Common Presentations of Two Uncommon Diseases

1. Common Presentations of Two Uncommon Diseases Stevens-Johnson Syndrome And Angioedema Domenic Martinello, MD Anna-Jaques Department of Emergency Medicine

2. Primer on Abbreviations • SJS – Stevens-Johnson Syndrome • EM – ErythemaMultiforme • TEN – Toxic Epidermal Necrolysis • AE – Angioedema • HAE – Hereditary Angioedema

3. Statistics • Rather uncommon conditions: • SJS: 0.5-7 cases per million • Type I HAE: 1 per 100,000 • Type II HAE : 1 Per 50,000 • 0.2-0.7% of people on ACE Inhibitors • Not technically rare, you can expect to see at least 1-2 cases during your career!

4. “Stevens-Johnson Syndrome” • Is actually a part of the spectrum of disease that begins with ErythemaMultiforme (EM) and ends with Toxic Epidermal Necrolysis (TEN) • Would be unreasonable to discuss one without the others as the entire spectrum must be understood.

5. ErythemaMultiforme • First described in 1866 • Self-limited disease • Originally unknown cause • Symmetrical “target lesions” • Diseases classified as: • EM Minor • EM Major • SJS/TEN Syndrome

6. EM Minor vsMajor • EM Minor: • Classic target lesions • Doesn’t involve mucous membranes • EM Major / SJS • Involves mucous membranes • Epidermal detachment <10% of BSA • More on this later

7. EM “target” lesions

8. Mucous Membrane Lesions

9. EM Pathophysiology • Poorly understood at best • Appears to be a hypersensitivity reaction • Medications, bacteria, fungi, viruses, chemical products • Most common cause of EM is herpes virus • Medications cause more SJS/TEN than EM • Lymphocytic infiltration at dermal-epidermal junction causes lesions

10. EM Course • Tends to be benign and self limited • Mortality of EM essentially 0% • 4-6 weeks of symptoms and then resolution is the norm • Treatment is removal of offending agent if possible and supportive care

11. EM Presentation • Sudden onset of rapidly spreading target lesions with or without mucous membrane involvement. • Spreads centripetally • Lesions “burn” but do not itch • Prodrome of fevers, myalgia, headache, sore throat, nausea, vomiting, diarrhoea or other symptoms in 50% of cases

12. EMS Care • Treat like a burn if they are over large surface areas • Provide fluids, analgesics if needed • Reassurance and transport

13. Hospital Care • “Hugs, drugs, and work notes” • Patients sometimes need pain control • NSAIDS are mainstay of care • Patients need reassurance and follow-up • Patients should rest until lesions disappear • More for the emotional well-being than true medical necessity • Rarely skin biopsy as outpatient for unusual cases • HSV Viral serology sometimes useful

14. Stevens-Johnson Syndrome • First described in 1922 • Immune complex hypersensitivity reaction • Formerly called EM Major • This is changing now • More closely related to TEN than EM

15. SJS vs TEN classification • SJS: • <10% BSA dermal detachment • Which is also criteria for EM Major… • “Overlap” SJS-TEN • 10-30% dermal detachment • TEN • >30% dermal detachment

16. Dermal detachment?

17. Dermal Detachment (cont) • Breakdown of dermal-epidermal junction • Causes skin sloughing • Much like a burn • Same treatment! • Nikolsky Sign • Sliding finger over skin causes epidermal tearing • “wet tissue paper test”

18. SJS Physiology • Immune complex-mediated hypersensitivity reaction • Drugs, viruses, bacteria, malignancy • Cocaine is newly-discovered cause • Mirtazepine • TNF-alpha antagonists • Infliximab, etanercept, adalimumab • Treatments for autoimmune diseases • 50% of cases have no identified cause

19. Cellular processes • Mechanism presumed to be related to Fas and its ligand FasL • Cell death receptor or “death protein” • Causes apoptosis (cell death) resulting in separation of dermis and epidermis • Other possibly related processes: • TNF-alpha, cytokines, and a yet-to-be isolated “killer effector molecule”

20. Clinical Presentation • Tends to begin with a nonspecific upper respiratory infection type prodrome • 1-14 days, fevers, chills, malaise, sore throat, headache • Nonpruriticmucocutaneous lesions erupt • Oral or mucous membrane involvement • May cause severe pain and lead to food/drink aversion and dehydration

21. Lesion Evolution • Begin as macules • Develops into papules, bullae, urticarial plaques, or confluent erythema • Typically TARGET lesions (much like EM) • Palms and soles MOST common • Sloughing, blistering, and desquamation of mucous membranes

22. SJS Skin Lesions

23. Common Culprits for SJS • NSAIDS • Sulfonamides • BACTRIM • Allopuronal • Dilantin • Trileptal • Fluroquinolones • Cipro/Flagyl/Etc • Most new anticonvulsants • Immune modulators • HIV Medications • Various Cancers • Viruses • HSV, HIV, Influenza, hepatitis, mumps • Bacteria • Strep, diptheria, brucellosis, tularemia, typhoid, mycoplasma • Fungi, Malaria, parasites of many varieties

24. Most Common Cause? Upward of 50% of cases are idiopathic or have no identifiable cause

25. EMS Pre-hospital treatment • Treat it like a BURN! • Fluids • Parkland formula • 4 ml NS/LR x %BSA x weight in kg = total • 50% in first 8 hours, 50% over following 16 hours • Pain medication • Attempt to leave as much of the skin intact as possible by avoiding manipulation • Be aware of heat and fluid losses!

26. Burn Calculation

27. Emergency Dept Care • Sadly, not much different • Treat as a burn • Steroids now to be avoided • Increased mortality • Try to identify and remove offending medications/agents • Monitor for infection • Manage fluids / electrolytes • Human IVIG being studied as treatment and prophylaxis for high risk people • Not yet approved

28. Mortality • Much like burns, based on total BSA affected • <10% BSA: 1-5% mortality • >30% BSA up to 50% mortality • Can affect internal organs (more of a TENS presentation) • Anteriour uveitis and vision loss • Multi organ dysfunctions (usually GI) • Can cause necrosis and shock

29. Toxic Epidermal Necrolysis • An extension of SJS • Requires involvement of mucous membranes and >30% BSA • A life threatening emergency • Same pathology as SJS • Same causes and prodrome • Essentially “severe SJS” • Though SJS is considered mild TEN

30. Severity Score SCORETEN (“Score-TEN”) Predicts Mortality Risk for patients with TEN • Age >40 years • Heart rate >120 beats per minute • Cancer or hematologic malignancy • Involved body surface area >10% • BUN > 28 mg/dL • bicarbonate 20 mEq/L • Blood glucose > 252 • 0 to 1 factor = 3% • 2 factors = 12% • 3 factors = 35% • 4 factors = 58% • 5 or more factors = 90%

31. Treatment • Just like SJS this is treated the same • Burn care • Pain control • Infection observation • Organ damage can be devastating and sometimes requires surgical care • Particularly necrotic bowel • Studies on IVIG, but no approval yet

32. Angioedema

33. Angioedema • Defined as rapid swelling of the dermis, subcutaneous tissue, and mucosa • This includes mucosa like the GI tract • SIMILAR to hives but those occur in the epidermis (and some dermis involvement) • Ranges from benign to life threatening

34. Pathophysiology Primer • C1 esterase is a serine protease that is involved in the regulation of bradykinin, a potent vasoactive substance. Low levels of this protease results in the activation of the kallikrein-kinin system, the complement cascade, and the fibrinolytic system and results in the release of vasoactive peptides such as bradykinin, considered to be the most important regulatory complement involved in many molecular cascades.Release of vasoactive substances causes vasodilatation of endothelial cells as well as smooth muscle bowel contraction.

35. Pathway • Here you go:

36. Breakdown of AE • SEVEN major types • Hereditary • Type I • Type II • Type III • ACE-Inhibitor Induced • Acquired • Urticarial • Idiopathic

37. HAE Types I and II • Typically a problem with the C1 compliment process • Quantitative or qualitative problem with C1 Esterase Inhibitor (C1-INH) from a defective C1NH gene • Type I has inhibitor deficiency • Type II has inhibitor dysfunction • Not clinically distinguishable

38. HAE Type III • Seen ONLY in females • X-Linked dominant trait • No C1-INH problem, normal C1NH • Mechanism still debated • Can be precipitated by pregnancy and oestrogen administration

39. ACE-Inhibitor AE • One of the key chemicals in the cascade to angioedema involves bradykinin • High levels of bradykinin cause angioedema • Angiotensin-converting-enzyme (ACE) lowers bradykinin • Medications that INHIBIT ACE increases bradykinin

40. Acquired angioedema • Caused by circulating antibodies to the C1-INH protein • Type I – seen in B-cell proliferative diseases (Lymphoma) • C1-INH is consumed through a complex process starting with B-Cell membrane immune complexes and generates a lot of C1 consuming C1-INH, leaving the remainder of the C1 free to act. • Type II – Also often from lymphoma • IgG and IgM directed at the C1-INH causes destruction of the C1-INH protein

41. Urticarial AE • Related to Histamine Release • Seen as the swelling with allergic and anaphylactic reactions • Hypersensitivity reaction • Allergen binds to Mast cell and causes degranulation of histamine • Also releases tryptase • Histamine release causes vascular permeability • Common issue with opiates, contrast media (for CT scans), and anaesthesia • Also a less common pathway is proteases activating C3a, C4a, and C5a which are “anaphylactiod” chemicals

42. Idiopathic AE • The “everything else” category • Many cases do not have a known biochemical cause. • Medications, infections, and sometimes no known stimuli at all

43. Presentation

44. Evaluation • This is one of the times that PHYSICAL EXAM must ABSOLUTELY come before any history is obtained. • Patients MAY have a potentially UNSTABLE airway • Airway stable now does not mean stable in 5 minutes • Dynamic sometimes progressive condition • Keep your airway gear handy • Keep surgical airway gear in mind

45. Airway Maintenance • The general rule is if there is ANY question of airway compromise with angioedema: • INTUBATE EARLY • Delay in intubation can result in haemodynamic collapse, failed or impossible airway, need for surgical airway, or death!

46. History • Once an airway has been identified as stable, it is best to try and determine what caused the condition • Medication list is a MUST • Exposure to insects, chemicals, foods • History of similar attacks

47. EMS Treatment • For all intents and purposes treat it like any allergic reaction • H1 and H2 blockers • Steroids • Subcutaneous Epinephrine • HAE will notrespond to these interventions, Allergic AE will. • DO THEM ANYWAY! • People with HAE can have anaphylactic reactions too!

48. Hospital treatment • Urticarial / Allergic • Benadryl, H2 blocker, Steroids, Epi • Airway PRN • HAE • Replacement of C1 inhibitor • Addition of Kallikrein Inhibitor • Decreases Bradykinin

49. Hospital Treatment of HAE • Replacing C1-INH • The only treatment until now was fresh frozen plasma which contains varying degrees of C1-INH • Danazol (anabolic steroid) can also help during attacks, though must be taken orally (increases C1 inhibitor levels) • Recently approved synthetic C1-INH (Cinryze); also human C1-esterase- INH (Berinert) [not available in US] and human C1-INH (Conestat Alpha) [not available in US] • Bradykininproduction inhibition • Kalbitor is a kallikrein inhibitor recently approved for injection • Reduces conversion of kininogen to bradykinin • Available at AJ!

50. Emergency Procedures • Cricothyroidotomy may be necessary in these patients if left too long