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  1. 1. Angioedema
  2. 2. Outline • Angioedema • Classification • Clinical presentation • C1 inhibitor • Hereditary Angioedema • Acquired Angioedema • Idiopathic Angioedema
  3. 3. Angioedema • Localized, transient, episodic edema of the deeper layers of the dermis and subcutaneuous tissue or of the mucosa of the GI tract, respiratory tract • Result of interstitial edema from mediators affecting capillary and venule permeability • Caused by extravasation of plasma in the affected areas, which at times is accompanied by nonspecific, minimal cellular infiltrate Frigas and Nzeako: Clinical Reviews in Allergy and Immunology
  4. 4. Episodes of angioedema may be classified in two broad categories: • Acute angioedema (single episode) • Acute recurrent angioedema (three or more episodes of angioedema within a 3-6 month period) Frigas and Nzeako: Clinical Reviews in Allergy and Immunology
  5. 5. Classification Frigas and Nzeako: Clinical Reviews in Allergy and Immunology
  6. 6. Major caused of urticaria and angioedema 1. Drug reactions 2. Food or food additives 3. Inhalation, ingestion of, or contact with Ag 4. Transfusion reaction 5. Infection : bacterial, fungal, viral, and helminthic Allen P. Kaplan : Middleton’s Allergy 7 edition
  7. 7. 6. Insects (papular urticaria) 7. Collagen vascular diseases 8. Malignancy: angioedema with acquired C1 and inactivator ( INH) depletion 9. Physical urticarias 10. Urticaria pigmentosa: systemic mastocytosis Allen P. Kaplan : Middleton’s Allergy 7 edition
  8. 8. 11. Hereditary diseases 1. Hereditary angioedema 2. Familial cold urticaria 3. C3b inactivator deficiency 4. Amyloidosis with deafness and urticaria (Muckle-Wells syndrome) 12. Chronic autoimmune urticaria and angioedema 13. Chronic idiopathic urticaria and angioedema 14. Idiopathic angioedema Allen P. Kaplan : Middleton’s Allergy 7 edition
  9. 9. M. Bas: Allergy 2007
  10. 10. Kanokvalai Kulthanan et al: Clinical and Developmental Immunology 2007
  11. 11. Kanokvalai Kulthanan et al: Clinical and Developmental Immunology 2007
  12. 12. Clinical presentation • Angioedema of the skin is nonpitting, with ill-defined margins • Skin is swollen, tender, and warm • Frequently a burning sensation is present, but pruritus is typically uncommon (fewer mast cell and sensory nerve ending) • Attacks of angioedema may last a few days and usually resolve spontaneously Frigas and Nzeako: Clinical Reviews in Allergy and Immunology
  13. 13. • The time from onset of angioedema to complete obstruction of the upper airway may vary from minutes to 14 hr • Intestinal obstruction may result from angioedema of the wall of the GI tract • Nausea, vomiting, and abdominal pain may be severe at times, mimicking acute abdomen, rarely diarrhea Frigas and Nzeako: Clinical Reviews in Allergy and Immunology
  14. 14. • Fever and leukocytosis are unusual in angioedema • Cases of cerebral angioedema, leading to migraine and transient ischemic attacks have been described Frigas and Nzeako: Clinical Reviews in Allergy and Immunology
  15. 15. Kanokvalai Kulthanan et al: Clinical and Developmental Immunology 2007
  16. 16. Kanokvalai Kulthanan et al: Clinical and Developmental Immunology 2007
  17. 17. C1 Inhibitor • Complement regulatory protein • C1 INH is an α2-globulin of 105 kDa and is synthesized mainly by hepatocytes • Major functions inhibition of autoactivation C1, bind to C1r and C1s and dissociates the C1 complex (C1r2-C1s2-C1-INH2 complex) • Inactivation of the coagulation factors XIIa, XIIf, and XIa, direct inhibition of activated kallikrein Kathleen E. Sullivan: Middleton’s Allergy 7 edition
  18. 18. Kathleen E. Sullivan: Middleton’s Allergy 7 edition
  19. 19. Kathleen E. Sullivan: Middleton’s Allergy 7 edition
  20. 20. Hereditary angioedema (C1 INHIBITOR DEFICIENCY) • 1 in 10,000 to 1 in 150,000 • Located in chromosome 11q13.1 • Heterozygous, AD but 20-25% Spontaneous mutation • Mildly increased susceptibility to infection and increased risk of SLE ( chronic consumption of C2, C4) • Angioedema not associate with urticaria Kathleen E. Sullivan: Middleton’s Allergy 7 edition
  21. 21. • Hx – Involvement airway in the absence of anaphylaxis – abdominal episodes – a positive family history – angioedema arising after trauma • 5% of people who carry a C1 inhibitor mutation are asymptomatic Kathleen E. Sullivan: Middleton’s Allergy 7 edition
  22. 22. • Half of patients have had episodes before the age of 10 years • Episodes may be as infrequent as 1/year or as frequent as 1/month and the frequency and the severity of episodes do not correlate with laboratory features Kathleen E. Sullivan: Middleton’s Allergy 7 edition
  23. 23. • The extremities, face, or genitalia are most often involved • Involved GI – abdominal pain, vomitting, rarely diarrhea • 1/3 of patients with C1 inhibitor deficiency had undergone an appendectomy or exploratory laparotomy for abdominal pain Kathleen E. Sullivan: Middleton’s Allergy 7 edition
  24. 24. • Involved airway, upper respiratory tract swelling leading to respiratory arrest • Mortality rate high as 30–40%, is mostly a result of obstruction of the upper airway • Angioedema typically progresses for 1–2 days and resolves in another 2–3 days • Common precipitants are illness, hormonal fluctuations, trauma, and stress Kathleen E. Sullivan: Middleton’s Allergy 7 edition
  25. 25. • C1 inhibitor promoter is androgen responsive, men have fewer problems in general than female patients • May also explain the common complaint that symptoms vary with menstruation • Mechanism underlying the angioedema is not completely clear but relates to the role of C1 inhibitor as an inhibitor of both the classical complement pathway activation and as an inhibitor of the kinin pathway
  26. 26. •C1 inhibitor deficiency is thought to lead to angioedema through loss of inhibitory activity for the intrinsic coagulation pathway •Factor XII (Hageman factor) activation leads to the activation of bradykinin, which is one of the most potent vasodilators known •bradykinin leads to vascular leak, and hence, angioedema •cleavage product of C2b, C2- kinin is produced by plasmin •Plasmin is itself activated by factor XII •C2-kinin has some effect on vasodilation •activation of factor XII is often due to vascular damage and collagen expose
  27. 27. • Type I : is a concomitant decrease in protein levels and function • Type II :is associated with the production normal but dysfunctional protein ( most common 85%) • Recommended that both antigenic and functional levels • Typical functional level is approximately 25–40% of normal in both types Kathleen E. Sullivan: Middleton’s Allergy 7 edition
  28. 28. • Ideally, the episodes of angioedema are prevented • Most common strategy for prevention is the use of attenuated androgens • In children, the use of androgens is discouraged due to concerns about closure of the epiphyses and tranexamic acid is often used Kathleen E. Sullivan: Middleton’s Allergy 7 edition
  29. 29. • Short-term prophylaxis for dental procedures, surgical procedures, or other situations where significant trauma • Attenuated androgens are typically used, then FFP is usually given prior to the event • Europe and Austaria, pasteurized C1 inhibitor concentrate is available for both short-term prophylaxis and treatment and is very effective Kathleen E. Sullivan: Middleton’s Allergy 7 edition
  30. 30. • Episodes also occur in children, pre-adolescent girls and adolescent girls • may be on an antifibrinolytic agent that is much less effective than an attenuated androgen • Acute episodes arise in the undiagnosed patient or in non-compliant patients, corticosteroids, epinephrine, and antihistamines have no effect – Supportive care and close observation, pharyngeal swelling can progress to airway compromise in a few hours – Narcotics are appropriate for abdominal pain Kathleen E. Sullivan: Middleton’s Allergy 7 edition
  31. 31. • C1 inhibitor concentrate is best option where available • Antifibrinolytics to reduce the severity and length of the episode and attenuated androgens may do the same (do not begin effect for 24 hr) • FFP and aprotinin have been used for acute episodes • FFP is thought to provide active substrate to enhance further edema and is not routinely used and side effects with aprotinin have limited its use Kathleen E. Sullivan: Middleton’s Allergy 7 edition
  32. 32. • Polycystic ovary syndrome (increased luteinizing hormone and testosterone are not seen, Ultrasounds demonstrate polycystic ovaries and Menstrual irregularities ) is seen in approximately one-third of female patients with C1 inhibitor deficiency • attenuated androgen therapy improves the polycystic ovaries Kathleen E. Sullivan: Middleton’s Allergy 7 edition
  33. 33. • Pregnancy poses a particular risk to both the mother and the fetus • Hormonal shifts of pregnancy lead to an increased risk of angioedema • Delivery is itself traumatic and an affected mother has a 50% chance of transmitting the disorder to her offspring Kathleen E. Sullivan: Middleton’s Allergy 7 edition
  34. 34. • Europe, C1 inhibitor is given prophylactically • USA, low-dose androgens (risks of androgenization of the baby) • FFP could be administered prophylactically; however, there are no data on this strategy Kathleen E. Sullivan: Middleton’s Allergy 7 edition
  35. 35. Acquired C1 INH deficiency • Nonhereditary angioedema characterized by normal C1-INH • Age of onset is after 30 years • Caldwell and colleagues described the first patient in 1972 • Mostly associated with lymphoproliferative disorders Lorenza Chiara Zingale: Immunol Allergy Clin N Am
  36. 36. C1-INH or the classic complement pathway was consumed by the neoplastic lymphatic tissues Autoimmune mechanism
  37. 37. • 1986, Jackson and colleagues, discovered an autoreactive immunoglobulin G against C1-INH • Autoimmune mechanism could be the cause of acquired C1-INH deficiency • Because the first patients who had autoantibodies to C1-INH looked otherwise healthy
  38. 38. • 1985, Geha and colleagues, mechanism of complement consumption • Paraproteins had immunoglobulins against the idiotypic determinants of the M components • Idiotype–anti-idiotype immune complexes fixed C1q and consumed C1-INH • Direct proof in vivo increased consumption of C1-INH was provided in 1986 by Melamed and colleagues (injected patients with radiolabeled C1-INH and C1q)
  39. 39. Acquired C1-INH deficiency was divided into two separate forms – type I, paraneoplastic, mainly associated with lymphatic malignancies or other diseases – type II, autoimmune, caused by autoantibodies to C1-INH
  40. 40. • Only 14% of patients with acquired C1 inhibitor deficiency had no associated medical condition • Lymphoproliferative diseases and acquired C1- inhibitor deficiencies • Many from B cell lymphoproliferative diseases that ranged from monoclonal gammopathies of undetermined significance (MGUS) to true malignancies (NHL) • NHL is markedly increased in patients who have angioedema and acquired C1-INH deficiency
  41. 41. • Variant rarely occurs in association with malignancies of the rectum, stomach, and breast; rheumatoid arthritis and systemic lupus erythematosus; Churg-Strauss vasculitis; lupus anticoagulant; erythrocyte sensitization; livedo reticularis; and infections with human immunodeficiency virus, hepatitis C and B viruses, Echinococcus granulosus, and Helicobacter pylori
  42. 42. • The differences between the two forms are absence of family history, late onset of symptoms (after the fourth decade of life), and response to treatment • C1-INH function and antigen, C4 and C1q markedly reduced (usually far below 50% of normal), with a normal C3 • C1-INH antigen can be normal, when elevated amounts of cleaved inactive C1-INH circulate in plasma
  43. 43. • Autoantibodies to C1-INH may be detected as immunoglobulins preventing C1-INH function or binding C1-INH • Alsenz and colleagues developed a solid- phase ELISA for detectin immunoglobulins binding to C1-INH coated to microtiter plates (simple and highly sensitivity)
  44. 44. • Course of and prognosis for angioedema with acquired C1-INH deficiency depend on the underlying disease and the availability of proper therapy for life- threatening angioedema • Angioedema attacks usually resolve without treatment, patients are exposed to the risk for laryngeal edema
  45. 45. • Successful treatment of the underlying disease has been shown to resolve angioedema symptoms • immunosuppressive regimens (cyclophosphamide, with or without steroids) have been used for suppressing the formation of anti–C1-INH autoantibodies in isolated patients who had acquired C1-INH deficiency
  46. 46. • For long-term prevention of angioedema recurrences, patients are treated with attenuated androgens and antifibrinolytic agents • Acquired C1-INH deficiency are often resistant to attenuated androgens but better response to antifibrinolytic agents
  47. 47. Frigas and Nzeako: Clinical Reviews in Allergy and Immunology
  48. 48. M. Bas: Allergy 2007
  49. 49. Treatment Adult Pediatric Comments Tranexamic acid 1–3g/day p.o. as 25–50mg/kg b.i.d.– Not available in the (Cyklokapron divided doses for t.i.d. as prophylaxis, USA prophylaxis, 1g p.o. 1.5g/day for acute q. 3–4h until episode episodes (available resolves for acute as i.v. form) episodes Epsilon 1g p.o. t.i.d. as 100mg/kg q.4–6h The only aminocaproic acid prophylaxis, 1g/h as not to exceed antifibrinolytic (Amicar) i.v. therapy for acute 30g/day as therapy. available in the attacks Oral syrup available USA, has modest for prophylaxis but efficacy. Cannot be established: 6g/day used in neonates. for children Oral dosing has <11years and significant GI side 12g/day for children effects >11years has been used successfully Kathleen E. Sullivan: Middleton’s Allergy 7 edition
  50. 50. Treatment Adult Pediatric Comments Danazol (Danocrine) 200mg p.o. q.d. as a 50–200mg p.o. q.d. Concern about starting point for as a starting point androgenization and prophylaxis (titrate for prophylaxis premature closure of to effect), 400– (titrate to effect) and the epiphyses limits 600mg p.o. q.d. for consider q.o.d. or q. the use of acute episode or 3 days in pre- attenuated short-term adolescent children; androgens in prophylaxis can use up to children. Titration to 400mg p.o. desired effect is short-term recommended prophylaxis rather than to laboratory criteria Oxandrolone 2.5–20mg p.o. t.i.d. 0.1mg/kg per day as Has less (Oxandrin) as prophylaxis prophylaxis. Not androgenizing (titrate to effect). Not proven as short- effects than Danazol proven as short- term prophylaxis or term prophylaxis or treatment in a formal treatment clinical trial Kathleen E. Sullivan: Middleton’s Allergy 7 edition
  51. 51. Bruce L:Immunol Allergy Clin N Am
  52. 52. Treatment Adult Pediatric Comments Fresh frozen plasma 1000U as treatment 10–30U/kg as Very rapid effect, (FFP) treatment (up to especially useful in 500–1000U total pregnancy C1 inhibitor 1000U as treatment 10–30U/kg as Very rapid effect, concentrate treatment (up to especially useful in 500–1000U total) pregnancy Icatibant Bradykinin receptor antagonist; awaiting trial results DX-88 Kallikrein inhibitor, has shown efficacy in early trials; could be available later in 2007 Kathleen E. Sullivan: Middleton’s Allergy 7 edition
  53. 53. Bruce L:Immunol Allergy Clin N Am
  54. 54. • ACE inhibitors, estrogen replacement therapy, and oral contraceptives should be avoided in patients with either HAE or AAE
  55. 55. Idiopathic recurrent Angioedema • Three or more episodes of angioedema have occurred within a period of 6 months to 1 year without any cause being identified • Diagnosis is made after a comprehensive evaluation has ruled out the known causes of angioedema Evangelo Frigas:Immunol Allergy Clin N Am
  56. 56. • Women are affected slightly more often than men, and at presentation 50% of patients are found to have both urticaria and angioedema • Angioedema alone in chonic urticaria and angioedema, 20% Evangelo Frigas:Immunol Allergy Clin N Am
  57. 57. • Excessive production or decreased catabolization of molecules that increase vascular permeability • Histamine, tryptase, prostaglandin F2α from mast cells, and bradykinin from inappropriate and excessive activation of the complement and kallikrein systems Evangelo Frigas:Immunol Allergy Clin N Am
  58. 58. • Food allergens (especially shellfish, nuts, and peanuts), latex, and insect venoms as well as several medications can release histamine from sensitized mast cells and may produce angioedema on an IgE-mediated basis • Some medications (narcotics, polymyxin, d- tubocurarine) may cause angioedema owing to their ability to cause direct mast cell degranulation in the absence of IgE antibodies against the drug
  59. 59. • Pathogenesis of idiopathic recurrent angioedema with or without urticaria is not known
  60. 60. • Initial work-up includes the following laboratory tests: complement C4, C1q, CH50, C1 esterase inhibitor by functional and quantitative assays, and a panel for mast cell-mediator screening, which includes measurements of tryptase and calcitonin in the serum and histamine, N- methylhistamine, and prostaglandin F2α in a 24-hour urine collection.
  61. 61. • CBC, chemistry group, serum protein electrophoresis, total serum IgE, ESR, and a thyroid cascade, which includes testing for antithyroid antibodies • Allergy skin tests or specific IgE blood tests are performed to rule out latex and food allergy
  62. 62. • Devided into “histaminergic” and “non- histaminergic” depend on response or lack respons to antihistamine • Isolated elevation of prostaglandin F2α in the urine but normal levels of the other mediators, patients may benefit from treatment with aspirin
  63. 63. • step 1, we usually start with a nonsedating or less-sedating antihistamine, such as fexofenadine, cetirizine, loratadine, or desloratadine, taken during the daytime • step 2 by adding a sedating antihistamine such as doxepin, hydroxyzine, or diphenhydramine, usually taken at bedtime • step 3, cyclosporine, nifedipine, methotrexate, androgens, warfarin
  64. 64. • treatment trials for 2 to 4 months with either colchicine 0.6 mg once or twice daily or dapsone 25 mg twice daily and titrated up to 100 mg twice daily, or sulfasalazine 500 mg once or twice daily • recombinant interferon α, ASA • Systemic glucocorticoids, although very effective for the majority of patients with recurrent angioedema
  65. 65. • prednisone 20 mg for 5 to 7 days usually without tapering • Omalizumab (case report 3 case hige IgE)
  66. 66. Summery • Classification Angioedema • C1 INH • HAE • AAE • Idiopathic angioedema • Treatmeant