Anaphylaxis

By Mary C. Tobin M.D.

INTRODUCTION:

Anaphylaxis in its broadest sense represents a spectrum of clinical events fromsneezing to shock depending on end organ sensitivity. Anaphylaxis ischaracterized as an explosive event resulting from release of histamine andpreformed mediators causing profound end organ dysfunction (cardiac,respiratory, GI, dermatologic, neurologic).

Immediate hypersensitivity reactions to foreign proteins were first appreciated4000 years ago, in descriptions of insect sting fatalities. Reactions tostinging insects still claim 50 lives annually. Subsequently, the use of horseserums, (tetanus, diphtheria) and penicillin focused attention on theoverwhelming effect antigens in the right host could quickly elicit. Theseeffects are varied and encompass clinical manifestations such as hypotension,cardiac arrhythmias, asthma, urticaria, angioedema, profuse diarrhea, nausea,vomiting and rhinitis. In l966 Drs. K. and T. Ishizaka identified theimmunoglobulin in humans primarily responsible for these reactions, IgE. Inthe last 22 years, fascinating insights into the mechanism of this immunologicreaction, both in its "normal gate-keeper" function and its role in diseasehave been described.

DEFINITIONS:

IMMEDIATE HYPERSENSITIVITY: The result of re-exposure to an antigen capable ofeliciting an IgE response in a susceptible individual producing a clinicalreaction (flushing, urticaria, etc.), within seconds to minutes as a result ofdegranulation of mast cells/basophils. Non-immunologic stimuli can alsoprovoke basophil/mast cell degranulation without prior exposure (radiocontrastmedia, morphine) producing a reaction mimicking an IgE immediatehypersensitivity response.

ATOPY: Describes the genetic predisposition to produce increased amounts ofIgE antibody against common environmental antigens. This tendency is manifestby 20% of the population and is apparent clinically as anaphylaxis, asthma,eczema, hayfever, urticaria and angioedema dependent upon end organsusceptibility.

ALLERGY: The term allergy was originally coined in 1906 by von Pirquet meaning"changed reactivity of the host when meeting an agent on a second or subsequentoccasion". Allergy has become synonymous with the type I hypersensitivity.

LATE PHASE RESPONSE: Reoccurrence of clinical symptoms four to twelve hoursafter antigen exposure mediated by the basophil, histamine releasing factors(HRF), the eosinophil and platelet activating factor.

I. MAJOR COMPONENTS OF TYPE I REACTIONS

A. IgE

1. Is glycoprotein MW 190,000 which is heat labile.

2. Has a serum half life of 2-3 days. Regulated by T cell factors(IgE binding factors) GEF, GIF.

3. Binds to basophils and mast cell through a high affinity

Fc receptor.

4. Basal level is controlled by host factors: sex, age, race, skinand mucosal permeability.

5. Is 95% bound to cells for 3-4 weeks. Low IgE level is transmittedas an autosomal dominant.

6. Alternate pathway activation of complement is triggered byIgE-immune complexes. Is found in greater amounts in allergic individuals, andis a heterogeneous population (IgE+) (IgE-). IgE+ represents the response tohistamine releasing factors. The greater the number of IgE+ an individual hasthe greater chance for disease through late phase response.

7. Normal increase in IgE with parasitic infections where IgEdependent binding of macrophages and eosinophils to parasites has beendocumented to cause cytotoxic reactions.

8. Low affinity Fc receptors for IgE are found on T-cells, B-cells,monocytes, macrophages, eosinophils and platelets indicating a regulatoryfunction.

B. Mast cell

1. Has high affinity receptors for IgE (105 /mast cell).

2. Composed of two distinct populations:

a. Connective tissue mast cell: Predominantly found in skinw/stains intensely with metachromatic dyes. Forms prostaglandin D2 asmetabolite

b. Mucosal mast cell: Found in lung and lamina propria of

the gut. Leukotriene C4 is major metabolite.

3. Has rounded nucleus with metachromatic staining granules, up to1,000.

4. Has heterogeneous granules related to age, and polyanion ofgranule, i.e., Heparin sulfate or Chondroitin sulfate.

5. Originates in bone marrow.

6. Increases host response to parasitic infections.

C. Basophil

1. Is a polymorphonuclear leukocyte generated in the bone marrow.

2. Comprises 0.2% to 1% of nucleated cells in bone marrow and

peripheral blood.

3. Has lobulated nucleus with large metachromatic granules.

4. Has high affinity receptors for IgE.

5. Generates leukotriene C4.

6. Promotes late phase response i.e., asthma, contact dermatitisthrough IgE+ and histamine releasing factors.

7. Produce from precursors in the blood and bone marrow under theinfluence of IL-3.

D. Eosinophil

1. Plays a major role in allergic inflammation and disease.

2. Composes less than 3% of circulating population of peripheralleukocytes.

3. Has bilobed nucleus with refractile cytoplasmic granules stainingbright red with login.

4. Originates in bone marrow under influence of granulocyte -macrophage colony stimulating factors and by T-lymphocyte factors, IL 3 and5.

5. Responds to chemoattractant properties of C5a, PAF, LTB4.

6. Contains major basic protein (MBP), cationic protein and neurotoxincontribute to sloughing of airway epithelium and killing of parasites.

7. Is a major component of the late phase response.

E. Histamine Releasing Factors (HRF)

1. Produced by platelets, macrophages, lymphocytes.

2. Have a MW 15-30K, shared by a "family" of molecules.

3. Causes mediator release in the late phase as the result of HRF-

basophil interaction in individuals with increased IgE+.

4. Selectively causes release in atopics (IgE+).

5. May discriminate between "extrinsic" and "intrinsic" asthma andanaphylaxis.

II. MECHANISM OF IMMEDIATE HYPERSENSITIVITY

A. Antigen interacts with antigen specific cell-surface bound IgE.(dimer) on mast cells.

B. Generates a signal through the cross-linking of Fce IgE receptors.

C. Membrane lipid and adenine metabolism is initiated.

D. Granule solubilization and release of preformed amines, proteins,peptides and proteoglycans from granules occurs.

III. MEDIATORS OF IMMEDIATE HYPERSENSITIVITY

A. Preformed Mediators

1. Histamine is primary preformed vasoactive mediator in basophils andmast cells.

a. Acts on H1 to contact smooth muscles, increase vascularpermeability, and generate prostaglandins.

b. Acts on H2 to increase vascular permeability, gastric acidsecretion, stimulate suppressor lymphocytes, decrease PMN enzyme release,chemotaxis mast cell and basophil histamine release.

c. Acts on H3 receptors to inhibit neurotransmitter and histaminerelease.

2. ECF-A (mast cell) preformed attracts and deactivates eosinophilsand increases eosinophils' complement receptors.

3. HMW-NCF (mast cell) attracts and deactivates neutrophils.

4. Tryptase in the mucosal mast cell is a preformed enzyme whichcleaves C3.

5. Kallikrein similar to plasma kallikrein cleaves bradykinin from HMWKininogenase and activated Hageman factor.

B. Newly Formed Mediators

1. PAF is generated by mast cells, macrophages, neutrophils and

eosinophils.

a. Aggregates platelets.

b. Releases platelet amines.

c. Generates platelet thromboxane.

d. Attracts eos, neutrophils.

2. Arachidonic acid metabolites, leukotrienes (C,D,E) are generated

by mast cells and basophils.

a. Constrict smooth muscle.

b. Increase vascular permeability.

c. Synergistic with histamine.

d. Cause cardiac depression.

e. Inhibit lymphocyte response to mitogen.

3. Leukotriene B4 (LTB4) is most potent chemotactic factor forneutrophils and eosinophils.

4. Prostaglandin D2 (mast cell) causes constriction on bronchialsmooth muscle.

5. Adenosine inhibits platelet aggregation, is potentbronchoconstrictor and enhances mast cell release.

C. Granule - Associated Mediators

1. Heparin sulfate is the major preformed proteoglycan which bindshistamine, inhibits complement activation, acts as a anticoagulant, bindsplatelet factor 4 and tryptase.

2. Chondroitin 4 an 6 sulfate is preformed in the basophil to bindhistamine

IV. REGULATION OF MAST CELL DEGRANULATION

A. Intracellular cyclic nucleotides modulate mediator release.

1. Increased cAMP depresses mediator release.

2. Increased cGMP enhances mediator release.

3. Ca2 ion stores, intra and extracellular, modify Ag mediatedhistamine release.

B. Basophils and mast cells have additional surface receptors.

1. Beta receptors are present on mast cells and basophils which whenstimulated increase cAMP.

2. Beta receptors may be abnormal or decreased in atopic disease.

3. Beta agonists (isoproterenol, epinephrine) increase cAMP.

4. Alpha adrenergic receptors present on smooth muscle causevasoconstriction.

5. Cholinergic stimulation increases mucus secretion and smooth muscleconstriction.

6. Alpha, beta and cholinergic receptor abnormalities predisposeatopic individuals to end organ sensitivity.

7. Mast cells and basophils have for C3a, c5a anaphylatoxin generatedby complement activation.

C. Eosinophils and neutrophils modulate responses provoked by mast cellsand basophils in the late phase response.

V. CLINICAL MANIFESTATIONS OF ANAPHYLAXIS

A. Reactions are due to release of preformed mediators (histamine) andgeneration of leukotrienes, PAF. Severe reactions are marked by massiveswelling of respiratory tract, constriction of bronchial smooth muscle andmassive vasodilatation through mediator effect on capillary permeability.

1. Fatalities result in 3% of cases.

2.Significant upper and lower respiratory obstruction represent cause ofdeath 70% of cases.

3. Cardiac arrhythmias and dysfunctions represent 24% of fatal cases.

4. Risk factors for fatalities include:

a. protracted course

b. Beta blockers

c. adrenal insufficiency

B. Host factors relevant to development of anaphylaxis include:

1. Antigen dose and mode of administration

2. Genetic predisposition

3. Stress/Chronic disease

4. Nutritional Status

C. Anaphylaxis may be uniphasic, biphasic or protracted.

1. Laryngeal edema occurs more frequently in protracted (57%) or biphasic(40%) cases.

2. With oral agents biphasic or prolonged reactions are more common thanperceived previously.

3. Glucocorticoids do not reproducibly prevent biphasic or protractedanaphylaxis.

4. Patients with reactions need to be observed for greater than 12 hoursespecially if upper airway obstruction is involved.

D. Mechanisms involve IgE (atopy), IgE (non atopic) and non IgE.

1. Drugs IgE (non atopic).

a. Antibiotics - prototype is penicillin. Reactions rates are 0.7% to 8%(4-15 cases/10,000 courses of PCN) 20% of the population claim a history of PCNallergy. There is a 10% reaction rate with a negative history. Forty percentreaction rate with positive history. Skin testing is performed with the majordeterminant pencilloyl-poly-L-lysine (PrePen) and minor determinant (benzylpenicillin). Positive minor determinant skin test is associated withanaphylaxis. If skin tests are negative less than 3% chance of anaphylaxis.Desensitization is possible in a controlled environment. (cephalosporins,tetracyclines, nitrofurantoin, streptomycin, chloramphenicol, bacitracin,neomycin, amphotericin B).

Non IgE - vancomycin, polymyxins.

2. Foreign Proteins IgE (non atopic).

a. Insulin

b. PTH

c. ACTH

d. Asparaginase

e. Chymopapain

f. Penicillinase

g. Seminal Plasma

h. Antilymphocyte globulin

i. Hymenoptera venom

j. Fire ant venom

Insect Stings cause 50 fatalities annually. Patients with systemicreactions can receive venom specific therapy (bee, wasp, yellow jacket, hornetand fire ant). Immunotherapy is maintained at 100 micrograms per antigen for60 months. Specific IgE and IgG titers can then help predict continued need fortherapy.

3. Therapeutic agents (IgE).

a. allergic extracts

b. muscle relaxants

c. estradiol

d. hydrocortisone

e. methylprednisolone

f. protamine

g. ethylene oxide

h. thiopental

i. local anesthetics

i. Reactions are usually secondary to bisulfites or epinephrine. Todocument safety of a particular agent provocative skin testing can beperformed.

ii. Chemically there are two groups Group I (benzoic acid ester) orGroup II (amide). There is cross reactivity in Group I not in Group II. If areaction with a Group I agent occurs (Novocaine) a Group II agent (carbocaine)can be selected.

j. vaccines

k. streptokinase

4. Foods (IgE atopic).

Fatalities usually occur in victims with prior knowledge i.e., pastanaphylaxis. Usually it is a meal away from home, with alcohol, denial,reliance on p.o. antihistamines and no Epi-Pen.

a. milk

b. egg white

c. nuts

d. citrus

e. wheat

f. soybean/legumes/peanuts

g. seeds (sunflower, pumpkin)

h. grains

i. cottonseed

j. fish

k. shellfish

l. bananas

m. beets

n. corn

o. safflower

p. chamomile tea

5. Therapeutic agents (Non IgE) Reactions are secondary to anaphylatoxinproduction.

a. Radiocontrast media reactions occur in 20% of all procedures. Patientswith prior reactions have a 17-35% change of subsequent reaction. Pretreatmentwith antihistamines 50mg IM l hr. before the procedure and Prednisone 50mg 13,7 and 1 hr. before the procedure has provided effective protection in 93% ofpatients with prior reactions (Greenberger et.al.). Reaction is not related toiodine. Atopics allergic to shellfish have a slightly increased risk. Lowosmolality contrast media has decreased reactions with increased patientcomfort.

b. Transfusion reaction

c. Gamma globulin infusion

6. Modulators of Arachidonic acid metabolism. Reactions are secondary toincreases in by products of lipooxygenase pathway.

a. ASA

b. Nonsteroidal anti-inflammatory agents

c. Azo dyes

d. Yellow dye #5

e. Benzoates

7. Bisulfites which are used as sanitizing agents for food containers andfermentations equipment. FDA allows in non-thiamine containing foods. Sprayedon fresh vegetables, shellfish, beer, and wine. Ingest 20-100 mg per restaurantmeal. Also found in medications. Mechanism of action thought to be secondaryto stimulation of afferent cholinergic reflex arc by sulfur dioxide causingmassive cholinergic discharge.

8. Exercise-induced anaphylaxis characterized by cutaneous warmth, pruritus,urticaria and vascular collapse. More common in atopics. may be related tospecific food ingestion prior to exercise.

9. Idiopathic anaphylaxis (73 pts. reported by Boxer et.al.) no clearreproducible triggers.

a. Usually more common in atopic females (59%)

b. Reactions are infrequent 1-6 x a year (mild) (52%)

c. Reactions are frequent 48% requiring maintenance antihistamines (H1) andprednisone. Remission has required an average of 1 yr. of prednisonetherapy.

10. Progesterone allergy females who are frequently atopic demonstratesensitivity to medroxyprogesterone documented by skin testing. Treatmentinvolves use of androgens or oophorectomy/hysterectomy.

E. Treatment

1. Epinephrine 0.3 - 0.ml (1:1000) S.C.

2. If profound hypotension, use IV Epinephrine 2-3 ml (1:10,000), althoughincrease incidence of arrhythmias. Repeat dose every 15-20 min. asnecessary.

3. Supportive therapy with fluids, vasopressors as necessary.

4. Addition of H1 blockers, H2 blockers

5. Corticosteroids (2-4 mg/kg q 4-6 hrs.) are helpful in preventing the latephase response.

6. Glucagon 1mg bolus in patients on Beta blockers.

F. Prevention of anaphylaxis and anaphylactic death

1. Thorough drug allergy history

2. Give drug orally rather than parenterally when possible

3. Patients to wait in office 30 minutes after drug administration

4. Check all drugs for proper labelling

5. Predisposed patients to carry warning identification

6. Predisposed patients taught self-injection of epinephrine

7. When antiserum essential, use human

8. Skin test and desensitize when appropriate