Dangerous Rashes
Dangerous Rashes
Authors: Matthew T. Spencer, MD, Assistant Professor of Emergency Medicine, Department of Emergency Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY; and Linda L. Spillane, MD, Associate Professor of Emergency Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY.
Peer Reviewers: Jonathan Glauser, MD, FACEP, Cleveland Clinic Foundation, Department of Emergency Medicine, MetroHealth Medical Center Residency Program, Emergency Medicine, Cleveland, OH; and Catherine A. Marco, MD, FACEP, Clinical Professor, Department of Surgery, University of Toledo College of Medicine, Toledo, OH; Attending Physician, St. Vincent Mercy Medical Center, Toledo, OH.
Dermatologic complaints are common presentations in the emergency department and the emergency physician should have a working knowledge of the most common of these complaints. Although it is unrealistic to assume that the average emergency physician has expert knowledge of all causes of rash, there are a number of uncommon rashes with a high rate of morbidity and mortality that the emergency physician should be able to identify. Although this article cannot cover all causes of dangerous rashes, it will provide an overview of the most common so that the practicing emergency physician will be better able to recognize and manage them in the emergency department.
—Sandra M. Schneider, MD, FACEP, Editor
Introduction
A substantial number of emergency department visits each year are made for rashes. A small subset of these visits will be for a rash that is associated with a life-threatening condition. It is imperative that the emergency physician be knowledgeable about the clinical presentation, diagnosis, and management of patients presenting with "dangerous rashes." This review will provide an overview of a few of those conditions. The life-threatening rash usually is an external sign of a generalized systemic or immune response stimulated by an infection, toxin, medication, or disease process. Although most patients with life-threatening rashes appear ill, patients who present early in the course of illness may appear well but deteriorate rapidly. History and a high index of suspicion are crucial in making the diagnosis. Although these rashes can be classified in a variety of ways, for the purpose of this review they fit into four basic categories: petechial rashes (Rocky Mountain spotted fever, meningococcemia), desquamating rashes (Stevens-Johnson syndrome, toxic epidermal necrolysis, staphylococcal scalded skin syndrome), bullous/blistering rashes (pemphigus vulgaris, bullous pemphigoid), and purpuric rashes (warfarin-induced skin necrosis). This article will review the epidemiology, clinical presentation, and management for each of these conditions.
Petechial Rash
Rocky Mountain Spotted Fever. Rocky Mountain spotted fever (RMSF) is a vasculitis caused by infection of endothelial cells by the tick-borne bacterium Rickettsia rickettsii, which is transmitted in the saliva of ticks during a bite. Its vectors are the American dog tick (Dermacentor variabilis) in the eastern United States, Rocky Mountain wood tick (Deracentor andersoni) in the Rocky Mountain states, and the brown dog tick (Rhipicephalus sanguineus) in Arizona.1-4 It has the greatest mortality (5-20%) of any tick-borne disease and occurs in the United States with an estimated annual incidence of approximately 2.2 cases per million population.1,3 Although RMSF has been reported in all 48 contiguous states except Vermont and Maine, the majority (56%) occur in only five: North Carolina, South Carolina, Tennessee, Oklahoma, and Arkansas.1,4-6 RMSF has a spring to summer predominance; however, cases have been reported in all months of the year.
Patients present with sudden onset of headache, fever, chills, malaise, myalgias, photophobia, nausea, vomiting, anorexia, and rash 2-14 days after a tick bite.1,5,6 However, only 60-65% of those with confirmed cases of RMSF remember being bitten by a tick.5,6 Rash develops in 50-80% of adults and more than 90% of children.1 The rash begins as macular lesions on the wrists and ankles 2-4 days after the onset of fever, and classically spreads in a centripetal fashion to cover the entire body, including the palms and soles.1,4 (See Figure 1 and Figure 2.) The lesions generally do not become petechial in appearance until day five or six.1 RMSF can lead to severe morbidity such as prolonged fever, amputation, renal failure, myocarditis, meningoencephalitis, deafness, learning disability, hypotension, acute respiratory distress syndrome, and multiple organ failure.
| Figure 1. Petechial Lesions on the Upper Extremity Associated with Rocky Mountain Spotted Fever |
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| Image used with permission from Logical Images Inc. |
| Figure 2. Rash of Rocky Mountain Spotted Fever in a Young Girl |
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| Image used with permission from Logical Images Inc. |
The differential diagnosis for RMSF includes meningococcemia, viral exanthems, disseminated gonorrhea, secondary syphilis, leptospirosis, thrombotic thrombocytopenic purpura, and Kawasaki disease.1 The diagnosis should be made clinically based on history and physical examination. Clinicians should maintain a high index of suspicion in those with fever of unknown origin, especially in the spring and summer. A history of exposure to a tick, travel to an endemic area, and similar symptoms in family members, co-workers, or pet dogs are all suggestive.1 Common laboratory findings for RMSF are an increased level of immature bands, thrombocytopenia, mild transaminase elevation, and hyponatremia.1,2,4 The diagnosis can be confirmed with a four-fold or greater titer increase in two serum IgG and IgM samples taken 2-3 weeks apart or through polymerase chain reaction (PCR) taken from a skin biopsy in those too early to see a rise in antibody titers.1 Treatment never should be based on serologic confirmation.
The treatment of RMSF includes supportive care and antibiotics. The antibiotic of choice for both adults and children is doxycycline.1,4 Dosages of 100 mg two times per day for adults, and 2.2 mg/kg per dose up to 100 mg twice per day for children. The only contraindications for doxycycline therapy for RMSF are allergy to tetracycline-class antibiotics and pregnancy.1 Doxycycline is used even in small children in this instance since the chance of teeth staining from a single course of medication is extremely small. Chloramphenicol is the treatment of choice in these settings, but it should be used with caution during the third trimester of pregnancy because of the risk of gray baby syndrome.1 Treatment should be continued until 3 days after the fever has resolved or a minimum of 5-7 days. Prophylactic antibiotic therapy for asymptomatic patients who recently have been bitten by a tick is not recommended, even in endemic areas.1
Meningococcemia. Meningococcemia is sepsis caused by Neisseria meningitidis, a gram-negative encapsulated diplococcus with multiple serotypes, only five of which (A, B, C, W135, and Y) are considered clinically significant. In the United States serotypes B, C, and Y cause more than 90% of meningococcal disease. Humans are the only known natural reservoir for N. meningitidis, with nasopharyngeal carriage rates of 10-20% in the general population and up to 95% in more crowded populations such as military recruits.7 It is transmitted via large respiratory droplets, and although cases occur year round, most occur in the winter and early spring. In the United States there are 1400-3000 cases of meningococcal disease each year with an annual incidence of 0.5-1.1 per 100,000 population.8 Despite its susceptibility to a wide range of available antibiotics, meningococcal disease has an overall case-fatality ratio of 10-14% but is up to 40% in those with meningococcemia.8,9 Those who survive often have significant neurologic disability, limb loss, or hearing loss.8,9
Patients with meningococcal disease present in a variety of ways. Approximately 50% present with meningitis with or without meningococcemia and can rapidly deteriorate.10 Patients present with sudden onset of fever, chills, malaise, myalgias, headache, vomiting, rash, altered mental status, and nuchal rigidity. In infants the symptoms can be more nonspecific and of slower onset.9,11 Meningococcemia occurs in 5-20% of all patients with meningococcal disease and is characterized by sudden onset of fever, malaise, myalgias, and rash.9,10 The rash associated with meningococcemia often begins as erythematous lesions that mimic a simple viral exanthem and then develop into petechiae and purpura. It can be located anywhere on the body but is most often found on the trunk and extremities. (See Figure 3.) Lesions generally are small and irregularly shaped, with the purpura slightly raised and often painful.12 (See Figure 4.) In a group of pediatric patients with a petechial rash and fever, Nielsen et al identified five clinical variables with a sensitivity of 97% and false negative rate of 12% in identifying meningococcal disease when two or more clinical criteria were present.13 Those criteria are: universal distribution of the rash; maximum diameter of the largest lesion over 2 mm; characteristic appearance of the lesions; nuchal rigidity; and poor overall condition.13 They also found that if the rash was only present in the distribution of the superior vena cava (only present above the nipple line) there was an extremely low risk of meningococcal disease.13
| Figure 3. Purpuric and Petechial Lesions on the Lower Extremities in a Patient with Meningococcemia |
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| Image used with permission from Logical Images Inc. |
| Figure 4. Characteristic Small Irregular Shaped Petechial Lesions on the Torso in Meningococcemia |
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| Image used with permission from Logical Images Inc. |
The differential diagnosis for meningococcemia includes any petechial rashes such as Rocky Mountain spotted fever, leptospirosis, vasculitis, endocarditis, and enteroviral infection.7,12
The diagnosis is suspected on the basis of clinical presentation and can be confirmed using blood or cerebrospinal fluid (CSF) culture or CSF gram stain. Polymerase chain reaction also may be used to identify N. meningitidis DNA even without the presence of live organisms, but it currently is not available in the United States.9,11,12
Emergency physicians must maintain a high index of clinical suspicion and be aggressive in the early treatment of patients with suspected meningococcemia since they can decompensate quickly. The mainstay of therapy is empiric broad spectrum antibiotics covering N. meningitidis, resistant S. pneumoniae, and H. influenzae as soon as the diagnosis is suspected. Ceftriaxone (2 grams or 100 mg/kg/day every 12 hours) or cefotaxime (2 grams or 50-75 mg/kg every 4-6 hours) plus vancomycin (1 gram or 10-15 mg/kg every 6-12 hours) in adults and children older than 1 month of age is recommended.7,9,14 Doxycycline should be added if there is a suspicion of rickettsial disease. If N. meningitidis has been confirmed, then the treatment of choice is penicillin G 250,000 U/kg/day administered in divided doses every four hours, or chloramphenicol 100 mg/kg/day divided every 6 hours for penicillin-allergic patients.14 Chemoprophylaxis for close contacts of infected individuals also should be undertaken within 24 hours since they have a high risk of contracting disease. A close contact is anyone who lives in the same household as the patient, daycare contacts, and anyone who has had direct contact with oral secretions (kissing, mouth-to-mouth resuscitation, or intubation and suctioning without mask protection).9,11,12,15 The drug of choice for chemoprophylaxis is rifampin 600 mg in adults or 5-10 mg/kg in children every 12 hours for 2 days.9 Other options are ciprofloxacin (500 mg in a single dose) for adults or ceftriaxone (250 mg in adults or 125 mg in children) as a single intramuscular injection.9 Ceftriaxone is the drug of choice during pregnancy.
Desquamating Rash
Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, life-threatening syndromes that represent a clinical spectrum of disease from less severe (SJS) to severe (TEN). Histologically the two are indistinguishable showing complete epidermal necrosis and perivasculitis of the superficial dermis, but they differ epidemiologically and based on amount of skin involvement. SJS occurs with an estimated annual incidence of 1.2-6.0 cases per million population while TEN occurs with an annual incidence of 0.4-1.3 cases per million population.16-19 Both are more common in women and the elderly, but present in patients of all ages and races.16,17,19 Bullous lesions with epidermal sloughing and mucous membrane involvement are characteristic. Epidermal loss of less than or equal to 10% total body surface area (TBSA) must be present to make the diagnosis of SJS. Between 10% and 30% TBSA involves a more severe form of the disease that is considered a combination of SJS and TEN, and more than 30% TBSA is considered to be TEN. The majority of cases of SJS (75%) are a result of a drug reaction, but some cases have resulted from infection (Mycoplasma pneumonia), vaccination, or systemic disease.17,19,20 Essentially all cases of TEN are a result of a drug reaction, although rare cases have been reported due to infection, food additives, fumigants, and contact with chemicals.17,19,21 The most common medications implicated are antibiotics (sulfonamides most commonly), anticonvulsants, oxicam nonsteroidal anti-inflammatory drugs (NSAIDS), and allopurinol.17 The overall mortality of patients with SJS and TEN varies from 5-50%, with a scoring system called the SCORTEN system developed by Bastuji-Garin, et al using clinical variables to predict mortality for these patients.21,22 There are seven clinical variables. (See Table 1.) Patients receive one point for each variable they possess, and prognosis is estimated by the overall score. (See Table 2.)
| Table 1. SCORTEN Clinical Variables22 |
| 1 SCORTEN point is scored for each clinical variable present in the first 24 hours of admission.22
1. Epidermal involvement ≥ 10% TBSA 2. Heart rate ≥ 120 beats per minute 3. Age ≥ 40 years 4. History of malignancy 5. Urea > 10 mmol/liter (28 mg/dL) 6. Glucose > 14 mmol/liter (252 mg/dL) 7. Bicarbonate < 20 mmol/liter |
| Table 2. Predicted Mortality Based on Overall SCORTEN Score22 |
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Patients present with a 2-3 day prodrome of cough, fever, sore throat, myalgias, malaise, headache, and anorexia.16,19 The rash begins with discrete, dark red, macular lesions that are painful and warm. (See Figure 5.) These discrete lesions then become confluent and necrotic with the epidermis sloughing in sheets and leaving the moist beefy red dermis exposed.16,19 (See Figure 6.) Often there are target lesions consisting of 3 rings: an inner dark red lesion surrounded by a lighter pink layer and then a darker pink outer ring.19 Nikolsky's sign is positive (when firm sliding pressure is applied to healthy appearing skin and leads to blister formation or skin sloughing). (See Figure 7.) Mucous membrane involvement is present in 92-100% of cases with the oropharynx (see Figure 8) and conjunctiva most commonly involved, but urethra, esophageal, tracheal, gastrointestinal, and renal involvement also is possible.16,19 Approximately 1 in 7 patients can suffer from d'emblee, which is an extremely severe form of disease that involves 100% epidermal sloughing within 24 hours of the onset of the rash.19 The skin heals over 1-3 weeks and usually does not scar unless there is a secondary infection; however, abnormal pigmentation does occur in up to 88% of cases.19 Mucosal lesions take longer to heal and are more likely to scar resulting in symblephara (scarring of the conjunctiva under the eyelids), phimosis, vaginal synechiae (adhesions), and esophageal stenosis.19 Skin biopsy reveals full thickness necrosis of the epidermis and a perivasculitis of the superficial dermis.17,19
| Figure 5. Stevens-Johnson Syndrome with Characteristic Macular Lesions on the Torso |
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| Image used with permission from Logical Images Inc. Image courtesy of Steven Oberlender, MD. |
| Figure 6. Widespread Sloughing of the Epidermis in a Patient with Toxic Epidermal Necrolysis |
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| Image used with permission from Logical Images Inc. |
| Figure 7. Positive Nikolsky's Sign |
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| Image used with permission from Logical Images Inc. |
| Figure 8. Stevens-Johnson Syndrome with Typical Oropharyngeal Mucous Membrane Involvement |
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| Image used with permission from Logical Images Inc. Image courtesy of Steven Oberlender, MD. |
The differential diagnosis includes TEN, staphylococcal scalded skin syndrome (SSSS), acute severe graft-versus-host reaction, paraneoplastic pemphigus, generalized fixed drug eruption, toxic shock syndrome, and Kawasaki syndrome.16,19-21 The diagnosis of SJS and TEN is based primarily on clinical presentation in combination with skin biopsy and immunofluorescence.
TEN and SJS are true dermatologic emergencies requiring intense supportive care, and all patients should be admitted or transferred to a burn center or intensive care unit and dermatological consultation obtained immediately.21 Skin lesions should be treated exactly as if due to thermal injury with environmental temperature control, aseptic technique, and clean bandages, while silver sulfadiazine should be avoided since sulfonamides are such a frequent etiology.23 Intravenous fluid requirements are only two-thirds to three-quarters that of similar surface area thermal injury.23 All medications should be discontinued, especially those started within the past 3-4 weeks.16 Other therapeutic options include high dose systemic steroids, human intravenous immunoglobulin, cyclosporin, cyclophosphamide, N-acetylcysteine, and plasmapharesis, although many of these remain controversial and are best initiated in concert with the consultant.16,17,19,21,23 The most common cause of mortality in these patients is sepsis due to Staphylococcus aureus or Pseudomonas aeruginosa.16,17,19,21 Other causes of death include pneumonia, pulmonary edema, pulmonary embolism, myocardial infarction, renal failure, hypovolemia, gastrointestinal bleeding, and recurrent pneumothoraces.19,21
Staphylococcal Scalded Skin Syndrome. Staphylococcal scalded skin syndrome (SSSS) is a rare, systemic, blistering disorder of the skin that occurs as a result of infection by certain strains of Staphylococcus aureus that release circulating exfoliative toxins. The primary exfoliative toxins responsible for disease in humans are serotypes A and B which act at the stratum granulosum of the epidermis to cause intra-epidermal splitting and bullae formation.24,25 SSSS has an incidence of 0.09-0.13 cases per million population, and although most cases are seen in children younger than 5 years of age, up to 36% of cases occur in adult patients.26-28 The majority of adult patients are immune-compromised or have comorbid medical conditions such as renal failure, chronic alcoholism, or malignancy.29 In children, SSSS has a mortality of less than 5% but in adults it can be up to 60%, usually secondary to complications from comorbid medical problems.27,29,30
The clinical presentation of SSSS consists of a primary infection involving the conjunctiva, nasopharynx, ear, urinary tract, or skin leading to fever, malaise, and skin tenderness affecting primarily the flexural areas.12,27,31 The palms, soles, and mucous membranes usually are spared.31 Over the next 24-48 hours, flaccid bullae develop over the erythematous regions, coalesce, and rupture revealing a moist erythematous base that generally heals without scarring.12,27 (See Figure 9.) Nikolsky's sign is positive over the areas of erythema.12,27,31,32 Staphylococcus aureus is not isolated from fluid contained within the bullae, only from the site of primary infection.33
| Figure 9. Widespread Desquamation Associated with Staphylococcal Scalded Skin Syndrome |
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| Image used with permission from Logical Images Inc. |
The primary differential diagnosis for SSSS is SJS or TEN but it is easily differentiated by skin biopsy. The diagnosis of SSSS is made based on clinical presentation (erythema, desquamation or bullae formation), isolation of exfoliative producing Staphylococcus aureus, and skin biopsy revealing intra-epidermal cleavage of the stratum granulosum.12,27,28,32
The mainstay of therapy for SSSS is anti-staphylococcal antibiotics to eliminate the primary focus of infection. Most exfoliative toxin-producing strains of Staphylococcus aureus are penicillin-resistant and there are rare cases of methicillin-resistant strains causing SSSS.34 The antibiotic therapies of choice are penicillinase, semisynthetic penicillins such as dicloxacillin, nafcillin, methicillin, or oxacillin; however, first-generation cephalosporins, vancomycin, or macrolides also provide adequate coverage.12,29 For pediatric patients with SSSS if the lesions are localized (less than 5% total body surface area), in an otherwise well-appearing child, outpatient therapy with oral antibiotics can be attempted as long as there is close follow-up within 24 hours.32 The majority of patients, however, will require inpatient management with parenteral antibiotics and adjunctive therapy including wound care, temperature control, intravenous fluid administration, nutritional care, and analgesics.27
Bullous/Blistering Rash
Pemphigus Vulgaris. Pemphigus vulgaris is a rare, life-threatening, autoimmune disease of the skin and mucous membranes. Lesions result from autoimmune antibodies against keratinocyte cell-surface antigens, primarily desmoglein 3, causing acantholysis and blister formation just above the basal cell layer of the epidermis.35 Age of onset is most common in the fourth and fifth decades of life but can affect those of any age. It has an equal male to female ratio and an incidence of 0.75-5.0 cases per million per year, but varies from country to country with a higher incidence in some ethnic populations such as those of Mediterranean or Jewish descent.35 The mortality for patients with pemphigus vulgaris was 60-90% prior to the development of corticosteroid medications, but has decreased to 5-10% since their use has become routine and is now related more to the side effects of chronic high-dose steroid use than the disease itself.36,37
Patients develop flaccid blisters of the skin and mucous membranes usually starting on the oral mucosa and often not appearing on the skin until months later.38 These blisters rupture soon after formation, resulting in painful, non-healing ulcers. (See Figure 10.) They are irregular in shape, multiple, and arise from healthy mucosa and skin. The most common locations in the mouth are the buccal and labial mucosa, palate, and tongue, while the scalp, face, and upper torso are the most common skin locations.35 (See Figure 11.) A positive Nikolsky's sign is characteristic of the disease.35,38
| Figure 10. Oral Ulcers Resulting from Blister Rupture in a Patient with Pemphigus Vulgaris |
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| Image used with permission from Logical Images Inc. |
| Figure 11. Multiple Intact and Ruptured Blisters Associated with Pemphigus Vulgaris |
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| Image used with permission from Logical Images Inc. |
The differential diagnosis for pemphigus vulgaris includes bullous pemphigoid, erythema multiforme, porphyria cutanea tarda, impetigo, SSSS, pyoderma gangrenosum, and linear IgA bullous dermatosis.35,38 The diagnosis is made by a combination of clinical presentation, skin biopsy, and the presence of circulating and tissue-fixed antibodies against keratinocytes identified using direct and indirect immunofluorescence.35
The treatment of choice for pemphigus vulgaris is either topical or systemic corticosteroids, although there is no single proven regimen. Adjuvant therapies such as plasmapheresis, azathioprine, cyclophosphamide, intravenous immunoglobulin, cyclosporin, methotrexate, mycophenolic acid, gold, dapsone, antimalarials, tetracycline, or minocycline also are used for those who do not respond to steroids alone or in an effort to reduce the overall steroid dose.35 The goal of therapy is to induce remission so that all medication can be discontinued, and this goal is achieved in most patients at least temporarily. Treatment in the emergency department should be based on the severity of the disease at the time of presentation. Those with only a few lesions may be treated with topical high-potency corticosteroid ointments, such as clobetasol, or intralesional corticosteroid injections using triamcinolone.35 Those with mild but more extensive disease should be started on systemic corticosteroids such as prednisone at dosages of 40-60 mg per day, and those with severe disease should receive 60-100 mg of prednisone per day.38 All patients should be referred for dermatology follow-up within 48 hours. Patients also should be educated to avoid factors that can exacerbate lesion formation such as dental work, sunshine, radiographs, stress, and trauma.35
Bullous Pemphigoid. Bullous pemphigoid is the most common autoimmune blistering skin disorder in the world with an annual incidence of between 2 and 30 cases per million population varying by geographic location.39-41 It is a disease of the elderly with an increased incidence with increasing age. There is no racial preference, but it is twice as common in men as in women.40 It has a one-year mortality of 25-40% that is greatest for those older than 83 years of age and those with many comorbid medical problems, with the most common cause of death being sepsis, cardiovascular disease, or stroke, not the condition itself.39,40,42 Remission generally occurs within 2-5 years and is hastened by treatment. Recurrent episodes are rare after remission and usually mild in severity.40,43 Bullous pemphigoid develops as a result of autoantibodies and complement deposition on the epidermal basement membrane leading to subepidermal blister formation. Autoantibodies are directed against the specific antigens BP230 and BP180, which are components of the epidermal basement membrane adhesion complex.39,40
Patients present with a generalized eruption of tense blisters that can appear anywhere but have a preference for the lower abdomen, inner thighs, groin, and flexor surfaces of the arms and legs, and are often associated with complaints of severe pruritis.39,40,43 (See Figure 12.) Blisters can arise from normal or erythematous skin and heal without scarring after rupture.39,40,43 Nikolsky's sign is negative.40 Mucous membrane involvement is common (30%) but generally mild. Up to two-thirds of patients may develop pruritic urticarial plaques or erythematous lesions prior to bullae formation.40
| Figure 12. Bullous Pemphigoid with Blisters on the Flexural Surface of the Upper Extremity |
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| Image used with permission from Logical Images Inc. |
The differential diagnosis for bullous pemphigoid includes SJS, TEN, fixed drug eruption, impetigo, pemphigus vulgaris, and bullous lichen planus. The diagnosis may be suspected clinically and then must be confirmed through the use of direct immunofluorescence of perilesional skin that shows linear deposition of IgG and complement along the basement membrane zone.39,40,43
The mainstay of therapy is low-dose systemic corticosteroids (0.5 mg/kg/day) or high-potency topical corticosteroids (clobetasol proprionate 40 g/day divided BID) to control symptoms and induce remission.39,40,42,43 Other therapeutic options include antibacterials such as tetracycline, erythromycin, or minocycline alone or in combination with nicotinamide or corticosteroids, as well as azathioprine, methotrexate, mycophenolate mofetil, dapsone, plasmapheresis, cyclophosphamide, and intravenous immunoglobulin.39,40 In the emergency department treatment with topical clobetasol for local disease or oral prednisone for more extensive disease along with prompt dermatologic referral is recommended.
Purpuric Rash
Warfarin-Induced Skin Necrosis. Warfarin sodium was discovered in 1941 and is now the most commonly prescribed anticoagulant in the United States. Warfarin inhibits coagulation by reducing the synthesis and activity of the vitamin K-dependent clotting factors II, VII, IX, X, protein C, and protein S.44,45 Vitamin K is a cofactor that is required for carboxylation of these clotting factors during their biosynthesis in the liver mitochondria. Warfarin directly competes with vitamin K, leading to the synthesis of clotting factors that have not been carboxylated and so cannot bind calcium for activation. Warfarin-induced skin necrosis is a rare but well described disorder resulting in significant morbidity and, rarely, mortality in 0.01 to 0.1% of those taking warfarin sodium for anticoagulation.46,47 It was first described in 1943 by Flood, et al., and misdiagnosed as thrombophlebitis migrans disseminata.48 In 1954, Verhagen became the first to associate skin necrosis with oral anticoagulation when he reported a series of cases in the Netherlands, and it has since been reported in more than 200 cases world-wide.47,49 The exact mechanism of action by which warfarin causes skin necrosis is not known; however, its association with protein C deficiency and resistance, as well as protein S deficiency has led to the theory that it is due to a relative hypercoagulable state that results from protein C and S depletion during early anticoagulation with warfarin, leading to thrombosis of the microvasculature and necrosis of the skin and underlying subcutaneous tissue.50-55
The clinical presentation is quite distinctive and predictable. Those affected generally are obese middle-age women (female to male predominance of 4:1) undergoing anticoagulation with warfarin for thromboembolic disease.44,46,47,56 Rarely, those undergoing anticoagulation for other causes such as atrial fibrillation or coronary artery disease have been involved. Although most patients are middle-aged, there is a wide age-range with cases reported in patients ranging from 16-93 years of age.46,57 Patients first present with pain and often a poorly demarcated area of erythema 1-10 days after initiation of warfarin therapy, with most lesions appearing between days 3 and 6.46,47 Although early presentation is more common, there have been cases reported up to 17 months after starting warfarin.46,47,58 Petechial hemorrhage rapidly develops in the area of involvement, coalescing into larger dark red or blue-black areas of ecchymosis. These ecchymotic areas usually have sharply demarcated borders and a surrounding halo of erythema.47,59 (See Figure 13.) Hemorrhagic bullae form next, eventually sloughing to reveal gangrenous underlying tissue necrosis. Lesions can form anywhere but most often involve the lower half of the body and have a tendency to form in areas with a large amount of adipose tissue such as the lower abdomen, breast, thigh, and buttocks.44,46,47 (See Figure 14.)
| Figure 13. Typical Lesion Associated with Warfarin-Induced Skin Necrosis Showing Sharply Demarcated Border and Surrounding Area of Erythema |
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| Image used with permission from Logical Images Inc. |
| Figure 14. Lower Extremity Lesions Resulting from Warfarin-Induced Skin Necrosis |
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| Image used with permission from Logical Images Inc. |
The differential diagnosis for warfarin-induced skin necrosis includes hemorrhage, necrotizing fasciitis, purpura fulminans, microembolization, and cellulitis.57,59 The diagnosis of warfarin-induced skin necrosis is a clinical one supported by tissue biopsy that reveals necrosis, hemorrhage, and venous thrombosis.
The treatment for warfarin-induced skin necrosis is supportive, but early discontinuation of warfarin and rapid reversal with vitamin K, coupled with heparin anticoagulation may prevent progression of skin necrosis.44,50,56,59,60 Vitamin K can be administered subcutaneously, orally, or intravenously in doses of 10 mg to 20 mg and should return the prothrombin time back to normal within six hours.45,53 Intravenous vitamin K should be administered cautiously since there is a high risk of anaphylaxis. Heparinization should occur through the use of an unfractionated heparin drip or low molecular weight heparin in standard weight-based dosages. Some recommend the use of fresh frozen plasma or protein C concentrate to rapidly restore protein C and S levels.51,53 Prostacyclin also has been proposed as therapy with some encouraging initial results, but more research is necessary before it can be recommended.50 Overall, surgical intervention such as debridement or skin grafting is required in more than 50% of patients and rarely amputation is necessary.47 Warfarin-induced skin necrosis is thought to be prevented by avoiding an initial large loading dose of warfarin (start with 10 mg or less) and maintaining heparinization for five days or until the initial prothrombin time is therapeutic, whichever is longer.50,53,55 Patients have been successfully restarted on warfarin therapy after an episode of skin necrosis without recurrence.54
Conclusion
The patient who presents to the emergency department with a chief complaint of rash may have a benign or potentially life-threatening condition. Knowledge of classic dermatologic presentations of life-threatening disease processes will help the emergency physician identify and manage the patient presenting with a potentially deadly rash.
References
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Dermatologic complaints are common presentations in the emergency department and the emergency physician should have a working knowledge of the most common of these complaints.Subscribe Now for Access
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