Anaphylaxis is defined as "a serious allergic reaction that is rapid in onset and may cause death".[1] It typically results in a number of symptoms including an itchy rash, throat swelling, and low blood pressure. Common causes include insect bites, foods, and medications.
On a pathophysiologic level, anaphylaxis is caused by the release of mediators from certain types of white blood cells triggered either by immunologic or non-immunologic mechanisms. It is diagnosed based on the presenting symptoms and signs. The primary treatment is injection of epinephrine, with other measures being complementary.
Worldwide 0.05–2% of people are estimated to have anaphylaxis at some point in their life and rates appear to be increasing. The term comes from the Greek words ἀνά ana, against, and φύλαξις phylaxis, protection.
Signs and symptoms of anaphylaxis.
Anaphylaxis typically presents with many different symptoms over minutes or hours[2][3] with an average onset of 5 to 30 minutes if exposure is intravenous and 2 hours for foods.[4] 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%)[3] with usually two or more being involved.[5]
Hives and flushing on the back of a person with anaphylaxis
Symptoms typically include generalized hives, itchiness, flushing or swelling of the lips.[6] Those with swelling or angioedema may describe a burning sensation of the skin rather than itchiness.[4] Swelling of the tongue or throat occurs in up to about 20% of cases.[7] Other features may include a runny nose and swelling of the conjunctiva.[8] The skin may also be blue tinged because of lack of oxygen.[8]
Respiratory symptoms and signs that may be present, including shortness of breath, wheezes or stridor.[6] The wheezing is typically caused by spasms of the bronchial muscles[9] while stridor is related to upper airway obstruction secondary to swelling.[8] Hoarseness, pain with swallowing, or a cough may also occur.[4]
Coronary artery spasm may occur with subsequent myocardial infarction, dysrhythmia, or cardiac arrest.[3][5] Those with underlying coronary disease are at greater risk of cardiac effects from anaphylaxis.[9] The coronary spasm is related to the presence of histamine-releasing cells in the heart.[9] While a fast heart rate resulting from low blood pressure is more common,[8] a Bezold–Jarisch reflex has been described in 10% of cases, where a slow heart rate is associated with low blood pressure.[10] A drop in blood pressure or shock (either distributive or cardiogenic) may result in the feeling of lightheadedness or loss of consciousness.[9] Rarely very low blood pressure may be the only sign of anaphylaxis.[7]
Gastrointestinal symptoms may include crampy abdominal pain, diarrhea, and vomiting.[6] There may be confusion, a loss of bladder control or pelvic pain similar to that of uterine cramps.[6][8] Dilation of blood vessels around the brain may cause headaches.[4] A feeling of anxiety or of "impending doom" has also be described.[5]
Anaphylaxis can occur in response to almost any foreign substance.[11] Common triggers include venom from insect bites or stings, foods, and medication.[10][12] Foods are the most common trigger in children and young adults while medications and insect bites and stings are more common in older adults.[5] Less common causes include: physical factors, biological agents such as semen, latex, hormonal changes, food additives such as monosodium glutamate and food colors, and topical medications.[8] 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.[5][13] Exercise induced events are frequently associated with the ingestion of certain foods.[4] During anesthesia, neuromuscular blocking agents, antibiotics, and latex are the most common causes.[14] The cause remains unknown in 32-50% of cases, referred to as "idiopathic anaphylaxis".[15]
Many foods can trigger anaphylaxis; this may occur upon the first known ingestion.[10] Common triggering foods vary around the world. In Western cultures, ingestion of or exposure to peanuts, wheat, tree nuts, shellfish, fish, milk, and eggs are the most prevalent causes.[3][5] Sesame is common in the Middle East, while rice and chickpea are frequently encountered as sources of anaphylaxis in Asia.[5] Severe cases are usually the result of ingesting the allergen,[10] 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 are able to tolerate these foods.[11]
Any medication may potentially trigger anaphylaxis. The most common are β-lactam antibiotics (such as penicillin) followed by aspirin and NSAIDs.[3][16] Other antibiotics are implicated less frequently and the reactions to NSAIDs are agent specific meaning that if one is allergic to one NSAID they can typically tolerate a different one.[16] Other relatively common causes include chemotherapy, vaccines, protamine and herbal preparations.[5][16] Some medications (vancomycin, morphine, x-ray contrast among others) cause anaphylaxis by directly triggering mast cell degranulation.[10]
The frequency of a reaction to an agent partly depends on the frequency of its use and partly on its intrinsic properties.[17] Anaphylaxis to penicillins or cephalosporins only occurs after they bind to proteins inside the body with some agents binding more easily than other.[4] Anaphylaxis to penicillin occurs once in every 2,000 to 10,000 courses of treatment, with death occurring in less than one in every 50,000 courses of treatment.[4] Anaphylaxis to aspirin and NSAIDs occurs in about one in every 50,000 persons.[4] If someone has a reaction to penicillins their risk of a reaction to cephalosporins is greater but still less than one in 1000.[4] The old radiocontrast agents caused reactions in 1% of cases while the newer lower osmolar agents cause reactions in 0.04% of cases.[17]
Venom from stinging or biting insects such as Hymenoptera (bees and wasps) or Triatominae (kissing bugs) may induce anaphylaxis in susceptible people.[3][18] Previous systemic reactions, which are anything more than a local reaction around the site of the sting, are a risk factor for future anaphylaxis;[19][20] however, half of fatalities have had no previous systemic reaction.[21]
People with atopic diseases such as asthma, eczema, or allergic rhinitis are at high risk of anaphylaxis from food, latex, and radiocontrast but not injectable medications or stings.[5][10] One study in children found that 60% had a history of previous atopic diseases, and of those who die from anaphylaxis more than 90% have asthma.[10] Those with mastocytosis or of a higher socioeconomic status are at increased risk.[5][10] The longer the time since the last exposure to the agent in question the lower the risk.[4]
Anaphylaxis is a severe allergic reaction of rapid onset affecting many body systems.[1][22] 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.[22]
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 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.[4][22] There is also an immunologic mechanism that does not rely on IgE, but it is not known if this occurs in humans.[22]
Non-immunologic mechanisms involved 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.[13][22]
Anaphylaxis is diagnosed based on clinical criteria.[5] When any one of the following three occurs within minutes/hours of exposure to an allergen there is a high likelihood of anaphylaxis:[5]
- Involvement of the skin or mucosal tissue plus either respiratory difficulty or a low blood pressure
- Two or more of the following symptoms:-
- a. Involvement of the skin or mucosa
- b. Respiratory difficulties
- c. Low blood pressure
- d. Gastrointestinal symptoms
- Low blood pressure after exposure to a known allergen
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 utility if the cause is food or if the person has a normal blood pressure,[5] and they are not specific for the diagnosis.[11]
There are three main classifications of anaphylaxis. Anaphylactic shock is associated with systemic vasodilation that results in low blood pressure which is by definition 30% lower than the person's baseline or below standard values.[7] Biphasic anaphylaxis is the recurrence of symptoms within 1–72 hours with no further exposure to the allergen.[5] Reports of incidence vary, with some studies claiming as many as 20% of cases.[23] The recurrence typically occurs within 8 hours.[10] It is managed in the same manner as anaphylaxis.[3] Pseudoanaphylaxis or anaphylactoid reactions are a type of anaphylaxis that does not involve an allergic reaction but is due to direct mast cell degranulation.[10][24] Non-immune anaphylaxis is the current term use by the World Allergy Organization[24] with some recommending that the old terminology no longer be used.[10]
Allergy testing may help in determining the trigger. Skin allergy testing (such as patch testing) is available for certain foods and venoms.[11] Blood testing for specific IgE can be useful to confirm milk, egg, peanut, tree nut and fish allergies.[11] Skin testing is available to confirm penicillin allergies but is not available for other medications.[11] 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.[24]
It can sometimes be difficult to distinguish anaphylaxis from asthma, syncopy, and panic attacks.[5] Asthma however typically does not have itching or gastrointestinal symptoms, syncope presents with pallor rather than a rash, and a panic attack may have flushing but does not have hives.[5] Other conditions that may present similarly include: scrombroidosis and anisakiasis.[10]
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.[25] Other signs are laryngeal edema, eosinophilia in lungs, heart and tissues, and evidence of myocardial hypoperfusion.[26] Laboratory findings could detect increased levels of serum tryptase, increase in total and specific IgE serum levels.[26]
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. 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.[5]
Anaphylaxis is a medical emergency that may require resuscitation measures such as airway management, supplemental oxygen, large volumes of intravenous fluids, and close monitoring.[3] Administration of epinephrine is the treatment of choice with antihistamines and steroids often used as adjuncts.[5] 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.[10][23][27][4]
An old version of an EpiPen auto-injector
Epinephrine (adrenaline) is the primary treatment for anaphylaxis with no absolute contraindication to its use.[3] It is recommended that an epinephrine solution be given intramuscularly into the mid anterolaterial thigh as soon as the diagnosis is suspected. The injection may be repeated every 5 to 15 minutes if there is insufficient response.[5] A second dose is needed in 16 to 35% of episodes[10] with more than two doses rarely required.[5] The intramuscular route is preferred over subcutaneous administration because the latter may have delayed absorption.[28] Minor adverse effects from epinephrine include tremors, anxiety, headaches, and palpitations.[5]
People on β-blockers may be resistant to the effects of epinephrine.[10] In this situation if epinephrine is not effective intravenous glucagon can be administered which has a mechanism of action independent of β-receptors.[10]
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.[29] Epinephrine autoinjector used for self-administration typically in two doses, one for adults or children who weigh more than 25 kg and one for children who weigh 10 to 25 kg.[30]
Antihistamines (both H1 and H2), while commonly used and assumed effective based on theoretical reasoning, are poorly supported by evidence. A 2007 Cochrane review did not find any good-quality studies upon which to base recommendations[31] and they are not believed to have an effect on airway edema or spasm.[10] 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.[23] Nebulized salbutamol may be effective for bronchospasm that does not resolve with epinephrine.[10] Methylene blue has been used in those not responsive to other measures due to its presumed effect of relaxing smooth muscle.[10]
People prone to anaphylaxis are advised to have an "allergy action plan", and parents are advised to inform schools of their children's allergies and what to do in case of an anaphylactic emergency.[32] The action plan usually includes use of epinephrine auto-injectors, the recommendation to wear a medical alert bracelet, and counseling on avoidance of triggers.[32] 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.[3]
In those in whom the cause is known and prompt treatment is available, the prognosis is good.[33] Even if the cause is unknown, if appropriate preventative medication is available, the prognosis is generally good.[4] If death occurs, it is usually due to either respiratory (typically asphyxia) or cardiovascular causes (shock),[10][22] with 0.7–20% of cases resulting in death.[4][9] There have been cases of death occurring within minutes.[5] Outcomes in those with exercise-induced anaphylaxis are typically good, with fewer and less severe episodes as people get older.[34]
The incidence of anaphylaxis is 4–5 per 100,000 persons per year,[10] with a lifetime risk of 0.5–2%.[5] Rates appear to be increasing: incidence in the 1980s was approximately 20 per 100,000 per year, while in the 1990s it was 50 per 100,000 per year.[3] The increase appears to be primarily for food-induced anaphylaxis.[35] The risk is greatest in young people and females.[3][10]
Currently, anaphylaxis leads to 500–1,000 deaths per year (2.4 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).[10] Mortality rates have decreased between the 1970s and 2000s.[36] In Australia, death from food-induced anaphylaxis occur primarily in women while deaths due to insect bites primarily occur in males.[10] Death from anaphylaxis is most commonly triggered by medications.[10]
The term "aphylaxis" was coined by Charles Richet in 1902 and later changed to "anaphylaxis" due to its nicer quality of speech.[11] He was subsequently awarded the Nobel Prize in Medicine and Physiology for his work on anaphylaxis in 1913.[4] The phenomenon itself however has been described since ancient times.[24] The term comes from the Greek words ἀνά ana, against, and φύλαξις phylaxis, protection.[37]
There are ongoing efforts to develop sublingual epinephrine to treat anaphylaxis.[10] Subcutaneous injection of the anti-IgE antibody omalizumab is being studied as a method of preventing recurrence, but it is not yet recommended.[5][38]
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