Anaphylaxis

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Anaphylaxis
Classification and external resources

Swelling of the face such that the boy is unable to open his eyes. This reaction was due to an allergen exposure.
ICD-10 T78.2
ICD-9 995.0
DiseasesDB 29153
MedlinePlus 000844
eMedicine med/128
MeSH D000707

Anaphylaxis is a serious allergic reaction that begins suddenly and may cause death.[1] Anaphylaxis typically has a number of symptoms including an itchy rash, throat swelling, and low blood pressure. Common causes include insect bites, foods, and medications.

Anaphylaxis is due to the release of mediator proteins from certain types of white blood cells. Mediator proteins are substances that can start an allergic reaction or make the reaction more severe. Their release can be caused either by an immune system reaction or by another cause that is not related to the immune system. Anaphylaxis is diagnosed based on the person’s symptoms and signs. The primary treatment is injection of epinephrine, which is sometimes combined with other medications.

Worldwide, about 0.05–2% of people have anaphylaxis at some point in their lives. Rates appear to be increasing. The term comes from the Greek words ἀνά ana, against, and φύλαξις phylaxis, protection.

Signs and symptoms[change | edit source]

Signs and symptoms of anaphylaxis.

Anaphylaxis typically produces many different symptoms over minutes or hours.[2][3] Symptoms appear within an average of 5 to 30  minutes if the cause is a substance that enters the body directly into the blood stream (intravenously). The average is 2 hours if the cause is a food the person ate.[4] The most common areas affected include: skin (80–90%), lungs and breathing pathways (70%), stomach and intestines (30–45%), heart and blood vessels (10–45%), and central nervous system (10–15%).[3] Two or more of these systems are usually involved.[5]

Skin[change | edit source]

Hives and flushing on the back of a person with anaphylaxis

Symptoms typically include raised bumps on the skin (hives), itchiness, red face or skin (flushing), or swollen lips.[6] Those with swelling under the skin (angioedema) may feel that their skin is burning instead of itching.[4] The tongue or throat may swell in up to 20% of cases.[7] Other features may include a runny nose and swelling of the mucous membrane on the surface of the eye and eyelid (conjunctiva).[8] The skin may also have a blue color (cyanosis) due to a lack of oxygen.[8]

Respiratory[change | edit source]

Respiratory symptoms and signs include shortness of breath, low-pitched difficult breathing (wheezes), or high-pitched difficult breathing (stridor).[6] Low-pitched breathing is typically due to spasms of the muscles in the lower part of the airway (bronchial muscles).[9] High-pitched breathing is due to swelling in the upper airway, which narrows the breathing passages.[8] Hoarseness, pain with swallowing, or a cough may also occur.[4]

Cardiac[change | edit source]

The heart’s blood vessels may contract suddenly (coronary artery spasm) because of the release of histamine from certain cells in the heart.[9] This interrupts the blood flow to the heart, which may cause heart cells to die (myocardial infarction), or the heart may beat too slowly or too quickly (cardiac dysrhythmia), or the heart may stop beating altogether (cardiac arrest).[3][5] People who already have heart disease are at greater risk of cardiac affects from anaphylaxis.[9] While a fast heart rate due to low blood pressure is more common,[8] 10% of people who suffer from anaphylaxis may have a slow heart rate (bradycardia) with low blood pressure. (The combination of a slow heart rate and low blood pressure is known as Bezold–Jarisch reflex).[10] The person may feel lightheaded or may lose consciousness due to a drop in blood pressure. This low blood pressure may be caused by the widening of blood vessels (distributive shock) or by a failure of the heart’s ventricles (cardiogenic shock).[9] In rare cases, very low blood pressure may be the only sign of anaphylaxis.[7]

Other[change | edit source]

Symptoms from the stomach and intestines may include crampy abdominal pain, diarrhea, and vomiting (throwing up).[6] The person may have confused thoughts, may lose control of their bladder, and may have pain in the pelvis that feels like cramps in the uterus.[6][8] Widening of blood vessels around the brain may cause headaches.[4] The person may also feel anxious or imagine that they are about to die.[5]

Causes[change | edit source]

Anaphylaxis can be caused by the body’s 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. Medications and insect bites and stings are more common triggers in older adults.[5] Less common causes include physical factors, biological agents (such as semen), latex, hormonal changes, food additives (such as monosodium glutamate (MSG) and food coloring), and medications that are applied to the skin (topical medications).[8] Exercise or temperature (either hot or cold) may also trigger anaphylaxis by causing certain tissue cells (known as mast cells) to release chemicals that start the allergic reaction.[5][13] Anaphylaxis caused by exercise is often also linked to eating certain foods.[4] If anaphylaxis occurs while a person is receiving anesthesia, the most common causes are certain medications that are given to produce paralysis (neuromuscular blocking agents), antibiotics, and latex.[14] In 32-50% of cases, the cause is not known (idiopathic anaphylaxis).[15]

Food[change | edit source]

Many foods can trigger anaphylaxis, even when the food is eaten for the first time.[10] In Western cultures, the most common causes are eating or being in contact with peanuts, wheat, tree nuts, shellfish, fish, milk, and eggs.[3][5] In the Middle East, sesame is a common trigger food. In Asia, rice and chickpeas often cause anaphylaxis.[5] Severe cases are usually caused by eating the food,[10] but some people have a severe reaction when the trigger food touches some part of the body. Children can outgrow their allergies. By age 16, 80% of children with anaphylaxis to milk or eggs and 20% with a single case of anaphylaxis to peanuts are able to eat these foods without problems.[11]

Medication[change | edit source]

Any medication may cause anaphylaxis. The most common are β-lactam antibiotics (such as penicillin) followed by aspirin and NSAIDs.[3][16] If a person is allergic to one NSAID they can usually use a different one without triggering anaphylaxis.[16] Other common causes of anaphylaxis include chemotherapy, vaccines, protamine (found in sperm), and medications made from herbs.[5][16] Some medications, including vancomycin, morphine, and drugs used to improve X-ray images (radiocontrast agents), cause anaphylaxis by damaging certain cells in the tissues, causing them to release histamine (mast cell degranulation).[10]

The frequency of a reaction to a medication partly depends on how often it is given to people and partly on the way the medication works in the body.[17] Anaphylaxis to penicillins or cephalosporins only occurs after they bind to proteins inside the body, and some bind more easily than others.[4] Anaphylaxis to penicillin occurs once in every 2,000 to 10,000 people who are treated. Death occurs in less than one in every 50,000 people who are treated with penicillin.[4] Anaphylaxis to aspirin and NSAIDs occurs in about one in every 50,000 people.[4] If someone has a reaction to penicillins, their risk of a reaction to cephalosporins is greater, but the risk is still less than one in 1000.[4] Older medications that were used to improve X-ray images (radiocontrast agents) caused reactions in 1% of cases. Newer, lower osmolar radiocontrast agents cause reactions in 0.04% of cases.[17]

Venom[change | edit source]

Venom from stinging or biting insects such as bees and wasps (Hymenoptera) or kissing bugs (Triatominae) may cause anaphylaxis.[3][18] If a person had a reaction to venom in the past, and it was more than a local reaction around the site of the sting, they have a greater risk for anaphylaxis in the future.[19][20] However, half of the people who die of anaphylaxis have had no previous widespread (systemic) reaction.[21]

Risk factors[change | edit source]

People with atopic diseases such as asthma, eczema, or allergic rhinitis have a high risk of anaphylaxis from food, latex, and radiocontrast agents. These people do not have a higher risk from injectable medications or stings.[5][10] One study in children with anaphylaxis found that 60% had a history of previous atopic diseases. More than 90% of children who die from anaphylaxis have asthma.[10] People who have disorders caused by too many mast cells in their tissues (mastocytosis) or who are wealthier are at increased risk.[5][10] The longer the time since the last exposure to the agent that caused anaphylaxis, the lower the risk of a new reaction.[4]

Mechanisms[change | edit source]

Anaphylaxis is a severe allergic reaction that starts suddenly and affects many body systems.[1][22] It is due to the release of inflammatory mediators and cytokines from mast cells and basophils. Their release is typically due to an immune system reaction, but may be caused by damage to these cells that is not related to an immune reaction.[22]

Immunologic[change | edit source]

When anaphylaxis is caused by an immune response, immunoglobulin E (IgE) binds to the foreign material that starts the allergic reaction (the antigen). The combination of IgE bound to the antigen activates FcεRI receptors on mast cells and basophils. The mast cells and basophils react by releasing inflammatory mediators such as histamine. These mediators increase the contraction of bronchial smooth muscles, cause blood vessels to widen (vasodilation), increase the leakage of fluid from blood vessels, and depress the actions of the heart muscle.[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[change | edit source]

When anaphylaxis is not caused by in immune response, the reaction is due to an agent that directly damages mast cells and basophils, causing them to release histamine and other substances that are usually associated with an allergic reaction (degranulation). Agents that can damage these cells include contrast medium for X-rays, opioids, temperature (hot or cold), and vibration.[13][22]

Diagnosis[change | edit source]

Anaphylaxis is diagnosed based on clinical facts.[5] When any one of the following three occurs within minutes/hours of exposure to an allergen, it is very likely that the person has anaphylaxis:[5]

  1. Involvement of the skin or mucosal tissue plus either respiratory difficulty or a low blood pressure
  2. Two or more of the following symptoms:-
    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

If a person has a bad reaction to an insect sting or a medication, blood tests for tryptase or histamine (released from mast cells) might be useful in diagnosing anaphylaxis. However these tests are not very useful if the cause is food or if the person has a normal blood pressure,[5] and they cannot rule out a diagnosis of anaphylaxis.[11]

Classification[change | edit source]

There are three main classifications of anaphylaxis. Anaphylactic shock happens when blood vessels get wider throughout most of the body (systemic vasodilation), which causes low blood pressure that is at least 30% lower than the person's normal blood pressure or 30% below standard values.[7] Biphasic anaphylaxis is diagnosed when symptoms return within 1–72 hours even though the person has had no new contact with the allergen that caused the first reaction.[5] Some studies claim that as many as 20% of anaphylaxis cases are biphasic.[23] The symptoms return they typically return within 8 hours.[10] The second reaction is treated in the same way as the original anaphylaxis.[3] Pseudoanaphylaxis or anaphylactoid reactions are older names for anaphylaxis that is not due to an allergic reaction, but is due to direct injury to mast cells (mast cell degranulation).[10][24] The current name used by the World Allergy Organization is “non-immune anaphylaxis” [24] . Some people recommend that the older terms should no longer be used.[10]

Allergy testing[change | edit source]

Skin allergy testing being carried out on the right arm

Allergy testing may help to determine what caused a person’s anaphylaxis. Skin allergy tests (such as patch tests) are available for certain foods and venoms.[11] Blood tests for specific antibodies can be useful to confirm milk, egg, peanut, tree nut and fish allergies.[11] Skin tests can confirm penicillin allergies, but there are no skin tests for other medications.[11] Non-immune forms of anaphylaxis can only be diagnosed by checking the person’s history or by exposing the person to an allergen that may have caused a reaction in the past. There are no skin or blood tests for non-immune anaphylaxis.[24]

Differential diagnosis[change | edit source]

It can sometimes be difficult to distinguish anaphylaxis from asthma, fainting due to lack of oxygen (syncopy), and panic attacks.[5] People with asthma typically do not have itching or stomach or intestine symptoms. When a person faints, the skin is pale and does not have a rash. A person who is having a panic attack may have flushed skin but does not have hives.[5] Other conditions that may have similar symptoms include food poisoning from spoiled fish (scombroidosis) and infection from certain parasites (anisakiasis).[10]

Prevention[change | edit source]

The recommended way to prevent anaphylaxis is to avoid whatever caused the reaction in the past. When this is not possible, there may be treatments to make the body stop reacting to a known allergen (desensitization). Treatment of the immune system (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 foods including milk, eggs, nuts and peanuts; however, these treatments often have bad side effects. Desensitization is also possible for many medications; however, most people should simply avoid the problem medication. In those who react to latex, it may be important to avoid foods that contain substances that are similar to the one that caused the immune response (cross-reactive foods), such as avocados, bananas, and potatoes among others.[5]

Management[change | edit source]

Anaphylaxis is a medical emergency that may require lifesaving measures such as airway management, supplemental oxygen, large volumes of intravenous fluids, and close monitoring.[3] Epinephrine is the treatment of choice. Antihistamines and steroids are often used in addition to epinephrine.[5] Once a person has returned to normal, they should be watched in the hospital for 2 to 24 hours to make sure symptoms do not return, as they might if the person has biphasic anaphylaxis.[4][10][23][25]

Epinephrine[change | edit source]

An old version of an EpiPen auto-injector

Epinephrine (adrenaline) is the primary treatment for anaphylaxis. There is no reason why it should not be used (no absolute contraindication).[3] It is recommended that an epinephrine solution be injected into the muscle of the mid anterolateral thigh as soon as anaphylaxis is suspected.[5] The injection may be repeated every 5 to 15 minutes if the person is not responding well to the treatment.[5] A second dose is needed in 16 to 35% of cases.[10] More than two doses are rarely required.[5] Injection into the muscle (intramuscular administration) is preferred over injection under the skin (subcutaneous administration), where the medication may be absorbed too slowly.[26] Minor problems from epinephrine include tremors, anxiety, headaches, and palpitations.[5]

Epinephrine may not work in people who are taking B-blockers.[10] In this situation, if epinephrine is not effective, intravenous glucagon can be administered. Glucagon has a mechanism of action that does not involve β-receptors.[10]

If necessary, epinephrine can also be injected into a vein (intravenous injection) using a dilute solution. Intravenous epinephrine, however, has been linked to irregular heartbeats (dysrhythmia) and heart attacks (myocardial infarction).[27] Epinephrine autoinjectors, which allow people with anaphylaxis to inject epinephrine into a muscle themselves, are typically available in two doses, one for adults or children who weight more than 25 kg and one for children who weight 10 to 25 kg.[28]

Adjuncts[change | edit source]

Antihistamines are commonly used in addition to epinephrine. They were thought to be effective based on theoretical reasoning, but there is very little evidence that antihistamines actually are effective in anaphylaxis treatment. A 2007 Cochrane review did not find any good-quality studies that could be used to recommend them.[29] Antihistimines are not believed to have an effect on fluid buildup or spasms in the airway.[10] Corticosteroids are unlikely to make a difference if a person is currently having an episode of anaphylaxis. They may be used in the hope of decreasing the risk of biphasic anaphylaxis, but their effectiveness in preventing future anaphylaxis is uncertain.[23] Salbutamol that is given through a breathing device (nebulizer) may be effective when epinephrine does not relieve bronchospasm symptoms.[10] Methylene blue has been used in those not responsive to other measures because it may relax smooth muscle.[10]

Preparing[change | edit source]

People who are at risk for anaphylaxis are advised to have an "allergy action plan". Parents should inform schools of their children's allergies and what to do in case of an anaphylactic emergency.[30] The action plan usually includes use of epinephrine auto-injectors, the recommendation to wear a medical alert bracelet, and counseling on how to avoid triggers.[30] Treatment to make the body less sensitive to the substance that is causing the allergic reaction (allergen immunotherapy) is available for certain triggers. This type of therapy may 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]

Outlook[change | edit source]

There is a good chance of recovery when the cause is known and the person is treated quickly.[31] Even if the cause is unknown, if medication is available to stop the reaction, the person usually makes a good recovery.[4] If death occurs, it is usually due to either a respiratory cause (typically closing off of the airway) or a cardiovascular cause (shock).[10][22] Anaphylaxis causes death in 0.7–20% of cases.[4][9] Some deaths have happened within minutes.[5] People who have exercise-induced anaphylaxis typically have good outcomes, with fewer and less severe episodes as they get older.[15]

Likelihood[change | edit source]

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. The number of people with anaphylaxis 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 anaphylaxis caused by food.[32] 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] Death rates have decreased between the 1970s and 2000s.[33] In Australia, anaphylaxis deaths due to food occur primarily in women while deaths due to insect bites primarily occur in men.[10] Death from anaphylaxis is most commonly triggered by medications.[10]

History[change | edit source]

The term "aphylaxis" was coined by Charles Richet in 1902 and later changed to "anaphylaxis" because it sounded nicer.[11] He was later awarded the Nobel Prize in Medicine and Physiology for his work on anaphylaxis in 1913.[4] The reaction itself, however, has been reported since ancient times.[24] The term comes from the Greek language|Greek words ἀνά ana, against, and φύλαξις phylaxis, protection.[34]

Research[change | edit source]

There are ongoing efforts to develop epinephrine that can be applied under the tongue (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][35]

References[change | edit source]

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