Bullous Drug Eruption Staphylococcal Scalded Skin Syndrome (SSSS)

Home , Bullous pemphigoid, Drug eruption

Jordan Jamerson Evaluation of an acute Don’t be rash. bullous presentation Presentation:

❖ 68 yo M with signiﬁcant skin rash

❖ Recently diagnosed with BLE cellulitis, started on bactrim and keﬂex ~2 weeks ago and completed them 2 days prior to presentation.

❖ Noted improvement in initial redness and tenderness. However, 3 days prior to presentation, he developed a red, nonpruritic, slightly tender rash on lower/upper extremities. Rash spread to include thighs, groin, abdomen, palms, soles, periocular. Denied oral, ocular, perianal involvement.

❖ Also reported recent cold ❖ PMH: Hepatitis C, glaucoma, h/o TBI (w/o h/o seizures) hypoglycemia, HTN, BPH

❖ Allergies: NKDA. Reports taking bactrim in past without reaction

❖ Medications: statin, tamsulosin, and a blood pressure medications. Recently stopped adderall.

❖ ROS: + subjective chills.

❖ Denies subjective fever, N, V, D, lightheadedness, loss of sensation, vision changes, chest pain, palpitations, dysuria. Physical exam

❖ Vitals: 99.7, HR 122, RR 20, BP 138/62, pulse ox 100% on RA, pain score 7.

❖ General: non-toxic, well appearing, NAD although appearing uncomfortable, AOx3

❖ Cardiopulm: Tachycardic, breathing well on RA

❖ Skin: 1. Chest and UE: erythematous morbilliform, maculopapular eruption, appears to have progressed since initial photographs by primary team. No scale overlying with some pinpoint vesicular areas - no pustules noted 2. Feet and LE: diffuse erythema, mild edema. Upper calves bilaterally demonstrate patches of superﬁcial bullae, easily sloughed with overlying morbilliform eruption 3. Erythematous morbilliform eruption extends up to legs to upper thighs and involved inguinal area 4. Patient declined examination of genital area 5. No sloughing or necrotic changes noted in oral mucosa, no erythema or conjunctivitis changes 6. Palms with erythematous macules, no distinct targeted or bull noted Terminology

• PAPULE - Raised lesion less than 10 mm

• MACULE - flat lesion. Some people use this term when the lesion is less than 10 mm and use PATCH when it is larger, while others use macule for all flat lesions. Macules can be any color: red, brown, white, etc. If you close your eyes and run your hand over the area and cannot feel it, it is likely a patch or macule.

• PLAQUE - Raised lesion greater than 10 mm.

• NODULE - Similar to papule or plaque, but deeper and more solid

• WHEAL - Evanescent, pink, slightly elevated lesion due to edema. Also called URTICARIA or HIVES. Lesions will blanch (unlike purpura).

• VESICLE - Elevated blister containing clear fluid, less than 10 mm.

• BULLA (pl. BULLAE) - Elevated blister containing clear fluid, larger than10 mm.

• PUSTULE - Same as vesicle, except that it contains pus instead of clear serous fluid

• EROSION - Superficial defect in skin, not all the way through the epidermis.

• ULCER - Defect or excavation of the skin, deeper than erosion; extends at least into the dermis.

• MACULOPAPULAR - Combination of macules and papules. Usually used for non-specific drug rashes and viral exanthems. Usually used when there is no scale. (AKA morbilliform)

Hand rash mnemonic

❖ MRS TECK/H ❖ Meningococcemia ❖ Rubella/RMSF ❖ Syphilis/SJS/(scabies) ❖ TSSS/TEN ❖ EM/Endocarditis ❖ Coxsackie ❖ Kawasaki’s ❖ Herpes (HSV, VZV)

Labs/Imaging

❖ Hct 41.3 ❖ Glucose 83 ❖ AST 39 ❖ ESR 30 ❖ BUN 18 ❖ ALT 46 ❖ CRP 83.6 ❖ Cr 1.02 ❖ Total protein 7.6 ❖ WBC 19.7 ❖ Na 136 ❖ Albumin 3.8 ❖ N 84% ❖ K 4.6 ❖ P 4.0 ❖ L 8% ❖ Cl 105 ❖ Mg 2.3 ❖ M 5% ❖ CO2 22 ❖ troponin neg ❖ E 2% ❖ Ca 9.3 ❖ BNP 55 ❖ B 0% ❖ Tbili 0.6 ❖ LA 1.4 ❖ LE dopplers negative ❖ Alk Phos 116 ❖ Hgb: 14.1 for DVT Differential:

❖ SSSS ❖ Acute generalized exanthematous pustulosis (AGEP) ❖ Linear IgA dermatosis ❖ Toxic shock syndrome ❖ Drug hypersensitivity syndrome (DRESS) ❖ Bullous pemphigoid ❖ Pemphigus vulgaris ❖ Paraneoplastic pemphigus ❖ Dermatitis herpetiformis ❖ Sweet’s syndrome ❖ Acute graft-versus-host disease ❖ SJS/TEN ❖ EM ❖ Bullous drug eruption Staphylococcal scalded skin syndrome (SSSS)

❖ SA toxin mediated

❖ Usually newborns/infants/young children. M>F

❖ Can be seen in adults with impaired immune system or renal function. ❖ prodrome of F, sore throat, malaise, irritability, purulent rhinorrhea, conjunctivitis ❖ Facial erythema -> scarlatiniform eruption generalizes to body -> Flaccid bullae (24-48h) -> positive nikolsky -> exfoliated skin is superﬁcial (subcorneal - toxins against desmoglein 1) ❖ Widespread ❖ Can see circumolar erythema and mild facial edema, lip ﬁssuring, purulent conjunctivitis ❖ Mucous membrane and palms/soles are spared. ❖ Desquamation for up to 5 days ❖ No scarring following reepithelization ❖ Txt: antibiotics Differential:

❖ Acute febrile pustular eruption ❖ high fever (102.2 degrees F) for about a week ❖ non-follicular pustules ❖ Following medications (primarily antibiotics: penicillins, macrolides; however, possible with multiple medications), mercury ingestion, viral infection. ❖ All ages

❖ Burning, pruritus ❖ Marked neutrophilia ❖ Nikolsky sign may be positive. ❖ Mucous membrane involvement with erosions of mouth/ tongue can appear. ❖ Facial edema occurs in 1/3 of patients. ❖ Spontaneous healing in 2 weeks followed by desquamation. ❖ Afebrile, no pustules.

❖ Symptomatic therapy, +/- topical mupirocin Differential:

❖ Immune-mediated. ❖ Idiopathic or medication-induced ❖ Grouped or annular vesicles,or bullae on elbows, knees, buttocks (extensor surfaces). ❖ children: onset <5y and often perioral or perineal ❖ >4th decade ❖ May appear on edge of previous blister giving a “collarette” appearance. ❖ Tense blisters, unique histology -> DIF demonstrates linear IgA deposition at epidermal-dermal junction ❖ Favors extensor surfaces ❖ Certain medications: most commonly vancomycin ❖ others include phenytoin, amoxicillin, piroxicam, lithium, diclofenac, captopril, IL-2, IFN-gamma, and d-penicillamine ❖ In drug-induced reactions, mucosal involvement is less likely ❖ Burning, pruritus common complaints. ❖ Mucosal eruptions are common, can be severe, typically in idiopathic cases ❖ Txt: d/c medication. Dapsone, topical steroids, immunosuppressants Differential:

❖ Exotoxin-mediated (GAS and SA) ❖ Superantigen -> massive nonspeciﬁc activation of T cells ❖ Range: mild to shock and end organ failure ❖ Erythema of palms and soles followed by desquamation in 1-3 weeks ❖ Erythema of mm (strawberry tongue and conjunctival hyperemia)

❖ SA: Diffuse scarlatiniform exanthem on the trunk -> extremities. Fever, hypotension. Tampons, surgical packing, abscesses, surgical mesh ❖ GAS: severe pain in extremity with or w/o underlying STI. Prodrome of fever, diarrhea, myalgia. Macular erythroderma not commonly seen. Often positive blood cultures. Mortality rates higher. Shock and multigrain failure occur 48-72 h after initial presentation. Risk factors include bites, lacerations, varicella infections. ❖ Both can demonstrate confusion, coma, renal impairment, liver impairment, ards, DIC ❖ supportive therapy, antibiotics Differential:

❖ Drug reaction with eosinophilia and systemic symptoms (fever, rash, internal organ involvement) ❖ - typically hepatitis, but can also effect kidneys and hematological system, and, more rarely, pneumonitis, pericarditis, or myocarditis ❖ Can also see pharyngitis, LAD, facial edema, nephritis ❖ Pink to dark red, symmetric morbilliform eruption +/- pustules

❖ Can also see urticarial plaques, atypical targeted lesions, vesicles, mucosal involvement ❖ Best classiﬁed as having TEN/SJS and treated accordingly ❖ Occur between 1-3 weeks after initiating new medication, but can be months later ❖ Commonly: anticonvulsants, sulfonamides, NSAIDS, minocycline, allopurinol, metronidazone, dapsone, nevirapine, clopidogrel, ticlopidine ❖ Skin biopsy: may show common drug eruption but may demonstrate keratinocyte necrosis (as seen in EM, SJS/TEN) ❖ stop medication, +/- systemic corticosteroids, supportive care ❖ No eosinophils or AST/ALT/Cr changes Differential:

❖ Chronic AI supepidermal (IgG hemidesmosome adhesion complex) causing tense bullae, MC in elderly ❖ can be extensive or localized, flexural predilection ❖ filled with serous or blood-tinged fluid ❖ resolve without scarring, milia may arise with healing

❖ pruritic ❖ MM involvement is rare ❖ Commonly seen with other AI diseases ❖ XRT or medications (lasix, NSAIDS, captopril, penicillamine, some antibiotics) have been associated with BP. ❖ May also follow inﬂammatory skin diseases or vaccination ❖ Negative nikolsky’s sign ❖ Often self-limiting, can become chronic

❖ Txt: prednisone, +/- systemic antibiotics, avoid mechanical trauma, topical steroids or intralesional, tetracycline and nicotinamide, dapsone, azathioprine, IVIG, rituximab Differential:

❖ Chronic AI intraepidermal bullae ❖ IgG autoantibodies against desmoglein causing pacantholysis ❖ More common in those with AI h/o and Jewish ancestry ❖ Flaccid bullae, erosions, crust ❖ Commonly affect mucosal surfaces (conjunctiva and oral mucosal) ❖ Large areas can denude ❖ +Nikolsky’s sign ❖ +Asboe-Hansen ❖ Txt: topical steroids, oral steroids, cytotoxic drugs, minimize trauma, dietary modiﬁcations Differential:

❖ Severe, immunologically medicated mucocutaneous disorder ❖ Develops in the setting of current or past h/o malignancy, often hematologic (often lymphoma/ CLL) ❖ Can affect multiple organs ❖ Symptoms include painful cutaneous and oral lesion 2/2 vesicles and bullae. Severe eye, esophageal, genital mucosa irritation may occur, including pulmonary involvement (bronchiolitis obliterans) ❖ hemorrhagic crusting of lips ❖ shallow ulcerations of buccal, labial, lingual mucosa ❖ cutaneous lesions range: lichen planus, EM, pemphigus, bullous pemphigoid, linear IgA ❖ ocular involvement ❖ esophageal and genital mucosa - ulcers, erosions Differential:

❖ Chronic, pruritic AI blistering d/o associated with gluten-sensitive enteropathy ❖ IgA immune complex deposition in the papillary dermis (against epidermal transglutaminase) ❖ Intermittent pruritic papulovesicular eruption grouped over extensor surfaces of extremities (elbows, knees, shoulders, buttocks) often excoriated with pinpoint erosions. Intact vesicles are rare. ❖ many experience complete remission with strict gluten-free diet ❖ Increased risk of developing Hashimoto’s thyroiditis, non-Hodgkin’s lymphoma, and GI lymphomas ❖ More common in Caucasians and M>W ❖ May worsen with iodides and certain NSAIDs Differential:

❖ AKA acute febrile neutrophilic dermatosis ❖ multiple painful erythematous plaques associated with a fever ❖ Deep red, thick, sharply demarcated plaques or nodules that appear vesiculated without expressible fluid. Ulcers and bull may occur, more often with underlying malignancy. ❖ lesions often appear in areas of skin trauma ❖ usually seen on extremities, but may occur on head, neck, or trunk ❖ All ages; however, most often seen in women 20-60 ❖ Other symptoms include headaches, myalgias, malaise, arthralgias ❖ Respiratory system can be affected. Infiltrates on car and cough. ❖ Can also affect the GI tract, MS, kidneys, heart, CNS ❖ Mucosal involvement can occur but are infrequent. ❖ Unclear etiology. Considered reactive. Associated with numerous inflammatory, infectious, and malignant processes. Also pregnancy and antibiotics (bactrim, minocycline, G-CSF ❖ Responds very well to systemic corticosteroids. Differential:

❖ h/o BMT Differential:

❖ Rare. 1-2/million per year for SJS and 0.4-1.2/million per year for TEN ❖ All age groups and races, F>M, 100x more common in association with HIV ❖ High fevers, skin tenderness, mucosal erosions, skin detachment 1-3 weeks following initiation of offending antibiotic and ~2 months after initiation of anticonvulsant. ❖ Spectrum. SJS <10% of BSA. TEN > 30% BSA. SJS may rapidly evolve into TEN, both can have unpredictable course. ❖ Primary lesions are typically dusky red macules on trunk centrifugal spread. Possible atypical target lesions. Hours to days, epidermal - dermal detachment with serosanguineous fluid filling flaccid blister (epidermal- dermal detachment). Erosions and ulcerations with bleeding dermis exposed. +nikolsky’s and asboe-hansen sign. Ocular, oral, genital mucosa affected >90% of cases, demonstrating hemorrhagic crust, bullae, and denudation with involvement. ❖ ROS concerning for mucosal involvement: painful eyes, painful swallowing, dysuria, diarrhea, sore throat, difficulty swallowing, inflammation around/in mouth, cough and respiratory distress ❖ Medication history (NSAIDS, antibiotics, anticonvulsants) is strongly associated with disease development in >80% cases. Likely 2/2 to inability to detoxify drug metabolites resulting in cell death due to cytotoxic T cell response. ❖ More rare cases include immunizations and infections as offending agents. ❖ Diagnose: skin biopsy, elevated ESR, leukocytosis, eosinophilia are common. ❖ Monitor with CBC, CMP, urine output. ❖ Panculture (swabs from potentially infected areas, blood and urine Cx), +/- blood gases, baseline chest films, GI films to evaluate possible involvement. ❖ SCORTEN: estimates mortality of TEN

❖ Age >40

❖ HR >120 bpm

❖ Malignancy

❖ Involved BSA > 10%

❖ Serum bicarbonate < 20 mEq/L

❖ Blood glucose > 252 mg/dL

❖ Mortality estimates based on above:

❖ 0 - 1: greater than or equal to 3.2%

❖ 2: greater than or equal to 12.1%

❖ 3: greater than or equal to 35.3%

❖ 4: greater than or equal to 58.3%

❖ 5 or more: greater than or equal to 90%

❖ SCORTEN score 2, 12.1% mortality for SJS -> progressed to SCORTEN 3, 35% mortality for SJS by the following morning Complications

❖ Dehydration, acute malnutrition

❖ Infection of skin, mucous membranes, lungs, septicemia

❖ ARDS

❖ GI ulceration, perforation, intussusception

❖ Shock and multiple organ failure

❖ Thromboembolism and DIC ❖ Discontinue inciting medication

❖ Supportive therapy, preferably at burn unit

❖ Consultation with specialists

❖ Supportive care:

❖ Wound care - nanocrystalline gauze material containing silver ions or petrolatum based gauze pads. None with sulfa products.

❖ Fluid and electrolyte management - correct for water loss

❖ Nutritional supplementation - may require NGT and supplementation

❖ Temperature regulation - treatment as burn victim with concern for heat loss. Increase room temperature (86-89.6 degrees)

❖ Superinfections - high risk for sepsis/infection. Pan-culture routinely throughout hospital stay. Systemic antibiotics not recommended prophylactically. Sterile handling and reverse isolation.

❖ Ocular care - vigorous lubrication. Lysis of adhesions. Immediate ophthalmologic consultation to reduce risk of damage

❖ Oral: mouthwashes and topical oral anaesthetic

❖ Gential: if ulcerated, steroids to prevent intravaginal adhesions, soft vaginal dilators

❖ Lungs: aerosols, physiotherapy, bronchial aspiration, may require intubation and mechanical ventilation

❖ GU: +/- catheter, culture for infection

❖ Heparin for ppx ❖ Speciﬁc therapies:

❖ Corticosteroids: controversial, may increase risk of complications (infections, impair wound healing) without clinical beneﬁt.

❖ IVIg: mixed, considered effective. Severe, rare complications include coagulopathies, ARF, anaphylaxis, aseptic meningitis. Consider checking IgA levels prior to administration as deﬁciency can lead to anaphylaxis

❖ Cyclosporine

❖ Plasmapheresis: mixed (can consider with IVIg)

❖ Anti TNF alpha monoclonal antibodies

❖ Cyclophosphamide

❖ Pain/pruritus management with opiods/antihistamines Differential:

❖ Similar histological features as SJS/TEN ❖ No risk of progression to TEN ❖ Cause is usually 2/2 viral, including HSV, mycoplasma, varicella, parapoxvirus, adenovirus, coxsackievirus, HIV, hepatitis, salmonella, etc. (may be recurrent) ❖ More common in males ❖ Characteristic target lesions ( 3 distinct color zones, <3cm in diameter, central zone that has bulla or crust), commonly on extremities (face and UE>palms, neck, trunk>LE), can be papular. In more severe EM, papules can become larger and run into each other forming large blisters than may form and burst. ❖ EM minor and major. Major includes mucosal involvement and systemic symptoms (fever, arthralgias, and asthenias) ❖ Progression is usually complete within 72h, then remains ﬁxed for up to 2 weeks, and then resolves without sequelae Differential:

❖ Pemphigus-like ❖ intraepidermal = ﬂaccid ❖ d-penicillamine, captopril, gold, antibiotics (penicillin, cephalexin, rifampicin), phenylbutazone, phenytoin, levodopa, phenobarbital, piroxicam, progesterone, propanolol ❖ Pemphigoid-like blisters ❖ subepidermal = tense

❖ d-penicillamine, antibiotics (penicillins, sulfas), captopril, furosemide, practolol, clonidine, tolbutamide, sulfasalazine, PUVA ❖ +/-mucosal lesion ❖ DIF positive in ~70% of cases ❖ Eruption resolves w/i months of discontinuing medication ❖ Therapy: ❖ prednisone 1 mg/kg ❖ other therapies include mycophenolate motel, azathioprine, dapsone, tetracycline, cyclosporin A, FK 506 Differential:

“Intact epidermis with prominent sub-epidermal edema with a superficial perivascular and interstitial lymphocytic infiltrate…parakeratosis with a few scattered neutrophils… overlying epidermis is intact and viable without necrotic keratinocytes identified…ddx includes bullous drug eruption …less likely EM, bullous type…early SJS cannot be excluded” Brief course

❖ Higher care: ICU, burn unit

❖ IVF

❖ Topical TAC 0.1% qd-bid

❖ Dry dressings

❖ Blood cultures, high risk of infection: No growth at 5 days. Did not develop further decompensation, no evidence of infection.

❖ Leukocytosis, recent cellulitis: initiated on Vanc

❖ Eventually transferred to San Antonio burn unit for higher care, added short course of prednisone (12 days, received 5 days), and dicloxacillin/amoxicillin q6h for venous stasis dermatitis. Benadryl and tramadol prn pruritus

❖ Patient improved with above therapy. Formal dx: Bullous drug eruption 2/2 Bactrim.

❖ Follow up with Derm 1 month after hospitalization: rash resolved. Never picked up prednisone after discharged. Bullous drug reaction - resolved. Stasis dermatitis with keratoderma of soles of feet - Continue TAC on bilateral LE prn and urea 40% for LE and feet for scaling. References

❖ Thank you to visualdx.com and dermnetz.com for great photos and explanations for various disease processes.

❖ http://vandypem.org/trauma/burns/

❖ http://torontodermatologycentre.com/UserFiles/File/ Dermatologic%20signs%20-%20jcms%2006.pdf