnosis of anaphylaxis is therefore paramount to improve patient outcomes.

Pathophysiology of Anaphylaxis: The IgE-Mediated Response

Anaphylaxis is predominantly an IgE-mediated (Type 1) hypersensitivity reaction. This process involves the rapid release of chemical mediators from mast cells and basophils upon re-exposure to a specific antigen. The sequence of events involves IgE crosslinking on the surface of these cells, leading to the aggregation of high-affinity receptors and subsequent degranulation.

The released chemical mediators are potent and diverse, including:

• Preformed mediators: Histamine, tryptase, carboxypeptidase A, and proteoglycans, which are rapidly released upon mast cell activation.
• Newly synthesized mediators: Arachidonic acid metabolites such as leukotrienes, prostaglandins, and platelet-activating factors, produced through the activation of phospholipase A, cyclooxygenases, and lipoxygenases.
• Cytokines: TNF-alpha (tumor necrosis factor), playing a role in both immediate and late-phase inflammatory responses.

These mediators exert a wide range of effects on the body:

• Histamine: Increases vascular permeability and causes vasodilation, leading to hypoperfusion of tissues. The body compensates by increasing heart rate and cardiac contractility.
• Prostaglandin D2: Acts as a potent bronchoconstrictor and constricts both cardiac and pulmonary arteries. It also exacerbates peripheral vasodilation, contributing to vital organ hypoperfusion.
• Leukotrienes: Enhance bronchoconstriction and vascular permeability, and contribute to airway remodeling in chronic allergic conditions.
• Platelet-activating factor: Also acts as a bronchoconstrictor and increases vascular permeability, further compounding respiratory distress and circulatory compromise.
• TNF-alpha: Activates neutrophils, contributing to leukocytosis, and promotes the synthesis of chemokines, amplifying the inflammatory cascade.

Histopathological Changes in Anaphylaxis

The rapid degranulation of mast cells and basophils is the central histopathological event in anaphylaxis. This degranulation, triggered by the immunological cascade described above, releases the chemical mediators responsible for the systemic clinical manifestations of anaphylaxis. Understanding this cellular mechanism is crucial for comprehending the rapid onset and severity of symptoms in anaphylactic reactions.

Recognizing Anaphylaxis: History, Physical Examination, and Symptom Presentation

Clinical presentation of anaphylaxis can be highly variable, often starting with seemingly mild allergic symptoms that can rapidly escalate. The initial symptoms and their progression depend significantly on the route of antigen exposure. Cutaneous manifestations such as flushing, pruritus, and urticaria are common, but notably, they might appear after respiratory symptoms, especially in cases of oral antigen exposure.

Key warning signs and symptoms that should raise suspicion for anaphylaxis include:

• Respiratory symptoms: Subjective sensation of throat fullness or a “lump in the throat,” persistent throat clearing, difficulty breathing, hoarseness, wheezing, and stridor. These symptoms indicate potential airway compromise and necessitate immediate intervention.
• Cutaneous symptoms: Flushing, itching (pruritus), hives (urticaria), and angioedema (swelling, particularly of the face, lips, tongue, or eyelids).
• Cardiovascular symptoms: Lightheadedness, dizziness, fainting (syncope), and hypotension.
• Gastrointestinal symptoms: Abdominal pain, cramping, nausea, vomiting, and diarrhea.

Given the rapid progression of anaphylaxis, typically within minutes to an hour of exposure, swift recognition and treatment are critical. A significant proportion of anaphylaxis-related fatalities occur within the first hour of symptom onset, underscoring the importance of immediate action. The faster the onset and progression of symptoms, the more severe the anaphylactic reaction is likely to be. Morbidity and mortality are primarily associated with airway obstruction and distributive shock. Early diagnosis of anaphylaxis and aggressive treatment significantly improve patient outcomes.

It’s important to recognize that anaphylactic reactions can be biphasic in up to 20% of cases. Even after initial symptoms resolve with treatment, a recurrence of symptoms can occur, typically peaking 8 to 11 hours later. While clinically significant biphasic reactions are less frequent (4-5% of diagnosed anaphylaxis cases), the potential for a delayed, severe reaction should not be overlooked. Post-treatment monitoring is essential.

Beyond the commonly recognized respiratory, cutaneous, and cardiovascular symptoms, healthcare providers should also be vigilant for other signs of end-organ hypoperfusion, which may include abdominal symptoms, hypotonia, syncope, or incontinence. Gastrointestinal symptoms are present in a considerable proportion of patients (25-30%). It is crucial to remember that anaphylaxis can manifest without prominent respiratory symptoms, and clinicians should maintain a broad differential in patients presenting with rapid onset multisystem symptoms, even in the absence of obvious airway involvement.

Diagnostic Criteria for Anaphylaxis: Clinical Evaluation

The diagnosis of anaphylaxis is primarily clinical, relying on the recognition of characteristic signs and symptoms rather than laboratory tests. Given the rapid and potentially fatal course of anaphylaxis, immediate clinical judgment is paramount. Laboratory or other diagnostic tests should not delay prompt treatment.

Clinical criteria have been established to aid in the timely diagnosis of anaphylaxis and prevent delays in treatment. These criteria, based on expert consensus, are particularly useful when the presentation is not straightforward.

Clinical Criteria for Anaphylaxis (Detailed Breakdown)

Anaphylaxis is highly likely when one of the following criteria is met within minutes to hours of an event:

1. Acute onset of illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-tongue-uvula) AND at least ONE of the following:

   • Respiratory compromise: Dyspnea, wheezing, stridor, hypoxemia. Persistent cough or throat clearing can be early indicators.
   • Reduced blood pressure or associated symptoms of end-organ dysfunction: Hypotension (systolic BP < 90 mm Hg or > 30% decrease from baseline), syncope, incontinence, hypotonia.

2. Two or more of the following that occur rapidly after exposure to a likely allergen (minutes to several hours):

   • Skin-mucosal involvement: Generalized hives, pruritus, flushing, angioedema.
   • Respiratory compromise: Dyspnea, wheezing, stridor, hypoxemia. Persistent cough or throat clearing can be early indicators.
   • Reduced blood pressure or associated symptoms: Hypotension (systolic BP < 90 mm Hg or > 30% decrease from baseline).
   • Persistent gastrointestinal symptoms: Cramping abdominal pain, vomiting.

3. Reduced blood pressure occurs rapidly after exposure to a known allergen (minutes to several hours):

   • Hypotension (systolic BP < 90 mm Hg or > 30% decrease from baseline).

Alt: Clinical criteria for anaphylaxis diagnosis flowchart, outlining symptoms and exposure scenarios leading to anaphylaxis consideration.

It is crucial to emphasize that these criteria are guidelines to aid in diagnosis of anaphylaxis, and treatment should not be withheld while waiting for all criteria to be fulfilled. In situations where anaphylaxis is suspected, particularly with airway involvement or hypotension, immediate treatment is paramount.

Angioedema can sometimes mimic anaphylaxis, particularly in its presentation with oral swelling and potential airway compromise. A key differentiating feature is urticaria, which is typically present in anaphylaxis but not always in angioedema. However, in situations of diagnostic uncertainty, it is always safer to err on the side of caution and treat aggressively for anaphylaxis.

Laboratory tests have limited utility in the acute diagnosis of anaphylaxis. Serum histamine levels are transiently elevated and not clinically helpful due to their rapid metabolism. Serum tryptase, released from mast cells, can be elevated for several hours after an anaphylactic event and may be used retrospectively to support the diagnosis, but it lacks sensitivity for acute diagnosis and should not delay immediate treatment.

Kounis syndrome, or allergic angina, is a less common but serious manifestation of anaphylaxis, involving myocardial ischemia or infarction in the context of an allergic reaction. This highlights the systemic impact of anaphylaxis and the potential for cardiovascular complications.

Anaphylaxis Management and Treatment Strategies

Immediate Triage and Airway Management

In any suspected allergic reaction, immediate triage is essential due to the potential for rapid progression to anaphylaxis. Airway management is the absolute priority. Assess the patient for airway patency and signs of impending airway compromise, such as perioral edema, stridor, or angioedema. These are high-risk indicators necessitating immediate airway intervention, potentially including definitive airway management (intubation). Delaying airway management can make intubation increasingly difficult due to progressive swelling, potentially necessitating a surgical airway.

Decontamination and Offending Agent Removal

Once the airway is secured and stabilized, the next priority is to discontinue exposure to the offending agent, if known. For insect stings, remove any remaining stingers. Gastric lavage is generally not recommended in cases of ingestion as it is unlikely to be effective and may delay more critical treatments.

Epinephrine: The First-Line Treatment

Epinephrine (adrenaline) is the cornerstone of anaphylaxis treatment. It should be administered intramuscularly (IM) at a dose of 0.3 to 0.5 mg (0.3 to 0.5 mL of 1:1,000 concentration). For pediatric patients, the recommended IM dose is 0.01 mg/kg or 0.15 mg for smaller children. Intramuscular administration into the mid-anterolateral thigh is preferred over subcutaneous or intravenous routes due to faster absorption and more reliable serum concentrations.

Repeated studies have shown that healthcare providers often delay epinephrine administration. It is crucial to recognize that epinephrine is the treatment of choice, and the benefits of prompt administration far outweigh the risks of withholding it. Most patients require only a single dose, but repeat doses can be given every 5 to 10 minutes as needed until symptoms improve.

For patients requiring multiple epinephrine doses, a continuous intravenous (IV) epinephrine infusion may be considered. If IV epinephrine is necessary, a diluted concentration of 1:10,000 is required. An initial IV bolus of 0.1 mg (1 mL of 1:10,000) given over 5-10 minutes can be followed by a continuous infusion starting at 1 microgram per minute, titrated to effect. However, IV epinephrine carries a higher risk of cardiovascular complications, such as arrhythmias and chest pain, necessitating careful monitoring. In patients on beta-blockers, close blood pressure monitoring is particularly important due to the risk of unopposed alpha-adrenergic effects of epinephrine, which can lead to severe hypertension.

Fluid Resuscitation and Supportive Therapies

Anaphylaxis-induced distributive shock is often responsive to both epinephrine and intravenous fluid resuscitation. For hypotension, an initial bolus of 1 to 2 liters (or 10 to 20 mL/kg in children) of isotonic crystalloid solution should be administered. Albumin or hypertonic solutions are not typically indicated in the initial management of anaphylactic shock.

Adjunctive Treatments: Corticosteroids, Antihistamines, Bronchodilators, Vasopressors, and Glucagon

In addition to epinephrine and fluid resuscitation, adjunctive therapies are frequently used in anaphylaxis management. These include corticosteroids, antihistamines, inhaled bronchodilators, and in some cases, vasopressors and glucagon. These agents can be helpful in managing refractory anaphylaxis, preventing biphasic reactions, and alleviating persistent symptoms.

• Corticosteroids: While evidence specifically supporting their use in acute anaphylaxis is limited, corticosteroids are commonly administered to potentially reduce the duration of symptoms and prevent biphasic reactions. Their use in anaphylaxis protocols is often extrapolated from their established efficacy in managing reactive airway diseases. Methylprednisolone (80 to 125 mg IV) or hydrocortisone (250 to 500 mg IV) are commonly used in the acute phase, often followed by oral prednisone (40 to 60 mg daily for 3-5 days). For patients with unknown triggers or limited follow-up, a longer steroid taper (up to 2 weeks) may be considered. Corticosteroids with minimal mineralocorticoid activity, such as dexamethasone and methylprednisolone, are preferred, especially in patients at risk of fluid retention.

• Antihistamines: H1-antihistamines, such as diphenhydramine (25 to 50 mg IV/IM), are frequently used as adjunctive therapy. While their clinical benefit in acute anaphylaxis is not definitively proven, they are beneficial in managing milder allergic reactions and can help alleviate cutaneous symptoms like pruritus and urticaria. In severe cases, H2-antihistamines like famotidine (20 mg IV) or cimetidine (300 mg IV) may be added, as there is evidence suggesting histamine receptor crossover selectivity. Intravenous administration is preferred initially for rapid effect, with a transition to oral antihistamines once the patient is stabilized if continued therapy is needed.

• Bronchodilators: Inhaled beta-agonists, such as albuterol (alone or in combination with ipratropium bromide), are first-line treatments for bronchospasm associated with anaphylaxis, particularly in patients with a history of asthma or reactive airway disease. For refractory wheezing, intravenous magnesium sulfate can be considered, using dosing regimens similar to those for severe asthma exacerbations.

• Vasopressors: Vasopressors other than epinephrine may be required in patients with persistent hypotension despite epinephrine and fluid resuscitation, or in cases where high-dose epinephrine is causing unacceptable side effects (arrhythmias, chest pain). Treatment guidelines for hypotensive shock should be followed in selecting and titrating alternative vasopressors.

• Glucagon: Glucagon is the reversal agent for beta-blocker overdose and can be used in anaphylaxis refractory to standard treatments in patients taking beta-blockers. Beta-blockade can theoretically reduce the effectiveness of epinephrine. Glucagon can counteract this effect. Potential side effects include nausea, vomiting, hypokalemia, dizziness, and hyperglycemia.

Emerging Therapies: Sirtuin 6

Research is ongoing to identify novel therapeutic targets for anaphylaxis. Sirtuin 6 (Sirt6), a NAD-dependent deacetylase, is being investigated for its potential role in modulating mast cell activation. Sirt6 activation has been shown to suppress protein tyrosine phosphatase receptor type C transcription, leading to negative regulation of the FcεRI signaling cascade in mast cells. This suggests that Sirt6 activation may offer a potential therapeutic strategy for mitigating anaphylactic responses, although it remains investigational.

Differential Diagnosis of Anaphylaxis

The differential diagnosis for anaphylaxis is broad and includes conditions that can mimic its signs and symptoms. Conditions to consider include:

• Angioedema (hereditary or acquired)
• Anxiety or panic attacks
• Cardiac arrhythmias
• Asthma exacerbation
• Carcinoid syndrome
• Epiglottitis
• Foreign body airway obstruction
• Gastroenteritis
• Mastocytosis
• Myocardial ischemia/infarction
• Seizure
• Vasovagal syncope
• Vocal cord dysfunction

A careful history and physical examination, along with consideration of the clinical context, are crucial in differentiating anaphylaxis from these other conditions.

Prognosis and Patient Monitoring After Anaphylaxis

With prompt diagnosis of anaphylaxis, appropriate treatment, and monitoring, the prognosis is generally good, and the risk of mortality is low. Rapid access to medical care and timely recognition of anaphylaxis are critical determinants of patient outcome. As previously noted, a significant proportion of fatalities occur within the first hour of symptom onset.

Hospital admission is required in a minority of patients (approximately 4% or less) presenting to the emergency department with acute allergic reactions. However, in cases of anaphylaxis requiring epinephrine, complete symptom resolution is expected with treatment. Emergency department observation for at least 4 hours is typically recommended to monitor for biphasic reactions. If no further intervention is needed during this observation period, the patient can be discharged with an epinephrine autoinjector prescription and appropriate follow-up.

Admission to an intensive care unit (ICU) is advised for patients requiring airway intervention, those with refractory anaphylaxis, or those deemed unstable. Patients with a history of biphasic reactions, severe anaphylaxis, beta-blocker use, older age, living alone, or with poor access to healthcare are at higher risk and should be monitored for a longer duration.

Upon discharge, in addition to an epinephrine autoinjector, prescriptions for antihistamines and corticosteroids for 3 to 5 days are often appropriate. If the trigger is unknown and follow-up with an allergist is delayed, a longer course of corticosteroids with a taper (1 to 2 weeks) may be considered. Prescribing multiple epinephrine autoinjectors to be kept in various locations (home, work, school, vehicle) is prudent. Patients should be educated on the importance of carrying their epinephrine autoinjector at all times and using it promptly if symptoms recur. Patients with severe allergic reactions and anaphylaxis who take beta-blockers are at higher risk for prolonged or more severe reactions, and alternative medication classes should be considered if feasible. Medical alert bracelets or necklaces are also recommended to ensure prompt recognition of their allergy in future emergencies.

Potential Complications of Anaphylaxis

Complications of anaphylaxis, if not promptly and effectively managed, can be serious and life-threatening. These include:

• Wheezing and bronchospasm
• Stridor and upper airway obstruction
• Hypoxemia
• Hypotension and cardiovascular collapse
• End-organ dysfunction due to hypoperfusion
• Death

Early diagnosis of anaphylaxis and immediate treatment are essential to minimize the risk of these complications.

Prevention and Patient Education for Anaphylaxis

Prevention of anaphylaxis primarily relies on avoidance of known triggers. Patient education plays a crucial role in preventing future episodes and ensuring prompt self-management in case of accidental exposure. Key aspects of patient education include:

• Trigger avoidance: Detailed counseling on identifying and avoiding specific allergens (foods, medications, insect venoms, latex, etc.).
• Epinephrine autoinjector education: Comprehensive training on the proper use of epinephrine autoinjectors, including when and how to administer the injection. Patients should be instructed to administer epinephrine at the first signs of anaphylaxis and not delay treatment.
• Carrying epinephrine: Emphasize the importance of carrying epinephrine autoinjectors at all times and ensuring they are readily accessible in various environments.
• Medical alert identification: Recommendation to wear medical alert bracelets or necklaces to inform healthcare providers of their allergy in emergency situations.
• Biphasic reaction awareness: Educate patients about the possibility of biphasic reactions and the need for continued monitoring even after initial symptoms resolve.
• Follow-up with an allergist: Referral to an allergist and immunologist for further evaluation, allergy testing to identify specific triggers, and development of a comprehensive allergy management plan, which may include allergen immunotherapy in select cases.

Alt: Skin hives due to anaphylaxis, illustrating a common cutaneous symptom of severe allergic reaction.

Key Takeaways and Clinical Pearls for Anaphylaxis Diagnosis and Management

• Rapid onset, multisystem involvement: Anaphylaxis is characterized by a rapid onset of symptoms affecting multiple organ systems, often including skin, respiratory, cardiovascular, and gastrointestinal systems.
• Clinical diagnosis: Diagnosis of anaphylaxis is primarily clinical, based on recognizing characteristic signs and symptoms, and should not be delayed for laboratory testing.
• Epinephrine is first-line: Epinephrine is the first-line treatment for anaphylaxis and should be administered intramuscularly without delay at the first signs of a reaction.
• Airway management is critical: Assess and manage the airway as the absolute priority in anaphylaxis management.
• Consider biphasic reactions: Be aware of the possibility of biphasic reactions, and monitor patients for several hours after initial treatment.
• Patient education is essential: Comprehensive patient education on trigger avoidance, epinephrine autoinjector use, and emergency preparedness is crucial for preventing future episodes and ensuring prompt self-management.
• No contraindication to epinephrine in anaphylaxis: There are no absolute contraindications to epinephrine use in anaphylaxis. The benefits of epinephrine in treating anaphylaxis far outweigh any potential risks.

Enhancing Interprofessional Team Outcomes in Anaphylaxis Care

Anaphylaxis management requires a coordinated interprofessional team approach to optimize patient outcomes. Effective communication and collaboration among physicians, nurses, pharmacists, and other healthcare providers are essential.

Pharmacists play a key role in educating patients and families about anaphylaxis, proper epinephrine autoinjector use, and the importance of carrying epinephrine at all times. They can also ensure that patients receive appropriate prescriptions for epinephrine autoinjectors and other medications for allergy management.

Nurses are critical in the initial assessment, triage, and administration of emergency treatments for anaphylaxis. They monitor patients closely, recognize signs of deterioration or biphasic reactions, and provide ongoing patient education and support.

Physicians are responsible for the diagnosis of anaphylaxis, directing treatment strategies, and coordinating follow-up care, including referral to allergists and immunologists for long-term allergy management.

All healthcare workers should be educated on the recognition of anaphylaxis symptoms and the proper administration of epinephrine. Regular anaphylaxis drills and educational programs can improve preparedness and response times in healthcare settings.

By working collaboratively and leveraging the expertise of each team member, healthcare professionals can significantly improve the diagnosis of anaphylaxis, ensure timely and effective treatment, and enhance patient safety and outcomes.

Review Questions on Anaphylaxis Diagnosis

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Disclosure: Kevin McLendon declares no relevant financial relationships with ineligible companies.

Disclosure: Britni Sternard declares no relevant financial relationships with ineligible companies.