Allergy and Anaphylaxis

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Chapter 75 Allergy and Anaphylaxis

Susan A. Vassallo, MD

1 When was anaphylaxis first described?

In 2641 BC, a wasp from the Hymenoptera order (wasps, bees, ants, sawflies) stung Pharaoh Menes. The events were described in hieroglyphics, and this is believed to be the first recorded death of anaphylaxis. Another important event occurred during a cruise on the yacht of Prince Albert of Monaco when the prince asked Professor Charles Richet to apply his immunology skills in the study of the Portuguese man-of-war (Physalia or jelly). These invertebrates live in the Mediterranean Sea and are highly poisonous. In the early 1900s Richet worked at the Musée Océanographique de Monaco. Along with Paul Portier, he extracted the Physalia poison with glycerol, injected dogs with this mixture, and was able to reproduce the symptoms of Physalia poisoning (1902). He expected a second injection would be harmless, but instead his dogs “showed serious symptoms: vomiting, blood diarrhea, syncope, unconsciousness, asphyxia and death” (Nobel Lecture, 1913). Richet created the word anaphylaxis to describe this phenomenon. Phylaxis is protection in Greek, and the prefix ana implies away from protection. Anaphylaxis therefore means “that state of an organism in which it is rendered hypersensitive, instead of being protected.” Richet was awarded the Nobel Prize in Physiology and Medicine in 1913 for his discovery of anaphylaxis.

2 How often does anaphylaxis occur?

The incidence of anaphylaxis ranges from one to three people per 10,000. This includes allergic reactions to food, drugs, latex, and Hymenoptera. Lethal anaphylaxis probably occurs in 0.65% to 2.0% of recorded allergic events or in one to three per million people.

3 What are the immune mechanisms that lead to anaphylaxis?

The final common pathway for anaphylaxis is mast cell activation and subsequent release of vasoactive mediators—both preformed and newly generated substances. Preformed mediators include histamine and tryptase stored in cell granules. Newly generated mediators are synthesized at the time of antigen exposure and include leukotrienes (LTC4, LTD4, LTE4), prostaglandins (PGD2), platelet-aggregating factor (PAF), and cytokines. In the past, the leukotrienes were not well defined and were simply called “slow-reacting substances of anaphylaxis,” or SRS-A. It is now known that leukotrienes, prostaglandins, and PAF are much more potent bronchoconstrictors than histamine.

4 How are immunologic reactions in anaphylaxis classified?

The Gell and Coombs classification (1963) described four types of immunologic reactions (see Table 75-1). A fifth type of reaction, termed idiopathic, was added to the classification system several years later.

Table 75–1 Gell and Coombs Classification of Immunologic Reactions

Type Description Mediator
I Immediate hypersensitivity IgE usually
II Cytotoxic or cytolytic IgG, IgM
III Immune complex disease Antigen-antibody
IV Delayed hypersensitivity T cells
V Idiopathic Unknown

5 What substances activate mast cells?

image Immunoglobulin (Ig) E (IgE) antibodies. IgE antibodies fixed to mast cell surfaces are cross-linked on exposure to an antigen. This initiates cell degranulation and release of mediators.

image IgG and IgM antibodies. Immunologists have created knockout mice that lack the gene for synthesis of IgE antibody. These mice can still develop anaphylaxis via IgG antibodies and complement.

image Complement-mediated reactions. Complement is the term given to plasma and cell membrane proteins that activate the release of inflammatory mediators. Complement activation occurs as a cascade of reactions. IgG or IgM antibody-antigen binding, heparin-protamine complexes, and radiocontrast dye activate the classic pathway. Endotoxins, certain drugs, and radiocontrast dyes can activate the alternate pathway.

image Activated T cells can stimulate mast cell degranulation in a delayed hypersensitivity reaction.

image Direct mast activation. Direct mast cell activation can occur in the absence of antibody or complement. Drugs such as morphine, vancomycin, and d-tubocurarine can cause histamine release, especially if administered quickly.

image Bradykinin is thought to be involved in the systemic inflammatory response system and in angioedema associated with angiotensin-converting enzyme inhibitors. Kinins can mediate a nonhistamine anaphylactoid reaction. Certain polygeline plasma expanders (e.g., Haemaccel) have been implicated in anaphylactoid reaction during anesthesia.

6 How frequently do neuromuscular blocking drugs (NMBDs) cause anaphylaxis, and what is the mechanism?

NMBDs have long been considered the most common cause of intraoperative anaphylaxis in adults. This is true in all published studies from Australia, New Zealand, the United Kingdom, France, Norway, Belgium, and Spain. These drugs have accounted for 54% to 69% of reactions, depending on the study. Within this drug class, succinylcholine and rocuronium are the most common causes. Succinylcholine is a quaternary ammonium ion and is a flexible molecule that can cross-link two IgE molecules more easily than nondepolarizing muscle relaxants with a rigid backbone (e.g., pancuronium or vecuronium).

There are five important points to remember when considering allergy, anaphylaxis, and NMBDs:

image Quaternary and tertiary ammonium ions are present in many drugs, cosmetics, and food products. Sensitization can occur outside of the operating room, and a serious reaction can occur with first exposure to a NMBD.

image Cross-sensitivity between NMBDs can occur in up to 60% of people.

image NMBDs can cause adverse reactions without IgE antibody mediation. This mechanism of action is via direct mast cell degranulation and release of histamine and other inflammatory mediators. Isoquinolinium compounds such as d-tubocurarine, metocurine, atracurium, and mivacurium are more likely to cause mast cell degranulation.

image Anaphylaxis to NMBDs is rare in the United States but is reported more frequently in Europe, especially France. An important recent paper has challenged the results of previous French skin test studies. This investigation found that undiluted rocuronium and vecuronium extracts produced a positive wheal and flare response in 50% and 40% of nonatopic anesthesia-naïve volunteers, respectively. However, a dilution of 1:1000 did not yield any skin response at 15 minutes. Although their study was small (30 healthy adults), the authors questioned the reliability of skin prick testing with undiluted solutions of rocuronium and vecuronium when making the diagnosis of allergy. An accompanying editorial supported the recommendations for using dilute test extracts and suggested that the incidence of NMBD allergy may be overestimated.

image No demonstrated evidence exists for improved outcomes with preoperative screening of sensitivity to NMBDs.

7 How common are latex allergies?

Although its incidence is decreasing, it is still the second most common cause of intraoperative anaphylaxis in adults. Latex is harvested from the Hevea brasiliensis tree and is used in hundreds of medical products. Latex remains the most common cause of intraoperative anaphylaxis in children. Certain subsets of patients have a higher risk of latex allergy:

image Children with myelodysplasia or bladder exstrophy or children who have had multiple surgeries

image Health care workers exposed to latex

image Atopic individuals who have asthma, allergic rhinitis, and certain food allergies (e.g., bananas, kiwi, avocado)

image Workers in the rubber industry

Latex allergy can present as a type I immediate hypersensitivity reaction mediated by IgE antibodies with the prototypical features of anaphylaxis: hypotension, tachycardia, bronchoconstriction, or cardiovascular collapse. Latex allergy also can present as a type IV T cell–mediated delayed hypersensitivity reaction that is due to chemicals added as accelerators in the manufacture of latex gloves.

8 How often are antibiotics involved in anaphylaxis?

Penicillin is still the most common cause of anaphylaxis among the general population of the United States and the leading cause of death from anaphylaxis; it accounts for a few hundred deaths each year. Most reactions occur in patients with history of prior exposure to penicillin.

Penicillin is a low-molecular-weight drug. Penicillin can produce four types of the reactions described in the Gell and Coombs classification. It is immunogenic only after binding to tissues and forming a protein hapten complex. The β-lactam ring of penicillin opens to form a penicilloyl group, which is termed the major determinant. Derivatives of penicillin are formed in small amounts and are termed minor determinants. IgE antibodies specific for these derivatives also can mediate anaphylaxis to penicillin.

9 How do you treat the patient who reports a reaction to penicillin? Is it safe to administer a cephalosporin?

image Patients with an allergy to penicillin have three times the risk for having anaphylaxis to any other drugs.

image A patient with a history of penicillin allergy should not receive antibiotics with a similar structure (e.g., imipenem).

image A patient with a positive skin test to penicillin should not receive cephalosporins.

image Most patients who report an allergy to penicillin had never been skin tested.

image Some authors suggest that it appears to be safe to administer cephalosporins to patients who claim to be allergic to penicillin. However, no conclusion can be made concerning patients who report severe or anaphylactic reactions to penicillin, because these patients were excluded from studies.

10 How frequent is anaphylaxis to propofol?

The original preparations of propofol contained Cremophor EL and caused hypersensitivity reactions on injection. Today, both the brand and generic formulations contain propofol, soybean oil, glycerol, and sodium hydroxide. The trade brand (Zeneca) contains egg lecithin and the preservative disodium edetate. The generic brand (Baxter) contains egg yolk phospholipid and sodium metabisulfite as a preservative.

Most studies report an incidence of propofol anaphylaxis of 1 in 60,000. One group in France has reported an incidence of 1%. Propofol can cause adverse reactions via IgE antibodies. Occasionally it is associated with nonspecific local histamine release, rash, pruritus, or flushing.

A frequent question regarding propofol is the potential for cross-sensitivity in a patient who is allergic to eggs. The egg lecithin in propofol is purified egg yolk, and most people with egg allergy are sensitive to ovalbumin, the primary protein in egg white. Theoretically, there should be no risk of cross-sensitivity. During phase I trials, propofol was inadvertently given to people with egg allergies without obvious complications. However, the manufacturers of propofol warn that it should not be given to people with egg allergies or soybean allergies. Propofol should not be given to anyone with a history of soybean allergy.

11 How frequent is anaphylaxis to heparin?

Heparin is a large-molecular-weight acidic mucopolysaccharide, and it is derived from bovine or porcine lung. Type 1 IgE immediate hypersensitivity reactions have occurred in humans, although they are rare. More commonly, heparin can induce a thrombocytopenia (HIT), which is mediated by IgG and IgM antibodies directed against platelet factor 4 antigen. This is a delayed adverse reaction usually seen after a few days of heparin therapy. HIT is very rare when low-molecular-weight heparin is used.

12 Are there cases of anaphylaxis to skin and oral disinfectants?

Chlorhexidine is used commonly as a disinfectant before surgery or invasive procedures, including central line placement. Allergy to chlorhexidine is usually mild and limited to cutaneous reactions. In the past few years, reports of intraoperative anaphylaxis to this compound have increased. Typically, hypotension, tachycardia, and cardiovascular collapse occur 24 minutes after application. Because chlorhexidine is also used in toothpastes, mouthwashes, contact lens solutions, and topical antiseptic ointments, significant potential exists for exposure and sensitization to this chemical in the general population.

13 What happens to the patient when anaphylaxis occurs?

Histamine, a preformed mediator, causes vasodilatation, resulting hypotension, and reflex tachycardia. Increased vascular permeability causes edema and urticaria. Cytokines (e.g., tumor necrosis factor), PGD2, the leukotrienes, and PAF are also potent vasodilators.

Bronchoconstriction, increased mucus secretions, and airway edema can occur in varying stages. A patient might complain of rhinitis, dyspnea, wheezing, or agitation. An anesthetized patient might have decreased airway compliance and increased inspiratory pressure.

Vasodilatation causes erythema, and increased vascular permeability can lead to a wheal and flare, which is an area of local edema and redness. In more severe episodes, angioedema can occur. An awake patient might complain of itching, nausea, abdominal pain, or cramping.

14 How should anaphylaxis be treated?

See Box 75-1.

Box 75-1 Management of Anaphylaxis

1. Remove antigen if detected.

2. Administer 100% oxygen.

3. Administer intravenous fluids.

4. Discontinue antibiotic infusion; discontinue blood, fresh frozen plasma, platelet transfusion, if in progress.

5. Adjust epinephrine dose for the clinical scenario:

For bronchospasm: Start at low doses 0.1 to 0.5 mcg/kg IV (or 5-10 mcg), and increase as needed.
For hypotension: Start at 1 to 5 mcg/kg IV, and increase as needed.
For an infusion: Start at 0.05 to 0.1 mcg/kg/min IV (or 0.5-5 mcg/min), and increase as needed.
For cardiac arrest:
Pediatric: 10 mcg/kg (0.1 mL/kg of a 1:10,000 solution)
Adult: 0.5 to 1 mg; titrate to response, as higher doses may be needed

6. Vasopressin can be used when anaphylaxis is refractory to epinephrine therapy. Start with low doses: 5 to 10 units IV, and increase to 40 units if necessary. Infusion: 0.4 units per minute.

7. Secondary therapy: antihistamine

H1: diphenhydramine: 0.5 to 1 mg/kg IV

Optional: H2: ranitidine: 1 mg/kg IV

8. Secondary therapy: steroids (dose for anaphylaxis)

Hydrocortisone: 1 to 1.5 mg/kg IV

Methylprednisolone: 1 mg/kg IV

IV, Intravenous.

15 What tests can confirm or negate the diagnosis of anaphylaxis in a patient?

In vitro tests:

image Histamine. Histamine has a very short half-life, on the order of minutes. Histamine levels are not usually performed because it is easy to miss the peak, especially if the team is resuscitating the patient.

image Tryptase. Serum tryptase is a protease, and it is a marker only for mast cell degranulation. Its half-life is 2 hours, and the level may remain elevated for a few hours after an acute event. However, occasionally tryptase can be released by mast cells without evidence of IgE, IgG, or IgM antibody mediation. Tryptase levels do not always increase during vancomycin administration or with peanut food allergy.

image IgE, IgG, IgM levels. Total antibody levels are not routinely measured unless there is a concern of immunologic disease (such as multiple myeloma) or absence of certain antibody classes (e.g., congenital IgA deficiency).

image Radioallergosorbent test (RAST). A radioactive marker is used to identify IgE antibodies to a specific antigen. The key point is to isolate and test for the active antigen; otherwise a false-negative result might occur. A substance can have several antigenic components. For example, at least 11 natural rubber latex antigens exist. In the allergy world in general, RAST is considered less reliable (lower sensitivity and lower specificity) than skin testing, although these rates have improved since the introduction of the Pharmacia CAP RAST method.

image Enzyme-linked immunosorbent assay (ELISA). This test uses enzyme activity rather than radioactivity to measure IgE levels for a specific antigen. Both RAST and ELISA have false-positive and false-negative rates, specific for each test and antigen. The availability of a test and its clinical utility can be very different things.

image Antigens

image RAST for measurement of IgE antibodies is available for some NMBDs, propofol, morphine, meperidine, penicillin, barbiturates, aprotinin, protamine, and latex.
image ELISA looking for IgE antibodies and IgG antibodies is available for most of these drugs. Both RAST and ELISA have turnaround times of 4 to 7 days because they must be sent out to regional immunology laboratories.

In vivo tests:

image In vivo tests include skin tests (subcutaneous and intradermal); provocation and challenge tests are performed in an allergist’s office. The tests must be done at least 4 to 6 weeks after a suspected allergic reaction because recent mast cell degranulation may have depleted mediator stores. If skin tests are performed shortly after a reaction, there is the possibility of a false-negative result. Antihistamines must be discontinued 5 days before skin testing. Skin testing can demonstrate whether hypersensitivity is mediated by antibodies; skin tests do not evaluate whether a nonantibody-mediated sensitivity reaction has occured (e.g., nonspecific mast cell degranulation, which is a side effect of some medications).

image Skin tests are available for NMBDs, propofol, fentanyl, latex, chlorhexidine, and local anesthetics. Skin testing before local anesthetics are needed is helpful, especially if the diagnosis is unclear. Although skin testing is the best available method for identification of sensitivity to NMBDs, it is not infallible. Anaphylaxis to cisatracurium after negative skin testing has occurred. The sensitivity and specificity of skin tests to NMBDs are greater than 95%. No skin tests exist for cefazolin, hydromorphone, or midazolam.

image Penicilloyl polylysine (Pre-Pen) is a commercially available skin test reagent to look for IgE antibodies associated with penicillin. It is positive in up to 85% of patients with β-lactam allergy. The remaining 15% of allergic patients react to minor determinants. These antigens are not commercially available and are prepared in a few specialty centers only for in-house use. Curiously, the anaphylactic reactions are seen more commonly in patients who react to the minor determinants of penicillin.

16 Is there any role for anti-IgE therapy in acute anaphylaxis?

Omalizumab (Xolair; Genentech) is a monoclonal IgG antibody that binds to the Cε3 domain of IgE. It is a second-line drug in patients with moderate to severe asthma.

TNX-901 is a humanized IgG1 monoclonal antibody against IgE; it inhibits the binding of IgE to mast cells and basophils. This drug has been studied in people with peanut allergy and was associated with an increase in the threshold of sensitivity to oral peanut challenge.

Key Points Allergy and Anaphylaxisimage

1. Five possible immunologic reactions are involved in anaphylaxis, including immediate hypersensitivity, cytotoxicity, immune complex disease, delayed hypersensitivity, and idiopathic.

2. Several things can activate mast cells and cause anaphylaxis including antibodies (IgE, IgG, IgM), drugs directly activating mast cells, complement-mediated reactions, bradykinin, and activated T cells.

3. Penicillin is still the most common cause of anaphylaxis in the general population.

4. Patients who have anaphylaxis have vasodilation and increased endothelial permeability that leads to hypotension, tachycardia, edema, erythema, and urticaria. Bronchoconstriction leads to hypoxia and tachypnea.

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16 O’Sullivan S., McElwain J.P., Hogan T.S. Kinin-mediated anaphylactoid reaction implicated in acute intra-operative pulseless electrical activity. Anaesthesia. 2001;56:771–772. (comment)

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