Anaphylaxis

Anaphylaxis (Greek: {{#invoke:Lang|lang}} 'up' + {{#invoke:Lang|lang}} 'guarding') is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of the use of emergency medication on site.<ref name="Samp2006">Template:Cite journal</ref><ref name="Tint10">Template:Cite book</ref> 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.<ref name="Overview - Anaphylaxis">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="NIH2015" />

These symptoms typically start in minutes to hours and then increase very rapidly to life-threatening levels.<ref name="NIH2015" /> 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.<ref name="Overview - Anaphylaxis" />

Cause, mechanism, and diagnosis

Common causes include allergies to insect bites and stings, allergies to foods—including nuts, 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;<ref>Template:Cite book</ref> 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.<ref name="Overview - Anaphylaxis"/><ref name=NIH2015/> 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.<ref name="Overview - Anaphylaxis"/><ref name=NIH2015>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name=Khan11>Template:Cite journal</ref> 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.<ref name="Overview - Anaphylaxis"/><ref name=NIH2015/>

Prevention and management

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".<ref name=NIH2015/><ref name=EAACI2014>Template:Cite journal</ref> Additional doses of epinephrine may be required.<ref name=NIH2015/> Other measures, such as antihistamines and steroids, are complementary.<ref name=NIH2015/> Carrying an epinephrine autoinjector, commonly called an "epipen", and identification regarding the condition is recommended in people with a history of anaphylaxis.<ref name=NIH2015/> Immediately contacting ambulance / EMT services is always strongly recommended, regardless of any on-site treatment.<ref name="Overview - Anaphylaxis"/> Getting to a doctor or hospital as soon as possible is absolutely required in all cases, even if it appears to be getting better.<ref name="Overview - Anaphylaxis"/>

Epidemiology, prognosis, and history

Worldwide, 0.05–2% of the population is estimated to experience anaphylaxis at some point in life.<ref name=World11/> Globally, as underreporting declined into the 2010s, the rate appeared to be increasing.<ref name=World11>Template:Cite journal</ref> It occurs most often in young people and females.<ref name=EAACI2014/><ref name=CEA11>Template:Cite journal</ref> About 99.7% of people hospitalized with anaphylaxis in the United States survive.<ref>Template:Cite journal</ref>

Etymology

The word is derived from Template:Langx, and Template:Langx.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite book</ref>

Signs and symptoms

File:Signs and symptoms of anaphylaxis.svg

Signs and symptoms of anaphylaxis

Anaphylaxis typically presents many different symptoms over minutes or hours<ref name=EAACI2014/><ref>Template:Cite journal</ref> with an average onset of 5 to 30 minutes if exposure is intravenous and up to 2 hours if from eating food.<ref name=Rosen2010/> 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%)<ref name=Review09>Template:Cite journal</ref> with usually two or more being involved.<ref name=World11/>

Skin

File:Rash on the chest of a person with anaphylaxis.jpg

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.<ref name="Samp2006" /> Those with angioedema may describe a burning sensation of the skin rather than itchiness.<ref name=Rosen2010/> Swelling of the tongue or throat occurs in up to about 20% of cases.<ref name=Shock10/> Other features may include a runny nose and swelling of the conjunctiva.<ref name=Aus06/> The skin may also be blue tinged because of lack of oxygen.<ref name=Aus06/>

Respiratory

Respiratory symptoms and signs that may be present include shortness of breath, wheezes, or stridor.<ref name="Samp2006" /> The wheezing is typically caused by spasms of the bronchial muscles<ref name=Cardio08/> while stridor is related to upper airway obstruction secondary to swelling.<ref name=Aus06>Template:Cite journal</ref> Hoarseness, pain with swallowing, or a cough may also occur.<ref name=Rosen2010/>

Cardiovascular

While a fast heart rate caused by low blood pressure is more common,<ref name=Aus06/> a Bezold–Jarisch reflex has been described in 10% of people, where a slow heart rate is associated with low blood pressure.<ref name=CEA11/> A drop in blood pressure or shock (either distributive or cardiogenic) may cause the feeling of lightheadedness or loss of consciousness.<ref name=Cardio08/> Rarely very low blood pressure may be the only sign of anaphylaxis.<ref name=Shock10/>

Coronary artery spasm may occur with subsequent myocardial infarction, dysrhythmia, or cardiac arrest.<ref name=World11/><ref name=Review09/> Those with underlying coronary disease are at greater risk of cardiac effects from anaphylaxis.<ref name=Cardio08/> The coronary spasm is related to the presence of histamine-releasing cells in the heart.<ref name=Cardio08/>

Other

Gastrointestinal symptoms may include severe crampy abdominal pain, and vomiting.<ref name="Samp2006" /> There may be confusion, a loss of bladder control or pelvic pain similar to that of uterine cramps.<ref name="Samp2006" /><ref name=Aus06/> Dilation of blood vessels around the brain may cause headaches.<ref name=Rosen2010/> A feeling of anxiety or of "impending doom" has also been described.<ref name=World11/>

Causes

Anaphylaxis can occur in response to almost any foreign substance.<ref name=His11/> Common triggers include venom from insect bites or stings, foods, and medication.<ref name=CEA11/><ref>Template:Cite book</ref> Foods are the most common trigger in children and young adults, while medications and insect bites and stings are more common in older adults.<ref name=World11/> Less common causes include: physical factors, biological agents such as semen, latex, hormonal changes, food additives and colors, and topical medications.<ref name=Aus06/> 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.<ref name=World11/><ref name="APLS07">Template:Cite book</ref><ref>Template:Cite journal</ref> Events caused by exercise are frequently associated with cofactors such as the ingestion of certain foods<ref name=Rosen2010/><ref name=Pravetton2016rev>Template:Cite journal</ref> or taking an NSAID.<ref name=Pravetton2016rev/> In aspirin-exacerbated respiratory disease (AERD), alcohol is a common trigger.<ref name= Stevens2015>Template:Cite journal</ref><ref name= Cardet2014/> During anesthesia, neuromuscular blocking agents, antibiotics, and latex are the most common causes.<ref>Template:Cite journal</ref> The cause remains unknown in 32–50% of cases, referred to as "idiopathic anaphylaxis."<ref name="editor 2010 223">Template:Cite book</ref> Six vaccines (MMR, varicella, influenza, hepatitis B, tetanus, meningococcal) are recognized as a cause for anaphylaxis, and HPV may cause anaphylaxis as well.<ref>Template:Cite book</ref>

Food and alcohol

Many foods can trigger anaphylaxis; this may occur upon the first known ingestion.<ref name=CEA11/> 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.<ref name=World11/><ref name=Review09/> Sesame is common in the Middle East, while rice and chickpeas are frequently encountered as sources of anaphylaxis in Asia.<ref name=World11/> Severe cases are usually caused by ingesting the allergen,<ref name=CEA11/> 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.<ref name=His11/> Any type of alcohol, even in small amounts, can trigger anaphylaxis in people with AERD.<ref name= Stevens2015/><ref name= Cardet2014>Template:Cite journal</ref>

Medication

Any medication may potentially trigger anaphylaxis. The most common are β-lactam antibiotics (such as penicillin) followed by aspirin and NSAIDs.<ref name=Review09/><ref name=WHO2015>Template:Cite journal</ref> Other antibiotics are implicated less frequently.<ref name=WHO2015/> 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.<ref>Template:Cite journal</ref> Other relatively common causes include chemotherapy, vaccines, protamine and herbal preparations.<ref name=World11/> Some medications (vancomycin, morphine, x-ray contrast among others) cause anaphylaxis by directly triggering mast cell degranulation.<ref name=CEA11/>

The frequency of a reaction to an agent partly depends on the frequency of its use and partly on its intrinsic properties.<ref name=Drug01>Template:Cite journal</ref> Anaphylaxis to penicillin or cephalosporins occurs only after it binds to proteins inside the body with some agents binding more easily than others.<ref name=Rosen2010/> 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.<ref name=Rosen2010/> Anaphylaxis to aspirin and NSAIDs occurs in about one in every 50,000 persons.<ref name=Rosen2010/> If someone has a reaction to penicillin, his or her risk of a reaction to cephalosporins is greater but still less than one in 1,000.<ref name=Rosen2010/> The old radiocontrast agents caused reactions in 1% of cases, while the newer lower osmolar agents cause reactions in 0.04% of cases.<ref name=Drug01/>

Venom

Venom from stinging or biting insects such as Hymenoptera (ants, bees, and wasps) or Triatominae (kissing bugs) may cause anaphylaxis in susceptible people.<ref name=EAACI2014/><ref name="Klotz">Template:Cite journal</ref><ref name=2001simonga>Template:Cite journal</ref> Previous reactions that are anything more than a local reaction around the site of the sting, are a risk factor for future anaphylaxis;<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> however, half of fatalities have had no previous systemic reaction.<ref>Template:Cite journal</ref>

Risk factors

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.<ref name=World11/><ref name=CEA11/> 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.<ref name=CEA11/> Those with mastocytosis or of a higher socioeconomic status are at increased risk.<ref name=World11/><ref name=CEA11/>

Pathophysiology

Anaphylaxis is a severe allergic reaction of rapid onset affecting many body systems.<ref name=Tint10/><ref name=Khan11/> 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.<ref name=Khan11/>

Interleukin (IL)–4 and IL-13 are cytokines important in the initial generation of antibody and inflammatory cell responses to anaphylaxis.<ref name="v005"/>

Immunologic

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.<ref name=Khan11/><ref name=Rosen2010/> There is also a non-immunologic mechanism that does not rely on IgE, but it is not known if this occurs in humans.<ref name=Khan11/>

Non-immunologic

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.<ref name=Khan11/><ref name=APLS07/> Sulfites may cause reactions by both immunologic and non-immunologic mechanisms.<ref>Template:Cite book</ref>

Diagnosis

Anaphylaxis is diagnosed on the basis of a person's signs and symptoms.<ref name=World11/> When any one of the following three occurs within minutes or hours of exposure to an allergen there is a high likelihood of anaphylaxis:<ref name=World11/>

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.<ref name=World11/>

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,<ref name=World11/> and they are not specific for the diagnosis.<ref name=His11/>

Classification

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.<ref name=Shock10>Template:Cite journal</ref>
2. Biphasic anaphylaxis is the recurrence of symptoms within 1–72 hours after resolution of an initial anaphylactic episode.<ref name="pmid32001253"/> Estimates of incidence vary, between less than 1% and up to 20% of cases.<ref name="pmid32001253"/><ref name=BI05/> The recurrence typically occurs within 8 hours.<ref name=CEA11/> It is managed in the same manner as anaphylaxis.<ref name=EAACI2014/>
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.<ref name=CEA11/><ref name="His10">Template:Cite book</ref> Non-immune anaphylaxis is the current term, as of 2018, used by the World Allergy Organization<ref name=His10/> with some recommending that the old terminology, "anaphylactoid", no longer be used.<ref name=CEA11/>

Allergy skin testing

File:Allergy skin testing.JPG

Skin allergy testing being carried out on the right arm

File:Epikutanni-test.jpg

Patch test

Allergy testing may help in determining the trigger. Skin allergy testing is available for certain foods and venoms.<ref name=His11/> Blood testing for specific IgE can be useful to confirm milk, egg, peanut, tree nut and fish allergies.<ref name=His11/>

Skin testing is available to confirm penicillin allergies, but is not available for other medications.<ref name=His11/> 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.<ref name=His10/>

Differential diagnosis

It can sometimes be difficult to distinguish anaphylaxis from asthma, syncope, and panic attacks.<ref name=World11/> 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.<ref name=World11/> Other conditions that may present similarly include: scrombroidosis and anisakiasis.<ref name=CEA11/>

Post-mortem findings

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.<ref name="v005">Template:Cite journal</ref> Other signs are laryngeal edema, eosinophilia in lungs, heart and tissues, and evidence of myocardial hypoperfusion.<ref name=DaBroi/> Laboratory findings could detect increased levels of serum tryptase, increase in total and specific IgE serum levels.<ref name=DaBroi>Template:Cite journal</ref>

Prevention

Template:See also 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.<ref name=World11/> For example, many people develop an itchy throat, cough, or lip swelling during immunotherapy.<ref>Template:Cite journal</ref> 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.<ref name=World11/>

Management

Anaphylaxis is a medical emergency that may require resuscitation measures such as airway management, supplemental oxygen, large volumes of intravenous fluids, and close monitoring.<ref name=EAACI2014/> Passive leg raise may also be helpful in the emergency management.<ref name="Simons 2010 pp. S161–S181">Template:Cite journal</ref>

Administration of intravenous fluid bolus and epinephrine is the treatment of choice with antihistamines used as adjuncts.<ref>Template:Cite journal</ref> 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.<ref name=CEA11/><ref name=Rosen2010/><ref name=BI05/><ref name=UK08>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Epinephrine

File:Epipen.jpg

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.<ref name=EAACI2014/> 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.<ref name=EAACI2014/> A second dose is needed in 16–35% of episodes with more than two doses rarely required.<ref name=EAACI2014/> The intramuscular route is preferred over subcutaneous administration because the latter may have delayed absorption.<ref name=EAACI2014/><ref name=Epi10>Template:Cite journal</ref> 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.<ref name="pmid32001253">Template:Cite journal</ref> Minor adverse effects from epinephrine include tremors, anxiety, headaches, and palpitations.<ref name=World11/>

People on β-blockers may be resistant to the effects of epinephrine.<ref name=CEA11/> In this situation if epinephrine is not effective intravenous glucagon can be administered which has a mechanism of action independent of β-receptors.<ref name=CEA11/>

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.<ref name=EAACI2014/> 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.<ref>Template:Cite journal</ref>

Adjuncts

Antihistamines (both H1 and H2), while commonly used and assumed effective based on theoretical reasoning, are poorly supported by evidence.<ref>Template:Cite journal</ref><ref name=She2007/> A 2007 Cochrane review did not find any good-quality studies upon which to base recommendations<ref name=She2007>Template:Cite journal</ref> and they are not believed to have an effect on airway edema or spasm.<ref name=CEA11/> 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.<ref name=BI05>Template:Cite journal</ref> Nebulized salbutamol may be effective for bronchospasm that does not resolve with epinephrine.<ref name=CEA11/> Methylene blue has been used in those not responsive to other measures due to its presumed effect of relaxing smooth muscle.<ref name=CEA11/>

Preparedness

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.<ref name=Mart08>Template:Cite journal</ref> 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.<ref name=Review09/>

Prognosis

In those in whom the cause is known and prompt treatment is available, the prognosis is good.<ref name="Harris2007">Template:Cite book</ref> Even if the cause is unknown, if appropriate preventive medication is available, the prognosis is generally good.<ref name=Rosen2010/> Usually death occurs due to either respiratory failure (typically involving asphyxia) or cardiovascular complications, such as cardiovascular shock,<ref name=Khan11/><ref name=CEA11/> with 0.7–20% of cases causing death.<ref name=Rosen2010>Template:Cite book</ref><ref name=Cardio08>Template:Cite journal</ref> There have been cases of death occurring within minutes.<ref name=World11/> Outcomes in those with exercise-induced anaphylaxis are typically good, with fewer and less severe episodes as people get older.<ref name="editor 2010 223"/>

Epidemiology

The number of people who get anaphylaxis is 4–100 per 100,000 persons per year,<ref name=CEA11/><ref name=Tej2015>Template:Cite journal</ref> with a lifetime risk of 0.05–2%.<ref>Template:Cite book</ref> About 30% of affected people get more than one attack.<ref name=Tej2015/> Exercise-induced anaphylaxis affects about 1 in 2000 young people.<ref name=Pravetton2016rev/>

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.<ref name=Review09/> The increase appears to be primarily for food-induced anaphylaxis.<ref>Template:Cite journal</ref> The risk is greatest in young people and females.<ref name=EAACI2014/><ref name=CEA11/>

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).<ref name=CEA11/> Another estimate from the United States puts the death rate at 0.7 per million.<ref>Template:Cite journal</ref> Mortality rates have decreased between the 1970s and 2000s.<ref>Template:Cite journal</ref> In Australia, death from food-induced anaphylaxis occur primarily in women while deaths due to insect bites primarily occur in males.<ref name=CEA11/> Death from anaphylaxis is most commonly triggered by medications.<ref name=CEA11/>

History

The conditions of anaphylaxis has been known since ancient times.<ref name="His10" /> French physician François Magendie had described how rabbits were killed by repeated injections of egg albumin in 1839.<ref>Template:Cite journal</ref> However, the phenomenon was discovered by two French physiologists Charles Richet and Paul Portier.<ref name=":1" /> 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,<ref>Template:Cite journal</ref> specifically to study on the toxin produced by cnidarians (like jellyfish and sea anemones).<ref name=":1">Template:Cite journal</ref> Richet and Portier boarded Albert's ship Princesse Alice II for ocean exploration to make collections of the marine animals.<ref name=":0">Template:Cite journal</ref>

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)<ref>Template:Cite journal</ref> and sea anemone (Actinia sulcata).<ref name=":2">Template:Cite journal</ref> 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 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.<ref name=":2" /> Thus, instead of inducing tolerance (prophylaxis) which they expected, they discovered effects of the toxin as deadly.<ref>Template:Cite journal</ref>

In 1902, Richet introduced the term aphylaxis to describe the condition of lack of protection. He later changed the term to anaphylaxis on grounds of euphony.<ref name="His11">Template:Cite journal, citing May CD, "The ancestry of allergy: being an account of the original experimental induction of hypersensitivity recognizing the contribution of Paul Portier", J Allergy Clin Immunol. 1985 Apr; 75(4):485–495.</ref> The term is from the Greek {{#invoke:Lang|lang}}, {{#invoke:Lang|lang}}, meaning "against", and {{#invoke:Lang|lang}}, {{#invoke:Lang|lang}}, meaning "protection".<ref name="Dict">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> On 15 February 1902, Richet and Portier jointly presented their findings before the Societé de Biologie in Paris.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Ring 2014 54–61">Template:Citation</ref> The moment is regarded as the birth of allergy (the term invented by Clemens von Pirquet in 1906) study (allergology).<ref name="Ring 2014 54–61"/> Richet continued to study on the phenomenon and was eventually awarded the Nobel Prize in Physiology or Medicine for his work on anaphylaxis in 1913.<ref name=":0" /><ref>Template:Cite journal</ref>

Research

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.<ref name=CEA11/><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Subcutaneous injection of the anti-IgE antibody omalizumab is being studied as a method of preventing recurrence, but it is not yet recommended.Template:Update after<ref name=World11/><ref>Template:Cite journal</ref>

External links

• Template:NICE and Anaphylaxis pathway
• {{#invoke:citation/CS1|citation

|CitationClass=web }}