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Serious Drug Rashes in Children
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HAPTER 10
Serious Drug Rashes in Children Joanna Burch, MD Assistant Professor of Dermatology and Pediatrics, University of Colorado School of Medicine, Denver, Colorado
William Weston, MD Professor of Dermatology and Pediatrics, University of Colorado School of Medicine, Denver, Colorado
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any cutaneous reactions to drugs are transient, non–life threatening, and benign. However, there are 3 serious and potentially life-threatening drug reactions that are detailed in this review: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and the drug rash, eosinophilia, and systemic symptoms (DRESS) syndrome. All 3 syndromes have some features in common in that they involve severe damage to skin, mucosa, or both, and they can be caused by similar drugs.1-4 The severe drug rashes have been classified by their clinical and histologic features, despite some overlapping features among the 3.1-16 There are no molecular or biochemical diagnostic tests available. SJS and TEN have such overlapping features in a few cases that some authorities consider them as part of a spectrum of the same disease, whereas others believe that the purely mucosal involvement in many patients with SJS versus the purely cutaneous involvement of many patients with TEN makes them distinct entities.3,4,7,10 SJS, first reported in 1922 by 2 American physicians, is the most common serious drug reaction in childhood.17 TEN, first reported by Lyell18 in the United Kingdom in 1956, is next. DRESS syndrome, an acronym recently applied12 to anticonvulsant drug hypersensitivity, first accurately described in 1971,19 is the most severe drug reaction and the least seen in childhood.12-16 Advances in Pediatrics®, vol 52 Copyright 2005, Mosby, Inc. All rights reserved.
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Fortunately, each severe drug reaction pattern is rare in childhood. Although precise data are not available, the incidence of SJS is estimated to be 1 in 30,000 children20-22; TEN, 1 in 100,000 children20-22; and DRESS, only more recently characterized, is presumed to be less than 1 in 100,000.12-13,23 The association of any drug with a particular drug reaction or with a specific reaction is based upon 4 main factors that comprise a drug reaction history profile24: (1) in the clinical trials for that drug, the reaction was 2 times more common than observed in the placebo group; (2) after the drug was approved, there were many reports of the reaction occurring as an adverse event; (3) inadvertent rechallenge resulted in an identical syndrome; and (4) deliberate rechallenge resulted in the identical syndrome.25 The term erythema multiforme (EM) major is not used in this review. Patients reported as having EM major had SJS and a few had TEN.3,4,7,10 The term incorrectly implies that EM as described by von Hebra may progress to EM major or SJS. It does not.7,9 The 3 main serious cutaneous drug reactions in children are considered here in order of their frequency.
SJS CLINICAL FEATURES The most common of serious drug rashes, SJS is an acute eruption characterized by extensive areas of necrosis of 2 or more mucosal surfaces.2,7-9,17 The mucosal involvement in children is preceded by an upper respiratory illness up to 2 weeks before the onset of mucosal lesions. Low-grade fever, cough, rhinitis, and headache are seen.2,5 Mucosal involvement starts abruptly and always involves the lips and mouth, with hemorrhagic crusts on the lips as the most common finding (Fig 1). The eyes are the second most common mucosal area involved, and severe redness, erosions, and a purulent eye discharge are seen. In one study, anogenital involvement was seen in 50% of cases.26 In general, eye involvement is more frequently observed than anogenital involvement. Most cases involve mucosa only, and 30% will have some skin lesions as well, usually involving less than 10% of the body surface area.3-5,7,9,22 Occasionally, a child will begin with erosions in the mouth and other mucosal sites and later develop widespread cutaneous blisters. This is the condition some call EM major,22 but most authorities consider this a form of SJS.3-5,7,9 The skin lesions are seen as dusky, purpleappearing macules. These may fade with time, but some skin lesions will develop central bullae. The bullae are often flaccid and not
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round as seen in the center of EM lesions, but oval and elongated shapes are observed. In a few cases, red macules with central blisters are seen. The denudation of the mouth and lips is so painful that drinking and eating become quite difficult, often resulting in dehydration at presentation. The dehydration may contribute to the fever, as the fever often clears with rehydration. Rarely, severe involvement of the respiratory mucosa may occur, and sloughing of the mucosa may obstruct airways. Shedding of nails has been described, but both the pulmonary involvement and loss of nails may be the result of a mimic of SJS, paraneoplastic pemphigus (PNP). If either pulmonary or nail involvement is seen, serum for pemphigus autoantibodies should be obtained. DIFFERENTIAL DIAGNOSIS The most common mimics of SJS are Kawasaki disease and PNP because they present with involvement of the oral mucosa and conjunctiva.26 In Kawasaki disease, the lips are red and swollen but show no signs of necrosis, and the remainder of the mouth is uninvolved. The lips do not show hemorrhagic crusts. The eyes are red and the sclera injected in Kawasaki disease, but erosions are absent. In PNP, the lips may show hemorrhagic crusts, and severe intraoral erosions are present. Widespread skin lesions are also present with cuticular involvement with nail dystrophy, and progressive pulmonary involvement is far more frequent.27,28 SJS has a course of several weeks with subsequent healing, whereas PNP relentlessly progresses with more skin and mucosal involvement.
FIGURE 1. Hemorrhagic crusts on the lips of a boy with Stevens-Johnson syndrome.
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Children with Behçet syndrome may demonstrate oral shallow ulcers and eye involvement, but the oral lesions are focal and discrete, not widespread, and large areas of necrosis are absent. Primary herpes simplex gingivostomatitis in infants has severe oral and perioral blisters, but the eyes are not involved. Pemphigus vulgaris and recurrent oral EM may also have severe focal oral lesions, but usually the eyes are spared. Patients with TEN may develop some mucosal lesions after the onset of skin involvement, but usually only one mucosal surface is involved.3,7,10 Similarly, drug-induced linear IgA disease may occasionally demonstrate mucosal lesions, although the bullous reaction is primarily on skin and is more likely to mimic TEN.29 Finally, bullous lupus erythematosus may have mucosal lesions, although cutaneous lesions predominate, including target-like lesions.30 Histology, including immunofluorescence examination of the skin, and laboratory studies, such as evidence of antinuclear antibodies, PNP autoantibodies, leukopenia, and eosinophilia, will help distinguish PNP from SJS. HISTOPATHOLOGY The early findings are that of a lichenoid skin reaction with apoptosis of individual epidermal cells (keratinocytes) with a band-like infiltrate of lymphocytes and eosinophils in the dermis. In advanced lesions, large sheets of epidermal necrosis may be found.7,10,19,31 Immunofluorescent examination of the skin reveals IgM and C3 at the dermal-epidermal junction and around superficial blood vessels. In contrast, PNP will show separation within the epidermis plus a separation at the dermal-epidermal junction, and deposits of IgG both within the epidermis and at the dermal-epidermal junction.27,28,31 PRECIPITATING DRUGS Commonly, there is a delay from the onset of taking the drug to the onset of symptoms, from 14 to 56 days. Although 205 different drugs have been reported to precipitate SJS,1,2,4,5,10,20,21,32 the most commonly associated drugs in childhood are the sulfonamides, particularly the trimethoprim-sulfonamide combinations. Sulfonamides account for more than 50% of the SJS cases in childhood.2,7,8,21 Nonsteroidal anti-inflammatory drugs and the anticonvulsant drugs are the next most common. Drugs are predominantly responsible for SJS, but clinicians should recall that a few cases may be infectious in association, such as during Mycoplasma pneumoniae infections.33,34 Genetic factors may be important in determining which child may be susceptible to drug-induced SJS. Inability to metabo-
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TABLE 1. Finding the Offending Drug in a Child Receiving Multiple Drugs 1. Consider all drugs started in the past 2 months. 2. Be most suspicious of drugs started in the past 3 weeks. 3. Remember to consider OTC drugs, as NSAIDs are common causes of severe drug rashes. 4. Select first the drugs that have been frequently shown to cause serious drug rashes: a. Sulfonamides and other antibiotics b. Anticonvulsants c. NSAIDs 5. If the child is receiving more than one in these categories and has started the drug in the past 2 months, then all drugs in the category must be stopped. Abbreviations: OTC, Over-the-counter; NSAIDs, nonsteroidal anti-inflammatory drugs.
lize the drug35 or inappropriate immune responses (HLA-B 1502)36 have been implicated. COURSE AND SEQUELAE In SJS, lesions progress for 3 to 5 days, then begin to heal. The healing process typically takes at least 2 weeks. The most serious sequelae are those of conjunctival scarring and pseudomembrane formation, symblepharon with immobility of the eyelids, entropion, and inversion of the eyelashes.2,3,7 This can result in corneal scarring, restricted eyelid movement, dry eyes, and diminished vision. Healing of skin may result in loss of pigment in the affected areas because of the damage to epidermal melanocytes as well as keratinocytes.2,3 The cases described with severe pulmonary and nail consequences may be PNP instead of SJS.7,26,37 The mortality rate in childhood is currently estimated at 1%.20-22 MANAGEMENT A key to management is to stop the suspected offending drug. It is evident that continuation of the offending drug increases the morbidity and mortality.38 For drugs with longer half-lives, the prognosis is worse than for drugs with shorter half-lives.38 In the child receiving multiple drugs, it may be difficult to determine the likely offending drug, since there is no readily available laboratory test to identify the offending drug. Lymphocyte transformation tests have correlated in a few cases but are not available and take too long to set up to be of practical use in decision-making. Table 1 provides clinical guidelines for determining the offending drug. In addition to stopping the drug, the child should be admitted to a pediatric inten-
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sive care unit (ICU) or burn unit for supportive care with fluids and electrolytes replaced.39-41 The mortality can be significantly reduced with intensive pediatric care.7,8,40 The necrotic oral mucosa can be removed gently with warmed saline mouth rinses. Early consultation with ophthalmology is critical, as the major concern is conjunctival scarring and reduction in vision. Topical steroid eye drops and other eye care may be important. When able to eat and drink, the child often can be discharged from the hospital. The use of anti-inflammatory strategies remains controversial. Although systemic high-dose (3-4 mg/kg) steroids have been long recommended, there is no evidence to suggest they influence the illness.42-45 A child already receiving high-dose steroids was reported to develop SJS.46 Prolonged use of corticosteroids may increase the likelihood of complications and prolong hospitalization.42 Thus, most authorities who champion steroids do not recommend more than 4 days of therapy.45,47 Similarly, the introduction of high-dose (1-2 g/kg) intravenous immunoglobulins (IVIG), first reported in 1998 by Viard et al,48 has been adopted by many centers,48-53 although recent studies do not support the early claims of success.54-56 Data from retrospective analysis show that at best, IVIG administration reduces fever by 0.5 days and “stops progression of skin lesions.”48-53 This latter claim is more difficult to substantiate because the skin lesions begin healing shortly after the offending drug is stopped, even in the absence of anti-inflammatory therapy. In general, the use of IVIG or intravenous steroids is controversial. There is no double-blind, prospective, placebo-controlled study that supports either of these proposed therapies.
TEN CLINICAL MANIFESTATIONS In contrast to SJS, which is a rapidly developing mucocutaneous disease over 72 hours, TEN has a more slowly progressive onset over several days. At the onset there is fever and tender skin for 1 to 3 days.1,2,3-7,10,11 Then, painful red to dusky-red macules appear on the skin but with no mucosal involvement. The macules progress to develop dusky centers, then oval or elongated bullae. Lateral pressure on the red skin will result in easy separation of skin (Nikolsky sign). Eventually, large sheets of necrotic skin peel and shed, leaving large areas of denuded skin (Fig 2) that involve from 30% to 80% of the body surface area.1,2,3-7,10,11 Areas of unaffected skin within the necrotic areas are seen, so-called “islands of sparing.” Mucosal in-
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volvement occurs in about 20% of patients, with oral mucosal involvement mimicking that of SJS. Attempts to distinguish TEN from SJS emphasize the less than 10% of body surface area involved in SJS and the more than 30% in TEN.3-8,10 This simple but artificial distinction generally can be applied to most children, but there are about 10% of children with drug reactions who will have between 10% and 30% of body surface area involved plus mucosal lesions, and these are considered “overlap” cases. Unlike SJS, healing is prolonged in TEN, often requiring 3 to 5 weeks for reepithelialization.1,2,4,10 Like SJS, the onset in TEN begins 14 to 56 days after starting the offending drug.2,6,8,10,11,20-23,57 The shedding of nails is far more common in TEN than SJS. A secondary bacterial infection of denuded skin with bacterial sepsis, especially with gram-negative bacteria, is a major cause of mortality.2,5,8 Exposure to herpes simplex virus (HSV) may result in disseminated HSV, similar to eczema herpeticum. Loss of protein, calcium, and fluids is severe and a major contributor to mortality. Some TEN patients have elevated liver enzymes and peripheral eosinophilia, features overlapping with DRESS syndrome. The clinician should view TEN as a “burn from inside out” and remember that burn care is a critical part of the management. The mortality rate in childhood is currently 30%, with most dying of bacterial sepsis. The initial evaluation of TEN should include a skin biopsy and the laboratory tests listed in Table 2. A specific severity of illness
FIGURE 2. Multiple areas of denuded skin and red, tender skin in a child with toxic epidermal necrolysis.
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J. Burch and W. Weston TABLE 2. Workup of a Child With Serious Drug Rash 1. 2. 3. 4. 5. 6. 7. 8.
Skin biopsy for histology Skin biopsy for immunofluorescence (snap-frozen) or special media Complete blood cell count Electrolytes including calcium BUN, creatinine Hepatic enzymes, albumin, and total protein Serum for pemphigus and paraneoplastic pemphigus autoantibodies Bacterial cultures of skin and mucosa
Abbreviation: BUN, Blood urea nitrogen.
score, called SCORTEN (Severity of Illness Score for TEN), was developed by using logistic regression equations that were translated into a probability of hospital mortality.58 Although developed for adult patients, it can be adapted to children excepting the age factor, and it may be useful in establishing a prognosis. DIFFERENTIAL DIAGNOSIS The acutely painful red skin that slowly progresses may be confused with the staphylococcal scalded skin syndrome (SSSS). SSSS has an abrupt onset of painful red skin and a superficial peeling that does not lead to bleeding.26 A preceding URI with rhinorrhea and conjunctivitis some 5 to 8 days before the appearance of red skin is common in SSSS and not in TEN. A skin biopsy will show full-thickness epidermal necrosis in TEN and a superficial separation of only a part of the epidermis (granular layer and stratum corneum) in SSSS. The overlaps between TEN and SJS are discussed in the differential diagnosis of SJS. Drug-induced linear IgA disease may mimic TEN and demonstrate large bullous lesions.29 Serum for immunofluorescent examination or a biopsy specimen will differentiate these 2 entities. Severe cutaneous reactions in lupus erythematosis may also mimic TEN. Histology and an antinuclear antibody test will differentiate them.30 TEN is also seen in the acute rejection phase of graft-versushost disease.59,60 HISTOPATHOLOGY TEN is characterized by a subepidermal blister with full-thickness necrosis of the overlying epidermis and a sparse superficial perivascular infiltrate of lymphocytes.31 Earliest lesions may demonstrate satellite cell necrosis with a lymphocyte touching a dying keratinocyte. There is often some sweat duct injury with apoptosis of ductal
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cells and sometimes, necrosis of the entire duct. Immunofluorescent examination reveals nonspecific collections of immunoglobulins in the mid dermis. In contrast, drug-induced linear IgA disease shows linear deposits of IgA at the dermal-epidermal junction. It has been suggested that the widespread keratinocyte apoptosis seen in TEN is mediated by the interaction of Fas-CD95 and its ligand, Fas-L.61 The death receptor Fas is normally present on keratinocytes, with little Fas-L expression under basal conditions. The keratinocytes in patients with TEN appear to express increased amounts of FasL, which may be a trigger for the widespread epidermal destruction in this disorder. Other factors, such as tumor necrosis factor-␣, are overexpressed in TEN and likely contribute to keratinocyte necrosis.62 PRECIPITATING DRUGS Of the 219 drugs reported to cause TEN,32 the nonsteroidal antiinflammatory drugs are the most common, followed by sulfonamides and anticonvulsants.1,2,5,8,11,20-23,35 Many of the same drugs that are implicated in SJS may also cause TEN. Whether the difference is in genetic differences in metabolism of the drug, in immune responsiveness, or in a combination of events is not known. As in SJS, the offending drug must be stopped.38 MANAGEMENT Childhood TEN should be managed as a burn.2,7,11,39-41,44 Admission to a pediatric burn unit is preferred, or if not available, a pediatric ICU.11,39-41,63-65 After stopping the drug, replacement of fluids and electrolytes as in burn protocols is recommended, with the applications of biologic dressings or skin grafts to reduce infection and mortality.11,39-41,63-65 Various biologic dressings have been used, but the nonsticking dressings such as Mepitel are preferred. Antibiotic ointment can be applied over the mepitel and a secondary dressing such as Adaptic over that. The secondary dressings can be changed daily, and the primary dressing (Mepitel) can be changed every 3 days. Bacterial cultures of the denuded areas should be obtained initially, then every 2 days until healing. Whether IVIG is efficacious in TEN is controversial,50-54 with more recent studies indicating this treatment does not influence TEN.55,56 It is clear that steroid administration may increase infectious complications, especially if steroid treatment is continued longer than 4 days.42 If the child survives, long-term sequelae include scarring and contractures, loss of fingernails and toenails, and vitiligo.2,7,11,39-41,44
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DRESS SYNDROME CLINICAL FEATURES DRESS syndrome is a complex of findings that includes the progressive development of red, scaly skin, fever, generalized lymphadenopathy, enlargement of the liver and spleen, and later, multiorgan failure.11-16,59,65 In the literature, it has been called the dilantin hypersensitivity syndrome, the phenytoin hypersensitivity syndrome, the anticonvulsant hypersensitivity syndrome, the dilantin pseudolymphoma syndrome, and the anticonvulsant pseudolymphoma syndrome.11-16,65,66 DRESS syndrome is currently preferred. The onset of the DRESS syndrome is often characterized by fever alone, and recurrent fevers may be initially seen. The skin becomes red and tender but does not blister (Fig 3).11-16 The redness slowly spreads over days to involve most of the body with accompanying scale. At this stage, it is called an erythroderma. Daily shedding of scales is common, but in contrast to SJS and TEN, blisters and denudation of skin does not occur.11-16,59,65 Multiple transverse grooves are noted in the fingernails, and by the time erythroderma develops, enlargement of the liver and spleen and a generalized lymphadenopathy begin.11-16,59,65 Because the hepatosplenomegaly and generalized lymphadenopathy were reported in lymphomas, it was called the drug pseudolymphoma syndrome. Profound laboratory abnormalities develop during the progression of the syndrome, with leukocytosis and marked eosinophilia, profoundly elevated hepatic enzymes levels, and elevated blood urea nitrogen and creatinine
FIGURE 3. Red skin with uninvolved areas in a child with generalized lymphadenopathy and hepatosplenomegaly (DRESS syndrome).
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levels. Low calcium and albumin levels are the result of a continuous loss of scale from the erythrodermic skin. If the drug is continued, renal failure develops, followed by cardiac failure, and finally hepatic failure will ensue. The recovery phase is prolonged even after stopping the offending drug, requiring 3 to 5 weeks. DIFFERENTIAL DIAGNOSIS Lymphomas including the Sézary syndrome and cutaneous T-cell lymphoma may be confused with the DRESS syndrome.12-16,26 Stopping the offending agent is a critical step in the differential diagnosis, as the symptoms will slowly reverse in DRESS and progress in lymphomas. The exfoliative dermatitis may mimic psoriasis, atopic dermatitis, contact dermatitis, or Netherton syndrome. These conditions usually do not have the laboratory abnormalities or the hepatosplenomegaly observed in DRESS. HISTOPATHOLOGY In contrast to SJS and TEN, large areas of epidermal necrosis are absent.12-16,31 Instead, spongiosis, a psoriasiform epidermal proliferation, and perivascular collections of lymphocytes are found. Despite peripheral eosinophilia, excessive eosinophils in the skin may not be found. Biopsy specimens from some patients have band-like collections of eosinophils admixed with large CD30⫹ lymphocytes.31 Occasionally, lymphocytes in the epidermis may be found, and rarely, atypical lymphocytes within epidermal microabscesses are found.31 PRECIPITATING DRUGS Of the 43 drugs reported to cause the DRESS syndrome,32 the phenytoins are the most often implicated.12-16,59,65 It is recently evident that drugs that are not anticonvulsants, such as nonsteroidal antiinflammatory drugs and sulfonamides, may be responsible.12-16,32 Classically, the syndrome begins about 3 weeks after starting the drug, but the 14- to 56-day window reported in SJS and TEN can be applied to DRESS as well.12-16,65 COURSE AND SEQUELAE The hospital course is prolonged, and the multiorgan failure has mortality rates from 30% to 70%. Children who recover usually end up with normal skin but will have a nail dystrophy. MANAGEMENT As in SJS and TEN, stopping the drug is most critical.38 Even with discontinuation, DRESS syndrome may progress for a few days, and
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recovery is quite prolonged.12-16,59,65 The mortality rate is at least 30%. Oral corticosteroids and IVIG have been recommended by several authorities, but it is controversial as to whether they are beneficial.42,54,67 Admission to a pediatric ICU with high-quality supportive care is vital.40,52 In addition to intravenous fluid replacement, replacement of protein and calcium losses is often necessary, and a topical steroid ointment may improve the skin.12-16,40 Supportive care for multiorgan failure requires all the skills of a pediatric ICU team.
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12. Bocquet H, Bagot M, Roujeau JC: Drug-induced pseudolymphoma and drug hypersensitivity syndrome (drug rash with eosinophilia and systemic symptoms: DRESS). Semin Cutan Med Surg 15:250-257, 1996. 13. Shear NH, Spielberg SP: Anticonvulsant hypersensitivity syndrome. J Clin Invest 82:1826-1832, 1988. 14. Carroll J: Drug-induced hypersensitivity syndrome in pediatric patients. Pediatrics 108:485-492, 2001. 15. Baba M, Karakas M, Aksungar VL, et al: The anticonvulsant hypersensitivity syndrome. J Eur Acad Dermatol Venereol 17:399-401, 2003. 16. Begon E, Roujeau JC: [Drug hypersenitivity syndrome: DRESS (drug reaction with eosinophlia and systemic symptoms)]. Ann Dermatol Venereol 131:293-297, 2004. 17. Stevens AM, Johnson FC: A new eruptive fever associated with stomatitis and ophthalmia. Am J Dis Child 24:526–529, 1922. 18. Lyell A: Toxic epidermal necrolysis: An eruption resembling scalding of skin. Br J Dermatol 68:355-361, 1956. 19. From E, Simonsen EE: Febrile toxic hepatitis with eosinophilia lymphadenopathy and exanthema during phenytoin therapy. Ugeskr Laeger 133:2376-2377, 1971. 20. Chan HL, Stern RS, Arndt KA, et al: The incidence of erythema multiforme, Stevens–Johnson syndrome and toxic epidermal necrolysis: A population based study with particular reference to reactions caused by drugs among outpatients. Arch Dermatol 126:43-48, 1990. 21. Roujeau JC, Kelly JP, Naldi L, et al: Medication use and the risk of Steven-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med 333:1600-1608, 1995. 22. Rzany B, Mockenhaupt M, Baur S, et al: Epidemiology of erythema exsudativum multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis in Germany (1990-1992): Structure and results of a population-based registry. J Clin Epidemiol 49:769-773, 1996. 23. Rzany B, Correia O, Kelly JP, et al: Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis during first weeks of antiepileptic therapy: A case-control study. Lancet 353:2190-2194, 1999. 24. Sullivan JR, Shear NH: The drug hypersensitivity syndrome: What is the pathogenesis? Arch Dermatol 137:357-364, 2001. 25. Kauppinen K: Cutaneous reactions to drugs with special reference to severe bullous mucocutaneous eruptions and sulphonamides. Acta Derm Venereol Suppl (Stockh) 68:1-89, 1972. 26. Bachot N, Roujeau JC: Differential diagnosis of severe cutaneous drug eruptions. Am J Clin Dermatol 4:561-572, 2003. 27. Lemon MA, Weston WL, Huff JC: Childhood paraneoplastic pemphigus associated with Castleman’s tumor. Br J Dermatol 136:115-117, 1997. 28. Rybojad M, Leblanc T, Flageul B, et al: Paraneoplastic pemphigus in a child with a T-cell lymphoblastic lymphoma. Br J Dermatol 128:418422, 1993.
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J. Burch and W. Weston 29. Tran D, Kossard S, Shumack S: Phenytoin-induced linear IgA dermatosis mimicking toxic epidermal necrolysis. Australas J Dermatol 44:284286, 2003. 30. Mandelcorn R, Shear NH: Lupus-associated toxic epidermal necrolysis: A novel manifestation of lupus? J Am Acad Dermatol 48:525-529, 2003. 31. Weeden D: Skin Pathology, ed 2. London, Churchill-Livingstone, 2002. 32. Litt JZ: Litt’s Drug Eruption Reference Manual, ed 9. New York, Parthenon, 2003. 33. Sontheimer R, Garibaldi RA, Krueger GG: Stevens–Johnson syndrome associated with Mycoplasma pneumoniae infection. Arch Dermatol 114:241-244, 1978. 34. Tay YK, Huff JC, Weston WL: Mycoplasma pneumoniae infection is associated with Stevens-Johnson syndrome, not erythema multiforme (von Hebra). J Am Acad Dermatol 35:757-760, 1996. 35. Wolkenstein P, Charue D, Laurent P, et al: Metabolic predisposition to cutaneous adverse drug reactions. Role in toxic epidermal necrolysis caused by sulfonamides and anticonvulsants. Arch Dermatol 131:544551, 1995. 36. Chung WH, Hung SI, Hong HS, et al: Medical genetics: A marker for Stevens-Johnson syndrome. Nature 428:486, 2004. 37. Virant FS, Redding GJ, Novack AH: Multiple pulmonary complications in a patient with Stevens–Johnson syndrome. Clin Pediatr 23:412-413, 1984. 38. Garcia-Doval I, LeCleach L, Bocquet H, et al: Toxic epidermal necrolysis and Stevens-Johnson syndrome: Does early withdrawal of causative drugs decrease the risk of death? Arch Dermatol 136:323-327, 2000. 39. Prendiville JS, Hebert AA, Greenwald MJ, et al: Management of Stevens–Johnson syndrome and toxic epidermal necrolysis. J Pediatr 115:881-887, 1989. 40. Ghislain PD, Roujeau JC: Treatment of severe drug reactions: StevensJohnson syndrome, toxic epidermal necrolysis, and hypersensitivity syndrome. Dermatol Online J 8:5, 2002. 41. Spies M, Sanford AP, Aili Low JF, et al: Treatment of extensive toxic epidermal necrolysis in children. Pediatrics 108:1162-1168, 2001. 42. Rasmussen JE: Erythema multiforme in children: Response to treatment with systemic corticosteroids. Br J Dermatol 95:181-186, 1976. 43. Renfro L, Grant-Kels J, Feder HM Jr, et al: Controversy: Are systemic steroids indicated in the treatment of erythema multiforme? Pediatr Dermatol 6:143-145, 1989. 44. Roujeau JC: Treatment of severe drug eruptions. J Dermatol 26:718-722, 1999. 45. Kakourou T, Klontza D, Soteropoulau F, et al: Corticosteroid treatment of erythema multiforme major (Stevens–Johnson syndrome) in children. Eur J Pediatr 156:90-93, 1997.
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46. Samimi SS, Siegfried E: Stevens-Johnson syndrome developing in a girl with systemic lupus erythematosus on high-dose corticosteroid therapy. Pediatr Dermatol 19:52-55, 2002. 47. Martinez AE, Atherton DJ: High-dose systemic corticosteroids can arrest recurrences of severe mucocutaneous erythema multiforme. Pediatr Dermatol 17:87-90, 2000. 48. Viard L, Wehrli P, Bulloni R, et al: Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science 282:490-493, 1998. 49. Morici MV, Galen WK, Avinash K, et al: Intravenous immunoglobulin therapy for children with Stevens-Johnson syndrome. J Rheumatol 27: 2494-2497, 2000. 50. Metry DW, Jung P, Levy ML: Use of intravenous immunoglobulin in children with Stevens-Johnson syndrome and toxic epidermal necrolysis: Seven cases and review of the literature. Pediatrics 112:14301436, 2003. 51. Prins C, Vittorio C, Padilla RS, et al: Effect of high-dose intravenous immunoglobulin therapy in Stevens-Johnson syndrome: A retrospective, multicenter study. Dermatology 207:96-99, 2003. 52. Bachot N, Roujeau JC: Physiopathology and treatment of severe drug eruptions. Curr Opin Allergy Clin Immunol 1:293-298, 2001. 53. Stern RS: Improving the outcome of patients with toxic epidermal necrolysis and Stevens-Johnson syndrome. Arch Dermatol 136:410-411, 2000. 54. Bachot N, Roujeau JC: Intravenous immunoglobulins in the treatment of severe drug eruptions. Curr Opin Allergy Clin Immunol 3:269-274, 2003. 55. Bachot N, Revuz J, Roujeau JC: Intravenous immunoglobulin treatment for Stevens-Johnson syndrome and toxic epidermal necrolysis: A prospective noncomparative study showing no benefit on mortality or progression. Arch Dermatol 139:33-36, 2003. 56. Shortt R, Gomez M, Mittman N, et al: Intravenous immunoglobulin does not improve outcome in toxic epidermal necrolysis. J Burn Care Rehabil 25:246-255, 2004. 57. Ibia EO, Schwartz RH, Wiederman RL, et al: Antibiotic rashes in children. Arch Dermatol 136:849-854, 2000. 58. Bastuji-Huerin S, Fochard N, Bertocchi M, et al: SCORTEN: A severity of illness score for toxic epidermal necrolysis. J Invest Dermatol 115: 149-153, 2000. 59. Shin HT, Chang MW: Drug eruptions in children. Curr Probl Pediatr 31:207-234, 2001. 60. Villada G, Roujeau JC, Cordonnier C, et al: Toxic epidermal necrolysis after bone marrow transplantation. Study of nine cases. J Am Acad Dermatol 23:870-875, 1990. 61. Abe R, Shimizu T, Shibaki A, et al: Toxic epidermal necrolysis and Stevens-Johnson syndrome are induced by soluble Fas ligand. Am J Pathol 162:1515-1520, 2003.
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J. Burch and W. Weston 62. Nassif A, Moslehi H, le Gouvello S, et al: Evaluation of the potential role of cytokines in toxic epidermal necrolysis. J Invest Dermatol 123: 850-855, 2004. 63. Adzick NS, Kim SH, Bondoc CC: Management of toxic epidermal necrolysis in a pediatric burn center. Am J Dis Child 139:499-502, 1995. 64. Kelemen JJ III, Cioffi WG, McManus WF, et al: Burn center care for patients with toxic epidermal necrolysis. J Am Coll Surg 180:273-278, 1995. 65. Palmieri TL, Greenhaig DG, Saffle JR, et al: A multicenter review of toxic epidermal necrolysis treated in US burn centers at the end of the twentieth century. J Burn Care Rehabil 23:87-96, 2002. 66. Baba M, Karakas M, Aksungar VL, et al: The anticonvulsant hypersensitivity syndrome. J Eur Acad Dermatol 17:399-401, 2003. 67. Lee WC, Leung JL, Fung CW, et al: Spectrum of anticonvulsant hypersensitivity syndrome: Controversy of treatment. J Child Neurol 19:619623, 2004.
HAPTER 10
Serious Drug Rashes in Children Joanna Burch, MD Assistant Professor of Dermatology and Pediatrics, University of Colorado School of Medicine, Denver, Colorado
William Weston, MD Professor of Dermatology and Pediatrics, University of Colorado School of Medicine, Denver, Colorado
M
any cutaneous reactions to drugs are transient, non–life threatening, and benign. However, there are 3 serious and potentially life-threatening drug reactions that are detailed in this review: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and the drug rash, eosinophilia, and systemic symptoms (DRESS) syndrome. All 3 syndromes have some features in common in that they involve severe damage to skin, mucosa, or both, and they can be caused by similar drugs.1-4 The severe drug rashes have been classified by their clinical and histologic features, despite some overlapping features among the 3.1-16 There are no molecular or biochemical diagnostic tests available. SJS and TEN have such overlapping features in a few cases that some authorities consider them as part of a spectrum of the same disease, whereas others believe that the purely mucosal involvement in many patients with SJS versus the purely cutaneous involvement of many patients with TEN makes them distinct entities.3,4,7,10 SJS, first reported in 1922 by 2 American physicians, is the most common serious drug reaction in childhood.17 TEN, first reported by Lyell18 in the United Kingdom in 1956, is next. DRESS syndrome, an acronym recently applied12 to anticonvulsant drug hypersensitivity, first accurately described in 1971,19 is the most severe drug reaction and the least seen in childhood.12-16 Advances in Pediatrics®, vol 52 Copyright 2005, Mosby, Inc. All rights reserved.
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Fortunately, each severe drug reaction pattern is rare in childhood. Although precise data are not available, the incidence of SJS is estimated to be 1 in 30,000 children20-22; TEN, 1 in 100,000 children20-22; and DRESS, only more recently characterized, is presumed to be less than 1 in 100,000.12-13,23 The association of any drug with a particular drug reaction or with a specific reaction is based upon 4 main factors that comprise a drug reaction history profile24: (1) in the clinical trials for that drug, the reaction was 2 times more common than observed in the placebo group; (2) after the drug was approved, there were many reports of the reaction occurring as an adverse event; (3) inadvertent rechallenge resulted in an identical syndrome; and (4) deliberate rechallenge resulted in the identical syndrome.25 The term erythema multiforme (EM) major is not used in this review. Patients reported as having EM major had SJS and a few had TEN.3,4,7,10 The term incorrectly implies that EM as described by von Hebra may progress to EM major or SJS. It does not.7,9 The 3 main serious cutaneous drug reactions in children are considered here in order of their frequency.
SJS CLINICAL FEATURES The most common of serious drug rashes, SJS is an acute eruption characterized by extensive areas of necrosis of 2 or more mucosal surfaces.2,7-9,17 The mucosal involvement in children is preceded by an upper respiratory illness up to 2 weeks before the onset of mucosal lesions. Low-grade fever, cough, rhinitis, and headache are seen.2,5 Mucosal involvement starts abruptly and always involves the lips and mouth, with hemorrhagic crusts on the lips as the most common finding (Fig 1). The eyes are the second most common mucosal area involved, and severe redness, erosions, and a purulent eye discharge are seen. In one study, anogenital involvement was seen in 50% of cases.26 In general, eye involvement is more frequently observed than anogenital involvement. Most cases involve mucosa only, and 30% will have some skin lesions as well, usually involving less than 10% of the body surface area.3-5,7,9,22 Occasionally, a child will begin with erosions in the mouth and other mucosal sites and later develop widespread cutaneous blisters. This is the condition some call EM major,22 but most authorities consider this a form of SJS.3-5,7,9 The skin lesions are seen as dusky, purpleappearing macules. These may fade with time, but some skin lesions will develop central bullae. The bullae are often flaccid and not
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round as seen in the center of EM lesions, but oval and elongated shapes are observed. In a few cases, red macules with central blisters are seen. The denudation of the mouth and lips is so painful that drinking and eating become quite difficult, often resulting in dehydration at presentation. The dehydration may contribute to the fever, as the fever often clears with rehydration. Rarely, severe involvement of the respiratory mucosa may occur, and sloughing of the mucosa may obstruct airways. Shedding of nails has been described, but both the pulmonary involvement and loss of nails may be the result of a mimic of SJS, paraneoplastic pemphigus (PNP). If either pulmonary or nail involvement is seen, serum for pemphigus autoantibodies should be obtained. DIFFERENTIAL DIAGNOSIS The most common mimics of SJS are Kawasaki disease and PNP because they present with involvement of the oral mucosa and conjunctiva.26 In Kawasaki disease, the lips are red and swollen but show no signs of necrosis, and the remainder of the mouth is uninvolved. The lips do not show hemorrhagic crusts. The eyes are red and the sclera injected in Kawasaki disease, but erosions are absent. In PNP, the lips may show hemorrhagic crusts, and severe intraoral erosions are present. Widespread skin lesions are also present with cuticular involvement with nail dystrophy, and progressive pulmonary involvement is far more frequent.27,28 SJS has a course of several weeks with subsequent healing, whereas PNP relentlessly progresses with more skin and mucosal involvement.
FIGURE 1. Hemorrhagic crusts on the lips of a boy with Stevens-Johnson syndrome.
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Children with Behçet syndrome may demonstrate oral shallow ulcers and eye involvement, but the oral lesions are focal and discrete, not widespread, and large areas of necrosis are absent. Primary herpes simplex gingivostomatitis in infants has severe oral and perioral blisters, but the eyes are not involved. Pemphigus vulgaris and recurrent oral EM may also have severe focal oral lesions, but usually the eyes are spared. Patients with TEN may develop some mucosal lesions after the onset of skin involvement, but usually only one mucosal surface is involved.3,7,10 Similarly, drug-induced linear IgA disease may occasionally demonstrate mucosal lesions, although the bullous reaction is primarily on skin and is more likely to mimic TEN.29 Finally, bullous lupus erythematosus may have mucosal lesions, although cutaneous lesions predominate, including target-like lesions.30 Histology, including immunofluorescence examination of the skin, and laboratory studies, such as evidence of antinuclear antibodies, PNP autoantibodies, leukopenia, and eosinophilia, will help distinguish PNP from SJS. HISTOPATHOLOGY The early findings are that of a lichenoid skin reaction with apoptosis of individual epidermal cells (keratinocytes) with a band-like infiltrate of lymphocytes and eosinophils in the dermis. In advanced lesions, large sheets of epidermal necrosis may be found.7,10,19,31 Immunofluorescent examination of the skin reveals IgM and C3 at the dermal-epidermal junction and around superficial blood vessels. In contrast, PNP will show separation within the epidermis plus a separation at the dermal-epidermal junction, and deposits of IgG both within the epidermis and at the dermal-epidermal junction.27,28,31 PRECIPITATING DRUGS Commonly, there is a delay from the onset of taking the drug to the onset of symptoms, from 14 to 56 days. Although 205 different drugs have been reported to precipitate SJS,1,2,4,5,10,20,21,32 the most commonly associated drugs in childhood are the sulfonamides, particularly the trimethoprim-sulfonamide combinations. Sulfonamides account for more than 50% of the SJS cases in childhood.2,7,8,21 Nonsteroidal anti-inflammatory drugs and the anticonvulsant drugs are the next most common. Drugs are predominantly responsible for SJS, but clinicians should recall that a few cases may be infectious in association, such as during Mycoplasma pneumoniae infections.33,34 Genetic factors may be important in determining which child may be susceptible to drug-induced SJS. Inability to metabo-
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TABLE 1. Finding the Offending Drug in a Child Receiving Multiple Drugs 1. Consider all drugs started in the past 2 months. 2. Be most suspicious of drugs started in the past 3 weeks. 3. Remember to consider OTC drugs, as NSAIDs are common causes of severe drug rashes. 4. Select first the drugs that have been frequently shown to cause serious drug rashes: a. Sulfonamides and other antibiotics b. Anticonvulsants c. NSAIDs 5. If the child is receiving more than one in these categories and has started the drug in the past 2 months, then all drugs in the category must be stopped. Abbreviations: OTC, Over-the-counter; NSAIDs, nonsteroidal anti-inflammatory drugs.
lize the drug35 or inappropriate immune responses (HLA-B 1502)36 have been implicated. COURSE AND SEQUELAE In SJS, lesions progress for 3 to 5 days, then begin to heal. The healing process typically takes at least 2 weeks. The most serious sequelae are those of conjunctival scarring and pseudomembrane formation, symblepharon with immobility of the eyelids, entropion, and inversion of the eyelashes.2,3,7 This can result in corneal scarring, restricted eyelid movement, dry eyes, and diminished vision. Healing of skin may result in loss of pigment in the affected areas because of the damage to epidermal melanocytes as well as keratinocytes.2,3 The cases described with severe pulmonary and nail consequences may be PNP instead of SJS.7,26,37 The mortality rate in childhood is currently estimated at 1%.20-22 MANAGEMENT A key to management is to stop the suspected offending drug. It is evident that continuation of the offending drug increases the morbidity and mortality.38 For drugs with longer half-lives, the prognosis is worse than for drugs with shorter half-lives.38 In the child receiving multiple drugs, it may be difficult to determine the likely offending drug, since there is no readily available laboratory test to identify the offending drug. Lymphocyte transformation tests have correlated in a few cases but are not available and take too long to set up to be of practical use in decision-making. Table 1 provides clinical guidelines for determining the offending drug. In addition to stopping the drug, the child should be admitted to a pediatric inten-
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sive care unit (ICU) or burn unit for supportive care with fluids and electrolytes replaced.39-41 The mortality can be significantly reduced with intensive pediatric care.7,8,40 The necrotic oral mucosa can be removed gently with warmed saline mouth rinses. Early consultation with ophthalmology is critical, as the major concern is conjunctival scarring and reduction in vision. Topical steroid eye drops and other eye care may be important. When able to eat and drink, the child often can be discharged from the hospital. The use of anti-inflammatory strategies remains controversial. Although systemic high-dose (3-4 mg/kg) steroids have been long recommended, there is no evidence to suggest they influence the illness.42-45 A child already receiving high-dose steroids was reported to develop SJS.46 Prolonged use of corticosteroids may increase the likelihood of complications and prolong hospitalization.42 Thus, most authorities who champion steroids do not recommend more than 4 days of therapy.45,47 Similarly, the introduction of high-dose (1-2 g/kg) intravenous immunoglobulins (IVIG), first reported in 1998 by Viard et al,48 has been adopted by many centers,48-53 although recent studies do not support the early claims of success.54-56 Data from retrospective analysis show that at best, IVIG administration reduces fever by 0.5 days and “stops progression of skin lesions.”48-53 This latter claim is more difficult to substantiate because the skin lesions begin healing shortly after the offending drug is stopped, even in the absence of anti-inflammatory therapy. In general, the use of IVIG or intravenous steroids is controversial. There is no double-blind, prospective, placebo-controlled study that supports either of these proposed therapies.
TEN CLINICAL MANIFESTATIONS In contrast to SJS, which is a rapidly developing mucocutaneous disease over 72 hours, TEN has a more slowly progressive onset over several days. At the onset there is fever and tender skin for 1 to 3 days.1,2,3-7,10,11 Then, painful red to dusky-red macules appear on the skin but with no mucosal involvement. The macules progress to develop dusky centers, then oval or elongated bullae. Lateral pressure on the red skin will result in easy separation of skin (Nikolsky sign). Eventually, large sheets of necrotic skin peel and shed, leaving large areas of denuded skin (Fig 2) that involve from 30% to 80% of the body surface area.1,2,3-7,10,11 Areas of unaffected skin within the necrotic areas are seen, so-called “islands of sparing.” Mucosal in-
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volvement occurs in about 20% of patients, with oral mucosal involvement mimicking that of SJS. Attempts to distinguish TEN from SJS emphasize the less than 10% of body surface area involved in SJS and the more than 30% in TEN.3-8,10 This simple but artificial distinction generally can be applied to most children, but there are about 10% of children with drug reactions who will have between 10% and 30% of body surface area involved plus mucosal lesions, and these are considered “overlap” cases. Unlike SJS, healing is prolonged in TEN, often requiring 3 to 5 weeks for reepithelialization.1,2,4,10 Like SJS, the onset in TEN begins 14 to 56 days after starting the offending drug.2,6,8,10,11,20-23,57 The shedding of nails is far more common in TEN than SJS. A secondary bacterial infection of denuded skin with bacterial sepsis, especially with gram-negative bacteria, is a major cause of mortality.2,5,8 Exposure to herpes simplex virus (HSV) may result in disseminated HSV, similar to eczema herpeticum. Loss of protein, calcium, and fluids is severe and a major contributor to mortality. Some TEN patients have elevated liver enzymes and peripheral eosinophilia, features overlapping with DRESS syndrome. The clinician should view TEN as a “burn from inside out” and remember that burn care is a critical part of the management. The mortality rate in childhood is currently 30%, with most dying of bacterial sepsis. The initial evaluation of TEN should include a skin biopsy and the laboratory tests listed in Table 2. A specific severity of illness
FIGURE 2. Multiple areas of denuded skin and red, tender skin in a child with toxic epidermal necrolysis.
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Skin biopsy for histology Skin biopsy for immunofluorescence (snap-frozen) or special media Complete blood cell count Electrolytes including calcium BUN, creatinine Hepatic enzymes, albumin, and total protein Serum for pemphigus and paraneoplastic pemphigus autoantibodies Bacterial cultures of skin and mucosa
Abbreviation: BUN, Blood urea nitrogen.
score, called SCORTEN (Severity of Illness Score for TEN), was developed by using logistic regression equations that were translated into a probability of hospital mortality.58 Although developed for adult patients, it can be adapted to children excepting the age factor, and it may be useful in establishing a prognosis. DIFFERENTIAL DIAGNOSIS The acutely painful red skin that slowly progresses may be confused with the staphylococcal scalded skin syndrome (SSSS). SSSS has an abrupt onset of painful red skin and a superficial peeling that does not lead to bleeding.26 A preceding URI with rhinorrhea and conjunctivitis some 5 to 8 days before the appearance of red skin is common in SSSS and not in TEN. A skin biopsy will show full-thickness epidermal necrosis in TEN and a superficial separation of only a part of the epidermis (granular layer and stratum corneum) in SSSS. The overlaps between TEN and SJS are discussed in the differential diagnosis of SJS. Drug-induced linear IgA disease may mimic TEN and demonstrate large bullous lesions.29 Serum for immunofluorescent examination or a biopsy specimen will differentiate these 2 entities. Severe cutaneous reactions in lupus erythematosis may also mimic TEN. Histology and an antinuclear antibody test will differentiate them.30 TEN is also seen in the acute rejection phase of graft-versushost disease.59,60 HISTOPATHOLOGY TEN is characterized by a subepidermal blister with full-thickness necrosis of the overlying epidermis and a sparse superficial perivascular infiltrate of lymphocytes.31 Earliest lesions may demonstrate satellite cell necrosis with a lymphocyte touching a dying keratinocyte. There is often some sweat duct injury with apoptosis of ductal
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cells and sometimes, necrosis of the entire duct. Immunofluorescent examination reveals nonspecific collections of immunoglobulins in the mid dermis. In contrast, drug-induced linear IgA disease shows linear deposits of IgA at the dermal-epidermal junction. It has been suggested that the widespread keratinocyte apoptosis seen in TEN is mediated by the interaction of Fas-CD95 and its ligand, Fas-L.61 The death receptor Fas is normally present on keratinocytes, with little Fas-L expression under basal conditions. The keratinocytes in patients with TEN appear to express increased amounts of FasL, which may be a trigger for the widespread epidermal destruction in this disorder. Other factors, such as tumor necrosis factor-␣, are overexpressed in TEN and likely contribute to keratinocyte necrosis.62 PRECIPITATING DRUGS Of the 219 drugs reported to cause TEN,32 the nonsteroidal antiinflammatory drugs are the most common, followed by sulfonamides and anticonvulsants.1,2,5,8,11,20-23,35 Many of the same drugs that are implicated in SJS may also cause TEN. Whether the difference is in genetic differences in metabolism of the drug, in immune responsiveness, or in a combination of events is not known. As in SJS, the offending drug must be stopped.38 MANAGEMENT Childhood TEN should be managed as a burn.2,7,11,39-41,44 Admission to a pediatric burn unit is preferred, or if not available, a pediatric ICU.11,39-41,63-65 After stopping the drug, replacement of fluids and electrolytes as in burn protocols is recommended, with the applications of biologic dressings or skin grafts to reduce infection and mortality.11,39-41,63-65 Various biologic dressings have been used, but the nonsticking dressings such as Mepitel are preferred. Antibiotic ointment can be applied over the mepitel and a secondary dressing such as Adaptic over that. The secondary dressings can be changed daily, and the primary dressing (Mepitel) can be changed every 3 days. Bacterial cultures of the denuded areas should be obtained initially, then every 2 days until healing. Whether IVIG is efficacious in TEN is controversial,50-54 with more recent studies indicating this treatment does not influence TEN.55,56 It is clear that steroid administration may increase infectious complications, especially if steroid treatment is continued longer than 4 days.42 If the child survives, long-term sequelae include scarring and contractures, loss of fingernails and toenails, and vitiligo.2,7,11,39-41,44
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DRESS SYNDROME CLINICAL FEATURES DRESS syndrome is a complex of findings that includes the progressive development of red, scaly skin, fever, generalized lymphadenopathy, enlargement of the liver and spleen, and later, multiorgan failure.11-16,59,65 In the literature, it has been called the dilantin hypersensitivity syndrome, the phenytoin hypersensitivity syndrome, the anticonvulsant hypersensitivity syndrome, the dilantin pseudolymphoma syndrome, and the anticonvulsant pseudolymphoma syndrome.11-16,65,66 DRESS syndrome is currently preferred. The onset of the DRESS syndrome is often characterized by fever alone, and recurrent fevers may be initially seen. The skin becomes red and tender but does not blister (Fig 3).11-16 The redness slowly spreads over days to involve most of the body with accompanying scale. At this stage, it is called an erythroderma. Daily shedding of scales is common, but in contrast to SJS and TEN, blisters and denudation of skin does not occur.11-16,59,65 Multiple transverse grooves are noted in the fingernails, and by the time erythroderma develops, enlargement of the liver and spleen and a generalized lymphadenopathy begin.11-16,59,65 Because the hepatosplenomegaly and generalized lymphadenopathy were reported in lymphomas, it was called the drug pseudolymphoma syndrome. Profound laboratory abnormalities develop during the progression of the syndrome, with leukocytosis and marked eosinophilia, profoundly elevated hepatic enzymes levels, and elevated blood urea nitrogen and creatinine
FIGURE 3. Red skin with uninvolved areas in a child with generalized lymphadenopathy and hepatosplenomegaly (DRESS syndrome).
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levels. Low calcium and albumin levels are the result of a continuous loss of scale from the erythrodermic skin. If the drug is continued, renal failure develops, followed by cardiac failure, and finally hepatic failure will ensue. The recovery phase is prolonged even after stopping the offending drug, requiring 3 to 5 weeks. DIFFERENTIAL DIAGNOSIS Lymphomas including the Sézary syndrome and cutaneous T-cell lymphoma may be confused with the DRESS syndrome.12-16,26 Stopping the offending agent is a critical step in the differential diagnosis, as the symptoms will slowly reverse in DRESS and progress in lymphomas. The exfoliative dermatitis may mimic psoriasis, atopic dermatitis, contact dermatitis, or Netherton syndrome. These conditions usually do not have the laboratory abnormalities or the hepatosplenomegaly observed in DRESS. HISTOPATHOLOGY In contrast to SJS and TEN, large areas of epidermal necrosis are absent.12-16,31 Instead, spongiosis, a psoriasiform epidermal proliferation, and perivascular collections of lymphocytes are found. Despite peripheral eosinophilia, excessive eosinophils in the skin may not be found. Biopsy specimens from some patients have band-like collections of eosinophils admixed with large CD30⫹ lymphocytes.31 Occasionally, lymphocytes in the epidermis may be found, and rarely, atypical lymphocytes within epidermal microabscesses are found.31 PRECIPITATING DRUGS Of the 43 drugs reported to cause the DRESS syndrome,32 the phenytoins are the most often implicated.12-16,59,65 It is recently evident that drugs that are not anticonvulsants, such as nonsteroidal antiinflammatory drugs and sulfonamides, may be responsible.12-16,32 Classically, the syndrome begins about 3 weeks after starting the drug, but the 14- to 56-day window reported in SJS and TEN can be applied to DRESS as well.12-16,65 COURSE AND SEQUELAE The hospital course is prolonged, and the multiorgan failure has mortality rates from 30% to 70%. Children who recover usually end up with normal skin but will have a nail dystrophy. MANAGEMENT As in SJS and TEN, stopping the drug is most critical.38 Even with discontinuation, DRESS syndrome may progress for a few days, and
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recovery is quite prolonged.12-16,59,65 The mortality rate is at least 30%. Oral corticosteroids and IVIG have been recommended by several authorities, but it is controversial as to whether they are beneficial.42,54,67 Admission to a pediatric ICU with high-quality supportive care is vital.40,52 In addition to intravenous fluid replacement, replacement of protein and calcium losses is often necessary, and a topical steroid ointment may improve the skin.12-16,40 Supportive care for multiorgan failure requires all the skills of a pediatric ICU team.
REFERENCES 1. Roujeau JC, Stern RS: Severe adverse cutaneous reactions to drugs. N Engl J Med 331:1272-1285, 1994. 2. Forman R, Koren G, Shear NH: Erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis in children: A review of 10 years’ experience. Drug Saf 25:965-972, 2002. 3. Bastuji-Garin S, Rzany B, Stern RS, et al: Clinical classification of cases of toxic epidermal necrolysis, Stevens–Johnson syndrome, and erythema multiforme. Arch Dermatol 129:92-96, 1993. 4. Lam NS, Yang YH, Wang LC, et al: Clinical characteristics of childhood erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis in Taiwanese children. J Microbiol Immunol Infect 37:366370, 2004. 5. Schopf E, Stuhmer A, Rzany B, et al: Toxic epidermal necrolysis and Stevens–Johnson syndrome. An epidemiological study from West Germany. Arch Dermatol 127:839-842, 1991. 6. Ruiz-Maldonado R: Acute disseminated epidermal necrosis types 1, 2, and 3: Study of 60 cases. J Am Acad Dermatol 13:623–635, 1985. 7. Leaute-Labreze C, Lamireau T, Chawki D, et al: Diagnosis, classification, and management of erythema multiforme and Stevens-Johnson syndrome. Arch Dis Child 83:347-352, 2000. 8. Shin HT, Chang MW: Drug eruptions in children. Curr Probl Pediatr 31:207-234, 2001. 9. Assier H, Bastuji-Garin S, Refuz J, et al: Erythema multiforme with mucous membrane involvement and Stevens-Johnson syndrome are clinically different disorders with distinct causes. Arch Dermatol 131:539543, 1995. 10. Auquier-Dunant A, Mochenhaupt M, Naldi L, et al: Correlations between clinical patterns and causes of erythema multiforme majus, Stevens-Johnson syndrome and toxic epidermal necrolysis: Results of an international prospective study. Arch Dermatol 138:1019-1024, 2002. 11. Ringheanu M, Laude TA: Toxic epidermal necrolysis in children: An update. Clin Pediatr 39:687-694, 2000.
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