ANGIOEDEMA: Pathophysiology and Management

1. ANGIOEDEMA: Pathophysiology and Management Stephanie Johnson PGY 3 Otololaryngology – Head and Neck Surgery October 15, 2008

2. Case • GM • 71 year old male, African American HPI: • Presented to the ER on Oct 5, 2005 • C/o swelling in mouth and face with increasing ‘tightening’ of his throat, prog over 24 hrs • Denies new medications, no med or food allergy • Never experienced these symptoms before

3. Case PMHx: • Hypertension • DM • COPD • Hypercholesterolemia • BPH • LBP FMHx: • No known history of angioedema

4. Case PSx: • Negative Social Hx: • 40 pack years tobacco smoking, negative for EtOH consumption

5. Case Meds: • Lisinopril • HCTZ • Simvastatin • Metformin • Atenolol Allergies: NKDA

6. Case Px: Vitals – VSS, sats 97% R/A • Increased WOB • No stridor or voice change • Edema of lips and tongue • Posterior pharyngeal wall not well visualized • FNL – unilateral BOT, lateral hypophyarngeal wall edema, unable to visualize hemilarynx

7. Case

8. Case DDx: • Angioedema • Allergic contact dermatitis • Facial cellulitis • Facial lymphedema • Autoimmune (Sjogren’s, SLE) • Hypothyroidism • SVC syndrome • Chelitis granulomatosa

9. Case Management: • Initially always ABCs! • Placed in monitored setting (ER - Resuscitation) • Meds: given Benadryl, dexamethazone, epi neb and sub q by ER physician • Patient taken to OR for attempted fiberoptic nasotracheal intubation +/-tracheotomy tube placement

10. ANGIOEDEMA

11. Background Definition: • Rapid nonpitting edema of the dermis, subcutaneous tissue, mucosa and submucosal tissues

12. Background

13. Background Areas of involvement: • Face • Lips • Larynx • Extremities • Genitals • Intestines • If involvement of face/larynx = potentially life-threatening • 94% of the time involves structures in the H&N**1

14. Background Epidemiology: • 10% of Americans have an episode once in their lifetime • Usu in 3rd/4th decades of life2 • M=F • Attacks usually self-limiting and resolve in 24-48 hours • Principal cause of mortality is a/w compromise

15. Background Basic Pathophysiology: • Increased vascular permeability in the submucosal, subcutaneous, and deep dermal tissues. • Mediated by vasoactive substances: • Histamine • Bradykinin • Products of complement cascade: C3a, C5a 1

16. Background 5 Main Causes: • Hereditary C1INH deficiency • Acquired C1INH deficiency • ACE inhibitors • Allergic reactions • Idiopathic

17. Background Can sub-divide the causes of angioedema by mediators involved: Bradykinin – Induced: • Hereditary or acquired C1 inhibitor deficiency • ACE inhibitors Histamine – Induced: • Allergic angioedema Unknown • Idiopathic

18. Bradykinin Bradykinin Peptide in blood coagulation subsystem ‘contact system’ Release regulated by C1-INH Stimulus for production: Toxins Injury/inflammation Ischemia Viral infections22

19. Kinin-Kallikrein System

20. Kinin-Kallikrein System • High molecular weight kininogen is combined with prekallikrein • Prekallikrein broken down by factor XIIa to kallikrein • Kallikrein then breaks high molecular weight Aminogen to bradykinin • Bradkinin is main mediator of vasopermeability22

21. Kinin-Kallikrein System C1-INH inhibits the reaction cascade at two points: • Prevents self-activation of factor XII (PreKK) • Inhibits release of bradykinin from HMW kininogen2

22. Bradykinin

23. Bradykinin Support for Bradykinin as mediator: • Cicardi (2003)15: showed increased levels of bradykinin in affected arms of patients • BUT increased bradykinin levels in normal patients taking ACEIs (prolongs survival of bradykinin)

24. 1. Hereditary Angioedema (HAE) Rare (1:50 000-1:150 000) Autosomal dominant No ethnic or sexual prediliction Individuals affected = usu heterozygous Disorder of C1 inhibitor (C1INH)2

25. Hereditary Angioedema (HAE) Genetics - C1INH: C1 inhibitor – heavily glycosylated serine protease inhibitor Chromosome 11q11-13.2 Single dysfunctional allele results in disease2

26. Hereditary Angioedema (HAE) C1INH: Only regulator of classical complement pathway activation Involved in: Contact system (XII and kallikrein) Complement cascade (C1r,C1s, MASP 2) Intrinsic coagulation cascade (XI, plasmin, tPA) Low levels C1INH OR dysfunctional C1INH = HAE2-4

27. Hereditary Angioedema (HAE) 2 types of HAE: • Type I (85%) • low levels of C1INH and functional deficiency • Type II (15%) • Normal protein concentration but functional defect2-4

28. Hereditary Angioedema (HAE) Diagnosis – Type I or II: • Measure C1INH antigen and functional levels • Type I – values <50% normal • Problem: • absolute C1INH level is NOT correlated with freq or degree of symptoms2,3

29. Hereditary Angioedema (HAE) Epidemiology: Onset of attacks usually w/in 2nd decade of life Time of onset to diagnosis 3-8 years

30. Hereditary Angioedema (HAE) Clinical Presentation: • Repeated episodes of edema (NON pruritic and NON pitting): • Face • Extremities • Genitals • Intestines (w/ pain, N/V/D) • Larynx (less common) **Combination and migratory attacks common2-4,15

31. Hereditary Angioedema (HAE) Clinical Presentation: • Laryngeal edema • Usually in 3rd decade of life • Lifetime incidence of 70% • Retrospective review (Bork, 2000): 40% pt’s lost family member to asphyxiation16

32. Hereditary Angioedema (HAE) Clinical Presentation: Erythema marginatum and macular rash in SOME patients ***NO urticaria Swelling increases over 24 hours then subsides over next 24-72 hours Frequency, duration and severity of symptoms VARIABLE even w/in same family2,3

33. Hereditary Angioedema (HAE) Clinical Presentation: • Recognized triggers: • OCP (Estrogen – containing) • Menses • Trauma • Infection • Stress • Dental surgery**(trigger for laryngeal attack)13,15

34. Hereditary Angioedema (HAE) Triggers: BUT all anecdotal evidence (no systematic investigation) EXCEPT estrogen (Bork 200316, Bouillet 200317) Female HAE patients have increased attacks during exposure to high levels of estrogens (pharmacologically or naturally).

35. Hereditary Angioedema (HAE) Labs: 1) C1INH - low levels, or elevated levels of dysfunctional C1 esterase inhibitor (detected by an immune assay). 2) Between attacks, low levels of C4 are noted13,15.

36. Hereditary Angioedema (HAE) Economic/Burden: Untreated patients lose up to 100-150 work days/year Morbidity ~50%2

37. Hereditary Angioedema (HAE) Diagnostic Criteria: A) Clinical: • Self-limited, angioedema without urticaria, recurrent and >12 hours • Self-remitting abdo pain without clear organic etiology, recurrent and >6hrs • Recurrent laryngeal edema23

38. Hereditary Angioedema (HAE) Diagnostic Criteria: B) Laboratory: • C1INH<50% at 2 sep determinations with patient at basal condition • C1INH function <50% “ • Mutation in C1INH gene altering protein syn/function *low C4 not mentioned in criteria although part of initial w/u23

39. Hereditary Angioedema (HAE) Supportive treatment: Laryngeal edema: Prudent use ETT intubation Monitored setting until resolution of attack Steroids/antihistamines NOT useful Neb epi may decrease the vascular component of edema but doesn’t change the underlying process

40. Hereditary Angioedema (HAE) Supportive treatment: Intestinal edema: Aggressive replacement fluid losses (3rd spacing and V/D) Pain management Non-sedating anti-emetics Avoid interventional procedures unless unusual s/s (hematemesis, hematochezia)

41. Hereditary Angioedema (HAE) Established Pharmacologic Treatments: Prophalaxis: • Androgen derivatives • Antifibrinolytic agents Acute attacks: 3) FFP (replacement) 4) Purified C1INH** (not available in US,Canada)4

42. Hereditary Angioedema (HAE) Mechanism of action: 1) Androgens (Danazol) • Stimulate hepatocytes and other cells to secrete more C1INH 2) Antifibrinolytics (Transexamic acid) • Inhibits fibrinolysis and reduces consumption of C1INH4

43. Hereditary Angioedema (HAE) Mechanism of action: 3) FFP • Replaces C1INH missing/dysfunctional in recipient • Purified C1INH • Replaces C1INH4

44. Hereditary Angioedema (HAE) Recent Study (CSL Behring): The I.M.P.A.C.T. trial (International Multi-centre Prospective Angioedema C1-inhibitor Trials19 • Phase III study conducted in N America and Europe • Comparing human pasteurized C1-INH vs placebo for speed of relief of symptoms • Studying patients with acute abdominal or facial HAE • Found

45. Hereditary Angioedema (HAE) Future Therapies: 2 Treatments Under Investigation: • DX-88 • Bradykinin Antagonist – Icatibant

46. Hereditary Angioedema (HAE) DX-88 • binds and inhibits proteolytic activity of kallikrein • 300x more specific than C1INH • Lumry et al (2006)20 showed successful resolution symptoms in all 215 attacks treated with DX-88

47. Kinin-Kallikrein System

48. Hereditary Angioedema (HAE) Bradykinin antagonist – Icatibant • potent, selective bradykinin receptor antagonist • Bork et al (2007)21 showed treatment considerably shortened duration of attacks compared with untreated attacks (1.0 hr vs several hrs)

49. Hereditary Angioedema (HAE) Resolution after attack - not well understood Theories: • Consumption of available substrates for kallikrein • Removal of trigger

50. 2. Acquired Angioedema (AAE) 2 Types: • Type I (AAE-I) • associated with other diseases, most commonly B-cell lymphoproliferative disorders • Type II (AAE-II) • an autoimmune process (autoantibody directed against the C1 inhibitor molecule (C1-INH)).