PEDIATRICS Vol. 108 No. 2 August 2001, pp. 485-492

EXPERIENCE AND REASON:
Drug-Induced Hypersensitivity Syndrome in Pediatric Patients

	ABSTRACT

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The antiepileptic hypersensitivity syndrome is a severe, multiorgan reaction to oral antiepileptics that manifests as fever, rash, lymphadenopathy, and hepatitis. This same reaction pattern also has been described following administration of a few unrelated medications. We report on 11 patients who had drug-induced hypersensitivity syndrome and were admitted to our pediatric service and review 94 cases of this syndrome in pediatric patients identified from the literature. We undertook this study to summarize the findings and alert clinicians to the severe internal organ involvement that can occur with this syndrome.

In 1988, Shear and Spielberg¹ suggested the term anticonvulsant hypersensitivity syndrome to describe a severe, multiorgan reaction to antiepileptics. Classically, the syndrome manifests as fever, rash, lymphadenopathy, and hepatitis.^1-5 This same reaction pattern also has been described following administration of a few unrelated medications (Table 1). Failure to recognize appropriately and discontinue the causative drug may result in increased severity and duration of internal organ involvement.^2,46-8

Drug-induced hypersensitivity syndrome (DIHS) has been reported to occur in all age groups, but this multisystem disorder has not been emphasized in the pediatric literature. However, accurate and timely diagnosis in the pediatric patient may be particularly challenging as 2 salient features of the syndrome, fever and rash, are common nonspecific signs of illness in children. An infectious cause, particularly viral illness, frequently is the initial diagnosis and may delay the discontinuation of the responsible medication.

We describe in detail a patient with DIHS and report on 10 additional patients who were admitted to the pediatric service at our institution from 1995 to 2000. All of these patients had features typical of this reaction, yet in several the correct diagnosis was not entertained initially. Because of the potential severity of this reaction, we believe that it is important for physicians who care for children to appreciate the broad spectrum of clinical findings associated with this disorder.

	METHODS

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Eleven pediatric patients with the diagnosis of DIHS were identified from a record of dermatology consults during a 5-year period (1995-2000) at Children's Hospital of Wisconsin, Milwaukee. The medical records of these patients were reviewed. We also reviewed the English-language literature on DIHS in pediatric patients. Our search strategy was to develop a list of key words that we thought might identify all literature pertaining to this syndrome in MEDLINE during the period January 1, 1966, through July 1, 2000. The key words used (alone and in combination with one another and the drugs listed in Table 1) were hypersensitivity reaction, hypersensitivity reaction syndrome, drug eruption, drug rash, and drug reaction. References of the selected articles were reviewed for possible relevant articles, yielding numerous additional references. We defined DIHS as the combination of fever, rash, and systemic involvement (of any internal organ) occurring in patients who were treated with oral or parenteral medication that is known to cause this reaction.^1,2,9 The term syndrome denotes that a constellation of clinical findings occur. Like all syndromes, a patient may lack one of the features yet still satisfy criteria for diagnosis. Cases that described severe drug-related cutaneous eruptions without involvement of other organ systems and those in which the patient age could not be verified were excluded.

	CASE REPORT

A 14-year-old black boy (Table 2, patient 11) presented 55 days after initiation of carbamazepine therapy (for the treatment of a conduct disorder) with a 2-day history of fever and rash. He was given the diagnosis of scarlet fever (Group A Streptococcus antigen test was negative) and treated with penicillin VK only to return 4 days later with increased lethargy, anorexia, fever, and cough. He then was thought to have a viral illness and an unrelated contact dermatitis. Penicillin was discontinued. After 5 days, he returned because of emesis, fever, upper respiratory symptoms, and worsening rash and was hospitalized. He had a generalized red, morbilliform eruption with desquamation of his hands and feet; bilateral axillary, submental, and inguinal lymphadenopathy; decreased bibasilar breath sounds; hepatosplenomegaly; and oliguria.

Abnormal laboratory studies included 23% eosinophilia, blood urea nitrogen of 63 mg/dL, creatinine of 6.5 mg/dL, lipase of 350 U/L, creatinine kinase of 4388 U/L, protime of 18.1 seconds, international normalized ratio of 3.05, partial thromboplastin time of 53.8 seconds, and elevated liver enzymes (aspartate transaminase of 308 U/L, alanine aminotransferase of 421 U/L, lactate dehydrogenase of 4180 U/L, and -glutamyltranspeptidase of 575 U/L). Titers were negative for hepatitis A and B, Epstein-Barr virus, human immunodeficiency virus, and cytomegalovirus. Throat, blood, stool, urine, and intravenous line catheter cultures all were negative for pathogens.

A diagnosis of DIHS was made 18 days after onset of symptoms, and carbamazepine was stopped after a total of 71 days of use. During the remainder of his hospitalization, the patient had worsening hepatitis (aspartate transaminase of 1157 U/L, alanine aminotransferase of 1687 U/L, lactate dehydrogenase of 9074 U/L, and -glutamyltranspeptidase of 575 U/L), pneumonitis requiring intubation, kidney failure requiring hemodialysis, myositis, and pancreatitis. Biopsies of the skin, muscle, kidney, and liver revealed an inflammatory reaction with focal areas of necrosis in all 4 organs. The patient was treated with intravenous methylprednisolone (10 mg/kg/dose) and oral prednisone (1-2 mg/kg/d). Alternative antiepileptics were not instituted.

The boy was discharged from the hospital on the 21st hospital day but required 2 subsequent hospitalizations. Nineteen weeks after the onset of his initial symptoms, he was transferred to another hospital, where he could be closer to family members. He was not subsequently seen in follow-up.

	RESULTS

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Eleven patients with DIHS were admitted to our pediatric service during a 5-year period. Their clinical characteristics and the responsible drugs are listed in Table 2. The median age was 12 years, and the range was 7 months to 17 years. There were 6 boys and 5 girls. Seven patients were white, 3 were black, and 1 was Hispanic.

All of our patients (100%) had a rash, which developed 7 to 60 days (median: 17 days) after the patient began the suspected drug. All had a generalized morbilliform eruption: 9% progressed to erythroderma, and 9% progressed to chronic exfoliative dermatitis. Vesicles or bullae occurred in 27%, and petechiae or purpura occurred in 45%. Edema, most notably involving the face, was detected in 8 patients (73%). Other significantly edematous areas included the hands, legs, feet, penis, and scrotum.

The mucous membrane findings were subtle but present in 8 patients (73%). Specifically, 2 (18%) had mild to moderate conjunctival injection, and 8 (73%) had erythema of the oral mucosa, tonsillar plaques, intraoral petechiae, white papules, or erosions.

Ten of 11 patients (91%) developed fever ranging from 38.7°C to 40.1°C. One patient (patient 9) had generalized erythroderma and hypothermia. Lymphadenopathy was present in 8 patients (73%), involving cervical, axillary, submandibular, inguinal, occipital, posterior auricular, and submental nodes.

In addition to skin and lymph nodes, 10 of 11 patients (91%) had involvement of at least 1 other organ system and 9 of 11 (82%) had involvement of at least 2 other organ systems. The liver was most commonly affected (82%), followed by the kidney (55%) and lung (45%). There was splenomegaly in 3 patients (27%), myositis in 2 (18%), and pancreatitis in 2 (18%).

Hematologic abnormalities occurred in all patients and included eosinophilia (73%), leukocytosis (73%), reactive lymphocytosis (45%), leukopenia (9%), neutropenia (9%), lymphopenia (9%), anemia, type unspecified (45%), anemia of chronic disease (9%), hemolytic anemia (9%), and warm antibody autoimmune hemolytic anemia with an aplastic-type picture (9%).

Seven patients (64%) tested positive for an acute or recent viral or bacterial infection. However, we did not perform an extensive panel of tests, and the studies varied from one patient to another. Therefore, we could not rule out antecedent or concurrent infections in patients who had negative test results.

The diagnosis of DIHS and subsequent discontinuation of the suspected drug occurred 0 to 18 days (median: 3 days) after the onset of signs and symptoms. The drugs were administered for a total of 7 to 71 days (median: 25 days). Two patients (18%) each subsequently received two cross-reacting aromatic antiepileptics.

Six of 11 patients required treatment because of progressive internal organ involvement. Intravenous or oral prednisone at doses of 0.5 to 2.0 mg/kg was administered for a period of 1 to 8 weeks. Signs and symptoms of DIHS requiring hospitalization lasted from 4 to 81+ days, beginning with the onset of rash and ending with the day of discharge. Long-term follow-up was not available for all patients, but 4 patients (6-9) who were seen in follow-up had persistent disease activity for 2 to 16 weeks after the medication had been discontinued.

Ninety-four cases of DIHS in pediatric patients were identified from the literature (Table 3). Seventy-seven (82%) followed the use of an antiepileptic medication, 9 (17%) were due to minocycline, 7 (7%) were due to a sulfa-based drug, and 1 (1%) followed use of dapsone. Patient age ranged from 1.5 to 17 years with a median age of 8 years. Thirty-six (38%) were female, 50 (53%) were male, and the gender was not declared in 8 (9%) of the patients.

	DISCUSSION

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Hypersensitivity syndrome reaction is the term that Shear et al¹ used to describe a specific multisystem idiosyncratic drug reaction. The initial reports were of patients who took aromatic antiepileptics^10,11; however, it now has become clear that this type of reaction pattern can be induced by other medications (Table 1). We chose the term drug-induced hypersensitivity syndrome to describe this adverse drug reaction. The overall population risk of DIHS secondary to use of antiepileptics is estimated to be between 1:1000 and 1:10 000.^12,13 A true incidence is difficult to determine because the variable presentation and diverse clinical and laboratory abnormalities have led to inaccurate reporting.^2,4 There are no data for the incidence of DIHS caused by nonantiepileptic medications.

There does not seem to be any age or gender variation.¹⁴ Although some reported studies showed a slightly increased incidence in black patients, this finding is controversial and may be attributable to the higher incidence of epilepsy in that population.^2,15 Siblings of patients with this hypersensitivity syndrome may have up to a 1:4 risk of a similar reaction.^1,13

The aromatic antiepileptics (phenytoin, phenobarbital, and carbamazepine) are the best studied of the drugs that cause DIHS. They have in common an aromatic benzene ring that is metabolized to arene oxides.¹² The exact mechanism of toxicity is not known, but in some patients it is postulated to involve a defect in the epoxide hydrolase enzymatic pathway, which normally degrades the toxic arene oxide metabolites formed during oxidation of the antiepileptics.^6,16,17 These arene oxide metabolites may be cytotoxic directly or act as haptens, leading to a secondary immune or hypersensitivity reaction.¹⁸ It should be noted that although lamotrigine contains an aromatic ring structure, it does not seem to cross-react with the traditional antiepileptics, perhaps because it is not metabolized to active metabolites through the cytochrome p450 system.

Once a patient has DIHS to one aromatic antiepileptic, exposure to another can cause an even more severe reaction.^1,4,19 This was evidenced in patient 10, who was treated with phenytoin followed by phenobarbital, which resulted in extensive internal organ involvement.

A defect in glutathione transferase-mediated enzymatic breakdown has been suggested as a cause for DIHS following use of sulfonamides.^12,20,21 The mechanisms of toxicity of the other medications listed in Table 1 are not known.

Clinical Features

Patients with DIHS typically present with fever, rash, and internal organ involvement. Fever almost invariably is present and often is the initial sign. Both steady temperature elevations and spiking fevers have been described. Fever may be present for several days before the development of other signs and symptoms.

Cutaneous findings were present in all of our patients (Table 2) and in 98% of reported patients (Table 3). The rash generally begins on the face, upper trunk, and proximal extremities as dusky red papules and macules, which coalesce into larger patches or a generalized erythroderma (Fig 1). As the reaction progresses, the cutaneous eruption becomes less erythematous and there often is thick, plate-like, brawny desquamation of the skin, particularly on the palms and soles (Fig 2). If the patient is not examined during the acute phase of the syndrome, then the erythema may resolve and the skin instead will appear ichthyotic, particularly in deeply pigmented skin (Fig 3). The skin changes can persist for several weeks after discontinuation of the drug. Severe epidermal necrosis, such as is seen in erythema multiforme and toxic epidermal necrolysis, has been reported but did not occur in our patients.^6,22 A striking feature of DIHS is the prominent edema of the face, particularly in the periorbital area (Fig 4).

View larger version (116K): [in this window] [in a new window]   Fig. 1.   Generalized distribution of the eruption in DIHS (patient 2).

View larger version (133K): [in this window] [in a new window]   Fig. 2.   Thick plate-like desquamation of the palms in DIHS (patient 11).

View larger version (121K): [in this window] [in a new window]   Fig. 3.   Ichthyotic appearance of the eruption of DIHS in a black patient (patient 11).

View larger version (106K): [in this window] [in a new window]   Fig. 4.   Periorbital edema in DIHS (patient 2).

Frequently, there is inflammation of the mucosal surfaces, including mild conjunctivitis, strawberry tongue, pharyngitis, and oral ulcerations. A high percentage of our patients had mucosal changes; however, widespread ulcerations as are observed in patients with Stevens-Johnson syndrome or toxic epidermal necrolysis were not present. Likewise, the limbal conjunctivitis and bright red swelling of the lips as are seen in classic Kawasaki disease were not observed. Genital erosions and ulcerations have been reported²³; however, genital involvement was limited to nonmucosal surfaces in our patients.

Lymphadenopathy can be localized or generalized¹⁴ and usually is symmetric. In our series of patients and the cases reviewed, a majority of patients had enlarged cervical lymph nodes. Because the lymphadenopathy can be marked and the diagnosis of DIHS overlooked, nodes sometimes are biopsied. Histopathologic changes range from benign lymphoid hyperplasia to cells that suggest malignancy.¹⁵ There also have been reports of atypical lymphoid hyperplasia, which, nevertheless, usually resolves.²

Much of the morbidity of DIHS is related to inflammation of internal organs. The extent and severity of systemic involvement reported in pediatric patients is variable, and any organ system may be involved (Table 4). Furthermore, patients may be asymptomatic. The liver was the most frequently involved organ in the published pediatric cases (61%) that we reviewed and in our series (81%) as well. Severity ranged from mild hepatomegaly to liver failure.^6,22,24 The hepatitis frequently is described as nonicteric and may escape detection if liver markers are not evaluated.

Hematologic abnormalities include lymphocytosis, leukopenia, eosinophilia, anemia (including aplastic anemia), and alterations in the platelet count.^6,11,19,25 Kidney involvement (nephritis, hematuria, proteinuria) was seen in 15% of the pediatric patients in our review. Pancreatitis, pneumonitis, pulmonary edema, myositis, myocarditis and hyper- and/or hypothyroidism are among the other findings that have been described or were seen in our patients.^2226-30 Central nervous system manifestations have been reported rarely.²⁶

The laboratory abnormalities that accompany the above-described systemic findings also show wide variability. Signs and symptoms of internal involvement may lag behind the cutaneous eruption by several weeks and often persist for weeks to months after the acute episode, as was demonstrated in several of our patients. There is no evidence that DIHS is dose related. Physicians must be aware that some patients may continue to deteriorate for weeks after the causative agent has been discontinued.^1,4,15 Failure to recover promptly on discontinuation of the drug, therefore, should not cause the physician to dismiss the diagnosis of a hypersensitivity reaction. Repeat hospitalization for worsening or persisting symptoms is not uncommon, as was noted in 27% of our cases.

There were no deaths in our series. There was 1 fatality in the reported cases. There may be some reporting bias with regard to the severity of the published cases and our own cases. It is possible that less-severe cases are not reported and/or do not elicit dermatology consultation.

Differential Diagnosis

Differentiation of DIHS from bacterial and viral infection is the most challenging aspect of diagnosing and caring for these patients. Other possible diagnoses, including Kawasaki disease, serum sickness, serum sickness-like reaction, acute lymphoma, and collagen vascular diseases, are more easily excluded on the basis of well-established diagnostic criteria and laboratory testing. Serum sickness-like reaction, classically associated with cefaclor use, can be distinguished by the presence of urticarial lesions and lack of internal organ involvement.

Many of our patients originally received a diagnosis of having a viral illness, and in fact 45% of patients in our series had serology positive for a recent or concurrent infection. Several recent reports emphasized a possible role for viral infection as a cofactor in DIHS. Human herpesvirus 6 infection in patients with drug hypersensitivity reactions has been documented in 3 patients.^31-33 A proposed mechanism for the role of viruses in hypersensitivity reactions suggests that immunologic modifications that accompany DIHS may be a factor. For example, patients with viral infection may form autoantibodies against the enzymes involved in the cytochrome p450 system of drug detoxification, thus rendering the patient unable to metabolize the drug properly.^31-34 Alternatively, viral infections may be an epiphenomenon facilitated by DIHS.³⁵ None of our patients was tested for human herpesvirus-6. There never has been a standard panel of viral tests performed in DIHS patients; thus, one can only speculate on the role of viruses until more data are available.

Evaluation and Treatment

Because this syndrome is difficult to diagnose and there is neither a set of diagnostic criteria nor a standard workup for DIHS, there has been little consistency in the evaluation of patients. Table 4 summarizes the systemic findings reported in pediatric DIHS patients and can help guide evaluation of patients. At the least, complete blood count, liver enzymes, and urinalysis should be obtained. In addition, baseline and follow-up thyroid testing have been recommended recently. The lymphocyte toxicity assay is an in vitro tool used to detect an individual's susceptibility to drug toxicity by determining lymphocyte susceptibility to toxic metabolites. It is not available for clinical use.²

Children with severe skin findings, inability to maintain fluid status (especially difficult in erythrodermic patients), or evidence of systemic involvement should be hospitalized for further evaluation. Often, supportive therapy is the only necessary treatment.^12,14 Skin care may include the use of topical steroids to alleviate symptoms. Oral and intravenous steroids (1-2 mg/kg/d) sometimes are used in patients with systemic involvement; however, there have been no randomized, controlled trials to prove that they shorten the duration of the reaction or affect morbidity or mortality.³⁶ Six of our 11 patients (55%) were treated with intravenous and/or oral steroids. Long-term follow-up is advised as skin and/or systemic involvement can continue for several weeks, as was demonstrated by 4 of our patients who had liver and/or skin involvement when seen in follow-up 2 to 16 weeks after discontinuation of medication. Three of these patients had been treated with oral steroids.

	CONCLUSION

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Prompt recognition of DIHS and immediate discontinuation of the causative drug is of utmost importance in the treatment of these patients to prevent or minimize more serious sequelae involving other organs.^2,46-8 Patients and their families should be counseled regarding the diagnosis of DIHS, and patients should be labeled allergic to the appropriate medications. Timely diagnosis and discontinuation of the medication undoubtedly will reduce the morbidity of DIHS.

Maria C. Carroll, MD^*
Kimberly A. Yueng-Yue, MD
Nancy B. Esterly, MD^*,
Beth A. Drolet, MD^*,
Departments of ^* Dermatology and  Pediatrics
Medical College of Wisconsin
Milwaukee, WI 53226

	FOOTNOTES

Kimberly A. Yeung-Yue, MD, is a former student of the Medical College of Wisconsin.

Received for publication Sep 28, 2000; accepted Mar 26, 2001.

Reprint requests to (B.A.D.) Medical College of Wisconsin, Department of Dermatology, 9200 W. Wisconsin Ave, Milwaukee, WI 53226. E-mail: drolet{at}mcw.edu

	ABBREVIATIONS

DIHS, drug-induced hypersensitivity syndrome.

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Top Abstract Introduction Methods Results Discussion Conclusion References

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