Keywords

These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Pearls

  • Allergy skin prick testing—a wheal greater than 3 mm is considered positive

  • Eosinophils contain peroxidase, neurotoxin, cationic protein, Charcot Leyden crystal protein, and major basic protein which induces release of histamine from mast cells and damages epithelial cells

  • In vitro allergy testing is indicated if there is an inability to discontinue medications that would interfere with skin testing or prevent treatment of an anaphylactic response

Epidemiology

  • Increasing incidence over the past 20 years

    • Increased allergen exposure

    • More hygienic living conditions for general population

  • ~30 % of adults and ~40 % of children affected

  • Seasonal allergies affect 20 % of population with perennial affecting 40 % of population

  • Productivity lost approximately $639 million/year

  • NHANES (National Health and Nutrition Examination Survey) study (2005): 53.9 % of study population tested positive to at least one antigen

Risk Factors

  • Exposure to cigarette smoke

  • Family history of atopy

  • Higher socioeconomic status

  • First born or only child

  • Elevated total IgE

Pathophysiology

Immunology

Classification

  • Innate

    • Nonspecific response to foreign substances—not dependent on antigen recognition

    • For example, epithelial barrier, cellular and humoral defenses, complement activation

  • Adaptive

    • Specific response to foreign body—requires prior exposure/sensitization

    • Antigen recognition

      • Naturally acquired—contact with agent

      • Artificially acquired—vaccination

    • For example, antibodies, cytokines, T cells

Characteristics

  • Recognition: self vs. non-self

  • Surveillance

  • Memory

  • Specificity

  • Diversity

Components

  • Lymphocytes

    • Derived from bone marrow progenitor cells

    • T lymphocytes (cellular immunity)—all have CD2 and CD3 positivity

      • Bone marrow derived → maturation in thymus

      • Recognize fragments of foreign proteins via interaction with Major Histocompatibility Complex (MHC)

        • Cell bound proteins responsible for presenting antigens to T cells for recognition and proliferation of clonal lines

        • MHC 1: present on all nucleated cells

        • MHC 2: on antigen presenting cells and B cells

      • CD4 cells (T-helper cells) → primarily MHC2 interaction

        • 60 % of T lymphocytes—primarily located in periphery

        • TH0 cells: naïve cells → activated by intracellular pathogens or allergens

        • TH1 cells: mature subset which mediates defense against intracellular microbial infections

          • Major products IL-2 and IFN-gamma

        • TH2 cells: mature subset which down regulates TH1 and augments B-cell and Ig production

          • Major products IL- 4, 5, 6, and 10

      • CD8 cells (T-cytolytic cells) → primarily MHC1 interaction

        • 30 % of peripheral T lymphocytes

        • Defense against virus infected cells → mediates cell lysis

        • Response mediated by IL-2

      • T regulatory cells (Treg)

        • Modulate immune system, maintain tolerance to self-antigens, prevention of autoimmunity

        • Exploited in the therapeutic process of allergy immunotherapy

    • B lymphocytes (Humoral Immunity)

      • Mature in bone marrow → migrate to lymph nodes and spleen

      • T-dependent activation: B-cell processes antigen and express MHC 2 receptor allowing CD4 cell recognition → T-cell stimulates B cells via IL 2 and 4 secretion

      • T-independent activation: B-cell surface receptors activated by large antigens

        • Upon activation of B-cell via either pathway, cell produces plasma cells which secrete immunoglobulins

        • Made of two light and two heavy chains each with variable and constant chains—allows for diversity

        • Allows antigen recognition, interaction with complement, phagocytosis

          • IgD: distinct function unknown, receptor on naïve B cells, minor activation of basophils and mast cells

          • IgA: dimer found in secretions/mucosa, often mediates first-line immune defense for pathogens entering the body via the oral cavity

          • IgM: pentamer antibody

            • high avidity seen in early immune responses

          • IgE: binds to allergens and triggers release of histamine and other mediators—hypersensitivity reactions

          • IgG: major antibody in late immune responses

            • Crosses placenta to provide neonatal immunity

            • Complement fixation

      • CD19 and CD21 positivity

  • Natural Killer Cells

    • Maturation in bone marrow

    • Secrete cytokines

    • Role in innate immunity → kill virus infected cells

    • Activated by IL-2 → antibody-dependent cellular cytotoxicity

    • CD 16 and CD 56 positivity

  • Antigen Presenting Cells

    • Located within skin, lymph nodes, and spleen

    • Process antigens for presentation via MHC 1 and 2 to T cells

    • For example, macrophages, Dendritic cells, B cells, Langerhans cells, monocytes

  • Cytokines

    • Proteins secreted that allow for immunomodulation, pro-inflammation, and anti-inflammatory effects → intercellular “communication”

    • Modes of secretion:

      • Autocrine: cellular activation produces cytokine which affects secreting cell

      • Paracrine: cellular activation produces cytokine which affects nearby cells

      • Endocrine: cellular activation produces distant cellular effects

      • Role in inflammation

        • IL-1: stimulate IL-2 secretion, phagocyte activation, pyrogen

        • IL-2: stimulate T cells, B cells, and NK cells

        • IL-6: acute phase response

        • IL-12: proliferation of CD8, NK cells, IFN-gamma production, induce TH1 cells, suppress TH2

        • IL-18: induces IFN-gamma, enhances NK cell activity

        • Interferon (IFN): activates macrophages and NK cells, antiviral properties, increase MHC proteins, cytotoxic effects

          • Type I: IFN-alpha, beta → potent antiviral effects

          • Type II: IFN-gamma → potent immunomodulator, increases MHC expression

        • TNF: acute phase response, pyrogen

      • Role in allergy

        • IL-4: induces B cells and mast cells to increase IgE production

        • IL-5: activation and maturation of eosinophils

        • IL-13: induces B cells and mast cells to increase IgE production, induction of adhesion molecules at allergic sites

  • Complement

    • Allows for the augmentation of immune function, mediates the interaction of antigen and antibody

    • Activation via two distinct pathways:

      • Classical pathway

        • Primary pathway

        • Activation via immune complexes, IgG and IgM of the C1 complex

      • Alternative pathway

        • Secondary pathway

        • Activated by viruses, bacteria, parasites, IgA, IgG via C3

      • Lectin pathway

        • Similar to classical pathway but utilize mannose-binding lectin instead of C1

    • Activation leads to opsonization “tagging,” cellular migration and activation, cellular death via lysis

  • Cells important in the allergic response

    • Neutrophils

      • Cell margination and migration to site of inflammation

      • Opsonized particles are recognized and undergo phagocytosis

    • Eosinophils

      • Receptors for cytokines, IgG and IgE which allow localization to inflamed endothelium

      • Contains peroxidase, neurotoxin, cationic protein, Charcot Leyden crystal protein, and major basic protein

        • Major basic protein → induces release of histamine from mast cells and damages epithelial cells

    • Monocytes

      • Immature-macrophages

      • Produces IL-1 allowing vascular permeability and production of acute phase proteins

    • Basophils

      • Circulating granulocytes rich in histamine and heparin

      • High-affinity IgE receptors → release histamine and cytokines IL-4, IL-13

      • Express IL-4

    • Mast cells

      • Granulocyte rich in histamine and heparin

      • Contained within connective tissue and mucosa—e.g., skin, mucosal lining of mouth and nose

      • When activated → histamine and cytokines TNF-alpha, IL-3, -4, -6, -8, -10, -11

Classification of Hypersensitivity Reactions: Gell and Coombs

  • Type I

    • Mediator: IgE hypersensitivity

    • Time: Immediate

    • Agents: environmental, food, medications

    • Mechanism: secondary to degranulating mast cells → histamine

    • Manifestations: systemic and localized anaphylaxis, sneezing, urticaria, congestion, wheals

  • Type II

    • Mediator: IgG cytotoxicity hypersensitivity

    • Mechanism: antibody-directed against cell surface antigens → cell destruction via complement activation

    • Manifestations: Hemolytic anemia, transfusion reactions, Goodpasture syndrome, Myasthenia gravis

  • Type III

    • Mediator: Immune complex mediated hypersensitivity (IgG)

    • Agents: Bacterial antigen, medications

    • Mechanism: Antigen–Antibody complex deposited on the surfaces of small vasculature, joints, and glomeruli with complement activation → massive infiltration of neutrophils

    • Manifestations: Serum sickness, post-streptococcal glomerulonephritis, angioedema, GI manifestations

  • Type IV

    • Mediator: Cell-mediated hypersensitivity

    • Time: Delayed—up to several days

    • Agents: poison ivy, nickel reactions, chemicals

    • Mechanism: Sensitized TH1 cells release cytokines → activate macrophages or CD8 cells → direct cellular damage and inflammation

    • Manifestations: dermatitis, granulomatous disease, fungal disease

Cellular Response of Allergic Reactions

  • First exposure

    • APC encounter allergen

      • Uptake and process → synthesize MHC2

      • Transform TH0 cells to TH2 via release of IL4

    • TH2 release IL4 → stimulate antigen-specific IgE production via B cells

    • Early response: within minutes of exposure to several hours

  • Reexposure

    • Memory B cells maintains antibody response

    • Reexposure allows rapid proliferation to plasma cells → secrete high-affinity IgE

    • IgE binds and sensitizes mast cell → cross linking occurs with antigen → destabilization of mast cells → degranulate and release:

      • Histamine

        • Main mediator of allergic reactions

        • Vessel permeability, vasodilation, mucus secretion, tissue edema, broncho- constriction

        • Receptors H1 and H2

      • Heparin

        • Anticoagulant

        • Enhances migration and phagocytosis

      • Leukotrienes

        • Derived from the lipoxygenase pathway

        • Vasodilation, mucus secretion, bronchial smooth muscle contraction, edema, increased vascular permeability

        • Act upon leukotriene receptors

      • Cytokines: allow cellular recruitment

      • PDG2: metabolite of arachidonic acid involved in innate and adaptive immune responses

      • PAF: mediator causing inflammation, platelet aggregation, and allergic response

  • Late response: within several hours after exposure

    • Cytokine release (primarily IL4) causes accumulation of

      • TH2 cells

        • Orchestrate and maintain inflammatory response → IL-3, -4, -5, -13

      • Eosinophils

        • Production of oxygen-free radicals → damage epithelium and promotes inflammation

        • Release major basic protein

      • Basophils

      • B cells

      • Neutrophils

Neurogenic Response to Allergen

  • Neurotransmitters play a pivotal role in pathogenesis

    • Altering secretions

    • Smooth muscle tone

    • Vasodilation

    • Cellular recruitment

  • “Neurogenic inflammation”

    • Activation of peripheral terminals of sensory neurons → release neurotransmitters to act on mast cells and vascular smooth muscle

      • Redness and warmth due to vasodilation

      • Swelling due to plasma extravasation

      • Hypersensitivity due to alterations in excitability

Allergic Rhinitis

Diagnosis

  • History

    • Primary symptoms, duration, frequency, alleviating/exacerbating factors, associated symptoms or conditions, recent changes in job, environment, diet

    • Past medical history: History of asthma, anaphylaxis, eczema, allergen exposure, formula intolerance

    • Past Surgical History: e.g., T + A, BMT, FESS

    • Family history: allergic rhinitis, asthma, eczema, angioedema, food intolerance, anaphylaxis

      • Chance of having atopy with:

        • 0 Allergic parents: 10–15 %

        • 1 Allergic parent: 30 %

        • 2 Allergic parents: 50 %

    • Social history: Living accommodations, tobacco exposure, occupation

    • Medication use

  • Physical

    • Eyes: lid edema and erythema, injection of conjunctiva and sclera, chemosis, itching, watery, photophobia, “allergic shiners,” “Dennies lines”

    • Nose: supratip crease, facial grimacing, itching, nasal obstruction, inferior turbinate hypertrophy, rhinorrhea, increased mucus, sneezing

    • Ears: Tympanic membrane retraction, eustachian tube dysfunction, middle ear effusion

    • Oropharynx: “cobblestoning” of posterior pharyngeal wall, hypertrophy of lateral pharyngeal bands, mouth breathing, angioedema

    • Laryngeal: excess secretions, vocal fold edema, laryngeal drying, erythematous arytenoids, viscous mucus

    • Possible related systemic findings:

      • Skin: eczema, contact dermatitis, urticaria,

      • Lungs: wheezing, dyspnea, cough

Diagnostic Testing

  • In Vivo testing

    • Although testing is generally safe, necessary medications and airway equipment to treat systemic anaphylaxis must be available

    • Skin Testing

      • Epicutaneously

        • Prick test

          • More specific testing than intradermal (fewer false-positive results)

          • False-negative rate is 5 %

          • Various antigens introduced in controlled manner—to determine reactivity and severity

          • Few drops of selected antigen are placed on skin surface after small prick with needle

          • Reaction >3 mm in diameter is considered positive

      • Intradermal

        • Typically recommended to be performed after negative prick test, but specific sensitivity is suspected.

        • Not appropriate for food allergens due to high risk of false positives and risk of anaphylaxis

        • Small amount of allergen injected subcutaneously

        • More reproducible and sensitive testing than prick testing (fewer false negatives)

        • Skin end point titration

          • Intradermal injections of allergen at increasing concentrations starting with an anticipated non-reacting dose

          • Wheal which initiates positive reaction is safe starting point for immunotherapy

          • Technique

            • Start with diluent injection (inert) typically forms 5 mm wheal measured at 10 min

            • Injection of antigen at lowest reactive concentration (increasing concentration 1:5) until wheal enlarges by 2 mm → “endpoint”

              “Endpoint”: concentration that produces positive wheal that continues to increase in size

              Considered safe point for starting skin testing

            • Injection of next stronger concentration that results in further 2 mm in growth → confirmatory concentration

            • 13 mm growth → major reaction, testing stopped

          • Factors which affect wheal response:

            • Recent exposure

            • Prior immunotherapy

            • Area of body tested—i.e., upper back → lower arm

            • Age of patient—pediatric and geriatric tend to have less response

            • Medications: steroids, leukotriene inhibitors, bronchodilators, NSAIDs

  • In Vitro testing

    • Serum test

    • Detects specific IgE to allergens

      • Suspected allergen bound to insoluble material → patient serum added

        • If IgE present in serum → binding to allergen occurs

        • Marker labeled anti-IgE added → washed

        • Detection of marker

          • Radiation: RAST (Radioallergosorbent test)

          • Fluorescent: ELISA

    • Indications:

      • Inability to discontinue medications that would interfere with skin testing or prevent treatment of an anaphylactic response—i.e., antihistamines, H2 blockers, tricyclic anti depressants, long-term topical steroids, β-blockers

      • Severe eczema or psoriasis precluding skin testing

      • Extraordinarily high sensitivity to suspected allergens that may lead to potentially serious side effects (i.e., anaphylaxis)

      • Poorly controlled reactive airway disease

    • Scoring:

      • 0–6 Based on level of IgE in specimen

    • More specific in determining allergen sensitivity, less sensitive than skin tests

Management of Allergy Symptoms

Nonpharmacologic

  • Avoidance

    • Goals include:

      • Remove sources of allergens

      • Remove accumulated allergens

      • Prevent allergens from returning

    • Outdoor

      • Pollen

        • Types

          • Trees—February through May

          • Grass—June through August

          • Weeds—August until frost

        • Counts highest in morning, hot, dry windy days

        • Strategies of avoidance:

          • Shift outdoor activities to evening

          • Keep doors and windows closed, utilize AC

      • Mold (can be found both outdoor and indoor)

        • Present year round

    • Indoor

      • Dust mites

        • Keep surfaces clear

        • Remove carpeting

        • HEPA filters

        • Wash sheets and pillow case weekly in hot water >130°

      • Pet Dander

        • Avoidance of pet, especially keeping pet out of bed and bedroom

        • Eliminate carpeting

Pharmacologic Therapy

  • Symptomatic Relief

    • Decongestants

      • Reduce blood flow → agonistic action on alpha 1 and 2 adrenergic receptors

        • Endothelial cells within nasal vessels

        • Contraction of sphincters of the venous plexus within turbinate

      • Oral agents

        • Less chance for rebound congestion

        • Systemic effects: irritability, insomnia, headache, tachycardia, hypertension, increased intraocular pressure, urinary retention

        • Caution use in patients: hypertension, coronary disease, hyperthyroidism, glaucoma, urinary retention

        • For example, pseudoephedrine and phenylephrine

      • Topical nasal agents

        • Rapid onset <5 min with duration of 6 h

        • High local potency with fewer systemic effects

        • Over use >3–5 days leads to lost effectiveness and rebound congestion. Long-term use can lead to rhinitis medicamentosa

        • For example, oxymetazoline, neosynephrine, phenylephrine

  • Maintenance

    • Antihistamines

      • Competitively bind to H1 receptors → reduced vascular permeability, smooth muscle contraction, mucus secretion, vasodilation, pruritis

      • Oral

        • First Generation—available over the counter, cheap

          • Limited due to potential for sedative effects → high lipophilicity → crosses blood brain barrier

          • Anticholinergic effects → dry mucus membranes, urinary retention, constipation, tachycardia, blurred vision: limit use in elderly

          • For example, diphenhydramine, chlorpheniramine, hydroxyzine

        • Second Generation

          • Lower CNS penetration and thus less sedating

          • Less anticholinergic effects

          • Lower interaction with cytochrome P 450

          • Better specificity for H1 receptor blockade

          • For example, loratidine, cetirizine, fexofenadine

      • Topical nasal spray

        • Advantage of delivering high local concentration

        • Allows higher anti-inflammatory effects, reduction of systemic exposure, reducing potential for systemic side effects

        • Typically recommended for patients with seasonal allergic rhinitis

        • For example, azelastaline

    • Anti-leukotriene

      • Limited role given the lack of efficacy noted

      • Combined use with antihistamines typically with additive effect

      • Synthesis blockade

        • Blockade of 5-lipoxygenase → prevention of LTA4 synthesis formation

        • For example, Zileuton

      • Receptor blockade

        • Reduces number of peripheral blood eosinophils

        • For example, Montelukast, zafirlukast

    • Corticosteroids

      • Available as oral, injection or topical intranasal delivery

        • Multiple anti-inflammatory effects

          • Decreased capillary permeability

          • Promotes IL-10 production and IL-1 receptor antagonism

          • Decreased arachidonic metabolism → decreased prostaglandins, leukotrienes, thromboxane

          • Allows inhibition of cytokines and chemokines

          • Decreased recruitment and migration of eosinophils

          • Decreased activity of basophils and mast cells

          • Decreased migration of APC, T cells, B cells

      • Topical Intranasal delivery

        • Recommended for persistent nasal congestion

        • Systemic absorption and side effects are a theoretical concern but not well supported by the literature

          • (i.e., Inhibition of growth in children, metabolic disturbances, glaucoma, cataract formation, immunosuppression, skin thinning)

        • Effectiveness

          • Effective for all symptoms of SAR and PAR

          • Appropriate for mixed rhinitis

          • Clinical response equivocal for all available steroids

        • Topical side effects: Local burning, stinging, irritation, dryness

        • For example, beclomethasone, budesonide, flunisolide, triamcinolone, fluticasone, mometasone

    • Mast cell stabilizers

      • Inhibit Ca2+-dependent mast cell degranulation

      • Inhibit migration and survival of macrophages, eosinophils, monocytes

      • When used prophylactically can prevent and treat symptoms, although commonly need to be used as adjunct and not first-line therapy

      • Side effects: nasal burning, stinging, sneezing

      • For example, Cromolyns, olpatadine (dual antihistamine/mast cell stabilizer)

    • Anticholinergic agents

      • Muscarinic receptor blockade → inhibits rhinorrhea, congestion, and sneezing

      • Side effects: dry mouth, dizziness, blurred vision, conjunctivitis, hoarseness

      • Typically suggested for treatment of rhinorrhea

      • Caution in use with elderly with glaucoma and urinary retention

      • For example, ipratropium

Immunomodulation

  • Allergen-specific immunotherapy

    • Treats IgE-mediated allergy → regular and progressive doses of appropriate allergen → downregulation of immune response and control of symptoms

    • Benefits include:

      • Improvement in quality of life

      • Reduction of symptoms

      • Decrease reliance on medications

      • Long-term benefit after stopping treatment if they complete 3–5 years of therapy

      • Decrease risk of developing asthma

      • Prevent new sensitizations

    • Indications for therapy

      • Demonstration of IgE-mediated disease correlates with symptoms

      • Insufficient response to avoidance and pharmacotherapy

      • Significant side effects with medical therapy

      • Unable to comply with medical therapy and avoidance of allergens

      • Moderate to severe symptoms which last for majority of year or spanning across 2 or more seasons

    • Effective to following antigens:

      • Grass

      • Tree

      • Pollen

      • Animal dander

      • Insect venom

      • House dust mites

      • Mold

    • Relative contraindications

      • Concomitant therapy with beta-blocker

      • Contraindication to administration of epinephrine

      • Non-compliance of patient

      • Autoimmune disease

      • Pregnancy

      • Uncontrolled asthma

      • HIV or other immunodeficiency

    • Mechanism of action

      • With initial treatments → 2–3 months of increased antigen-specific IgE followed by gradual decline over 2 years

        • Decline does not correlate to clinical improvement

      • With decline in IgE → rise in IgG1 and IgG4

        • Increase in IgG4 correlates with symptom relief

      • Increase in antigen-specific suppressor T cells

      • Shift TH2 cells to TH1 via increased IFN-gamma and IL12

      • Decline in levels of pro-allergenic cytokines

      • Reduced basophil, mast cell and lymphocyte reactivity

      • Blunting of post-seasonal rise in specific IgE antibody

      • Gradual decrease in symptoms with repeated exposure to same allergen level

    • Schedule of treatment

      • Total treatment period is 3–5 years

      • Escalation phase → first year

        • Rapid escalation versus standard schedules

          • Allows for the attainment of maintenance doses in as low as 6 days through the use of increased frequency dosing (q 3–4 h) versus 3–6 months with standard schedules

          • The most rapid of escalation schedules typically necessitate hospitalization during the escalation period

      • Maintenance phase → up to 5 years

        • Every 1 week for first year, every 2 weeks for second year, every 3 weeks for third year

    • Modes of Delivery

      • Subcutaneous Immunotherapy (SCIT)

      • Sublingual Immunotherapy (SLIT)

    • Comparing SCIT and SLIT

      • Safety:

        • Fatal reactions from SCIT occur at rate of 1 in 2–2.5 million → 3.4 deaths/year

        • Between 2006 and 2009, six possible reported anaphylaxis in SLIT patients, none resulting in fatalities

      • Efficacy:

        • A 2007 Cochrane meta-analysis showed that immunotherapy reduced medication use, decreased clinical symptoms, and improved quality of life.

        • Efficacy has been shown to last as long as 3 years post immunotherapy cessation.

        • SLIT still has minor edge over SCIT in total efficacy, although many studies showing nearing equivalence

      • Dosing

        • Optimum SCIT maintenance dose is 5–20 μg of major allergen

        • Optimum SLIT maintenance dose not elucidated, but median monthly dosing is 49× that of SCIT

      • Cost

        • As of 2013, SLIT is not currently covered by insurance companies and considered an out of pocket expense.

        • Cost of SCIT varies dramatically according to insurance plans, while SLIT varies between practices

        • When loss of productivity and travel expense is added into the cost of SCIT, SLIT may be comparable in cost and more convenient for the patient.

    • Complications

      • Typically secondary to

        • Presence, severity, control status of asthma

        • Dosing—inadvertent mistakes in antigen selection or concentration calculation

        • Accelerated dosing schedules

        • Treatment during peak pollen season

        • Extensive sensitivity to allergen

      • Local

        • SCIT: induration, wheal

        • SLIT: oral itching, irritation

      • Systemic

        • SCIT: coughing, wheezing, shortness of breath, urticarial, anaphylaxis

        • SLIT: Gastointestinal, i.e., abdominal pain, nausea, vomiting; can also have anaphylaxis

  • Monoclonal Antibody

    • Recombinant humanized monoclonal anti-IgE antibody → forms complexes with free IgE → blocks interaction with receptors on mast cells and basophils

      • Profound reductions

        • Nasal eosinophils

        • IgE receptors on dendritic cells

        • T and B cells

    • Onset of action: typically 7–14 days

    • Clinical benefit shown in seasonal AR and perennial AR

    • Typically recommended for patient with refractory AR

    • Well tolerated with low rate of anaphylaxis

    • Disadvantage: Costly

Severe Manifestations of Allergic Response

Anaphylaxis

  • Definition

    • Immediate, severe, whole body, life-threatening, immunologic reaction characterized by the contraction of smooth muscle and dilatation of capillaries

  • Epidemiology

    • Approximately 1,000 deaths/year in the United States

    • One of every 3,000 patients suffers an anaphylactic reaction in the US hospitals every year

    • Risk of death is twofold:

      • Airway edema—asphyxiation

      • Hypotension—shock/organ failure

    • Causes: Food (e.g., peanuts) → idiopathic → insect stings (e.g., bees) → medications (e.g., Beta-Lactam antibiotics)

  • Treatment

    • Epinephrine: alpha- and beta-agonist

      • Adult dose: 0.3–0.5 cm3 (1:1,000) IM or SC

      • Pediatric dose: 0.01 mg/kg (1:1,000) IM or SC

      • May repeat dose in 10–15 min

      • 10 % dose reduction with concomitant Monoamide oxidase inhibitors (MAOI) and Tricyclic Antidepressants (TCA)

    • Antihistamine: H1 and H2 antagonists

      • Effect on symptoms, i.e., hives, but no effect on hypotension, shock or airway obstruction

      • H1 blocker: Diphenhydramine 1 mg/kg IV or IM

      • H2 blocker: Ranitidine or Cimetidine via IV push

    • Steroids:

      • Typically used in asthmatic patients

      • Beneficial for late phase reactions

      • Prednisone 40 mg PO

      • Dexamethasone 20 mg IV

    • Bronchodilators:

      • Beta-agonist: Albuterol to break bronchospasm or overcome beta-blockade

      • Anticholinergic: Ipratropium

    • Dopamine: useful for maintenance of blood pressure

      • Initial dose 1 mcg/kg/min IV and titrate to 20 mcg/kg/min

      • Doses below 10 mcg typically act as beta-agonist

Angioedema

  • Hereditary angioedema

    • Classification

      • Type I: 80 %—secondary to decreased production of C1-esterase inhibitor (C1-INH)

      • Type II: 20 %—normal or elevated functionally impaired C1-INH

    • Importance of C1-INH

      • Complement cascade: C1-INH prevents activation of C1

        • Preventing activation of C4, C3, C5

        • Decrease capillary permeability, fluid extravasation, edema

      • Kallikrein/kinin system:

        • C1-INH inactivates: Factor XII, plasmin, kallikrein

        • Prevents kininogen to be converted to bradykinin

        • Decrease vasodilation, nonvascular smooth muscle contraction, edema

    • Symptoms: edema of one of following organs

      • Skin

      • GI tract

      • Respiratory tract

    • Clinical Presentation

      • Symptoms associated with trauma, medical procedures, emotional stress, menstruation, infections, medication use (i.e., ACE-inhibitors)

      • Typically symptoms last 2–5 days with spontaneous resolution

      • Non-pitting skin edema

      • Facial area involvement (lips, eyelids, tongue)

      • Laryngeal involvement must be ruled out

    • Testing:

      • C1-INH levels

      • C1q levels

      • C2 and C4 levels—typically markedly decreased/undetectable

      • Genetic screening: autosomal dominant trait

    • Management

      • Genetic counseling

      • Intravenous C1 esterase inhibitor concentrate

      • Attenuated androgens, i.e., danazol, stanozolol

      • Trial of antihistamines, glucocorticoids, epinephrine

        • Although some reports suggest no response

      • Intubation if airway involved

      • Cessation of any offending agents, i.e., ACE-Inhibitors

  • Acquired Angioedema

    • Secondary to increased destruction or metabolism of C1-INH

    • Typically noted in patients with rheumatologic disorders, B-cell lymphoproliferative disease, IgG autoantibodies against C1-INH

  • ACE-Inhibitor therapy Induced

    • Associated with 0.1–0.5 % of patients

    • No sex predominance

    • Onset may occur during first week to as far as several years post initiation

    • Symptom resolution with 24–48 h

    • Typically with normal C1-INH levels and function

    • Treatment: discontinue ACE-I, start antihistamines, anticholinergics, corticosteroids