Hypersensitivity reactions/Urticaria/Angioedema

There are 4 types of hypersensitivity reactions.

• • Type I: Exposure to antigen results in formation of IgE.

    • Antigen reacts with CD4 cells, which then differentiate to TH² cells with release of IL-3, IL-4, and IL-5. IL-5 stimulate eosinophils, and IL-4 activates IgE producing B cells.

    • IgE bind to mast cells.

    • Subsequent exposure to same antigen results in binding of antigen which also crosslinks to IgE already bound to mast cells and basophils (presensitized from earllier encounter with antigen); triggering degranulation of the mast cells and basophils. There is release of vasoactive amines (e.g. histamine), that act at postcapillary venules. Thus, vascular permeability is increased, leading to edema and increased smooth muscle contraction and eventually bronchoconstriction.

    • Early phase reaction occurs within 5 - 30 min: vasodilatation, increased vascular permeability, increased smooth muscle contraction.

      • Ag binds to IgE bound to mast cells > degranulation of mast cells > release of mediators.

    • Late phase reaction occurs 2 - 24 hours and last for days: Infiltration by neutrophils, eosinophils, basophils, monocytes > mucosal damage by released mediators

    • Anaphylactic-type reaction - anaphylaxis, hives, drugs, insect venoms, food, hayfever or allergic rhinitis, bronchial asthma, atopic dermatitis.

    • Si & Sx: onset is abrupt (within 30 min of exposure to ag). Rash, nausea, vomiting, swelling of face, lips, tongue, wheezing, stridor, hypotension, tachycardia. Death can occur from airway obstruction.

    • Test: Scratch test, radioimmunosorbent assay. Serum tryptase is a marker of anaphylaxis.

    • Anaphylactoid reactions now called pseudoallergic reaction, clinically appear as IgE-mediated but are the result of non-IgE-mediated mast cells degranulation.

Urticaria (hives) are raised, flat-topped, well-demarcated pruritic skin lesions with surrounding erythema. An individual lesion lasts minutes to hours. Central clearing cause an annular lesion and is often seen after antihistamine use.

Angioedema is a deeper lesion causing painful areas of skin-colored, localized swelling. It can occur anywhere on the body, but most often involves the tongue, lips, or eyelids.

Classification:

• • Acute urticaria w/w/o angioedema is defined as an episode lasting <6 weeks. Allergic reaction to a medication or food, but may be related to underlying infection, recent insect sting, or exposure (contact or inhalation) to an allergen. Patient can develop hypersensitivity to a food, medication, or self-care product that previously had been used without problems.

  • Chronic urticaria w/w/o angioedema is defined as episodes lasting for >6 weeks. Many possible causes including medications, autoimmunity, self-care products, and physical triggers. Etiology remains unidentified in >80% of cases.

Etiology:

• • Allergic: drugs (ACE-I), food, inhalant, or contact allergen

  • Transfusion reactions

  • Infections

  • Insects

  • Autoimmune diseases

  • Malignancy

  • Physical urticaria: dermographism, cold, cholinergic, pressure, vibratory, solar, and aquagenic

  • Mastocytosis

  • Hereditary diseases

  • Idiopathic

History:

• • Detailed history to identify triggers and rule out systemic causes.

  • Determine if the lesion lasts >24 hours, in which case, the diagnosis of urticarial vasculitis must be investigated by a skin bx.

  • Any changes in environmental exposures, foods, medications, personal care products, etc. should be determined.

  • Urticaria and angioedema can occur together.

  • Any h/o of dental procedures or oral trauma.

Physical examination:

• • Complete exam of affected and nonaffected skin.

  • Urticaria appears as erythematous, raised lesions that blanch with pressure.

  • Angioedema often involves the face, tongue, extremities, or genitalia, and may be asymmetric.

DDx:

• • Allergic reactions to drugs, foods, insects, inhalants, or contact allergen.

  • Physical urticaria.

  • Mast cell releasibility syndromes such as systemic mastocytosis and cutaneous mastocytosis, including urticaria pigmentosa, should be considered.

  • Urticarial vasculitis presents with urticaria-like lesions that do not fade within 24 hours. It is a systemic vasculitis characterized by vascular damage with findings of fragmentation of neutrophils, red cell extravasation, and swelling of endothelial cells on bx.

  • Angioedema without urticaria should lead to consideration of specific entities.

  • Use of ACEIs or ARBs can be associated with angioedema at any point in the course of therapy.

  • Hereditary angioedema (HAE), or C1 esterase inhibitor (C1 INH) deficiency, is inherited in an autosomal dominant pattern.

  • Acquired C1 INH deficiency presents similarly to HAE but is typically associated with an underlying lymphoproliferative d/o or connective tissue disease.

Dxtic testing/Labs:

Epicutaneous skin testing and patch testing when indicated.

• • CBC, CMP, ESR, UA, LFTs, hepatitis serologies.

  • All patients with angioedema without urticaria should be screened with a C4 level, which is reduced during and between attacks of HAE. If the C4 is reduced, check a quantitative and functional C1 INH assay.

  • Acquired C1 INH deficiency Pts have reduced C1q, C1 INH, and C4 levels, or autoantibody to C1 INH with low C4 and C1 INH levels but a normal C1 level.

  • Skin bx if individual lesions persist for >24 hours to rule out urticarial vasculitis.

    • Bx. of acute urticarial lesions reveals dilation of small venules and capillaries located in the superficial dermis with widening of the dermal papillae, flattening of the rete pegs, and swelling of collagen fibers.

    • Chronic urticaria has dense, non-necrotizing, perivascular infiltrate consisting of T lymphoctyes, mast cells, eosinophils, basophils, and neutrophils.

Tx:

• • Consider placing patients with angioedema in the ICU.

  • All potential causes should be eliminated. Most cases resolve < 1 week.

  • Medication review

  • Elimination of all self-care products

  • In acute urticaria in the presence of anaphylaxis with systemic symptoms such as hypotension, laryngeal edema, or bronchospasm, treate with epinephrine, 0.3 - 0.5 mL of a 1:1000 sol IM.

  • Acute urticaria: 2G oral antihistamine such as cetirizine, levocetirizine, fexofenadine, desloratadine, or loratadine until the hives have cleared. 1G antihistamine such as hydroxyzine may be added as an evening dose.

    • Oral corticosteroids may be helpful to prevent relapse.

  • Chronic urticaria:

    • Antihistamines for a period of 6 months, and then lowered to the level needed to maintain symptom control.

    • 2G oral antihistamine such as cetirizine, levocetirizine, fexofenadine, desloratadine, or loratadine.

    • Classic H1 antihistamines, such as hydroxyzine, 25 mg PO q4 - 6h or prn, can be added for better control of lesions or for breakthrough lesions.

  • Hereditary and Acquired Angioedema (Disorder of C1-inhibitor):

    • Laryngeal attacks or severe abdominal attacks: C1INHRP is 1st line agent. Other options include FFP and tranexamic acid. Rehydration.

    • Chronic therapy: Androgens, for unknown reasons, raise the C1 esterase inhibitor. The most frequently used androgens are danazol and stanazol.

Adverse drug reactions.

Classification:

• • Type A drug reaction: toxicites due to drug metabolism. Dose dependent and predictable. Constitutes the majority of ADR

  • Type B drug reaction: idiosyncratic drug reactions and immune-mediated reactions. Not dose dependent. Reactions can occur with relatively low doses of the drug, usually on rexposure after an initial sensitization to the drug. Pseudoallergic reactions are the result of non-IgE-mediated mast cell degranulation.

Predisposing factors: history of atopy, type of medication used, and comorbid conditions.

Etiology:

B-lactam sensitivity. PCN and other beta-lactam ABx. PCN has a high incidence of immunologic reaction as a result of its chemical structure.

NSAIDs

Clinical Presentation:

• • Urticaria, angioedema, wheezing and anaphylaxis are all characteristics of IgE mediated (type 1) reactions.

  • Sx usually occur on rexposure. Manifest <1 hours.

  • Maculopapular exanthema are the most common cutaneous manifestation of drug allergy. Reactions are mediated by T cell and typically delayed onset, occurring between 2 - 14 days of exposure to culprit medications. Lesions typically start on the trunk, especially in dependent areas, and spread to extremities. Rarely, rashes progress to DRESS (drug reaction with eosinophilia and sytemic symptoms) or SJS (Stevens-Johnson Syndrome).

  • DRESS is serious ADR (antiepileptic, allopurinol, NSAIDs, and some ABx and BB), presents with rash and fever. Systemic involvement with manifestation of hepatitis, eosinophilia, pneumonitis, lymphadenopathy, and nephritis. Occurs 2 - 6 weeks after introduction of medications.

  • Erythema multiforme, SJS, and TEN are serious reactions involving primarily the skin. EM has target lesions. SJS and TEN have varying degress of skin sloughing and mucous membranes (<10% of the epidermis in SJS and >30% in TEN).

Tx:

D/c drug. Avoid drug. Care in ICU for severe adverse reactions like SJS

• • Type II: IgG, IgM antibodies bind to fixed antigen on cells or in the extracellular matrix, leading to lysis by complement or phagocytosis. Three specific mechanisms by which reactions occur:

    • Complement-dependent reactions: Ab fixes to ag evokes complement to fix to Ab-ag complex and cause direct cell lysis through production of MAC (membrane attack complex), or the complement can coat cells with C3b (an opsonin) and promote phagocytosis of the antigen.

    • Antibody-dependent cell-mediated cytotoxicity: Cells that have rcp to Fc portion of IgG, such as neutrophils, eosinophils, macrophages, and natural-killer (NK) cells, mediate removal of antigen. E.g.: Transfusion reactions, erythroblastosis fetalis, and autoimmune hemolytic anemia, ITP.

    • Antibody-mediated cellular dysfunction: Ab themselves affect the function of ag. E.g.: Graves disease is due to Ab that activates TSH rcp, resulting in hyperthyroidism. Myasthenia gravis is due to abs against ACh rcp impairing neuromuscular transmission.

    • Other examples: rheumatic fever, bullous pemphigoid

    • Test: Direct and indirect Coombs.

• • Type III: Ab (IgG) binds to antigen, forms an immune complex. The immune complex can form insitu or circulate and become deposited in organs, where they cause damage. The immune complex activate complement. Neutrophils are attracted to the site, and they release lysosomal enzymes.

    • E.g. serum sickness, SLE, Arthus reaction, PAN, RA, hypersensitivity pneumonitis, PSGN

    • Si & Sx: Fever, utricaria, arthralgias, proteinuria, lymphadenopathy occurring 5 - 10 days after antigen exposure.

    • Test: Immunofluorescent staining.

• • Type IV: Delayed response by sensitized T-lymphocytes that encounter antigen, and release lymphokines leading to macrophage activation. No antibody involvement.

    • Delayed-type reaction: CD4 helper T cells (TH¹) sensitized from previous exposure to an ag secretes IF-gamma > activation of monocytes, macrophages > IL-12 > causing differentiation of TH1 cells. Stimulation of macrophages results in granulomas (collections of epitheloid histiocytes)

      • TB (tuberculin reaction), TB, sarcoidosis, histoplasmosis, berylliosis, leprosy, contact dermatitis,

    • Cell mediated cytotoxicity: CD8 cells sensitized previously, kill antigen bearing cells. Ag. presented by class I MHC molecules > perforin-granzyme system and the FAS-FAS ligand system leading to apoptosis.

    • Tpe-I DM, multiple sclerosis, GB syndrome, Hashimoto's thyroiditis, GVHD

Orolingual agioedema without urticaria (especially those with recurrent episodes), diagnostic tests should include the following:

• C4 level

• C1 esterase inhibitor (C1-INH) quantitative and functional measurements

• C1q level

These studies will help to establish or rule out C1-INH deficiency–associated angioedema, either hereditary or acquired. The Joint Taskforce on Practice Parameters’ 2013 update of the 2000 angioedema practice parameters include diagnostic testing to differentiate among subtypes of angioedema without urticaria. Such tests include measurements of C1-INH, C4, and C1q levels, as well as of C1-INH function, with the following results:

• C1 INH-HAE Type I – Low levels of C1-INH protein and function, low C4, but normal C1q;

• C1 INH-HAE Type II – Normal levels of C1-INH protein, but low levels of C4 and C1-INH function, normal C1q;

• FXII-HAE and U-HAE (previously known as HAE Type III, or HAE with normal C1 INH) – Normal levels of C1-INH protein and function, normal C4 and C1q;

• C1 INH-AAE (previously known as AAE) – Low levels of C1-INH protein and function, low C4 and low C1q;

• ACEI-AAE, IH-AAE and InH-AAE – Normal levels of C1-INH protein and function, normal C4 and C1q;

C1-INH-HAE types I and II are characterized by low levels of C1-INH or elevated levels of dysfunctional C1-INH, as detected by an immune assay. Between attacks, low levels of C4 are noted. Elevated prothrombin fragment F1 + 2 and D-dimer are associated with acute attacks in HAE. Whether these markers have value in monitoring other types of angioedema requires additional research.

Screening tests

Screening laboratory studies have limited value in most cases. For recurrent angioedema without a clear trigger, clinicians may consider the following tests:

• Complete blood count (CBC) with differential

• Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level

• D-dimer level

• Urinalysis

• Comprehensive metabolic profile

• Antinuclear antibody (ANA) testing

• CH50 level

Consider thyroid studies, including levels of thyroid-stimulating hormone, free T4, and thyroid autoantibody (antimicrosomal or antithyroglobulin), particularly in women or in patients with a family history of thyroid disease or other autoimmune diseases.

Other studies

If the initial laboratory tests yield abnormal results or if a specific medical condition is suspected, additional tests may be needed. Evaluation for possible occult infection can be considered.

Chronic infection is a potential cause of unexplained angioedema (with or without urticaria). With this consideration, the diagnostic approach for detecting potential chronic infection may be considered.

Other tests to consider if the history and physical examination findings suggest specific problems include the following:

• Stool analysis for ova and parasites

• H pylori workup

• Hepatitis B and C workup

• Rheumatoid factor

• Cryoglobulin levels

• Imaging studies

Assays for serum histamine–releasing factors and evaluation for specific autoantibodies (anti-immunoglobulin E [IgE] receptor and anti-IgE) are performed by some research centers. These tests are not approved by the US Food and Drug Administration (FDA) and currently are available from only a few laboratories (eg, National Jewish Health, Denver, CO; IBT Reference Lab, Lenexa, KS).

When the CH50 or C4 level is low, additional tests for C1-INH function and C1q level should be considered. Patients with a low C1q level may require additional hematologic evaluation.

• Hereditary angioedema (HAE), or C1 esterase inhibitor (C1 INH) deficiency, is inherited in an autosomal dominant pattern.

• Acquired C1 INH deficiency presents similarly to HAE but is typically associated with an underlying lymphoproliferative disorder or connective tissue disease.

Management of HAE (Canadian Approach)