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

Anaphylaxis

• 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

Urticaria

• 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)

Angioedema

• 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

Desensitization

• 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)
•