Aaron Bruce, DO, FAOCD, FACMS Dermatology and Mohs Micrographic Surgery Montana Skin Cancer and Dermatology Center, PC Bozeman, MT

. Emergency: An acute illness with an almost immediate risk to life or long term health. . Focusing on common presentations in non-pregnant adults. . Practical take home points will be emphasized. . Copious images! . RED- Erythroderma . SWOLLEN- . SJS-TEN . Vascular . Infectious . 65 year old male presents with acute onset and scale over 98% of his body. Extremities are edematous. BP 95/68, Temp 100.7, tachycardic and shivering. Mucosa are normal. History did reveal a life long history of Atopic Dermatitis.

. Also called exfoliative dermatitis . Defined as generalized redness or scaling . Vesicles and pustules are usually absent . May present with acute hair loss . Mucosal surfaces are spared

. Erythroderma is not a specific diagnosis, but a clinical manifestation.

. 50% cases have underlying dermatosis . , Atopic, Chronic Actinic, Seb Derm, PRP, Contact

. (20%) . Anti-epileptics, Allopurinol, PCN, Sulfonamides, Vanc, CCB, Cimetidine, Dapsone, Gold, Lithium, Quinidine.

. Malignancy (11%) . CTCL (Sezary) or Paraneoplastic

. Idiopathic (17%)

. Reported to have overall Mortality approaching 20% . Most will need to be admitted . Cease any possible contributing agents or unnecessary meds . Aggressive supportive care and fluid regulation . Treat any underlying or contributing conditions/infections

. Most end up getting systemic steroids but utilizing wet wraps, faster and safer resolution can be obtained. . Moisten the skin first, bath or shower. 5+ minutes, warm but not too hot. . Gently pat down with towels and but in general keep patient a little wet. . Quickly Coat all involved skin with steroid ointment. Liberally grease them down tip to tale. . Soak several towels in warm water. Wring out and place on the bed. . The patient then lies down on the bed and you proceed to cover them with warm damp towels. Tuck all the towels around the patient so most of the surface area makes contact. Then put several dry towels and blanket over to keep warm. . Leave for 2-3 hours. Repeat 2x a day. . Impressive improvement will be noticed in 12-24 hours. . Triamcinolone 0.1% OINTMENT 454gm tub. . Face and genitals: 0.25% OINTMENT

. Buy your nurse a latte!

. Similar treatment can treat severe stasis dermatitis in 48-72 hours. . Severe stasis dermatitis

TAC 0.1% ointment applied under saran wrap occlusion and covered with socks or Coban/Ace wraps done nightly. . RED- Erythroderma . SWOLLEN- Angioedema . SJS-TEN . Vascular . Infectious . Paraneoplastic . A 40 year old diabetic female was started on an ACE inhibitor about a week ago for hypertension. . She calls your office stating her lips, cheeks and left hand are swollen. She also complains of abdominal pain. Your astute phone nurse mentions the patients voice was more soft spoken than usual.

. Now most common exogenous cause of angioedema seen in emergency rooms . Usually has no associated urticaria . Due to increased bradykinin levels secondary to inhibition of kinin degradation . Can cause dramatic swelling of tongue, pharynx, or larynx – may require intubation or tracheostomy acutely . Airway is more commonly involved with ACE Induced angioedema vs other causes . Angioedema develops in 0.1% to 0.5% of those receiving the drug . Onset from 1st week of use to 2-3 years of use . Symptoms resolve within 24-48 hours of cessation of drug . Most commonly seen with captopril and enalopril, but described with all ACE inhibitors . Genetic factors may be important . Subjects with a history of angioedema from other causes are more susceptible to ACE-induced angioedemaSlater JAMA 1988 . Face and lips most commonly involved but laryngeal edema reported . Risk factors include obesity, prior endotracheal intubation and face and neck surgery . ACE inhibitors will trigger attacks in those with HAE, so avoid in these patients

Jain Chest 1992 Management . Stop drug and use other classes of antihypertensive agents . ALL ACE inhibitors are to be avoided . Management of angioedema depends on site of involvement – securing the airway by intubation may be necessary . ACE receptor antagonists are generally considered to be safe

Johnson SP, Jacobsen J, Monster TBM et al. Am. J.Med.118:1428-1429, 2005 DIFFERENTIAL DIAGNOSIS OF

ACUTE. IgE ANGIOEDEMAmediated allergic reactions to food, drugs, venoms etc. . Histamine-releasing drugs (e.g. opioids, RCM), pseudoallergens in food . Adverse reactions to certain medications: NSAIDs, ACE- inhibitors . Chronic urticaria with angioedema . Idiopathic or exercise induced anaphylaxis . C1-Esterase Inhibitor deficiency (hereditary or acquired) . Gleich syndrome: recurrent angioedema and high eosinophil counts of unknown etiology . Angioedema in hypereosinophilic syndrome . Etiology: . Often idiopathic . Medications . angiotensin-converting- enzyme inhibitor in 10-25% of cases . Penicillin . NSAID . Allergens (foods, radiographic contrast media) . Physical agents (cold, vibration, etc) . C1 esterase inhibitor deficiency: hereditary vs associated with autoimmune disorder or malignancy . Management . Airway management . Antihistamines . Cool compresses . Avoid triggers . For pts with C1 esterase inhibitor deficiency: Acute management vs short term vs long term prophylaxis: androgens (danazol and stanozolol), C1 esterase inhibitor concentrate, antifibrinolytics, icatibant (selective antagoist of bradykinin B2 receptor)

. RED- Erythroderma . SWOLLEN- Angioedema . SJS-TEN . Vascular . Infectious • 44 year old male reports worsening rash over the last 2 days with a 5 day history of sore throat, fever, myalgias. – Has not taken antibiotics but has been using ibuprofen.

28 . Pathophysiology: . Drug induced mucocutaneous reaction . Culprit medications: Sulfonamides, anticonvulsants, allopurinol, NSAIDs. Usually given 1-3 weeks before onset . Genetic susceptibility . SJS and TEN are continuum . SJS: BSA < 10% . SJS/TEN overlap: BSA 10-30% . TEN: BSA > 30% • Prodromal Symptoms – Malaise, rhinitis, sore throat, body aches, and fever. – Followed by the abrupt development of a macular rash that may or may not appear as target lesions. – Mucous membrane involvement may precede rash in TEN – Macular exanthem usually starts centrally and then spreads to the extremities

• Bullae form within the rash and large sheets of epidermis separate from the dermis. – Involved skin is exquisitely tender to palpation. – Nikolsky Sign (+)

30

• Mucous membrane involvement develops

• Conjunctival and corneal involvement may lead to permanent scarring and blindness. – Full thickness of epidermis involved

• Mortality rate 15-20% – as high as 50% in elderly patients

• Life-threatening metabolic derangements, sepsis, respiratory failure, and gastrointestinal hemorrhage may occur and are compounded by underlying comorbidities.

33

SJS

35 Bullous SJS/TEN

36 . Supportive Care . Discontinue offending agent, fluid replacement, electrolyte balance, ophthalmologic assessment and aggressive infection control . Systemic corticosteroids remain controversial . no benefit and associated with increased mortality secondary to infection

. Admission to a Burn ICU . Fluid replacement . Per Parkland Formula with Ringer’s Lactate . Goal UOP 0.5cc/kg/hr . Wound Care (no Silvadine = Sulfa) . Infection control . IVIG per local protocol . Fas ligand (FasL) expression hypothesized as the “death ligand” induced for abnormal apoptosis of epidermal cells .  in SJS/TEN patients . Pooled human immunoglobulin contain anti-Fas antibodies that have been shown in vitro to impede apoptosis when pre-incubated with 37 keratinocytes 1. The hair-bearing scalp is spared even in severe disease.

2. Neutropenia is associated with a poor prognosis.

3. Cross reactions within anticonvulsants are common. The first 8 weeks of treatment have the highest risk of TEN and previous anticonvulsant therapy portends a tenfold increased risk.

4. Patients with previous SJS/TEN to one medication class are higher risk for developing SJS/TEN to other medication classes.

38 . RED- Erythroderma . SWOLLEN- Angioedema . SJS-TEN . Vascular . Infectious . Calciphylaxis . Vasculitis (PAN) . Purpura fulminans/DIC . Arterial thrombosis . 54 y/o female on HD presented with tender, lumpy, indurated plaques on abdomen and lateral thighs. . Mottled skin ulcerates, exposing necrotic SC adipose tissue . Necrosis progresses and despite intensive wound care, pt dies of sepsis . Painful skin lesions with superficial violaceous nodules on tips of digits, ankles, thighs or buttocks . Progressed to hemorrhagic eruptions with ischemic necrosis . Bilaterally symmetrical, superficial, maintained persistent distal pulses . Pathogenic Factors . Uremic milieu + high Ca . Ca content of skin noted to be high in HD pts and higher when dialysate Ca concentrations of 4.0 meq/L. Lowering dialysate Ca improved CUA in some pts. Also avoiding ca based po4 binders . Presence of high PTH levels

. Primary: calcium salts accumulate in media of small arteries . lumen narrows • Secondary Lesion • Infarcts of the subcut tissue and skin comprise the secondary lesions, responsible for initial clinical manifestations of the syndrome. • Before skin ulcerations, tissue ischemia leads to hard lumpy and/or plaque- like charac to the SC tissue. . Primary lesion alone not sufficient to initiate infarction ie, thrombosis or reduced perfusion contribute . Thrombi often found in primary lesios . Preexisting disturbances of coagulation are relevant to the pathogenesis: protein c/s and cryofibrinogen . Also iron dextran suggested to aggravate or initiate the secondary lesions . Consistent localization of secondary lesions in body areas of greatest adiposity . Women deposit more of their fat in SC than internal adipose stored . Bleyer, et al AJKD 1998 identified obesity and low serum alb as highly predictive of CUA . Risk of calciphylaxis increased with increased weight . 1-4% of ESRD population . Increasing prevalence suspected due to incr use of vit d analogues and calcium based p04 binders, in addition to increased reporting • Whites > Blacks • Females > Males 3:1 • Obesity confers risk . Mortality: 60-80% . Sepsis from infected/necrotic skin lesions . Higher mortality in proximal dz than acral dz . Systemic Vasculitis . Warfarin Necrosis . Lupus . Polyarteritis of SLE . HSP . Pancreatic panniculitis . Weber-Christian Syndrome: panniculitis sometimes with necrotic ulcers . Acquired protein C deficiency . Normalization of Ca x P product . Aggressive wound care with debridement of necrotic tissue and systemic Abx therapy . HD with low dialysate Ca concentration no greater than 2.5 meq/L . Avoid Ca containing po4 binders . Local injections in adipose areas where lesions usu develop should be avoided . Other potential triggers: blood products, corticosteroids, immunosuppressant should be avoided . RED- Erythroderma . SWOLLEN- Angioedema . SJS-TEN . Vascular . Infectious . Meningococcemia . Rickettsioses/RMSF . Staph scalded skin and TSS . Necrotizing Fasciitis . Etiology . Neisseria meningitides (gram neg diplococcus) spread by respiratory route . Often seen in young adults and children . Risk factor: asplenia, immunoglobulin or terminal complement deficiencies . Dermatologic findings . Abrupt onset of maculopapular or petechial eruption on acral surface, trunk or lower extremities -> progression to purpura in hours . Angular edge with “gun metal gray” center . +/- mucosal involvement . Clinical presentation . Flu like symptoms: fever, chills, malaise . DIC, shock, death

. 61 y/o male who regularly hikes and gardens presents to the ER with Fever, weakness, and myalgias. He did report tick exposure, but can’t remember exactly when. No rash was seen on exam. He seems somewhat confused, which his wife says is not baseline. “A second peak incidence of disease occurs in males over age 60. This is in contrast to the constant rate of disease seen in females after age 14. Absence of the typical skin rash (“spotless”), atypical features, and greater severity characterize RMSF in the el- derly.” . Clinical presentation . Triad: fever, headache and rash (only in 60%) . Can have variety of organ involvement (cardiogenic shock, hepatic failure, renal failure, meningismus and DIC) . Mortality is 30-70% if untreated vs 3-7% if treated . Dermatologic findings . Purpuric macules and papules . Starts on the wrists and ankles within 2 weeks-> spread to palms, soles-> to trunk and face . Over 2-4 days, the skin will become hemorrhagic and petechial . May have eschar at site of bite . “Spotless” RMSF occurs approx 10% of the time First starts on wrists and ankles . Greatest odds of survival if treatment started within 5 days of symptoms. Most diagnostic tests remain negative for at least 7 days. Thus, best diagnosed on clinical grounds and treated empirically. . Helpful signs, thrombocytopenia, hyponatremia, elevated LFTs . History of exposure high grass, dogs etc… may help as most don’t recall a tick exposure. . Treatment is Doxycycline first line and Chloramphenicol as distant 2nd line . Confirmatory test however is skin biopsy of rash with the appropriate immunostains, or the gold standard, indirect immunofluorescence assay with R. rickettsii antigen on two paired serum samples. (IgM and IgG)

. RED- Erythroderma . SWOLLEN- Angioedema . SJS-TEN . Vascular . Infectious