An update on pediatric cutaneous drug eruptions James E. Song MD, Robert Sidbury MD, MPH PII: DOI: Reference:
S0738-081X(14)00039-X doi: 10.1016/j.clindermatol.2014.02.005 CID 6822
To appear in:
Clinics in Dermatology
Please cite this article as: Song James E., Sidbury Robert, An update on pediatric cutaneous drug eruptions, Clinics in Dermatology (2014), doi: 10.1016/j.clindermatol.2014.02.005
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James E Song, MD* Department of Dermatology University of California, Irvine 1002 Health Sciences Rd Irvine, CA 92612 Phone: (847) 312-7000 [email protected]
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AN UPDATE ON PEDIATRIC CUTANEOUS DRUG ERUPTIONS
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Robert Sidbury, MD, MPH Department of Pediatrics Division of Dermatology Seattle Children’s Hospital University of Washington School of Medicine Box 359300 – A7916 Seattle, WA 98105 Phone: (206) 987-2158 Fax: (206) 987-2217 [email protected] *Corresponding Author
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Abstract
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One of the early lessons learned in dermatology training is “any drug, any rash.” This maxim quickly summarizes the vast array of cutaneous reactions that can be seen in response to systemic medications. Herein we will review common and unusual drug eruptions in pediatric patients that span the morphologic spectrum. These reactions can have an equally broad range of severity, from harmless to lethal, and by the end of this article the reader will be better equipped to sort one from the other.
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Introduction
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The list of drug-related cutaneous reactions can be daunting, even for the experienced dermatologist, as there have been over 25 different patterns described in the literature [1]. A systematic assessment is essential to efficiently and effectively winnow this imposing list into a practical recommendation when drug eruption is in the clinical differential. Sorting by morphology, including morbilliform, urticarial, bullous, pustular and psoriasiform, is one approach; sorting by distribution another. While not exhaustive, we will touch on some of the more common patterns and highlight new and unusual presentations in the literature. Morbilliform
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Morbilliform, also known as “maculopapular” or “exanthematous”, drug eruptions are the most common morphologic type seen in children [1]. Eruptions typically occur within the first week of exposure to the offending agent. Some patients may react after their initial exposure, while others can develop it after years of having used the same medication without complication Morbilliform drug eruptions present as widespread pink to salmon-colored macules and papules that usually start on the head, neck or upper trunk then spread symmetrically downward and become confluent (Figure 1). Patients may complain of pruritus though it is not uncommon to be completely asymptomatic. Virtually any drug can cause a morbilliform drug reaction but beta-lactam antibiotics have been most frequently implicated. Viral infection may increase the likelihood of developing a cutaneous drug reaction. Up to 95% of patients who have an active Epstein-Barr virus (EBV) infection will develop a moribilliform eruption when treated with ampicillin [2]. In part because clinicians are keen to “first, do no harm” drug allergy labels are often assigned without obvious indication because even a small chance of an avoidable drug reaction seems too high. The problem arises in chronically ill children who can quickly amass a clinically constraining list of “allergies.” One strategy gaining traction is
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the use of terms like “probable” or “possible” drug allergy when there is doubt. This may help clinicians to best weigh the risk-benefit ratio of future drug re-challenge. Urticarial
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Acute Drug-induced Urticaria
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Drug-induced urticaria comprises approximately 5% of all cutaneous drug eruptions, making it the second most common type of skin eruption [3]. Lesions are usually pruritic and appear as raised, edematous papules and plaques with central pallor. Some patients have only scattered lesions, while others generalize. Angioedema can accompany these urticarial eruptions and is most easily appreciated around the eyes, lips, and mucous membranes.
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The hallmark feature of acute drug-induced urticaria is its evanescent nature. Lesions should last less than 48 hours, although new lesions may continue to arise. Lesions that last longer than 24-48 hours should expand the differential and may indicate skin biopsy to rule out other considerations including urticarial vasculitis. Immunologic and non-immunologic mechanisms are involved in urticarial drug reactions. Type I IgEmediated hypersensitivity reaction accounts for the majority of urticarial eruptions and are most often elicited by penicillin or derivatives [4]. Non-immunologic mechanisms, as seen with narcotic analgesics and radio-contrast media, may also cause urticarial eruptions,
Serum Sickness Like Reaction
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When an urticarial eruption is accompanied by systemic findings, a serumsickness like reaction (SSLR) must be considered. Patients present with skin rash, fever, and arthralgia within 7 to 21 days of exposure to the causative agent [5,6]. Periocular edema is common and the rash may have a strikingly ecchymotic appearance (Figure 2). Lymphadenopathy and eosinophilia may also be present. Unlike true-serum sickness, SSLR is not a type III reaction, and therefore, correspondingly frank arthritis, hypocomplementemia, vasculitis, or nephropathy are not typically seen. Cefaclor is the most commonly implicated drug, with an estimated risk of 0.024% to 0.2% [6]. With the exception of cefprozil, no cross-reactivity with other cephalosporins has been reported [7]. Treatment involves withdrawal of the offending medication or trigger as able, supportive care including antihistamines for itch if helpful, and systemic steroids may be required if joint symptoms are limiting.
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Giant Urticaria
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Facial or acral edema Associated symptoms Common Trigers
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Mucous Membrane involvement
< 24 hrs Trunk, extremities, face Oral edema common, no erosions or blisters + Pruritus
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Duration of lesions Location
Erythema Multifrome Days to weeks Palms, soles
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Giant Urticaria
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Giant urticaria is a distinctive morphologic form of urticaria that generally occurs in children aged 1-5 years old. Lesions are characterized by annular, arcuate, and polycylic wheals with associated angioedema (Figure 3). Giant urticaria has long been mistaken for erythema multiforme (EM) on account of its distinctive targetoid morphology. Accordingly, Shah et al proposed the term “urticaria multiforme” to help promote this important distinction [8]. Giant urticaria may also be mistaken for SSLR when fever and acral edema accompany the skin eruption and discrimination may not be possible though the duration of the lesions may be informative. Unlike SSLR and EM, the lesions in giant urticaria do not last more than 24-48 hours. Systemic antibiotics and antipyretics have been the most frequently reported offenders [9,10] though giant urticaria most often occurs in the wake of a viral illness.
Antibiotics, immunizations, viral illnesses
Erosions and blisters may be present Pruritus, burning HSV, mycoplasma
Serum Sickness-Like Reactions Days to weeks Trunk, extremities, face, hands and feet Oral edema common, no erosions or blisters + Lympadenopathy, arthralgia, myalgia Antibiotics
*Adapted from Shah et al. Table 1. Distinguishing features of Giant Urticaria, Erythema Multiforme, and Serum Sickness-Like Reactions Bullous Fixed Drug Eruptions Fixed drug eruptions (FDE) are characterized by the development of lesions in the same anatomic location after challenge with an offending agent. Lesions appear as sharply demarcated, round-to-oval shaped, dusky, gunmetal colored plaques that may include a central blister. FDE’s have a predilection for the genitalia, perianal area, lips, and the hands and feet, although anybody surface can be affected. When the genitalia are involved, the diagnosis may be obscured by the child’s inability to specifically express
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their symptoms. Pruritus, restlessness, urinary retention, or painful micturition may be their only complaints [11]. As such, the clinician needs a high index of suspicion to make the diagnosis and should always consider FDEs as a potential organic mimic of child abuse.
Linear IgA Bullous Dermatosis
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Numerous drugs have been reported to cause FDEs but the most common are sulfonamides, antipyretics (acetaminophen), analgesics (ibuprofen) and antibiotics [12]. In children, phenobarbital, hydroxyzine, methylphenidate, and rifampin have also been reported [11,13-15]. The drug most frequently reported to cause FDE in all age groups is trimethoprim-sulfamethoxazole (TMP-SMX) [16]. In one study, TMP-SMX was the culprit in over 50% of the children studied [17]. Patients may present weeks to months after the blisters have appeared, leaving them only with a non-specific hyperpigmented patch.
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Linear IgA bullous dermatosis (LABD) is a rare autoimmune subepidermal blistering disorder that is characterized by linear deposition of IgA along the basement membrane zone [18]. Peak incidence is seen in preschoolers and adults over the age of sixty. The classic picture is a cluster of tense bullae arranged in an annular configuration over an urticarial base, often likened to a “crown of jewels” (Figure 4). The flexural and extensor surfaces, torso and oral mucosa can be involved, giving them an appearance that may be clinically indistinguishable from bullous pemphigoid, erythema multiforme, and dermatitis herpetiformis. As with FDE, groin involvement is common in LABD and should be ruled out when child abuse is considered. Up to two-thirds of cases have been associated with a drug etiology, with vancomycin being the classic example [18]. Non-steroidal anti-inflammatory drugs (NSAIDs), other antibiotics, diuretics, and anti-eplieptics have also been reported in adults, though not as well documented in children [19]. Trimethoprim-sulfamethoxazole and amoxicillin-clavulanic acid have both been recently reported to cause LABD in children [18,20]. Compared to the idiopathic form of LABD, drug-induced forms have a more predictable course with resolution within weeks of withdrawal of the offending agent and a lower incidence of mucosal involvement [21].
Pseudoporphyria Pseudoporphyria (PP) is an uncommon drug-induced blistering eruption [6]. PP may resemble porphyria cutanea tarda (PCT) with photodistributed vesicles and bullae,
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increased skin fragility, and scarring involving the dorsum of the hands and forearms and distinction may require porphyrin studies. Alternatively it may present like erythropoietic protoporphyria (EPP) with erythema, burning, angular cicatrix formation and thickened skin texture, particularly on the face [22]. Naproxen is the most frequent offender and is of particular interest because of its use in patients with juvenile arthritis. A prospective study by Lang et. al found that 12% of patients who were being treated for juvenile idiopathic arthritis (JIA) with naproxen for at least 4 weeks developed EPP-like PP [23]. Interestingly, blue/gray eye color has been found to be an independent risk factor for PP and therefore must be used with caution in such patients. [24].
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Coma Blisters
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Coma blisters are uncommon skin eruptions that are seen in patients with impaired consciousness. The original case was described in a patient who was heavily sedated due to barbiturate intoxication [25]. Since then, other anticonvulsants have been reported, including certain benzodiazepines such as clobazam, and valproic acid [26]. These blisters are most often seen in pressure areas, particularly over bony prominences. The key histological feature that defines coma blisters is eccrine necrosis. Until recently, coma blisters were thought to be a self-limiting process that did not require withdrawal of the offending agent. Basu et al., however, reported a 9-year-old boy with biopsy proven coma blisters that continued to develop worsening lesions until the culprit was completely removed [26].
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Erythema multiforme/Stevens Johnson syndrome/Toxic epidermal necrolysis Controversy still exists whether erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and Toxic Epidermal Necrolysis (TEN) are related conditions on a spectrum or separate entities. Erythema multiforme (EM) classically presents as symmetric, target-shaped, edematous papules that involve the acral surfaces (Figure 5). These lesions will have three distinct zones of color, sometimes with a central blister. Mucosal involvement can be seen, although it is usually mild and limited to the oral cavity. About half the cases are preceded by a prodromal phase that resembles an upper respiratory tract infection. A minority of cases may be associated with medications, but EM is thought to be primarily a hypersensitivity reaction to an infection [27]. The differential diagnosis includes FDE and acute urticaria. Stevens-Johnson syndrome by definition will involve at least two mucosal sites, most often but not limited to the eyes and mouth. Skin manifestations are varied and include erythematous or purpuric macules, classic target lesions, atypical target lesions,
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and flaccid blisters. The prodromal phase may be more severe than EM, characterized by high-grade fever, arthralgias, and malaise. Skin lesions follow shortly after and progress to epidermal necrosis and sloughing that is limited to 10% of the body surface area [28]. Drugs have been associated with approximately 50% of the cases in children, with penicillin, sulfonamides, and anticonvulsants being the most common offenders in both SJS and TEN [29,30]. If clinically appropriate suspect medications should be avoided. When infectious triggers such as mycoplasma are possible these should be treated pending confirmatory cultures and independent SJS risks associated with treatment balanced against optimal management of the potential infection.
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Toxic epidermal necrolysis is the most severe of the three conditions, with at least 30% or more skin surface involvement. Like SJS, the skin lesions of TEN are preceded by a prodrome of fever, sore throat, and malaise, although temperatures are typically higher than those seen with SJS. Skin lesions usually begin as ill-defined erythematous macules with purpuric centers, but 50% of cases actually start with frank erythroderma [28]. Affected skin can be quite painful and at times disproportionate to clinical findings [31]. Rapid progression to blistering and full-thickness epidermal necrosis is the hallmark of this devastating process. Up to 90% of adult cases are due to medications, but this figure is lower in pediatric cases [32].
Drug-induced Acne
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Pustular
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Drug-induced acne is a common adverse drug reaction seen most often in patients taking systemic steroids, antipsychotics, antituberculosis drugs, immunomodulating agents and epidermal growth factor receptor inhibitors [33]. Unlike true acne vulgaris, drug-induced acne is is monomorphic, and tends to involve the trunk and upper extremities with small sterile pustules (Figure 6). Acne-prone individuals appear to be at the highest risk, as prepubescent and elderly patients are rarely affected [1]. Diagnosis is usually straightforward and resolution can take up to weeks after the offending agent is discontinued.
Acute Generalized Exanthematous Pustulosis (AGEP) Acute generalized exanthematous pustulosis (AGEP) is an uncommon drug reaction seen primarily in adults though pediatric cases are increasingly recognized. Numerous etiologies have been reported, including viral infections, mercury hypersensitivity, and vaccinations, but AGEP is thought to be primarily a medication reaction [34]. Patients develop fever and generalized erythema within hours to days of exposure to the offending agent. Widespread, non-follicular, sterile pustules follow.
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Generalized pustular psoriasis can present similarly and must be excluded. The lesions of pustular psoriasis “lake” together in contrast AGEP pustules which tend to be more discrete. Another entity to consider in the differential is Hand-Foot-and-Mouth disease, which is most frequently caused by coxsackievirus A16. Afflicted patients will often develop a fever and sore mouth that is followed by a papular, vesicular or pustular eruption localized primarily on the palms, soles, buttocks and mouth.
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AGEP usually clears within 7 to 10 days following drug withdrawal but patients may develop generalized desquamation. Leukocytosis with neutrophilia, an elevated erythrocyte sedimentation rate and mild eosinophilia may be also present [35]. Importantly, there are no signs of internal organ involvement.
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Beta-lactam and macrolide antibiotics are the most common offenders, although isolated cases have been reported with TMP-SMX, isoniazid, doxycycline, carbamazepine, oral nystatin, methylphenidate, oral ketoconazole and acetaminophen [35-37]. Pathogenesis is incompletely understood though patch testing, which can be used to help detect certain drug allergy diagnoses, suggests a possible delayed-type hypersensitivity reaction[38]. Eruptions are usually self-limiting though a mortality rate as high as 5% has been reported. [39].
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Acral
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Distribution nicely complements morphology in the assessment of some distinctive medication reactions. Acral rashes are important to recognize as they are often alarming to patients and providers. The differential diagnosis includes entities such as Raynaud’s phenomenon, vasculitis, and erythromelalgia all of which may have a challenging work up.
Acrocyanosis Acrocyanosis is symmetric, painless, discoloration of distal extremities that is often accompanied by local hyperhidrosis of the hands and feet [40]. Like Raynaud’s phenomenon, acrocyanosis is thought to be a vasospastic disorder however discoloration and coolness to touch do not improve with warming. [40]. Drugs known to cause acrocyanosis are butylnitrate, interferon- , amphotericin B deoxycholate, and certain vasopressors [41-43]. In the pediatric population, two drugs in particular are worth noting. Propranolol, a non-cardioselective beta-blocker, is increasingly used for the treatment of infantile hemangiomas [44]. Nonselective beta-blockers decrease skin temperature and extremity
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blood flow and in certain individuals, acrocyanosis can develop [45,46]. Thoumazet et al reported several cases of acrocyanosis in their recent propranolol trial for orbital hemangiomas[47]. In our experience acrocyanosis is a common side effect in infants treated with propranolol for hemangioma. If asymptomatic and otherwise well without signs or symptoms of cardiopulmonary compromise then this need not necessarily interrupt treatment.
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Imipramine is a tricyclic antidepressant that is widely used in children and adolescents for the treatment of enuresis, attention deficit hyperactivity disorder (ADHD), depression and anxiety disorder. While anticholingeric and antihistaminic effects are well known side effects of impiramine, acrocyanosis is not. Ayyelbaum and Kapoor reported the first cases of impramine-induced acrocyanosis in children being treated for hyperkinetic and psychotic disorders [48]. More recently, Karakaya et al. reported a case of a 10 year-old-boy being treated for ADHD and primary nocturnal enuresis that developed bluish discoloration and coldness of the hands and feet after the 3rd week of impramine treatment [49]. The cyanosis completely resolved two weeks after impiramine was discontinued.
Chilbains (pernio)
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Chilbains, also known as pernio, is another cause of symmetric discoloration of the digits. Patients will present with symmetric, tender, violaceous papules and plaques most commonly on the dorsal aspects of the fingers and toes [50]. Prolonged exposure of tissue to near-freezing temperatures leading to tissue necrosis and vasomotor instability is thought to be causal[40]. Pernio has also been associated with a number of drugs, many of which have a direct vasoconstrictor effect. Chronic crack-cocaine users can develop what is referred to as “crack hands:” the triad of perniosis, finger pulp atrophy, and clawlike curvature of the nails [51]. Likewise, in pediatric patients, psychostimulants are starting to be reported as causes of pernio. Al Aboud et al. recently reported a case of a 9year-old female with a history of attention deficit hyperactivity disorder (ADHD) that developed bluish toe discoloration six months after being started on extended-release mixed amphetamine salts (Adderall-XR) [52]. The patient experienced complete resolution of her symptoms two weeks after discontinuation of the medication.
Acral Erythema Chemotherapy-induced acral erythema (CIAE) is a distinct drug reaction seen in oncology patients undergoing treatment with high-dose chemotherapy. It is characterized by symmetric, painful, erythema of the palms and soles which may progress to blistering
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and desquamation [53]. Numerous chemotherapeutic agents have been implicated, including 5-fluorouracil, cytarabine, methotrexate, cyclophosphamide, paclitaxel, mercaptopurine, mitotane, hydroxyurea, etoposide, and doxorubicin [54-59]. CIAE has been described primarily in adult patients but the paucity of published pediatric cases underestimates its frequency in our experience. [60,61].
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While cytarabine is the most commonly implicated agent in adults, methotrexate is more common in children [55,62]. The first cases of methotrexate-induced acral erythema were seen in patients receiving high-dose intravenous methotrexate therapy though acral erythema after following oral methotrexate has been reported [61]. Clinical manifestations usually appear within 1 day to 3 weeks of initiation and resolve within 1 to 2 weeks of discontinuation of chemotherapy [53]. Pathogenesis remains unclear though it is most likely a combination of toxic and allergic mechanisms [61]. Treatment is generally supportive, with saline compresses, general wound care, and topical and systemic steroids.
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Psoriasiform
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Drug-induced psoriasis is well documented. Such eruptions may be seen in patients with pre-existing psoriasis, or those without a personal or family history. Lesions typically improve with drug withdrawal though persistent disease is possible [63]. A number of drugs have been reported to cause or exacerbate psoriasis but most frequently cited are -blockers, lithium, antimalarials, nonsteroidal anti-inflammatory agents and tetracyclines [64]. None of these drugs are used to independently treat psoriasis. Conversely, tumor necrosis factor- inhibitors have been shown very effective in the treatment of pediatric psoriasis[65] as well as other inflammatory diseases such as rheumatoid arthritis, ankylosing spondylitis and in particular inflammatory bowel disease. However, there have been numerous reports of new onset or exacerbation of psoriasis[66,67] in patients taking these “biologics” for other indications. Palm and soles involvement is seen frequently (Figure 7). In one case series that analyzed 127 individual reports, a disproportionate 40% of cases resulted in palmoplantar pustulosis [66]. Refractory scalp involvement has also been recently characterized[68]. There have been a number of etiologies proposed to explain the association between TNF- blockade and psoriasis. The most promising one lies in the balance between TNF and INF- , as invitro studies have shown that relative decreases in the former and increases in the latter can lead to induction or worsening of psoriasis[69-71]. An intriguing presentation of drug-induced psoriasis is “napkin” involvement in infants treated with propranolol for hemangiomas. No cases have yet been published but we have seen two such cases develop within weeks of treatment initiation in otherwise
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unaffected infants. In both cases, psoriatic lesions were relatively refractory while on systemic beta- blockade but resolved quickly following drug discontinuation.
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Conclusion
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Pediatric drug eruptions are common and span the spectrum from barely noteworthy (eg morbilliform amoxicillin eruptions in the setting of EBV) to potentially life-threatening TEN. They are frequently confused with viral exanthems and even graft versus host disease in the proper context. Familiarity with common pediatric presentations of drug eruption is essential to avoid therapeutic misdirection.
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42 Campo-Voegeli A, Estrach T, Marti RM, Corominas N, Tuset M, Mascaro JM: Acrocyanosis induced by interferon alpha(2a). Dermatology 1998;196:361-363. 43 Ozaras R, Yemisen M, Mete B, Mert A, Ozturk R, Tabak F: Acrocyanosis developed with amphotericin b deoxycholate but not with amphotericin b lipid complex. Mycoses 2007;50:242. 44 Leaute-Labreze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taieb A: Propranolol for severe hemangiomas of infancy. N Engl J Med 2008;358:2649-2651. 45 Gerber JG, Nies AS: Beta-adrenergic blocking drugs. Annu Rev Med 1985;36:145164. 46 McSorley PD, Warren DJ: Effects of propranolol and metoprolol on the peripheral circulation. Br Med J 1978;2:1598-1600. 47 Thoumazet F, Leaute-Labreze C, Colin J, Mortemousque B: Efficacy of systemic propanolol for severe infantile haemangioma of the orbit and eyelid: A case study of eight patients. Br J Ophthalmol 2011 48 Appelbaum PS, Kapoor W: Imipramine-induced vasospasm: A case report. Am J Psychiatry 1983;140:913-915. 49 Karakaya I, Aydogan M, Coskun A, Gokalp AS: Acrocyanosis as a side effect of tricyclic antidepressants: A case report. Turk J Pediatr 2003;45:155-157. 50 McCleskey PE, Winter KJ, Devillez RL: Tender papules on the hands. Idiopathic chilblains (perniosis). Arch Dermatol 2006;142:1501-1506. 51 Payne-James JJ, Munro MH, Rowland Payne CM: Pseudosclerodermatous triad of perniosis, pulp atrophy and 'parrot-beaked' clawing of the nails--a newly recognized syndrome of chronic crack cocaine use. J Forensic Leg Med 2007;14:65-71. 52 Al Aboud A, Abrams M, Mancini AJ: Blue toes after stimulant therapy for pediatric attention deficit hyperactivity disorder. J Am Acad Dermatol 2011;64:1218-1219. 53 Baack BR, Burgdorf WH: Chemotherapy-induced acral erythema. J Am Acad Dermatol 1991;24:457-461. 54 Tsuruta D, Mochida K, Hamada T, Ishii M, Wakasa K, Hashimoto S, Takekawa KE: Chemotherapy-induced acral erythema: Report of a case and immunohistochemical findings. Clin Exp Dermatol 2000;25:386-388. 55 Waltzer JF, Flowers FP: Bullous variant of chemotherapy-induced acral erythema. Arch Dermatol 1993;129:43-45. 56 Ogawa H, Sugiyama H, Tani Y, Soma T, Yamagami T, Tatekawa T, Oji Y, Kubota T, Kimura T, Inoue K, Nakagawa M, Sasaki K, Matsunashi T, Miyake S, Kishimoto T: High incidence of chemotherapy-induced acral erythema in female patients with non-hodgkin's lymphoma treated with the vacop-b regimen. Leuk Lymphoma 1998;29:171-177. 57 Walker IR, Wilson WE, Sauder DN, Benger AM, Browman G: Cytarabine-induced palmar-plantar erythema. Arch Dermatol 1985;121:1240-1241. 58 Doyle LA, Berg C, Bottino G, Chabner B: Erythema and desquamation after high-dose methotrexate. Ann Intern Med 1983;98:611-612. 59 Ikeda H, Kawano H, Kitaura T, Kimura A, Kihira K: Acral erythema associated with high-dose methotrexate infusion. Ann Pharmacother 1999;33:646. 60 Werchniak AE, Chaffee S, Dinulos JG: Methotrexate-induced bullous acral erythema in a child. J Am Acad Dermatol 2005;52:S93-95. 61 Varela CR, McNamara J, Antaya RJ: Acral erythema with oral methotrexate in a child. Pediatr Dermatol 2007;24:541-546. 62 Millot F, Auriol F, Brecheteau P, Guilhot F: Acral erythema in children receiving highdose methotrexate. Pediatr Dermatol 1999;16:398-400. 63 Tsankov N, Angelova I, Kazandjieva J: Drug-induced psoriasis. Recognition and management. Am J Clin Dermatol 2000;1:159-165.
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64 Dika E, Varotti C, Bardazzi F, Maibach HI: Drug-induced psoriasis: An evidencebased overview and the introduction of psoriatic drug eruption probability score. Cutan Ocul Toxicol 2006;25:1-11. 65 Paller AS, Siegfried EC, Eichenfield LF, Pariser D, Langley RG, Creamer K, Kricorian G: Long-term etanercept in pediatric patients with plaque psoriasis. J Am Acad Dermatol 2010;63:762-768. 66 Ko JM, Gottlieb AB, Kerbleski JF: Induction and exacerbation of psoriasis with tnfblockade therapy: A review and analysis of 127 cases. J Dermatolog Treat 2009;20:100-108. 67 Wollina U, Hansel G, Koch A, Schonlebe J, Kostler E, Haroske G: Tumor necrosis factor-alpha inhibitor-induced psoriasis or psoriasiform exanthemata: First 120 cases from the literature including a series of six new patients. Am J Clin Dermatol 2008;9:1-14. 68 Perman MJ, Lovell DJ, Denson LA, Farrell MK, Lucky AW: Five cases of anti-tumor necrosis factor alpha-induced psoriasis presenting with severe scalp involvement in children. Pediatr Dermatol 2012;29:454-459. 69 de Gannes GC, Ghoreishi M, Pope J, Russell A, Bell D, Adams S, Shojania K, Martinka M, Dutz JP: Psoriasis and pustular dermatitis triggered by tnf-{alpha} inhibitors in patients with rheumatologic conditions. Arch Dermatol 2007;143:223-231. 70 Hida S, Ogasawara K, Sato K, Abe M, Takayanagi H, Yokochi T, Sato T, Hirose S, Shirai T, Taki S, Taniguchi T: Cd8(+) t cell-mediated skin disease in mice lacking irf-2, the transcriptional attenuator of interferon-alpha/beta signaling. Immunity 2000;13:643-655. 71 Nestle FO, Conrad C, Tun-Kyi A, Homey B, Gombert M, Boyman O, Burg G, Liu YJ, Gilliet M: Plasmacytoid predendritic cells initiate psoriasis through interferon-alpha production. J Exp Med 2005;202:135-143.
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Figure 2 Marginated erythematous polycyclic plaques on trunk in a child with Serum Sickness like Reaction (SSLR) to ceclor Figure 3 Polycylic urticarial plaques with ecchymotic centers in Giant Urticaria due to Augmentin
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Figure 4 Diffuse, annular, vesicular plaques in a child with Linear IgA Bullous Dermatosis secondary to vancomycin
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Figure 5 Classic target lesion on dorsal hand in child with Erythema Multiforme Figure 6 Monomorphic truncal pustules secondary to Steroid Acne
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Figure 7 Plantar psoriasis induced by TNF-a inhibitor therapy for Crohns disease
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S0738-081X(14)00039-X doi: 10.1016/j.clindermatol.2014.02.005 CID 6822
To appear in:
Clinics in Dermatology
Please cite this article as: Song James E., Sidbury Robert, An update on pediatric cutaneous drug eruptions, Clinics in Dermatology (2014), doi: 10.1016/j.clindermatol.2014.02.005
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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James E Song, MD* Department of Dermatology University of California, Irvine 1002 Health Sciences Rd Irvine, CA 92612 Phone: (847) 312-7000 [email protected]
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AN UPDATE ON PEDIATRIC CUTANEOUS DRUG ERUPTIONS
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Robert Sidbury, MD, MPH Department of Pediatrics Division of Dermatology Seattle Children’s Hospital University of Washington School of Medicine Box 359300 – A7916 Seattle, WA 98105 Phone: (206) 987-2158 Fax: (206) 987-2217 [email protected] *Corresponding Author
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Abstract
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One of the early lessons learned in dermatology training is “any drug, any rash.” This maxim quickly summarizes the vast array of cutaneous reactions that can be seen in response to systemic medications. Herein we will review common and unusual drug eruptions in pediatric patients that span the morphologic spectrum. These reactions can have an equally broad range of severity, from harmless to lethal, and by the end of this article the reader will be better equipped to sort one from the other.
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Introduction
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The list of drug-related cutaneous reactions can be daunting, even for the experienced dermatologist, as there have been over 25 different patterns described in the literature [1]. A systematic assessment is essential to efficiently and effectively winnow this imposing list into a practical recommendation when drug eruption is in the clinical differential. Sorting by morphology, including morbilliform, urticarial, bullous, pustular and psoriasiform, is one approach; sorting by distribution another. While not exhaustive, we will touch on some of the more common patterns and highlight new and unusual presentations in the literature. Morbilliform
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Morbilliform, also known as “maculopapular” or “exanthematous”, drug eruptions are the most common morphologic type seen in children [1]. Eruptions typically occur within the first week of exposure to the offending agent. Some patients may react after their initial exposure, while others can develop it after years of having used the same medication without complication Morbilliform drug eruptions present as widespread pink to salmon-colored macules and papules that usually start on the head, neck or upper trunk then spread symmetrically downward and become confluent (Figure 1). Patients may complain of pruritus though it is not uncommon to be completely asymptomatic. Virtually any drug can cause a morbilliform drug reaction but beta-lactam antibiotics have been most frequently implicated. Viral infection may increase the likelihood of developing a cutaneous drug reaction. Up to 95% of patients who have an active Epstein-Barr virus (EBV) infection will develop a moribilliform eruption when treated with ampicillin [2]. In part because clinicians are keen to “first, do no harm” drug allergy labels are often assigned without obvious indication because even a small chance of an avoidable drug reaction seems too high. The problem arises in chronically ill children who can quickly amass a clinically constraining list of “allergies.” One strategy gaining traction is
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the use of terms like “probable” or “possible” drug allergy when there is doubt. This may help clinicians to best weigh the risk-benefit ratio of future drug re-challenge. Urticarial
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Acute Drug-induced Urticaria
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Drug-induced urticaria comprises approximately 5% of all cutaneous drug eruptions, making it the second most common type of skin eruption [3]. Lesions are usually pruritic and appear as raised, edematous papules and plaques with central pallor. Some patients have only scattered lesions, while others generalize. Angioedema can accompany these urticarial eruptions and is most easily appreciated around the eyes, lips, and mucous membranes.
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The hallmark feature of acute drug-induced urticaria is its evanescent nature. Lesions should last less than 48 hours, although new lesions may continue to arise. Lesions that last longer than 24-48 hours should expand the differential and may indicate skin biopsy to rule out other considerations including urticarial vasculitis. Immunologic and non-immunologic mechanisms are involved in urticarial drug reactions. Type I IgEmediated hypersensitivity reaction accounts for the majority of urticarial eruptions and are most often elicited by penicillin or derivatives [4]. Non-immunologic mechanisms, as seen with narcotic analgesics and radio-contrast media, may also cause urticarial eruptions,
Serum Sickness Like Reaction
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When an urticarial eruption is accompanied by systemic findings, a serumsickness like reaction (SSLR) must be considered. Patients present with skin rash, fever, and arthralgia within 7 to 21 days of exposure to the causative agent [5,6]. Periocular edema is common and the rash may have a strikingly ecchymotic appearance (Figure 2). Lymphadenopathy and eosinophilia may also be present. Unlike true-serum sickness, SSLR is not a type III reaction, and therefore, correspondingly frank arthritis, hypocomplementemia, vasculitis, or nephropathy are not typically seen. Cefaclor is the most commonly implicated drug, with an estimated risk of 0.024% to 0.2% [6]. With the exception of cefprozil, no cross-reactivity with other cephalosporins has been reported [7]. Treatment involves withdrawal of the offending medication or trigger as able, supportive care including antihistamines for itch if helpful, and systemic steroids may be required if joint symptoms are limiting.
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Giant Urticaria
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Facial or acral edema Associated symptoms Common Trigers
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Mucous Membrane involvement
< 24 hrs Trunk, extremities, face Oral edema common, no erosions or blisters + Pruritus
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Duration of lesions Location
Erythema Multifrome Days to weeks Palms, soles
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Giant Urticaria
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Giant urticaria is a distinctive morphologic form of urticaria that generally occurs in children aged 1-5 years old. Lesions are characterized by annular, arcuate, and polycylic wheals with associated angioedema (Figure 3). Giant urticaria has long been mistaken for erythema multiforme (EM) on account of its distinctive targetoid morphology. Accordingly, Shah et al proposed the term “urticaria multiforme” to help promote this important distinction [8]. Giant urticaria may also be mistaken for SSLR when fever and acral edema accompany the skin eruption and discrimination may not be possible though the duration of the lesions may be informative. Unlike SSLR and EM, the lesions in giant urticaria do not last more than 24-48 hours. Systemic antibiotics and antipyretics have been the most frequently reported offenders [9,10] though giant urticaria most often occurs in the wake of a viral illness.
Antibiotics, immunizations, viral illnesses
Erosions and blisters may be present Pruritus, burning HSV, mycoplasma
Serum Sickness-Like Reactions Days to weeks Trunk, extremities, face, hands and feet Oral edema common, no erosions or blisters + Lympadenopathy, arthralgia, myalgia Antibiotics
*Adapted from Shah et al. Table 1. Distinguishing features of Giant Urticaria, Erythema Multiforme, and Serum Sickness-Like Reactions Bullous Fixed Drug Eruptions Fixed drug eruptions (FDE) are characterized by the development of lesions in the same anatomic location after challenge with an offending agent. Lesions appear as sharply demarcated, round-to-oval shaped, dusky, gunmetal colored plaques that may include a central blister. FDE’s have a predilection for the genitalia, perianal area, lips, and the hands and feet, although anybody surface can be affected. When the genitalia are involved, the diagnosis may be obscured by the child’s inability to specifically express
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their symptoms. Pruritus, restlessness, urinary retention, or painful micturition may be their only complaints [11]. As such, the clinician needs a high index of suspicion to make the diagnosis and should always consider FDEs as a potential organic mimic of child abuse.
Linear IgA Bullous Dermatosis
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Numerous drugs have been reported to cause FDEs but the most common are sulfonamides, antipyretics (acetaminophen), analgesics (ibuprofen) and antibiotics [12]. In children, phenobarbital, hydroxyzine, methylphenidate, and rifampin have also been reported [11,13-15]. The drug most frequently reported to cause FDE in all age groups is trimethoprim-sulfamethoxazole (TMP-SMX) [16]. In one study, TMP-SMX was the culprit in over 50% of the children studied [17]. Patients may present weeks to months after the blisters have appeared, leaving them only with a non-specific hyperpigmented patch.
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Linear IgA bullous dermatosis (LABD) is a rare autoimmune subepidermal blistering disorder that is characterized by linear deposition of IgA along the basement membrane zone [18]. Peak incidence is seen in preschoolers and adults over the age of sixty. The classic picture is a cluster of tense bullae arranged in an annular configuration over an urticarial base, often likened to a “crown of jewels” (Figure 4). The flexural and extensor surfaces, torso and oral mucosa can be involved, giving them an appearance that may be clinically indistinguishable from bullous pemphigoid, erythema multiforme, and dermatitis herpetiformis. As with FDE, groin involvement is common in LABD and should be ruled out when child abuse is considered. Up to two-thirds of cases have been associated with a drug etiology, with vancomycin being the classic example [18]. Non-steroidal anti-inflammatory drugs (NSAIDs), other antibiotics, diuretics, and anti-eplieptics have also been reported in adults, though not as well documented in children [19]. Trimethoprim-sulfamethoxazole and amoxicillin-clavulanic acid have both been recently reported to cause LABD in children [18,20]. Compared to the idiopathic form of LABD, drug-induced forms have a more predictable course with resolution within weeks of withdrawal of the offending agent and a lower incidence of mucosal involvement [21].
Pseudoporphyria Pseudoporphyria (PP) is an uncommon drug-induced blistering eruption [6]. PP may resemble porphyria cutanea tarda (PCT) with photodistributed vesicles and bullae,
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increased skin fragility, and scarring involving the dorsum of the hands and forearms and distinction may require porphyrin studies. Alternatively it may present like erythropoietic protoporphyria (EPP) with erythema, burning, angular cicatrix formation and thickened skin texture, particularly on the face [22]. Naproxen is the most frequent offender and is of particular interest because of its use in patients with juvenile arthritis. A prospective study by Lang et. al found that 12% of patients who were being treated for juvenile idiopathic arthritis (JIA) with naproxen for at least 4 weeks developed EPP-like PP [23]. Interestingly, blue/gray eye color has been found to be an independent risk factor for PP and therefore must be used with caution in such patients. [24].
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Coma blisters are uncommon skin eruptions that are seen in patients with impaired consciousness. The original case was described in a patient who was heavily sedated due to barbiturate intoxication [25]. Since then, other anticonvulsants have been reported, including certain benzodiazepines such as clobazam, and valproic acid [26]. These blisters are most often seen in pressure areas, particularly over bony prominences. The key histological feature that defines coma blisters is eccrine necrosis. Until recently, coma blisters were thought to be a self-limiting process that did not require withdrawal of the offending agent. Basu et al., however, reported a 9-year-old boy with biopsy proven coma blisters that continued to develop worsening lesions until the culprit was completely removed [26].
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Erythema multiforme/Stevens Johnson syndrome/Toxic epidermal necrolysis Controversy still exists whether erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and Toxic Epidermal Necrolysis (TEN) are related conditions on a spectrum or separate entities. Erythema multiforme (EM) classically presents as symmetric, target-shaped, edematous papules that involve the acral surfaces (Figure 5). These lesions will have three distinct zones of color, sometimes with a central blister. Mucosal involvement can be seen, although it is usually mild and limited to the oral cavity. About half the cases are preceded by a prodromal phase that resembles an upper respiratory tract infection. A minority of cases may be associated with medications, but EM is thought to be primarily a hypersensitivity reaction to an infection [27]. The differential diagnosis includes FDE and acute urticaria. Stevens-Johnson syndrome by definition will involve at least two mucosal sites, most often but not limited to the eyes and mouth. Skin manifestations are varied and include erythematous or purpuric macules, classic target lesions, atypical target lesions,
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and flaccid blisters. The prodromal phase may be more severe than EM, characterized by high-grade fever, arthralgias, and malaise. Skin lesions follow shortly after and progress to epidermal necrosis and sloughing that is limited to 10% of the body surface area [28]. Drugs have been associated with approximately 50% of the cases in children, with penicillin, sulfonamides, and anticonvulsants being the most common offenders in both SJS and TEN [29,30]. If clinically appropriate suspect medications should be avoided. When infectious triggers such as mycoplasma are possible these should be treated pending confirmatory cultures and independent SJS risks associated with treatment balanced against optimal management of the potential infection.
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Toxic epidermal necrolysis is the most severe of the three conditions, with at least 30% or more skin surface involvement. Like SJS, the skin lesions of TEN are preceded by a prodrome of fever, sore throat, and malaise, although temperatures are typically higher than those seen with SJS. Skin lesions usually begin as ill-defined erythematous macules with purpuric centers, but 50% of cases actually start with frank erythroderma [28]. Affected skin can be quite painful and at times disproportionate to clinical findings [31]. Rapid progression to blistering and full-thickness epidermal necrosis is the hallmark of this devastating process. Up to 90% of adult cases are due to medications, but this figure is lower in pediatric cases [32].
Drug-induced Acne
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Pustular
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Drug-induced acne is a common adverse drug reaction seen most often in patients taking systemic steroids, antipsychotics, antituberculosis drugs, immunomodulating agents and epidermal growth factor receptor inhibitors [33]. Unlike true acne vulgaris, drug-induced acne is is monomorphic, and tends to involve the trunk and upper extremities with small sterile pustules (Figure 6). Acne-prone individuals appear to be at the highest risk, as prepubescent and elderly patients are rarely affected [1]. Diagnosis is usually straightforward and resolution can take up to weeks after the offending agent is discontinued.
Acute Generalized Exanthematous Pustulosis (AGEP) Acute generalized exanthematous pustulosis (AGEP) is an uncommon drug reaction seen primarily in adults though pediatric cases are increasingly recognized. Numerous etiologies have been reported, including viral infections, mercury hypersensitivity, and vaccinations, but AGEP is thought to be primarily a medication reaction [34]. Patients develop fever and generalized erythema within hours to days of exposure to the offending agent. Widespread, non-follicular, sterile pustules follow.
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Generalized pustular psoriasis can present similarly and must be excluded. The lesions of pustular psoriasis “lake” together in contrast AGEP pustules which tend to be more discrete. Another entity to consider in the differential is Hand-Foot-and-Mouth disease, which is most frequently caused by coxsackievirus A16. Afflicted patients will often develop a fever and sore mouth that is followed by a papular, vesicular or pustular eruption localized primarily on the palms, soles, buttocks and mouth.
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AGEP usually clears within 7 to 10 days following drug withdrawal but patients may develop generalized desquamation. Leukocytosis with neutrophilia, an elevated erythrocyte sedimentation rate and mild eosinophilia may be also present [35]. Importantly, there are no signs of internal organ involvement.
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Beta-lactam and macrolide antibiotics are the most common offenders, although isolated cases have been reported with TMP-SMX, isoniazid, doxycycline, carbamazepine, oral nystatin, methylphenidate, oral ketoconazole and acetaminophen [35-37]. Pathogenesis is incompletely understood though patch testing, which can be used to help detect certain drug allergy diagnoses, suggests a possible delayed-type hypersensitivity reaction[38]. Eruptions are usually self-limiting though a mortality rate as high as 5% has been reported. [39].
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Acral
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Distribution nicely complements morphology in the assessment of some distinctive medication reactions. Acral rashes are important to recognize as they are often alarming to patients and providers. The differential diagnosis includes entities such as Raynaud’s phenomenon, vasculitis, and erythromelalgia all of which may have a challenging work up.
Acrocyanosis Acrocyanosis is symmetric, painless, discoloration of distal extremities that is often accompanied by local hyperhidrosis of the hands and feet [40]. Like Raynaud’s phenomenon, acrocyanosis is thought to be a vasospastic disorder however discoloration and coolness to touch do not improve with warming. [40]. Drugs known to cause acrocyanosis are butylnitrate, interferon- , amphotericin B deoxycholate, and certain vasopressors [41-43]. In the pediatric population, two drugs in particular are worth noting. Propranolol, a non-cardioselective beta-blocker, is increasingly used for the treatment of infantile hemangiomas [44]. Nonselective beta-blockers decrease skin temperature and extremity
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blood flow and in certain individuals, acrocyanosis can develop [45,46]. Thoumazet et al reported several cases of acrocyanosis in their recent propranolol trial for orbital hemangiomas[47]. In our experience acrocyanosis is a common side effect in infants treated with propranolol for hemangioma. If asymptomatic and otherwise well without signs or symptoms of cardiopulmonary compromise then this need not necessarily interrupt treatment.
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Imipramine is a tricyclic antidepressant that is widely used in children and adolescents for the treatment of enuresis, attention deficit hyperactivity disorder (ADHD), depression and anxiety disorder. While anticholingeric and antihistaminic effects are well known side effects of impiramine, acrocyanosis is not. Ayyelbaum and Kapoor reported the first cases of impramine-induced acrocyanosis in children being treated for hyperkinetic and psychotic disorders [48]. More recently, Karakaya et al. reported a case of a 10 year-old-boy being treated for ADHD and primary nocturnal enuresis that developed bluish discoloration and coldness of the hands and feet after the 3rd week of impramine treatment [49]. The cyanosis completely resolved two weeks after impiramine was discontinued.
Chilbains (pernio)
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Chilbains, also known as pernio, is another cause of symmetric discoloration of the digits. Patients will present with symmetric, tender, violaceous papules and plaques most commonly on the dorsal aspects of the fingers and toes [50]. Prolonged exposure of tissue to near-freezing temperatures leading to tissue necrosis and vasomotor instability is thought to be causal[40]. Pernio has also been associated with a number of drugs, many of which have a direct vasoconstrictor effect. Chronic crack-cocaine users can develop what is referred to as “crack hands:” the triad of perniosis, finger pulp atrophy, and clawlike curvature of the nails [51]. Likewise, in pediatric patients, psychostimulants are starting to be reported as causes of pernio. Al Aboud et al. recently reported a case of a 9year-old female with a history of attention deficit hyperactivity disorder (ADHD) that developed bluish toe discoloration six months after being started on extended-release mixed amphetamine salts (Adderall-XR) [52]. The patient experienced complete resolution of her symptoms two weeks after discontinuation of the medication.
Acral Erythema Chemotherapy-induced acral erythema (CIAE) is a distinct drug reaction seen in oncology patients undergoing treatment with high-dose chemotherapy. It is characterized by symmetric, painful, erythema of the palms and soles which may progress to blistering
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and desquamation [53]. Numerous chemotherapeutic agents have been implicated, including 5-fluorouracil, cytarabine, methotrexate, cyclophosphamide, paclitaxel, mercaptopurine, mitotane, hydroxyurea, etoposide, and doxorubicin [54-59]. CIAE has been described primarily in adult patients but the paucity of published pediatric cases underestimates its frequency in our experience. [60,61].
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While cytarabine is the most commonly implicated agent in adults, methotrexate is more common in children [55,62]. The first cases of methotrexate-induced acral erythema were seen in patients receiving high-dose intravenous methotrexate therapy though acral erythema after following oral methotrexate has been reported [61]. Clinical manifestations usually appear within 1 day to 3 weeks of initiation and resolve within 1 to 2 weeks of discontinuation of chemotherapy [53]. Pathogenesis remains unclear though it is most likely a combination of toxic and allergic mechanisms [61]. Treatment is generally supportive, with saline compresses, general wound care, and topical and systemic steroids.
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Psoriasiform
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Drug-induced psoriasis is well documented. Such eruptions may be seen in patients with pre-existing psoriasis, or those without a personal or family history. Lesions typically improve with drug withdrawal though persistent disease is possible [63]. A number of drugs have been reported to cause or exacerbate psoriasis but most frequently cited are -blockers, lithium, antimalarials, nonsteroidal anti-inflammatory agents and tetracyclines [64]. None of these drugs are used to independently treat psoriasis. Conversely, tumor necrosis factor- inhibitors have been shown very effective in the treatment of pediatric psoriasis[65] as well as other inflammatory diseases such as rheumatoid arthritis, ankylosing spondylitis and in particular inflammatory bowel disease. However, there have been numerous reports of new onset or exacerbation of psoriasis[66,67] in patients taking these “biologics” for other indications. Palm and soles involvement is seen frequently (Figure 7). In one case series that analyzed 127 individual reports, a disproportionate 40% of cases resulted in palmoplantar pustulosis [66]. Refractory scalp involvement has also been recently characterized[68]. There have been a number of etiologies proposed to explain the association between TNF- blockade and psoriasis. The most promising one lies in the balance between TNF and INF- , as invitro studies have shown that relative decreases in the former and increases in the latter can lead to induction or worsening of psoriasis[69-71]. An intriguing presentation of drug-induced psoriasis is “napkin” involvement in infants treated with propranolol for hemangiomas. No cases have yet been published but we have seen two such cases develop within weeks of treatment initiation in otherwise
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unaffected infants. In both cases, psoriatic lesions were relatively refractory while on systemic beta- blockade but resolved quickly following drug discontinuation.
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Conclusion
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Pediatric drug eruptions are common and span the spectrum from barely noteworthy (eg morbilliform amoxicillin eruptions in the setting of EBV) to potentially life-threatening TEN. They are frequently confused with viral exanthems and even graft versus host disease in the proper context. Familiarity with common pediatric presentations of drug eruption is essential to avoid therapeutic misdirection.
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References
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42 Campo-Voegeli A, Estrach T, Marti RM, Corominas N, Tuset M, Mascaro JM: Acrocyanosis induced by interferon alpha(2a). Dermatology 1998;196:361-363. 43 Ozaras R, Yemisen M, Mete B, Mert A, Ozturk R, Tabak F: Acrocyanosis developed with amphotericin b deoxycholate but not with amphotericin b lipid complex. Mycoses 2007;50:242. 44 Leaute-Labreze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taieb A: Propranolol for severe hemangiomas of infancy. N Engl J Med 2008;358:2649-2651. 45 Gerber JG, Nies AS: Beta-adrenergic blocking drugs. Annu Rev Med 1985;36:145164. 46 McSorley PD, Warren DJ: Effects of propranolol and metoprolol on the peripheral circulation. Br Med J 1978;2:1598-1600. 47 Thoumazet F, Leaute-Labreze C, Colin J, Mortemousque B: Efficacy of systemic propanolol for severe infantile haemangioma of the orbit and eyelid: A case study of eight patients. Br J Ophthalmol 2011 48 Appelbaum PS, Kapoor W: Imipramine-induced vasospasm: A case report. Am J Psychiatry 1983;140:913-915. 49 Karakaya I, Aydogan M, Coskun A, Gokalp AS: Acrocyanosis as a side effect of tricyclic antidepressants: A case report. Turk J Pediatr 2003;45:155-157. 50 McCleskey PE, Winter KJ, Devillez RL: Tender papules on the hands. Idiopathic chilblains (perniosis). Arch Dermatol 2006;142:1501-1506. 51 Payne-James JJ, Munro MH, Rowland Payne CM: Pseudosclerodermatous triad of perniosis, pulp atrophy and 'parrot-beaked' clawing of the nails--a newly recognized syndrome of chronic crack cocaine use. J Forensic Leg Med 2007;14:65-71. 52 Al Aboud A, Abrams M, Mancini AJ: Blue toes after stimulant therapy for pediatric attention deficit hyperactivity disorder. J Am Acad Dermatol 2011;64:1218-1219. 53 Baack BR, Burgdorf WH: Chemotherapy-induced acral erythema. J Am Acad Dermatol 1991;24:457-461. 54 Tsuruta D, Mochida K, Hamada T, Ishii M, Wakasa K, Hashimoto S, Takekawa KE: Chemotherapy-induced acral erythema: Report of a case and immunohistochemical findings. Clin Exp Dermatol 2000;25:386-388. 55 Waltzer JF, Flowers FP: Bullous variant of chemotherapy-induced acral erythema. Arch Dermatol 1993;129:43-45. 56 Ogawa H, Sugiyama H, Tani Y, Soma T, Yamagami T, Tatekawa T, Oji Y, Kubota T, Kimura T, Inoue K, Nakagawa M, Sasaki K, Matsunashi T, Miyake S, Kishimoto T: High incidence of chemotherapy-induced acral erythema in female patients with non-hodgkin's lymphoma treated with the vacop-b regimen. Leuk Lymphoma 1998;29:171-177. 57 Walker IR, Wilson WE, Sauder DN, Benger AM, Browman G: Cytarabine-induced palmar-plantar erythema. Arch Dermatol 1985;121:1240-1241. 58 Doyle LA, Berg C, Bottino G, Chabner B: Erythema and desquamation after high-dose methotrexate. Ann Intern Med 1983;98:611-612. 59 Ikeda H, Kawano H, Kitaura T, Kimura A, Kihira K: Acral erythema associated with high-dose methotrexate infusion. Ann Pharmacother 1999;33:646. 60 Werchniak AE, Chaffee S, Dinulos JG: Methotrexate-induced bullous acral erythema in a child. J Am Acad Dermatol 2005;52:S93-95. 61 Varela CR, McNamara J, Antaya RJ: Acral erythema with oral methotrexate in a child. Pediatr Dermatol 2007;24:541-546. 62 Millot F, Auriol F, Brecheteau P, Guilhot F: Acral erythema in children receiving highdose methotrexate. Pediatr Dermatol 1999;16:398-400. 63 Tsankov N, Angelova I, Kazandjieva J: Drug-induced psoriasis. Recognition and management. Am J Clin Dermatol 2000;1:159-165.
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64 Dika E, Varotti C, Bardazzi F, Maibach HI: Drug-induced psoriasis: An evidencebased overview and the introduction of psoriatic drug eruption probability score. Cutan Ocul Toxicol 2006;25:1-11. 65 Paller AS, Siegfried EC, Eichenfield LF, Pariser D, Langley RG, Creamer K, Kricorian G: Long-term etanercept in pediatric patients with plaque psoriasis. J Am Acad Dermatol 2010;63:762-768. 66 Ko JM, Gottlieb AB, Kerbleski JF: Induction and exacerbation of psoriasis with tnfblockade therapy: A review and analysis of 127 cases. J Dermatolog Treat 2009;20:100-108. 67 Wollina U, Hansel G, Koch A, Schonlebe J, Kostler E, Haroske G: Tumor necrosis factor-alpha inhibitor-induced psoriasis or psoriasiform exanthemata: First 120 cases from the literature including a series of six new patients. Am J Clin Dermatol 2008;9:1-14. 68 Perman MJ, Lovell DJ, Denson LA, Farrell MK, Lucky AW: Five cases of anti-tumor necrosis factor alpha-induced psoriasis presenting with severe scalp involvement in children. Pediatr Dermatol 2012;29:454-459. 69 de Gannes GC, Ghoreishi M, Pope J, Russell A, Bell D, Adams S, Shojania K, Martinka M, Dutz JP: Psoriasis and pustular dermatitis triggered by tnf-{alpha} inhibitors in patients with rheumatologic conditions. Arch Dermatol 2007;143:223-231. 70 Hida S, Ogasawara K, Sato K, Abe M, Takayanagi H, Yokochi T, Sato T, Hirose S, Shirai T, Taki S, Taniguchi T: Cd8(+) t cell-mediated skin disease in mice lacking irf-2, the transcriptional attenuator of interferon-alpha/beta signaling. Immunity 2000;13:643-655. 71 Nestle FO, Conrad C, Tun-Kyi A, Homey B, Gombert M, Boyman O, Burg G, Liu YJ, Gilliet M: Plasmacytoid predendritic cells initiate psoriasis through interferon-alpha production. J Exp Med 2005;202:135-143.
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Figure 2 Marginated erythematous polycyclic plaques on trunk in a child with Serum Sickness like Reaction (SSLR) to ceclor Figure 3 Polycylic urticarial plaques with ecchymotic centers in Giant Urticaria due to Augmentin
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Figure 4 Diffuse, annular, vesicular plaques in a child with Linear IgA Bullous Dermatosis secondary to vancomycin
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Figure 5 Classic target lesion on dorsal hand in child with Erythema Multiforme Figure 6 Monomorphic truncal pustules secondary to Steroid Acne
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Figure 7 Plantar psoriasis induced by TNF-a inhibitor therapy for Crohns disease
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