Recurrent idiopathic anaphylaxis

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Recurrent idiopathic anaphylaxis
Presented by Wat Mitthamsiri, M.D.
May2, 2014

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Recurrent idiopathic anaphylaxis

  1. 1. Recurrent (Idiopathic?) Anaphylaxis By Wat Mitthamsiri, MD. Allergy and Clinical Immunology Fellow King Chulalongkorn Memorial Hospital
  2. 2. Outline Case presentation Review of anaphylaxis – Definition – Diagnostic criteria Review of idiopathic anaphylaxis – Definition – Estimated incidence – Classification – Theories of pathogenesis – Differential diagnosis – Investigations – Approach – Therapy and management – Prognosis and future therapy
  3. 3. CASE
  4. 4. A 40 years old Thai woman Oct 2012 • Facial edema, no wheezing • -> Dx: R/O anaphylaxis from “Tiffy” Nov 2012 • Wrist pain with multiple PIP pain and erythematous rash on extremities • -> W/U RF&ANA: Negative • -> On NSAIDs -> Improved -> Stop NSAID 21 Feb 2013 • Facial edema and wheezing • -> Dx: Anaphylaxis, Admit
  5. 5. A 40 years old Thai woman 26 Feb 2013 • Edema occurred again • No medical Rx 20 Mar 2013 • Oral ulcer -> Got colchicine from clinic • After 9 tablets taken (1 hr after last tablet) -> facial edema, lungs clear
  6. 6. A 40 years old Thai woman 20 Mar 2013 • Hx of penicillin, Bactrim, Brufen, ASA, colchicines, diclofenac allergy (no detail about symptom) • W/U: – Serum tryptase 1.9 – C3=1.23, C4=0.4 (0.1-0.4), CH50 = 75% • R/O Complement deficiency • HM: Atarax, CPM, cetirizine • Refer to KCMH
  7. 7. A 40 years old Thai woman 9 Apr 2013 • At GenMed Clinic -> Initial W/U • CBC: Hct 39.4, Hb 13.4, WBC 9010 (N 47, L 44, E 2.3), plt 334000 • AST 17, ALT 24, ALP 68 • UA WNL • -> Sent to Allergy Clinic
  8. 8. A 40 years old Thai woman 23 Apr 2013: 1st KCMH Allergy Clinic visit • Hx of facial/orbital angioedema – Probable anaphylactic reaction R/O from Tiffy, ASA, Brufen • Symptoms usually occurred 15-30 min post tablet and persisted for 2 days • There were 2 episodes that occurred without any medication • PH: Mild AR, no AA, no CRS • PE: No nasal polyp
  9. 9. A 40 years old Thai woman 23 Apr 2013: (Continued) • Imp: – Recurrent severe angioedema with probable anaphylaxis – NSAIDs/analgesic sensitivity (angioedema) • W/U: SIgE to mixed food -> Negative • Rx: Adrenaline kit, cetirizine 1x2, montelukast 1x2, prednisolone(5) 3x2 • After went home and do some cleaning -> symptoms occurred again
  10. 10. A 40 years old Thai woman 29 Apr 2013 • Symptom occurred 40 min after meal with “นํ้าพริก” 7 May 2013 • F/U -> Taper Prednisolone(5) to 2x2, continue montelukast, cetirizine
  11. 11. A 40 years old Thai woman 17 May 2013 • After exhaustive workout (without any medication, or food within 5 hr), she had erythroderma at extremities, facial edema, no itching • She went to a hospital – > Adrenaline im – > 10 min after that, symptoms improved – > Completely resolved after 1 day
  12. 12. A 40 years old Thai woman 17 May 2013 (continued) • PE: Steroid acne found • W/U: Baseline serum tryptase • Rx: – Stop antihistamine (prevention of obscuring late detection of anaphylaxis) – Increased prednisolone(5) to 4x3 for 10 days, then 3x3 – Continue cetirizine, montelukast – Add ranitidine(150) 1x1
  13. 13. A 40 years old Thai woman 9 Jul 2013 • During June, she had 2 severe generalized urticaria episodes with mild angioedema – 1 of these had chest tightness without wheezing. – She self-injected adrenaline both times -> symptoms improved within 10 min but completely resolved after 1 day
  14. 14. A 40 years old Thai woman 9 Jul 2013 (continued) • She said that eating jackfruit caused neck tightness without other symptom • BUT she can wear rubber gloves and boots • W/U: ANA, CH50, C3, C4 • Rx: RM 17 May 2013
  15. 15. A 40 years old Thai woman 11 Aug 2013 • During housekeeping -> palpitation, facial edema, rash • -> Adrenaline self-injection 25 Sept 2013 • During housekeeping -> palpitation, facial edema, rash • -> Adrenaline self-injection
  16. 16. A 40 years old Thai woman 1 Oct 2013 • Result W/U came back: – Serum tryptase 2.21 (<13.5 ug/L) – ANA <1:80 – CH50 – 39.5, C3 = 136, C4 = 38.8 • Additional W/U: total IgE level • Assessment: – Decreasing severity on each attack
  17. 17. A 40 years old Thai woman 1 Oct 2013 • Rx: – Stop montelukast – Continue prednisolone(5) 3x3, cetirizine, ranitidine – Add ketotifen 1x2 7 Jan 2014 • F/U – > Decrease prednisolone(5) to 2x3 for 2 wk, then 6x1 for 2 wk, then 6x1 AD + 5x1 AD
  18. 18. A 40 years old Thai woman 9 Feb 2014 • 2 days after adjusting prednisolone to 6x1, at about 17.00, while sitting on the back of a truck – > Chest tightness with erythroderma without wheezing – > Adrenaline self-injection and went to a hospital – > Received 3 more unknown iv injection and observed until 23.00 – > HM: Prednisolone(5) 3x3 until 25 Feb 2014, then 6x1 – > Continued other medication
  19. 19. A 40 years old Thai woman 3 Mar 3014 • F/U: • Lab results back: – Total IgE 453 (normal <100) IU/mL • Rx: – Prednisolone(5) 6x1 for 1 mo, then 5x1 for 1 mo, then 4x1 for 1 mo
  20. 20. Summary of attacks • Totally 11 probable anaphylaxis attacks in 1 year and 5 months – 2 R/O from drugs (Tiffy, colchicine) – 1 R/O from food (นํ้าพริก) – 1 R/O from contact banyan resin – 4 R/O from exertion – 4 attacks occurred spontaneously
  21. 21. REVIEWS Anaphylaxis
  22. 22. Definitions • A “severe, life-threatening, generalized or systemic hypersensitivity reaction.” – Allergic anaphylaxis: Mediated by an immunologic mechanism • e.g., IgE, IgG, and immune-complex- complement related – Nonallergic anaphylaxis: Anaphylaxis from a nonimmunologic reaction S G A Brown, et al., Middleton’s Allergy 8th edition, 2013, 1237-1259.
  23. 23. Definitions S G A Brown, et al., Middleton’s Allergy 8th edition, 2013, 1237-1259.
  24. 24. Diagnostic criteria: 1 of these • 1) Acute onset of an illness (minutes to several hours) – With involvement of the skin, mucosal tissues, or both (e.g., generalized hives, pruritus or flushing, swollen lips-tongue- uvula) – And at least one of the following: • Respiratory compromise (e.g., dyspnea, wheeze- bronchospasm, stridor, reduced PEF, hypoxemia) • Reduced BP or associated symptoms of end- organ dysfunction (e.g., hypotonia [collapse], syncope, incontinence) Sampson HA et al.. J Allergy Clin Immunol 2006;117: 391-7.
  25. 25. Diagnostic criteria: 1 of these • 2) >/=2 of the following that occur rapidly after exposure to a likely allergen for that patient (minutes to several hours): – Involvement of skin-mucosal tissue • e.g., generalized hives, itch-flush, swollen lips-tongue- uvula – Respiratory compromise • e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia – Reduced BP or associated symptoms of end-organ dysfunction • e.g., hypotonia [collapse], syncope, incontinence – Persistent gastrointestinal symptoms • e.g., crampy abdominal pain, vomiting Sampson HA et al.. J Allergy Clin Immunol 2006;117: 391-7.
  26. 26. Diagnostic criteria: 1 of these • 3) Reduced BP after exposure to known allergen for that patient (minutes to several hours): – Infants and children: • Low systolic BP (age specific) or greater than 30% decrease in systolic BP* – Adults: • Systolic BP less than 90 mm Hg or greater than 30% decrease from their baseline Sampson HA et al.. J Allergy Clin Immunol 2006;117: 391-7.
  27. 27. REVIEWS Idiopathic anaphylaxis
  28. 28. Idiopathic anaphylaxis Definition • Idiopathic anaphylaxis is anaphylaxis not explained by a proved or presumptive cause or stimulus • A diagnosis of exclusion after other causes have been considered PA. Greenberger, Immunol Allergy Clin N Am 27 (2007) 273–293
  29. 29. Estimated incidence • Antibiotics: 22% of all drug-related episodes, 1.9-27.2 million US • Latex: 2.7-16 million US • Perioperative anaphylaxis: 9%-19% of complications • Radiocontrast media: 0.16% of ionic media, 0.03% of nonionic media administration • Hymenoptera stings: 0.4%-0.8% of children, 3% of adults • Food: 0.0004% of the US per year • NSAIDs: Varied between reports • Antisera: 2-10% of cases that used the agents • Hemodialysis-associated: 21 cases in 260,000 dialysis • Idiopathic: – 2/3 of adults presenting to allergist/immunologist – Extrapolated data: 20,592 to 47,024 cases in U.S. population S G A Brown, et al., Middleton’s Allergy 8th edition, 2013, 1237-1259.
  30. 30. Estimated incidence S G A Brown, et al., Middleton’s Allergy 8th edition, 2013, 1237-1259.
  31. 31. Estimated incidence S G A Brown, et al., Middleton’s Allergy 8th edition, 2013, 1237-1259.
  32. 32. Classification • By frequency and presentation PA. Greenberger, Immunol Allergy Clin N Am 27 (2007) 273–293 K Lenchner, et al., Curr Opin Allergy Clin Immunol 3 (2003) 305–311
  33. 33. Classification • By treatment difficulty PA. Greenberger, Immunol Allergy Clin N Am 27 (2007) 273–293 K Lenchner, et al., Curr Opin Allergy Clin Immunol 3 (2003) 305–311
  34. 34. Classification • By variations PA. Greenberger, Immunol Allergy Clin N Am 27 (2007) 273–293 K Lenchner, et al., Curr Opin Allergy Clin Immunol 3 (2003) 305–311
  35. 35. Theories of pathogenesis PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014 • Hidden allergen – Food additives? – Food itself? – Latex?
  36. 36. Theories of pathogenesis PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014 • Aberrant cytokine profile lowering the threshold for mast cell degranulation – Increase in Th2 cytokines (IL-4, IL-5, and IL-13)
  37. 37. Theories of pathogenesis PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014 • Female hormone effect on mast cells and/or basophils – Episodes are more common in females patients… why?
  38. 38. Theories of pathogenesis PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014 • An alteration in the T-cell population – Current acute idiopathic anaphylaxis patients had a higher percentage of CD3+HLA-DR+ cells than those in remission – Patients with breakthrough episodes during prednisone Rx and who were in remission had significantly higher percentage of activated B cells (CD19+CD23+) than normal volunteers
  39. 39. Theories of pathogenesis PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014 • Increased sensitivity to histamine at the target organ site – Patients with idiopathic anaphylaxis had • Increased sensitivity to the injection of histamine • Equal sensitivity to histamine as CIU patients • Less reactivity to histamine than AR/asthma patients – Impaired inactivation of PAF
  40. 40. Theories of pathogenesis PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014 • Presence of serum histamine releasing factor • Presence of IgE autoantibodies – No evidence whether these antibodies are active in producing mast cell degranulation
  41. 41. Theories of pathogenesis PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014 • Spontaneously increased mast cells? – A study of mast cell no. from skin Bx • Normal, 38 cells/mm2 • Idiopathic anaphylaxis or unexplained flushing, 72 cells/mm2 • Urticaria pigmentosa or indolent systemic mastocytosis, nonlesional skin, 168 cells/mm2 • Urticaria pigmentosa, lesional skin, 597 cells/mm2 • indolent systemic mastocytosis, lesional skin, 721 cells/mm2
  42. 42. Differential diagnosis PA. Greenberger, Immunol Allergy Clin N Am 27 (2007) 273–293
  43. 43. Differential diagnosis PA. Greenberger, Immunol Allergy Clin N Am 27 (2007) 273–293
  44. 44. Differential diagnosis PA. Greenberger, Immunol Allergy Clin N Am 27 (2007) 273–293
  45. 45. Differential diagnosis PA. Greenberger, Immunol Allergy Clin N Am 27 (2007) 273–293
  46. 46. Differential diagnosis PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014
  47. 47. Differential diagnosis PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014
  48. 48. Differential diagnosis PA. Greenberger, Immunol Allergy Clin N Am 27 (2007) 273–293
  49. 49. Investigations PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014 • Skin tests to foods or to drugs – Using standard commercially available extracts – Using fresh food • Serum-specific IgE to foods and drugs • Diagnostic-therapeutic trial with prednisone • Oral challenge
  50. 50. Investigations PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014 • Serum anti-alpha-gal IgE • Baseline and during anaphylaxis serum tryptase • Baseline and during anaphylaxis 24- hr urinary histamine metabolites • Prostaglandin D2 (urine or plasma or urinary metabolite 9a, 11b- prostaglandin F2)
  51. 51. Investigations PA. Greenberger, Immunol Allergy Clin N Am 27 (2007) 273–293 • Peripheral blood c-KIT mutation for codon D816V • Bone marrow examination • Skin biopsy • Bone scan • Complement (C4) determination
  52. 52. Approach K Lenchner, et al., Curr Opin Allergy Clin Immunol 3 (2003) 305–311
  53. 53. Approach K Lenchner, et al., Curr Opin Allergy Clin Immunol 3 (2003) 305–311
  54. 54. Approach K Lenchner, et al., Curr Opin Allergy Clin Immunol 3 (2003) 305–311
  55. 55. Approach K Lenchner, et al., Curr Opin Allergy Clin Immunol 3 (2003) 305–311
  56. 56. Therapy of anaphylaxis S G A Brown, et al., Middleton’s Allergy 8th edition, 2013, 1237-1259. • IMMEDIATE ACTION – Perform assessment. – Check airway and secure if needed. – Rapidly assess level of consciousness. – Vital signs • TREATMENT – Epinephrine – Supine position, legs elevated – Oxygen – Tourniquet proximal to injection site
  57. 57. Therapy of anaphylaxis S G A Brown, et al., Middleton’s Allergy 8th edition, 2013, 1237-1259. • DEPENDENT ON EVALUATION – Start peripheral intravenous fluids – H1 and H2 antihistamines – Vasopressors – Corticosteroids – Aminophylline – Glucagon – Atropine – Electrocardiographic monitoring – Transfer to hospital
  58. 58. Therapy of anaphylaxis S G A Brown, et al., Middleton’s Allergy 8th edition, 2013, 1237-1259.
  59. 59. Therapy of anaphylaxis S G A Brown, et al., Middleton’s Allergy 8th edition, 2013, 1237-1259.
  60. 60. Therapy of anaphylaxis S G A Brown, et al., Middleton’s Allergy 8th edition, 2013, 1237-1259.
  61. 61. Long-term managements PA. Greenberger, Immunol Allergy Clin N Am 27 (2007) 273–293 • For IA-I patient (<5 attacks/year or <2 attacks in 2 months) – Expectant management with the triple therapy should an episode occur • Epinephrine, prednisone, and H1 antagonist – H1 antagonist should be used daily – Epinephrine and prednisone must be available at all times
  62. 62. Long-term managements PA. Greenberger, Immunol Allergy Clin N Am 27 (2007) 273–293 • For IA-F patient (6 attacks/year or >/=2 attacks in 2 months) – Empiric treatment = helpful in reducing the frequency and severity • Prednisone 60-100 mg OD for 7 days and then 60 mg AD • Cetirizine(10) OD (or equivalent H1 antagonist) • Optional albuterol 2 mg b.i.d/t.i.d
  63. 63. Additional managements S G A Brown, et al., Middleton’s Allergy 8th edition, 2013, 1237-1259. • Obtain thorough Hx for drug allergy • Administer drugs orally rather than iv • Check all drugs for proper labeling. • Keep patients in the office 20 to 30 minutes after injections. • observation period after mAb Rx: – 2 hr for the first 3 injections – 30 minutes for subsequent injections
  64. 64. Additional managements S G A Brown, et al., Middleton’s Allergy 8th edition, 2013, 1237-1259. • Have patient wear and carry warning identification tags
  65. 65. Additional managements S G A Brown, et al., Middleton’s Allergy 8th edition, 2013, 1237-1259. • Teach self-injection of epinephrine, and advise patients to carry an epinephrine autoinjector.
  66. 66. Additional managements S G A Brown, et al., Middleton’s Allergy 8th edition, 2013, 1237-1259. • Use preventive techniques when patients undergo a procedure or take an agent that places them at risk – Pretreatment – Provocative dose challenge – Desensitization
  67. 67. Additional managements PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014 • Avoid taking drugs that might complicate treatment or worsen an event – Beta-adrenergic blocking agents – ACEI/ARB – Monoamine oxidase inhibitors – Certain TCA (eg, amitriptyline)
  68. 68. Drug avoidance PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014 • Beta-adrenergic blocking agents – Antagonize the beta- stimulatory effects of endogenously secreted and exogenously administered epinephrine.
  69. 69. Drug avoidance PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014 • ACEI/ARB – Block the compensatory response to hypotension that is induced by the activity of angiotensin-2 – Prevent the catabolism of kinins, which are synthesized during an anaphylactic event
  70. 70. Drug avoidance PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014 • MAOI – Prevent epinephrine catabolism by inhibiting its degradation by monoamine oxidase
  71. 71. Drug avoidance PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014 • TCA – Prevent epinephrine catabolism by preventing reuptake of norepinephrine at nerve endings
  72. 72. Additional managements PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014
  73. 73. Additional managements PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014
  74. 74. Prognosis PA. Greenberger, Immunol Allergy Clin N Am 27 (2007) 273–293 • Rate of remission (no episodes for 1 year and no prednisone) was: – 48% in patients who had IA-G – 40% in patients who had IA-A • The prognostic factors for remission or prednisone responsiveness remain uncertain
  75. 75. Prognosis PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014 • Vast majority of patients gradually improve – Including patients who have frequent episodes and require prednisone and H1 (and/or H2 antagonists or albuterol) for months or even 2 to 3 years • Episodes decline in frequency • Remissions occur in many instances but not necessarily in the absence of empiric treatment
  76. 76. Future therapy P Warrier, et al., Ann Allergy Asthma Immunol (2009) 102, 257-258 • Omalizumab – Very helpful for prevention of attacks – No current consensus dosage for IA – Reported successful dosages • 300 mg q 4 weeks for 14 months • 375 mcg sc q 2 weeks for 12-yr old boy PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014 T J Pitt, et al., J Allergy Clin Immunol (2010) 126:2, 415
  77. 77. Future therapy PA. Greenberger, et al., Article In-press, J Allergy Clin Immunol Pract 2014 • Methylene blue – A novel potential treatment for refractory anaphylaxis – Competitive inhibitor of guanylate cyclase, which may block vasodilation caused by nitric oxide – Adult dosage: Methylene blue 1%, 1-2 mg/kg in 100 mL of 5D/NSS iv drip over 20 minutes
  78. 78. Take home message • Idiopathic anaphylaxis is a diagnosis of reasonable exclusion • Acute Mx: The same as other anaphylaxis • For IA-F – 3-month empiric course of prednisone and H1 antagonist, +/- albuterol, be used to reduce the number and severity • For IA-I – Expectant management with the triple therapy of epinephrine, prednisone, and H1 antagonist be used
  79. 79. Take home message • Epinephrine should be available to patient at all time • Patient education (especially self- injection of epinephrine) and identification tag is very important • Remission can occur
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