Urticaria, Angioedema, and Anaphylaxis

1. Urticaria, Angioedema, and Anaphylaxis Grace Cho, MD August 10, 2010 Cooper University Hospital

2. Urticaria (or hives)

3. Urticaria (or hives) a kind of skin rash notable for dark red, raised, itchy bumps. Tow categories; by allergic reactions or non-allergic causes. Acute urticaria; lasting less than 6 weeks (of an allergic trigger). Chronic urticaria (hives lasting longer than six weeks) , rarely due to an allergy.

4. Acute vs Chronic Allergic trigger Viral exanthem Bacterial infection Parasitic infection Food; adult-shell fish, children-peanut Idiopathic Autoimmune cause in 30-40 %

5. Drug-induced urticaria has been known to result in severe cardiorespiratory failure. ASA, NSAID, Pcn, Vancomycin, Opiates, Anticonvulasants……

6. Physical urticarias Aquagenic: Reaction to water Cholinergic: Reaction to body heat, such as when exercising or after a hot shower Cold (Chronic cold urticaria): Reaction to cold, such as ice, cold air or water - worse with sudden change in temperature

7. Physical urticarias Delayed Pressure: Reaction to standing for long periods, bra-straps, elastic bands on undergarments, belts Dermatographic: Reaction when skin is scratched (very common) Heat: Reaction to hot food or objects Solar: Reaction to direct sunlight (rare, though more common in those with fair skin)

10. Angioedema the swelling occurs in a lower layer of the dermis , as well as in the hypodermis. around the mouth, in the throat, in the abdomen, or in other locations. Urticaria and angioedema sometimes occur together in response to an allergen in severe cases can be fatal.

11. Pathophysiology Urticaria are caused by the release of histamine and other mediators of inflammation (cytokines) from cells in the skin. causing leakage of capillaries in the dermis, and resulting in an edema which persists until the interstitial fluid is absorbed into the surrounding cells.

12. Pathophysiology Allergic urticaria  Histamine and other pro-inflammatory substances are released from mast cells in the skin and tissues in response to the binding of allergen-bound IgE antibodies to high affinity cell surface receptors. Basophils and other inflammatory cells are also seen to release histamine and other mediators

14. Pathophysiology Autoimmune urticaria  About 30 % of patients with chronic urticaria spontaneously develop auto-antibodies directed at the receptor FceRI located on skin mast cells. Chronic stimulation of this receptor leads to chronic hives. Patients often have other autoimmune conditions such as autoimmune thyroiditis.

15. Treatment for urticaria Avoid trigger Antihistamine; diphenhydramine, hydroxyzine, cetirizine and other H1 receptor antagonists. These are taken on a regular basis to protective effect, lessening or halting attacks.

16. Treatment for urticaria Stress management Additionally, methods similar to psychological pain management can be used The H2-receptor antagonists such as cimetidine and ranitidine Tricyclic antidepressants, such as doxepin For very severe outbreaks, an oral corticosteroid such as Prednisone is sometimes prescribed.

17. Hereditary angioedema (HAE)

18. erythema marginatum of HAE

19. HAE Urticaria is very rare in HAE, and the absence of urticaria is a strong clinical differentiator between HAE and allergic angioedema. Repeated episodes of swelling without urticaria should prompt suspicion of HAE. Peripheral swelling is common with HAE, erythema marginatum can occur. Pain with peripheral swelling can occur, especially when weight-bearing areas are affected by swelling.

20. HAE Recurrent swelling and/or abdominal attacks without urticaria (erythema marginatum in ~25% of cases may be confused with urticaria) Long-duration attacks, requiring several days to resolve No response to antihistamines or corticosteroids ;Family history in ~75% of patientsDevelops in childhood

21. HAE Recurrent angioedema lasting > 24 hours; Recurrent, colicky abdominal pain

22. HAE Pathophysiology In almost all cases, symptoms are caused by deficient C1-INH levels (type I) or dysfunctional C1-INH (type II). A minority of patients have type III HAE, which does not involve C1-INH. C1-INH regulates a variety of steps in the contact, complement, and coagulation pathways

23. Pathophysiology of HAE. Low C1-INH levels or dysfunctional C1-INH can allow uncontrolled release of bradykinin, leading to increased vascular permeability and edema.

24. HAE lab findings low C4 levels low C1-INH level or function are necessary to confirm a diagnosis of type I or II HAE.

25. Treatment for HAE Human C1-INH concentrate, which replaces the C1-INH deficiency, or Ecallantide, which reduces bradykinin formation and the resulting angioedema by inhibiting kallikrein. only approved in the United States in late 2009.

26. To Reduce the Risk of HAE Attacks  Infections may trigger HAE attacks by activating complement and should be treated promptly. Estrogens, such as contraceptives and hormone replacement therapy, increase the risk for HAE and should be avoided if possible ; it may involve lowering of C1-INH levels or increasing factor XII and prekallikrein levels.

27. To Reduce the Risk of HAE Attacks ACE inhibitors also increase HAE risk by slowing the catabolism of bradykinin, thereby increasing bradykinin levels and the risk of swelling. Stress, either physical or psychological, increases the risk for HAE attacks. Short-term medical prophylaxis should be considered when such stresses are expected

28. Long-term HAE Prophylaxis Androgens Attenuated androgens are a time-tested and effective approach to HAE prophylaxis. result from increased hepatic biosynthesis of C1-INH.

29. Long-term HAE Prophylaxis The commonly used agents include danazol, stanozolol, oxandrolone, and methyltestosterone. danazol and stanozolol are approved for HAE prophylaxis, but only danazol is currently commercially available in the United States.

30. Long-term HAE Prophylaxis C1-INH Concentrate A nanofiltered human plasma-derived C1-INH concentrate has been approved by the FDA for HAE prophylaxis

31. Long-term HAE Prophylaxis Antifibrinolytic Agents Antifibrinolytics are used for HAE prophylaxis in Europe but are not approved or widely used in the United States. They are generally considered less effective than androgens.

32. Long-term HAE Prophylaxis Antifibrinolytic Agents useful when androgens and C1-INH agents are contraindicated (eg, in children or pregnant women) or have intolerable adverse effects. Tranexamic acid 1-3 g/day in 3 equal doses is regarded as the fibrinolytic agent of choice. The other commonly used agent, epsilon-aminocaproic acid 8-12 g/day in 4 equal doses, is considered to be less effective and to have a worse adverse-event profile.

33. Short term HAE Prophylaxis Because surgical and dental procedures can trigger an HAE attack, prophylactic therapy should be considered for patients with HAE before they undergo a procedure.

34. Short term HAE Prophylaxis C1-INH concentrate should be administered 1-2 hours before the procedure; Androgens should be provided as a short course starting 7-10 days before the procedure and continuing for 48 hours afterward; and

35. Short term HAE Prophylaxis Fresh frozen plasma is regarded by some authorities as being more effective than androgens. However, to minimize this risk of viral infection, solvent-detergent plasma is preferred; should be administered several hours before the procedure.

36. In summary HAE HAE is a rare disease resulting from C1-INH deficiency or dysfunction. The characteristic symptom is angioedema without urticaria, which may affect the extremities (usually causing discomfort), bowels (often causing severe pain), or face and larynx (life-threatening due to possible airway closure).

37. In summary HAE Treatment for acute HAE attacks includes supportive care (pain relief and fluid replacement for abdominal attacks, airway maintenance for laryngeal attacks) and treatment with medications specific to the contact pathway.

38. In summary HAE human C1-INH concentrate, which replaces the C1-INH deficiency, or ecallantide, which reduces bradykinin formation and the resulting angioedema by inhibiting kallikrein. Note that these medications were only approved in the United States in late 2009.

39. In summary HAE Patients may also require prophylactic therapy. Long-term therapy with C1-INH concentrate, attenuated androgens, or antifibrinolytics should be considered for patients with a history of frequent and/or severe HAE attacks. Short-term prophylaxis should be considered for patients planning to experience stress, such as dental procedures or surgery.

41. Anaphylaxis systemic, immediate hypersensitivity reaction caused by exposure to a specific antigen. the four types of hypersensitivity reactions,

42. 4 types of hypersensitivity reactions Anaphylactic Cytotoxic Immune complex Cell mediated

43. Anaphylaxis activated immunoglobulin E (IgE), which reacts with effector cells (mast cells and basophils).

45. Anaphylaxis These cells, in turn, release histamine, serotonin, leukotrienes, and prostaglandins and induce a range of signs and symptoms

47. CAUSES OF ANAPHYLAXIS including foods, insect stings, medications, latex rubber, and radiocontrast dyes. In many cases, the cause is not identified and the reaction is described as idiopathic. Research has shown that up to two thirds of all anaphylactic reactions are idiopathic.

48. Hymenoptera (stinging insects ) and Anaphylaxis The order Hymenoptera includes Apis species, ie, bees (European, African), Vespids (wasps, yellow jackets, hornets), and ants.

49. Pathophysiology Hymenoptera Stings and anaphylaxis Anaphylaxis may occur and is typically a result of sudden systemic release of mast cells and basophil mediators.

50. Pathophysiology Hymenoptera Stings and anaphylaxis Target organs are the skin, vascular system, and respiratory system. immunoglobulin E (IgE)–mediated allergic reactions.

51. Mortality/Morbidity Large local reactions occur in 17-56% of those stung. Individuals with large local reactions have a 5-10% risk of subsequent development of a severe systemic reaction if re-stung. Wasps and bees cause about 100 deaths yearly in the United States.

52. History Rapid onset of symptoms is the rule; 50% of deaths occur within 30 minutes of the sting, and 75% occur within 4 hours. Fatal allergic reactions can occur as the first generalized reaction. Far more common, however, is a fatal reaction following a previous, milder generalized reaction. The shorter the interval since the last sting, the more likely it is that a severe reaction will take place.

54. Local reactions Hymenoptera Stings and anaphylaxis Pain , Edema is marked and may extend to 10 cm from site of envenomation. Bleeding may occur at site of sting. Pruritus is common. Vasodilation may produce a sensation of warmth. Nausea or vomiting may occur without generalization. Visceral pain may occur with stings in the gastrointestinal (GI) tract after ingestion of the insect.

55. Generalized (systemic) reactions Urticaria Confluent red rash Shortness of breath, wheezing Edema in airway, tongue, or uvula Weakness, syncope Anxiety, confusion Chest pain

56. Treatment of Anaphylaxis Stop offending drug or blood product Consider tourniquet proximal to site Airway Breathing Circulation Vital signs

57. VA Pre hospital care Provide supplemental oxygen if possible Diphenhydramine limits the size of the local reaction. Clean the wound and remove the stinger if present. Apply ice or cool packs. Elevate the extremity to limit edema.

58. VA Treatment Intramuscular or subcutaneous epinephrine should be initiated immediately in the event of severe reaction. Epi 1: 1000 0.01 ml/kg IM

59. VA Emergency Department Care Oxygen Epi 1:1000 0.01 ml/kg IM every 5 minutes, then infusion if necessary B-agonist Nebulized prn Corticosteroids ; Methylprednisolone 1-2 mg/kg IV q6 H2 blockers such as ranitidine and cimetidine may be given intravenously. In cases of refractory anaphylaxis, glucagon may be helpful if concomitant beta-blockers are preventing adequate response to epinephrine treatment.

60. VA Emergency Department Care Glucagon 1-5 mg IV over 5 min , then 5-15 ug/min infusion Volume resuscitation, IV NS Vasopressors such as dopamine can be used to provide vascular support. Patients developing respiratory arrest require ventilatory support. Blood products may be required in the event of disseminated intravascular coagulation (DIC).

61. VA Further Inpatient Care Consider further inpatient care for all patients with life-threatening reactions. (bimodal, or for protracted cases) Observe for sufficient duration -Rebound phenomena may occur up to 12 hours after sting. Respiratory and circulatory support may be needed if secondary organ damage has occurred.

62. Prophylactic meds allergic to Radiocontrast or Latex Oral or IV regimen; Benadryl 50 mg PO or IV 1 H pre op Prednisone 50 mg PO or IV 13, 7, and 1 H pre op

63. What next after VA? Refer pt to allergist for VA testing and IT prn Provide means to self-administer epinephrine and diphenhydramine to all patients with generalized reactions, advise them to wear medic alert bracelets.

64. What next after VA? Continue treatment with steroids for 3-5 days. Continue administering antihistamines for at least 24 hours continuous dosing. Cool sting sites for 12 hours. Keep extremities with stings elevated for 12 hours when development of edema may present difficulties.

65. Advice to prevent VA Avoid using perfumes or hygiene products that include perfumes, as these may attract flying Hymenoptera. Avoid wearing bright colors. Avoid bare feet Avoid known hive or nest locations.

66. Advice to prevent VA Do not use noisy equipment such as lawn mowers, edgers, or blowers within 50 yards of beehives or 150 yards of Africanized bee colonies. Do not smash arms when confronted by bees or wasps because smashing one often incites others to sting.

67. Medicolegal Pitfalls Failure to remove stinger may produce infection or granulomatous reaction. Failure to observe patient after treating a generalized reaction may result in unobserved rebound. Failure to provide means of self-treatment Refer these patients to an allergist for assessment.

68. Trivia Which sex of stinging insects is able to sting? M or F vs both Is that a bee or wasp that can sting repeatedly? Or both/neither? Which one has more venom; bee or hornet? Or both same? What is wiser? To stay still or to run away when the bee is landing on you.

69. Trivia The stinger is a modified egg-laying apparatus; so, only females can sting. Bees can only sting once. The stinger then will not come out. To escape, the bee rips its body away and flies off to die soon. It dies in order to sting. For that reason, a bee will only sting if it feels either its life is in immediate danger, or the hive is in danger (for those species that live in colonies; most bees do). Wasps and hornets can sting over and over again. They do not die from that. The positive side is that they do not deliver as much venom in a single sting than a bee so a single sting from a wasp or hornet tends to be less painful (an exception being the European hornet).

70. Q & A

71. References Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med. 2008;359:1027-1036. Abstract Gompels MM, Lock RJ, Abinun M, et al. C1 inhibitor deficiency: consensus document. Clin Exp Immunol. 2005;139:379-394. Abstract Frank MM. 8. Hereditary angioedema. J Allergy Clin Immunol. 2008;121(suppl):S398-S401. Bernstein JA. Hereditary angioedema: a current state-of-the-art review, VIII: current status of emerging therapies. Ann Allergy Asthma Immunol. 2008;100(suppl2):S41-S46. Zuraw BL. Hereditary angioedema: a current state-of-the-art review, IV: short- and long-term treatment of hereditary angioedema: out with the old and in with the new. Ann Allergy Asthma Immunol. 2008;100(suppl2):S13-S18. Byrd JB, Adam A, Brown NJ. Angiotensin-converting enzyme inhibitor-associated angioedema. Immunol Allergy Clin North Am. 2006;26:725-737. Abstract Gern J, Busse W ; Contemporary Diagnosis and management of Allergic Diseases