ANAPHYLAXIS

Anaphylaxis is a medical emergency that requires immediate diagnosis and treatment. Definitions of anaphylaxis have conflicted over the years, but recent clarity has emerged based on consensus symposia. In simple terms, "anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death."1,2 More detailed revisions of the definition2 for health professionals using clinical criteria suggest anaphylaxis is highly likely when any one of the three criteria listed in criteria dx. The traditional nomenclature for anaphylaxis reserves the term anaphylactic for immunoglobulin E (IgE)-dependent reactions and the term anaphylactoid for IgEindependent events, which do not require a sensitizing exposure. As the final pathway in classic anaphylactic and anaphylactoid reactions is identical, anaphylaxis is the term now used to refer to both IgE and non-IgE reactions (e.g., IgEindependent, IgG- and immune complex complementmediated).3 Hypersensitivity is an inappropriate immune response to generally harmless antigens. Anaphylaxis represents the most dramatic and severe form of immediate hypersensitivity. Anaphylaxis occurs as part of a clinical continuum. It can begin with relatively minor symptoms and rapidly progress to a life-threatening respiratory and cardiovascular reaction.

Patophysiology : A better understanding of the pathophysiology of anaphylaxis is beginning to unfold. Studies have highlighted the role of regulation of mast cell activation in the progression to anaphylaxis. Understanding the mechanisms of anaphylaxis offers potential therapeutic interventions for the prophylactic or emergency treatment of this life-threatening condition. Anaphylaxis, for the most part, is believed to arise from the activation of mast cells and basophils through a mechanism generally understood to involve crosslinking of IgE and aggregation of the high-affinity receptors for IgE. Upon activation, mast cells and/or basophils quickly release preformed mediators from secretory granules that

include histamine, tryptase, carboxypeptidase A, and proteoglycans. Downstream activation of phospholipase A2, followed by cyclooxygenases and lipoxygenases, produces arachidonic acid metabolites, including prostaglandins, leukotrienes, and platelet-activating factor. The inflammatory cytokine, tumor necrosis factor- is released as a preformed mediator, and also as a late-phase mediator with other cytokines and chemokines. Many of these mediators are believed responsible for the pathophysiology of anaphylaxis. Histamine stimulates vasodilation and increases vascular permeability, heart rate, cardiac contraction, and glandular secretion. Prostaglandin D2 is a bronchoconstrictor, pulmonary and coronary vasoconstrictor, and peripheral vasodilator. Leukotrienes produce bronchoconstriction, increase vascular permeability, and promote airway remodeling. Platelet-activating factor is also a potent bronchoconstrictor and increases vascular permeability. Tumor necrosis factor- activates neutrophils, recruits other effector cells, and enhances chemokine synthesis. These overlapping and synergistic physiologic effects contribute to the overall pathophysiology of anaphylaxis that variably presents with generalized urticaria and angioedema, bronchospasm, and other respiratory symptoms; hypotension, syncope, and other cardiovascular symptoms; and nausea, cramping, and other GI symptoms. Clinical Features : Anaphylaxis is the most severe life-threatening form of a systemic allergic reaction, often involving respiratory or cardiovascular compromise. The clinical signs of systemic allergic reactions include diffuse urticaria and angioedema. At times, these major symptoms are accompanied by any of the following: abdominal pain or cramping, nausea, vomiting, diarrhea, bronchospasm, rhinorrhea, conjunctivitis, dysrhythmias, and/or hypotension.6 Even mild, localized urticaria can progress to full anaphylaxis, and even to death. The classic presentation of anaphylaxis begins with pruritus, cutaneous flushing, and urticaria. These symptoms are followed by a sense of fullness in the throat, anxiety, a sensation of chest tightness, shortness of breath, and lightheadedness. As the cascade progresses, decreased level of consciousness, respiratory distress, and circulatory collapse may ensue. In its severest form, loss of consciousness and cardiorespiratory arrest may result. A complaint of a "lump in the throat" and hoarseness heralds life-threatening laryngeal edema in a patient with symptoms of anaphylaxis. In the vast majority of patients, signs and symptoms begin suddenly, often within 60 minutes of exposure. In general, the faster the onset of symptoms, the more severe the reaction, as evidenced by the fact that one half of anaphylactic fatalities occur within the first hour. After the initial signs and symptoms have abated, patients are at risk for a recurrence of symptoms. The exact incidence of this biphasic phenomenon is unclear, although it has been reported in 3% to 20% of patients.10 The effect is caused by a second phase of mediator release, peaking 4 to 8 hours after the initial exposure and exhibiting itself clinically 3 to 4 hours after the initial clinical manifestations have cleared. The late-phase allergic reaction is primarily mediated by the release of newly generated cysteinyl leukotrienes, the former slowreacting substance of anaphylaxis. PATOF&MANIFESTATION : Individuals differ in the time of appearance of symptoms and signs, but the hallmark of the anaphylactic reaction is the onset of some manifestation within seconds to minutes after introduction of the antigen, generally by injection or less commonly by ingestion. There may be upper or lower airway obstruction or both. Laryngeal edema may be experienced as a "lump" in the throat, hoarseness, or stridor, while bronchial obstruction is associated with a feeling

of tightness in the chest and/or audible wheezing. Patients with bronchial asthma are predisposed to severe involvement of the lower airways. Flushing with diffuse erythema and a feeling of warmth may occur. A characteristic feature is the eruption of well-circumscribed, discrete cutaneous wheals with erythematous, raised, serpiginous borders and blanched centers. These urticarial eruptions are intensely pruritic and may be localized or disseminated. They may coalesce to form giant hives, and they seldom persist beyond 48 h. A localized, nonpitting, deeper edematous cutaneous process, angioedema, may also be present. It may be asymptomatic or cause a burning or stinging sensation. In fatal cases with clinical bronchial obstruction, the lungs show marked hyperinflation on gross and microscopic examination. The microscopic findings in the bronchi, however, are limited to luminal secretions, peribronchial congestion, submucosal edema, and eosinophilic infiltration, and the acute emphysema is attributed to intractable bronchospasm that subsides with death. The angioedema resulting in death by mechanical obstruction occurs in the epiglottis and larynx, but the process also is evident in the hypopharynx and to some extent in the trachea. On microscopic examination, there is wide separation of the collagen fibers and the glandular elements; vascular congestion and eosinophilic infiltration also are present. Patients dying of vascular collapse without antecedent hypoxia from respiratory insufficiency have visceral congestion with a presumptive loss of intravascular blood volume. The associated electrocardiographic abnormalities, with or without infarction, in some patients may reflect a primary cardiac event mediated by mast cells or may be secondary to a critical reduction in blood volume. The angioedematous and urticarial manifestations of the anaphylactic syndrome have been attributed to the release of endogenous histamine. A role for the cysteinyl leukotrienes in causing marked bronchiolar constriction seems likely. Vascular collapse without respiratory distress in response to experimental challenge with the sting of a hymenopteran was associated with marked and prolonged elevations in blood histamine and intravascular coagulation and kinin generation. The finding that patients with systemic mastocytosis and episodic vascular collapse excrete large amounts of PGD2 metabolites in addition to histamine suggests that PGD 2 is also of importance in the hypotensive anaphylactic reactions. The PAF level can be elevated in the serum of patients with anaphylaxis, and its concentration is correlated inversely with the constitutive level of the acetylhydrolase involved in its inactivation. The actions of the array of mast cell-derived mediators are likely additive or synergistic at the target tissues.

URTICARIA & ANGIOEDEMA : Urticaria and angioedema may appear separately or together as cutaneous manifestations of localized nonpitting edema; a similar process may occur at mucosal surfaces of the upper respiratory or gastrointestinal tract. Urticaria involves only the superficial portion of the dermis, presenting as wellcircumscribed wheals with erythematous raised serpiginous borders and blanched centers that may coalesce to become giant wheals. Angioedema is a welldemarcated localized edema involving the deeper layers of the skin, including the subcutaneous tissue. Recurrent episodes of urticaria and/or angioedema of less than 6 weeks' duration are considered acute, whereas attacks persisting beyond this period are designated chronic. Urticarial eruptions are distinctly pruritic, may involve any area of the body from the scalp to the soles of the feet, and appear in crops of 12- to 36-hour duration, with old lesions fading as new ones appear. Most of the physical urticarias (cold, cholinergic, dermatographism) are an exception, with individual lesions lasting less than 2 hours. The most common sites for urticaria are the extremities and face, with angioedema often being periorbital and in the lips. Although self-limited in duration, angioedema of the upper respiratory tract may be life-threatening due to laryngeal obstruction, while gastrointestinal involvement may present with abdominal colic, with or without nausea and vomiting, and may result in unnecessary surgical intervention. No residual discoloration occurs with either urticaria or angioedema unless there is an underlying process leading to superimposed extravasation of erythrocytes. The pathology is characterized by edema of the superficial dermis in urticaria and of the subcutaneous tissue and deep dermis in angioedema. Collagen bundles in affected areas are widely separated, and the venules are sometimes dilated. Any perivenular infiltrate consists of lymphocytes, monocytes, eosinophils, and neutrophils that are present in varying combination and numbers. Perhaps the best-studied example of IgE- and mast cell-mediated urticaria and angioedema is cold urticaria. Cryoglobulins or cold agglutinins may be recognized in up to 5% of these patients. Immersion of an extremity in an ice bath precipitates angioedema of the distal portion with urticaria at the air interface within minutes of the challenge. Histologic studies reveal marked mast cell degranulation with associated edema of the dermis and subcutaneous tissues. The histamine level in the plasma of venous effluent of the cold-challenged and angioedematous extremity is markedly increased, but no such increase appears in the plasma of effluent of the contralateral normal extremity. Elevated levels of histamine have been found in the plasma of venous effluent and in the fluid of suction blisters at experimentally induced lesional sites in patients with dermographism, pressure urticaria, vibratory angioedema, light urticaria, and heat urticaria. By ultrastructural analysis, the pattern of mast cell degranulation in cold urticaria resembles an IgE-mediated

response with solubilization of granule contents, fusion of the perigranular and cell membranes, and discharge of granule contents, whereas in a dermographic lesion there is additional superimposed zonal (piecemeal) degranulation. Elevations of plasma histamine levels with biopsy-proven mast cell degranulation have also been demonstrated with generalized attacks of cholinergic urticaria and exercise-related anaphylaxis precipitated experimentally in subjects exercising on a treadmill while wearing a wet suit; however, only subjects with cholinergic urticaria have a concomitant decrease in pulmonary function. Up to 40% of patients with chronic urticaria have an autoimmune cause for their disease including autoantibodies to IgE (5-10%) or, more commonly, to the a chain of FcRI (35-45%). In these patients, autologous serum injected into their own skin can induce a wheal and flare reaction involving mast cell activation. The presence of these antibodies can also be recognized by their capacity to release histamine or induce activation markers such as CD63 or CD203 on basophils. An association with antibodies to microsomal peroxidase and/or thyroglobulin has been observed often with clinically significant Hashimoto's thyroiditis. In vitro studies reveal that these autoantibodies can mediate basophil degranulation with enhancement by serum as a source of the anaphylatoxic fragment, C5a. Hereditary angioedema is an autosomal dominant disease due to a deficiency of C1INH (type 1) in about 85% of patients and to a dysfunctional protein (type 2) in the remainder. In the acquired form of C1INH deficiency, there is excessive consumption due either to immune complexes formed between anti-idiotypic antibody and monoclonal IgG presented by B cell lymphomas or to an autoantibody directed to C1INH. C1INH blocks the catalytic function of activated factor XII (Hageman factor) and of kallikrein, as well as the C1r/C1s components of C1. During clinical attacks of angioedema, C1INH-deficient patients have elevated plasma levels of bradykinin, particularly in the venous effluent of an involved extremity, and reduced levels of prekallikrein and high-molecular-weight kininogen, from which bradykinin is cleaved. The parallel decline in the complement substrates C4 and C2 reflects the action of activated C1 during such attacks. Mice with targeted disruption of the gene for C1INH exhibit a chronic increase in vascular permeability. The pathobiology is aggravated by administration of an ACE inhibitor (captopril) and is attenuated by breeding the C1INH null strain to a bradykinin 2 receptor (Bk2R) null strain. As ACE is also described as kininase II, the use of blockers results in impaired bradykinin degradation and explains the angioedema that occurs idiosyncratically in hypertensive patients with a normal C1INH.