1. Hereditary Angioedema: Diagnosis and Therapeutic Interventions
Alexander L. Ramirez, M.D.
Chief, Otolaryngology McKay Dee Hospital

2. Will Smith in “Hitch”
2005

3. Introduction
Recurrent episodes of angioedema WITHOUT urticaria or pruritus
Skin or mucosal tissue (Upper airway or GI)
Self limited, but if larynx involved risk of fatal asphyxiation
Mortality was 30% prior to treatments available now

4. UFC Fight

6. Hereditary Angioedema
Recurrent bouts of swelling
Skin
GI Tract
Upper Airway
First described in 1888 by Sir William Osler

7. Pathophysiology C1 Inhibitor Deficiency or Dysfunction
C1 INH circulates in blood as an acute phase protein
C1 INH inhibit spontaneous activation of the complement pathway
Although named for complement inhibitory activity, active in many systems
C1 Inhibitor

8. Pathophysiology
Complement pathway, Bradykinin pathway, Lectin pathway, Clotting pathway, Fibrinolytic pathway
Most important physiologic inhibitor of kallikrein.
Without C1 INH, bradykinin production unchecked and escalades
Bradykinin is a vasodilator that causes swelling and angioedema

9. Bradykinin Pathway C1 INH blocks here
C1 INH blocks production of Bradykinin
Excess Bradykinin leads to capillary leak= Angioedema

10. Bradykinin Pathway

12. Classical Pathway C1 INH C4 is cleaved so levels decrease
C1q binds Ag-Ab complex to activate
C1 INH
C1 INH displaces C1 complex so that its no longer active
C4 is cleaved so levels decrease
Abbas Ak et al. Cellular and Molecular immunology. Eight Edition

13. Hereditary Angioedema
Type I
C1 INH deficiency
Type II
C1 INH dysfunctional
Type III
diagnosed by genetic testing

14. Hereditary Angioedema
Prevalence 1:50,000 (type I) to 1:200,00 (type II)
Male = Females
No ethnic differences
AD variable penetrance
25% de novo mutations

15. Age of onset usually in 20’s
50% first attack before age 10
75% by age 15
Symptoms worse around puberty

16. Other causes of Angioedema
Often confused for Allergic Angioedema

17. Types of Angioedema Syndrome Pathophysiology Affected Prevalence
HAE type I
C1 INH deficiency
All
1:50,000
HAE type II
C1 INH dysfunction
1:250,000
HAE Type III
unknown, normal C1 function
all, woman
unknown
Acquired C1 INH deficiency
Excessive consumption of C1 INH
Older
ACE I
Inhibition of Bradykinin catabolism
all, more in African American
1:250
Allergic
Histamine response
all
1:50

18. Acquired C1 INH deficiency
Lymphoma
Rheumatoid arthritis
CLL Myeloma
SLE
W. macroglobulinemia
Stomach, Breast, Pancrease, Colon, rectal, bladder cancer
Cryoglobulinemia
Zingale LC, et al. Immunol Allerg Clinic N. Am. 2006, 26:

19. Triggers Physical Trauma Dental work intubation tongue piercing
snoring
riding a bike

20. Triggers Infection: H. Pylori
Hormonal changes: increase with puberty, pregnancy associated with more attacks
Medications
Estrogen containing meds (HRT, OCP)
Tamoxifen (Estrogen Rec modulator agonist/antagonist actions.
ACE inhibitors (ARBs ?)

21. Hereditary Angioedema

22. Clinical Characteristics
Course
Gradual worsening over 24 hrs slow recovery over hrs
Skin
Frequency
Twice a week to less than once a year GI
Onset
50% by age 10, worsening after puberty
ENT

23. Prodromal Changes Occur within 24 hrs of onset of angioedema
Serpentine, mottled, “chicken wire” pattern of erythematous discoloration
Occur within 24 hrs of onset of angioedema
Fatigue, nausea, myalgia, flu symptoms
Prodromal rash that can be mistaken for urticaria
26% of patients
erythema marginatum

24. Cutaneous attacks 97% of episodes
Extremities, Face and Genitals are most common
No pitting

25. Cutaneous attacks Starts with tingling, sensation of fullness
Progress to swelling in 2- 3 hrs.
Builds over 24 hrs and subsides in 72 hrs

26. Cutaneous attacks Temporarily disfiguring Pain and Dysfunction
Productivity loss of days a year
Type to enter a caption.

27. GI Attacks Varying degrees of GI colic from bowel wall edema
Always painful
75% N/V, abd distention
40% diarrhea
70% prodrome: fatigue, irritability, sensitivity to noise, hunger, erythema marginatum
Attacks last 4 days

31. ENT Most attack one location at time, but combo can occur Self-limited
50% will have all three locations

32. Laryngeal Attacks
Isolation or in conjunction with swelling of lips, tongue, palate
50% will have in their lifetime
Triggers: tooth extraction, oral surgery, URI
Develops of hrs (mean is 7); however, can be fulminant (9 yo died in 20 minutes)
1% require intubation/surgical intervention

33. Edematous epiglottis and AE fold
Laryngeal edema
Edematous epiglottis and AE fold

34. 3 phases 1. Predyspnea (4 hrs): globus sensation
2. Dyspnea (41 min): from onset of SOB to LOC
3. Loss of consciousness (10 min): from LOC to death
Opportunity to intervene

35. Supraglottic Edema
Edematous arytenoids

36. Facial soft tissue swelling
Airway Compromise
Lip Swelling
Base of Tongue
Swelling

37. Diagnosis
C4: 90% are low (50% less than normal) if even not during attack, but may be normal in small percentage of Asx patients so repeat)
C1 INH: low (less than 30%) in type I, may be normal in type II.
C1 INH Function: normal in type I, low (30% below normal) than type II

38. Classical Pathway C1 INH C4 is cleaved so levels decrease
C1q binds Ag-Ab complex to activate
C1 INH
C1 INH displaces C1 complex so that its no longer active
C4 is cleaved so levels decrease
Abbas Ak et al. Cellular and Molecular immunology. Eight Edition

39. @McKay sends out to ARUP, takes1-4 day
Lab Evaluation
@McKay sends out to ARUP, takes1-4 day

40. Clinical Diagnosis
Recurrent episodes of angioedema without urticaria or puritis, lasting 2-5 days
Unexplained recurrent episodes of colicky abdominal pain (esp if cutaneous angioedema)
Unexplained laryngeal edema
Angioedema without ACE, NSAIDs, or hx of allergic cause
FH of angioedema
Low C4 in patient with angioedema.
No benefit of antihistamines (if C4 levels normal can give)

41. Treatment prior to 2008, not many options 30% mortality
Now several FDA approved options.

42. Treatment of Acute Attacks
Bradykinin mediated
Does NOT respond to epinephrine, antihistamines, glucocorticoids
Goal: replace C1 INH or block production/function of bradykinin
Response within 2 hrs

43. First Line Therapies C1 INH plasm derived concentrates
Recombinant human C1 INH
Icatibant (bradykinin receptor antagonist)
Ecallantide (recombinant Kallikrein Inhibitor)
Cost: $5000 to $10000

44. pd C1 INH plasma derived C1 INH concentrate pooled from human plasma
administer IV
best studied off all the C1 INH
two types: Cinryze (Shire) and Berinert (Behring)

45. Plasma Derived C1 INH

46. pd C1INH
routine prophylaxis against angioedema attacks in adolescent and ddults (cinryze)
treatment of acute abdominal facial or laryngeal attacked of HAE(Berinert)

47. Traditional place in practice
Prophylaxis
Has been well established
Can be administered by HC provider in clinic/home or by the patient
Treatment
for acute attack in the ED
Cinryze is FDA approvedment for treatment
Dosing 1000 units IV over 10 minutse. ay give second doses 60 mints later
20 units /kg IV at rate of 4 ml/min

48. pdC1 INH Berinert (Behring) 20 units/kg
vial of drug contains 500 units of pdC1INH
through peripheral IV over 10 minutes
Must not shake because will denature
stabilize improve in 30 minutes and resolution by 2 hrs
<5% require second does
SE: HA and fever
Disease transmission: never been reported over 100 million units

50. Reconstitution

51. pdC1 INH Cinryze (Shire) and Berinert (Behring) 20 units/kg
vial of drug contains 500 units of pdC1INH
through peripheral IV over 10 minutes
Must not shake because will denature
stabilize improve in 30 minutes and resolution by 2 hrs
<5% require second does
SE: HA and fever
Disease transmission: never been reported over 100 million units

52. Dosing & Administration
For IV use only
Can be given IV push or IV drip over 10 min
administer within 3 hrs of reconstitution
Prophylaxis (Cinryze): units IV over 10 minutes Q3-4 days
Acute attack (Berinert): 20 units /kg IV at rate of 4 ml/min

53. Adverse Effects Common Headaches (7-28%) Nausea (1.8% -18%)
Rash 3.5% -10%
serious: hypersensitivity, DVT, MI, PE

54. Precautions Hypersensitivity reactions can occur
Thrombotic events have been reports in high dose pd C1 INH
Theoretical risk of transmission infectious agenst, e.g. HIV, HCV, CJD, etc

55. Efficacy of pd C1 INH Treatment (35)
1000 units pdC1 INH over 10 minutes
repeat in 60 minutes if needed.
Placebo (33)
10 cc NS over 10 minutes
NEJM 2010
37 sites
N=68

56. Results Median time to sx relief CI 1.17-4.95 , p<0.02
% patient with onset relief within 4 hrs
60% vs 42%, p=0.06
Time to complete resolution
12.3 hrs vs 25 hrs, p=0.04

57. Prophylaxis Trial # of attacks N=22 patients, 24 weeks
6.26 vs (CI ) p<0.001
Average severity
1.3 vs 1.9, p<0.001
Av duration of attack
2.1 vs 3.4, p=0.002
Number of injections
4.7 vs 15.4, p<0.001
# days of swelling
10.22 vs 29.6, p<0.001

58. Haegarda pd C1 INH SQ for prophylaxis by Behring
Home injections, FDA approved 2017
pasteurized, lyophilized from pools of human plasma
N=90, 40 IU/kg or 60 IU/kg twice weekly
SE: injection site, hypersensitivity, nasopharngitis, dizziness

59. Recombinant C1 INH
Ruconest became available in 2014 FDA approved for acute attacks in adolescents and adults (not for <13 years old)
milk of transgenic rabbits
plasma free so no risks of transmission of virus
Same activity but shorter half life
Dose: 50 units/kg (rounded up to the nearest vial ) IV
Vial: contains 2100 units
May repeat second dose, max dose is 4200 units
Reconstitute with sterile water, Inject in peripheral IV over 5 min
SE: HA, N, diarhea. Don’t given if Rabbit allergy
Never compared head to head with pd C1INH

60. median time of onset 75 to 90 minutes
Recombinant C1 INH
60 min
2 hrs
60 min prior
24 hrs
4 hrs
8 hrs
median time of onset 75 to 90 minutes

61. Ruconest
Clinical Study, Ruconest vs placebo see sx relief in 90 min vs 152 min compared to placebo
97% patient needed just one treatment
93% of patient stopped attacks for more than 3 days
Raised C1 INH to normal > 94% of patients

62. Ruconest
Clinical Study, Ruconest vs placebo see sx relief in 90 min vs 152 min compared to placebo
97% patient needed just one treatment
93% of patient stopped attacks for more than 3 days
Raised C1 INH to normal > 94% of patients

63. Recombinant C1 INH SE: headache 9% Nausea 2% Diarrhea 2%
may cause anaphylaxis, rabbit allergy
pregnancy category B

64. Icatibant Bradykinin receptor antagonist by Firazyr,
Available in 2011 (patient >18 yo)
Dose: 30 mg, given SQ slowly in abdomen
can be self administered
A second injection may be given after 6 hrs, a third as well. Max 3 does in 24 hrs.
SE: pain at injection site, Nausea, GI colic, fever
Contraindication: unstable angina because reduce coronary blood flow in animal studies

65. Ecallantide
Kaliikrein inhibitor blocks the production of bradykinin by inhibiting kalidrein
Genetically engineered in yeast, Pichia Pastoris
FDA approved in 2008 (age >12)
3 placebo controlled studies showed Ecallantide more than placebo in improving sx
anaphylaxis reported in 2-3% in clinical trials
SQ injection
Langhurt H. Lancet. 2012:379,

66. Ecallantide Adult dose 30 mg, comes in 10 mg vials
SQ injection so more convienet: three injection separate areas: and, upper arm, and thigh
anatomic distant from the site of angioedema
A second dose may be given 1 hr to 24 hrs after the first
Not recommended outside a hospital given anaphylaxis

67. Second Line Therapy Plasma
Two types: solvent/detergent treated plasma vs FFP
S/D plasma preferred because lower risk of viral transmission
Dose: 2 units of plasma, may repeat every 2-4 hrs until improvement
comorbid condition: ml/kg because risk of fluid overload
No studies: effectiveness is suggested by case reports
Plasma could theoretically make things worse because has prekallikrein and HMW kininogen
risk: disease transmission S/D treatment inactivates enveloped viruses (HIV, HTLV, HBV, HCV, but not prions or nonenveloped viruses
FFP is pooled from single donor and they undergo testing

68. Treatment @ home C1 INH concentrate (plasma derived or recombinant)
given IV
Icatibant (bradykinin antagonist) SQ int
Ecallantide: three SQ injection by trained nurse at home

69. Testing Family
If the diagnosis is made, testing should be done of children, parents and siblings

70. “So if you don’t know, now you know”
Notorious BIG via the Broadway Musical Hamilton