Robin P. Gehris, MD

"Drug rash" is a common pediatric complaint in both inpatient and outpatient settings. This term, however, denotes a clinical category and is not a precise diagnosis. Proper identification and classification of drug eruptions in children are important for determining the possibility of-and preventing progression to-internal involvement. Accurate identification is also important so that patients and their parents can be counseled to avoid future problematic drug exposures.

In this article, we provide pertinent information about several cutaneous drug reactions encountered in clinical practice. We emphasize those clinical features that are especially important for clinicians who may be diagnosing and managing these classic eruptions in the pediatric population.

GENERAL APPROACH TO A SUSPECTED DRUG ERUPTION

A detailed history is essential to establish the temporal relationship of the eruption to prior drug exposure and exposure to cross-reacting medications. It is also important to be aware of patterns of drug metabolism, interactions, and toxicities.


	Figure 1 – The exanthematous drug eruption in this child demonstrates confluent areas of morbilliform erythema with small white areas of sparing.

 The most common drug eruptions in children are morbilliform or exanthematous reactions.

 Onset can be anywhere from 1 to 2 weeks following medication administration and may occur or persist even after the responsible drug is discontinued, especially when that drug has a prolonged half-life. The time from medication administration to onset of the drug eruption is reduced with rechallenge.

Note that the likelihood of a reaction occurring is increased in patients who have a coexisting viral infection. Some have hypothesized that the presence of the viral infection may induce the body's immune system to respond to the drug differently than it normally would, thereby increasing the risk of a reaction.

 The agents that most frequently cause exanthematous drug eruptions are anticonvulsants and antibiotics. Medications that have been implicated include penicillins,

 These eruptions consist of erythematous flat macules and papules that begin on the trunk and extend in a symmetrical fashion to become generalized (

). The palms and soles are often affected, but mucous membranes are spared. After 1 to 2 weeks, the erythema darkens and superficial layers of skin may desquamate, resulting in residual dyspigmentation. Patients may complain of fever and pruritus, but they generally appear nontoxic and healthy.

 In addition to an exanthematous drug eruption, consider viral exanthems with palmoplantar involvement as well as toxic shock syndrome and Kawasaki disease

; however, these last 2 entities are typically accompanied by fever and irritability or other systemic signs, such as hemodynamic instability. It is especially important to distinguish between an exanthematous drug eruption and drug hypersensitivity syndrome, also known as drug reaction with eosinophilia and systemic symptoms (DRESS). In DRESS, a similar rash is accompanied by systemic symptoms and possibly elevated transaminase levels; thus, we recommend obtaining a complete blood cell (CBC) count and a hepatic function panel in any patient with an extensive exanthematous drug eruption who has a fever or any other systemic symptoms to rule out this entity. For more information, see the discussion of DRESS below. In patients in whom there are no liver function test abnormalities, the diagnosis of an exanthematous drug eruption is typically made empirically, on the basis of the clinical picture and a suggestive history of medication use.

 In patients with exanthematous drug eruptions, treatment is supportive. Discontinue the offending drug, and use antihistamines, mild topical corticosteroids, and bland emollients as needed for pruritus. Pigmentary changes will resolve with time and sun avoidance.


	Figure 2 – The urticarial drug eruption in this patient consists of polycyclic wheals with no bruising.

 Many patients experience urticaria, or hives, at some point in their lifetimes; in about 10% of cases, medications are to blame.

 Urticarial eruptions are a type I hypersensitivity reaction. Acute urticaria is defined by the presence of hives, or wheals, for a total duration of less than 6 weeks. Most cases of urticaria in children appear to have an infectious origin (viral, bacterial, or airborne fungal)

; the next most common causes-both far less common than infection-are drugs and foods.

 In children younger than 6 months, a medication is the least likely cause.

 The most common pharmacological causes of acute urticaria are penicillins,

 Individual lesions develop within hours to days of the drug exposure and usually last less than 24 hours in a given location, instead migrating to different locations each day. Patients have transient, well-circumscribed, erythematous edematous wheals of variable shapes and sizes on the skin and mucous membranes, with associated intense pruritus (

). The hives may be concentrated on the trunk and proximal extremities or become generalized. The lesions commonly resolve in 1 to 2 weeks, assuming the offending drug has been discontinued; they do not produce residual bruising or tenderness.


	Figure 3 – In this urticarial drug eruption, the wheals have central pallor but lack the 3 distinct zones of color change that are typically seen in erythema multiforme.

 The 2 entities in the differential diagnosis of an urticarial drug eruption to which it is most important to give careful consideration are erythema multiforme and urticarial vasculitis. It has been our experience that erythema multiforme is incorrectly diagnosed in many patients with an urticarial drug eruption because the edema from the urticaria can result in some surrounding pallor and some central pallor or duskiness, which can appear-falsely-to be a type of targetoid pattern (

). Such an appearance should not be confused with the 3 distinct zones of color change that occur in erythema multiforme (

), which usually results from reactivated herpes simplex virus type 1 rather than from drug ingestion. In addition, children with urticarial drug eruptions seldom have oral or mucosal lesions, while such lesions may be seen in children with erythema multiforme-and the lesions of erythema multiforme tend to remain fixed over a 24-hour period, while those of urticarial drug eruptions tend to migrate from day to day. A biopsy or consultation with a dermatological specialist can also help distinguish between the 2 entities.


	Figure 4 – In this erythema multiforme lesion, 3 distinct zones of color change are evident.

Urticarial vasculitis and urticarial drug eruptions differ in that the lesions of an urticarial drug eruption tend to migrate within 24 hours, are unaccompanied by pain or tenderness, and heal without bruising-whereas in urticarial vasculitis, joint pain and rheumatologic symptoms can also be seen, a burning sensation is more common, and the hives have a dusky purpuric center and usually resolve with postinflammatory dyspigmentation. Although drugs are sometimes implicated in urticarial vasculitis, the condition is most often idiopathic; other causes include infections, autoimmune processes, and neoplastic processes. When distinguishing between urticarial vasculitis and urticarial drug eruption on the basis of clinical clues proves difficult, a CBC count, sedimentation rate, urinalysis, and skin biopsy can be helpful.

 In patients with urticarial drug eruptions, treatment is symptomatic. Discontinue the causative medication, and treat with oral antihistamines and bland emollients until the eruption has completely subsided. In severe cases, oral corticosteroids may have a role. However, we recommend a several-day trial of antihistamines before concluding that a patient requires oral corticosteroids, since the majority of patients improve over several days simply from discontinuation of the offending drug and antihistamine therapy.

 This is a self-limited allergic reaction with rash and systemic symptoms. Unlike true serum sickness, which is a type III hypersensitivity reaction, SSLR has not been associated with vasculitis, renal disease, low complement levels, or circulating immune complexes.

 Onset of SSLR is usually 1 to 3 weeks after drug exposure, with resolution 2 to 3 weeks after discontinuation.

 The most common causative agent is cefaclor.

 One retrospective study by Ibia and colleagues

 confirmed that cefaclor caused more cutaneous eruptions and SSLR than other antibiotics in a private pediatric practice. Less commonly encountered triggers include penicillins,

 No crossreactivity has been documented in SSLR between cefaclor and other cephalosporins.

 The eruption of SSLR may be morbilliform, urticarial, or purpuric, although typically the lesions are urticarial with a lilac or dusky center. Fever, malaise, arthralgias/arthritis, lymphadenopathy, splenomegaly, and peripheral eosinophilia may also develop.

 Oral antihistamines and corticosteroids are indicated on an "as-needed" basis for severe systemic symptoms.

 This is a pseudoallergic reaction and the most common adverse drug reaction associated with vancomycin infusion. Because it is not a true allergy, red man syndrome may occur after the first dose. Note that it is very rare for patients to have a true IgE-mediated anaphylactic reaction to vancomycin.

 Patients in whom red man syndrome develops have erythema and facial flushing that may progress to erythroderma or urticaria.

 Red man syndrome can be prevented by pretreating with oral or parenteral antihistamines and decreasing the rate of vancomycin infusion.

 Certain medications may cause dose-dependent non–immune-mediated cell damage in the skin with exposure to sunlight.

 Doxycycline is a commonly encountered cause of phototoxicity in children. Onset is usually within 30 minutes of UV radiation exposure in patients receiving systemic therapy.

 Other drugs that can cause phototoxic reactions include isotretinoin, tetracycline,

 The cutaneous findings in phototoxic reactions are similar to an exaggerated sunburntype reaction, with erythema without edema at sun-exposed sites (

). Patients often complain of burning and pruritus. Photo-onycholysis has also been documented with doxycycline-associated phototoxicity, with erythema and separation of the nail plate from the nail bed.


	Figure 5 – The phototoxic drug eruption on this boy's shoulders has the appearance of an exaggerated sunburn-like response.

 Phototoxicity should be differentiated from a photoallergic reaction, which is presumed to be a type IV hypersensitivity reaction to systemic or topical exposure to an agent.

 Photoallergic reactions require a period of sensitization: the cutaneous eruption occurs up to 2 weeks after exposure to UV radiation, and it can reoccur on reexposure to the culprit medication. Phototoxic reactions, on the other hand, occur within hours of sun exposure in any patient exposed to sufficiently high doses of the drug and UV light. Phototoxic reactions can be avoided by minimizing sun exposure. However, to prevent a photoallergic reaction in a patient who is allergic to a particular agent, sun exposure must be avoided completely in the setting of ingestion of the allergen.

 Discontinuation of the offending agent, if possible, and avoidance of sun exposure are key aspects of management. Topical treatment of the skin with soothing creams, emollients, and topical corticosteroids can provide symptomatic relief. Onycholysis resulting from doxycycline-induced phototoxicity will resolve over several months.

POTENTIALLY LIFE-THREATENING DRUG ERUPTIONS


	Figure 6 – The confluent erythematous eruption with mild facial swelling seen in this teenaged boy was accompanied by elevated transaminase levels. Drug reaction with eosinophilia and systemic symptoms (DRESS) was diagnosed.

 Also called drug hypersensitivity syndrome, DRESS is an exanthematous drug eruption with systemic involvement. Onset is 1 to 6 weeks after initiation of a medication and may occur weeks to months after the culprit medication has been discontinued. Mortality in DRESS approaches 10%.

 DRESS has been documented with antibiotics (sulfamethoxazole, minocycline, nitrofurantoin),

 anticonvulsants (phenytoin, carbamazepine, lamotrigine),

 Patients with DRESS have an exanthematous rash with facial edema (

). Erythematous flat macules on the face and upper body become confluent, dusky red, and papular, with subsequent desquamation. The eruption is pruritic and generally spares mucosal surfaces.

The rash is usually preceded by fever and malaise, with or without pharyngitis and cervical lymphadenopathy. The liver, kidneys, heart, lungs, brain, and thyroid may be involved. Laboratory studies show atypical lymphocytosis and eosinophilia.

 DRESS is diagnosed on the basis of the presence of an exanthematous eruption accompanied by elevated liver enzyme levels; however, other laboratory abnormalities reflecting involvement of any of the organs listed above should raise suspicion for this entity and direct prompt treatment.

 The first step is to stop the offending drug. Timely administration of systemic corticosteroids to mitigate internal organ involvement is also crucial, and topical corticosteroids together with oral antihistamines can aid in symptomatic relief. DRESS may continue to progress even after the offending medication has been stopped, and relapse may occur after systemic corticosteroids have been tapered.

It is important to monitor blood counts, liver and renal function, thyroid function, and cardiac function in affected patients.


	Figure 7 – These photos of a boy with Stevens-Johnson syndrome show the classic pattern of mucosal erosions and intact bullae.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).

 SJS and TEN are variants of a single hypersensitivity disorder. SJS is defined by epidermal detachment on less than 10% of the total body surface area; TEN is defined by epidermal detachment on more than 30% of the body surface area. A transitional condition encompasses those patients who fall between the 2 classifications. Mucosal involvement is more common in SJS. In children, SJS is more common than TEN; however, both conditions have been described in all age-groups from neonates to adults. Onset is within the first 8 weeks of exposure to the causative agent. The usual disease course is 1 month. Mortality in SJS is about 5%, and as high as 30% to 35% in TEN.

 Common causes of SJS/TEN include drugs, infection with 

 species or other organisms, vaccines, autoimmune disease, and malignancy. In pediatric patients, drugs are implicated in half of all SJS diagnoses as well as in most cases of TEN.

 have been associated with both SJS and TEN. The risk of drug-induced SJS/TEN is increased in patients with HIV infection and those with a slow acetylator phenotype, who may have impaired ability to metabolize the toxic components of some of these drugs.

 Patients with SJS or TEN often have a prodrome of fever and constitutional symptoms, including malaise, headache, sore throat, rhinorrhea, cough, myalgias, arthralgias, vomiting, diarrhea, and/or painful skin. In both entities, the rash consists of facial and truncal erythematous macules with dusky purpuric centers (targetoid) that become progressively more generalized. Flaccid blisters develop and detach, leaving superficial erosions (

). The Nikolsky sign (extension of blisters with lateral pressure) is present. In patients with TEN, more widespread erythema develops, with epithelial necrosis and detachment (


	Figure 8 – This patient, in whom bullae and erosions clearly cover more than 30% of the body surface area, has toxic epidermal necrolysis (TEN).

Mucosal involvement is more common in SJS, with lesions in these areas appearing up to 2 days before the onset of cutaneous findings. Oral, conjunctival, and anogenital mucous membranes may demonstrate blistering, erosions, ulcerations, and hemorrhagic crusting. For a diagnosis of true SJS, at least 2 mucosal surfaces must be involved.

In severe cases, internal organ involvement can result in nephritis, renal failure, hepatitis, hepatosplenomegaly, pneumonitis, arthritis, or myocarditis. Ophthalmological consequences can include conjunctivitis, photophobia, corneal ulcerations, and uveitis-with sequelae ranging from keratoconjunctivitis sicca to blindness. Other potential complications include bacterial superinfection and sepsis, dehydration and electrolyte disturbance, temperature dysregulation, and end-organ failure. Mucocutaneous sequelae include dyschromia, nail dystrophy or absence, and strictures of the esophagus and the urethral and anogenital mucosae.

 This includes Kawasaki disease, erythema multiforme, staphylococcal scalded skin syndrome, graft versus host disease, and paraneoplastic pemphigus. Skin biopsy and the presence of the clinical features listed above can help confirm a diagnosis of SJS/TEN.

 Patients require hospitalization, with ICU or burn unit admission in severe cases. Any medications that are suspected of having contributed to the development of the condition should immediately be discontinued, and any medications that may cross-react with the causative agent should be avoided in the future. Adequate hydration, nutrition, and pain control should be provided. Skin should be kept clean and erosions dressed with bland emollients. Consult the ophthalmology team promptly if there is any suspicion of eye involvement, and consult a urologist early in the course of urethral discomfort for advice on preventing urethral adhesions or strictures.

Systemic corticosteroids have been used within the first few days of syndrome onset; however, because the risk of secondary infection and poor wound healing is increased with these agents, we strongly discourage their use. It has been our clinical experience that intravenous immunoglobulin has resulted in the most impressive halting of disease progression. However, no well-done, double-blind, placebo-controlled studies supporting its use have been published; thus, a careful discussion with the patient and family-about the evidence and the pros and the cons of treatment-is advised.

 Carder KR. Hypersensitivity reactions in neonates and infants. 

 Shiohara T, Inaoka M, Kano Y. Drug-induced hypersensitivity syndrome (DIHS): a reaction induced by a complex interplay among herpesviruses and antiviral and antidrug immune responses. 

 Millikan LE, Feldman M. Pediatric drug allergy. 

 Ibia EO, Schwartz RH, Wiedermann BL. Antibiotic rashes in children: a survey in a private practice setting. 

Hurwitz Clinical Pediatric Dermatology: A Textbook of Skin Disorders of Childhood and Adolescence

. 3rd ed. Philadelphia: Elsevier Saunders; 2006:508-510, 526-528, 532-538.

 Buchmiller BL, Khan DA. Evaluation and management of pediatric drug allergic reactions. 

Articles

“Drug rash” is a common pediatric complaint in both inpatient and outpatient settings. This term, however, denotes a clinical category and is not a precise diagnosis. Proper identification and classification of drug eruptions in children are important for determining the possibility of-and preventing progression to-internal involvement. Accurate identification is also important so that patients and their parents can be counseled to avoid future problematic drug exposures.

Drug Eruptions: The Benign-and the Life-Threatening

Answers: 1. C; 2. E; 3. A; 4. B; 5. D; 6. F"Diaper rash" is the most common skin disease affecting infants in the western world. It is usually assumed to be caused either by irritants in the stool or urine or by a candidal infection. Although candidal diaper dermatitis and irritant contact diaper dermatitis are both extremely common, these are by no means the only causes of dermatoses in the diaper region. Here we review a number of other causes of diaper rash and provide clinical clues to help differentiate among these conditions.

1 – Irritant or Allergic Contact Diaper Dermatitis

This typically presents maximally on the areas of the skin that are most in contact with the irritant or allergen (

). These include the convex areas of the groin but not the hidden folds. This single finding is the most useful clue for distinguishing between contact diaper dermatitis and diaper rash caused by candidal infection-which, in contrast, favors the folds.

The most common irritants in the diaper area are stool and urine. Fragrances and harsh soaps in bathing products can also cause a dermatitis; however, when bathing products are to blame, the dermatitis is usually more generalized, extending beyond the diaper area.

The most common cause of a truly allergic diaper dermatitis is the blue dye-known as disperse blue dye-that is used in many brands of colorful diapers. The folds are almost always completely spared in infants with diaper dye contact dermatitis; also, the shape of this type of rash is a strong clue to the diagnosis. In both dye-allergy dermatitis and the more common irritant dermatitis, the edges of the rash are usually perfectly squared off.

Treatment of both irritant and allergic contact dermatitis includes removal of the offending agent and short-term use (no more than 2 weeks in most cases) of low-potency topical corticosteroid creams. Dye-free diapers are increasingly easy to find and are even sometimes less expensive than their colorful alternatives!

2 – Candidal or Monilial Diaper Dermatitis

The classic clinical findings in this type of diaper rash are erythema and maceration in the inguinal creases (

). The erythema is often described as "beefy red," and the maceration gives the skin the false appearance of being wet. In addition to involvement of the folds, candidal diaper dermatitis is often associated clinically with the appearance of satellite pustules emanating from the folds and forming a confluent array on the convex skin surfaces. The diagnosis is made almost solely on the basis of the clinical appearance; the history is often unhelpful, and culture is not required for confirmation.

Treatment of candidal diaper dermatitis usually consists of application of one of the topical azole antifungal creams. These agents have broader antifungal coverage than either nystatin or other over-the-counter topical antifungal therapies. The inclusion of topical corticosteroid creams in the treatment regimen is almost never necessary and is not advised. Moreover, use of combination creams that contain both antifungal agents and mid-to high-potency topical corticosteroids should be strictly avoided; such creams can be unsafe because they usually contain a higher-potency topical corticosteroid than would otherwise be prudent to use in the groin area-and because the action of the corticosteroid often counteracts the action of the antifungal in the cream.

3 – Intertrigo With Group A Î²-Hemolytic Streptococcal Superinfection

Rarely, children present with skin findings reminiscent of candidal diaper dermatitis but with extensive involvement of noninguinal areas (such as the nuchal, antecubital, and popliteal spaces) (

) and an especially moist-looking appearance without satellitosis. In such cases, it is important to obtain a specimen for culture to check for group A Î²-hemolytic streptococci. If culture results are positive, initiate treatment with a topical antibiotic ointment, such as mupirocin ointment.

This bacterial infection usually occurs as a complication of intertrigo, a dermatitis that develops in the intertriginous areas of the skin as a result of prolonged or excessive exposure to moisture and an overgrowth of yeast. Thus, treatment also involves keeping these areas dry and applying a topical azole antifungal or wash in addition to the mupirocin to speed resolution. Unless an infant is febrile, oral antibacterial therapy is usually unnecessary.

This common skin disease affects up to 2% of persons in the United States. Psoriasis is usually thought of as an adult disease; however, in 2% of affected persons, it develops before the age of 2 years. The elbows, knees, hands, feet, and scalp are the areas of the body that are most often affected. However, there is a form of psoriasis known as inverse psoriasis that affects the folds. Inverse psoriasis is seen in both adults and children; in infants it can present as a diaper rash (

Typical clinical findings in inverse psoriasis are a diffuse, light pink erythema that starts in the groin folds; a dry appearance (as opposed to the maceration seen in candidiasis); and an absence of satellite pustules. Additional, more classic psoriatic lesions may be seen elsewhere on the body. A history of psoriasis in other family members can help confirm the diagnosis, but a family history is not always present.

Treatment of diaper psoriasis consists of intermittent use of mild topical corticosteroids, similar to those used to treat seborrheic dermatitis. If mild corticosteroids are not effective as monotherapy, topical immunomodulators may be added after a discussion of their offlabel use and black box warning is had with the family.

Seborrheic dermatitis (not pictured) is another noninfectious skin disease that commonly affects the diaper area. Although seborrheic dermatitis of the scalp, or cradle cap, is familiar to all pediatricians, seborrheic dermatitis can affect the entire body. The most common presentation of seborrheic diaper dermatitis is a diffuse diaper rash in association with classic cradle cap. The diaper rash can be differentiated from candidiasis on the basis of findings of diffuse erythema without accentuation of the folds and without satellite pustules.

Seborrheic dermatitis is thought to be at least in part a hypersensitivity reaction to an overgrowth of 

 yeast, which is found on the scalp and in the diaper area during the first 6 to 12 months of life. Treatment includes application of topical azole antifungal creams or washes in conjunction with intermittent use of very mild topical corticosteroids, such as hydrocortisone 1% to 2.5% cream. Again, combination creams containing both an antifungal and a mid- to high-potency corticosteroid should never be used in the groin area.

This is 1 of 2 rare and serious systemic diseases that commonly cause diaper rashes (the other is Langerhans cell histiocytosis). The rash of acrodermatitis enteropathica (AE) has been described as looking like "malignant seborrhea"-in other words, like seborrheic dermatitis, it commonly affects both the diaper area and the face; however, the typical findings of seborrheic dermatitis are accentuated and there is increased inflammation. It presents as a recalcitrant eczematous and crusted dermatitis perianally and periorally (

). The complete failure of the rash to respond to the usual topical therapy for seborrheic dermatitis also helps distinguish AE from seborrhea.

AE is associated with systemic zinc deficiency, which can result from either poor absorption of dietary zinc or malnutrition. AE typically develops when an infant is weaned from breast milk to formula; the zinc in breast milk is thought to be more bioavailable and readily absorbed than the zinc in infant formula. The exception to this clinical scenario is one in which the maternal breast milk is deficient in zinc; in this case, the deficiency-and the resultant AE-develops while the infant is still breast-feeding. AE can be diagnosed by checking the patient's zinc level or, for more rapid results, by checking the level of serum alkaline phosphatase, a zinc-dependent enzyme that can be low in cases of zinc deficiency. Treatment in most cases is with oral zinc supplementation; improvement is dramatic, usually within 1 week.

This multisystem disease can present as a severe diaper rash that is unresponsive to multiple topical therapies. Like the diaper rash of AE, Langerhans cell histiocytosis (LCH) has been described as a more malignant version of seborrheic dermatitis. Clinically, LCH appears as crusted papules with surrounding petechiae or pinpoint hemorrhage (

). Lymphadenopathy may or may not be present, and if systemic progression has begun, the infant may be irritable or appear jaundiced. It is not advisable to wait for these symptoms to develop before proceeding with the systemic workup. When treating a patient with a particularly recalcitrant diaper dermatitis, it is appropriate to consider immediate referral to a pediatric dermatologist for punch biopsy to rule out cutaneous LCH. If the biopsy confirms the presence of Langerhans cells, then a full systemic workup and possible treatment with systemic therapy should be implemented by a pediatric oncologist, since diabetes insipidus, skeletal involvement, pulmonary disease, hepatic disease, or bone marrow involvement may develop in affected children.

Conclusion
Although each of the previous disease processes can present with the chief complaint of "diaper dermatitis," the astute clinician can distinguish among them on the basis of subtle differences and other clinical clues-and by careful follow-up to ensure that first-line treatment has led to the expected clinical improvement. When an infant fails to improve as expected, it is always helpful to question the original diagnosis and consider the more uncommon causes of diaper dermatitis.

Match the photographs of the rashes with the correct diagnosis.

Robin P. Gehris, MD

Articles

Drug Eruptions: The Benign-and the Life-Threatening

Can You Distinguish Among These Diaper Dermatoses?