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Anaphylaxis
Anaphylaxis
Anaphylaxis
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Anaphylaxis
SpecialtyEmergency medicine, allergy and immunology
SymptomsItchy rash, throat swelling, numbness, shortness of breath, lightheadedness, low blood pressure,[1] vomiting
Usual onsetOver minutes to hours[1]
TypesAnaphylactoid reaction, anaphylactic shock, biphasic anaphylaxis
CausesInsect bites, foods, medications,[1] drugs/vaccines
Diagnostic methodBased on symptoms[2]
Differential diagnosisAllergic reaction, asthma exacerbation, carcinoid syndrome[2]
TreatmentEpinephrine, intravenous fluids[1]
MedicationEpinephrine, corticosteroids, antihistamines
Frequency0.05–2%[3]

Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of the availability of on-site treatments while not under medical care.[4][5] It typically causes more than one of the following: an itchy rash, throat closing due to swelling that can obstruct or stop breathing; severe tongue swelling that can also interfere with or stop breathing; shortness of breath, vomiting, lightheadedness, loss of consciousness, low blood pressure, and medical shock.[6][1]

These symptoms typically start in minutes to hours and then increase very rapidly to life-threatening levels.[1] Urgent medical treatment is required to prevent serious harm and death, even if the patient has used an epinephrine autoinjector or has taken other medications in response, and even if symptoms appear to be improving.[6]

Common causes include allergies to insect bites and stings, allergies to foods—including nuts, peanuts , milk, fish, shellfish, eggs and some fresh fruits or dried fruits; allergies to sulfites—a class of food preservatives and a byproduct in some fermented foods like vinegar; allergies to medications – including some antibiotics and non-steroidal anti-inflammatory drugs (NSAIDs) like aspirin;[7] allergy to general anaesthetic (used to make people sleep during surgery); allergy to contrast agents – dyes used in some medical tests to help certain areas of the body show up better on scans; allergy to latex – a type of rubber found in some rubber gloves and condoms.[6][1] Other causes can include physical exercise, and cases may also occur in some people due to escalating reactions to simple throat irritation or may also occur without an obvious reason.[6][1] Although allergic symptoms usually appear after prior sensitization to an allergen, IgE cross-reactivity with homologous proteins can cause reactions upon first exposure to a new substance.[8] The mechanism involves the release of inflammatory mediators in a rapidly escalating cascade from certain types of white blood cells triggered by either immunologic or non-immunologic mechanisms.[9] Diagnosis is based on the presenting symptoms and signs after exposure to a potential allergen or irritant and in some cases, reaction to physical exercise.[6][1]

The primary treatment of anaphylaxis is epinephrine injection into a muscle, intravenous fluids, then placing the person "in a reclining position with feet elevated to help restore normal blood flow".[1][10] Additional doses of epinephrine may be required.[1] Other measures, such as antihistamines and steroids, are complementary.[1] Carrying an epinephrine autoinjector, commonly called an "epipen", and identification regarding the condition is recommended in people with a history of anaphylaxis.[1] Immediately contacting ambulance / EMT services is always strongly recommended, regardless of any on-site treatment.[6] Getting to a doctor or hospital as soon as possible is required in all cases, even if it appears to be getting better.[6][11]

Worldwide, 0.05–2% of the population is estimated to experience anaphylaxis at some point in life.[3] Globally, as underreporting declined into the 2010s, the rate appeared to be increasing.[3] It occurs most often in young people and females.[10][12] About 99.7% of people hospitalized with anaphylaxis in the United States survive.[13]

Etymology

[edit]

The word is derived from Ancient Greek: ἀνά, romanized: ana, lit. 'up', and Ancient Greek: φύλαξις, romanized: phylaxis, lit. 'protection'.[14][15]

Signs and symptoms

[edit]
Signs and symptoms of anaphylaxis

Anaphylaxis typically presents many different symptoms over minutes or hours[10][16] with an average onset of 5 to 30 minutes if exposure is intravenous and up to 2 hours if from eating food.[17] The most common areas affected include: skin (80–90%), respiratory (70%), gastrointestinal (30–45%), heart and vasculature (10–45%), and central nervous system (10–15%)[18] with usually two or more being involved.[3]

Skin

[edit]
Urticaria and flushing on the chest of a person with anaphylaxis

Symptoms typically include generalized hives, itchiness, flushing, or swelling (angioedema) of the affected tissues.[4] Those with angioedema may describe a burning sensation of the skin rather than itchiness.[17] Swelling of the tongue or throat occurs in up to about 20% of cases.[19] Other features may include a runny nose and swelling of the conjunctiva.[20] The skin may also be blue tinged because of lack of oxygen.[20]

Respiratory

[edit]

Respiratory symptoms and signs that may be present include shortness of breath, wheezes, or stridor.[4] The wheezing is typically caused by spasms of the bronchial muscles[21] while stridor is related to upper airway obstruction secondary to swelling.[20] Hoarseness, pain with swallowing, or a cough may also occur.[17]

Cardiovascular

[edit]

While a fast heart rate caused by low blood pressure is more common,[20] a Bezold–Jarisch reflex has been described in 10% of people, where a slow heart rate is associated with low blood pressure.[12] A drop in blood pressure or shock (either distributive or cardiogenic) may cause the feeling of lightheadedness or loss of consciousness.[21] Rarely very low blood pressure may be the only sign of anaphylaxis.[19]

Coronary artery spasm may occur with subsequent myocardial infarction, dysrhythmia, or cardiac arrest.[3][18] Those with underlying coronary disease are at greater risk of cardiac effects from anaphylaxis.[21] The coronary spasm is related to the presence of histamine-releasing cells in the heart.[21]

Other

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Gastrointestinal symptoms may include severe crampy abdominal pain and vomiting.[4] There may be confusion, a loss of bladder control or pelvic pain similar to that of uterine cramps.[4][20] Dilation of blood vessels around the brain may cause headaches.[17] A feeling of anxiety or of "impending doom" has also been described.[3]

Causes

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Anaphylaxis can occur in response to almost any foreign substance.[22] Common triggers include venom from insect bites or stings, foods, and medication.[12][23] Foods are the most common trigger in children and young adults, while medications and insect bites and stings are more common in older adults.[3] Less common causes include: physical factors, biological agents such as semen, latex, hormonal changes, food additives and colors, and topical medications.[20] Physical factors such as exercise (known as exercise-induced anaphylaxis) or temperature (either hot or cold) may also act as triggers through their direct effects on mast cells.[3][24][25] Events caused by exercise are frequently associated with cofactors such as the ingestion of certain foods[17][26] or taking an NSAID.[26][27]Anaphylaxis caused by a combination of exercise and consumption of certain foods is known as food-dependent exercise-induced anaphylaxis (FDEIA).[28] In aspirin-exacerbated respiratory disease (AERD), alcohol is a common trigger.[29][30] During anesthesia, neuromuscular blocking agents, antibiotics, and latex are the most common causes.[31] The cause remains unknown in 32–50% of cases, referred to as "idiopathic anaphylaxis."[32] Six vaccines (MMR, varicella, influenza, hepatitis B, tetanus, meningococcal) are recognized as a cause for anaphylaxis, and HPV may cause anaphylaxis as well.[33]

Food and alcohol

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Many foods can trigger anaphylaxis; this may occur upon the first known ingestion.[12] Common triggering foods vary around the world due to cultural cuisine. In Western cultures, ingestion of or exposure to peanuts, wheat, nuts, certain types of seafood like shellfish, milk, fruit and eggs are the most prevalent causes.[3][18] Sesame is common in the Middle East, while rice and chickpeas are frequently encountered as sources of anaphylaxis in Asia.[3] Severe cases are usually caused by ingesting the allergen,[12] but some people experience a severe reaction upon contact. Children can outgrow their allergies. By age 16, 80% of children with anaphylaxis to milk or eggs and 20% who experience isolated anaphylaxis to peanuts can tolerate these foods.[22] Any type of alcohol, even in small amounts, can trigger anaphylaxis in people with AERD.[29][30]

Medication

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Any medication may potentially trigger anaphylaxis. The most common are β-lactam antibiotics (such as penicillin) followed by aspirin and NSAIDs.[18][34] Other antibiotics are implicated less frequently.[34] Anaphylactic reactions to NSAIDs are either agent specific or occur among those that are structurally similar meaning that those who are allergic to one NSAID can typically tolerate a different one or different group of NSAIDs.[35] Other relatively common causes include chemotherapy, vaccines, protamine and herbal preparations.[3] Some medications (vancomycin, morphine, x-ray contrast among others) cause anaphylaxis by directly triggering mast cell degranulation.[12]

The frequency of a reaction to an agent partly depends on the frequency of its use and partly on its intrinsic properties.[36] Anaphylaxis to penicillin or cephalosporins occurs only after it binds to proteins inside the body with some agents binding more easily than others.[17] Anaphylaxis to penicillin occurs once in every 2,000 to 10,000 courses of treatment, with death occurring in fewer than one in every 50,000 courses of treatment.[17] Anaphylaxis to aspirin and NSAIDs occurs in about one in every 50,000 persons.[17] If someone reacts to penicillin, his or her risk of a reaction to cephalosporins is greater but still less than one in 1,000.[17] The old radiocontrast agents caused reactions in 1% of cases, while the newer, lower osmolar agents cause reactions in 0.04% of cases.[36]

Venom

[edit]

Venom from stinging or biting insects such as Hymenoptera (ants, bees, and wasps) or Triatominae (kissing bugs) may cause anaphylaxis in susceptible people.[10][37][38] Previous reactions that are anything more than a local reaction around the site of the sting, are a risk factor for future anaphylaxis;[39][40] however, half of the fatalities have had no previous systemic reaction.[41]

Risk factors

[edit]

People with atopic diseases such as asthma, eczema, or allergic rhinitis are at high risk of anaphylaxis from food, latex, and radiocontrast agents but not from injectable medications or stings.[3][12] One study in children found that 60% had a history of previous atopic diseases, and of children who die from anaphylaxis, more than 90% have asthma.[12] Those with mastocytosis, mast cell activation syndrome (MCAS) or of a higher socioeconomic status are at increased risk.[3][12][42]

Pathophysiology

[edit]

Anaphylaxis is a severe allergic reaction of rapid onset affecting many body systems.[5][9] It is due to the release of inflammatory mediators and cytokines from mast cells and basophils, typically due to an immunologic reaction but sometimes non-immunologic mechanism.[9]

Interleukin (IL)–4 and IL-13 are cytokines important in the initial generation of antibody and inflammatory cell responses to anaphylaxis.[43]

Immunologic

[edit]

In the immunologic mechanism, immunoglobulin E (IgE) binds to the antigen (the foreign material that provokes the allergic reaction). Antigen-bound IgE then activates FcεRI receptors on mast cells and basophils. This leads to the release of inflammatory mediators such as histamine. These mediators subsequently increase the contraction of bronchial smooth muscles, trigger vasodilation, increase the leakage of fluid from blood vessels, and cause heart muscle depression.[9][17] There is also a non-immunologic mechanism that does not rely on IgE, but it is not known if this occurs in humans.[9]

Non-immunologic

[edit]

Non-immunologic mechanisms involve substances that directly cause the degranulation of mast cells and basophils. These include agents such as contrast medium, opioids, temperature (hot or cold), and vibration.[9][24] Sulfites may cause reactions by both immunologic and non-immunologic mechanisms.[44]

Diagnosis

[edit]

Anaphylaxis is diagnosed on the basis of a person's signs and symptoms.[3] When any one of the following three occurs within minutes or hours of exposure to an allergen there is a high likelihood of anaphylaxis:[3]

  1. Involvement of the skin or mucosal tissue plus either respiratory difficulty or a low blood pressure causing symptoms
  2. Two or more of the following symptoms after a likely contact with an allergen:
    a. Involvement of the skin or mucosa
    b. Respiratory difficulties
    c. Low blood pressure
    d. Gastrointestinal symptoms
  3. Low blood pressure after exposure to a known allergen

Skin involvement may include: hives, itchiness, or a swollen tongue, among others. Respiratory difficulties may include: shortness of breath, stridor, or low oxygen levels, among others. Low blood pressure is defined as a greater than 30% decrease from a person's usual blood pressure. In adults, a systolic blood pressure of less than 90 mmHg is often used.[3]

During an attack, blood tests for tryptase or histamine (released from mast cells) might be useful in diagnosing anaphylaxis due to insect stings or medications. However these tests are of limited use if the cause is food or if the person has a normal blood pressure,[3] and they are not specific for the diagnosis.[22]

Classification

[edit]

There are three main classifications of anaphylaxis.

  1. Anaphylactic shock is associated with systemic vasodilation that causes low blood pressure, which is by definition 30% lower than the person's baseline or below standard values.[19]
  2. Biphasic anaphylaxis is the recurrence of symptoms within 1–72 hours after resolution of an initial anaphylactic episode.[45] Estimates of incidence vary between less than 1% and up to 20% of cases.[45][46] The recurrence typically occurs within 8 hours.[12] It is managed in the same manner as anaphylaxis.[10]
  3. Anaphylactoid reaction, non-immune anaphylaxis, or pseudoanaphylaxis, is a type of anaphylaxis that does not involve an allergic reaction but is due to direct mast cell degranulation.[12][47] Non-immune anaphylaxis is the current term, as of 2018, used by the World Allergy Organization[47] with some recommending that the old terminology, "anaphylactoid", no longer be used.[12]

Allergy skin testing

[edit]
Skin allergy testing being carried out on the right arm
Patch test

Allergy testing may help in determining the trigger. Skin allergy testing is available for certain foods and venoms.[22] Blood testing for specific IgE can be useful to confirm milk, egg, peanut, tree nut, and fish allergies.[22]

Skin testing is available to confirm penicillin allergies, but is not available for other medications.[22] Non-immune forms of anaphylaxis can only be determined by history or exposure to the allergen in question, and not by skin or blood testing.[47]

Differential diagnosis

[edit]

It can sometimes be difficult to distinguish anaphylaxis from asthma, syncope, and panic attacks.[3] Asthma however typically does not entail itching or gastrointestinal symptoms, syncope presents with pallor rather than a rash, and a panic attack may have flushing but does not have hives.[3] Other conditions that may present similarly include: scrombroidosis and anisakiasis.[12]

Post-mortem findings

[edit]

In a person who died from anaphylaxis, autopsy may show an "empty heart" attributed to reduced venous return from vasodilation and redistribution of intravascular volume from the central to the peripheral compartment.[43] Other signs are laryngeal edema, eosinophilia in lungs, heart and tissues, and evidence of myocardial hypoperfusion.[48] Laboratory findings could detect increased levels of serum tryptase, an increase in total and specific IgE serum levels.[48]

Prevention

[edit]
See also: Allergen immunotherapy

Avoidance of the trigger of anaphylaxis is recommended. In cases where this may not be possible, desensitization may be an option. Immunotherapy with Hymenoptera venoms is effective at desensitizing 80–90% of adults and 98% of children against allergies to bees, wasps, hornets, yellowjackets, and fire ants. Oral immunotherapy may be effective at desensitizing some people to certain food including milk, eggs, nuts and peanuts; however, adverse effects are common.[3] For example, many people develop an itchy throat, cough, or lip swelling during immunotherapy.[49] Desensitization is also possible for many medications, however it is advised that most people simply avoid the agent in question. In those who react to latex it may be important to avoid cross-reactive foods such as avocados, bananas, and potatoes among others.[3]

Management

[edit]

Anaphylaxis is a medical emergency that may require resuscitation measures such as airway management, supplemental oxygen, large volumes of intravenous fluids, and close monitoring.[10] Passive leg raise may also be helpful in the emergency management.[50]

Administration of intravenous fluid bolus and epinephrine is the treatment of choice with antihistamines used as adjuncts.[51] A period of in-hospital observation for between 2 and 24 hours is recommended for people once they have returned to normal due to concerns of biphasic anaphylaxis.[12][17][46][52]

Epinephrine

[edit]
An old version of an EpiPen brand auto-injector

Epinephrine (adrenaline) (1 in 1,000) is the primary treatment for anaphylaxis with no absolute contraindication to its use.[10] It is recommended that an epinephrine solution be given intramuscularly into the mid anterolateral thigh as soon as the diagnosis is suspected. The injection may be repeated every 5 to 15 minutes if there is insufficient response.[10] A second dose is needed in 16–35% of episodes with more than two doses rarely required.[10] The intramuscular route is preferred over subcutaneous administration because the latter may have delayed absorption.[10][53] It is recommended that after diagnosis and treatment of anaphylaxis, the patient should be kept under observation in an appropriate clinical setting until symptoms have fully resolved.[45] Minor adverse effects from epinephrine include tremors, anxiety, headaches, and palpitations.[3]

People on β-blockers may be resistant to the effects of epinephrine.[12] In this situation, if epinephrine is not effective, intravenous glucagon can be administered, which has a mechanism of action independent of β-receptors.[12]

If necessary, it can also be given intravenously using a dilute epinephrine solution. Intravenous epinephrine, however, has been associated both with dysrhythmia and myocardial infarction.[10] Epinephrine autoinjectors used for self-administration typically come in two doses, one for adults or children who weigh more than 25 kg and one for children who weigh 10 to 25 kg.[54]

Adjuncts

[edit]

Antihistamines (both H1 and H2), while commonly used and assumed effective based on theoretical reasoning, are poorly supported by evidence.[55][56] A 2007 Cochrane review did not find any good-quality studies upon which to base recommendations[56] and they are not believed to affect airway edema or spasm.[12] Corticosteroids are unlikely to make a difference in the current episode of anaphylaxis, but may be used in the hope of decreasing the risk of biphasic anaphylaxis. Their prophylactic effectiveness in these situations is uncertain.[46] Nebulized salbutamol may be effective for bronchospasm that does not resolve with epinephrine.[12] Methylene blue has been used in those not responsive to other measures due to its presumed effect of relaxing smooth muscle.[12]

Preparedness

[edit]

People prone to anaphylaxis are advised to have an allergy action plan. Parents are advised to inform schools of their children's allergies and what to do in case of an anaphylactic emergency. The action plan usually includes use of epinephrine autoinjectors, the recommendation to wear a medical alert bracelet, and counseling on avoidance of triggers.[57] Immunotherapy is available for certain triggers to prevent future episodes of anaphylaxis. A multi-year course of subcutaneous desensitization has been found effective against stinging insects, while oral desensitization is effective for many foods.[18]

Prognosis

[edit]

In those in whom the cause is known and prompt treatment is available, the prognosis is good.[58] Even if the cause is unknown, if appropriate preventive medication is available, the prognosis is generally good.[17] Usually, death occurs due to either respiratory failure (typically involving asphyxia) or cardiovascular complications, such as cardiovascular shock,[9][12] with 0.7–20% of cases causing death.[17][21] There have been cases of death occurring within minutes.[3] Outcomes in those with exercise-induced anaphylaxis are typically good, with fewer and less severe episodes as people get older.[32]

Epidemiology

[edit]

The number of people who get anaphylaxis is 4–100 per 100,000 persons per year,[12][59] with a lifetime risk of 0.05–2%.[60] About 30% of affected people get more than one attack.[59] Exercise-induced anaphylaxis affects about 1 in 2000 young people.[26]

Rates appear to be increasing: the numbers in the 1980s were approximately 20 per 100,000 per year, while in the 1990s, it was 50 per 100,000 per year.[18] The increase appears to be primarily for food-induced anaphylaxis.[61] The risk is greatest in young people and females.[10][12]

Anaphylaxis leads to as many as 500–1,000 deaths per year (2.7 per million) in the United States, 20 deaths per year in the United Kingdom (0.33 per million), and 15 deaths per year in Australia (0.64 per million).[12] Another estimate from the United States puts the death rate at 0.7 per million.[62] Mortality rates have decreased between the 1970s and 2000s.[63] In Australia, death from food-induced anaphylaxis occur primarily in women while deaths due to insect bites primarily occur in males.[12] Death from anaphylaxis is most commonly triggered by medications.[12]

History

[edit]

The conditions of anaphylaxis have been known since ancient times.[47] French physician François Magendie had described how rabbits were killed by repeated injections of egg albumin in 1839.[64] However, the phenomenon was discovered by two French physiologists Charles Richet and Paul Portier.[65] In 1901, Albert I, Prince of Monaco requested Richet and Portier join him on a scientific expedition around the French coast of the Atlantic Ocean,[66] specifically to study on the toxin produced by cnidarians (like jellyfish and sea anemones).[65] Richet and Portier boarded Albert's ship Princesse Alice II for ocean exploration to make collections of the marine animals.[67]

Richet and Portier extracted a toxin called hypnotoxin from their collection of jellyfish (but the real source was later identified as Portuguese man o' war)[68] and sea anemone (Actinia sulcata).[69] In their first experiment on the ship, they injected a dog with the toxin in an attempt to immunise the dog, which instead developed a severe reaction (hypersensitivity). In 1902, they repeated the injections in their laboratory and found that dogs normally tolerated the toxin at the first injection, but on re-exposure, three weeks later with the same dose, they always developed fatal shock. They also found that the effect was not related to the doses of toxin used, as even small amounts in secondary injections were lethal.[69] Thus, instead of inducing tolerance (prophylaxis), which they expected, they discovered effects of the toxin as deadly.[70]

In 1902, Richet introduced the term aphylaxis to describe the condition of lack of protection. He later changed the term to anaphylaxis on the grounds of euphony.[22] The term is from the Greek ἀνά-, ana-, meaning "against", and φύλαξις, phylaxis, meaning "protection".[71] On 15 February 1902, Richet and Portier jointly presented their findings before the Societé de Biologie in Paris.[72][73] The moment is regarded as the birth of allergy (the term invented by Clemens von Pirquet in 1906) study (allergology).[73] Richet continued to study the phenomenon and was eventually awarded the Nobel Prize in Physiology or Medicine for his work on anaphylaxis in 1913.[67][74]

Research

[edit]

There are ongoing efforts to develop sublingual epinephrine to treat anaphylaxis. Trials of sublingual epinephrine, currently called AQST-108 (dipivefrin) and sponsored by Aquestive Therapeutics, are in phase 1 trials as of December 2021.[12][75] Subcutaneous injection of the anti-IgE antibody omalizumab is being studied as a method of preventing recurrence, but it is not yet recommended.[needs update][3][76]Omalizumab-associated anaphylaxis has been observed in less than 0.1% of patients treated for moderate to severe persistent allergic asthma using subcutaneous omalizumab injections.[77]

References

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[edit]
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Anaphylaxis

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from Grokipedia
Anaphylaxis is a severe, potentially life-threatening allergic reaction that occurs rapidly—often within minutes—after exposure to an , involving the sudden release of chemical mediators from immune cells that affect multiple organ systems, leading to symptoms such as airway constriction, , and shock. This multisystem disorder is mediated primarily by (IgE) antibodies, though non-IgE pathways can also contribute, and it requires immediate administration of epinephrine to reverse its effects and prevent fatality. Common triggers of anaphylaxis include foods such as peanuts, tree nuts, shellfish, and milk; insect stings from bees, wasps, or fire ants; medications like antibiotics (e.g., penicillin) or nonsteroidal anti-inflammatory drugs; and other substances such as latex or exercise in some cases, with idiopathic reactions occurring without an identifiable cause in up to 20-30% of episodes. Risk factors that increase susceptibility include a history of prior anaphylactic episodes, asthma, other atopic allergies, cardiovascular disease, and conditions like mastocytosis that predispose individuals to exaggerated mediator release. Epidemiologically, the lifetime prevalence is estimated at 1–5% in the general population (as of 2025), with incidence rising in developed countries, particularly among children and young adults, and an annual U.S. mortality rate of approximately 200–300 deaths (as of 2020) despite available treatments. Symptoms of anaphylaxis typically manifest suddenly and can include skin reactions such as , flushing, or itching; respiratory distress with wheezing, , or throat swelling; cardiovascular effects like rapid or weak pulse, , or syncope; and gastrointestinal issues including , , or , often accompanied by a . In severe cases, biphasic reactions—where symptoms recur after initial resolution—occur in about 20% of patients, underscoring the need for prolonged monitoring. Diagnosis is primarily clinical, based on the acute onset of symptoms involving at least two organ systems (e.g., skin and respiratory) or after likely exposure, without reliance on laboratory tests for confirmation during an acute event. Treatment centers on immediate intramuscular epinephrine as the first-line intervention, followed by supportive measures such as supplemental oxygen, intravenous fluids, antihistamines, and corticosteroids, with all patients requiring evaluation to mitigate risks of complications like or . Prevention strategies emphasize avoidance, carrying auto-injectable epinephrine, and developing personalized action plans, particularly for at-risk individuals.

Signs and Symptoms

Skin Manifestations

Skin manifestations are the most common initial presentation of anaphylaxis, occurring in 80-90% of cases, though their absence does not exclude the diagnosis. These symptoms typically onset rapidly, within minutes of exposure to the triggering allergen, and can involve superficial or deeper layers of the skin. Cutaneous signs often serve as early indicators, prompting timely intervention to prevent progression to more severe systemic effects. Urticaria, or , represents the hallmark symptom of anaphylaxis, characterized by pruritic, raised wheals that can appear suddenly and spread to cover large areas of the body. These lesions result from localized degranulation and release, leading to increased . Accompanying sensory signs include intense pruritus (itching), flushing (diffuse ), and piloerection (), which may precede visible changes and signal the onset of the reaction. Angioedema involves swelling in deeper dermal and subcutaneous tissues, frequently affecting the lips, eyelids, tongue, or periorbital regions, and can cause significant discomfort or functional impairment. In severe cases, manifestations may progress to generalized (widespread redness) due to or pallor from and hypoperfusion, reflecting the systemic nature of the response. These changes underscore the variability in presentation, emphasizing the need for prompt recognition regardless of the exact pattern.

Respiratory Symptoms

Respiratory symptoms are among the most common manifestations of anaphylaxis, occurring in 50-70% of episodes, and can lead to rapid airway compromise if not addressed promptly. Initial upper airway signs often include , , and sneezing, which may precede more severe involvement and signal the onset of the reaction. These symptoms reflect early mucosal and can occur alongside skin flushing, further indicating systemic involvement. As the reaction progresses, laryngeal edema develops, causing swelling of the upper airway that manifests as , hoarseness, or changes in voice quality, potentially obstructing airflow and requiring immediate intervention. tightness serves as a critical early warning sign, often described by patients as a sensation of closing or constriction, which demands urgent administration of epinephrine to prevent escalation. Lower airway involvement typically presents as , leading to wheezing, , and dyspnea, which can severely impair ventilation. In advanced cases, untreated respiratory distress may result in and , marking significant decompensation with reduced and bluish discoloration of the skin or mucous membranes due to inadequate . These symptoms underscore the potential for anaphylaxis to cause life-threatening within minutes, emphasizing the need for swift recognition and treatment.

Cardiovascular Effects

Cardiovascular effects represent a critical component of anaphylaxis, often leading to hemodynamic instability and potentially fatal shock through widespread and impaired cardiac function. Involvement of the cardiovascular system occurs in 30-45% of anaphylaxis episodes, with symptoms ranging from mild to profound circulatory collapse. These changes primarily stem from mediator-induced peripheral , which reduces systemic and preload, exacerbating the risk in patients with preexisting . Profound , typically defined as a systolic below 90 mmHg or a drop greater than 30% from baseline, is a hallmark of severe anaphylaxis and correlates with increased mortality. An initial compensatory tachycardia is common, driven by baroreceptor activation in response to vasodilation and hypovolemia, with heart rates often exceeding 100 beats per minute. In severe cases, this can progress to bradycardia, which is uncommon and observed in fewer than 5% of cases, particularly as myocardial depression sets in due to direct mediator effects on cardiac contractility, vagal stimulation, or exhaustion of compensatory mechanisms; bradycardia often precedes cardiac arrest. The resulting distributive shock features relative intravascular volume depletion from capillary leakage and vasodilation, leading to inadequate tissue perfusion despite normal or increased cardiac output initially. Reduced cerebral and systemic perfusion manifests as syncope, , or altered mental status, affecting approximately 10-15% of patients and signaling imminent . , reported in 8-16% of cases with cardiac involvement, may mimic acute due to coronary vasospasm (Kounis syndrome type I) or plaque rupture in those with underlying , triggered by and other mediators. These symptoms underscore the need for rapid recognition, as cardiovascular collapse accounts for the majority of anaphylaxis-related fatalities.

Gastrointestinal and Other Symptoms

Gastrointestinal symptoms are common in anaphylaxis and may manifest as , , , or cramping, reflecting the systemic release of mediators affecting and mucosal tissues. These signs occur in 17% to 33% of cases across all ages, with higher rates of or (up to 24%) observed in children and adolescents. In severe reactions, or can develop due to heightened gastrointestinal motility and . Neurologic and sensory symptoms often precede or accompany other manifestations, including , a , anxiety, confusion, or a metallic in the , which arise from cerebral hypoperfusion or direct effects. These prodromal signs, such as or , can signal the onset of a reaction but are subjective and vary by individual. Genitourinary involvement is less frequent and may include uterine cramps or in females, resulting from impacting reproductive . In extreme cases, seizure-like activity or loss of consciousness can occur, typically linked to profound or hypoxia, affecting fewer than 15% of patients. Rare "other" symptoms encompass ocular effects such as conjunctival injection, , or tearing, and occasional joint involvement like , which contribute to the multisystem nature of anaphylaxis but are not diagnostic hallmarks. These atypical presentations underscore the need for prompt recognition in clinical settings.

Causes and Risk Factors

Food and Medication Triggers

Food and medication triggers are among the most frequent causes of anaphylaxis, particularly through IgE-mediated leading to rapid systemic reactions upon exposure. In children, allergens account for approximately 30-37% of anaphylactic episodes, with the most common culprits being , tree nuts, milk, eggs, , and sesame seeds. These proteins in foods provoke after oral ingestion, often resulting in symptoms within minutes to hours; even trace amounts can trigger severe reactions due to the dose-independent nature of IgE responses. Additionally, certain fruits such as bananas, avocados, kiwis, and chestnuts may cross-react with proteins in sensitized individuals, potentially exacerbating food-related anaphylaxis in those with , affecting 30-50% of such cases. Medications contribute to about 20% of overall anaphylaxis cases across all ages, with antibiotics like penicillins being the leading pharmaceutical triggers due to their beta-lactam structure eliciting IgE antibodies. Nonsteroidal drugs (NSAIDs), such as ibuprofen and aspirin, are also prominent, often causing reactions through inhibition rather than solely IgE mechanisms, while monoclonal antibodies like rituximab can induce via release or true IgE-mediated pathways during infusion. Vaccines, though rare, may provoke anaphylaxis from components like egg proteins in some formulations or stabilizers, with an incidence of approximately 1 per million doses. Drug exposures occur via multiple routes—intravenous, oral, or topical—bypassing gastrointestinal barriers and accelerating onset compared to . Alcohol serves as a rare exacerbator rather than a direct trigger, promoting vasodilation that can lower the threshold for anaphylactic responses when combined with other allergens, though true ethanol-induced anaphylaxis is exceptionally uncommon.

Insect Venom and Other Allergens

Insect stings from Hymenoptera species, including bees (Apis mellifera), wasps (Vespula species), yellow jackets (Vespula and Dolichovespula species), hornets, and fire ants (Solenopsis invicta), represent a significant extrinsic trigger for anaphylaxis, particularly in adults. Yellow jacket stings are among the most common culprits in temperate regions like the United States, due to their aggressive behavior and prevalence in outdoor environments. Venom is delivered directly via the insect's stinger, which in bees remains embedded in the skin, releasing additional venom through muscle contraction, whereas wasps and yellow jackets can sting multiple times. Systemic reactions occur in approximately 3% of adults following stings, accounting for 15-25% of all anaphylaxis cases in this population. Multiple simultaneous stings can exacerbate severity by increasing the venom dose, leading to both allergic and toxic effects, such as multi-organ involvement or shock. Beyond insect venoms, other non-ingestible allergens can precipitate anaphylaxis through procedural or environmental exposures. Radiocontrast media, used in diagnostic imaging such as computed tomography scans, are iodinated compounds administered intravenously, with reactions typically occurring within 30 minutes of injection. These are often anaphylactoid rather than IgE-mediated but mimic true anaphylaxis clinically, affecting about 0.6-3% of recipients, with severe cases in 0.04-0.2%. involves physical activity as the primary trigger, sometimes requiring a cofactor like recent food intake (food-dependent exercise-induced anaphylaxis, or FDEIA), where symptoms arise only when exertion follows ingestion of specific triggers such as or ; this form is rare, comprising less than 5% of anaphylaxis episodes. Idiopathic anaphylaxis, characterized by recurrent episodes without an identifiable trigger despite thorough evaluation, accounts for 30-60% of adult cases and up to 10% in children. These reactions often occur in individuals with a history of , and while the exact mechanism remains unclear, they necessitate prompt recognition to distinguish from other forms. In clinical settings, overlap with medication-related reactions may occur during procedures involving contrast agents, but and procedural triggers predominate in community-onset cases.

Risk Factors for Severity

Several patient-related factors influence the severity of anaphylaxis outcomes. Asthma is a prominent risk factor, as it significantly heightens the likelihood of life-threatening or fatal reactions, with case series indicating that 70-96% of deaths from food-induced anaphylaxis occur in individuals with pre-existing asthma. Cardiovascular disease, including conditions like hypertension or coronary artery disease, also elevates the risk of severe cardiovascular collapse during anaphylaxis, with studies showing increased odds of hospitalization and fatality in affected patients. Age plays a role as well; infants and young children may experience more rapid progression due to immature immune responses and smaller airways, while adults over 50 or 65 years face higher mortality risks from comorbidities and delayed recognition. A history of prior severe anaphylactic reactions further predisposes individuals to more intense future episodes, necessitating heightened vigilance. Situational factors can exacerbate anaphylaxis severity by augmenting the allergic response or hindering effective intervention. Delayed administration of epinephrine is a critical modifier, associated with biphasic reactions—where symptoms recur after initial resolution—in up to 20% of cases, often leading to prolonged or worsened outcomes.61217-3/abstract) Concomitant exercise, alcohol ingestion, or can intensify reactions through mechanisms like increased or impaired physiological reserve. Use of beta-blockers, which counteract epinephrine's effects, substantially worsens and , increasing the odds of severe anaphylaxis in patients on these medications. Genetic and clonal disorders involving s, such as , markedly elevate the risk of severe anaphylaxis even with minor triggers, due to excessive mediator release. Patients with exhibit higher rates of life-threatening reactions, often independent of identifiable allergens, with elevated baseline levels serving as a predictor of severity.

Pathophysiology

Immunologic Mechanisms

Anaphylaxis is primarily classified as a reaction, mediated by (IgE) antibodies that trigger rapid activation of effector cells such as mast cells and . This immunologic process begins with an initial sensitization phase, during which exposure to an leads to the production of allergen-specific IgE by B cells, facilitated by T helper 2 (Th2) cell-derived cytokines like interleukin-4 (IL-4) and IL-13, which promote B-cell class switching. The discovery of IgE as the key antibody in allergic reactions was made by Teruko and Kimishige Ishizaka in 1966, identifying it as the reaginic antibody responsible for immediate . Upon subsequent exposure to the same , the culminates in the phase, where the cross-links IgE molecules bound to the high-affinity FcεRI receptors on the surface of sensitized mast cells and . This cross-linking initiates an intracellular signaling cascade involving kinases such as Lyn and Syk, phospholipase Cγ, and , leading to calcium influx and rapid of these cells within minutes. releases preformed mediators, including and , as well as newly synthesized lipid mediators like leukotrienes (LTC4, LTD4, LTE4), platelet-activating factor (PAF), and (PGD2), which collectively drive the systemic effects of anaphylaxis. In addition to immediate mediator release, the IgE-mediated cascade amplifies through a , where mast cells and secrete Th2 cytokines such as IL-4 and IL-13, further promoting IgE production and recruiting additional inflammatory cells in a late-phase response. Complement-derived anaphylatoxins, C3a and C5a, can enhance this IgE-dependent process by binding to their receptors (C3aR and C5aR) on mast cells, potentiating and mediator release during allergic reactions. These mediators contribute to the characteristic of anaphylaxis, such as , , and increased .

Non-Immunologic Mechanisms

Non-immunologic mechanisms of anaphylaxis, also known as pseudoallergic or anaphylactoid reactions, involve the direct activation of effector cells such as mast cells and without the involvement of (IgE) antibodies, leading to the release of mediators like and leukotrienes that produce symptoms mimicking true allergic anaphylaxis. These pathways are particularly evident in scenarios where no allergen-specific is identifiable. Although the clinical manifestations overlap with those of immunologic anaphylaxis, the underlying processes differ by bypassing adaptive immunity. Direct activation represents a primary non-immunologic pathway, where certain substances trigger independently of IgE cross-linking. Cationic agents such as opioids and radiocontrast media bind to the Mas-related X2 (MRGPRX2) on s, inducing calcium influx and rapid mediator release. For instance, and other opioids stimulate release via this receptor, contributing to and during perioperative or diagnostic procedures. Similarly, iodinated radiocontrast agents provoke reactions in up to 1-3% of administrations, primarily through MRGPRX2-mediated effects rather than immune . Complement activation provides another key non-immunologic route, generating anaphylatoxins that amplify responses. Agents like certain intravenous fluids, plasma expanders (e.g., dextrans), or even infections can initiate the classical or alternative complement pathways, producing C3a and C5a fragments that directly stimulate , , and endothelial cells to release vasoactive mediators. This mechanism is implicated in reactions to Cremophor EL-containing formulations, such as those in some preparations, where complement-derived anaphylatoxins enhance and contraction. Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) exemplify pseudoallergic reactions through (COX) inhibition, shifting metabolism toward increased production of cysteinyl s. In susceptible individuals, aspirin blocks COX-1, reducing protective prostaglandins like PGE2 while elevating levels, which promote , mucosal , and systemic effects resembling anaphylaxis. This pathway underlies up to 22% of reported food-induced anaphylactic episodes exacerbated by concurrent NSAID use. Idiopathic anaphylaxis occurs when no clear trigger is identified, comprising 30-60% of adult cases and potentially involving non-immunologic pathways such as hypersensitive responses or neuronal influences. Proposed mechanisms include intrinsic instability driven by cytokines or, less conclusively, neuronal factors like release, though direct evidence remains limited. These episodes highlight the complexity of anaphylaxis, where non-IgE stimuli may underlie recurrent, unpredictable reactions.

Diagnosis

Clinical Classification

Anaphylaxis is clinically classified based on established diagnostic criteria that emphasize rapid recognition through acute onset and multi-organ involvement, primarily developed by organizations such as the World Allergy Organization (WAO) and the European Academy of and Clinical Immunology (EAACI). The WAO criteria, updated in 2020, define anaphylaxis as an acute onset (minutes to several hours) of illness involving skin or mucosal tissue changes (such as generalized , pruritus, flushing, or of the , , or ) plus at least one of the following: respiratory compromise (e.g., dyspnea, , , reduced , or ), reduced or associated symptoms of end-organ dysfunction (e.g., , syncope, or incontinence), or, after exposure to a likely for that patient, acute onset of severe gastrointestinal symptoms such as crampy or repetitive (particularly with non-food triggers). These criteria align closely with EAACI guidelines, which similarly prioritize simultaneous involvement of at least two organ systems following exposure to facilitate immediate in emergency settings. Severity grading of anaphylaxis aids in real-time assessment and management prioritization, with a WAO update providing a structured system for systemic allergic reactions that includes anaphylaxis. Mild reactions (Grade 1) are limited to symptoms in one , such as localized , mild pruritus, or isolated , without respiratory or cardiovascular involvement. Moderate reactions (Grade 2) involve more widespread symptoms, including generalized urticaria, persistent , , or mild respiratory features like . Severe reactions (Grade 3 or higher) feature life-threatening compromise, such as leading to shock, severe , or with increased , often requiring multiple interventions. This grading underscores that skin involvement alone typically indicates mild severity, while progression to respiratory or gastrointestinal symptoms signals moderate risk, and or shock denotes severe cases. A subset of anaphylaxis cases involves biphasic reactions, where symptoms recur after initial resolution without re-exposure to the trigger, typically 1 to 72 hours later, with a onset around 8 to 11 hours. These second waves can range from mild to severe and are more common following initial severe episodes or those requiring multiple epinephrine doses. The 2024 GA²LEN/WAO consensus report incorporates age-specific symptom recognition to improve diagnostic accuracy, particularly in infants and young children where classic signs may be absent or atypical. For example, in infants, indicators include a hoarse cry suggesting laryngeal involvement, repetitive lip licking for mucosal changes, persistent unexplained , , or abrupt irritability, rather than verbal reports of dyspnea. For mild cases without respiratory or cardiovascular compromise, guidelines recommend a approach with close monitoring rather than immediate epinephrine, allowing observation for progression while ensuring rapid access to treatment.

Diagnostic Testing

Diagnostic testing for anaphylaxis primarily involves laboratory assessments to confirm activation and identify the underlying after the acute event, as the diagnosis is initially clinical. Serum measurement is a key acute , with levels elevating due to during anaphylaxis. concentrations typically peak 1-2 hours after symptom onset and return to baseline within 6-24 hours. The normal baseline serum level is less than 11.4 ng/mL, and an elevation above this absolute threshold during or shortly after the reaction supports the . However, current guidelines recommend assessing relative elevation from the patient's baseline level using the formula: acute > (baseline × 1.2 + 2) ng/mL, which provides greater diagnostic accuracy, particularly in individuals with elevated baseline levels due to hereditary alpha-tryptasemia (HαT). Baseline should be measured in patients with recurrent or idiopathic anaphylaxis, venom allergy, or suspected disorders to enable this calculation. A negative result (whether absolute or relative) does not exclude anaphylaxis, with overall sensitivity around 60-80% depending on timing and baseline. To identify specific triggers, allergy testing is performed once the patient is stable, typically weeks after the episode to avoid interference from recent activation. Skin prick testing involves applying allergen extracts to the skin and pricking the surface to detect immediate IgE-mediated hypersensitivity, producing a wheal-and-flare reaction in positive cases. Intradermal testing, which injects a small amount of allergen into the dermis, is more sensitive but carries a higher risk of systemic reactions and is used when skin prick results are negative but suspicion remains high. These tests help confirm sensitivity to common triggers such as foods, insect venoms, or medications. Specific IgE blood tests, such as the ImmunoCAP assay, quantify allergen-specific IgE antibodies in serum, providing an alternative to skin testing for patients with skin conditions or those unable to undergo cutaneous procedures. These assays are reliable for diagnosing IgE-mediated allergies to various triggers and are not affected by recent anaphylactic episodes. For suspected drug-induced anaphylaxis, where skin or IgE tests may be less reliable, the evaluates functional IgE-dependent of in vitro upon exposure to the suspected drug. is particularly useful for confirming allergies to antibiotics, neuromuscular blocking agents, and other medications, offering high specificity as a safer alternative to challenges. Positive results indicate drug-specific activation, aiding in precise trigger identification.

Differential Diagnosis

The differential diagnosis of anaphylaxis encompasses a range of conditions that can present with similar acute symptoms such as , respiratory distress, or cutaneous manifestations, necessitating careful clinical evaluation to exclude mimics and ensure appropriate management. Distinguishing features often rely on the presence or absence of allergic triggers, the rapidity of onset, and specific vital sign patterns or laboratory findings. Vasovagal syncope typically occurs in response to emotional stress, , or orthostatic changes, leading to transient and without the urticaria, , or respiratory involvement seen in anaphylaxis; it resolves quickly with recumbent positioning. Panic attacks may mimic anaphylaxis through , , and a , but lack systemic signs like , pruritus, or mucosal , and are often associated with psychosocial triggers rather than allergens. , a bradykinin-mediated disorder, presents with non-pruritic swelling of the face, extremities, or airway without urticaria, distinguishing it from histamine-driven anaphylaxis; a family history of similar episodes and absence of allergic precipitants further support this diagnosis. Septic shock, resulting from overwhelming infection, features and alongside fever, , and , contrasting with the allergen-triggered, rapid-onset of anaphylaxis that lacks infectious signs. Myocardial infarction can cause acute , dyspnea, and due to , but is identified by ECG abnormalities, elevated cardiac enzymes, and absence of allergic cutaneous or gastrointestinal symptoms. help differentiate shock types: anaphylactic shock shows warm extremities with and low-normal temperature, while often includes fever and initially warm skin, and from presents with cool, clammy skin and pulmonary congestion. Asthma exacerbation may overlap with anaphylaxis in causing wheezing and respiratory distress, but is typically isolated to the airways without , urticaria, or gastrointestinal involvement, and responds to bronchodilators alone. Foreign body aspiration leads to sudden , , or unilateral wheezing from mechanical obstruction, without the multi-organ allergic features or history of exposure in anaphylaxis. , arising from neuroendocrine tumors, can produce episodic flushing, , and due to serotonin release, but occurs chronically without identifiable allergens and is confirmed by elevated urinary 5-hydroxyindoleacetic acid levels. Angioedema without accompanying urticaria raises suspicion for bradykinin-mediated processes, such as hereditary angioedema or ACE inhibitor-induced reactions, rather than IgE-mediated anaphylaxis, which more commonly includes hives and pruritus.

Post-Mortem Findings

Fatal anaphylaxis is a rare event, with an estimated incidence of 0.5 deaths per million person-years based on a systematic review of global epidemiological data. Autopsy examinations in such cases often reveal non-specific macroscopic findings due to the rapid progression of the reaction, which can lead to death within one hour in the majority of instances. Common observations include laryngeal and pharyngeal edema in approximately 41% of cases, pulmonary congestion and edema in up to 100%, and petechial hemorrhages on the heart, lungs, or pleural surfaces in about 18%, attributable to hypoxia and cardiovascular collapse. In roughly 41% of autopsies, no distinctive gross abnormalities are identified, underscoring the need for supplementary microscopic and biochemical analyses to confirm the diagnosis. Microscopically, evidence of mast cell degranulation is a hallmark finding, particularly in the , , and , where for demonstrates strong positivity and extracellular dispersion indicative of mediator release. tissues frequently show alveolar , congestion, and focal hemorrhages, with degranulated s clustered around airways and vessels. In the , similar degranulation patterns may be observed, especially in cases triggered by ingested allergens, reflecting systemic . Biochemical markers provide critical diagnostic support, with serum tryptase levels elevated above 40 µg/L in nearly all tested fatal cases, often reaching means of 133.5 µg/L, due to its prolonged compared to other mediators. Post-mortem histamine concentrations in blood or tissues can also be markedly increased, supporting anaphylaxis when exceeding normal ranges, though its short limits reliability if death occurs rapidly after onset. Allergen-specific IgE detection in post-mortem serum further corroborates the trigger in select cases. These findings parallel ante-mortem symptoms like airway obstruction but are distinguished by their forensic context in confirming .

Management

Epinephrine Administration

Epinephrine, also known as adrenaline, is the first-line treatment for anaphylaxis, rapidly reversing life-threatening symptoms by counteracting the effects of massive mediator release from mast cells and basophils.01304-2/fulltext) Administered promptly upon recognition of anaphylaxis, it stabilizes cardiovascular and respiratory compromise, preventing progression to shock or airway obstruction.00072-7/fulltext) The standard is intramuscular () injection into the anterolateral , which provides reliable absorption compared to other sites or routes. For adults and children weighing more than 30 kg, the dose is 0.3 to 0.5 mg of epinephrine (1:1000 solution); for children, it is 0.01 mg/kg, with a maximum of 0.3 mg for those under 30 kg. If symptoms persist or recur, doses may be repeated every 5 to 15 minutes as needed, up to a maximum of three doses before seeking emergency care. Self-injectable auto-injectors, such as EpiPen, facilitate rapid delivery in community settings. Epinephrine exerts its effects through activation of alpha- and beta-adrenergic receptors. Alpha-adrenergic stimulation causes , which increases and reduces edema by decreasing in tissues like the skin, mucosa, and . Beta-adrenergic effects include bronchodilation to relieve airway obstruction, increased via enhanced and contractility, and suppression of mediator release from mast cells. Delays in epinephrine administration are associated with increased risks of morbidity and mortality, as later use correlates with more severe biphasic reactions, prolonged , and higher hospitalization rates.30469-6/fulltext) In cases of food-induced anaphylaxis, failure to administer epinephrine before the onset of severe symptoms has been linked to fatal outcomes.30621-X/fulltext) As of 2025, intranasal epinephrine (neffy) has emerged as an alternative delivery option, approved by the FDA in August 2024 for adults and children weighing at least 30 kg, and extended in March 2025 to children aged 4 years and older weighing 15 kg or more. This 2 mg (for those ≥30 kg) or 1 mg (for 15-30 kg) formulation offers a needle-free method, potentially improving for those hesitant about injectors, though IM remains the preferred route in most guidelines.

Adjunctive Therapies

Adjunctive therapies in anaphylaxis management serve to support the primary intervention of epinephrine by addressing secondary symptoms such as cutaneous reactions, , and , though they do not reverse life-threatening manifestations. Antihistamines, including H1 blockers like diphenhydramine or and H2 blockers such as , are used to alleviate itching, , flushing, and other histamine-mediated skin symptoms, with H1 and H2 combinations showing superior relief compared to H1 alone. These agents have a slower and minimal impact on or airway obstruction, making them unsuitable as substitutes for epinephrine; they are recommended only after initial stabilization, with adult doses typically 25-50 mg IV or PO for H1 blockers. Corticosteroids, such as or , are administered to mitigate late-phase reactions that may occur hours after the initial episode, potentially reducing the risk of biphasic anaphylaxis, but they have no role in the immediate treatment of acute symptoms due to their delayed onset of 4-6 hours. Guidelines do not support routine use in the acute phase, as evidence from systematic reviews shows inconclusive benefits for shortening symptoms or preventing recurrence, though they are commonly given intravenously (e.g., 1-2 mg/kg in children or 40-80 mg in adults) if absorption is impaired. For respiratory distress, inhaled bronchodilators like albuterol (salbutamol) are employed as adjuncts to treat and wheezing, particularly in patients with underlying , with nebulized doses of 2.5-5 mg recommended after epinephrine administration. In cases of cardiovascular compromise, intravenous fluids such as 0.9% normal saline are essential to counteract from , with initial boluses of 20 mL/kg in children or 1-2 L in adults titrated to response, potentially requiring up to 5 L in severe . In patients on beta-blockers who exhibit refractory despite epinephrine, is indicated to enhance cardiac inotropy and chronotropy via cyclic AMP pathways, bypassing beta-receptor blockade; an initial IV dose of 1 mg in adults (or 20-30 mcg/kg in children, max 1 mg) may be repeated or followed by infusion. This approach is supported by case reports and expert consensus, with monitoring for side effects like required.

Emergency Preparedness

Individuals at risk for anaphylaxis should receive a prescription for epinephrine auto-injectors (EAIs) based on their weight, history of reactions, and risk factors such as or prior severe episodes, with two doses recommended due to the potential for biphasic reactions. Dosing is typically 0.01 mg/kg intramuscularly, with options including 0.1 mg for infants weighing 7.5-15 kg, 0.15 mg for children 15-30 kg, and 0.3 mg for those ≥30 kg or adults. Training on EAI use is essential and should involve hands-on practice with trainer devices provided with prescriptions, along with counseling on administration into the mid-outer at the first sign of reaction, regardless of symptom severity. Anaphylaxis action plans are personalized documents that outline known triggers (e.g., specific foods like or medications), early symptoms (e.g., , throat tightness, difficulty ), and step-by-step response protocols, including immediate EAI administration followed by additional care. These plans must include contact information for emergency services and healthcare providers, with annual reviews recommended to ensure relevance, particularly after severe reactions or life transitions. In school settings, policies require stocking undesignated EAIs for any student in need, with all but one U.S. state permitting this practice; storage must be secure yet accessible, at controlled temperatures (66-77°F), and staff training on recognition, administration, and post-use reporting is mandatory, often annually. Workplace policies similarly emphasize clear guidelines for EAI storage, employee education on anaphylaxis signs, and immediate access to emergency response, integrated into broader health and safety protocols. Activation of 911 or emergency medical services is advised immediately after EAI use if symptoms are severe, persist, or recur, to facilitate transport to a medical facility for monitoring. Updated care plans as of 2025 incorporate age-specific checklists, such as weight-based EAI dosing for infants and tailored symptom monitoring for children (e.g., behavioral changes in toddlers versus in adults), to enhance preparedness in educational and childcare environments.

Prevention

Trigger Avoidance Strategies

Trigger avoidance is a cornerstone of anaphylaxis prevention, focusing on identifying and minimizing exposure to known allergens or triggers to reduce the risk of recurrent episodes. Vigilant avoidance of culprit allergens has been shown to prevent recurrence in patients with identifiable triggers, though complete elimination can be challenging due to cross-contamination or hidden exposures. For individuals with a history of anaphylaxis, personalized from allergists on trigger identification and avoidance strategies is essential to improve and minimize emergency interventions. For food-related anaphylaxis, which accounts for a significant portion of cases, strict adherence to allergen-free diets is critical. Patients must meticulously read food labels to identify major allergens such as , tree nuts, milk, eggs, , , soy, and , as required by labeling laws in many countries. Advisory labels like "may contain" or "processed in a facility with" should also be avoided to mitigate risks from potential cross-contact. Mobile applications that scan product barcodes and check ingredients against user-specified allergens, such as ContentChecked or similar tools, can aid in real-time decision-making during shopping. Medication-triggered anaphylaxis requires thorough review of personal and family medical histories to identify and avoid culprit drugs, such as certain antibiotics (e.g., penicillins) or NSAIDs. Patients should inform all healthcare providers of their anaphylaxis history and carry a detailed alert card or medical ID to ensure safe alternatives are selected. In cases of sting-induced anaphylaxis, preventive measures include using insect repellents containing on exposed skin, wearing protective clothing in endemic areas, and avoiding outdoor activities during peak seasons. Additionally, all at-risk patients should carry two epinephrine auto-injectors at all times, as timely self-administration can halt progression to severe reactions. may serve as an adjunct for select patients with allergies, but avoidance remains the primary strategy.

Desensitization and Immunotherapy

Desensitization and represent immune-modulating approaches aimed at reducing to specific triggers in anaphylaxis, offering alternatives to lifelong avoidance for certain . These therapies work by gradually exposing the to increasing doses of the , promoting tolerance and decreasing the risk of severe reactions. While avoidance remains the primary prevention strategy, desensitization protocols can enable patients to tolerate unavoidable exposures, such as stings or essential medications. Venom immunotherapy (VIT) is a well-established treatment for anaphylaxis induced by stings, such as those from bees, wasps, and hornets. Administered via subcutaneous injections, VIT involves an initial build-up phase to reach a , followed by ongoing injections to sustain protection. It is particularly recommended for individuals with systemic reactions to stings and evidence of IgE sensitization. VIT is 75–98% effective in preventing anaphylaxis upon re-sting, with higher efficacy observed for yellow jacket venom compared to honeybee . For food allergies, oral immunotherapy (OIT) and sublingual immunotherapy (SLIT) are options to desensitize patients, primarily targeting common triggers like . OIT entails daily ingestion of gradually increasing doses under medical supervision to raise the reaction threshold. In 2020, the FDA approved Palforzia, a peanut OIT product, for desensitization in children aged 4–17 years with confirmed , marking the first such approval for a food therapy. Clinical trials have shown that peanut OIT enables a of patients to tolerate higher doses without severe reactions, though sustained unresponsiveness requires ongoing and long-term adherence. Ongoing trials are exploring OIT and SLIT efficacy in younger children and other foods, such as and . Omalizumab (Xolair), an anti-IgE monoclonal antibody, is another immune-modulating therapy approved by the FDA on February 16, 2024, for the reduction of allergic reactions, including anaphylaxis, that may occur with accidental exposure to one or more food allergens in adults and children aged 1 year and older with IgE-mediated food allergy. Administered via subcutaneous injection every 2 or 4 weeks, omalizumab binds to free IgE, preventing its interaction with high-affinity receptors on immune cells, thereby lowering the risk of severe reactions to trace amounts of allergens. Clinical trials, including a phase 3 study published in 2024, demonstrated that omalizumab significantly increased the threshold for allergic reactions to multiple foods compared to placebo, with many patients tolerating 10-fold higher doses without symptoms. It is used as an adjunct to avoidance and does not replace the need for epinephrine in emergencies. Rapid desensitization protocols are utilized for patients requiring drugs that previously caused anaphylaxis, particularly in where alternatives may be limited. These supervised procedures involve administering the offending agent—such as platinum-based chemotherapeutics (e.g., ) or taxanes (e.g., )—in exponentially increasing doses over several hours to temporarily induce tolerance for that treatment session. Protocols are tailored to the drug and reaction severity, often using a multi-step in a controlled setting. Studies report high success rates, with over 90% of procedures allowing full dosing without severe reactions in large cohorts of patients.

Prognosis and Epidemiology

Short-Term and Long-Term Outcomes

With prompt treatment, the from anaphylaxis is less than 1%. Biphasic reactions, characterized by a recurrence of symptoms after initial resolution, occur in 5-20% of cases, typically within 72 hours, and are associated with greater initial reaction severity and the need for multiple epinephrine doses. In the long term, anaphylaxis survivors often experience heightened anxiety and diminished due to fear of recurrence and lifestyle restrictions. Approximately 30% of patients face recurrent episodes over follow-up periods ranging from 1.5 to 25 years. Fatalities are notably higher among individuals with , who comprise 70-75% of in certain series, such as those involving food-induced anaphylaxis, owing to compromised respiratory function. Specialist follow-up, including allergist evaluation and education on use, reduces the risk of severe recurrences and readmissions by improving trigger identification and management strategies.

Incidence and Prevalence

Anaphylaxis incidence varies widely across populations and regions, with global estimates ranging from 50 to 2,000 episodes per million person-years. A of worldwide data reported an average incidence of approximately 46 cases per 100,000 population per year, though rates can differ significantly based on diagnostic criteria and reporting methods. As of 2024, the global incidence remains approximately 46 per 100,000 person-years, with case fatality rates under 0.001% when treated promptly. In , all-cause anaphylaxis incidence has been documented at 1.5 to 7.9 per 100,000 person-years, while pediatric rates show even broader variation from 1 to 761 per 100,000 person-years. Over the past two decades, incidence has risen nearly twofold in several regions, including the and parts of Asia, potentially due to increased awareness, diagnostic improvements, and environmental factors. Prevalence of anaphylaxis, defined as the proportion of individuals ever experiencing the condition, is estimated at 0.05% to 5.1% globally (as of 2023), with lifetime in around 0.3%. Rates are notably higher among children, where pediatric prevalence ranges from 0.04% to 1.8%, and in atopic individuals, who face elevated risk due to underlying allergic predispositions. In the United States, anaphylaxis affects 1.6-5.1% of the (as of 2023), with some estimates suggesting up to 5% among adults. Demographic patterns highlight increased occurrence in specific groups; for instance, higher prescription rates of epinephrine auto-injectors occur in children under 17, reflecting elevated risk in this age group. is the leading trigger in children, accounting for about 50% of pediatric anaphylaxis cases, underscoring the burden in young populations.

History

Etymology

The term "anaphylaxis" was coined in 1902 by French physiologists Paul Portier and during their research on immunization against toxins. It derives from the Greek roots "ana-" (ἀνά), meaning "against" or "back," and "phylaxis" (φύλαξις), meaning "protection" or "guarding," reflecting the paradoxical observed instead of immunity. The concept emerged from experiments in which Portier and Richet attempted to immunize dogs against the of the Actinia sulcata, only to find that a second, small dose induced severe shock and death, contrasting with the expected protective response. Richet later elaborated on the term's in his 1913 Nobel Lecture, explaining it as a state where an becomes hypersensitive rather than protected, for which he received the in Physiology or Medicine that year for the discovery of anaphylaxis.

Key Historical Developments

The discovery of anaphylaxis is credited to French physiologists Paul Portier and Charles Richet, who in 1902 observed severe hypersensitivity reactions in dogs following a second exposure to low doses of sea anemone toxin during experiments aboard Prince Albert I of Monaco's yacht, Princesse Alice. This finding, initially aimed at developing protective sera against marine toxins, demonstrated that prior sensitization could paradoxically heighten susceptibility to fatal shock rather than confer immunity, marking the first experimental description of the phenomenon in animals. Richet later received the 1913 Nobel Prize in Physiology or Medicine for this work, which laid the foundation for understanding immune-mediated hypersensitivity. By the 1920s, anaphylaxis was recognized in humans through case reports of severe reactions, particularly following therapeutic injections of foreign sera such as horse-derived antitoxins for or . Physicians documented sudden collapses and deaths in patients, with R.W. Lamson compiling 40 such fatal cases by 1924, attributing them to serum-induced shock and emphasizing the risks of repeated exposure. These observations extended the animal model to clinical practice, highlighting anaphylaxis as a systemic response in sensitized individuals, though diagnostic criteria remained rudimentary. Epinephrine, used since the early 1900s, became more standardized in administration protocols during the 1940s through wartime medical advancements, with its vasoconstrictive and bronchodilatory effects proven effective in reversing and airway obstruction during acute episodes, reducing mortality in serum therapy reactions and establishing it as first-line intervention amid rising awareness of iatrogenic anaphylaxis. The early 2000s saw the development of formal guidelines by organizations like the American Academy of Allergy, Asthma & Immunology (AAAAI) and the World Allergy Organization (WAO), with the AAAAI/ACAAI's 2004 practice parameters providing evidence-based definitions, diagnostic algorithms, and management strategies to standardize care globally. These built on prior ad hoc recommendations, emphasizing prompt epinephrine use and patient education. The 2014 International Consensus on Anaphylaxis (ICON), a collaborative effort by AAAAI, ACAAI, and WAO, further refined diagnostic criteria and addressed biphasic reactions. Subsequent updates, including the 2020 WAO Anaphylaxis Guidance and the AAAAI/ACAAI's 2020 and 2023 practice parameter updates, incorporated new evidence on risk factors, epinephrine dosing, and management of biphasic reactions (symptoms recurring 1–72 hours after initial resolution), recommending extended observation periods of 4–6 hours or longer in high-risk cases to address persistent gaps in prediction and recognition. In 2024, the U.S. Food and Drug Administration approved the first nasal epinephrine spray (Neffy) for anaphylaxis treatment, offering a needle-free alternative to auto-injectors and improving accessibility.

Research

Current Investigations

Recent studies have highlighted the significant role of the gut microbiome in the of food allergies, which often culminate in anaphylaxis. Dysbiosis in the , characterized by reduced diversity and altered bacterial composition, precedes the onset of food sensitization and contributes to immune dysregulation that promotes IgE-mediated responses. For instance, of allergens by gut can modulate the severity of IgE-driven reactions, with certain metabolites either exacerbating or mitigating allergic . Advancements in biomarker discovery for anaphylaxis extend beyond the traditional reliance on serum tryptase levels. Emerging research identifies alternative mediators such as platelet-activating factor (PAF), , chymase, and carboxypeptidase A3 as potential diagnostic tools, particularly in cases where tryptase elevation is absent or delayed. A 2025 evaluated the diagnostic accuracy of these biomarkers, finding that combinations including PAF-acetylhydrolase improve sensitivity for confirming anaphylaxis in acute settings. Additionally, serum levels of MRGPRX2 have shown promise as a long-term predictor for iodinated contrast media-induced anaphylaxis, offering insights into pseudo-allergic pathways. Epidemiological investigations reveal persistent gaps in anaphylaxis reporting and classification, complicating accurate estimates. Underreporting remains a major issue, with up to 48% of cases fulfilling diagnostic criteria but not properly coded as anaphylaxis, leading to underestimated incidence rates. Idiopathic anaphylaxis, where no trigger is identified despite thorough , accounts for approximately 30% of adult cases and poses diagnostic challenges due to its unpredictable nature. Studies from 2024 and 2025 have advanced understanding of heterogeneity in anaphylaxis, emphasizing tissue-specific variations in and mediator release. s exhibit diverse phenotypes across tissues, influencing their responsiveness to allergens and contribution to systemic reactions, as detailed in recent updates on biology. For example, of regenerating liver 2 (PRL2) has been identified as a negative regulator of FcεRI-mediated , potentially explaining variability in anaphylactic severity. Breakthroughs in intestinal mast cell research underscore their pivotal role in gut-specific anaphylaxis. A 2025 study demonstrated that leukotrienes derived from intestinal s are key mediators of the anaphylactic response to ingested antigens, highlighting a distinct pathway from systemic mast cell activation. This finding reveals how gut-resident mast cells orchestrate rapid local , offering new mechanistic insights into food-induced anaphylaxis.

Emerging Therapies and Guidelines

In 2024, the U.S. Food and Drug Administration approved neffy, the first epinephrine nasal spray for the emergency treatment of type I allergic reactions, including anaphylaxis, in adults and pediatric patients weighing at least 30 kg (2 mg dose), with a 1 mg dose approved in March 2025 for children weighing 15-30 kg. This needle-free alternative to intramuscular injections addresses barriers such as needle phobia and ease of administration, with clinical trials demonstrating comparable pharmacokinetics and efficacy to approved epinephrine auto-injectors. Anti-IgE biologics, such as (Xolair), represent a promising adjunctive for preventing anaphylactic reactions in patients with IgE-mediated food allergies. Approved by the FDA in February 2024 for reducing allergic responses, including anaphylaxis, following accidental exposure to multiple foods, omalizumab binds free IgE to inhibit its interaction with mast cells and . Phase III trials, including the OUtMATCH study, showed that omalizumab protected approximately 68% of treated patients from moderate-to-severe reactions during single-food challenges, compared to 5% with , thereby enhancing tolerance thresholds without replacing emergency treatments. The 2024 international consensus report on anaphylaxis, developed by the Global Allergy and Airways Patient Platform (GA²LEN) in collaboration with organizations including the World Allergy Organization (WAO) and American Academy of Allergy, Asthma & Immunology (AAAAI), provides updated guidelines emphasizing individualized management strategies. This report advocates for in select low-risk cases post-initial treatment, where patients are monitored for biphasic reactions without immediate additional interventions if stable, to optimize resource use in emergency settings. It also stresses the development of personalized anaphylaxis action plans tailored to patient age, comorbidities, and trigger profiles, incorporating education on emerging options like nasal epinephrine to improve adherence and outcomes. Ongoing clinical trials are exploring inhibitors targeting novel pathways in anaphylaxis, such as those modulating activation. Preclinical studies, including the 2025 research on intestinal -derived , suggest potential for inhibitors like zileuton to prevent food-induced anaphylaxis, though data remain limited as of November 2025.

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