ANAPHYLAXIS

An acute, often explosive, IgE-mediated systemic reaction that occurs in a previously sensitized person who receives the sensitizing antigen.

Anaphylaxis occurs when antigen (proteins, polysaccharides, or haptens coupled with a carrier protein) reaches the circulation. The most common causative antigens are parenteral enzymes, blood products, beta-lactam antibiotics and many other drugs, allergen immunotherapy (desensitization), and insect stings. beta-blockers, even as eyedrops, may aggravate anaphylactic reactions. Anaphylaxis can be aggravated or even induced de novo by exercise, and some patients have recurrent symptoms for no identifiable reason. Histamine, leukotrienes, and other mediators are generated or released when the antigen reacts with IgE on basophils and mast cells. These mediators cause the smooth muscle contraction (responsible for wheezing and GI symptoms) and vascular dilation that characterize anaphylaxis. Vasodilation and escape of plasma into the tissues causes urticaria and angioedema and results in a decrease in effective plasma volume, which is the major cause of shock. Fluid escapes into the lung alveoli and may produce pulmonary edema. Obstructive angioedema of the upper airway may also occur. Arrhythmias and cardiogenic shock may develop if the reaction is prolonged.

Anaphylactoid reactions are clinically similar to anaphylaxis, but may occur after the first injection of certain drugs (polymyxin, pentamidine, opioids) and contrast media. They have a dose-related, toxic-idiosyncratic mechanism rather than an immunologically mediated one. Aspirin and other NSAIDs can cause reactions in susceptible patients.

Symptoms and Signs

Symptoms vary, and rarely does any one patient develop all the symptoms. Typically, in 1 to 15 min (but rarely after as long as 2 h), the patient feels uneasy, becomes agitated and flushed, and complains of palpitations, paresthesias, pruritus, throbbing in the ears, coughing, sneezing, urticaria and angioedema, and difficulty breathing owing to laryngeal edema or bronchospasm. Nausea, vomiting, abdominal pain, and diarrhea are less common. Shock may develop within another 1 or 2 min, and the patient may convulse, become incontinent, become unresponsive, and die. Primary cardiovascular collapse can occur without respiratory symptoms. Recurrent episodes of anaphylaxis in the same person are usually characterized by the same symptoms.

Prophylaxis

Patients with the greatest risk of drug anaphylaxis are those who have reacted previously to that drug, but anaphylactic death may occur without such a history. Since the risk of a reaction to xenogenic antiserum is high, routine skin testing before giving the serum is mandatory, and prophylactic measures may be needed. Routine skin testing before other drug treatment is neither practicable nor reliable, except perhaps for penicillin therapy.

Long-term immunotherapy (desensitization) is effective and appropriate in preventing anaphylaxis from insect stings, but it has rarely been tried in patients with a history of drug or serum anaphylaxis. Instead, if treatment with a drug or serum is essential, rapid desensitization must be performed under controlled conditions.

A patient with a previous anaphylactoid reaction to an x-ray contrast agent can be given the agent again with reasonable safety (if its use is essential) by pretreatment with prednisone 50 mg po q 6 h for 3 doses, diphenhydramine 50 mg po 1 h beforehand, and ephedrine (if not contraindicated) 25 mg po 1 h beforehand for adults. The use of iso-osmotic contrast media is preferred as an additional safety measure.

Treatment

Immediate treatment with epinephrine is imperative. Epinephrine is an antagonist to the effects of the chemical mediators on smooth muscle, blood vessels, and other tissues.

For mild reactions (eg, generalized pruritus, urticaria, angioedema, mild wheezing, nausea, and vomiting), 0.01 mL/kg aqueous epinephrine 1:1000 sc (usual dose 0.3 to 0.5 mL in adults) should be given. If an antigen injected into an extremity caused the anaphylaxis, a tourniquet should be applied above the injection site and 1/2 of the above dose of epinephrine also injected into the site to reduce systemic absorption of the antigen. A second injection of epinephrine subcutaneously may be needed. After symptoms resolve, an oral antihistamine should be given for 24 h.

For more severe reactions, with massive angioedema but without evidence of cardiovascular involvement, adult patients should be given diphenhydramine 50 to 100 mg IV in addition to the above treatment to forestall laryngeal edema and to block the effect of further histamine release. When the edema responds, 0.005 mL/kg of an aqueous suspension of long-acting epinephrine 1:200 sc (maximum dose, 0.15 mL) can be given for its 6- to 8-h effect; an oral antihistamine should be given for the next 24 h.

For asthmatic reactions that do not respond to epinephrine, IV fluids should be started, and (if the patient is not on theophylline) theophylline 5 mg/kg IV can be given over 10 to 30 min, followed by 0.5 mg/kg/h, more or less, to maintain a theophylline blood level of 10 to 20 µg/mL (55 to 110 µmol/L). Endotracheal intubation or tracheostomy may be needed, with O₂ at 4 to 6 L/min.

The most severe reactions usually involve the cardiovascular system, causing severe hypotension and vasomotor collapse. IV fluids should be rapidly infused and the patient should be recumbent with legs elevated. Epinephrine (1:100,000) should be given slowly IV (5 to 10 µg/min) with close observation for development of side effects, including headache, tremulousness, nausea, and arrhythmias. The underlying severe hypotension may be due to vasodilation, hypovolemia from loss of fluid, myocardial insufficiency (rarely), or a combination of these. Each reaction has a specific treatment, and often the treatment of one exacerbates the others. The appropriate therapy may be clarified if central venous pressure (CVP) and left atrial pressure can be measured. A low CVP and normal left atrial pressure indicate peripheral vasodilation and/or hypovolemia. Vasodilation should respond to epinephrine (which will also retard the loss of intravascular fluid).

Hypovolemia is usually the major cause of the hypotension. The CVP and left atrial pressure are both low, and large volumes of saline must be given, with BP monitored until the CVP rises to normal. Colloid plasma expanders (eg, dextran) are rarely necessary. Only if fluid replacement does not restore normal BP should treatment be started cautiously with vasopressor drugs (eg, dopamine, norepinephrine).

Cardiac arrest may occur, requiring immediate resuscitation. Further therapy depends on ECG findings.

When all the above measures have been instituted, diphenhydramine (50 to 75 mg IV slowly over 3 min) may then be given for treatment of slow-onset urticaria, asthma, laryngeal edema, or hypotension. Complications (eg, MI, cerebral edema) should be watched for and treated appropriately. Patients with severe reactions should be observed in the hospital for 24 h after recovery in case of relapse.

Those who had an anaphylactic reaction to an insect sting should carry and use a pre-filled syringe of epinephrine for prompt self-treatment of any future reaction. They should be referred for venom immunotherapy (desensitization).

DISORDERS OF VASOACTIVE MEDIATORS

Disorders with manifestations of vasoactive mediators derived from mast cells and other sources (even though an IgE-mediated or other immunologic mechanism may not be involved).

Urticaria and Angioedema
(Hives; Giant Urticaria; Angioneurotic Edema)

Urticaria is local wheals and erythema in the superficial dermis. Angioedema is a deeper swelling due to edematous areas in the deep dermis and subcutaneous tissue and may also involve mucous membranes.

Etiology

Acute urticaria and angioedema are essentially anaphylaxis limited to the skin and subcutaneous tissues and can be due to drug allergy, insect stings or bites, desensitization injections, or ingestion of certain foods (particularly eggs, shellfish, or nuts). Some reactions occur explosively after ingestion of minute amounts. Others (eg, reactions to strawberries) may occur only after overindulgence and possibly result from direct (toxic) mediator liberation. Urticaria may accompany or even be the first symptom of several viral infections, including hepatitis, infectious mononucleosis, and rubella. Some acute reactions are unexplained, even when recurrent. If acute angioedema is recurrent, progressive, painful rather than pruritic, and not associated with urticaria, a hereditary enzyme deficiency should be considered.

Chronic urticaria and angioedema lasting > 6 wk are more difficult to explain, and only in exceptional cases can a specific cause be found. The reactions are rarely IgE-mediated. Occasionally, chronic ingestion of an unsuspected drug or chemical is responsible; eg, from penicillin in milk; from the use of nonprescription drugs; or from preservatives or other food additives. Chronic underlying disease (SLE, polycythemia vera, lymphoma, or infection) should be ruled out. Though often suspected, controllable psychogenic factors are rarely identified. Urticaria caused by physical agents is discussed under Physical Allergy, below. A few patients with intractable urticaria have thyroid disease. Occasionally, urticaria may be the first or only visible sign of cutaneous vasculitis.

Symptoms and Signs

In urticaria, pruritus (generally the first symptom) is followed shortly by the appearance of wheals that may remain small (1 to 5 mm) or enlarge. The larger ones tend to be clear in the center and may be noticed first as large rings (> 20 cm across) of erythema and edema. Ordinarily, crops of hives appear and subside; a lesion may remain in one site for several hours, then disappear, only to reappear elsewhere. If a lesion persists >= 24 h, the possibility of vasculitis should be considered.

Angioedema is characterized by a more diffuse and painful swelling of loose subcutaneous tissue, dorsum of hands or feet, eyelids, lips, genitalia, and mucous membranes. Edema of the upper airways may produce respiratory distress, and the stridor may be mistaken for asthma.

Diagnosis

The cause of acute urticaria or acute angioedema is usually obvious. Even when it is not, diagnostic tests are seldom required because of the self-limited, nonrecurrent nature of these reactions. In chronic urticaria, an underlying chronic disease should be ruled out by a detailed history and physical examination and routine screening tests. Eosinophilia is uncommon in urticaria. Other tests (eg, stool examination for ova and parasites, serum complement, antinuclear antibody, and sinus or dental x-rays) are not helpful without additional clinical indications.

Treatment

Since acute urticaria generally subsides in 1 to 7 days, treatment is chiefly palliative. If the cause is not obvious, all nonessential drugs should be stopped until the reaction has subsided. Symptoms usually can be relieved with an oral antihistamine, such as diphenhydramine 50 to 100 mg q 4 h, hydroxyzine 25 to 100 mg bid, or cyproheptadine 4 to 8 mg q 4 h. If these cause drowsiness (which occurs in a minority of patients), one of the nonsedating antihistamines should be used.
A glucocorticoid (eg, prednisone 30 to 40 mg/day po) may be needed for more severe reactions, especially when associated with angioedema. Topical glucocorticoids are of no value. Epinephrine 1:1000, 0.3 mL sc, should be the first treatment for acute pharyngeal or laryngeal angioedema. This may be supplemented with a nebulized beta-agonist (eg, albuterol) and an IV antihistamine (eg, diphenhydramine 50 to 100 mg). This usually prevents airways obstruction, but intubating or performing a tracheostomy and administering O₂ might be necessary.

In chronic urticaria, spontaneous remissions occur within 2 yr in about 1/2 of cases. Control of stress often helps reduce the frequency and severity of episodes. Certain drugs (eg, aspirin) may aggravate symptoms, as will alcohol, coffee, and tobacco smoking; if this occurs, they should be avoided. When urticaria is brought on by aspirin, sensitivity to NSAIDs and to tartrazine (a food- and drug-coloring additive) should be investigated.

Oral antihistamines with a tranquilizing effect are usually beneficial (eg, for adults, hydroxyzine 25 to 50 mg bid or cyproheptadine 4 to 8 mg q 4 to 8 h; for children, hydroxyzine 2 mg/kg/day divided q 6 to 8 h, and cyproheptadine 0.25 to 0.5 mg/kg/day divided q 8 to 12 h). Doxepin 25 to 50 mg bid may be the most effective drug for some adults. Often, H₂ blockers (such as ranitidine 150 mg bid) are added. All reasonable measures should be tried before initiating glucocorticoids, because glucocorticoids may have to be continued indefinitely.