ANGIOEDEMA

Andrew Coughlin, M.D.

Farrah Siddiqui, M.D.

The University of Texas Medical Branch (UTMB Health

Department of Otolaryngology

Grand Rounds Presentation

April 25, 2012

Differentiate types of Angioedema

Understand acute and chronic management

Discuss new medications that may impact

treatment

OBJECTIVES

WHAT TO DO WHEN FACED WITH

THIS?

Milton (1876)

First described clinical features

Quinke (1882)

“acute circumscribed edema of the skin”

Osler (1888)

Angioneurotic edema (Nervous System)

Donaldson and Evans (1963)

Defined C1-INH deficiency

HISTORY

25% Incidence of Urticaria or Angioedema

Men = Women

Generally presents 3 rd and 4 th decades

Immunologic and Non-Immunologic causes

SCOPE OF DISEASE (13)

URTICARIA

Generalized, erythematous, pruritic papules in the papillary dermis

URTICARIA

Serpiginous

Immune Mediated (cross linking IgE)

Penicillin/Foods

Complement Mediated

Ag/Ab complexes in serum sickness

Non-Immune Mediated

Alcohol, Trauma, NSAIDs, Vancomycin, Contrast

Autoimmune Mediated

Circulating autoantibodies

***Mast Cell Degranulation***

MECHANISMS OF URTICARIA

1. Nonpitting

2. Abrupt Onset

3. Asymmetric

4. Well defined

ANGIOEDEMA

EYE/FACIAL ANGIOEDEMA

EXTREMITY ANGIOEDEMA

GENITAL ANGIOEDEMA

GASTROINTESTINAL ANGIOEDEMA

Allergic Angioedema

Ace Inhibitor Induced Angioedema

Chronic Idiopathic Angioedema

Acquired Angioedema

Hereditary Angioedema

TYPES

ALLERGIC ANGIOEDEMA

Most Common Type

Classic histamine response

Trigger

Food

Drugs

Bee Sting

Urticaria Present

Complement assays normal

ALLERGIC ANGIOEDEMA

ALLERGIC EDEMA

Cutaneous and laryngeal swelling

Urticaria

Wheezing

Vomiting

Diarrhea

Hypotension

Rapid progression

Inciting event often identified

ACE-INHIBITOR INDUCED

ANGIOEDEMA (AIIA)

FUNCTION OF BRADYKININ

Potent endothelium vasodilator

Contraction of non-vascular smooth muscle

Increases vascular permeability

Involved in mechanism of pain

Incidence of 0.1-0.2%

Increased Bradykinin

Airway edema is the most common

presentation

Complement assay normal

ACE-INHIBITOR-INDUCED ANGIOEDEMA

Most similar to HAE

No Family History

Deficiency of C1-INH due to

Type I: Lymphoproliferative Disorder (MDS/MGUS)

Type II: Autoimmune Disorder (SLE)

4th decade of life

All complement assays are low including

C1q

ACQUIRED ANGIOEDEMA

Wastebasket term

Urticaria present

Laryngeal edema rare

Complement assays normal

CHRONIC IDIOPATHIC ANGIOEDEMA

Symptom Duration

Previous Events

Rheumatologic disorders

Other Autoimmune Disorders

Rashes

Pruritis

Family History

HISTORY

OTHER POSSIBLE

CAUSES?

http://1.bp.blogspot.com/_Fd2Fryp9wz0/TQg84FXXtSI/AAAAAAAABlE/h0gnkg2r09U/s1600/Acute_epiglottitis.jpg

CLASSIC RADIOGRAPHIC FINDING (6)

Incidence

1 in 100,000 in the United States

Increased in countries that do not vaccinate

Organism

H. influenza/Staph/Strep

History

Stridor

Voice muffling or “Hot Potato Voice”

Sore throat

Odynophagia/dysphagia

Recent URI

EPIGLOTTITIS (6)

Febrile

Drooling/inability to handle secretions

Tachycardia

Toxic appearance of patient

Tripod position - Sitting up on hands, with

the tongue out and the head forward

Stridor (Inspiratory) Respiratory Distress

PHYSICAL EXAM

WHO IS THIS MAN?

KARL FRIEDRICH WILHELM VON LUDWIG

“OF A CERTAIN TYPE OF

INFLAMMATION OF THE THROAT,

WHICH DESPITE THE MOST SKILLFUL

TREATMENT

IS ALMOST ALWAYS FATAL”

DEFINITION OF ANGINA?

ANGINA

1. Latin throat inflammation

2. Greek anchonē strangling, from anchein to

strangle

First Known Use: 1578

LUDWIGS ANGINA (8)

LUDWIGS ANGINA (8)

LUDWIGS ANGINA (8)

LUDWIGS ANGINA (16)

Bilateral submandibular cellulitis

Dental Origin 80-90% (16)

Mortality 50% 8%

Generally Polymicrobial

Staph/Strep/Bacteroides

Higher incidence of Staph and black pigmented bacteroides

(14)

Predisposed

DM2/Alcoholism/Neutropenia

65% suppurative complications

LUDWIGS ANGINA

Manage Airway

Wolfe et al.(17) showed tracheostomy not

required in 29 patients with apparent Ludwigs

Intubation was required in 19/29 (65%)

IV antibiotics

Supportive Care

TREATMENT

HEREDITARY

ANGIOEDEMA (HAE)

15-30K ED visits per year (2)

Incidence

1/50,000 – 1/100,000

Most often presents 2nd decade

Mean frequency of events 45.3 days (18)

HEREDITARY ANGIOEDEMA

EPIDEMIOLOGY

Autosomal Dominant

Chromosome 11

200 mutations described

20-25% are spontaneous mutations

Type 1 (85%)

Decreased circulating C1-INH

Type 2 (15%)

Dysfunctional C1-INH

GENETICS (2)

EFFECTS OF C1-INH

Swelling Diffuse, Nonpitting, Nonpruritic edema

• Affected sites (4)

Extremities 47%

GI Tract 33%

Oral/Laryngeal Involvement 6%

50% will have at least 1 event in a lifetime (2)

Mortality rate of 30% if left untreated

CHARACTERISTICS

EXTREMITY EDEMA

GASTROENTESTINAL EDEMA

First occurs in 2nd decade

Delay of 10-20 years in diagnosis (1,2)

Swelling occurs over several hours

Reversible Disability within 1-5 days (4)

Preceding Prodrome 40-80% (5,15)

Erythema Marginatum (non-pruritic)

Substantial Fatigue

Local discomfort

TIMING

ERYTHEMA MARGINATUM

NATURAL HISTORY

Infection

Stress

Menstruation

OCP’s

Trauma

Dental Work

TRIGGERS (10)

CBC

Helpful only to r/o infectious causes

Bradykinin levels

Elevated in limbs affected compared to normal side

(10)

Complement

C1-INH, C4, C2, C1q

LAB TESTING

DIAGNOSTIC CRITERIA (10)

TREATMENT OF HAE

Antihistamines, steroids, and epinephrine have no role

Avoidance of triggers when known Infection

Stress

Menstruation

OCP’s

Trauma

Dental Work

TREATMENT

Do not alter bradykinin levels

Successful treatment reported with

antihistamines as part of protocol

Grant et al. 2007

Patients with ACEi-Induced Angioedema were

extubated significantly earlier than those not treated

with antihistamines

ANTIHISTAMINES (1,7)

Danazol/Stanazolol/Oxandrolone

Mechanism

Not well understood

Increase C1-INH and C4

Side Effects

Weight gain, acne, vasomotor sxs, menstrual

irregularities, HTN, CAD, Virilization, hepatic

neoplasms, hair growth

Must also monitor LFTs

ANDROGENS

Tranexamic Acid/Aminocaproic Acid

Used if Androgens are contraindicated

Unknown Mechanism (no effects on C1-INH in

serum)

Poor response

Side effects

Nausea, diarrhea, vertigo, cramps, Orthostasis, fatigue

Increased thrombosis, tumors, teratogen

ANTIFIBRINOLYTIC AGENTS

Androgens are contraindicated

Antifibrinolytics with caution

Baker et al. (3)

6 pregnant women

1-2 times a week

None had angioedema event

All had normal babies on delivery

Attempt regional anesthesia for cesarean

WHAT ABOUT PREGNANCY?

Contains

C1-INH

Proteases and substrates to prolong attack

Therefore FFP should only be used in

prophylactic setting

FRESH FROZEN PLASMA

Present in Europe over 25 years

Increases amount of circulating C1-INH

Best in patients with:

Repeat Attacks (>2/month)

Laryngeal Attacks

Anxiety or poor quality of life

Those not responding to androgens therapy

Cinryze is $2437.50 per vial; at this benchmark

monthly cost of therapy would range between

$36562 to $48750 per patient

C1 INHIBITOR (CINRYZE)

NOVEL THERAPIES

Lumry et al. 2011

Randomized placebo controlled trial

Bradykinin receptor 2 blocker

Constituitively expressed

Participates in bradykinin vasodilation

ICATIBANT

ICATIBANT EFFECTS

Only 8 patients in the treatment arm

Time to ≥50% reduction in symptoms

2.5 hours for Icatibant

3.2 hours for Placebo

*Approved for >18y/o in the United States

*Costs $6800 per treatment

ICATIBANT FOR LARYNGEAL

ATTACKS

A recombinant protein synthesized in the yeast

Pichia pastoris

Inhibits plasma kallikrein

Shown to decrease length and severity of attacks

Small risk of anaphylaxis Limits home administration

*Approved for >16 y/o in the US

*Cost per dose is $9540 per treatment

ECALLANTIDE

ACTION OF ECALLANTIDE

WHAT TO DO WHEN FACED WITH

THIS?

Ishoo et al. (1999)

Otolaryngology-Head and Neck Surgery

80 patient (93 episodes)

Retrospective review 1985-1995

Categorized by

1. Anatomic site

2. Treatment setting

PREDICTING AIRWAY RISK IN

ANGIOEDEMA: STAGING SYSTEM BASED

ON PRESENTATION

Acute Airway Management in 9.7%

Voice changes/hoarseness/dyspnea/stridor

(p<0.05)

Only Stage III and IV patients

ICU stay if:

ACEi use (p = 0.05)

Voice changes/hoarseness/dyspnea/rash

(p<0.05)

OVERALL RESULTS

Al-Khudari et al. (2011)

Laryngoscope

Prospective review of 40 patients

What was studied?

1. Need for airway evaluation

2. Level of care

MANAGEMENT OF ACEI-INDUCED

ANGIOEDEMA

Assessment by PGY3

Diphenhydramine 50mg IV q 8-12 hours

Famotidine 20mg IV q 12 hours

Dexamethasone 10mg IV q 8 hours

1. Mild oral edema

2. No laryngeal edema

3. Normal clinical status

Discharged Home from ED

1. Severe Oral Edema 2. Supraglottic edema with visible glottis

Monitored on the floor or in ICU

1. Obstructed glottis

2. Drooling

3. Respiratory Fatigue

Intubation

Twice daily examination

Laryngoscopy if symptoms changed

Extubation over tube exchanger once

1. Cuff leak test positive

2. Mental status appropriate

Discharged w/wo steroid taper

ADDITIONAL PROTOCOL

Average Age 62.9 years

African Americans 92.5%

Lisinopril 87.5%

Days on ACEi 233 days

Time to Resolution 29 hours

DEMOGRAPHICS

Dysphagia 44.7%

Voice Changes 42.1%

Shortness of

Breath

23.1%

Drooling 7.5%

PRESENTING SYMPTOMS

Discharged from

ED

42.5%

Admit to Floor 7.5%

Admit to ICU 50%

ADMISSION

Older patients (67.2 vs 58.1 years)

Presented with dyspnea

Involvement of

FOM

Soft Palate

Aryepiglottic Folds

Epiglottis

Multiple sites involved

FACTORS FOR ICU ADMISSION

Multiple airway sites

p=0.008

Soft Palate swelling

p=0.047

Upper lip swelling

p=0.008

FACTORS FOR AIRWAY EDEMA

Prolonged symptoms from onset to

resolution

p=0.046

Massive Tongue Edema

p=0.008

FACTORS FOR INTUBATION (15%)

MASSIVE TONGUE EDEMA

Assessment by PGY3

Diphenhydramine 50mg IV q 8-12 hours

Famotidine 20mg IV q 12 hours

Dexamethasone 10mg IV q 8 hours

1. Mild oral edema

2. No laryngeal edema

3. Normal clinical status

Discharged Home from ED

1. Severe Oral Edema 2. Supraglottic edema with visible glottis

Monitored on the floor or in ICU

1. Obstructed glottis

2. Drooling

3. Respiratory Fatigue

Intubation

Secure the Airway (based on risk factors)

If known HAE

Cyrinze, Icatibant, Ecallantide acutely

If Unknown Cause

Antihistamines/Steroids/Epinephrine as needed

Thorough History/Physical exam

Complement levels

Prophylactic medications if indicated

SUMMARY OF THERAPY

1 . A l - K h u d a r i S , L o o c h t a n M J , P e t e r s o n E , Y a r e m c h u k K L . M a n a g e m e n t o f a n g i o t e n s i n - c o n v e r t i n g e n z y m e i n h i b i t o r - i n d u c e d

a n g i o e d e m a . L a r y n g o s c o p e . 2 0 1 1 N o v ; 1 2 1 ( 1 1 ) : 2 3 2 7 - 3 4 .

2 . A n o n J B . H e r e d i t a r y a n g i o e d e m a : a c l i n i c a l r e v i e w f o r t h e o t o l a r y n g o l o g i s t . E a r N o s e T h r o a t J . 2 0 1 1 J a n ; 9 0 ( 1 ) : 3 2 - 9 .

3 . B a k e r I , S h e f f e r A , C h r i s t e n s e n I , e t a l . C i n r y z e ™ r e p l a c e m e n t t h e r a p y i n h e r e d i t a r y a n g i o e d e m a a n d p r e g n a n c y

[ a b s t r a c t ] . I A l l e r g y C l i n I m m u n o l 2 0 0 9 ; 1 2 3 ( 2 ) : S 1 0 6 - S 1 0 6 .

4 . B o r k K , M e n g G , S t a u b a c h P , H a r d t J . H e r e d i t a r y a n g i o - o e d e m a : n e w f i n d i n g s c o n c e r n i n g s y m p t o m s , a f f e c t e d o r g a n s ,

a n d c o u r s e . A m J M e d 2 0 0 6 ; 1 1 9 : 2 6 7 – 7 4 .

5 . B y g u m A . H e r e d i t a r y a n g i o - o e d e m a i n D e n m a r k : a n a t i o n w i d e s u r v e y . B r J D e r m a t o l 2 0 0 9 ; 1 6 1 : 1 1 5 3 – 5 8 .

6 . G o m p f S G a n d D y n e P L . E p i g l o t t i t i s . h t t p : / / e m e d i c i n e . m e d s c a p e . c o m / a r t i c l e / 7 6 3 6 1 2 - o v e r v i e w L a s t u p d a t e d J u l y 1 4 ,

2 0 1 1 .

7 . G r a n t N N , D e e b Z E , C h i a S H . C l i n i c a l e x p p e r i e n c e w i t h a n g i o t e n s i n - c o n v e r t i n g e n z y m e i n h i b i t o r - i n d u c e d a n g i o e m a .

O t o l a r y n g o l H e a d N e c k S u r g . 2 0 0 7 ; 1 3 7 : 9 3 1 - 9 3 5 .

8 . H a r t m a n n R W . L u d w i g ' s A n g i n a i n C h i l d r e n . A m F a m P h y s i c i a n . 1 9 9 9 J u l 1 ; 6 0 ( 1 ) : 1 0 9 - 1 1 2 .

9 . I s h o o E , S h a h U K , G r i l l o n e G A , S t r a m J R , F u l e i h a n N S . P r e d i c t i n g a i r w a y r i s k i n a n g i o e d e m a : s t a g i n g s y s t e m b a s e d o n

p r e s e n t a t i o n . O t o l a r y n g o l H e a d N e c k S u r g . 1 9 9 9 S e p ; 1 2 1 ( 3 ) : 2 6 3 - 8 .

1 0 . L o n g h u r s t H , C i c a r d i M . H e r e d i t a r y a n g i o - o e d e m a . L a n c e t . 2 0 1 2 F e b 4 ; 3 7 9 ( 9 8 1 4 ) : 4 7 4 - 8 1 .

1 1 . L u m r y W R , L i H H , L e v y R J , P o t t e r P C , F a r k a s H , M o l d o v a n D , R i e d l M , L i H , C r a i g T , B l o o m B J , R e s h e f A . R a n d o m i z e d

p l a c e b o - c o n t r o l l e d t r i a l o f t h e b r a d y k i n i n B ₂ r e c e p t o r a n t a g o n i s t i c a t i b a n t f o r t h e t r e a t m e n t o f a c u t e a t t a c k s o f

h e r e d i t a r y a n g i o e d e m a : t h e F A S T - 3 t r i a l . A n n A l l e r g y A s t h m a I m m u n o l . 2 0 1 1 D e c ; 1 0 7 ( 6 ) : 5 2 9 - 3 7 .

1 2 . M a r t e l l o J L , W o y t o w i s h M R , C h a m b e r s H . E c a l l a n t i d e f o r t r e a t m e n t o f a c u t e a t t a c k s o f h e r e d i t a r y a n g i o e d e m a . A m J

H e a l t h S y s t P h a r m . 2 0 1 2 A p r 1 5 ; 6 9 ( 8 ) : 6 5 1 - 7 .

1 3 . P a l m e r M , R o s e n b a u m S , M i l l s L , S a n d e r s G . C l i n i c a l P r a c t i c e G u i d l i n e : I n i t i a l e v a l u a t i o n a n d m a n a g e m e n t o f p a t i e n t s

p r e s e n t i n g w i t h a c u t e u r t i c a r i a o r a n g i o e d e m a . A m e r i c a n A c a d e m y o f E m e r g e n c y M e d i c i n e .

w w w . a a e m . o r g / e d u c a t i o n / u r t i c a r i a _ a n g i o e d e m a . p h p . L a s t u p d a t e d J u l 2 0 0 6 .

1 4 . P a t e l M . C h e t t i a r T P . W a d e e A A . I s o l a t i o n o f S t a p h y l o c o c c u s a u r e u s a n d b l a c k - p i g m e n t e d b a c t e r o i d e s i n d i c a t e a h i g h

r i s k f o r t h e d e v e l o p m e n t o f L u d w i g ' s a n g i n a . O r a l S u r g e r y O r a l M e d i c i n e O r a l P a t h o l o g y O r a l R a d i o l o g y & E n d o d o n t i c s .

2 0 0 9 N o v ; 1 0 8 ( 5 ) : 6 6 7 - 7 2

1 5 . P r e m a t t a M J , K e m p J G , G i b b s J G , M e n d e C , R h o a d s C , C r a i g T J . F r e q u e n c y , t i m i n g , a n d t y p e o f p r o d r o m a l s y m p t o m s

a s s o c i a t e d w i t h h e r e d i t a r y a n g i o - o e d e m a a t t a c k s . A l l e r g y A s t h m a P r o c 2 0 0 9 ; 3 0 : 5 0 6 – 1 1 .

1 6 . R a n a R S , M o o n i s G . H e a d a n d N e c k I n f e c t i o n a n d I n f l a m m a t i o n . R a d i o l C l i n N A m 4 9 ( 2 0 1 1 ) 1 6 5 – 1 8 2 .

1 7 . W o l f e M M . D a v i s J W . P a r k s S N . I s s u r g i c a l a i r w a y n e c e s s a r y f o r a i r w a y m a n a g e m e n t i n d e e p n e c k i n f e c t i o n s a n d L u d w i g

a n g i n a ? J o u r n a l o f C r i t i c a l C a r e . 2 0 1 1 F e b ; 2 6 ( 1 ) : 1 1 - 4 .

1 8 . Z a n i c h e l l i A , V a c c h i n i R , B a d i n i M , P e n n a V , C i c a r d i M . S t a n d a r d c a r e i m p a c t o n a n g i o - o e d e m a b e c a u s e o f h e r e d i t a r y C 1

i n h i b i t o r d e f i c i e n c y : a 2 1 - m o n t h p r o s p e c t i v e 2 s t u d y i n a c o h o r t o f 1 0 3 p a t i e n t s . A l l e r g y 2 0 1 0 ; 6 6 : 1 9 2 – 9 6 .

REFERENCES