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Case 20-2009: A 79-Year-Old Woman with a Blistering Cutaneous Eruption

Mathew M. Avram, M.D., J.D., and Mai Hoang, M.D.

Pr e sen tat ion of C a se

Dr. Jordan M. Cummins (Dermatology): A 79-year-old woman was admitted to the burn unit of this hospital because of a blistering cutaneous eruption. Five days before admission, itching on her head and back and skin lesions on her abdomen developed. She saw her primary care provider at another facility. She had had polymyalgia rheumatica, giant-cell arteritis, and rheumatoid arthritis for many years, treated with prednisone. Hydroxychloroquine had been started approximately 2 weeks earlier. The hydroxychloroquine was stopped and loratadine was administered; prednisone was continued. The rash did not improve and gradually spread to her back, arms, and legs. Three days after the onset of symptoms, she was seen in the emergency department of another hospital. The prednisone was increased from 5 to 40 mg daily, and she was sent home. The rash increased in severity and became painful, sore throat with dysphagia developed, and the temperature rose to 38.8C. She returned to the emergency room the next day. She described burning pain of the eyes and skin, headache that was 8 on a scale of 0 to 10 (where 10 is the worst pain), light-headedness, poor oral intake, nausea, and puffy eyes. She did not have shortness of breath. On examination, she was alert and appeared weak and ill. The temperature was 36.5C, the blood pressure 139/69 mm Hg, the pulse 79 beats per minute, and the respiratory rate 16 breaths per minute, with 97% oxygen saturation while she was breathing ambient air. There was purulent drainage from the eyes. Crackles were heard at the bases of both lungs. The skin was warm and dry. Coalescing papules and plaques covered most of the skin surface, and there was desquamation involving approximately half the surface of the back. A slight exudate developed when the lesions were rubbed, which was thought to represent a weakly positive Nikolskys sign (ready removal of the epidermis with slight tangential pressure). The remainder of the examination was normal. Levels of phosphorus and magnesium and tests of renal function were normal; other laboratory-test results are shown in Table 1. Analysis of the urine revealed 1+ leukocyte esterase and was otherwise normal. An electrocardiogram showed a sinus rhythm, normal rate, with atrial premature complexes. Ondansetron, diphenhydramine, intravenous crystalloid solution, and acetaminophen were administered, followed by morphine. A biopsy of the skin was performed. Pathological examination of a frozen section reportedly showed vacuolization of the basal layer, epidermal
From the Departments of Dermatology (M.M.A.) and Pathology (M.H.), Massachusetts General Hospital; and the Departments of Dermatology (M.M.A.) and Pathology (M.H.), Harvard Medical School. N Engl J Med 2009;360:2771-7.
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spongiosis, and many neutrophils. The changes were interpreted as exfoliative dermatitis, possibly toxic epidermal necrolysis or the StevensJohnson syndrome. The patient was transferred by helicopter to this hospital for admission to the burn unit. On admission, she reported a sandy feeling in her eyes, and increasingly blurred vision. She had a history of macular degeneration, cardiac arrhythmia treated with a pacemaker, borderline hypercholesterolemia, and hypertension. There was no history of cold sores. She had had a tonsillectomy, cataract surgery, and bilateral knee replacements in the past. She lived alone, was active, did not smoke, and drank alcohol rarely. Medications on admission included prednisone (40 mg daily), digoxin, nadolol, esomeprazole, hydrochlorothiazide, pravastatin, lorazepam, calcium citrate, estradiol, a multivitamin formulated for age-related eye health (PreserVision), artificial tears, and metronidazole cream, as well as amoxicillin before dental procedures. She was allergic to sulfa drugs. On examination, the patient appeared ill. The temperature was 36.6C, the blood pressure 170/65 mm Hg, the pulse 54 beats per minute, and the respiratory rate 16 breaths per minute, with 94% oxygen saturation while she was breathing amTable 1. Results of Laboratory Tests. Test Hematocrit (%) White-cell count (per mm3) Differential count (%) Neutrophils Lymphocytes Monocytes Eosinophils Platelet count (per mm Sodium (mmol/liter) Potassium (mmol/liter) Chloride (mmol/liter) Carbon dioxide (mmol/liter) Glucose (mg/dl) Lipase (U/liter) Amylase (U/liter)
3)

bient air. There was purulent discharge in the eyes and erosions on the eyelids, trace injection of the conjunctiva, and serous crusting on the lips; no lesions were seen on the tongue or oropharynx. There was confluent macular erythema on the face, trunk, and limbs, extending to the knees. On the chest, abdomen, and thighs, there were innumerable nonfollicular pustules, 1 to 2 mm in diameter (Fig. 1A). On the back, there were extensive areas of superficial desquamation with a positive Nikolskys sign (Fig. 1B). There were targetoid macules and plaques on the trunk, legs, and palms (Fig. 1C and 1D), and there was no lymphadenopathy or hepatosplenomegaly; the remainder of the examination was normal. Skin involvement was estimated to be approximately 76% of body-surface area. Levels of calcium, phosphorus, magnesium, total protein, albumin, globulin, and cardiac enzymes were normal, as were tests of renal and liver function. Other laboratory-test results are shown in Table 1. An electrocardiogram showed nonspecific T-wave abnormalities but was otherwise normal; a chest radiograph was normal. Specimens of blood, urine, and nasal secretions were cultured. Immunization with tetanus and diphtheria toxoid was given in the emer-

Reference Range, Adults* 36.046.0 (women) 4,50011,000 4070 2244 411 08 150,000350,000 135145 3.44.8 100108 23.031.9 70110 1360 3100

Day of Admission, Other Hospital 38.8 23,100 95 2 3

On Admission, This Hospital 42.7 26,300 92 4 3 1 236,000

122 4.0 86 27 160

126 4.3 88 29.6 121 189 134

* Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at Massachusetts General Hospital are for adults who are not pregnant and do not have medical conditions that could affect the results. They may therefore not be appropriate for all patients. To convert the values for glucose to millimoles per liter, multiply by 0.05551.

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case records of the massachusetts gener al hospital

Figure 1. Photographs of the Patient on Admission. There are numerous nonfollicular pustules (1 to 2 mm in diameter) on the abdomen (Panel A). On the back, there were extensive areas of superficial desquamation with a positive Nikolskys sign (Panel B and inset). There were RETAKE 1st AUTHOR Avram ICM targetoid macules and plaques on the thighs (Panel C) and palms (Panel D). (Photographs courtesy of Dr. Jordan 2nd REG F FIGURE 1a-d M. Cummins, Dermatology, Massachusetts General Hospital.) 3rd
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gency department, and morphine and crystalloid liative dermatoses are typically serious medical AUTHOR, NOTE: concerns. solution were continued. An arterial catheter PLEASEtype has been reset. Figure has been redrawn and Please check carefully. was inserted. Dermatologic and ophthalmologic consultations were obtained, and erythromycin Acute Exfoliative Dermatoses exfoliative dermatoses include some of the ophthalmic ointment and eye JOB: 36026 were AcuteISSUE: 6-25-09 lubrication most feared cutaneous reactions to medications. initiated. Three that merit consideration are the Stevens A diagnostic procedure was performed. Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme. Differ en t i a l Di agnosis Dr. Mathew Avram: I am aware of the diagnosis in this case. This elderly woman has both pustular and exfoliative skin eruptions associated with fever. Her primary lesion is a pustule, which is defined as a pus-filled papule. The differential diagnosis of pustular eruptions is broad and encompasses both mild and severe dermatoses. The association of a pustular eruption with fever and exfoliation suggests a severe dermatosis. ExfoThe StevensJohnson Syndrome and Toxic Epidermal Necrolysis

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The StevensJohnson syndrome and toxic epidermal necrolysis are rare, severe drug reactions that constitute a medical emergency. The disorders are caused by the same medications and have nearly identical histologic features.1 They are distinguished by the proportion of body-surface area affected. A diagnosis of the StevensJohnson syn2773

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drome is made when eruptions cover 30% or less of body-surface area, and a diagnosis of toxic epidermal necrolysis is made when 50% or more of body-surface area is affected. If 30 to 50% of bodysurface area is involved, it is called StevensJohnson syndrometoxic epidermal necrolysis (SJSTEN) overlap. The most common culprits include antibiotic agents, anticonvulsant agents, nonsteroidal antiinflammatory drugs, and allopurinol.1,2 This patient was not taking any of these medications but had just begun taking hydroxychloroquine, a drug that has been reported to cause SJSTEN overlap. The eruptions are preceded by fever and influenza-like symptoms for a few days, followed by macular erythema, atypical target lesions, or both that usually begin on the face and trunk and rapidly progress to involve the trunk and mucosal surfaces. Bullae formation follows, with subsequent desquamation. The eruptions are characteristically painful, often requiring analgesics. Photophobia, dysphagia, and dysuria reflect mucosal involvement. This patient had painful, desquamating skin lesions with involvement of the eyes, and SJSTEN overlap was suspected. If this spectrum of disorders is suspected, a skin-biopsy specimen should be sent urgently for pathological interpretation of a frozen section. A rapid mechanism for establishing a diagnosis is the jelly roll, which involves peeling off affected epidermis from the underlying skin and rolling it around a cotton-swab stick. The epidermis can be immediately examined by frozen section to determine whether there is full-thickness epidermal necrosis. In this case, skin biopsy was thought to be suggestive of SJSTEN overlap.
Erythema Multiforme

This case had many similarities with the StevensJohnson syndrome, toxic epidermal necrolysis, and erythema multiforme. However, a key distinguishing feature was the presence of extensive generalized pustules, which are not seen in any of these disorders.
Drug Hypersensitivity with Eosinophilia and Systemic Symptoms (DRESS) Syndrome

The DRESS syndrome is characterized by the presence of both pustules and desquamation. It is most commonly associated with anticonvulsant agents, sulfonamides, and allopurinol; typically begins 2 to 6 weeks after the start of a new medication; and is sometimes preceded by fever and malaise.3 The rash begins with facial and hand swelling followed by a generalized rash with various appearances, including morbilliform, bullous, and targetoid, which is followed by pinpoint pustules and desquamation, which can involve the mucous membranes. Lymphadenopathy, hepatomegaly, and abnormal liver-function tests also occur. Although there are many similarities between this case and the DRESS syndrome, this rash did not present with facial or acral edema, the patient did not have lymphadenopathy or abnormal results of liverfunction tests, the pustules were larger than pinpoint, and there was no typical culprit medication.
Infectious Desquamating Eruptions

Erythema multiforme should also be considered in this case. It can produce a generalized eruption with bullae, oral involvement, and extensive desquamation mimicking the StevensJohnson syndrome. The characteristic lesion is the target lesion, consisting of three zones a central dusky discoloration or bulla, surrounded by a pale-colored edematous ring, encircled by erythema. However, erythema multiforme is typically preceded by an outbreak of herpes simplex virus, which this patient did not have, and is infrequently related to medication. It is a self-limited, often recurrent condition that typically persists for 1 to 4 weeks and typically requires only symptomatic care.
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Staphylococcal scalded skin syndrome occurs mostly in neonates and infants but can also occur in immunocompromised adults and those with renal disease.4 It begins with fever, skin tenderness, and erythema of the neck, groin, and axillae. Acral areas are spared. This is followed by a generalized superficial desquamation of skin in sheets over a period of hours to days. Skin-biopsy or jelly roll specimens for frozen section rapidly distinguish staphylococcal scalded skin syndrome from the other severe exfoliative dermatoses. Although this patient was receiving low-dose prednisone therapy, she did not have immunodeficiency or renal disease; furthermore, the pustular component of her rash is inconsistent with staphylococcal scalded skin syndrome.
Pustular Eruptions

Infectious

Candidiasis may cause a pustular eruption that is usually mild and confined to intertriginous areas, most commonly in patients who are obese and in
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those who have diabetes. In immunocompromised patients, however, candidiasis can disseminate and cause sepsis, with erythematous macules on the trunk and limbs that transform into papules and pustules that become purpuric, hemorrhagic, and ulcerative. In this case, the patient, although she was taking low-dose prednisone, was not immunocompromised and candidiasis is unlikely. Bacterial infections such as gonococcemia can be associated with generalized cutaneous pustules, but the morphologic features of this patients eruption are not typical of gonococcal pustules. Other conditions such as impetigo and bacterial folliculitis or furunculosis also do not fit the patients presentation.
Noninfectious

cur. Although this patients pustular eruption and the presence of systemic symptoms are consistent with pustular psoriasis, she does not have a personal or family history of psoriasis, making this diagnosis unlikely.
Acute generalized exanthematous pustulosis

Sweets syndrome (acute neutrophilic dermatosis) may present with fever, leukocytosis, and pustular skin lesions. It may be precipitated by infection, and in about 10% of cases, is due to an underlying malignant condition, most often leukemia. This patients presentation shares some features with Sweets syndrome, but extensive desquamation would be unusual for Sweets syndrome. SneddonWilkinson disease is a chronic pustular disease that occurs predominantly in middle-aged women and is characterized by annular and serpiginous collections of sterile pustules on the abdomen, axillae, and groin. Involvement of oral or other mucous membranes is rare. Monoclonal gammopathy may be present, and there is overlap with IgA pemphigus,5 an autoimmune disease directed at desmocollin. The distribution of the lesions and the presence of desquamation in this case are not typical of these disorders. Pustular psoriasis is a rare form of psoriasis that typically occurs in patients with a history of plaques and psoriatic arthritis or a strong family history of psoriasis. Precipitating factors include withdrawal of systemic corticosteroids and exposure to new medications; hydroxychloroquine has been reported to precipitate pustular psoriasis.6 The onset is rapid, with numerous pustules and lakes of pus in the palms, fingers, and at the edges of psoriatic plaques.7 The skin is tender; involvement of the mucous membranes is common and includes superficial erosions on oral mucosa and geographic tongue. The patient is typically ill Dr . M athe w Av r a ms Di agnosis and febrile, sometimes with erythroderma, hypocalcemia, and cachexia. Desquamation may oc- Acute generalized exanthematous pustulosis.

Acute generalized exanthematous pustulosis is a rare pustular eruption that is usually caused by a drug reaction, although about 5% of cases are viral, parasitic, or idiopathic in origin.8,9 Sulfonamides, terbinafine, quinolones, hydroxychloroquine, diltiazem, pristinamycin, ampicillin, and amoxicillin have been implicated.8 It typically occurs within 5 days after administration of the medication has begun, starting with erythema and progressing to hundreds of nonfollicular pustules, 1 to 4 mm in diameter, on an erythematous, edematous base. Atypical target lesions may also be present. Within a few days, there is widespread desquamation. Fever, usually above 38C, is universal. Neutrophilia and eosinophilia are common. Mucous-membrane involvement is seen in about 25% of cases. Typically, acute generalized exanthematous pustulosis is a clinical diagnosis. However, because it may mimic other conditions that require different therapies, such as SJSTEN overlap, or pustular psoriasis, skin biopsy can be useful. Acute generalized exanthematous pustulosis typically resolves within 15 days after discontinuation of the medication, without sequelae. This case closely resembles both acute generalized exanthematous pustulosis and pustular psoriasis with regard to the morphologic features of the skin lesions, the presence of desquamation, and the systemic symptoms. I favored the diagnosis of acute generalized exanthematous pustulosis because of the absence of a history of psoriasis. It is crucially important to repeat a skin biopsy when the clinical presentation does not fit with the pathological diagnosis which in this case is SJSTEN overlap. The slide of the frozen section of the skin-biopsy specimen obtained at the other hospital was reviewed here, and we also performed a biopsy of an intact pustule on the right thigh and sent the specimen for pathological examination and for bacterial, viral, and fungal cultures.

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Figure 2. Skin-Biopsy Specimen. At low magnification (Panel A), the stratum corneum appears normal. The epidermis shows spongiosis and RETAKE 1st AUTHOR Avram ICM subcorneal pustules (arrows) containing many neutro2nd REG F FIGURE phils; neutrophils are2a&b seen within the superficial also 3rd CASE TITLE portion of the epidermis (arrowheads). At higher magRevised EMail Line 4-C nification (Panel B), the papillary dermis is edematous SIZE Enon ARTIST: mst H/T H/T and contains scattered neutrophils and eosinophils.
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Dr. Mai Hoang: We reviewed the frozen section of the skin-biopsy specimen that had been performed at the other hospital. There was marked edema of the papillary dermis, which resulted in a separation of the epidermis from the dermis. Subcorneal pustules were present, and the epidermis appeared viable. These features are not consistent with SJSTEN overlap, in which full-thickness necrosis of the epidermis is seen. The histologic sections of the biopsy specimen of the skin of the thigh, performed at this hospital, show spongiosis and subcorneal pustules inA nat omic a l Di agnosis volving the epidermis (Fig. 2A) and containing neutrophils. The papillary dermis is edematous Acute generalized exanthematous pustulosis due (Fig. 2B) and contains an interstitial infiltrate of to hydroxychloroquine. neutrophils and occasional eosinophils. Special No potential conflict of interest relevant to this article was restains revealed no bacteria or fungi, and cultures ported.
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for bacteria, fungi, and viruses were negative. Immunofluorescence examination for IgG, IgA, IgM, complement, and fibrinogen was negative. These histologic features are consistent with acute generalized exanthematous pustulosis, which is characterized by spongiform superficial intraepidermal pustules, papillary dermal edema, and a polymorphous perivascular dermal infiltrate with eosinophils, neutrophils, and, occasionally, leukocytoclastic vasculitis with fibrinoid necrosis.9 The histologic differential diagnosis includes pustular psoriasis, subcorneal pustular dermatosis, pustular contact dermatitis, IgA pemphigus, bullous leukocytoclastic vasculitis, and drughypersensitivity syndrome. The major differential diagnosis in this case was pustular psoriasis. Both acute generalized exanthematous pustulosis and pustular psoriasis have subcorneal spongiform pustules. However, the presence of intraepidermal pustules, marked papillary dermal edema, eosinophils, and occasional necrotic keratinocytes is more indicative of acute generalized exanthematous pustulosis.9,10 In cases of IgA pemphigus, direct immunofluorescence studies would reveal intercellular deposition of IgA within the epidermis, and in cases of leukocytoclastic vasculitis, bullous lesions containing neutrophils may occur; in both cases, small-vessel vasculitis is present, which was not seen in this case. The DRESS syndrome may have pustules, but they are usually less pronounced than those seen in acute generalized exanthematous pustulosis or in this case. The pathogenesis of acute generalized exanthematous pustulosis is not known. However, there is evidence that T cells in patients with the disorder produce the neutrophil-attracting cytokine interleukin-8, which may promote pustule formation.11-13 Dr. Avram: Supportive care in the burn unit was continued while we awaited the results of examination of the skin-biopsy specimen. The pustules gradually resolved and cleared within 14 days after discontinuing hydroxychloroquine. The patient was discharged on the 16th hospital day. She returned to her usual state of health, and the rash has not recurred.

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References
1. Bachot N, Roujeau JC. Differential di-

agnosis of severe cutaneous drug eruptions. Am J Clin Dermatol 2003;4:561-72. 2. Mockenhaupt M, Viboud C, Dunant A, et al. StevensJohnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs: the EuroSCAR-study. J Invest Dermatol 2008;128:35-44. 3. Tas S, Simonart T. Management of drug rash with eosinophilia and systemic symptoms (DRESS syndrome): an update. Dermatology 2003;206:353-6. 4. Mockenhaupt M, Idzko M, Grosber M, Schpf E, Norgauer J. Epidemiology of staphylococcal scalded skin syndrome in Germany. J Invest Dermatol 2005;124: 700-3. 5. Yasuda H, Kobayashi H, Hashimoto T, Itoh K, Yamane M, Nakamura J. Sub-

corneal pustular dermatosis type of IgA pemphigus: demonstration of autoantibodies to desmocollin-1 and clinical review. Br J Dermatol 2000;143:144-8. 6. Vine JE, Hymes SR, Warner NB, Cohen PR. Pustular psoriasis induced by hydroxychloroquine: a case report and review of the literature. J Dermatol 1996;23:357-61. 7. Zelickson BD, Muller SA. Generalized pustular psoriasis: a review of 63 cases. Arch Dermatol 1991;127:1339-45. 8. Sidoroff A, Dunant A, Viboud C, et al. Risk factors for acute generalized exanthematous pustulosis (AGEP) results of a multinational case-control study (EuroSCAR). Br J Dermatol 2007;157:989-96. 9. Roujeau JC, Bioulac-Sage P, Bourseau C, et al. Acute generalized exanthematous pustulosis: analysis of 63 cases. Arch Dermatol 1991;127:1333-8.

10. Sidoroff A, Halevy S, Bavinck JN, Vail-

lant L, Roujeau JC. Acute generalized exanthematous pustulosis (AGEP) a clinical reaction pattern. J Cutan Pathol 2001;28: 113-9. 11. Britschgi M, Pichler WJ. Acute generalized exanthematous pustulosis, a clue to neutrophil-mediated inflammatory processes orchestrated by T cells. Curr Opin Allergy Clin Immunol 2002;2:325-31. 12. Schmid S, Kuechler PC, Britschgi M, et al. Acute generalized exanthematous pustulosis: role of cytotoxic T cells in pustule formation. Am J Pathol 2002;161: 2079-86. 13. Britschgi M, Steiner UC, Schmid S, et al. T-cell involvement in drug-induced acute generalized exanthematous pustulosis. J Clin Invest 2001;107:1433-41.
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