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
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ABSTRACT
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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.
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ESTABLISHING ETIOLOGY
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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 al18 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."
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DESCRIPTION OF THE CUTANEOUS REACTION
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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.
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CLASSIFICATION OF CADRs
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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.
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FIVE COMMON CADR PATTERNS IN CHILDREN
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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 H1 blockers are associated with fewer sedative effects when compared with first-generation H1 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 al44 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 al41 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 al5 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
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RECOGNITION OF SEVERE CADRs
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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
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RISK FACTORS FOR CADRs IN CHILDREN
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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
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INITIAL MANAGEMENT OF A CADR
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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.
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CONCLUSIONS
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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.
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FOOTNOTES
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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.
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ABSTRACT
ESTABLISHING ETIOLOGY
