Portier and Richet first coined the term anaphylaxis in 1902 when a second vaccinating dose of sea anemone toxin caused a dog’s death. The response was the opposite of prophylaxis and thus was referred to as anaphylaxis, meaning without protection.
Anaphylaxis is an acute systemic reaction caused by the release of mediators from mast cells and basophils. More than one organ system should be involved for the reaction to be considered anaphylaxis. The most common organ systems involved include the cutaneous, respiratory, cardiovascular, and gastrointestinal systems.
The phrase anaphylactic reaction usually refers to a type I hypersensitivity reaction with mast cell and basophil degranulation mediated by antigen binding of specific immunoglobulin E (IgE). The term anaphylactoid reaction refers instead to a non–IgE-mediated mechanism of mast cell/basophil activation. The term anaphylaxis refers to the physiologic events due to either mechanism.
When mast cells and basophils degranulate, whether by IgE- or non–IgE-mediated mechanisms, preformed histamine and newly generated leukotrienes and prostaglandins are released. The physiologic responses to these mediators include smooth muscle spasm in the respiratory and gastrointestinal tract, vasodilation, increased vascular permeability, and stimulation of sensory nerve endings. These physiologic events lead to the classic symptoms of anaphylaxis: flushing; urticaria; pruritus; bronchospasm; and abdominal cramping with nausea, vomiting, and diarrhea. Hypotension and shock can result from intravascular volume loss, vasodilation, and myocardial dysfunction. Increased vascular permeability can result in a shift of 50% of vascular volume to the extravascular space within 10 minutes.
Additional mediators activate other pathways of inflammation: the neutral proteases, tryptase and chymase; proteoglycans such as heparin and chondroitin sulfate; and chemokines and cytokines. These mediators can activate the kinin system, the complement cascade, and coagulation pathways. Working together, these inflammatory pathways recruit other inflammatory cells, including eosinophils and lymphocytes, resulting in prolonged, biphasic, and/or intensified reactions.
Despite the potential contribution of multiple mediators, histamine infusion alone is sufficient to produce most of the symptoms of anaphylaxis. Histamine mediates its effects through activation of histamine 1 (H1) and histamine 2 (H2) receptors. Vasodilation is mediated by both H1 receptors and H2 receptors. H2 receptors exert a direct effect on vascular smooth muscle, whereas H1 receptors stimulate endothelial cells to produce nitric oxide. Cardiac effects of histamine are largely mediated through H2 receptors. H1 receptors are primarily responsible for extravascular smooth muscle contraction (eg, bronchial tree, gastrointestinal tract). Both H1 receptors and H2 receptors mediate glandular hypersecretion.
The true incidence is unknown. Moneret-Vautrin et al recently reviewed the published literature and stated that severe anaphylaxis affects at least 1-3 persons per 10,000 population. Neugut et al estimated that 1-15% of the US population are at risk of experiencing an anaphylactic or anaphylactoid reaction. They estimated that the rate of actual anaphylaxis to food was 0.0004%, 0.7-10% for penicillin, 0.22-1% for radiocontrast media (RCM), and 0.5-5% after insect stings.
A population-based study from Olmsted County, Minnesota, detected an average annual incidence of anaphylaxis of 21 cases per 100,000 person-years. Ingestion of a suspect food was the cause in 36% of cases; a medication, allergy immunotherapy, or a diagnostic agent was the cause in 17% of cases; and an insect sting was the cause in 15% of cases. Thirty-two percent of cases were considered idiopathic. Episodes of anaphylaxis occurred more frequently in the summer months of July through September, which is attributable to insect stings.
In a study of patients referred to an allergy practice in Memphis, Tennessee, food was the cause of anaphylaxis in 34% of patients, medications in 20%, and exercise in 7% (insect sting anaphylaxis was excluded from the study). The cause of anaphylaxis was undetermined in 37% of patients. A separate study estimated the number of cases of idiopathic anaphylaxis in the United States to be 20,000-47,000 cases per year (approximately 8-19 episodes per 100,000 person-years).
Geographic location is not thought to exert a major effect on incidence. Two European studies detected a lower average annual incidence than found in the Olmsted County study (3.2 cases of anaphylactic shock per 100,000 person-years in Denmark; 9.8 cases of out-of-hospital anaphylaxis per 100,000 person-years in Munich, Germany). Rates in Europe range from 1-3 cases per 10,000. Simons and colleagues examined the rate of epinephrine prescriptions for a population of 1.15 million patients in Manitoba, Canada, and found that 0.95% of this population was prescribed epinephrine, an indicator of perceived risk that future anaphylaxis may occur.
Fatalities from anaphylaxis are infrequent but not rare. Estimates range from 0.65-2% of patients with anaphylaxis. The case-fatality rate from the Olmsted County study was 0.65%. Severe reactions to penicillin occur with a frequency of 1-5 cases per 10,000 patient courses, with fatalities in 1 case per 50,000-100,000 courses. Insect stings cause 25-50 deaths per year. Reactions to foods are thought to be the most common cause of anaphylaxis when it occurs outside of the hospital and are estimated to cause 125 deaths per year in the United States. Anaphylactoid reactions to RCM were estimated to have caused 500 deaths in 1982, although this number has likely decreased because of increased awareness and the use of pretreatment regimens and/or lower osmolar agents for patients with a history of RCM reaction.
In the United Kingdom, one half of fatal anaphylaxis episodes have an iatrogenic cause (ie, anesthesia, antibiotics, or radiocontrast), while foods and insect stings each account for a quarter of the fatal episodes.
The most common causes of death are cardiovascular collapse and laryngeal edema.
Race has no known effect on the risk of anaphylaxis.
In the Olmsted County study, men and women were equally affected.
The Memphis study showed a slight female predominance.
Earlier studies have suggested that episodes of anaphylaxis to intravenous muscle relaxants, aspirin, and latex are more common in women, while insect sting anaphylaxis is more common in men. These sex discrepancies are likely a function of exposure frequency.
Anaphylaxis can occur at any age. In the Olmsted County study, the age range was 6 months to 89 years. The mean age was 29 ±19 years. The Memphis study had an age range of 12-75 years, with a mean of 38 years.
Simons and colleagues noted the highest frequency of prescriptions for epinephrine in boys aged 12-17 months (5.3%). The rate was 1.4% for those younger than 17 years, 0.9% for those aged 17-64 years, and 0.3% for those aged 65 years or older.
Severe food allergy is more common in children than in adults. However, since severe food allergy often persists into adulthood, the frequency in adults may be rising.
Anaphylaxis to RCM, insect stings, and anesthetics has been reported to be more common in adults than in children. Whether this is a function of exposure frequency or increased sensitivity is unclear.
Other risk factors:
Atopy is risk factor. In the Olmsted County study, 53% of the patients with anaphylaxis had a history of atopic diseases (eg, allergic rhinitis, asthma, atopic dermatitis). The Memphis study detected atopy in 37% of the patients. Other studies have shown atopy to be a risk factor for anaphylaxis from foods, exercise-induced anaphylaxis, idiopathic anaphylaxis, radiocontrast reactions, and latex reactions. Underlying atopy does not appear to be a risk factor for reactions to penicillin or insect stings.
Route and timing of administration affect anaphylactic potential. The oral route of administration is less likely to cause a reaction, and the reaction is usually less severe, although fatal reactions occur following ingestions of foods by someone who is allergic. The longer the interval between exposures, the less likely an anaphylactic (IgE-mediated) reaction will recur. This is thought to be due to catabolism and decreased synthesis of specific IgE over time. This does not appear to be the case for anaphylactoid reactions.
Asthma is a risk factor for fatal outcomes.
Delay in administration of epinephrine is also a risk factor for fatal outcomes.
In most studies, the frequency of symptoms and signs of anaphylaxis are grouped together by organ system. For example, in the Olmsted County study, 100% of patients with anaphylaxis had cutaneous manifestations. This resulted from the study’s definition of anaphylaxis, which required one symptom of generalized mediator release, which was defined mostly by skin manifestations. Nevertheless, other studies have reported that 90% of patients have skin involvement. In the Olmsted County study, 69% had respiratory manifestations, 41% had cardiovascular involvement, and 24% had oral or gastrointestinal manifestations. Other studies have reported similar findings.
Patients often initially describe a sense of impending doom, accompanied by pruritus and flushing. This can evolve rapidly into the following symptoms, broken down by organ system:
Cutaneous/ocular – Flushing, urticaria, angioedema, cutaneous and/or conjunctival pruritus, warmth, and swelling
Respiratory – Nasal congestion, rhinorrhea, throat tightness, wheezing, shortness of breath, cough, hoarseness
Cardiovascular – Dizziness, weakness, syncope, chest pain, palpitations
Gastrointestinal – Nausea, vomiting, diarrhea, bloating, cramps
Neurologic – Headache (rare except in exercise-induced anaphylaxis) and seizure (very rare)
Symptoms usually begin within 5-30 minutes from the time the antigen is injected but can occur within seconds. If the antigen is ingested, symptoms usually occur within 2 hours, although symptoms often occur much faster, as with severe food allergy. In rare cases, symptoms can be delayed in onset for several hours.
The first priority should be to assess the patient’s respiratory and cardiac status.
Severe angioedema of the tongue and lips may obstruct airflow.
Laryngeal edema may manifest as stridor or severe air hunger.
Loss of voice, hoarseness, and/or dysphagia may occur.
Bronchospasm, airway edema, and mucus hypersecretion may manifest as wheezing. In the surgical setting, increased pressure of ventilation can be the only manifestation of bronchospasm.
Hypoxia can cause altered mental status.
Tachycardia is present in one fourth of patients, usually as a compensatory measure for intravascular volume loss.
Bradycardia is more suggestive of a vasovagal reaction, although it has been observed in true anaphylaxis.
Hypotension (and resultant loss of consciousness) may be observed secondary to capillary leak, vasodilation, and hypoxic myocardial depression.
Cardiovascular collapse with shock can occur immediately, without any other findings. This is an important consideration in the surgical setting.
The first sign of anaphylaxis is flushing, noted especially in the cheeks. Urticaria (hives) can occur anywhere on the body, often localizing to the palms, soles, and inner thighs. The lesions are erythematous, raised, highly pruritic, and of variable size.
Angioedema is also commonly observed. These lesions involve the deeper dermal layers of skin and are usually nonpruritic and nonpitting. Common areas of involvement are the larynx, lips, eyelids, hands, feet, and genitals.
Isolated, whole-body erythematous flushing is also occasionally observed.
Gastrointestinal: Vomiting, diarrhea, and abdominal distention are frequently observed.
IgE-mediated anaphylaxis: This is the classic form of anaphylaxis, whereby a sensitizing antigen elicits an IgE antibody response in a susceptible individual. The antigen-specific IgE antibodies then bind to mast cells and basophils. Subsequent exposure to the sensitizing antigen causes cross-linking of cell-bound IgE, resulting in mast cell (and/or basophil) degranulation. Typical examples of IgE-mediated anaphylaxis include the reactions to many drugs, insect stings, and foods.
Certain drugs cause IgE-mediated anaphylaxis. Most cases of IgE-mediated drug anaphylaxis in the United States are due to penicillin antibiotics.
Penicillin is metabolized to a major determinant, benzylpenicilloyl, and multiple minor determinants. Penicillin and its metabolites are haptens, small molecules that only elicit an immune response when conjugated with proteins.
Other beta-lactam antibiotics may cross-react with penicillins or may have unique structures that also act as haptens. The incidence rate of anaphylaxis to cephalosporins in penicillin-anaphylactic patients appears to be much less than the 10% frequently quoted. Pichichero recently reviewed this complicated literature and offers specific guidance for the use of cephalosporins in patients who have a history of IgE-mediated reactions to penicillin.
Patients with less well-defined reactions to penicillin have a very low risk (1-2%) of developing anaphylaxis to cephalosporins. The rate of skin-test reactivity to imipenem in patients with a known penicillin allergy is almost 50%. In contrast, no known in vitro or clinical cross-reactivity exists between penicillins and aztreonam.
Many other drugs have been implicated less frequently in IgE-mediated anaphylaxis.
In the surgical setting, anaphylactic reactions are most often due to muscle relaxants and latex but can also be due to hypnotics, antibiotics, opioids, colloids, and other agents. Volatile anesthetic agents can cause immune-mediated hepatic toxicity but have not been implicated in anaphylactic reactions.
Insect stings, that is, venoms from Hymenoptera insects (ie, bees, yellow jackets, hornets, wasps, fire ants), can elicit an IgE antibody response. From 0.5-3% of the population experience a systemic reaction after being stung.
Hypersensitivity to foods is now recognized as a worldwide problem in the industrialized world. In the United States, an estimated 4 million Americans have well-substantiated food allergies. In Montreal, 1.5% of early elementary school students were found to be sensitized to peanuts. Reactions to foods are thought to be the most common cause of anaphylaxis when it occurs outside of the hospital and are estimated to cause 125 deaths per year in the United States.
Certain foods are more likely than others to elicit an IgE antibody response and lead to anaphylaxis. Foods likely to elicit an IgE antibody response in all age groups include peanuts, tree nuts, fish, and shellfish. Foods likely to elicit an IgE antibody response in children include egg, soy, and milk.
An analysis of 32 fatalities thought to be due to food-induced anaphylaxis revealed that peanut was the likely responsible food in 62% of the cases. In placebo-controlled food challenges, peanut-sensitive patients can react to as little as 100 µg of peanut protein. The Olmsted County study, in agreement with earlier studies, found that food ingestion was the leading cause of anaphylaxis, accounting for as many as one third of all cases. Scombroid fish poisoning can occasionally mimic food-induced anaphylaxis. Bacteria in spoiled fish can decarboxylate histidine, producing a chemical with histaminelike activity.
Latex hypersensitivity is a phenomenon that has been recognized in the last 20 years, corresponding with the increased use of latex gloves because of the AIDS epidemic and the institution of universal precautions. In 1995, an estimated 8-17% of healthcare professionals were at risk for latex reactions. The incidence rate is already decreasing, at least in part, because of increased awareness, improved manufacturing practices, and a change to unpowdered latex and nonlatex gloves.
Allergen-specific immunotherapy can cause IgE-mediated anaphylaxis. Allergy injections are a common trigger for anaphylaxis. This is not unexpected because the treatment is based on injecting an allergen to which the patient is sensitive. However, life-threatening reactions are rare. A total of 46 deaths due to allergen immunotherapy and skin testing were reported from 1945-1987. Risk factors for severe anaphylaxis due to immunotherapy include poorly controlled asthma, concurrent use of beta-blockers, high allergen dose, errors in administration, and lack of a sufficient observation period following the injection.
Complement-mediated reactions are described. Anaphylaxis resulting from administration of blood products, including intravenous immunoglobulin, or animal antiserum is due, at least in part, to activation of complement. Immune complexes formed either in vivo or in vitro can activate the complement cascade. Certain byproducts of the cascade, namely plasma-activated complement 3 (C3a), plasma-activated complement 4 (C4a), and plasma-activated complement 5 (C5a), are called anaphylatoxins and are capable of causing mast cell/basophil degranulation.
Certain agents (ie, direct mast cell activators) are thought to cause direct, nonimmunologic release of mediators from mast cells. These include opiates, RCM, dextrans, protamine, and vancomycin. Mechanisms underlying these reactions are poorly understood but may involve specific receptors (eg, opioids) or non–receptor-mediated mast cell activation (eg, hyperosmolarity). Evidence also exists that RCM, dextrans, and protamine can activate several inflammatory pathways, including complement, coagulation, and vasoactive (kallikrein-kinin) systems.
Aspirin and nonsteroidal anti-inflammatory drugs
Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) have been placed in the anaphylactoid category in the past because reactions were thought to occur through the aberrant metabolism of arachidonic acid. Isolated cutaneous reactions to aspirin/NSAIDs and aspirin-sensitive asthma (often in association with nasal polyposis) are indeed mediated through non-IgE mechanisms. Blockade of cyclooxygenase by these drugs causes the 5-lipoxygenase pathway to shut down, resulting in an overproduction of leukotrienes. These patients have marked cross-reactivity between aspirin and most NSAIDs.
True anaphylaxis after taking these drugs appears to have a different mechanism that is more consistent with IgE-mediated anaphylaxis. With true anaphylaxis, the different cyclooxygenase inhibitors do not appear to cross-react. Anaphylaxis only occurs after 2 or more exposures to the implicated drug, suggesting a need for prior sensitization. Finally, patients with true anaphylaxis do not usually have underlying asthma, nasal polyposis, or urticaria. In one study of nearly 52,000 people taking NSAIDs, 35 developed anaphylactic shock.
This is a rare syndrome that can take one of two forms. The first form is food-dependent, requiring both exercise and the recent ingestion of particular foods to cause an episode of anaphylaxis. In these patients, exercise alone does not result in an episode, and eating the culprit food alone does not result in an episode.
The second form is characterized by intermittent episodes of anaphylaxis during exercise, independent of any food ingestion. Anaphylaxis will not necessarily occur during every episode of physical exertion.
Anaphylaxis associated with systemic mastocytosis
Anaphylaxis can be a manifestation of systemic mastocytosis, a disease characterized by excessive mast cell numbers.
Such patients appear to be at increased risk for food and venom reactions.
A syndrome of recurrent anaphylaxis without any consistent triggers (despite an exhaustive search for such) exists. This recurrent syndrome should be distinguished from a single episode of anaphylaxis in which the etiology may be unclear.
Most patients treated with antihistamines and steroids have complete remission following tapering of steroids.
Most of these patients are female, and atopy appears to be an underlying risk factor.
Two thirds of patients have 5 or fewer episodes per year, while one third have more than 5 episodes per year.