Allergy & Immunology

    Approach to Angioedema

    • On History:
    1. Is it angioedema? (ask for lips, eyelids, genitals, extremities).  Raised erythematous plaques lasting LESS THAN 48hrs.
    2. Hives or no hives (aka Urticaria.. determines whether it's mast-cell mediated or not.. see chart)
    3. Systemic Symptoms? (resp, GI, CVS)
    4. Triggers (food, drugs, insect, exercise, cold)



    (Source: Recreated from University of Toronto Lecture for undergraduate medicine in 2013)


    Common Environmental Allergens



    Type IV

    • "Delayed Hypersensitivity" reaction mediated by "T-cells
    • T-cell Mediated Mechanism
    • e.g. contact dermatitis, DRESS syndrome
    • Examples:
      • DRESS
      • TB Skin Test (Delayed hypersensitivity)
      • Poison Ivy




    • Acute Life Threatening immunologic reactions
    • Mechanism:
      • Severe allergic reaction occurs in response to:
        • Food / Environmental Proteins
        • Insect venom
        • Drugs
        • Latex
        • Blood transfusions
        • Other allergens.
        • Radiocontrast (special, b/c activates mast cells directly w/o IgE intermediary).
      • Due to IgE activation on basophils and mast cells, releasing histamine + other inflammatory cytokines.
      • Requires previous sensitization to the allergen, but often occurs without a known exposure hx.
    • Clinical Features
      • Reaction can be immediate, in several hours post-exposure, or days post exposure.
      • Skin: Urticaria
      • CV: Tachycardia (sometimes bradycardia)
        • Hypotension (histamine increases vascular permeability), large losses of circulating volume.
      • Airway: Stridor, Horseness, Wheezing
      • GI: Cramping abdo pain, vomiting, diarrhea
      • Angioedema (localized tissue edema)
        • Often lips, tongue, upper airway, GI tract, extremities.
        • Often a component of anaphylaxis, but can occur alone without other features of anaphylaxis
          • Possibly triggered by exposures (esp ACEi) or inherited/acquired disorder.
    • Highly likely if:
      • Acute onset of illness (minutes to hours) with involvement of skin, mucosal tissue or both (hives, pruritis, flushing, swollen lips/tongue, uvula) AND one of :
        • Resp compromise (dyspnea, wheeze-bronchospasm, stridor, hypoxemia)
        • Reduced BP or associated symptoms (hypotonia, syncope)
      • Two or more of following rapidly after exposure to a likely allergen: (≥2)
        • Involvement of skin/mucosal tissue or both.
        • Respiratory compromize
        • Reduced BP
        • .... (one more)
    • Another Definition:
      • Anaphylaxis Definition (Very controversial, how to define), but one common definition is:

        • Severe allergic reaction to any stimulus, having sudden onset involving at least two body organs with multiple symptoms.
    • Familial C1 Esterase Deficiency (aka familial angioedema)
      • IMPORTANT: does not respond to standard anaphylaxis agents (not IgE mediated)
      • Hereditary: (Often following trauma or illness, starts early in life)
      • Acquired: in Lymphoproliferative disorders
      • Airway management is essential due to laryngeal edema


    • Identified as one of three criteria (on up to date and purple book)
    • Management:
      • Nowadays rarely fatal, often patients die from laryngeal edema (airway emergency)
      • Mainstay of therapy:
        • Supportive: Oxygen, IV fluids
        • Inhaled B2-agonist
          • Ventolin, albuterol or racemic epinephrine can reduce bronchospasm and airway edema
        • *Epinephrine  *
          • IM preferred (SC is unreliable and slow absorption)
            • Epinephrine IM 0.3-0.5mL (1:1000 [1 mg/mL] solution) (0.3-0.5mg)
              • If does not work, then repeat q5-15m
            • Inject in anterolateral aspect of mid-third of thigh deep in muscle. (guidelines!)
          • IV (recommended only if profoundly hypotensive, in arrest, or unresponsive to IM epi)
            • Epinephrine IV 1mL (1:10,000 [0.1 mg/mL] solution) [0.1mg] aq sol'n infused over 5-10min, can repeat q10-20m.
          • IV Infusion --> Can create an infusion w/ crystalloid. (epinephrine IV 2-8 mcg/min)
          • For laryngeal edema can use:
            • 0.25mL of 1:100 epi sol'n (10mg/mL) added to 2mL of isotonic saline.
          • High dose, sustained dosing may be needed for severe anaphylaxis or with B-blocker use.
            • can also add glucagon 5-15 mcg/min IV infusion to provide another mechanism of sympathetic stimulation if B-blocker is used)
        • Antihistamines and steroids sometimes used to prevent worsening or recurrence.
          • Neither antihistamines nor steroids have sown to improve outcomes in anaphylaxis.  Neither would reverse bronchospasm quickly enough.
            • Antihistamines are typically effective for urticaria (not shock or airway)
            • Steroids are effective to prevent delayed recurrence.
        • Airway Support
          • NIPPV can be used, but intubation may be needed to prevent airway closure
          • Airway management is DIFFICULT, may need advanced techinques and anasthesia
        • Steroids
          • In theory prevents second phase reaction. (10-15% of anaphylaxis possible)
          • methylprednisolone 125mg IV or prednisone 50mg PO q6h
          • (Not critical, likely doesn't help that much, but we still often do it - prevents 2nd phase reaction)
        • Other:
          • REMOVE B-BLOCKERS  (get unopopsed alpha activity, get vagal stimulus and become bradycardic)
            • Give Glucagon 1mg amp q5-10m.
    • Concerns:
      • 1. Airway Obstruction (Main cause of fatality)
        • Look for stridor, facial/tongue swelling, drooling, inability to talk. 
      • 2. Bronchospasm
      • 3. Distributive Shock
        • IV epinephrine infusion (IV form raises risk of arrhythmia, rapid rise in BP, MI, stroke... CAREFUL!)
    • Discharge therapy
      • Epinephrine Auto-Injector
      • H1 +/- H2 antagonists (cetirizine/fexofenadine)
      • Corticosteroids
      • Proximity to medical therapy for 36-48hrs
      • Referral to Allergy/Immunology
      • Education (autoinjector use, etc..)
    • Source: Massachusetts Manual and MKSAP16


    • Acute <6w
    • Chronic >6w
    • Types:
      • type I (IgE mediated) Hypersensitivity (Mast cells)
      • Type II (Antibody mediates) Hypersensitivity
        • Complement activation causing direct cell degranulation (mismatched blood)
      • Type III (Immune complex mediated) Hypersensitivity
        • Some autoimmune diseases
      • Other autoimmune (CSU0
      • Nonimmunologic urticaria
        • Exogenous substances, etc..
      • Idiopathic
    • Management:
      • H1 receptor antagonists (1st line)
        • Diphenhydramine only IV option
        • Oral: Cetirizine (Reactine)
          • Diphenhydramine (Benadryl) + Hydroxyzine (Atarax) for hospital inpatients
            • Cogntive reduction + sedating
      • NOTE: other 2nd generation H1 antagonists
        • Cetirizine (Reactine)
        • Fexofenadine (Allegra)
        • ... etc..
      • H2 antihistamines (ranitidine) combination additive to H1 antihistamines.
      • Glucocorticoids
        • Reduce inflammatory histamines (stabilize mast cell membranes preventing degranulation)


    Chronic Spontaneous Urticaria (CSU)

    • Aka Chronic idiopathic Urticaria (CIU)
    • 50% --> autoimmune
    • 50% --> response to ill-defined viral illness
    • Autologous serum skin test (IgG against FeER).
    • Associated with autoimmune thyroid disease
    • Rarely ass'd with: SLE, HepB, HepC, lymphoma, etc..
    • Diagnosis:
      • Symptom + patient driven
      • Often skin testing not indicated (to prove to patient that this is not due to food allergy)
      • CBC, diff, ESR, CRP, Anti-thyroid antibodies, C3/C4, TSH
      • Other: QIG, SPEP, LST, HepB/C, ANA, H.pylori serology, etc..
    • Treatment:
      • 1st line: licensed does (5-10mg cetirizine, 60-120 of fexofenadine, 10 loraradine, 5mg desloratadine)
      • 2nd line: up tot four-fold up-dosing of 2nd gen AH
      • 3rd line: Add ranitidine and/or montelukast
      • 3rd line: other option is omalizumab (Xolair) - $$$ [anti-IgE ab]
      • 5rth line:
        • Plaquenil 200mg BID (if ANA positive)
        • Cyclosporine



    • Same as urticaria, but deeper layer
    • Varying presentation (localized non-pitting edema)
    • Not pruritic (can angioedema and urticaria together)
    • Lips, eyes, ear lobes, genitals (tissues that are easily extendable)
    • Workup:
      • CBC, diff, acute phase reactants, thyroperixodase antibodies, ANA, hepatitis, Hpylori, D-dimer
        • Acute: C4 level, allergic investigations
        • Chronic: C1 estarse inhibitor assay, etc..
    • Causes:
      • Allergic (IgE mediated)
      • Autoimmune angioedema/urticaria (Extension of CSU spectrum)
      • Hereditary Angioedema (C1 esterase inhibitor - either not enough or not working)
        • Screen: Chronically low C4 levels, C1 assay
        • Type I Low C1 esterase inh.
        • Type II - NO C1 esterase inh.
        • Type III - C1 inhibitor assay normal, must do gene testing for Factor XII?
      • Drugs (ACEi, NSAIDs, opioids) - if on ACE - dx'ed unless proven otherwise.
        • Usually happens in 1st year, but possible later.
        • Can takes weeks/months to resolve (when stop drug)
    • Can last hours to 2-3 days.
    • Management:
      • Epi, steroids, antihistamines
      • Hereditary: Can have C1 estarse given back to treat. (acquired + hereditary)


    Drug Reactions


    • Drug reaction with eosinophilia and systemic symptoms (DRESS)
      • Prev called "Anticonvulsant Hypersensitivity Syndrome"
    • Severe potentially life-threatening systemic drug hypersensitivity syndrome
      • Type IV hypersensitivity reaction --> Onset of the syndrome is delayed, usually occurring 10 days to several weeks after the start of the causative medication.
    • Common triggers: (Up to 6w post exposure)
      • Sulfonamide antibiotics
      • Allopurinol
      • Anticonvulsants (CLASSIC)
      • Vancomycin (new, b/c increased use)
    • Symptoms:
      • Exanthem rash on the face, trunk, and extremities, and they often have facial edema.
      • SYSTEMIC Inflammation:
        • Fever
        • Rash (not itchy, but uncomfortable)
        • Lymphadenopathy (75%)
        • Hypotension (If Severe)
        • Hepatitis
        • Nephritis
        • Eosinophilia
    • Fever (
    • Difficult to distinguish inadequate response to abx and sepsis vs. systemic drug reaction.
    • Management:
      • Stop the suspected medication immediately
        • switch to another medication that is unlikely to cross-react
      • Supportive care
      • Systemic Glucocorticoids (reduce systemic inflammation and lower the risk of end-organ damage)
        • IV pulse steroids



    • Only works for Type I, IgE-mediated reaction
    • progressively higher q20-30min until full dose is tolerated. 
    • IV or oral (safer as oral, but harder practically)
    • Once desensitized, drug must be continued daily for state to persist; disappears over days to weeks of drug is stopped.
    • Must be done with pump, mini bags, and often need high level nursing care (i.e. Step-down ICU)
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