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

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Presentation on theme: "Common Presentations of Two Uncommon Diseases Stevens-Johnson Syndrome And Angioedema Domenic Martinello, MD Anna-Jaques Department of Emergency Medicine."— Presentation transcript:

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

2 Primer on Abbreviations SJS – Stevens-Johnson SyndromeSJS – Stevens-Johnson Syndrome EM – Erythema MultiformeEM – Erythema Multiforme TEN – Toxic Epidermal NecrolysisTEN – Toxic Epidermal Necrolysis AE – AngioedemaAE – Angioedema HAE – Hereditary AngioedemaHAE – Hereditary Angioedema

3 Statistics Rather uncommon conditions:Rather uncommon conditions: SJS: cases per millionSJS: cases per million Type I HAE: 1 per 100,000Type I HAE: 1 per 100,000 Type II HAE : 1 Per 50,000Type II HAE : 1 Per 50, % of people on ACE Inhibitors % of people on ACE Inhibitors Not technically rare, you can expect to see at least 1-2 cases during your career!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 Erythema Multiforme (EM) and ends with Toxic Epidermal Necrolysis (TEN)Is actually a part of the spectrum of disease that begins with Erythema Multiforme (EM) and ends with Toxic Epidermal Necrolysis (TEN) Would be unreasonable to discuss one without the others as the entire spectrum must be understood.Would be unreasonable to discuss one without the others as the entire spectrum must be understood.

5 Erythema Multiforme First described in 1866First described in 1866 Self-limited diseaseSelf-limited disease Originally unknown causeOriginally unknown cause Symmetrical “target lesions”Symmetrical “target lesions” Diseases classified as:Diseases classified as: EM MinorEM Minor EM MajorEM Major SJS/TEN SyndromeSJS/TEN Syndrome

6 EM Minor vs Major EM Minor:EM Minor: Classic target lesionsClassic target lesions Doesn’t involve mucous membranesDoesn’t involve mucous membranes EM Major / SJSEM Major / SJS Involves mucous membranesInvolves mucous membranes Epidermal detachment <10% of BSAEpidermal detachment <10% of BSA More on this laterMore on this later

7 EM “target” lesions

8 Mucous Membrane Lesions

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

10 EM Course Tends to be benign and self limitedTends to be benign and self limited Mortality of EM essentially 0%Mortality of EM essentially 0% 4-6 weeks of symptoms and then resolution is the norm4-6 weeks of symptoms and then resolution is the norm Treatment is removal of offending agent if possible and supportive careTreatment 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.Sudden onset of rapidly spreading target lesions with or without mucous membrane involvement. Spreads centripetallySpreads centripetally Lesions “burn” but do not itchLesions “burn” but do not itch Prodrome of fevers, myalgia, headache, sore throat, nausea, vomiting, diarrhoea or other symptoms in 50% of casesProdrome 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 areasTreat like a burn if they are over large surface areas Provide fluids, analgesics if neededProvide fluids, analgesics if needed Reassurance and transportReassurance and transport

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

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

15 SJS vs TEN classification SJS:SJS: <10% BSA dermal detachment<10% BSA dermal detachment Which is also criteria for EM Major…Which is also criteria for EM Major… “Overlap” SJS-TEN“Overlap” SJS-TEN 10-30% dermal detachment10-30% dermal detachment TENTEN >30% dermal detachment>30% dermal detachment

16 Dermal detachment?

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

18 SJS Physiology Immune complex-mediated hypersensitivity reactionImmune complex-mediated hypersensitivity reaction Drugs, viruses, bacteria, malignancyDrugs, viruses, bacteria, malignancy Cocaine is newly-discovered causeCocaine is newly-discovered cause MirtazepineMirtazepine TNF-alpha antagonistsTNF-alpha antagonists Infliximab, etanercept, adalimumabInfliximab, etanercept, adalimumab Treatments for autoimmune diseasesTreatments for autoimmune diseases 50% of cases have no identified cause50% of cases have no identified cause

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

20 Clinical Presentation Clinical Presentation Tends to begin with a nonspecific upper respiratory infection type prodromeTends to begin with a nonspecific upper respiratory infection type prodrome 1-14 days, fevers, chills, malaise, sore throat, headache1-14 days, fevers, chills, malaise, sore throat, headache Nonpruritic mucocutaneous lesions eruptNonpruritic mucocutaneous lesions erupt Oral or mucous membrane involvementOral or mucous membrane involvement May cause severe pain and lead to food/drink aversion and dehydrationMay cause severe pain and lead to food/drink aversion and dehydration

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

22 SJS Skin Lesions

23 Common Culprits for SJS NSAIDSNSAIDS SulfonamidesSulfonamides BACTRIMBACTRIM AllopuronalAllopuronal DilantinDilantin TrileptalTrileptal FluroquinolonesFluroquinolones Cipro/Flagyl/EtcCipro/Flagyl/Etc Most new anticonvulsantsMost new anticonvulsants Immune modulatorsImmune modulators HIV MedicationsHIV Medications Various CancersVarious Cancers VirusesViruses HSV, HIV, Influenza, hepatitis, mumps BacteriaBacteria Strep, diptheria, brucellosis, tularemia, typhoid, mycoplasma Fungi, Malaria, parasites of many varietiesFungi, 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!Treat it like a BURN! FluidsFluids Parkland formulaParkland formula 4 ml NS/LR x %BSA x weight in kg = total4 ml NS/LR x %BSA x weight in kg = total 50% in first 8 hours, 50% over following 16 hours50% in first 8 hours, 50% over following 16 hours Pain medicationPain medication Attempt to leave as much of the skin intact as possible by avoiding manipulationAttempt to leave as much of the skin intact as possible by avoiding manipulation Be aware of heat and fluid losses!Be aware of heat and fluid losses!

26 Burn Calculation

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

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

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

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

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

32 Angioedema

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

36 Breakdown of AE SEVEN major typesSEVEN major types HereditaryHereditary Type IType I Type IIType II Type IIIType III ACE-Inhibitor InducedACE-Inhibitor Induced AcquiredAcquired UrticarialUrticarial IdiopathicIdiopathic

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

38 HAE Type III Seen ONLY in femalesSeen ONLY in females X-Linked dominant traitX-Linked dominant trait No C1-INH problem, normal C1NHNo C1-INH problem, normal C1NH Mechanism still debatedMechanism still debated Can be precipitated by pregnancy and oestrogen administrationCan be precipitated by pregnancy and oestrogen administration

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

40 Acquired angioedema Caused by circulating antibodies to the C1-INH proteinCaused by circulating antibodies to the C1-INH protein Type I – seen in B-cell proliferative diseases (Lymphoma)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.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 lymphomaType II – Also often from lymphoma IgG and IgM directed at the C1-INH causes destruction of the C1-INH proteinIgG and IgM directed at the C1-INH causes destruction of the C1-INH protein

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

42 Idiopathic AE The “everything else” categoryThe “everything else” category Many cases do not have a known biochemical cause.Many cases do not have a known biochemical cause. Medications, infections, and sometimes no known stimuli at allMedications, 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.This is one of the times that PHYSICAL EXAM must ABSOLUTELY come before any history is obtained. Patients MAY have a potentially UNSTABLE airwayPatients MAY have a potentially UNSTABLE airway Airway stable now does not mean stable in 5 minutesAirway stable now does not mean stable in 5 minutes Dynamic sometimes progressive conditionDynamic sometimes progressive condition Keep your airway gear handyKeep your airway gear handy Keep surgical airway gear in mindKeep surgical airway gear in mind

45 Airway Maintenance The general rule is if there is ANY question of airway compromise with angioedema:The general rule is if there is ANY question of airway compromise with angioedema: INTUBATE EARLYINTUBATE EARLY Delay in intubation can result in haemodynamic collapse, failed or impossible airway, need for surgical airway, or death!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 conditionOnce an airway has been identified as stable, it is best to try and determine what caused the condition Medication list is a MUSTMedication list is a MUST Exposure to insects, chemicals, foodsExposure to insects, chemicals, foods History of similar attacksHistory of similar attacks

47 EMS Treatment For all intents and purposes treat it like any allergic reactionFor all intents and purposes treat it like any allergic reaction H1 and H2 blockersH1 and H2 blockers SteroidsSteroids Subcutaneous EpinephrineSubcutaneous Epinephrine HAE will not respond to these interventions, Allergic AE will.HAE will not respond to these interventions, Allergic AE will. DO THEM ANYWAY!DO THEM ANYWAY! People with HAE can have anaphylactic reactions too!People with HAE can have anaphylactic reactions too!

48 Hospital treatment Urticarial / AllergicUrticarial / Allergic Benadryl, H2 blocker, Steroids, EpiBenadryl, H2 blocker, Steroids, Epi Airway PRNAirway PRN HAEHAE Replacement of C1 inhibitorReplacement of C1 inhibitor Addition of Kallikrein InhibitorAddition of Kallikrein Inhibitor Decreases BradykininDecreases Bradykinin

49 Hospital Treatment of HAE Replacing C1-INHReplacing C1-INH The only treatment until now was fresh frozen plasma which contains varying degrees of C1-INHThe 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)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]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] Bradykinin production inhibitionBradykinin production inhibition Kalbitor is a kallikrein inhibitor recently approved for injectionKalbitor is a kallikrein inhibitor recently approved for injection Reduces conversion of kininogen to bradykininReduces conversion of kininogen to bradykinin Available at AJ!Available at AJ!

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

51 Cricothyroidotomy Not for the faint of heartNot for the faint of heart May save a lifeMay save a life Early intubation can prevent theseEarly intubation can prevent these Know your equipment, practice often, hope you will NEVER have to do one.Know your equipment, practice often, hope you will NEVER have to do one.

52 Closing Thoughts EM is mild and self limitedEM is mild and self limited SJS and TEN can be life threateningSJS and TEN can be life threatening Angioedema has many causesAngioedema has many causes Most important is to identify allergic causes as those will respond to treatmentMost important is to identify allergic causes as those will respond to treatment Cricothyroidotomy can be lifesavingCricothyroidotomy can be lifesaving Know it, practice it, hopefully never use itKnow it, practice it, hopefully never use it

53 Questions? I will have an AJH soon for everyone to send their questions, messages, etc.I will have an AJH soon for everyone to send their questions, messages, etc. I apologize for delay in patient follow up. I now have home access to charts and follow-ups will be more timely.I apologize for delay in patient follow up. I now have home access to charts and follow-ups will be more timely.


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