Published online October 1, 2007
PEDIATRICS
Vol. 120
No. 4
October 2007, pp.
e1082-e1096
(doi:10.1542/peds.2005-2321)
Cutaneous Reactions to Drugs in Children
Alissa R. Segal, PharmD, PhCa,
Kevin M. Doherty, PharmDb,
John Leggott, MDc and
Barrett Zlotoff, MDd
a Department of Pharmacy Practice, Massachusetts College of Pharmacy & Health Sciences, Boston, Massachusetts
b Texoma Medical Center, Denison, Texas
c Department of Family and Community Medicine, School-Based Health Centers
d Department of Dermatology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
 |
ABSTRACT
|
|---|
Cutaneous eruptions are a commonly reported adverse drug reaction.
Cutaneous adverse drug reactions in the pediatric population
have a significant impact on patients' current and future care
options. A patient's recollection of having a "rash" when they
took a medication as a child is a frequent reason for not prescribing
a particular treatment. The quick detection and treatment of
cutaneous adverse drug reactions, plus identification of the
causative agent, are essential for preventing the progression
of the reaction, preventing additional exposures, and ensuring
the appropriate use of medications for both the current condition
and others as the patient ages. The purpose of this review is
to discuss a reasonable approach to recognition and initial
management of cutaneous adverse drug reactions in children.
Key Words: adverse drug reactions • children • dermatology • cutaneous reactions
Abbreviations: CADR—cutaneous adverse drug reaction • ADR—adverse drug reaction • FDA—Food and Drug Administration • ECE—exanthematous cutaneous eruption • EM—erythema multiforme • FDE—fixed drug eruption • NSAID—nonsteroidal antiinflammatory drug • SSLR—serum sickness–like reaction • DHS—drug hypersensitivity syndrome • SJS—Stevens-Johnson syndrome • TEN—toxic epidermal necrolysis
Cutaneous adverse drug reactions (CADRs) are a commonly reported type of adverse drug reaction (ADR).1 A large study of hospitalized adults found that ADRs occurred at a rate of 5.5% per drug exposure, of which 2.2% were CADRs.2,3 Likewise, CADRs account for the majority of ADRs in hospitalized children.4 Outpatient studies of CADRs estimate that 2.5% of children who are treated with a drug, and up to 12% of children treated with an antibiotic, will experience a CADR.5–8 Because viral exanthems are very common in children, clinicians are often faced with a diagnostic dilemma when children who are taking medications present with a rash. This review is designed to provide clinical pearls of wisdom regarding common skin reactions in children to enable providers to distinguish between reactions and infections.
Although CADRs account for a substantial proportion of reported ADRs, they are rarely considered serious.4–7 Nevertheless, CADRs are conspicuous and concerning to patients and their families and account for a substantial proportion of clinic visits.9 Providers who are confronted with mild eruptions often have limited time to conduct an exhaustive investigation into the cause. Furthermore, the pressing concerns of a child's family may motivate the clinician to label the child as "allergic" to a drug and discontinue its use.10
This approach has potential implications for a child's future care. A retrospective review in 1 hospital and clinic found that 80% of drug allergies attributed to β-lactam and sulfa antibiotics and only 30% of the cases that were related to opioid analgesics were found to be allergic in nature on the basis of the clinical description of the event.11 In children, misattribution of a cutaneous reaction to a drug might be even more common. A study of pediatric patients who were referred to an allergy clinic found that antibiotic-associated CADRs were reproducible with a drug rechallenge in only 8 of 62 patients.12 Another study confirmed true drug allergies in only 4% of the patients referred to their clinic.13 Because a known "allergy" is a contraindication for prescribing an associated drug, and possibly all drugs in the same class, a hasty diagnosis can unnecessarily limit therapeutic options, which can increase the risk of using medications that are more toxic, less effective, and more costly.14 In addition, an allergy label will remain with a child over a large proportion of his or her life. As adults, many patients will have difficulty recalling the details of an early cutaneous reaction, which leaves one to assume that the allergy was serious and the patient cannot use that particular drug. Therefore, good management of a CADR requires an efficient method of estimating the probability of a drug association, determining the likelihood of a relapse with drug rechallenge, and communicating this assessment to patients and their families.
The goal of this article is to outline and discuss a reasonable approach to recognize and initially manage CADRs in children. Topics include historical information that is useful in assessing the probability of a CADR, terminology associated with cutaneous reactions, mechanisms of CADRs, common CADR patterns in children, and drugs that are commonly associated with those patterns. Serious CADRs will be discussed with an emphasis on early recognition. Finally, strategies for managing the majority of acute CADRs will be presented.
|
ESTABLISHING ETIOLOGY
|
|---|
Causality assessments based on history have proven to be a worthy
method of estimating the probability of drug culpability of
an ADR.
15–20 Causality assessments often use questions
that weigh the biological plausibility of a drug causing a reaction.
1 Gathering such information is akin to taking a history of the
behavior of a particular drug in the population treated with
it. The Naranjo et al
18 assessment classifies a reaction to
a drug as "definite" when (1) there is a reasonable temporal
sequence after a drug level had been established in body fluids,
(2) followed by a recognized response to the suspected drug,
(3) confirmed by improvement after drug withdrawal, and (4)
the reaction reappeared on reexposure. A "probable" reaction,
in contrast, follows conditions 1 and 3 and cannot be explained
by the patient's condition but was not confirmed by a rechallenge
of the drug. A "possible" reaction follows condition 1 but involves
an unpredictable reaction that could be explained by the patient's
condition. Unless a rechallenge is performed, the vast majority
of CADRs in children can only, at best, be considered as possibly
associated to a drug.
Clinicians will often consult tertiary drug references or product labeling to associate drugs and adverse effects. There are some limitations to these information sources, particularly for children. Information for product labeling is drawn initially from preclinical trials. Children do not participate in these trials; therefore, potential differences in their physiology that could contribute to adverse drug effects are not measured. Many CADRs in children occur in conjunction with viral or autoimmune disorders.21 Subjects in preclinical trials are usually in good health or have a single disease condition for which a medicine is being tested. With regard to cutaneous reaction patterns, various reaction patterns are associated with different drugs, and yet all are reported in product-labeling monographs as 1 category: "rashes."
|
DESCRIPTION OF THE CUTANEOUS REACTION
|
|---|
Whether submitting an ADR report to the Food and Drug Administration
(FDA) or documenting the reaction in a medical chart, the best
approach is to describe the morphology, configuration, and course
of the reaction with detailed and apt terminology.
17 The mere
use of the term "rash" is nonspecific and inadequate.
16,22 For
example, exanthems are skin eruptions that often accompany viral
and streptococcal bacterial diseases.
22 Types of exanthems include
morbilliform eruptions that resemble measles and scarlatiniform
eruptions that resemble eruptions that accompany scarlet fever.
23
A CADR not accompanied by a viral or bacterial illness can be referred to as either a macular-papular eruption or, if it resembles measles, morbilliform.10 Drugs can produce many variants of macular-papular eruptions.22 Adequate descriptions of such reactions would include distribution, morphology, configuration, and progression. Exanthems or macular-papular eruptions are commonly erythematous macules and papules from 1 to 5 mm in diameter that may coalesce into patches and plaques, respectively. Eruptions begin on the face, neck, or upper torso and progress bilaterally and symmetrically toward the limbs. Exanthems are often accompanied by pruritis and mild fever. As the eruption resolves, the skin usually desquamates and occasionally leaves areas of hyperpigmentation or hypopigmentation.24 A good description of a cutaneous reaction will include as many of these details as possible. Table 1 includes definitions for terminology that is suitable for a descriptive report of a cutaneous reaction.
|
CLASSIFICATION OF CADRs
|
|---|
In general, ADRs are divided into 2 categories.
27–29 Type
A reactions that are related to the known pharmacologic effects
of a drug are dose dependant, predictable, mild to moderate
in severity, and account for the majority of ADRs. Type A reactions
can usually be recognized as common adverse effects reported
on drug labeling (Table
2). Conversely, type B reactions are
not related to the known pharmacologic effects of a drug and
are dose independent (even occurring at miniscule doses), unpredictable,
idiosyncratic, often serious, and account for a smaller proportion
of ADRs.
27,29 Such reactions have been categorized as immunologic
(true-allergy) hypersensitivity reactions, pseudoallergic, and
idiosyncratic drug reactions (Table
2).
10,27 CADRs in children
are often type B ADRs and can be unpredictable, mechanistically
complex, and difficult to identify.
|
FIVE COMMON CADR PATTERNS IN CHILDREN
|
|---|
At least 29 drug-related cutaneous reaction patterns have been
identified.
22 The 5 reactions described below are common in
the pediatric population.
21,30
Exanthematous Drug Eruptions
Exanthematous cutaneous eruptions (ECEs) are the most common kind of CADR in children21,22 (Fig 1). The eruption usually occurs abruptly during the first 5 to 14 days of treatment.22 Five percent to 10% of patients treated with ampicillin develop an ECE. This frequency increases substantially during a viral infection; as many as 95% of patients who are infected with the Epstein-Barr virus and treated with ampicillin develop an ECE22 (Tables 3 and 4 and Fig 2).
Management of an exanthematous cutaneous reaction includes discontinuation
of the likely culprit and supportive care. Initially, oral antihistamines
or corticosteroids can be helpful in alleviating more-severe
symptoms.
21 Second-generation H
1 blockers are associated with
fewer sedative effects when compared with first-generation H
1 blockers.
32–34 Cetirizine, a second-generation agent,
comes in a liquid formulation and can be used in children as
young as 6 months.
35
As the eruption resolves, desquamation often occurs. If pruritis is bothersome, low- to midpotency topical steroids (hydrocortisone, triamcinolone) and liberal bland, nonsensitizing emollients (petroleum jelly) can provide some relief. Topical diphenhydramine and lidocaine-containing products have often been associated with contact dermatitis and, therefore, are not recommended.21 In children with medium to darker skin tones, a postinflammatory hypopigmentation or hyperpigmentation can occur. This effect resolves over a period of months to years, and sun avoidance or protection should be recommended.
Urticaria
It is estimated that 15% to 25% of all persons experience urticaria during their lifetime.36,37 Because acute urticaria in children is usually mild, self-limiting, and short lived, it is difficult to estimate the prevalence in the general pediatric population38 (Table 5). Studies have demonstrated that acute urticaria, unlike chronic urticaria, results from immunoglobulin E–mediated or drug-induced mast cell degranulation.39 These eruptions occur in a generalized fashion but tend to occur more frequently in areas covered by clothing. The plaques, also known as wheals, hives, or welts, result from localized edema of the dermis. They appear as white, edematous zones that vary in size between a few millimeters to centimeters, are surrounded by erythema, and are often accompanied by pruritus40 (Figs 3 and 4). This is in contrast to erythema multiforme (EM), which includes a third central dusky blue-hued zone. Angioedema involves subcutaneous or submucosal tissues and can be an early symptom of impending anaphylaxis. Urticaria is usually transient, although between 9% and 32% of cases presenting to clinics or hospitals are chronic (lasting >6 weeks).41–44 Our discussion here will be restricted to acute urticaria.
Two recent prospective investigations found that infections
were associated with the majority of episodes of acute urticaria.
Sackesen et al
44 found that 58% of patients (aged 1–19
years) with an acute, single urticarial episode had an infection;
25% of these patients had positive urine-culture results (all
Escherichia coli), 13% were positive for
Chlamydia pneumoniae,
8% had positive
Streptococcus throat cultures, and 4% had positive
Mycoplasma pneumoniae or
Helicobacter pylori serologies. Seven
patients with positive urine-culture results had not been treated
with antibiotics, and the urticarial symptoms resolved with
treatment. Of the remaining reactions, 5% were associated with
drugs (aspirin) and 3% with foods. Mortureux et al
41 found somewhat
similar results in younger children (average age: 20 months).
Thirty-one percent (
n = 18) of the children tested positive
for viral infections, of which 12 were being treated with drugs
(including amoxicillin and erythromycin). In 3 cases, urticarial
eruptions returned with amoxicillin treatment. Other studies
have generally confirmed the prominent role of infections in
acute urticaria; however, some have implicated drugs in a higher
proportion of cases.
42,43,45–47
As described for exanthematous reactions, in the absence of other systemic symptoms (severe urticaria, respiratory distress, etc), the strongest association of a drug is obtained by means of a drug rechallenge at a later date when the child is well.21,45 If a drug is implicated, it should be discontinued. Providers are often concerned with cross-sensitivity between penicillins and cephalosporins. Recently, Apter et al48 found that 70% of patients experienced urticaria after receiving penicillins and cephalosporins. Genetic predisposition rather than cross-sensitivity is presumed to explain this phenomenon because of similar subsequent reactions to cephalosporins in patients with documented urticaria with sulfonamide antibiotics.
Antihistamine therapy remains the mainstay of management of acute urticarial reactions.48 Again, second-generation agents such as loratadine and cetirizine are recommended.49,50 With severe discomfort from pruritis, the sedative effects from hydroxyzine might be desirable, as well.47 Some success has been reported with low-dose doxepin (10 mg 3 times daily), an antidepressant medication that blocks both H1 and H2 receptors.51 Although the evidence is not conclusive, oral prednisolone added to antihistamine therapy can result in decreased itch and more-rapid rash resolution of acute urticaria.52,53 Of note, specialists have been found to use oral steroids less frequently than general practitioners.54
Fixed Drug Eruptions
Fixed drug eruptions (FDEs) occur almost anywhere on the skin and, curiously, reappear in the exact same location when an offending drug is readministered22,55 (Table 6). FDEs begin as soon as 30 minutes and as long as 2 months after drug ingestion.21,22,54 They initially appear as well-demarcated, solitary or multiple edematous papules or plaques. Their color varies from dusky red to violet (Fig 5). The lesions can be intensely pruritic.22 As the inflammation fades, the lesions become more round, and their color becomes grayish brown. The pigmented lesions can persist for years. Depending on the severity of the reactions, crusting and desquamation can occur in the postinflammatory phase. On rechallenge, the FDE will occur in the exact same location.55
As the diagnostic criteria for various cutaneous eruptions become
more stringent, the relative prevalence of FDEs seems to increase.
In a prospective and methodical study of pediatric outpatients
(aged 1–18 years) in India who presented with a CADR,
26% were diagnosed with macular-papular eruptions, 22% with
FDEs, and 6% with urticaria.
30 In contrast, Ibia et al
5 found
a higher proportion of urticarial eruptions. The authors of
this study surveyed parents by mail and did not distinguish
EM or miscellaneous eruptions from FDEs. Mild drug eruptions
(especially in relation to sulfamethoxazole and trimethoprim)
are often misdiagnosed as macular-papular eruptions.
56 FDEs
are probably underdiagnosed by most primary care providers.
56 Rechallenge remains the gold standard for diagnosis of FDEs
and is usually safe to perform at a later date, depending on
the severity of the initial reaction.
21
Many drugs have been associated with FDEs, although some, such as sulfamethoxazole and trimethoprim, are implicated frequently. Reactions can occur in a generalized fashion or only on the torso, torso and limbs, lips, or genitalia; the majority of reactions occur in multiple sites.57–62 Generalized eruptions have been significantly associated with phenytoin, whereas eruptions specific to tetracycline tend to involve the genitalia.59,60 Recently, ciprofloxacin has been associated with a substantial proportion of FDEs in India.63 FDEs are often missed when they are secondary to episodic use of nonsteroidal antiinflammatory drugs (NSAIDs) or laxatives that contain phenolphthalein.55,56 In addition, cross-reactivity has been reported between tetracycline derivatives, sulfonamides, and even unrelated anticonvulsant agents.64–66
When an FDE is suspected, the offending agent should be stopped, because continued administration can intensify the inflammation.22 Management is supportive, as described earlier. Treatment with topical steroids may hasten resolution of an FDE. If a rechallenge is performed at a later date, the initial challenge dose should be smaller than the normal therapeutic dose, but it can be cautiously increased until the reaction is elicited.67 In some cases, 2 to 3 times the original dose may be required to elicit a repeat reaction.67
Photosensitivity Reactions
Up to 8% of cutaneous drug eruptions are photosensitivity reactions, including phototoxic and photoallergic reactions.22,68–70 Drug-induced phototoxicity occurs when photoradiation interacts with a chemical within the skin to generate free radicals, which induces host cytotoxic effects. The site of the eruption coincides with sun-exposed areas of the skin, including the face, presternal area, and the dorsum of the hands.70
Phototoxic reactions are nonimmunologic and dose dependant and often occur soon after initial ingestion of the drug. There are 3 general variations of phototoxic reactions.70 The first is an intense and delayed erythema and edema that occurs 8 to 24 hours after exposure to sunlight. This reaction can involve hyperpigmentation and be a darker red than sunburn. Hydrochlorothiazide is an example of a trigger for this first type of phototoxic reaction. A second, more-immediate variation can occur within 30 minutes after light exposure and can last for a day or two (Fig 6). In this variant, erythema occurs without edema and is accompanied by local burning and pruritis. This more-immediate variation is often associated with doxycycline and the coal-tar derivatives such as anthracene and acridine. The third variant is associated with porphyrins and manifests as a rapid, transient, urticarial-like eruption that can be activated by room-lighting. Because the skin beneath the fingernails lacks melanin, phototoxic reactions that involve tetracyclines have been associated with onycholysis. By contrast, photoallergic reactions occur after a period of sensitization and can reoccur with small doses of the offending agent. Such reactions may appear with papulovesicular eruption, pruritis, and eczematous dermatitis 1 to 14 days after exposure to sunlight. Clinicians should include lupus and photoallergic reactions in their differential diagnosis when they evaluate a photograph-distributed eruption70–74 (Table 7).
Management of phototoxic reactions parallels that of minor burn
care.
21,70 Soothing creams and emollients can help with the
discomfort. In more-severe cases, vesicles form and rupture,
and topical antibiotic creams can be considered. For photoallergic
reactions, oral antihistamines and topical corticosteroids can
provide symptomatic relief.
21,70 Although it is preferable to
discontinue the offending agent, minimizing or eliminating light
exposure is an option when few or no alternate agents are available.
Avoidance of sunlight and application of sunscreens that block
UV-A and UV-B may be recommended with the awareness, however,
that sunscreens are the most common cause of photoallergic reactions.
75
Serum Sickness–Like Reactions
A true serum sickness reaction, a type III hypersensitivity reaction, occurs when antibody–antigen complexes deposit in the microvasculature of the skin and joints and activate a complement cascade that leads to an inflammatory response and tissue damage.76 In contrast to a true immunologic reaction, serum sickness–like reactions (SSLRs) do not exhibit the immune complexes, hypocomplementemia, vasculitis, and renal lesions that are seen in serum sickness reactions.22 SSLRs are characterized by fever, pruritis, urticaria, and arthralgias that usually begin 1 to 3 weeks after drug exposure and resolve soon after drug discontinuation.21 The urticarial skin eruption becomes more erythematous as the reaction progresses and can evolve into dusky centers with round plaques. SSLRs have been most commonly associated with cefaclor, with which SSLRs are estimated to occur in 0.024% of exposures in controlled clinical trials and 0.5% in published reports.77–82 Investigation of the mechanism of SSLRs that occur as a result of cefaclor use suggests a variant metabolic pathway.83 No cross-reactivity with other cephalosporins has been demonstrated.
The development of bacterial resistance to cefaclor has limited its utility in the treatment of pediatric infections.84 For this reason, SSLRs might be less common now than in the recent past. Case reports have implicated a number of other antiinfective agents in SSLRs, including penicillin, amoxicillin, cefprozil, sulfonamides, macrolides, ciprofloxacin, tetracyclines, rifampin, griseofulvin, and itraconazole.78–81,85–92 Bupropion and fluoxetine have also been implicated91–93 (Table 8).
Management is usually guided by symptomatology (as described
previously); however, more-severe symptoms such as arthralgias
could benefit from a short course of systemic corticosteroids.
21,91
|
RECOGNITION OF SEVERE CADRs
|
|---|
The risk of a severe CADR ranges between 1 in 1000 and 1 in
10000, depending on the kind of reaction and the culprit drug.
17,21,96,97 Early recognition and prompt discontinuation of the offending
agent can reduce mortality.
98 The most serious CADRs include
anaphylaxis, drug hypersensitivity syndrome (DHS, also referred
to as drug reaction with eosinophilia and systemic symptoms),
24 Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis
(TEN). Our discussion here will be restricted to DHS, SJS, and
TEN. In all cases, the likely culprit drugs should be discontinued
immediately. Table
9 compares these eruptions.
DHS can occur 1 to 6 weeks after the initiation of drug therapy.
97,99,100 The initial presentation of DHS can resemble SSLR (fever, exanthematous
eruption, lymphadenopathy, and eosinophilia); however, arthralgias
are rarely present with DHS.
97 The cutaneous eruption in DHS
often progresses from a macular erythema, which starts on the
face, upper trunk, and upper extremities, to a dusky reddish
and confluent papular rash that is pruritic and can often desquamate.
21,96,97 Edema is a hallmark of DHS, particularly in a facial distribution.
24 The confluence seen in DHS occurs in contrast to the more-distinct
and local areas of eruption seen in SSLRs. Visceral involvement
in DHS can include the kidneys, liver, heart, lung, thyroid,
and brain. Hepatitis is found in up to half of all cases.
99 In contrast to SJS and TEN, involvement of the mucous membranes
is rare. DHS is associated most commonly with aromatic anticonvulsant
agents, including phenytoin, carbamazepine, and phenobarbitol
(which are cross-reactive), and antibiotics such as minocycline
and sulfamethoxazole.
21,95–97,99,100
Controversy exists over the relationship between EM, SJS, and TEN.16,101–106 In this review we followed definitions of these conditions that were provided by the World Health Organization and distinguish EM from SJS and TEN.16,104
It is unclear whether EM is associated with medications, but it deserves mention because it is often confused with urticaria and FDE. EM occurs over a period of 12 to 24 hours and is usually self-limiting and benign.16,21,22,101,103,105,107 In about half of the cases the eruption is preceded by a relatively mild prodromal phase that resembles an upper respiratory infection. The papular lesions occur symmetrically on the extremities and are target-shaped, with 3 different-colored zones and a blister in the center clearly demarcated from the surrounding skin (Fig 7). Mucosal involvement is usually limited to the oral mucosa. EM has been associated most often with herpes simplex, followed by M pneumoniae; less commonly, orf and histoplasmosis are involved.21,24,108–111 The literature reports vary from 0% to 10% association with medications.110,112
SJS manifests as 2 mucosal sites of involvement in conjunction
with widespread skin lesions that may either be target-shaped
or consist of erythematous macules.
16,21,22,96,97,101–106,113,114 The prodromal phase of the eruption is more intense than that
seen with EM and includes fever, arthralgia, malaise, headache,
vomiting, diarrhea, and myalgia. Lesions almost always involve
the eyes, usually the mouth, and occasionally the upper airway,
gastrointestinal tract, myocardium, and/or kidneys (Fig
8).
Drugs are associated with
50% of the eruptions diagnosed as
SJS in children; anticonvulsant agents, penicillin, and sulfonamides
have been blamed for 90% of these cases.
103,107,113 One study
examined the result of discontinuing all potentially causative
drugs at the first sign of a blister or erosion (typical of
SJS or TEN) that was not explained by another cause.
98 The difference
in mortality was 11% for early recognition and drug withdrawal
versus 27% for late withdrawal (when the drugs had short elimination
half-lives).
98
With TEN, a morbilliform eruption occurs soon after drug administration
and is accompanied by large erythematous and tender areas of
the skin.
21,22,101–105,107,113,115–117 This symptom
rapidly progresses to blistering and exfoliation of the epidermis
that is characterized by widespread erythematous areas with
epithelial necrosis and epidermal detachment, which leaves bare
dermis (Fig
9). TEN is defined by >30% cutaneous surface
involvement. A positive Nikolsky sign (detachment of epidermis
with lateral pressure from a finger) is indicative of TEN.
118 SJS with >10% cutaneous involvement is often classified as
SJS/TEN overlap.
104 Extensive mucosal erosion is frequent. Prodromal
symptoms are often severe and include nausea, vomiting, angina,
high fever, malaise, and painful skin. Morbidity and mortality
is high (25%–50%), usually from fluid and electrolyte
imbalances and secondary bacterial infections. Up to 90% of
TEN cases in adults have been associated with drugs.
113 Although
a majority of TEN cases in children are touted to be drug related,
up to half the cases in 1 study could not be associated with
a specific cause.
117
|
RISK FACTORS FOR CADRs IN CHILDREN
|
|---|
Risk factors for cutaneous eruptions in children can be divided
into drug and patient factors. Drugs have been associated with
cutaneous reactions roughly in proportion to their use. All
of the epidemiologic studies cited in this review detected CADRs
and accounted for the proportions of culprit drugs associated
with those CADRs.
28,30,119 Both antibiotics and infections are
frequently associated with CADRs. In addition, anticonvulsant
agents (phenytoin, phenobarbitol) appear frequently as implicated
medicines in pediatric reactions. Drugs that are associated
with predictable type A reactions, such as phototoxic reactions,
are used with the understanding that a CADR may occur.
Patient risk factors include infection and the possibility of a genetic variation leading to altered metabolism of a drug, with a partially or fully immunologic consequence. Although little is known about the specific mechanisms, children with parents who have a true drug allergy are at a 15-fold relative risk for allergic reactions to the same drugs.28 Studies have found some links between genetic variation in drug metabolism and CADRs.12,13,120,121
|
INITIAL MANAGEMENT OF A CADR
|
|---|
Early pattern recognition and severity assessment of a CADR
are the cornerstones of initial management and prevention of
reaction progression. Always attempt to obtain a careful and
thorough history of the reaction and a good description of the
eruption. Refer to Table
10 for helpful questions to determine
the history and cause of a CADR. If the type of reaction is
easily recognizable, refer to the treatment section of the specific
reaction type in Tables 3 through 8
. Determination of the causative
agent is more difficult when patients are taking multiple medications.
Assessment of culprit drugs should be based on published associations.
If clarification is needed on the assessment, particularly with
severe, persistent, or recurrent CADRs, providers should contact
an allergist for additional testing and confirmation. After
this assessment, providers with definite associations to specific
medications should report the CADR to the FDA by completing
the MedWatch 3500 form online (
www.fda.gov/medwatch) or by calling
1-800-FDA-1088 (1-800-332-1088). Reporting of CADRs to the FDA
or in the publication of case reports is essential for the continued
evaluation of medications by providers for their patients who
experience these events. The management of CADRs for these patients
differs on the basis of the severity of the reaction. Table
11 provides suggestions for the management of mild and severe
reactions. Diagnosis of CADRs in any patient should be considered
provisional unless a rechallenge is performed.
|
CONCLUSIONS
|
|---|
CADRs account for the majority of ADRs. Up to 10% of young children
who are taking antibiotics could develop a cutaneous drug eruption.
The majority of the reactions are not true drug allergies and
will not occur at a later date when the child is rechallenged
with the drug. In cases of serious CADRs, prompt recognition
and drug cessation can mitigate the severity of the reaction.
Establishing firm associations between drugs and CADRs is a
relatively complex and subtle art. Previous familiarity with
history taking, typical reaction patterns, and the present state
of epidemiologic knowledge are necessary for timely assessments
and recommendations (Table
12).
As an antidote to the complexity of diagnosis, we recommend
Litt's
Drug Eruption Reference Manual22 and
The Pocketbook of Drug Eruptions and Interactions.
25 These handy references list
case reports that associate many specific cutaneous reactions
with various drugs.
|
FOOTNOTES
|
|---|
Accepted Mar 3, 2007.
Address correspondence to Alissa R. Segal, PharmD, PhC, Massachusetts College of Pharmacy & Health Sciences, Department of Pharmacy Practice, 179 Longwood Ave, Boston, MA 02115-5896. E-mail: alissa.segal{at}mcphs.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
|
REFERENCES
|
|---|
- Cutaneous drug reaction case reports: from the world literature.
Am J Clin Dermatol. 2003;4
:511
–521[CrossRef][Web of Science][Medline]
- Miller RR. Drug surveillance utilizing epidemiological methods: a report from the Boston Collaborative Drug Surveillance Program.
Am J Hosp Pharm. 1973;30
:585
–592
- Bigby M, Jick S, Jick H, Arndt K, et al. Drug-induced cutaneous reactions: a report from the Boston Collaborative Drug Surveillance Program on 15,438 consecutive inpatients, 1975 to 1982.
JAMA. 1986;256
:3358
–3363[Abstract/Free Full Text]
- Kushwaha KP, Verma RB, Singh YD, Rathi AK. Surveillance of drug induced diseases in children.
Indian J Pediatr. 1994;61
:357
–365[Medline]
- Ibia EO, Schwartz RH, Wiedermann BL. Antibiotic rashes in children: survey in a private practice setting.
Arch Dermatol. 2000;136
:849
–854[Abstract/Free Full Text]
- van der Linden PD, van der Lei J, Vlug AE, Stricker BH. Skin reactions to antibacterial agents in general practice.
J Clin Epidemiol. 1998;51
:703
–708[CrossRef][Web of Science][Medline]
- Cirko-Begovi
A, Vrhovac B, Bakran I. Intensive monitoring of adverse drug reactions in infants and preschool children.
Eur J Clin Pharmacol. 1989;36
:63
–65[CrossRef][Web of Science][Medline] - Kramer MS, Hutchinson TA, Flegel KM, Naimark L, Contardi R, Leduc DG. Adverse drug reactions in general pediatric outpatients.
J Pediatr. 1985;106
:305
–310[CrossRef][Web of Science][Medline]
- Johnson ML, Johnson KG, Engel A. Prevalence, morbidity, and cost of dermatologic diseases.
J Am Acad Dermatol. 1984;11
:930
–936[Web of Science][Medline]
- Gruchalla R. Understanding drug allergies.
J Allergy Clin Immunol. 2000;105
:S637
–S644[CrossRef][Web of Science][Medline]
- Pilzer JD, Burke TG, Mutnick AH. Drug allergy assessment at a university hospital and clinic.
Am J Health Syst Pharm. 1996;53
:2970
–2975[Abstract]
- Huang SW, Borum PR. Study of skin rashes after antibiotic use in young children.
Clin Pediatr (Phila). 1998;37
:601
–607[Abstract/Free Full Text]
- Martin-Munoz F, Moreno-Ancillo A, Dominguez-Noche C, et al. Evaluation of drug-related hypersensitivity reactions in children.
J Investig Allergol Clin Immunol. 1999;9
:172
–177[Web of Science][Medline]
- Preston SL, Briceland LL, Lesai TS. Accuracy of penicillin allergy reporting.
Am J Health Syst Pharm. 1994;51
:79
–84[Abstract]
- Karch FE, Lasagna L. Toward the operational identification of adverse drug reactions.
Clin Pharmacol Ther. 1977;21
:247
–254[Web of Science][Medline]
- Council for International Organization of Medical Sciences. Harmonizing use of adverse drug reaction terms: definitions of terms and minimum requirements for their use—respiratory disorders and skin disorders [published correction appears in Pharmacoepidemiol Drug Saf. 1997;6:293].
Pharmacoepidemiol Drug Saf. 1997;6
:115
–127[CrossRef][Web of Science][Medline]
- Roujeau JC, Stern R. Medical progress: severe cutaneous reactions to drugs.
N Engl J Med. 1994;331
:1272
–1285[Free Full Text]
- Naranjo CA, Busto U, Sellers EM, et al. A method of estimating the probability of adverse drug reactions.
Clin Pharmacol Ther. 1981;30
:239
–244[Web of Science][Medline]
- Kramer MS, Leventhal JM, Hutchinson TA, Feinstein AR. An algorithm for the operational assessment of adverse drug reactions: I. Background, description, and instructions for use.
JAMA. 1979;242
:623
–632[Abstract/Free Full Text]
- Hutchinson TA, Leventhal JM, Kramer MS, Karch FE, Lipman AG, Feinstein AR. An algorithm for the operational assessment of adverse drug reactions: II. Demonstration of reproducibility and validity.
JAMA. 1979;242
:633
–638[Abstract/Free Full Text]
- Shin HT, Chang MW. Drug eruptions in children.
Curr Probl Pediatr. 2001;31
:207
–234[CrossRef][Medline]
- Litt J.
Drug Eruption Reference Manual. New York, NY: Parthenon; 2000
- Taber's Cyclopedic Medical Dictionary. Philadelphia, PA: F. A. Davis Co; 2003. Available at: www.rxlist.com. Accessed January 3, 2003.
- Lookingbill DP, Marks JG Jr.
Principles of Dermatology. Philadelphia, PA: WB Saunders; 2000
- Litt J.
The Pocketbook of Drug Eruptions and Interactions. 2nd ed. New York, NY: Parthenon; 2001
- Rawlins MD. Clinical pharmacology: adverse reactions to drugs.
Br Med J (Clin Res Ed). 1981;282
:974
–976[Medline]
- Assem EK. Drug allergy and tests for its detection. In: Davies DM, Ferner RE, de Glanville H, eds.
Davies's Textbook of Adverse Drug Reactions. 5th ed. London, United Kingdom: Chapman & Hall Medical; 1998:791–815
- DeShazo RD, Kemp SF. Allergic reactions to drugs and biologic agents.
JAMA. 1997;278
:1895
–1906[Abstract/Free Full Text]
- Coombs R, Gell PGH. Classification of allergic reactions responsible for clinical hypersensitivity and disease. In: Coombs R, Gell PGH, Lachman PJ, eds.
Clinical Aspects of Immunology. Oxford, United Kingdom: Blackwell Scientific; 1975:761–781
- Sharma VK, Dhar S. Clinical pattern of cutaneous drug eruption among children and adolescents in north India.
Pediatr Dermatol. 1995;12
:178
–183[Web of Science][Medline]
- Drago F, Rampini E, Rebora A. Atypical exanthems: morphology and laboratory investigations may lead to an aetiological diagnosis in about 70% of cases.
Br J Dermatol. 2002;147
:255
–260[CrossRef][Web of Science][Medline]
- Horowitz R, Reynolds S. New oral antihistamines in pediatrics.
Pediatr Emerg Care. 2004;20
:143
–146[CrossRef][Web of Science][Medline]
- Simons FE. H1-antihistamines in children.
Clin Allergy Immunol. 2002;17
:437
–464[Medline]
- Ten Eick AP, Blumer JL, Reed MD. Safety of antihistamines in children.
Drug Saf. 2001;24
:119
–147[CrossRef][Web of Science][Medline]
- Simons FE, Silas P, Portnoy JM, et al. Safety of cetirizine in infants 6 to 11 months of age: a randomized, double-blind, placebo-controlled study.
J Allergy Clin Immunol. 2003;111
:1244
–1248[CrossRef][Web of Science][Medline]
- Tamayo-Sanchez L, Ruiz-Maldonado R, Laterza A. Acute annular urticaria in infants and children.
Pediatr Dermatol. 1997;14
:231
–234[Web of Science][Medline]
- Kanwar AJ, Greaves MW. Approach to the patient with chronic urticaria.
Hosp Pract. 1996;31
:175
–179, 183–184, 187–189[Medline]
- Kuby J. Immunology. In: Allen D, Julet MR, Maass DC, eds.
Hypersensitive Reactions. 3rd ed. New York, NY: WH Freeman; 1997:413–438
- Solley GO, Gleich GJ, Jordon RE, Schroeter AL. The late phase of the immediate wheal and flare skin reaction: its dependence upon IgE antibodies.
J Clin Invest. 1976;58
:408
–420[Web of Science][Medline]
- Carder KR. Hypersensitivity reactions in neonates and infants.
Dermatol Ther. 2005;18
:160
–175[CrossRef][Medline]
- Mortureux P, Léauté-Labrèze C, Legrain-Lifermann V, Lamireau T, Sarlangue J, Taïeb A. Acute urticaria in infancy and early childhood: a prospective study.
Arch Dermatol. 1998;134
:319
–323[Abstract/Free Full Text]
- Legrain V, Taïeb A, Sage T, Maleville J. Urticaria in infants: a study of forty patients.
Pediatr Dermatol. 1990;7
:101
–107[Web of Science][Medline]
- Balaban J. Medicaments as the possible cause of urticaria in children.
Acta Dermatovenerol Croat. 2002;10
:155
–159[Medline]
- Sackesen C, Sekerel BE, Orhan F, et al. The etiology of different forms of urticaria in childhood.
Pediatr Dermatol. 2004;21
:102
–108[CrossRef][Web of Science][Medline]
- Schuller DE. Acute urticaria in children: causes and an aggressive diagnostic approach.
Postgrad Med. 1982;72
:179
–185[Medline]
- Sakurai M, Oba M, Matsumoto K, Tokura Y, Furukawa F, Takigawa M. Acute infectious urticaria: clinical and laboratory analysis in nineteen patients.
J Dermatol. 2000;27
:87
–93[Medline]
- Bilbao A, Garcia JM, Pocheville I, et al. Round table: urticaria in relation to infections [in Spanish].
Allergol Immunopathol (Madr). 1999;27
:73
–85[Medline]
- Apter AJ, Kinman JL, Bilker WB, et al. Is there cross-reactivity between penicillins and cephalosporins?
Am J Med. 2006;119
:354.e11
–354.e19
- Twarog FJ. Urticaria in childhood: pathogenesis and management.
Pediatr Clin North Am. 1983;30
:887
–898[Web of Science][Medline]
- Kennard CD, Ellis CN. Pharmacologic therapy for urticaria.
J Am Acad Dermatol. 1991;25
:176
–187[Web of Science][Medline]
- Smith PF, Corelli RL. Doxepin in the management of pruritus associated with allergic cutaneous reactions.
Ann Pharmacother. 1997;31
:633
–635[Abstract]
- Poon M, Reid C. Do steroids help children with acute urticaria?
Arch Dis Child. 2004;89
:85
–86[Free Full Text]
- Zuberbier T, Ifflander J, Semmler C, Henz BM. Acute urticaria: clinical aspects and therapeutic responsiveness.
Acta Derm Venereol. 1996;76
:295
–297[Web of Science][Medline]
- Henderson RL Jr, Fleischer AB Jr, Feldman SR. Allergists and dermatologists have far more expertise in caring for patients with urticaria than other specialists.
J Am Acad Dermatol. 2000;43
:1084
–1091[CrossRef][Web of Science][Medline]
- Mahboob A, Haroon TS. Drugs causing fixed eruptions: a study of 450 cases.
Int J Dermatol. 1998;37
:833
–838[CrossRef][Web of Science][Medline]
- Morelli JG, Tay YK, Rogers M, Halbert A, Krafchik B, Weston WL. Fixed drug eruptions in children.
J Pediatr. 1999;134
:365
–367[Web of Science][Medline]
- Lee AY. Topical provocation in 31 cases of fixed drug eruption: change of causative drugs in 10 years.
Contact Dermatitis. 1998;38
:258
–260[CrossRef][Web of Science][Medline]
- Ozkaya-Bayazit E. Specific site involvement in fixed drug eruption.
J Am Acad Dermatol. 2003;49
:1003
–1007[CrossRef][Web of Science][Medline]
- Sharma VK, Dhar S, Gill AN. Drug related involvement of specific sites in fixed eruptions: a statistical evaluation.
J Dermatol. 1996;23
:530
–534[Medline]
- Thankappan TP, Zachariah J. Drug-specific clinical pattern in fixed drug eruptions.
Int J Dermatol. 1991;30
:867
–870[Web of Science][Medline]
- Nussinovitch M, Prais D, Ben-Amitai D, Amir J, Volovitz B. Fixed drug eruption in the genital area in 15 boys.
Pediatr Dermatol. 2002;19
:216
–219[CrossRef][Web of Science][Medline]
- Brown SG. Fixed drug eruptions in deeply pigmented subjects: clinical observations on 350 patients.
Br Med J. 1964;2(5416)
:1041
–1044
- Dhar S, Sharma VK. Fixed drug eruption due to ciprofloxacin.
Br J Dermatol. 1996;134
:156
–158[CrossRef][Web of Science][Medline]
- Tham SN, Kwok YK, Chan HL. Cross-reactivity in fixed drug eruptions to tetracyclines.
Arch Dermatol. 1996;132
:1134
–1135[Abstract/Free Full Text]
- Chan HL, Tan KC. Fixed drug eruption to three anticonvulsant drugs: an unusual case of polysensitivity.
J Am Acad Dermatol. 1997;36
:259[CrossRef][Web of Science][Medline]
- Tornero P, De Barrio M, Baeza ML, Herrero T. Cross-reactivity among p-amino group compounds in sulfonamide fixed drug eruption: diagnostic value of patch testing.
Contact Dermatitis. 2004;51
:57
–62[CrossRef][Web of Science][Medline]
- Kanwar AJ, Bharija SC, Singh M, Belhaj MS. Ninety-eight fixed drug eruptions with provocation tests.
Dermatologica. 1988;177
:274
–279[Web of Science][Medline]
- Selvaag E. Clinical drug photosensitivity: a retrospective analysis of reports to the Norwegian Adverse Drug Reactions Committee from the years 1970–1994.
Photodermatol Photoimmunol Photomed. 1997;13
:21
–23[Web of Science][Medline]
- Bligard CA, Storer JS. Photosensitivity in infants and children.
Dermatol Clin. 1986;4
:311
–319[Web of Science][Medline]
- Moore DE. Drug-induced cutaneous photosensitivity: incidence, mechanism, prevention and management.
Drug Saf. 2002;25
:345
–372[CrossRef][Web of Science][Medline]
- Drugs that cause photosensitivity.
Med Lett Drugs Ther. 1995;37
:35
–36[Medline]
- Ernst E, Rand JI, Barnes J, Stevinson C. Adverse effects profile of the herbal antidepressant St. John's wort (Hypericum perforatum L.).
Eur J Clin Pharmacol. 1998;54
:589
–594[CrossRef][Web of Science][Medline]
- Harth Y, Rapoport M. Photosensitivity associated with antipsychotics, antidepressants and anxiolytics.
Drug Saf. 1996;14
:252
–259[Web of Science][Medline]
- Vassileva SG, Mateev G, Parish LC. Antimicrobial photosensitive reactions.
Arch Intern Med. 1998;158
:1993
–2000[Abstract/Free Full Text]
- Fotiades J, Soter NA, Lim HW. Results of evaluation of 203 patients for photosensitivity in a 7.3-year period.
J Am Acad Dermatol. 1995;33
:597
–602[CrossRef][Web of Science][Medline]
- Lawley TJ, Bielory L, Gascon P, Yancey KB, Young NS, Frank MM. A prospective clinical and immunologic analysis of patients with serum sickness.
N Engl J Med. 1984;311
:1407
–1413[Abstract]
- Sanklecha MU. Cefaclor induced serum sickness like reaction.
Indian J Pediatr. 2002;69
:921[Medline]
- Martin J, Abbott G. Serum sickness like illness and antimicrobials in children.
N Z Med J. 1995;108
:123
–124[Web of Science][Medline]
- Hebert AA, Sigman ES, Levy ML. Serum sickness-like reactions from cefaclor in children.
J Am Acad Dermatol. 1991;25
:805
–808[Web of Science][Medline]
- Levine LR. Quantitative comparison of adverse reactions to cefaclor vs. amoxicillin in a surveillance study.
Pediatr Infect Dis. 1985;4
:358
–361[Web of Science][Medline]
- Platt R, Dreis MW, Kennedy DL, Kuritsky JN. Serum sickness-like reactions to amoxicillin, cefaclor, cephalexin, and trimethoprim-sulfamethoxazole.
J Infect Dis. 1988;158
:474
–477[Web of Science][Medline]
- Heckbert SR, Stryker WS, Coltin KL, Manson JE, Platt R. Serum sickness in children after antibiotic exposure: estimates of occurrence and morbidity in a health maintenance organization population.
Am J Epidemiol. 1990;132
:336
–342[Abstract/Free Full Text]
- Kearns GL, Wheeler JG, Childress SH, Letzig LG. Serum sickness-like reactions to cefaclor: role of hepatic metabolism and individual sensitivity.
J Pediatr. 1994;125
:805
–811[Web of Science][Medline]
- Rosenfeld RM, Culpepper L, Doyle KJ, et al. Clinical practice guideline: otitis media with effusion.
Otolaryngol Head Neck Surg. 2004;130(5 suppl)
:S95
–S118
- Parshuram CS, Phillips RJ. Retrospective review of antibiotic-associated serum sickness in children presenting to a paediatric emergency department.
Med J Aust. 1998;169
:116[Web of Science][Medline]
- Shapiro LE, Knowles SR, Shear NH. Comparative safety of tetracycline, minocycline, and doxycycline.
Arch Dermatol. 1997;133
:1224
–1230[Abstract/Free Full Text]
- Harel L, Amir J, Livni E, Straussberg R, Varsano I. Serum-sickness-like reaction associated with minocycline therapy in adolescents.
Ann Pharmacother. 1996;30
:481
–483[Abstract]
- Slama TG. Serum sickness-like illness associated with ciprofloxacin.
Antimicrob Agents Chemother. 1990;34
:904
–905[Abstract/Free Full Text]
- Parra FM, Pérez Elias MJ, Cuevas M, Ferreira A. Serum sickness-like illness associated with rifampicin.
Ann Allergy. 1994;73
:123
–125[Web of Science][Medline]
- Colton RL, Amir J, Mimouni M, Zeharia A. Serum sickness-like reaction associated with griseofulvin.
Ann Pharmacother. 2004;38
:609
–611[Abstract/Free Full Text]
- McCollom RA, Elbe DH, Ritchie AH. Bupropion-induced serum sickness-like reaction.
Ann Pharmacother. 2000;34
:471
–473[Abstract]
- Peloso PM, Baillie C. Serum sickness-like reaction with bupropion.
JAMA. 1999;282
:1817[Free Full Text]
- Waibel KH, Katial RK. Serum sickness-like reaction and bupropion.
J Am Acad Child Adolesc Psychiatry. 2004;43
:509[CrossRef][Web of Science][Medline]
- Park H, Knowles S, Shear NH. Serum sickness-like reaction to itraconazole.
Ann Pharmacother. 1998;32
:1249[CrossRef][Web of Science][Medline]
- Shapiro LE, Knowles SR, Shear NH. Fluoxetine-induced serum sickness-like reaction.
Ann Pharmacother. 1997;31
:927[Web of Science][Medline]
- Revuz J. New advances in severe adverse drug reactions.
Dermatol Clin. 2001;19
:697
–709[CrossRef][Web of Science][Medline]
- Knowles S, Shapiro L, Shear NH. Serious dermatologic reactions in children.
Curr Opin Pediatr. 1997;9
:388
–395[Medline]
- Garcia-Doval I, LeCleach L, Bocquet H, Otero XL, Roujeau JC. Toxic epidermal necrolysis and Stevens-Johnson syndrome: does early withdrawal of causative drugs decrease the risk of death?
Arch Dermatol. 2000;136
:323
–327[Abstract/Free Full Text]
- Kaur S, Sarkar R, Thami GP, Kanwar AJ. Anticonvulsant hypersensitivity syndrome.
Pediatr Dermatol. 2002;19
:142
–145[CrossRef][Web of Science][Medline]
- Carroll MC, Yueng-Yue KA, Esterly NB, Drolet BA. Drug-induced hypersensitivity syndrome in pediatric patients.
Pediatrics. 2001;108
:485
–492[Abstract/Free Full Text]
- Rzany B, Hering O, Mockenhaupt M, et al. Histopathological and epidemiological characteristics of patients with erythema exudativum multiforme major, Stevens-Johnson syndrome and toxic epidermal necrolysis.
Br J Dermatol. 1996;135
:6
–11[CrossRef][Web of Science][Medline]
- Auquier-Dunant A, Mockenhaupt M, Naldi L, et al. Severe cutaneous adverse reactions: correlations between clinical patterns and causes of erythema multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis—results of an international prospective study.
Arch Dermatol. 2002;138
:1019
–1024[Abstract/Free Full Text]
- Léauté-Labrèze C, Lamireau T, Chawki D, Maleville J, Taïeb A. Diagnosis, classification, and management of erythema multiforme and Stevens-Johnson syndrome.
Arch Dis Child. 2000;83
:347
–352[Abstract/Free Full Text]
- Bastuji-Garin S, Rzany B, Stern RS, Shear NH, Naldi L, Roujeau JC. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme.
Arch Dermatol. 1993;129
:92
–96[Abstract/Free Full Text]
- Chan HL, Stern RS, Arndt KA, et al. The incidence of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis: a population-based study with particular reference to reactions caused by drugs among outpatients.
Arch Dermatol. 1990;126
:43
–47[Abstract/Free Full Text]
- Hurwitz S. Erythema multiforme: a review of its characteristics, diagnostic criteria, and management.
Pediatr Rev. 1990;11
:217
–222[Abstract/Free Full Text]
- Villiger RM, von Vigier RO, Ramelli GP, Hassink RI, Bianchetti MG. Precipitants in 42 cases of erythema multiforme.
Eur J Pediatr. 1999;158
:929
–932[CrossRef][Web of Science][Medline]
- Tay YK, Huff JC, Weston WL. Mycoplasma pneumoniae infection is associated with Stevens-Johnson syndrome not erythema multiforme (von Hebra).
J Am Acad Dermatol. 1996;35
:757
–760[CrossRef][Web of Science][Medline]
- Weston WL. What is erythema multiforme?
Pediatr Ann. 1996;25
:106
–109[Web of Science][Medline]
- Carrozzo M, Togliatto M, Gandolfo S. Erythema multiforme: a heterogeneous pathologic phenotype [in Italian].
Minerva Stomatol. 1999;48
:217
–226[Medline]
- Schalock PC, Dinulos JGH, Pace N, Schwarzenberger K, Wegner JK. Erythema multiforme due to Mycoplasma pneumoniae infection in two children.
Pediatr Dermatol. 2006;23
:546
–555[CrossRef][Web of Science][Medline]
- Assier H, Bastuji-Garin S, Revuz J, Roujeau JC. Erythema multiforme with mucous membrane involvement and Stevens-Johnson syndrome are clinically different disorders with distinct causes.
Arch Dermatol. 1995;131
:539
–543[Abstract/Free Full Text]
- Schöpf E, Stühmer A, Rzany B, Victor N, Zentgraf R, Kapp JF. Toxic epidermal necrolysis and Stevens-Johnson syndrome: an epidemiologic study from West Germany.
Arch Dermatol. 1991;127
:839
–842[Abstract/Free Full Text]
- Ginsburg CM. Stevens-Johnson syndrome in children.
Pediatr Infect Dis. 1982;1
:155
–158[Web of Science][Medline]
- Revuz J, Penso D, Roujeau JC, et al. Toxic epidermal necrolysis: clinical findings and prognosis factors in 87 patients.
Arch Dermatol. 1987;123
:1160
–1165[Abstract/Free Full Text]
- Guillaume JC, Roujeau JC, Revuz J, Penso D, Touraine R. The culprit drugs in 87 cases of toxic epidermal necrolysis (Lyell's syndrome).
Arch Dermatol. 1987;123
:1166
–1170[Abstract/Free Full Text]
- Prendiville JS, Hebert AA, Greenwald MJ, Esterly NB. Management of Stevens-Johnson syndrome and toxic epidermal necrolysis in children.
J Pediatr. 1989;115
:881
–887[CrossRef][Web of Science][Medline]
- Fritsch PO, Sidoroff A. Drug-induced Stevens-Johnson syndrome/toxic epidermal necrolysis.
Am J Clin Dermatol. 2000;1
:349
–360[CrossRef][Medline]
- Sharma VK, Sethuraman G, Kumar B. Cutaneous adverse drug reactions: clinical pattern and causative agents—a 6 year series from Chandigarh, India.
J Postgrad Med. 2001;47
:95
–99[Medline]
- Rademaker M, Oakley A, Duffil MB. Cutaneous adverse reactions to drugs in the hospital setting.
N Z Med J. 1995;108
:165
–166[Web of Science][Medline]
- Ponvert C, Le Clainche L, de Blic J, Le Bourgeois M, Scheinmann P, Paupe J. Allergy to beta-lactam antibiotics in children.
Pediatrics. 1999;104(4)
. Available at: www.pediatrics.org/cgi/content/full/104/4/e45
- Salkind AR, Cuddy PG, Foxworth JW. The rational clinical examination: is this patient allergic to penicillin? An evidence-based analysis of the likelihood of penicillin allergy.
JAMA. 2001;285
:2498
–2505[Abstract/Free Full Text]
- Elias SS, Patel NM, Cheigh NH. Drug induced skin reactions. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds.
Pharmacotherapy: A Pathophysiologic Approach. 5th ed. Norwalk, CT: Appleton and Lange; 2002:1705–1716
PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics
CiteULike 
Connotea 
Del.icio.us 
Digg 
Facebook 
Reddit 
Technorati 
Twitter What's this?
TOP
ABSTRACT
ESTABLISHING ETIOLOGY
