Bullous Skin Lesions, Meet Emergency Medicine
/Bullous skin lesions, a subset of cutaneous blistering disorders, are a group of illnesses with predominately dermatologic findings that can occur in a wide variety of clinical settings, including autoimmune, pharmacologic reactions, infection, genetic disorders, or physical injury. This differential is broad and reflects the clinical diversity of their presentations - in this post we will parse through the specifics of bullous lesions as well as what there is to do for them acutely.
While blistering skin disorders are vast within a dermatology textbook, they all contain one important characteristic - blisters, which are clear watery fluid-filled lesions of the skin ranging in size from vesicles (<1cm diameter) to bullae (>1cm diameter). Bullae are further subdivided into flaccid, meaning they burst easily due to a thin wall, or tense bullae, which have a thicker wall and do not rupture easily.
Skn layers that define the level of separation in bullous diseases - courtesy of nursinghero via https://www.nursinghero.com/study-guides/cuny-csi-ap-1/integumentary-structures-and-functions
Blister formation occurs due to 3 processes:
Acantholysis: the loss of adhesion between cells within the epidermis
Spongiosis: Edema/swelling that accumulates between epidermal cells
Disassociation between the epidermis and dermis
While many blistering skin disorders are not life-threatening, a small subset of diseases exist that are emergent and require immediate intervention to reduce the morbidity/mortality rates. Mortality rates related to bullous skin lesions are typically related to disruption of the skin barrier and include subsequent dehydration, electrolyte imbalances, hypothermia, increased metabolic needs, and secondary infection leading to bacteremia and/or sepsis.
The first step is to determine what disease you are dealing with. The blisters can tell you many things, and it’s important to perform a thorough history and physical exam, specifically looking for the following:
Blister distribution:
Generalized or localized to one area?
Are the blisters grouped, linear, annular, or in a different configuration?
Blister Characteristics:
Vesicles or bullae?
Flaccid bullae or tense?
Is there mucous membrane involvement? (includes oral, nasal, ocular, and anogenital)
How old is the patient?
Have they had any recent new exposure or medications?
The following are bullous skin disorders with indications for urgent/emergent intervention, and more likely to present to an Emergency Department.
Pemphigus Vulgaris:
Pemphigus Vulgaris - Courtesy of Mohammed2018 via https://commons.wikimedia.org/wiki/File:Pemphgoid_vulgaris_same_patient.jpg
Pemphigus vulgaris is an acquired type 2 hypersensitivity reaction often seen in older adults, with the formation of autoimmune IgG antibodies against desmoglein 1 and/or desmoglein 3. It consists of flaccid intraepidermal bullae on both skin and mucosa caused by acantholysis. Oral mucosal bullae are often seen as erosions since they break down quickly. Pemphigus is Nikolsky sign positive (rubbing skin with light mechanical pressure will induce a blister), non-pruritic, and often sparing the palms and soles. Diagnosis is typically via skin biopsy performed by Dermatology, which will show tombstoning on H&E stain or reticular pattern noted on immunofluorescence. Treatment typically consists of IV Rituximab and oral high-dose steroids. Supportive care is key, with wound management and oral hygiene pivotal, including avoiding spicy, sharp, abrasive, or very hot food. Prior to immunosuppression, mortality rates ranged from 70% to almost 100% in 5 years. Now, mortality is estimated 5-10%, often related to complications from treatment.
What can you do from the Emergency Department if suspected?
Consult your Dermatology colleagues
Start high-dose steroids
Mild disease (<5% BSA, no oral mucosal involvement): 0.5 mg/kg/day
Moderate/severe disease (>5% BSA, oral mucosal involvement): 1 mg/kg/day
Symptom management: fluids and pain control
Bullous Pemphigoid
Bullous Pemphigoid courtedsy of mohammed2018 via https://commons.wikimedia.org/wiki/File:Pemphgoid_vulgaris_same_patient.jpg
Bullous Pemphigoid is more common than Pemphigus Vulgaris but is also less severe. It is an acquired type 2 hypersensitivity reaction commonly seen in older adults, with the formation of IgG antibodies against hemidesmosomes in the epidermal basement membrane. This forms tense blisters, typically located on the trunk and extremities. In contrast to Pemphigus Vulgaris, it spares the oral mucosa and often is Nikolsky sign negative. There can be a prodrome phase of pruritic, eczematous, papular, or urticaria-like lesions that may last weeks to months prior to bullae formation. Diagnosis is again with skin biopsy with Dermatology, showing a linear pattern of immunofluorescence at the epidermal-dermal junction. Treatment is with high-potency steroids and immunosuppressants.
What can you do from the Emergency Department if suspected?
Consult your Dermatology Colleagues
Start high-dose steroids
Symptom management: fluids and pain control
Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)
SJS/TEN is a drug-induced CD8 T cell-mediated reaction initiating the release of cytotoxic proteins that cause epidermal necrolysis at the dermal-epidermal junction, resulting in cell death via apoptosis. Typically, SJS will present within 1 week to 1 month after starting the new medication, initially presenting with fever and flu-like symptoms including malaise, sore throat, myalgias, and conjunctivitis. Patients then develop painful, diffuse erythematous and purpuric macules which progress to vesicles, bullae, and skin sloughing - sheet-like detachments with erosions. The acute phase of SJS lasts 7-9 days from initial symptoms until the process arrests and reepithelization begins. >90% of all cases have 2 or more mucous membranes involved, and cutaneous lesions can have a targetoid appearance similar to erythema multiforme. The differentiating factor between SJS and TEN is body surface area, with <10% being SJS, 10-20% SJS/TEN, and >30% being TEN.
Older adults are at higher risk, and there is a 2:1 female predominance. Additional risk factors include HIV, connective tissue disease, underlying malignancy, higher drug dose, or impaired renal function. Mortality rates range from 10-50% depending on the severity on presentation, patient age, and patient comorbidities.
Interestingly, there is a genetic predisposition of HLA subtypes, specifically HLA subtypes found within the Han Chinese population; HLA B*1502 have a higher risk of carbamazepine-induced SJS, while HLA B*5801 have a higher risk of allopurinol-induced SJS.
| High Risk Meds | Moderate Risk Meds | Low Risk Meds |
|---|---|---|
| Antibacterial sulfonamides | Diclofenac | Pantoprazole |
| Anticonvulsants: lamotrigine, carbamzepine, phenytoin | Doxycycline | Glucocorticoids |
| Oxicam NSAIDS: piroxicam and tenoixam | Amoxicillin/ampicillin | Omeprazole |
| Allopurinol | Ciprofloxacin | Terbinafine |
| Chlormezanone | Levofloxacin | Levetiracetam |
| Sulfasalazine | Rifampin | |
| Phenobarbital |
SJS/TEN complications are numerous, and should be considered at presentation:
Pulmonary involvement is common during the acute phase, including pneumonia, pulmonary edema, atelectasis, or acute respiratory failure.
GI involvement is not well defined, but can include abdominal pain, diarrhea, or hematemesis
Drug-induced liver injuries are common
Hematologic complications include anemia, leukopenia, and thrombocytopenia. DIC is an uncommon but potential complication. Bacteremia and sepsis occur in 30-50% of patients, with a 3-4x increase in mortality rates.
Patients with BSA >10%, hemoglobin of <10, and existing cardiovascular disease have an increased risk of bacteremia.
What can you do from the Emergency Department if suspected?
Discontinue the inciting drug
Laboratory evaluation for other organ involvement: CBC, Renal panel, LFTs, ESR, CRP
Chest x-ray to evaluate for pulmonary involvement
Consult your Dermatology Colleagues
TENS: admission to burn unit immediately
Supportive care: Fluids and pain control
Fluid requirement is 1/3rd lower than that of burn patients: 2 mL/kg/BSA affected
Consider providing the following adjuncts:
Stress ulcer prophylaxis
Monitor hyperglycemia and neutropenia
DVT prevention (inpatient)
Prophylactic antibiotics are NOT recommended
Steroids have limited evidence, and are therefore not recommended
Staphylococcal Scalded Skin Syndrome (SSSS)
SSSS courtesy of DermNet NZ via https://sml.snl.no/staphylococcal_scalded_skin_syndrome
SSSS is caused by two exfoliative toxins, toxin A and toxin B, produced by certain strains of Staph aureus. Typically, there is a focus of initial infection such as impetigo, bacterial conjunctivitis, or iatrogenic wounds that allow entry of the bacteria, which then undergoes hematogenous dissemination from the entry point. The toxins then act as serine protease enzymes to cleave desomoglein 1, causing the separation of keratinocytes within the stratum corneum (unlike SJS/TEN, which cleaves at the dermal-epidermal layer).
SSSS often occurs in children under age 6, but other vulnerable populations include adults with renal failure or immunosuppression. Initially, it presents as fever, malaise, and skin tenderness. This will progress to erythema localized to skin folds before developing diffuse cutaneous erythema within 48 hours, followed by wrinkled skin/flaccid bullae, erosions, and characteristic sheet-like desquamation. There is typically no mucous membrane involvement, however children will also have poor feeding resulting in fluid loss and dehydration.
The mainstay of treatment is antibiotics, which will cause improvement in erythema and pain in 2-3 days. Persistence of pain or erythema is more often seen in infants since they have lower renal clearance rates of the exfoliative toxin.
What can you do from the Emergency Department if suspected?
IV Antibiotics:
Oxacillin vs Nafcillin (penicillinase-resistant penicillins)
Cefazolin + Vancomycin
Generally clindamycin is not used due to high staph resistance rates
Supportive care: fluids and pain control
Consult your Dermatology colleagues
Post by Elle Rehfeldt, MD
Dr. Rehfeldt is a PGY-1 in Emergency Medicine at the University of Cincinnati
Editing by Ryan LaFollette, MD
Dr. LaFollette is an Associate Professor in Emergency Medicine at the University of Cincinnati and co-editor of TamingtheSRU.com
References
Musculoskeletal, Skin, and Connective Tissue. (n.d.). In Autoimmune Blistering Skin Disorder (pp. 480–481). essay.
Hull, C., MD, & Zone, J. J., MD (n.d.). Approach to the Patient with Cutaneous Blisters. UpToDate. Retrieved August 9, 2024, from https://www.uptodate.com/contents/approach-to-the-patient-with-cutaneous-blisters?search=cutaneous%20blistering%20disorders&source=search_result&selectedTitle=1%7E150&usage_type=default&display_rank=1
Hertl, M., MD, & Geller, S., MD (n.d.). Initial Management of pemphigus vulgaris and pemphigus foliaceus. UpToDate. Retrieved August 9, 2024, from https://www.uptodate.com/contents/initial-management-of-pemphigus-vulgaris-and-pemphigus-foliaceus?search=pemphigus%20vulgaris&source=search_result&selectedTitle=1%7E41&usage_type=default&display_rank=1
Leiferman, K. M., MD (n.d.). Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid. UpToDate. Retrieved August 9, 2024, from https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-bullous-pemphigoid-and-mucous-membrane-pemphigoid?search=bullous%20pemphigoid&source=search_result&selectedTitle=2%7E82&usage_type=default&display_rank=2#H588056
Sekula P, Dunant A, Mockenhaupt M, et al. Comprehensive survival analysis of a cohort of patients with Stevens-Johnson syndrome and toxic epidermal necrolysis. J Invest Dermatol 2013; 133:1197.
Roujeau JC, Kelly JP, Naldi L, et al. Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med 1995; 333:1600.
Hung SI, Chung WH, Liou LB, et al. HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci U S A 2005; 102:4134.
Chung WH, Hung SI, Hong HS, et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature 2004; 428:486.
Chen CB, Hsu TH, Chung-Yee Hui R, et al. Disseminated intravascular coagulation in Stevens-Johnson syndrome and toxic epidermal necrolysis. J Am Acad Dermatol 2021; 84:1782.
Lee, H. Y., MRCP (n.d.). Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis. UpToDate. Retrieved August 9, 2024, from https://www.uptodate.com/contents/stevens-johnson-syndrome-and-toxic-epidermal-necrolysis-pathogenesis-clinical-manifestations-and-diagnosis?search=sjs%2Ftens&source=search_result&selectedTitle=1%7E150&usage_type=default&display_rank=1#H1985340085
Koh HK, Chai ZT, Tay HW, et al. Risk factors and diagnostic markers of bacteremia in Stevens-Johnson syndrome and toxic epidermal necrolysis: A cohort study of 176 patients. J Am Acad Dermatol 2019; 81:686.
de Prost N, Mekontso-Dessap A, Valeyrie-Allanore L, et al. Acute respiratory failure in patients with toxic epidermal necrolysis: clinical features and factors associated with mechanical ventilation. Crit Care Med 2014; 42:118.
Lee, H. Y., MRCP (n.d.). Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae. UpToDate. https://www.uptodate.com/contents/stevens-johnson-syndrome-and-toxic-epidermal-necrolysis-management-prognosis-and-long-term-sequelae?search=sjs%2Ftens&source=search_result&selectedTitle=2%7E150&usage_type=default&display_rank=2#H3124721822
McMahon, P., MD (n.d.). Staphylococcal scalded skin syndrome. UpToDate. Retrieved August 9, 2024, from https://www.uptodate.com/contents/staphylococcal-scalded-skin-syndrome?search=staphylococcal%20scalded%20skin%20syndrome&source=search_result&selectedTitle=1%7E13&usage_type=default&display_rank=1
