Anaphylaxis Urticaria Angioedema

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Anaphylaxis Urticaria Angioedema

• Niraj Patel, MD, MS
• Section of Allergy and Immunology
• Texas Childrens Hospital Baylor College of
  Medicine

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Objectives

• Know the clinical presentation, diagnosis and
  treatment of anaphylaxis.
• Understand the pathophysiology of urticaria and
  angioedema
• Outline an approach for evaluation and treatment
  of patients with urticaria and/or angioedema
• The following will NOT be covered
• Anaphylaxis (in detail) Grand Rounds Jan 23
• Food Allergy Grand Rounds Feb 6
• Stinging Insect Hypersensitivity

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In case you fall asleep.

• Means that it was either on a Board exam or the
  examiners could easily write a question for it
• Look at the questions in this lecture. Many of
  them are similar to questions that appeared on a
  previous Board exam.

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What is anaphylaxis?

• Affects gt 1 organ system skin, respiratory,
  cardiovascular, GI symptoms
• 100,000 episodes per year in U.S.
• 1 fatality rate shock, larnygeal edema
• IgE vs nonIgE mechanisms

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Pathophysiology Immune Mechanisms

• Protein digestion
• Antigen processing
• Some Ag enters blood

IgE-Mediated
IgE-receptor
APC
Mast cell
Non-IgE Mediated
Histamine

• TNF-?
• IL-5

T cell
B cell
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Causes of Anaphylaxis

• Foods peanuts, egg, milk, shellfish, wheat,
  fish, soy
• Insect stings
• Drugs PCN, NSAIDs
• Contrast media
• Opiods

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Clinical Features and Diagnosis

• Skin Erythema, pruritis, hives, angioedema
• Respiratory laryngeal edema, wheezing, rhinitis,
  itching of palate, conjunctivitis
• Cardiovascular LOC, fainting, palpitations,
  sense of impending doom
• GI N/V/D, abdominal pain
• Diagnosis
• Clinical history
• Laboratory histamine, tryptase

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Management of Systemic Reactions

• Stabilize Epinephrine, IV, airway,
  O2 antihistamine, steroids
• Observe 3 hours (mild reaction) 6 hours
  (severe reaction)
• Prevent Epinephrine self administration Referra
  l to an allergist

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EpiPen

• EpiPen
• Injection carried with the patient at all times.
• Self-injection to lateral thigh.
• Use EpiPen, Jr. for children lt 20kgs.

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URTICARIA
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Urticaria

• Urticaria Hives
• Common condition, 15-25 at some time in their
  lives
• Type I hypersensitivity reaction
• Causes foods, drugs (no identifiable cause in
  50)

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Urticaria vs. Angioedema

• Urticaria superficial dermis
• Characterized by intense pruritis due to
  histamine effect
• Angioedema deeper dermal and subcutaneous
  layers
• May be pruritic but often is a deeper and dull
  discomfort burning quality

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Chronic Urticaria/Angioedema(Mast cell driven)
Urticaria
Angioedema
Urticaria Angioedema
Cooper, KD. J. Am. Acad. Derm 1991
25166 Sabroe et al., J. Am. Acad. Dermatol 1999
40 443-50
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Acute vs. Chronic Urticaria

• Acute Urticaria lasts 6-8 weeks or less
• Viral syndromes (especially in young children)
• Insect bites or stings (fire ants, scabies)
• Food induced reactions (eat this - get that)
• Medication related (antibiotics, NSAIDs,
  narcotics, angioedema due to ACE inhibitors)
• Chronic Urticaria lasting longer than 8 weeks
• Physical urticarias (dermographism, cholinergic,
  cold)
• Urticarial vasculitis
• Urticaria/angioedema associated with autoimmunity
• Autoimmune urticaria
• Idiopathic urticaria

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Cross reacting Antibiotics
Pichichero, Pediatrics 2005 1151048-57
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Cross reacting Antibiotics
Pichichero, Pediatrics 2005 1151048-57
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Urticaria - Mechanisms

• Immunologic
• IgE-mediated histamine, PAF, PGD2, LTC, LTD
• Foods/food additives
• Medications
• Hymenoptera venom
• Complement system activation
• Blood/blood products
• Neuropeptides
• Substance-P, Somatostatin, VIP
• Cytokines

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Underlying Mechanisms of Urticaria

• Non-Immunologic
• Direct mast cell activation
• Radio contrast dye, opiates, polymyxin
• Modulation of the mast cell responsiveness
• Arachidonic acid metabolism (NSAIDs, Aspirin)
• Miscellaneous
• Physical, Cold, Pressure

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Physical Urticarias

• May occur so intermittently as to appear acute
  but typically are chronic entities most
  idiopathic
• Physical Urticarias
• Symptomatic Dermatographism
• Cholinergic
• Cold Induced (Familial or Acquired)
• Vibratory (angioedema)
• Pressure induced, Solar, Aquagenic

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Symptomatic Dermatographism

• Simply scratching the skin promotes linear hives
  within minutes
• Delayed form described
• Typically is short-lived in duration (1/2 to 3
  hours) and responds readily to antihistamines

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Cholinergic Urticaria
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Cold-Induced Urticaria

• Familial (autosomal dominant) vs acquired
  (usually infection associated)
• Acquired form - positive ice-cube challenge
• Usually responds to cyproheptadine

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Delayed Pressure Urticaria
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Solar and Aquagenic Urticaria
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Schnitzlers Syndrome

• Non-pruritic urticaria/angioedema sparing the
  face
• Fever, bone pain, and weight loss
• Hepatomegaly and adenopathy in 50
• Monoclonal IgM greater than 10 gm/L
• Bence Jones proteinuria
• Increased sed rate, hyperfibrinogenemia
• Skin path PMN infiltration with leukocytoclastic
  vasculitis Janier, M. et al J Am Acad
  Dermatol 1989 20 206-11

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Hypocomplementemic Urticarial Vasculitis Syndrome
(HUVS)

• Urticaria and/or angioedema associated with
  depressed C4 levels
• Most often also associated with depressed C1q
  levels
• Various etiologies including autoantibodies to
  collagen-like fragments of C1q
• Wisnieski J et al Medicine 1995 74 24-41

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Antibodies Associated with Urticaria
IgG autoantibody to the IgE receptor 35
to 40 Antithyroglobulin antibody 8 Antimicrosom
al antibody 5 Both antibodies 14 One antibody
or both 27
Adapted from Ferrer M, et al. Int Arch Allergy
Immunol. 2002129254-260.
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Therapeutic Options

• Antihistamines for most with acute short-lasting
  urticaria
• Start with non-sedating, long-acting second
  generation H1 antagonists (Allegra, Zyrtec,
  Claritin) and supplement with short-acting,
  sedating H1 antagonists prn.
• Combination therapy if H1 antagonists do not
  suffice (30 of cases)
• Steroids and other immunosuppressants reserved
  for severe urticaria associated with angioedema
  of oropharnyx or other systemic signs, moderate
  to severe drug reactions, urticarial vasculitis,
  and refractory cases of CIU

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H1 Antagonists

• Previously felt to be only histamine receptor
  blockers
• Recent research now reveals that most of the
  second generation antihistamines have some mild
  anti-inflammatory properties
• Although less expensive, first generation
  antihistamines have potential for sedation and
  impaired performance

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Why Add an H2 Antagonist?

• There was a significantly higher proportion of
  patients without angioedema and urticaria at 2
  hours in the ranitidine group (70.5) compared
  with those in the placebo group (46.5,
  P.02)
• OR of improvement with ranitidine treatment
  added to H1 antagonist was 2.80 (95 CI 1.03 to
  8.08 P.048) Linn, J et al Ann Emergency
  Med 2000 36 462-8

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ImmunomodulationCyclosporine / Tacrolismus

• Inhibits IL-2, IL-3, IL-4, IFNgamma, GM-CSF, and
  TNF-alpha production
• Inhibits NF-AT, nuclear factor kappa beta
  (NF-KB), and PU box Maraoka K, et al. J Clin
  Invest 1996 97 2433-9
• Prevents GVHD
• Treatment psoriasis, RA, Crohns, Behcets,
  aplastic anemia, polymyositis, dermatomyositis F
  aulds D et al Drugs 1993 45 953-1040

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Cyclosporine

• Low dose (3 mg/kg) cyclosporine (CsA) effective
  in treating patients with CIU in 13/19 (full
  remission) and 6/19 (significant relief) compared
  to controls over three months Toubi E et al
  Allergy 1997 52 312-6
• DB, PC trial with 4mg/kg CsA revealed improvement
  in daily urticaria score (42 points max) by 12.7
  (vs 2.3 in placebo)
• Histamine release decreased from 36 to 5
  (plt0.0001)
• Autologous skin test also reduced in responders
• Grattan CE et al. Br J Dermatol 2000 143
  365-72

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ANGIOEDEMA
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C1 Inhibitor Functions

• Inhibits C1r and C1s of the complement system
• Inhibits activated factor XIIa and kallikrein
• An inhibitor of factor XIa and plasmin
• Inhibits activation of C1

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Hereditary Angioedema

• Autosomal dominant with incomplete penetrance.
• Spontaneous mutations in 50
• Diminished C4 between attacks
• Very low C4 during attacks
• HAE I
• Low levels of C1 esterase inhibitor
• HAE II
• Dysfunctional C1 INH
• HAE III (estrogen-dependent angioedema)
• Normal C1 INH amount and function
• Normal complement levels

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Laboratory Tests for C1 Inhibitor Deficiency

• C4 low C4d/C4 ratio always elevated
• C1 inhibitor protein low in about 85 of cases
• C1 inhibitor only functionally deficient in about
  15
• C1q antigen low in acquired deficiency
• Abnormal C1 inhibitor mobility (lower molecular
  weight) on SDS gel electrophoresis

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Acquired Angioedema (AAE)

• Rare Onset gt 50 yo negative familial history
• AAE, type I
• Lymphoproliferative disorder
• Monoclonal gamopathy, lymphoma, lymphocytic
  leukemia
• AAE, type II
• Autoantibodies to CI-INH
• Low C1q levels in addition to depletion of C4 and
  C2.

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Drug Induced Angioedema
Bradykinin responsible for swelling in angioedema
in patients with HAE Kaplan A et al J Allergy
Clin Immunol 2002109195-209
Angiotensin converting enzyme (ACE) inhibitors
interfere with metabolism of bradykinin via
interference with kininase Ii Gavras I
Kidney Int 1992 421020-29
Patients on angiotensin converting enzyme
blockers (ARBs) may not be at risk for
angioedema Gavras I Arch Int Med
2003 163 240-1
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ACE Inhibitor Angioedema

• Typically angioedema occurs shortly after
  start Slater E et al JAMA 1988 260 967-70
• Several reports of angioedema after several
  months
• Angioedema after 13 months of enalapril
  therapy Venable RJ J Fam Pract 1992 34
  201-4
• Report of angioedema after stopping and then
  restarting ace-inhibitor within 72 hours
• Dyer PD J Allergy Clin Immunol 1994 93
  947-8

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Treatment of Hereditary Angioedema

• Patient education very important test family
• No regular medication needed in many cases
• Prophylactic stanozolol or danozol
• Epsilon aminocaproic acid (EACA) an option
• Fresh frozen plasma before emergency surgery
• C1 inhibitor
• Symptomatic treatment during attacks
• Steroids and antihistamines are NOT effective!!!

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Summary

• Through several mechanisms a variety of mediators
  may lead to urticaria or angioedema
• Clinically, a causative agent is much more often
  identified in acute than in chronic
  urticaria/angioedema
• A number of medications are available to control
  chronic urticaria while awaiting a spontaneous
  remission
• Patients with angioedema without urticaria should
  be tested for C1 inhibitor deficiency

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Question 1

• Which of the following is thought to be non-IgE
  mediated cause of urticaria?
• Penicillin
• Aspirin
• Dog sensitivity
• Hymenoptera sting

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Question 2

• A 12-year-old boy presents with a 6-month history
  of a raised erythematous rash involving the
  trunk, arms, and legs that recurs daily. The rash
  is pruritic but resolves within 1 hour without
  bruising or discoloration. Despite trying various
  food elimination diets, his parents have seen no
  change in his symptoms. The rash resolves within
  15 minutes after taking diphenhydramine, but he
  is so sedated from the medication that he misses
  school. He is otherwise healthy, but his parents
  are frustrated. Of the following, the MOST
  appropriate initial long-term treatment for this
  boy's rash is
• Fexofenadine
• Hydroxyzine
• Ranitidine
• Prednisone
• Montelukast

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Question 3

• A father brings in his 7-year-old daughter to be
  evaluated for a rash and swelling on her entire
  body. These symptoms have been present for about
  2 weeks. After obtaining a careful history and
  performing a physical examination, you determine
  that the child has urticaria. Of the following,
  the MOST likely cause is
• artificial food coloring
• milk
• new laundry detergent
• shrimp
• upper respiratory tract viral infection

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Question 4
Low levels of this complement component most help
distinguish between hereditary and acquired
angioedemaA. C1qB. C2C. C3D. C4