Anaphylaxis/Drug Reactions Case File

Anaphylaxis/Drug Reactions Case File

Eugene C. Toy, MD, Gabriel M. Aisenberg, MD

Case 40

A 25-year-old man is being seen in the office for a 2-day history of low-grade fever and sore throat. He is otherwise healthy and takes no regular medications. After an evaluation, he is given an injection of intramuscular penicillin for presumed streptococcal pharyngitis. Within a few minutes of the penicillin injection, he begins to complain of swelling of his face and difficulty breathing. He is dyspneic and appears frightened. His heart rate is 130 beats per minute (bpm), blood pressure is 90/47 mm Hg, and respirations are 28 breaths per minute and shallow. His face and lips are edematous, and he can barely open his eyes because of swelling. He is wheezing diffusely, and he has multiple raised urticarial lesions on his skin. Oxygen is given by face mask, and an ambulance has been called.

▶ What is the most likely diagnosis?

▶ What is your next step?

ANSWERS TO CASE 40:

Anaphylaxis/Drug Reactions

Summary: A 25-year-old man presents with

• Facial edema and difficulty breathing minutes after receiving an injection of penicillin
• Tachypnea, tachycardia, and hypotension
• Diffuse wheezing and warm skin with multiple raised urticarial lesions

Most likely diagnosis: Anaphylaxis as a result of penicillin hypersensitivity.

Next step: Immediate administration of intramuscular epinephrine is the first priority; secondary measures include corticosteroids and antihistaminic H1 and H2 blockers. Close observation of the patient’s airway and oxygenation is also important, with possible endotracheal intubation if these becomes compromised.

ANALYSIS

Objectives

1. Describe the clinical presentation and emergency management of anaphylaxis. (EPA 1, 10)
2. Understand the diagnosis and complications of serum sickness. (EPA 4, 10)
3. Recognize and treat erythema multiforme minor and major. (EPA 1, 4)

Considerations

This young man developed manifestations of immediate hypersensitivity, with urticaria, facial angioedema, and bronchospasm. Penicillin is allergenic and leads to an immunoglobulin E (IgE)–mediated release of histamines and other vasoactive chemicals. Epinephrine given IM is the agent of choice in acute anaphylaxis. The route should be intramuscular and not subcutaneous because intramuscular injections (best in thigh) have faster and better absorption than the subcutaneous route. Epinephrine improves tissue edema by causing vasoconstriction. Antihistamines may also help. Because the airway is vulnerable to compromise as a result of severe edema, intubation to protect the airway is sometimes indicated. Meanwhile, measures should be taken to calm the patient and help to slow their respirations. Pulse oximetry is important. Because different ambulances have different capabilities, it is important to ask for emergency medical services for possible airway obstruction.

APPROACH TO:

Anaphylaxis

DEFINITIONS

ANAPHYLACTOID REACTIONS: Similar clinical picture to anaphylaxis with cutaneous, respiratory, cardiovascular, and gastrointestinal symptoms but not caused by immunologic mechanisms (eg, adverse reaction to iodinated contrast material).

ANAPHYLAXIS: Syndrome with varied mechanisms, clinical presentations, and severity that is an acute life-threatening reaction resulting from a type I hypersensitivity reaction (HSR), which is an IgE-mediated activation of mast cells. Mast cell degranulation results in release of histamine, interleukins, and other inflammatory mediators.

ANGIOEDEMA: Swelling of the lips, periorbital region, face, hands, or feet.

ARTHUS REACTION: An example of a type III HSR caused by the development of antigen-antibody immune complexes at the local site of injection of antigens into the skin, which presents with hemorrhage and significant edema.

TYPE I HYPERSENSITIVITY REACTION: IgE-mediated allergic response to environmental antigens.

TYPE II HYPERSENSITIVITY REACTION: IgM- or IgG-mediated damage to cells by either phagocytosis or activation of complement. Examples include autoimmune hemolytic anemia, immune thrombocytopenic purpura, hemolytic disease of the fetus and the newborn, and Goodpasture syndrome.

TYPE III HYPERSENSITIVITY REACTION: IgM- or IgG-mediated reaction with soluble antigens to form antibody-antigen complexes. The complexes activate complement, leading to release of chemotactic factors to attract neutrophils and induce inflammation and subsequent tissue damage. Examples include serum sickness and Arthus reaction.

TYPE IV HYPERSENSITIVITY REACTION: Mediated by T cells and monocytes and/or macrophages. Symptoms take a few days to manifest. Also referred to as delayed-type or cell-mediated HSR. Examples include the tuberculin skin test and poison ivy exposure.

URTICARIA: Heterogeneous, self-resolving skin reaction presenting with pruritic wheals characterized by central swelling and epidermal erythema surrounding the wheals. It usually takes about 24 hours but can take up to 48 hours to resolve without scarring the skin.

CLINICAL APPROACH

Pathophysiology

Common causes of anaphylaxis include drugs, Hymenoptera stings (bees, wasps), radiographic contrast media (anaphylactoid), blood products, latex in medical products, allergen immunotherapy injections, and foods. The most common cause of drug-related anaphylaxis is beta-lactam antibiotics such as penicillin. The most common cause of food-related anaphylaxis is peanuts, partly because of the frequency with which peanut products are included in other types of foods. In fact, peanut allergy has doubled in incidence in Western countries. A recent randomized trial suggested that introducing peanut products before the age of 1 seemed to decrease the development of peanut allergy (13.7% control vs 1.9% early exposure). It is important to note that almost any agent that can activate mast cells or basophils can cause an anaphylactic reaction. Approximately one-third of all cases of anaphylaxis are idiopathic.

History of Penicillin Allergy. Penicillin is the most common medication associated with anaphylaxis, reported by 10% of patients. Many reported “allergies” are actually adverse effects such as rashes or nausea and not IgE-mediated immediate hypersensitivity. Over time, individuals with true penicillin allergy may no longer have reactions. Careful history taking is important when a patient reports a penicillin allergy, including whether there were hives, throat tightening, swelling of the lips or mouth, or difficulty breathing. When the use of penicillin is critical and the history is unclear, the use of skin testing may be helpful.

When a patient reports a history highly suggestive of anaphylaxis, penicillin and cephalosporins should be avoided. When the history is suggestive of a non-IgE adverse effect, then a beta-lactam may be used, especially cephalosporin (since there is only about 10% cross-reactivity). When the history is unclear, penicillin skin testing may be helpful. If skin testing is unavailable, penicillin generally should be avoided, but cephalosporins are probably acceptable given the small cross-reactivity. When penicillin is the only choice in someone with known previous allergic reactions, desensitization protocols administered by pharmacists are viable options. This is the case for pregnant women or patients with AIDS in need of treatment for neurosyphilis.

Differential Diagnosis. Other considerations in the differential diagnosis of anaphylaxis include erythema multiforme major and minor. Erythema multiforme minor often occurs after herpes simplex virus (HSV) or other infections. It manifests as urticarial or bullous skin lesions. The pathognomonic finding is a target lesion, described as a lesion that is centrally inflamed but is surrounded by an area of less inflamed skin. Treatment includes management of the underlying cause when known, withdrawal of suspected causative drugs, and acyclovir if HSV involvement is suspected. Erythema multiforme major (Stevens-Johnson syndrome [SJS]) is similar to erythema multiforme minor but is more severe and involves two or more mucosal surfaces. It is also more likely to be induced by drugs such as sulfonamides or nonsteroidal anti-inflammatory drugs (NSAIDs). Skin findings may include petechiae, vesicles, bullae, and some desquamation of the skin. If the epidermal detachment involves less than 10% of the skin, it is considered SJS. If the epidermal detachment involves more than 30% of the skin, it is considered toxic epidermal necrolysis (TEN). Between 10-30% skin affected is considered the SJS/TEN overlap condition. Other symptoms include fever, headache, malaise, arthralgias, corneal ulcerations, arrhythmias, pericarditis, electrolyte abnormalities, seizures, coma, and sepsis.

Treatment involves withdrawal of the suspected offending agent, treatment of concurrent infections, aggressive fluid resuscitation and maintenance, and supportive treatment similar to burn care. Use of corticosteroids is controversial, but they are often prescribed.

Other Types of Drug Reactions. Most drug rashes are maculopapular and occur several days after starting treatment with an offending drug. They usually are not associated with other signs and symptoms, and they resolve several days after removal of the offending agent. Serum sickness, on the other hand, is an allergic reaction that occurs 7 to 10 days after primary administration, or 2 to 4 days after secondary administration, of a foreign serum or a drug (ie, a heterologous protein or a nonprotein drug). It is characterized by fever, polyarthralgia, urticaria, lymphadenopathy, and sometimes glomerulonephritis. It is a type III HSR, caused by the formation of immune complexes of IgG and the offending antigen. Treatment is based on symptomatology, as the disease usually is self-limiting. Treatment may include administration of antihistamines, aspirin, or NSAIDs and therapy for the underlying disease.

Finally, several other types of drug reactions do not fit into the categories discussed. Two of the most important types are iodine allergy and anticonvulsant drug hypersensitivity. “Iodine allergy” is often associated with radiologic contrast media. Reactions to contrast media are the result of the hyperosmolar dye causing degranulation of mast cells and basophils rather than a true allergic reaction. These reactions can be prevented by pretreatment with diphenhydramine, H2 blockers, and corticosteroids beginning 12 hours before the procedure. There is no evidence that a history of seafood allergy is related to adverse events from radiocontrast media. Phenytoin and other aromatic anticonvulsants have been associated with a hypersensitivity syndrome characterized by a severe idiosyncratic reaction, including rash and fever, often with associated hepatitis, arthralgias, lymphadenopathy, or hematologic abnormalities. The skin manifestations can range from skin rash to TEN. This reaction is not IgE mediated, and the exact mechanism remains unclear. Treatment is supportive, with withdrawal of the offending agent.

Clinical Presentation

The clinical presentation of anaphylactic reactions varies greatly, but the following guidelines are a good rule of thumb. Symptoms usually develop within 5 to 60 minutes following exposure, although a delayed reaction is possible. Symptoms and signs are variable and are listed in Table 40–1. The key fact to remember is that a true anaphylactic reaction is life threatening. Angioedema may occur with or without urticaria but is not anaphylaxis unless the reaction is associated with other life threatening processes, such as hypotension or laryngeal edema.

Treatment

Treatment of anaphylaxis begins with first assessing the ABCs (airway, breathing, circulation). Intubation, if required, should not be delayed. Second, epinephrine should be administered to help control symptoms and blood pressure. Epinephrine acts on alpha-adrenergic receptors and induces vasoconstriction, thus reversing peripheral vasodilation induced by inflammatory mediators and alleviating hypotension, angioedema, erythema, and urticaria. Epinephrine also acts on beta-adrenergic receptors, inducing bronchodilation, preventing further mast cell and basophil release of inflammatory mediators, and increasing myocardial contractility and cardiac output. Intramuscular epinephrine injected in the anterolateral thigh (vastus lateralis) leads to more rapid and higher peak levels than do subcutaneous or deltoid intramuscular injection. High doses of epinephrine are recommended because low doses can lead to increased release of inflammatory mediators, vasodilation, and hypotension. Intravenous epinephrine is reserved for patients with anaphylaxis unresponsive to intramuscular administration due to risk of myocardial infarction and fatal arrhythmias.

Corticosteroids are also frequently used in the treatment of anaphylaxis. Their role is unclear, but studies have shown that they decrease length of hospitalization, although they do not reduce the number of visits to the emergency department. The benefits of corticosteroids are thought to include inhibition of platelet and neutrophil aggregation and synthesis of inflammatory mediators, as well as increased response to beta-adrenergic agonists.

Additional treatment measures include placing the patient in a recumbent position, elevating the legs, administration of oxygen as needed, normal saline (NS) volume replacement and/or use of vasopressors as required, and administration of diphenhydramine 50 mg orally or intravenously every 4 hours as needed (Table 40–2).

CASE CORRELATION

• See also Case 41 (Urinary Tract Infection and Sepsis in the Elderly) and Case 42 (Vascular Catheter Infection in a Patient With Neutropenic Fever).

COMPREHENSION QUESTIONS

40.1 A 55-year-old accountant complains of facial and tongue swelling. He recently started using a new bath soap. His medical problems include osteoarthritis and hypertension, for which he takes acetaminophen and lisinopril, respectively. Which of the following is the most likely etiology?

A. Lisinopril

B. Soap hypersensitivity

C. Hypothyroidism

D. Acetaminophen

E. Food-related allergy

40.2 An 18-year-old man with epilepsy controlled with medication develops fever, lymphadenopathy, a generalized maculopapular rash, elevated transaminases, and arthralgias. He reports having been bitten by ticks while working in the yard outside. Which of the following is the most likely etiology?

A. Severe poison ivy dermatitis

B. Reaction to anticonvulsant medication

C. Acute human immunodeficiency virus (HIV) infection

D. Lyme disease

40.3 A 34-year-old man is brought to the emergency department for a severe allergic reaction caused by fire ant bites. He is treated with intramuscular epinephrine and intravenous corticosteroids. His oxygen saturation falls to 80%, and he becomes apneic. Which of the following is the best next step?

A. Intravenous diphenhydramine

B. Intravenous epinephrine

C. Oxygen by nasal cannula

D. Endotracheal intubation

E. Electrical cardioversion

40.4 A 57-year-old woman with congestive heart failure has a positive cardiac stress test. Cardiac catheterization is required to evaluate for coronary bypass grafting. She states that she has an allergy to iodine. Which of the following is the best next step?

A. Desensitization with increasing doses of oral iodine

B. Infusion of diphenhydramine during the procedure

C. Cancel the procedure and proceed to surgery

D. Diphenhydramine and corticosteroids the night before the procedure

ANSWERS

40.1 A. Angiotensin-converting enzyme (ACE) inhibitors are often associated with angioedema. Angioedema secondary to ACE inhibitors can occur at any subsequent point during use, not solely after the initial doses. Reactions to exogenous agents such as soap (answer B) typically result from a type IV HSR and usually present as a skin rash. Causes of anaphylactic reactions include drugs (answer D) and food (answer E). A true anaphylactic reaction is life threatening; it may present with angioedema with or without urticaria, but it also presents with other life threatening processes, such as hypotension. Drug allergies may present as an anaphylactic reaction or a drug rash; most drug rashes are maculopapular and occur several days after starting treatment with an offending drug and resolve with discontinuation of the drug. Hypothyroidism (answer C) is an autoimmune disease process most commonly caused by autoantibodies against thyroid peroxidase, thyroglobulin, and/or TSH receptors.

40.2 B. This is a common presentation of hypersensitivity syndrome associated with aromatic anticonvulsants (phenytoin, carbamazepine, phenobarbital). Poison ivy (answer A) is not associated with fever and lymphadenopathy. Lyme disease (answer D) is associated with erythema migrans, an erythematous annular rash with a central clearing (target lesion) developing within days of infection. HIV (answer C) is a less likely answer considering that a history of risk factors is not being presented.

40.3 D. This patient has developed airway obstruction due to an anaphylactic reaction. He requires intubation and mechanical ventilation to maintain oxygenation. The first step in treating anaphylaxis is assessing the ABCs. Intubation, if required, should not be delayed. Second, epinephrine (answer B) should be administered to help control symptoms and blood pressure. Additional treatment measures include placing the patient in a recumbent position, elevating the legs, administration of oxygen as needed (answer C), NS volume replacement and/or use of vasopressors as required, and administration of diphenhydramine 50 mg orally or intravenously every 4 hours as needed (answer A). Electrical cardioversion (answer E) is not indicated in the treatment of anaphylaxis.

40.4 D. Pretreatment with diphenhydramine, H2 blockers, and corticosteroids beginning 12 hours before the procedure greatly decreases the reaction to contrast dye. For patients presenting with clinical indication for rapid imaging, premedication should be given at least 5 hours prior to contrast administration (answer B). Therefore, there is no need to cancel the procedure and proceed with surgery (answer C). Desensitization (answer A) is not an appropriate treatment course since radiocontrast allergy is not a true allergic reaction.

CLINICAL PEARLS

▶ Anaphylaxis is characterized by respiratory distress caused by bronchospasm, cutaneous manifestations such as urticaria or angioedema, and gastrointestinal hypermotility. Patients may die as a consequence of air-way compromise or vascular collapse caused by widespread vasodilation.

▶ Treatment of anaphylaxis is immediate epinephrine, antihistamines, air-way protection, and blood pressure support as necessary. Corticosteroids may help prevent late recurrence of symptoms.

▶ Epinephrine is the immediate drug of choice in treating anaphylaxis.

▶ Serum sickness is an immune complex-mediated disease that may include fever, cutaneous eruptions, lymphadenopathy, arthritis, and glomerulonephritis. It usually is self-limited, but treatment may be necessary for renal complications.

▶ Erythema multiforme minor is characterized by urticarial or bullous eruptions, often with target lesions, usually following HSV infections. Erythema multiforme major (SJS) usually is caused by drugs and includes cutaneous and mucosal involvement.

REFERENCES

Austen KF. Allergies, anaphylaxis, and systemic mastocytosis. In: Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 19th ed. New York, NY: McGraw Hill; 2015;2707-2718. 

Brown AF. Anaphylactic shock: mechanisms and treatment. J Accid Emerg Med. 1995;12(2):89-100. 

CT and x-ray contrast guidelines: allergies and premedication. UCSF Department or Radiology & Biomedical Imaging. San Francisco, CA: UCSF. https://radiology.ucsf.edu /ct-and-x-ray-contrast-guidelines-allergies-and-premedication. Accessed August 10, 2019. 

Du Toit G, Roberts G, Sayre PH, et al. Randomized trial of peanut consumption in infants at risk for peanut allergy. N Engl J Med. 2015;372:803-815. 

Fine LM, Bernstein JA. Guideline of chronic urticaria beyond. Allergy Asthma Immunol Res. 2016;8(5):396-403. 

Grover VK, Babu R, Bedi SPS. Steroid therapy—current indications in practice. Indian J Anaesth. 2007;51(5):389-393. 

Gruchalla RS, Pirmohamed M. Antibiotic allergy. N Engl J Med. 2006;354:601-609. 

Kemp SF, Lockey RF, Simons FER; World Allergy Organization and hoc Committee on Epinephrine in Anaphylaxis. Epinephrine: the drug of choice for anaphylaxis—a statement of the World Allergy Organization. Allergy. 2008;63(8):1061-1070. 

Liyanage CK, Galappatthy P, Seneviratne SL. Corticosteroids in management of anaphylaxis; a systematic review of evidence. Eur Ann Allergy Clin Immunol. 2017;49(5):196-207. 

McLean-Tooke APC, Bethune CA, Fay AC, Spickett GP. Adrenaline in the treatment of anaphylaxis: what is the evidence? BMJ. 2003;327(7427):1332-1335. 

Roujeau JC, Stern RS, Wintroub BU. Cutaneous drug reactions. In: Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 19th ed. New York, NY: McGraw Hill; 2015:343-349. 

Sampson HA. Peanut allergy. N Engl J Med. 2002;346:1294-1299. 

Trcka J, Schmidt C, Seitz CS, Brocker EB, Gross GE, Trautmann A. Anaphylaxis to iodinated contrast material: nonallergic hypersensitivity or IgE-mediated allergy? AJR Am J Roentgenol. 2008;190(3):666-670. 

Valliant AA, Zito PM. Immediate hypersensitivity reactions. In: StatPearls [Internet]. Treasure Island, FL: StatPearls; 2019. https://www.ncbi.nlm.nih.gov/books/NBK513315/. Accessed April 22, 2020. 

Vittorio CC, Muglia JJ. Anticonvulsant hypersensitivity syndrome. Arch Intern Med. 1995;155:2285-2290. 

Wood JP, Traub SJ, Lipinski C. Safety of epinephrine for anaphylaxis in the emergency setting. World J Emerg Med. 2013;4(4):245-251.

HomeInternal Medicine Case FileAnaphylaxis/Drug Reactions Case File