ANAPHYLAXIS from Cecil Textbook of Medicine

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Goldman: Cecil Textbook of Medicine, 21st ed., Copyright © 2000 W. B.

Saunders Company

Chapter 275 - ANAPHYLAXIS

P. Kaplan

The term anaphylaxis arose from the experiments of Richer and Portier in the

early 1900s and meant the opposite of prophylaxis, i.e., a lack of

protection rather than the expected immunity. Nevertheless, the reaction is

indeed immune in nature and depends on the formation of IgE antibody, the

immunoglobulin responsible for typical allergic reactions. The initial

sensitization step induces the formation of IgE specifically directed to the

initiating substance. In anaphylaxis, the reaction is systemic in nature,

occurs rapidly after the administration of minute concentrations of the

offending material, and is potentially fatal. How the allergen is given can

dictate the manifestations and magnitude of the ensuing allergic reaction;

although all routes can lead to anaphylaxis, parenteral administration is

more likely than inhaled or ingested allergens to cause elevated circulating

levels of unaltered allergen and a systemic reaction. Thus parenteral

administration of medication and insect sting reactions (injected into

cutaneous vessels) are among the most common causes of anaphylaxis.

Anaphylactoid reactions are defined as systemic reactions that have the same

symptoms as anaphylaxis but are not due to an IgE-dependent mechanism and

are not usually immune. Examples include reactions to radiographic contrast

agents and non-steroidal anti-inflammatory drugs (e.g., acetylsalicylic

acid, indomethacin, ibuprofen).

EPIDEMIOLOGY AND ETIOLOGY.

The occurrence of anaphylaxis in the early 1900s was largely due to the use

of serum from animals immunized with various toxins or bacteria to treat

human illness. Most were due to diphtheria antitoxin injection. In the

antibiotic era, penicillin and sulfa drugs have become the leading causes of

fatal anaphylaxis. In recent years, between 100 and 500 deaths per year in

the United States have been attributed to penicillin. The insect order

Hymenoptera is responsible for about 40 deaths each year and is estimated to

cause 1 significant reaction per 10,000 individuals per year, with a

mortality of 0.2 per million in the United States. Estimates of

penicillin-induced anaphylaxis are 10 to 40 per 100,000 injections. Most

recently, allergy to the latex in surgical gloves has been seen in health

care workers or patients undergoing frequent procedures, e.g., children with

meningomyelocele, spina bifida, or congenital urogenital anomalies.

Although a history of atopy (allergic rhinitis, extrinsic asthma, atopic

dermatitis) might be expected to be associated with an increased likelihood

of anaphylactic reactions, atopic individuals appear to have, at worst, only

a slightly greater risk than non-atopics do. Thus anyone can have an IgE

response and clinical symptoms to the agents responsible for anaphylaxis. In

addition, no evidence has shown that race, gender, age, occupation, or

season intrinsically predisposes an individual to anaphylaxis.

Proteins, polysaccharides, and haptens are capable of eliciting systemic

reactions in humans (Table 275-1) . Proteins are the largest and most

diverse group and include antiserum, hormones, seminal plasma, enzymes,

latex, Hymenoptera venom (e.g., phospholipase A2 ), pollen allergens

administered for immunotherapy ( " allergy shots " ), and foods. Polysaccharides

such as dextrans are rarer causes. The most common etiologic agents are

low-molecular-weight drugs, which are not antigenic themselves but act as

haptens and become antigenic on reaction with host proteins. Such drugs

include antibiotics, local anesthetics, vitamins, and diagnostic reagents.

Food-induced anaphylaxis and anaphylactic reactions to an orally

administered drug can occur in very sensitive individuals.

TABLE 275-1 -- AGENTS CAUSING ANAPHYLAXIS

TYPE COMMON RARE

Proteins Venom (Hymenoptera) Hormones, (insulin, ACTH, vasopressin,

parathormone)

Pollen (ragweed, grass, etc.) Enzymes (trypsin, penicillinase)

Food (eggs, seafood, nuts, grains, beans, cottonseed oil, chocolate) Human

proteins (serum proteins, seminal fluid)

Horse and rabbit serum (antilymphocyte globulin)

Latex

Haptens and other low-molecular-weight substances Antibiotics (penicillins,

sulfonamides, cephalosporins, tetracyclines, amphotericin B, nitrofurantoin,

aminoglycosides) Vitamins (thiamine, folic acid)

Local anesthetics (lidocaine, procaine, etc.)

Polysaccharides Dextrans, iron-dextran

ACTH = adrenocorticotropic hormone.

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CLINICAL MANIFESTATIONS.

IgE-mediated reactions can cause symptoms involving the cutaneous,

respiratory, cardiovascular, gastrointestinal, and hematologic systems (Fig.

275-1) . The onset and manifestations vary according to the route of

administration, dose, release of and sensitivity to vasoactive substances,

and differing sensitivities of the organs to these substances. These

parameters can vary from person to person, and individuals tend to react in

a characteristic pattern. The initial manifestations can begin in seconds or

take as long as an hour to develop; in severe reactions the onset usually

occurs within 5 to 10 minutes of exposure. Initial manifestations often

include skin erythema, pruritus, a generalized feeling of warmth and/or

impending doom, light-headedness, shortness of breath, nausea, vomiting, or

a lump in the throat. Urticaria is the most common manifestation of

anaphylaxis. The rash is generalized and intensely pruritic and consists of

well-circumscribed, erythematous, raised wheals with serpiginous borders and

blanched centers. Angioedema may accompany urticaria and is typically

manifested as swelling of the face, eyes, lips, tongue, pharynx, or

extremities. The respiratory tract is commonly involved in fatal

anaphylaxis. The early stages of upper airway edema consist of hoarseness,

stridor, and/or dysphoria. Angioedema of the epiglottis and larynx can cause

mechanical obstruction and death by suffocation. The swelling can extend to

the hypopharynx and trachea. Between 25 and 50% of patients dying of

anaphylaxis have pathologic changes consistent with severe asthma. Pulmonary

hyperinflation, peribronchial congestion, submucosal edema, edema-filled

alveoli, and eosinophilic infiltration are noted. The patient experiences

shortness of breath, chest tightness, and wheezing. Severe hypoxemia and

hypercapnia can occur rapidly.

Cardiovascular collapse is among the most severe clinical manifestations of

anaphylaxis. The exact extent of fatal anaphylaxis is unknown inasmuch as

anaphylaxis can be associated with myocardial ischemia and ventricular

arrhythmias, each of which can cause or be caused by hypotension. Decreased

blood pressure may be caused by diffuse peripheral vasodilatation from the

release of vasodilatory mediators, decreased effective blood volume

secondary to leakage of fluid into tissues, hypoxemia, or primary cardiac

dysfunction.

Gastrointestinal manifestations can include nausea, vomiting, cramps, and

diarrhea. Central nervous system abnormalities can include delirium and

seizures, each of which may be due to hypoxemia and/or hypotension.

DIFFERENTIAL DIAGNOSIS.

The diagnosis of systemic anaphylaxis may be obvious when a typical history

of antecedent exposure to foreign antigenic material and a sequence of

events consistent with the syndrome are present. Confirmation usually

requires demonstration of IgE antibody to the substance by skin or

radioallergosorbent testing. When a history of exposure is absent or when

only a portion of the full syndrome is present, it may be difficult to

exclude a vascular, cardiac, or neurologic disorder. Possibilities to be

considered include acute myocardial infarction, pulmonary embolism, acute

asthma, hereditary angioedema, the exercise-induced anaphylactic syndrome,

cold urticaria, seizure disorder, anaphylactoid or idiosyncratic reaction,

transfusion reaction, or vasovagal reaction. Vasovagal reactions may occur

after an injection (e.g., penicillin, lidocaine [Xylocaine]) and include

symptoms such as pallor, sweating, bradycardia, nausea, and hypotension,

which can be confused with anaphylaxis. No cutaneous manifestations or

evidence of respiratory difficulty is present, and the diagnosis hinges on

the cause of the hypotension. In such instances, skin testing is negative.

Hereditary angioedema is due to the absence or dysfunction of C1 inhibitor

and is associated with laryngeal edema, peripheral angioedema, and acute

abdominal pain. It is typically an autosomal dominant disorder with a family

or prior history of typical episodes. Trauma and infections may precipitate

attacks of swelling. Patients with cold urticaria may have systemic symptoms

caused by water immersion, such as while swimming; diffuse urticaria,

angioedema, and hypotension may ensue. Anaphylactoid reactions can occur to

substances causing direct non-immune release of mast cell products (opiates,

tubocurare, dextrans, sulfobromophthalein), which can induce urticaria,

angioedema, chest tightness, wheezing, and hypotension. Aspirin and other

non-steroidal agents can cause upper and lower airway obstruction,

urticaria, and/or angioedema with no IgE involvement. These agents all

inhibit prostaglandin synthetase (cyclooxygenase) and shunt arachidonate

toward leukotriene synthesis. IgG-anti-IgA immune complexes may cause

anaphylaxis-like symptoms when IgA-deficient patients receive blood.

Complement activation appears to have a major role in such instances.

Finally, radiocontrast media reactions occur in about 1% of patients when

such agents are used. The mechanism is unknown but may relate to their

osmolarity. Newer agents seem to markedly diminish the incidence. A syndrome

of recurrent, apparently spontaneous episodes of anaphylaxis without an

identifiable exogenous agent is known as " idiopathic anaphylaxis. "

PATHOGENESIS.

Antigenic induction of IgE formation requires antigenic processing (see

Chapter 270) by dendrite cells or macrophages, T-cell help, and switching of

B lymphocytes from IgG synthesis to IgE synthesis. Interleukin-4 and

interleukin-13 are critical for the latter switch and function as T-cell

helper factors for IgE formation. Subsequent combination of antigen with IgE

bound

Figure 275-1 Acute anaphylaxis.

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to high-affinity receptors on mast cells and basophils (see Fig. 280-2)

causes the secretion of a variety of vasoactive substances that may be

responsible for the symptoms of anaphylaxis (see Fig. 275-1) . These

substances include histamine, prostaglandin D2 , leukotrienes C4 and D4 ,

and platelet activating factor

(1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine). Histamine is the major

secretory product of basophils and mast cells. It causes venular and

arterial vasodilation, increases vascular permeability, and causes a

decrease in diastolic blood pressure when systemic levels of approximately

2.5 ng/mL are reached. Histamine has direct inotropic and chronotropic

action when injected directly into cardiac muscle, effects that are

prevented by H1 - plus H2 -receptor antagonists. Prostaglandin D2 is

synthesized by mast cells but not by basophils. It is a peripheral

vasodilator. Leukotrienes C4 and D4 are produced by basophils and mast cells

and profoundly constrict the peripheral arterial and coronary circulation

and cause bronchoconstriction and decreased dynamic compliance. They also

cause venular dilation and increase vascular permeability. Platelet

activating factor is synthesized by mast cells but not basophils and causes

venular dilatation and an increase in cutaneous vascular permeability. When

infused into rabbits, it causes profound hypotension. Tryptase, a mast cell

granule constituent released with histamine, can be assayed in blood as an

indicator of anaphylaxis.

Bradykinin is a nine-amino acid peptide that may also contribute to the

symptoms of anaphylaxis and is generated by kininogen cleaved by enzymes

known as kallikreins. Kinins are peripheral vasodilators, cause systemic

hypotension, and constrict coronary vessels. Basophils and mast cells have a

kallikrein-like enzyme; organs containing glands (lung, nasal mucosa)

secrete a tissue kallikrein that digests low-molecular-weight kininogen to

release bradykinin. Plasma kinin formation is associated with contact

activation of Hageman factor, conversion of plasma prekallikrein to

kallikrein, and digestion of high-molecular-weight kininogen.

Anaphylaxis is associated with depletion of clotting Factors V, VII, and

fibrinogen, activation of complement, and depletion of high-molecular-weight

kininogen, consistent with acute intravascular coagulation. Clotting defects

such as a prolonged partial thromboplastin time are commonly seen.

Activation or depletion of these proteins is probably caused by enzymes

released from cells, including not only mast cells and basophils but also

monocyte-macrophages, eosinophils, and platelets. The latter group of cells

possesses high- and low-affinity receptors for IgE, which may mediate cell

secretion on contact with antigen.

PREVENTION AND TREATMENT.

Patients who have previously experienced anaphylactic episodes should wear a

Medic-Alert bracelet and be instructed regarding the importance of relating

details of their specific drug reactions before taking medications. The

medical history and medical record must include not only the allergic

history but also a description of the associated symptoms. The physician

must be aware of drugs containing cross-reacting antigens. For example,

patients with allergy to sulfa-containing antibiotics should avoid other

sulfa-containing substances such as chlorthiazide diuretics, furosemide,

sulfonylureas, and dapsone.

Fifteen per cent of allergic patients have a reaction if a cephalosporin is

substituted for penicillin because they share the presence of a beta-lactam

ring. Reactions with 2nd- and 3rd-generation cephalosporins may also occur,

but aztreonam is an exception.

When the patient has a history of drug allergy or of taking a drug suspected

of causing a reaction, it is appropriate to substitute another

non-cross-reacting therapeutic agent whenever possible. Penicillin causes

more anaphylactic reactions than any other drug, yet the history of

" allergy " is unreliable because close to 80% of patients with such a history

have negative skin tests to the major determinant (penicillin polylysine) or

a minor determinant mixture (penicillin, penicilloic acid, penicilloylamine)

and can tolerate the drug with impunity. Anaphylaxis is highly associated

with IgE antibody directed to these minor determinants. Thus a negative skin

test to the commercially available major determinant is insufficient testing

to administer the drug given a positive history. The addition of testing for

minor determinants with negative results renders anaphylaxis or even any

allergic reaction rare indeed. Avoidance, in sensitive patients, is the best

approach; nevertheless, in some circumstances the use of penicillin or other

agents by a known or suspected sensitive patient is necessary. In this event

the patient can be desensitized by gradually administering increasing

concentrations of the drug via specific oral/parenteral protocols. Such a

procedure should be carried out by experienced personnel in an intensive

care unit setting in which anaphylactic reactions can be effectively

treated.

If an anaphylactic reaction is encountered, epinephrine given early quickly

reverses most manifestations. When administered at a 1:1000 dilution (0.01

mL/kg with a maximum dose of 0.5 mL subcutaneously repeated every 20 minutes

as necessary), it is initial treatment once an adequate airway is in place.

Further exposure to the inducing substance should be limited. When an

anaphylactic reaction is initiated by an injection into the arm or leg, a

tourniquet may be applied to limit antigen absorption. In the case of a

honeybee sting, care should be taken to remove the stinger without

compressing the venom sac. Upper airway obstruction must be differentiated

from asthma because laryngeal and epiglottic edema may require endotracheal

intubation or emergency tracheostomy to provide an airway. Asthma can be

treated with epinephrine or the administration of an inhaled beta2

-sympathomimetic and/or intravenous aminophylline at a 6-mg/kg loading dose

over a period of 20 to 30 minutes, followed by 0.5 to 1 mg/kg/hour.

If any respiratory, vascular, or cardiac complications occur, an intravenous

line should be placed promptly and a sample of arterial blood obtained for

pH, P O2 , and P CO2 . Supplemental oxygen should be given to reduce

hypoxemia. The pulse, blood pressure, and respiratory rate are monitored,

and an electrocardiogram is obtained. Hypovolemic shock requires rapid

intravenous fluid administration. Additionally, 5 mL of a 1:10,000 solution

of epinephrine repeated every 5 to 10 minutes can be given intravenously to

patients in severe shock. A vasopressor such as dopamine (2 to 20

mug/kg/minute) is indicated to manage hypotension unresponsive to volume

expansion. This approach may increase cardiac output and improve blood flow

to the coronary, cerebral, renal, and mesenteric vascular beds. Higher doses

of dopamine or norepinephrine yield significant alpha-receptor stimulation,

which may increase blood pressure but constrict distal vascular beds. In

case of significant cardiac dysfunction, an arterial line and a Swan-Ganz

catheter should be placed.

Giving antihistamines at the onset of the acute episode may relieve

pruritus, urticaria, and angioedema. Once an intravenous line is placed, 50

to 100 mg of diphenhydramine can be given slowly as a bolus. An H2 -receptor

blocker may aid in the treatment of hypotension. Corticosteroids have no

value during the acute episode, yet steroids are often also administered

intravenously. It takes many hours before their first effect is seen. Thus

administration of steroids helps treat protracted asthma and late reactions

that can ensue 1 to 2 days beyond the initial insult.

Bochner BS, Lichtenstein LM: Anaphylaxis--Current concepts. N Engl J Med

324:1785, 1991. An additional review including approaches to therapy.

Gold M, Swartz JS, Braude BM, et al: Intraoperative anaphylaxis: An

association with latex sensitivity. J Allergy Clin Immunol 87:662, 1991.

Description of an increasingly recognized cause of anaphylactic reactions--

namely, exposure to latex products.

Sampson HA, Mendelson L, Rosen JP: Fatal and near fatal anaphylactic

reactions to foods in children and adolescents. N Engl J Med 327:380, 1992.

Description of dangerous anaphylactic reactions to foods in children,

including the course and confirmation by tryptase assay.

Wasserman SI: Anaphylaxis. In Kaplan AP (ed): Allergy, 2nd ed. Philadelphia,

WB Saunders, 1997, p 565. Textbook review of etiology, pathogenesis, and

treatment.

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