Pediatrics

Anaphylaxis

OVERVIEW: What every practitioner needs to know

Are you sure your patient has anaphylaxis? What are the typical findings for this disease?

Anaphylaxis is a serious multisystem allergic reaction that has a rapid onset and is potentially life-threatening.

The cutaneous, gastrointestinal tract, respiratory, and cardiovascular systems are commonly affected.

Cutaneous symptoms include pruritus, flushing, urticaria, and angioedema. Gastrointestinal tract symptoms include nausea, vomiting, abdominal cramps, and diarrhea. Respiratory symptoms include nasal congestion, rhinorrhea, sneezing, tightness in the throat, hoarse voice, dry cough, and dyspnea and wheezing, which can be severe. Life threatening cardiovascular effects include hypotension, syncope, and shock.

Less commonly, symptoms of headache, substernal chest pain and seizures may occur.

Most cases of anaphylaxis resolve after treatment, however, up to 20% of anaphylactic reactions can occur in a biphasic pattern. In these cases, a recurrence of symptoms can occur within 1-72 hours (typically within 8 hours), even after effective treatment of the immediate condition and no further exposure to the allergen.

What other disease/condition shares some of these symptoms?

Since anaphylaxis can affect almost any organ system, its symptomatology overlaps with many illnesses. Cutaneous symptoms may be a result of acute or chronic urticaria, and respiratory features may be similar to asthma exacerbations, foreign body aspiration (especially in children) and vocal cord dysfunction.

Food poisoning, in particular from scombroid fish, may present with symptoms similar to those of food-induced anaphylaxis. Some cases of vasovagal reaction, panic attack, mastocytosis, carcinoid syndrome, pheochromocytoma, C1 esterase inhibitor deficiency, and serum sickness can be confused with anaphylaxis as well.

What caused this disease to develop at this time?

Anaphylaxis is mediated by an IgE-dependent mechanism. In allergic individuals, IgE antibodies are produced in response to specific allergen exposure. These IgE molecules are fixed to high affinity IgE receptors (FceRI) on the surface of mast cells, basophils and various antigen-presenting cells, e.g., macrophages, dendritic cells, Langerhans cells. Upon re-exposure to allergen, cross-linking of these receptors leads to cell activation and mediator release.

Mast cells and basophils release preformed chemical mediators (i.e. histamine, tryptase, carboxypeptidase A, and proteoglycans) as well as newly generated mediators (i.e. leukotrienes, prostaglandins, platelet-activating factor, and various cytokines) that induce various symptoms of anaphylaxis.

Triggers for anaphylaxis include:

  • Food – the leading cause of outpatient anaphylaxis in most surveys. The most common food allergens are milk, egg, peanut, tree nuts, fish, shellfish, wheat and soy.

  • Medications – beta-lactams (penicillins), other antibiotics, aspirin, NSAIDs, biologics (i.e. cetuximab, infliximab, omalizumab).

  • Vaccines – reactions are more commonly due to excipients that are contained in the vaccine product (i.e. gelatin in MMR, egg in influenza), not the immunizing agent.

  • Immunotherapy (allergy desensitization).

  • Insect venom – stinging insects (yellow jacket, wasp), not usually from bites (mosquito, ticks).

  • Occupational exposures (e.g., latex, mice in lab workers).

  • Physical (e.g., exercise, cold) – non-immune perturbations of mast cells and basophils.

  • Idiopathic – diagnosis of exclusion.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

There are no reliable laboratory tests for diagnosing anaphylaxis.

Although elevated plasma histamine levels can be found in some cases, histamine has a very short half-life (increased for 15-60 min) so elevations will be transient and can easily be missed. In addition, special handling procedures are necessary for accurate results, including using a wide bore needle to obtain the sample, keeping the sample cold, centrifuging immediately, and freezing plasma promptly.

Elevated histamine levels are not specific to anaphylaxis; it can be elevated in other conditions such as scombroid poisoning. Urinary histamine and its metabolites, however, are elevated for longer periods and may be useful.

Tryptase is increased for a longer duration, from 15 minutes to 3 hours after symptom onset. It has low sensitivity and is often not elevated in food-induced anaphylaxis. In addition, it is seldom increased when hypotension or shock is absent. Serial measurements may be more helpful. Similar to histamine, tryptase is not specific for anaphylaxis as it can be elevated in cases of myocardial infarction or trauma.

Would imaging studies be helpful? If so, which ones?

Imaging studies are not helpful for diagnosing anaphylaxis.

Confirming the diagnosis

Although there is no universal agreement on the definition of anaphylaxis or the criteria for diagnosis, the Second Symposium on the Definition and Management of Anaphylaxis came to a general consensus. The general consensus regarding clinical criteria for the diagnosis of anaphylaxis is as follows:

Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled:

  1. Acute onset of an illness with involvement of the skin, mucosal tissue, or both, AND at least one of the following:

    • Respiratory compromis

    • Reduced BP or associated symptoms of end-organ dysfunction

  2. Two or more of the following that occur rapidly after exposure to a likely allergen for that patient (minutes to several hours):

    • Involvement of the skin-mucosal tissue

    • Respiratory compromise

    • Reduced BP or associated symptoms of end-organ dysfunction

    • Persistent gastrointestinal symptoms

  3. Reduced BP after exposure to known allergen for that patient (minutes to several hours):

    • Infants and children: low systolic BP (age-specific) or greater than 30% decrease in systolic BP

    • Adults: systolic BP < 90 mm Hg or greater than 30% decrease from that patient’s baseline

If you are able to confirm that the patient has anaphylaxis, what treatment should be initiated?

Epinephrine

The treatment of choice for anaphylaxis is epinephrine. Although there are no randomized controlled trials of epinephrine for the treatment of anaphylaxis, expert opinion/guidelines and fatality studies support the use of epinephrine as first-line treatment. The recommended dose is 0.01 mg/kg up to 0.5 mg. Additional doses can be given every 5-15 minutes as needed. Up to 20% of patients require a second dose of epinephrine to treat anaphylaxis.

Studies have shown that intramuscular administration in the lateral thigh achieves higher and faster peak plasma concentrations than injection in the deltoid either by subcutaneous or intramuscular administration. In severe reactions, intravenous administration may be necessary. In extremely severe cases of collapse where epinephrine and fluids are not effective, vasoconstrictors such as vasopressin may be required.

Antihistamines

H1-antihistamines are effective for the treatment of cutaneous symptoms, such as pruritus and urticaria, but not for respiratory symptoms, gastrointestinal symptoms or cardiovascular collapse (shock).

H2-antihistmines may be used concurrently with a H1-antihistamine to relieve urticaria, however, it does not have significant effects on pruritus or other symptoms. While serum histamine peaks early in anaphylaxis, it quickly returns to baseline even with persistent symptoms, suggesting that delay in administration of antihistamines following initial exposure or symptom-onset will reduce their effectiveness.

Animal studies have not shown a significant effect of antihistamines in the treatment of anaphylactic shock. Therefore, antihistamines (H1 and H2 antagonists) are considered second-line treatment for anaphylaxis. The onset of action of antihistamines is 1-2 hours, which is slow in comparison to the progression of anaphylactic symptoms.

Corticosteroids

Corticosteroids may have a role in preventing or ameliorating biphasic or protracted anaphylaxis, however, there are no randomized controlled trials to demonstrate their effectiveness. One study found that treatment with corticosteroids was not effective in preventing biphasic reactions, whereas another study demonstrated that corticosteroids prevented or reduced the severity of the late response. While far from definitive, these findings suggest that corticosteroids may be beneficial in some cases of anaphylaxis and are unlikely to have any adverse consequences.

Additional treatment measures

Other considerations include aggressive fluid resuscitation and supine positioning. When the respiratory status of a patient is not significantly compromised, elevation of the legs has been recommended by some authorities to enhance cardiac preload in cases of anaphylactic shock. Standing or sitting in the upright position promotes blood pooling in the lower extremities and has contributed to fatalities.

Supplemental oxygen and beta-agonists should be used to treat respiratory symptoms. Glucagon has potent inotropic and chronotropic actions and may be beneficial for the treatment of anaphylactic shock in patients who are on chronic beta-blockers if other treatments are ineffective.

Table I gives a summary of the medications used in the treatment of anaphylaxis.

Table I.

Medications used in the treatment of Anaphylaxis
Medication Dose Benefits Side effects
Epinephrine 0.01mg/kg of 1:1000 IM (maximum of 0.5mg in adults) Bronchodilation, decrease mucosal edema, increase heart rate, increase cardiac contraction force, increase blood pressure, vasocontriction Anxiety, pallor, tremor, palpitations, dizziness, headache Severe adverse effects (usually due to overdose – IV bolus, rapid IV push, incorrect concentration 1:1000 instead by 1:10,000 for IV) – pulmonary edema, hypertension, myocardial infarction
H1-Antihistamines Varies depending on medication Relieves cutaneous symptoms as well as sneezing and rhinorrhea First generation H1-antihistamines cause sedation and can impair cognitive functionOverdose can cause respiratory depression or coma
H2-Antihistamine Varies depending on medication; should be used in conjunction with H1-Antihistamine Has additive effect with H1-antihistamines to relieve cutaneous symptoms Ranitidine can cause hypotension if infused rapidly
Glucocorticoids Varies depending on medication Slow onset of action, but may prevent biphasic or protracted anaphylaxis Side effects unlikely when given as a short course

There are no randomized controlled trials providing high-quality evidence to support the role of epinephrine, H1 or H2 antihistamines, and glucocorticoids in the treatment of anaphylaxis. The current treatment recommendations are based on best available evidence because there are many barriers to conducting such trials. The main concern is that delay in treatment for anaphylaxis poses a significant risk of morbidity and mortality. Fatalities from anaphylaxis are often due to delayed administration of epinephrine. Furthermore, anaphylaxis is unpredictable in terms of timing, severity and duration of symptoms, and no laboratory test is available to confirm the diagnosis of anaphylaxis with a high degree of sensitivity or specificity.

What are the adverse effects associated with each treatment option?

The adverse effects of epinephrine include pallor, tremor, anxiety, palpitations, headache and dizziness. These effects are generally transient and mild. Serious side effects of pulmonary edema or hypertension are usually due to overdose, overly rapid IV infusion or IV infusion of the wrong dose (e.g., 1:1000 instead of 1:10,000).

The adverse effects of first-generation H1-antihistamines which cross the blood-brain barrier include sedation and impaired cognitive function. Second-generation H1-antihistamines cross the blood-brain barrier to a lesser extent so these adverse effects are significantly less likely to occur.

H2-antihistamines have few side effects, however, rapid infusion can result in hypotension.

Side effects common to glucocorticoids are unlikely to be seen in the short treatment courses commonly used for anaphylaxis.

What are the possible outcomes of anaphylaxis?

Anaphylaxis is a potentially life-threatening condition. Risk factors for severe or fatal anaphylaxis include certain patient groups such as infants, adolescents, pregnant women and the elderly, underlying asthma, cardiovascular disease, mastocytosis, and concurrent use of medications including beta-blockers and angiotensin-converting enzyme inhibitors.

Biphasic anaphylaxis with recurrence of symptoms usually within 4-8 hours may occur in up to 20% of cases. It is managed in the same manner as anaphylaxis. Although corticosteroids do not appear to have benefit in the initial treatment of acute anaphylaxis, methylprednisolone (IV), prednisone or prednisolone (PO) in doses of 1-2 mg/kg may help ameliorate or prevent a biphasic reaction. Repeated doses at 6-hour intervals may be used as indicated by the patient's clinical condition.

It is important that patients are referred to allergists to identify possible triggers of anaphylaxis and to learn allergen avoidance strategies. Furthermore, it is essential that patients are instructed on the use of self-injectable epinephrine, and all patients should be provided with an individualized emergency plan.

What causes this disease and how frequent is it?

Anaphylaxis is induced by a variety of triggers, including foods, medications, vaccines, and immunotherapy.

The lifetime prevalence of anaphylaxis from all causes ranges from 0.05-2% in the general population. Similar to other allergic conditions, the rate of anaphylaxis has increased in recent years, doubling from 21 per 100,000 person-years in the 1980s to 49.8 per 100,000 person-years in the 1990s.

The highest incidence occurs in children and adolescents. For children under 15 years of age, anaphylaxis is more common in boys. In contrast, anaphylaxis more often occurs in female adults. Approximately 1% of anaphylaxis cases are fatal.

How do these pathogens/genes/exposures cause the disease?

Various genes have been linked to atopy, asthma and atopic dermatitis, but no genetic factors have been definitively associated with anaphylaxis. Certain individuals may be at higher risk, including those with increased baseline serum tryptase or plasma histamine, decreased angiotensin-converting enzyme (ACE) activity, decreased platelet activating factor (PAF) acetylhydrolase activity or defects in other mediator degradation pathways.

What complications might you expect from the disease or treatment of the disease?

Biphasic reactions are defined as a recurrence of symptoms after resolution of the initial presentation. The rate of biphasic anaphylaxis has been reported to range between 3-20% in adults and one pediatric study reported biphasic reactions occurring in 6% of cases. The severity of the late-phase symptoms is highly variable, being either more or less severe than the initial symptoms. Unfortunately, the onset of the late-phase symptoms is also highly variable, ranging from 1 to 78 hours, with the majority occurring within 8 hours of the initial presentation.

Studies suggest that delayed administration, inadequate dosing or need for large doses of epinephrine to treat initial symptoms are risk factors for the development of biphasic reactions.

Are additional laboratory studies available; even some that are not widely available?

Several biomarkers for anaphylaxis have been reported to have potential utility in the diagnosis of anaphylaxis. These include measurement of serum mature beta-tryptase, mast cell carboxypeptidase A3, chymase, platelet-activating factor, bradykinin, cytokines, and urinary cysteinyl leukotriene E4 and 9-alpha-11-beta-prostaglandin F2.

These biomarkers are released at different times during anaphylactic reactions and patients often present to medical attention at varying times after symptom onset. Therefore it is possible that measurement of multiple biomarkers will be helpful in making an accurate diagnosis.

How can anaphylaxis be prevented?

There are no prophylactic drugs or vaccines for the prevention of anaphylaxis. The main-stay of treatment for allergies to food, medications, occupational exposures, insect stings, etc. is allergen avoidance and the use of emergency medications (e.g., epinephrine) for the treatment of allergic reactions due to accidental exposures.

There are several potential treatments for food allergy that are currently under investigation, including immunotherapy (oral, sublingual, epicutaneous), Chinese herbal medication, and modified recombinant vaccines.

Medication allergies can be managed with desensitization protocols.

Individuals with a history of anaphylaxis due to vaccines may be managed with modified administration schedules or administration in divided doses under observation.

The risk of insect venom-induced anaphylaxis can be reduced with venom-specific immunotherapy. Immunotherapy for insect stings is more than 98% effective in desensitizing allergic individuals.

Desensitization immunotherapy should be administered in a setting where appropriate personnel, equipment and medications are immediately available to treat anaphylaxis. Steps that can be taken to minimize the risk of anaphylaxis during desensitization include assessment of asthma status prior to administration, adjusting immunotherapy dose or injection frequency if symptoms of anaphylaxis occur, using appropriate diluted allergen extracts, and observation for 30 minutes after an immunotherapy injection.

What is the evidence?

Sampson, HA, Muñoz-Furlong, A, Campbell, RL. J Allergy Clin Immunol. vol. 117. 2006. pp. 391-7.

(A summary of the second international conference to develop a universally accepted definition of anaphylaxis, establish clinical criteria that would accurately identify cases of anaphylaxis with high precision, and review the evidence on the most appropriate management of anaphylaxis.)

Simons, FE. "Pharmacologic treatment of anaphylaxis: can the evidence base be strengthened". Curr Opin Allergy Clin Immunol. vol. 10. 2010. pp. 384-93.

Sheikh, A, Shehata, YA, Brown, SG, Simons, FE. "Adrenaline for the treatment of anaphylaxis: Cochrane systematic review". Allergy. vol. 64. 2009. pp. 204-12.

Sheikh, A, Ten Broek, V, Brown, SG, Simons, FE. "H1-antihistamines for the treatment of anaphylaxis: Cochrane systematic review". Allergy. vol. 62. 2007. pp. 830-7.

Choo, KJ, Simons, FE, Sheikh, A. "Glucocorticoids for the treatment of anaphylaxis". Cochrane Database Syst Rev. 2010 Mar 17. pp. CD007596.

Pumphrey, RS. "Lessons for management of anaphylaxis from a study of fatal reactions". Clin Exp Allergy. vol. 30. 2000. pp. 1144-50.

Cox, L, Nelson, H, Lockey, R. "Allergen immunotherapy: a practice parameter third update". J Allergy Clin Immunol. vol. 127. 2011. pp. S1-55.

Bock, SA, Muñoz-Furlong, A, Sampson, HA. "Fatalities due to anaphylactic reactions to foods". J Allergy Clin Immunol. vol. 107. 2001. pp. 191-3.

Bock, SA, Muñoz-Furlong, A, Sampson, HA. "Further fatalities caused by anaphylactic reactions to food, 2001-2006". J Allergy Clin Immunol. vol. 119. 2007. pp. 1016-8.

Pumphrey, RS, Gowland, MH. "Further fatal allergic reactions to food in the United Kingdom, 1999-2006". J Allergy Clin Immunol. vol. 119. 2007. pp. 1018-9.

Greenberger, PA, Rotskoff, BD, Lifschultz, B. "Fatal anaphylaxis: postmortem findings and associated comorbid diseases". Ann Allergy Asthma Immunol. vol. 98. 2007. pp. 252-7.

Simons, FE, Ardusso, LR, Bilò, MB. "International consensus on (ICON) anaphylaxis". World Allergy Organ J. vol. 7. 2014. pp. 9.

Muraro, A, Roberts, G, Worm, M. "EAACI Food Allergy and Anaphylaxis Guidelines Group. Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology". Allergy. vol. 69. 2014. pp. 1026-45.

Wood, RA, Camargo, CA, Lieberman, P. "Anaphylaxis in America: the prevalence and characteristics of anaphylaxis in the United States". J Allergy Clin Immunol. vol. 133. 2014. pp. 461-7.

Lieberman, P, Nicklas, RA, Randolph, C. "Anaphylaxis--a practice parameter update 2015". Ann Allergy Asthma Immunol. vol. 115. 2015 Nov. pp. 341-84.

(This practice parameter provides updated guidelines for the diagnosis and management of anaphylaxis using evidence from recent medical literature.)

Simons, FE, Ebisawa, M, Sanchez-Borges, M. "2015 update of the evidence base: World Allergy Organization anaphylaxis guidelines". World Allergy Organ J. vol. 8. 2015 Oct 28. pp. 32.

(This provides updated evidence supporting recommendations for the diagnosis and management of anaphylaxis.)

Lee, S, Hess, EP, Lohse, C. "Trends, characteristics, and incidence of anaphylaxis in 2001-2010: A population-based study". J Allergy Clin Immunol. 2016 Jun 4. pp. S0091-6749.

(These data show an increase in the rate of anaphylaxis between 2001-2010 and describe differences in triggers affecting different age groups.)
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