Streptokinase, anaphylaxis, Kounis syndrome

1. Streptokinase-induced
Anaphylaxis
Joey A. Tabula
Marvin L. Mendoza
30 April 2015

2. Outline
• Definition of anaphylaxis/anaphylactic shock
• Diagnosis and management of anaphylaxis
• Streptokinase-induced reactions including
anaphylaxis/anaphylactic shock
• Kounis Syndrome

3. History of Present Illness
• EM, 40-year old male patient
• Admitted for sudden, severe chest pain
• 10-day history of intermittent mild chest pain
• No previous consults or medications taken

4. History of Present Illness
• 3 hours PTA, patient experienced sudden chest
pain, NRS 10/10 associated with dyspnea and
diaphoresis  consult

5. History of Present Illness
• PMHx: HPN on amlodipine, no known food/drug
allergy, previous hospitalizations nor previous
streptokinase use
• FHx: denies atopic diseases
• P&SHx: cigarette smoker and occasional alcohol
beverage drinker; denies illicit drug use

6. History of Present Illness
Initial Physical Examination (ER)
BP 130/90, HR 86, RR 20, Temp afebrile
Awake, not in distress
Equal chest expansion and clear breath sounds
Adynamic precordium, normal rate and regular rhythm, no
heave/thrill
Full and equal pulses; no cyanosis
Acute STEMI Inferior Wall , Killip I
Hypertension Stage II

7. Course
• Pre-medicated with Diphenhydramine 50mg IV
and Hydrocortisone 100mg IV 30 minutes prior to
thrombolysis
• Given Streptokinase 1.5M units + 100 cc saline in
soluset to infuse for one hour

8. Course
• Other ACS meds given: aspirin, clopidogrel,
enoxaparin, captopril, carvedilol, atorvastatin,
lactulose
• After 30 minutes on streptokinase, patient
developed hypotension (BP 80/50) and vomiting;
no dyspnea/wheezing, flushing, rash, pruritus

9. Course
Anaphylaxis from Streptokinase
• Streptokinase infusion discontinued
• Hydration with 1L saline
• Delivered Epinephrine 1:1000 units 0.3cc IM
• BP improved to 90/60  MICU admission
• Referred to Allergy Service

10. Course
• Allergy Service
• Dx: ADE (anaphylaxis) to streptokinase
–Hydrocortisone 100mg IV q12
–Diphenhydramine 50mg IV q8 RTC
–Ranitidine 50mg IV q8 RTC
–Observe for 4 hours for biphasic reactions

11. Course
• No recurrence of hypotension
• No new complaints
• IV antihistamines shifted to oral form
• Hydrocortisone shifted to Prednisone
• Completed 5 days of antihistamines and steroid

12. Anaphylaxis
“a serious, life-threatening generalized or systemic
hypersensitivity reaction” and “a serious allergic reaction
that is rapid in onset and might cause death”
World Allergy Organization Guidelines for the Assessment and Management of Anaphylaxis
F. Estelle R. Simons, MD, FRCPC et al, 2011

13. Anaphylaxis
• In public health terms, anaphylaxis is considered to
be an uncommon cause of death (underdiagnosis,
under-reporting)
• The true global rate of occurrence of anaphylaxis
from all triggers in the general population is
unknown

14. Pathophysiology

17. Clinical Criteria
World Allergy Organization Guidelines for the Assessment and Management of Anaphylaxis
F. Estelle R. Simons, MD, FRCPC et al, 2011

18. IS THIS ANAPHYLACTIC SHOCK?

19. Management
Anaphylaxis is a medical
EMERGENCY.

20. Remove exposure to the trigger, i.e discontinue IV medication

21. Streptokinase (SK)
• Thrombolytic agent
• Enzyme secreted by streptococci
• Binds and activates plaminogen
• Compared with other thrombolytics, higher
incidence of allergic reactions (Dundar et al. Q J
Med, 2003.

22. SK-induced Reactions
• Sparse discussion in literature
• B type: not common, unpredictable
• 1.7-18% experience reactions mostly minor (rigors, rash,
minor angioedema)
• Significant proteinuria in first 24 hours (0.45g/L) and
resolved by day 5
Lynch et al. Clin Exp Immunol, 1993.
Lynch et al. Am J Cardiol, 1994.
De Oliviera et al. Ar Bras Cardiol, 2005.

23. SK-induced Minor Reactions
• Etiology unknown
• Not antibody-mediated
– Low titers of antistreptokinase IgG among patients who
reacted to streptokinase
• May involve complement activation
– Low levels of total complement (C3, C4, C3d) 1 year
post-reaction among patients who reacted to
streptokinase
Lynch et al. Clin Exp Immunol, 1993.

24. SK-induced Anaphylaxis and Serum-
Sickness
• Anaphylaxis
– Mast cell activation
– Can be mediated by IgE or C3a and C5a
– Etiology not clear
• Serum Sickness
– Related to circulation antibodies to SK

25. SK-induced Anaphylaxis
• Case Reports and Literature Review
– Presented with profound hypotension and rapidly
spreading erythematous rash (Tisdale et al. DICP, 1989)
– CP arrest after streptokinase (Bednarzyk et al. DICP,
1989)
– Review of literature: 5 more cases (Bednarzyk et al.
DICP, 1989)

26. Anaphylaxis
Drug Cases per 100,000 exposed
patients
Analgesics
Antibiotics
5-15
Parenteral Penicillin 32
Blood
Dextran
Pentoxifylline
Contrast media
35-95
Streptokinase 378 (150)
Plasma 284
ICSSA. Pharmacoepidemiol Drug Saf, 2003.
De Oliviera et al. Ar Bras Cardiol, 2005.

27. Related or Unrelated?
Myocardial Infarction
Anaphylaxis
Allergy Myocardial Infarction

28. Kounis Syndrome
• Also known as coronary hypersensitivity disorder
• First case in 1950 with penicillin
• 1991 – Kounis and Zavras made detailed
description
– Syndrome of allergic angina and allergic MI
Kounis NG. Clin Ther, 2013.

29. Subtypes
• Type I – normal or nearly normal coronary arteries
without risk factors for coronary artery disease
• Type II – with angiographic evidence of CAD when
the allergic events induce plaque erosion or rupture
• Type III - coronary artery stent thrombosis in which
aspirated thrombus specimens demonstrate
eosinophils and mast cells

30. Causality
• Drugs (even losartan)
• Scombroid syndrome or histamine fish poisoning
– Fish flesh contains the amino acid histidine, and when fish
infected with gram-negative bacteria containing the enzyme
histidine decarboxylase is ingested, then this enzyme
converts histidine into histamine
• Gelofusine
– component of various vaccines for children and constitutes
the main cause of sensitization in children.
• Latex

31. Treatment for Type I
• Treatment of the allergic event alone may abolish
symptoms.
• Hydrocortisone 1 to 2 mg/kg/d IV
• H1 and H2 antihistamines, such as diphenhydramine
(1–2 mg/kg) and ranitidine (1 mg/kg)
• Vasodilators such as CCB and nitrates may abolish
hypersensitivity-induced vasospasm.
• Nitroglycerin may cause hypotension and tachycardia

32. Treatment for Type II
• ACS protocol with corticosteroids and antihistamines.
• Vasodilators such as nitrates and CCBs are given when
appropriate.
• Beta-blockers may exaggerate coronary spasm
• Epinephrine may aggravate ischemia and worsen coronary
vasospasm in Kounis syndrome.
– In severe cases, sulfite-free epinephrine given IM is preferable
because it has a faster onset of action and maintains a more
stable concentration compared with the SC route (recommended
IM dose, 0.2– 0.5 mg [1:1000]).
• In patients receiving beta-blockers, epinephrine may be
ineffective.

33. Treatment for Type II
• Opioids such as morphine, codeine, and meperidine
– extreme caution in patients with Kounis syndrome
because they may induce massive mast-cell
degranulation and aggravate allergic reaction.
• Paracetamol
– not recommended, especially by IV, because it might
cause severe hypotension due to a reduction in cardiac
output.
• Fentanyl and its derivatives are weak mast-cell
triggers.

34. Treatment for Type III
• ACS protocol with urgent aspiration of intrastent thrombus,
– followed by histologic examination of aspirated material and
staining for eosinophils (hematoxylin and eosin) and mast cells
(Giemsa) should be undertaken.
• In patients in whom allergic symptoms develop after stent
implantation,
– antihistamines together with corticosteroids and mast-cell
stabilizers may relieve the symptoms.
• If symptoms persist, the underlying cause should be
ascertained and desensitization measures should be
applied.
• If these measures fail, stent extraction seems unavoidable.

35. Thanks!