algorithmic case-based approach to classify, diagnose and manage different angioedema types in adults and pediatrics with special attention to the emergency room management

1. Swelling..swelling
Ahmed Yehia, MD
Internal medicine,
immunology, allergy &
rheumatology

2. •A 50 years old 👴 presents
to the emergency room
with hypertensive urgency
& was given SL captopril &
2 hours later, he developed
hoarseness & presents like
this. What is the diagnosis?
What is the cause? How to
manage?
2

3. ACEi-mediated angioedema
• The emergency
physician gave
adrenaline,
antihistaminic &
hydrocortisone.
• But the condition
worsened with
progressive tongue
swelling.
• What next?
• Intubation should have
been considered earlier.

4. •The patient was flown
to the ICU, and was
kept sedated &
ventilated. 3 days
later the swelling had
subsided.

5. •A 50 years old lady on Ramipril
for 4 years for hypertension,
proteinuric CKD II & CHF
presents with this non-pitting,
non-painful swelling. She had a
similar attack a few days ago
with spontaneous resolution.
She has nocturnal dry cough
for 2 months. What is the
diagnosis? What is the cause?
8/7/2021 Ahmed Yehia 5

6. ACEi-mediated angioedema, when?
•AE risk is highest within the first
30 days of starting ACEi, although
the risk remains for the duration
of the ACEi use, with cases
documented in patients with
prolonged courses of multiple years.
8/7/2021 Ahmed Yehia 6

7. What is next?
• Stop ramipril & start prendopril.
• Stop ramipril & start candesartan.
• Stop ramipril & start bisoprolol.
• Stop ramipril & follow up only.
• Continue ramipril.

8. What is next?
• Stop ramipril & start prendopril.
• Stop ramipril & start candesartan.
• Stop ramipril & start bisoprolol.
• Stop ramipril & follow up only.
• Continue ramipril.
●In patients with a history of ACE inhibitor-induced
angioedema, we suggest not avoiding angiotensin-
receptor blockers (ARBs) if an ARB has advantages over
other agents for that patient (Grade 2C).

9. Case follow up
3 weeks later, she developed
a left leg localized swelling.
What next?

10. • The impact of discontinuation may
only be clear after several months,
some will have recurrent episodes,
particularly in the first few months
after ACEi discontinuation. Such
patients should remain off ACEi.
• Referral to an allergy expert should
be considered for patients who
continue to have episodes of AE
after 6 months.
Ahmed Yehia 8/7/2021 10

11. • A 50 years old lady on
Ramipril for 4 years for
hypertension, proteinuric CKD
II & CHF presents with this
non-pitting, non-painful
swelling associated with itchy
wheels. What is the cause?
Would you stop ramipril? How
to manage?

13. Trigger
temporary ++
vascular
permeability
Vasoactive
substance
passage of fluid
from the
intravascular
space to the
interstitial
space
localized
swelling of the
submucosal or
subcutaneous
tissues
AngioEdema

14. Vasoactive substance

16. AE
Histamine-mediated (usually with
urticaria)
Allergens
-Acute or CSU
cold urticaria,
vasculitis,
exercise,
episodic AE,
vibration-
induced, drug
reaction
Bradykinin-mediated (no urticaria)
HAE
I: -- C1-INH
level/functi
on
II: -- C1-INH
function
III: normal
C1-INH
Acquired
C1-INH--
Type I
++C1-INH
catabolism
(LPD, AID)
Type II
C1-INH
auto-
antibody
ACEi-
mediated
Drug: DPP-
IV#, ARBs,
rTPA,
sirolimus,
tacrolimus,
everolimus
Idiopathic (unknown etiology)
Histaminergic
Non-
histaminergic
8/7/2021
Ahmed Yehia
16

17. Cicardi M., Clin Rev Allergy Immunol 2016;51:162–169
Maurer et al. World Allergy Organization Journal 2018;11:5

18. Summary of final angioedema etiology,
N=450.

19. • A 50 years old lady on
Ramipril for 4 years for
hypertension, proteinuric CKD
II & CHF presents with this
non-pitting, non-painful
swelling associated with itchy
wheels. What is the cause?
Would you stop ramipril? How
to manage?
Back to our patient

20. Histamine-mediated angioedema
allergens
food, medications, exercise, bites,
stings, or latex
physically-induced
cold exposure, heat pressure, physical
activity, ultraviolet radiation, vibration
8/7/2021
Ahmed Yehia
20

21. Treatment of acute histaminergic
AE
Epinephrine
Steroids
Antihistamines

22. Acute histaminergic
AE
• Risk of anaphylaxis??
• This is (type 1 hypersensitivity).

23. •A 4 years old boy
presents to the ER with
an attack of sudden lid
swelling.
•What is the best next
step?
‫هذه‬
‫الصورة‬
‫بواسطة‬
‫كاتب‬
‫غير‬
‫معروف‬
‫مرخصة‬
‫باالسم‬
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24. Ask for allergens especially food  No.
Urticaria  No
ACEi  No
What is the best screening test if you suspect
hereditary AE (HAE)?
S. C4

25. Several systems regulate bradykinin
Coagulation Complement
Contact
pathways
8/7/2021
Ahmed Yehia
25

27. Excess
bradykinin
++production,
release
inhibition of its
breakdown
8/7/2021
Ahmed Yehia
27

28. Impact

29. PALE, POORLY
DEFINED EDGE,
PAINFUL
RATHER THAN
ITCHY,
PROLONGED,
USUALLY TAKE
MORE THAN A
DAY TO FADE.

30. Non-dependent
Non- symmetric
Not well-
demakated
•Non- pitting
•Non- pruritic
•Non- persistent

31. • A 50 years old lady on
Ramipril for 4 years for
hypertension, presents with
recurrent nausea, vomiting,
and abdominal pain. This
attack is so severe with
referral to a surgeon who
requested abdominal erect
x-ray & CT.

32. Gastrointestinal angioedema

33. •1/3 of patients with C1
inhibitor deficiency had
undergone an
appendectomy or
exploratory laparotomy
for abdominal pain.

34. Investigations
for AE
An extensive workup searching
for the cause of AE is often
unrevealing (90%).
Workup, including diagnostic
blood & allergy tests, is performed
according to results of the history
& physical examination.

35. Diagnosis of HAE
measurements of serum/plasma levels of
C1-INH function, C1-INH protein & C4.
family history (AD)
Clinical presentation

36. SUSPECT ACQUIRED
ANGIOEDEMA
• Angioedema similar to HAE, but later
onset (over 40 years)
• Constitutional symptoms
• Low C1q
• Lymphoma or monoclonal
gammopathy
• Anti-C1INH antibody
‫هذه‬
‫الصورة‬
‫بواسطة‬
‫كاتب‬
‫غير‬
‫معروف‬
‫مرخصة‬
‫باالسم‬
CC BY-SA

37. Underlying diseases; malignancy or immune
dysregulation
• Lymphoma
• CLL
• MGUS
• Multiple myeloma
• W. macoglobinemia
• Cryoglobulinemia
• Echinococcus granulosus
• SLE
• Rheumatoid arthritis
• AIHA
• Gastric tumor
• Carcinoma of breast, pancreas, bladder, colon,
rectum

38. Suspect Mast cell Dependent
when:
• Urticaria coexists with
angioedema
• Response to antihistamines
• Obvious trigger (i.e. drug, food)

41. INITIAL LAB: C4 ( THE BEST FOR SCREENING)
• Excellent screening tool for C1INH deficiency in patients > 1 yr
• Reduced C4 level between attacks in at least 95% of patients
• Normal C4 level during an attack strongly suggests a diagnosis other than C1INH
deficiency

42. • A 7 years old girl presents
with lip swelling & facial
palsy. Her tongue is fissured.
Her GP gave her cetirizine
with no response, What is
the diagnosis?

43. Melkersson–
Rosenthal syndrome
is a rare neurological
disorder
recurring facial
paralysis
swelling of the face
and lips (usually the
upper lip - cheilitis
granulomatosis)
folds and furrows in
the tongue (fissured
tongue).

46. FAMILY SCREENING
• Family members including
grandparents, parents, siblings,
children, and grandchildren of HAE-
1/2 patients should be screened for
C1-INH function, C1-INH protein, and
C4 plasma levels.

48. Pharmacologic management of HAE
on-demand
therapies
to abort AE
attacks
prophylactic treatments to
prevent attacks from starting.
short-term prophylaxis
(pre-procedural)
administered prior to a potential
attack trigger, such a medical or
dental procedure,
long-term prophylaxis
(suppression of attacks)
administered
regularly

49. COMMON TRIGGERS
Hormonal,
Pregnancy,
Puberty
Emotional, anxiety
URI, H. pylori
Even minimal
esp. oral cavity
,
aerodigestive
system

50. PRE-PROCEDURAL (SHORT-TERM) PROPHYLAXIS
C1-INH concentrate :
Berinert, Cinryze (1st
line)
as close as possible to
the start of the
procedure
Fresh frozen plasma
(FFP) (2nd line)
greater risk of blood
borne disease
transmission
Attenuated
androgens: Danazol
(5 days before & 2 to
3 days post event)
2.5-10 mg/kg/day,
maximum 600
mg/day
Antifibrinolytic drugs
Tranexamic acid (not
recommended by
most experts)

51. Reduction in the production of bradykinin
(the common therapeutic goal of
available HAE treatments), either by
replacement of low
or dysfunctional C1-
INH
targeting other steps
in the contact/kinin
pathway

54. HAE treatment options
Androgens
increase
the
circulating
level of C1-
INH by an
unknown
mechanism
C1-INH
replacement
therapies
Plasma
derived
(Berinert®,
Cinryze®,
Haegarda®)
recombinant
(Ruconest ®)
Selective
plasma
kallikrein
inhibitors
prevent the
conversion
of HMWK
& release
of BK
(ecallantide
[Kalbitor®]
lanadelumab
[Takhzyro™])
Icatibant
(Firazyr®)
selectively &
competitively
binds to
bradykinin type 2
receptors,
preventing
binding of
bradykinin &
initiating changes
in vascular
permeability that
produce swelling.

55. Zuraw BL and Christiansen SC. Middleton’s Allergy 8th edition
Finally

56. Cicardi M. Allergy 2014; 69: 602–616.

58. Conclusions

59. Conclusion

60. ‫جزاكم‬
‫هللا‬
‫خيرا‬