PEDIATRIC PHARMACOTHERAPY A Monthly Newsletter for Health Care Professionals from the University of Virginia Children’s Hospital Volume 18 Number 11 November 2012 DRESS Syndrome: Examples from the Pediatric Literature Marcia L. Buck, Pharm.D., FCCP, FPPAG he acronym Drug Reaction with Diagnostic Criteria T Eosinophila and Systemic Symptoms Two groups have developed specific criteria for (DRESS) was first used by Bocquet and making the diagnosis of DRESS.4,6,7 The colleagues in 1996 to describe patients exhibiting RegiSCAR program was developed by an a drug-induced condition characterized by an international study group investigating severe extensive rash, fever, lymphadenopathy, cutaneous reactions (SCAR).7 To meet the hematologic abnormalities, hepatitis, and definition of DRESS, patients must have three of involvement of the kidneys, lungs, heart, or the four main RegiSCAR criteria: an acute rash, pancreas.1 The onset of symptoms is often fever above 38◦ C, lymphadenopathy at two sites, delayed, occurring 2-6 weeks after drug involvement of at least one internal organ, and initiation. DRESS syndrome shares many abnormalities in lymphocyte and eosinophil characteristics in common with anticonvulsant counts. Additional criteria include hospitalization hypersensitivity syndrome (AHS), also referred and that the reaction is suspected to be drug- to as drug-induced hypersensitivity syndrome related. (DIHS), and appears to represent a variation in presentation rather than a distinctly different A Japanese consensus group has developed a syndrome. The incidence of DRESS has been second set of criteria for DRESS.7 The diagnosis estimated to be between 1 in 1,000 and 1 in requires meeting seven of the nine criteria in this 10,000 drug exposures. It carries a mortality rate system or all of the first five: a maculopapular of 10-20%, with most fatalities the result of liver rash developing > 3 weeks after drug initiation, failure. Treatment consists of supportive clinical symptoms continuing > 2 weeks after therapy, corticosteroids, and antihistamines.2-4 stopping therapy, fever > 38◦ C, liver abnormalities (ALT > 100 IU/L) or other organ Proposed Mechanisms involvement, leukocytosis, atypical lymphocytes, The pathogenesis of DRESS syndrome is not yet eosinophilia, lymphadenopathy, or HHV-6 well understood. Although it is considered an reactivation. idiosyncratic reaction, three potential causative factors have been identified among multiple Drugs Associated with DRESS cases: 1) a defect in drug metabolism resulting in More than 50 drugs have been linked to DRESS the failure to eliminate toxic reactive syndrome. The drugs most often reported with intermediates, 2) reactivation of human DRESS include anticonvulsants (particularly herpesvirus 6 (HHV-6), human herpesvirus 7 those with aromatic structures), sulfa derivatives, (HHV-7), Epstein-Barr virus (EBV), or antidepressants, nonsteroidal anti-inflammatory cytomegalovirus (CMV), which may serve as a drugs, and antimicrobials (Table).2,3,8 trigger for the reaction, and 3) a genetic predisposition that alters immune response.1-4 Table. Drugs associated with DRESS in two or more cases Based on these factors, Moling and colleagues Abacavir Lamotrigine successfully treated an adult with sulfasalazine- Allopurinol Mexiletine related DRESS using a combination of Amitriptyline Minocycline prednisone, N-acetylcysteine to neutralize Captopril Nevirapine reactive metabolites and reduce oxidative stress, Carbamazepine Oxcarbazepine and valganciclovir to reduce the effects of HHV- Cefixime Phenobarbital 6 reactivation.5 Further work is needed to Celecoxib Phenytoin establish the efficacy of this novel combination Dapsone Sulfasalazine and determine its potential role in the Hydroxychloroquine Sulfamethoxazole management of DRESS syndrome. Ibuprofen Vancomycin Recent Pediatric Case Reports vesiculation and patchy exocytosis. A diagnosis of DRESS was made, phenytoin was stopped, Phenytoin and prednisolone was started at a dose of 1 Cases of both AHS and DRESS have been mg/kg/day. The patient’s symptoms resolved reported in children taking phenytoin. In 2009, within a week. Prednisolone was continued for 2 Armin and colleagues described two cases.9 The weeks, followed by a 4-week taper. first patient, a 7-year-old boy with a complex medical history including chronic renal failure, Deka and colleagues described a 10-year-old boy developed fever and a skin rash which persisted who developed a high fever, cough, respiratory despite a month of antibiotics. His symptoms distress, hoarseness, and a rash while taking progressed to include lymphadenopathies and clonazepam, gabapentin, and phenytoin.11 His arthralgia, along with a mild anemia, leukopenia, symptoms progressed to include oral mucosal and an elevated erythrocyte sedimentation rate ulceration, lymphadenopathy, periorbital and (ESR). His symptoms failed to improve after extremity edema, hepatomegaly, and rales. stopping the antibiotics. Upon detailed review of Laboratory values revealed eosinophilia and the patient’s history, it was discovered that he elevated serum transaminases. Antibiotic had started therapy with phenytoin 2 months treatment with amoxicillin-clavulanic acid and earlier. A diagnosis of AHS was made and the vancomycin failed to produce improvement. A phenytoin was discontinued. The fever and rash diagnosis of DRESS was made, phenytoin was resolved within one week. At follow-up 3 weeks discontinued, and steroid therapy was started. later, all symptoms had resolved and all Within 48 hours, the patient defervesced and his laboratory tests were approaching normal values. symptoms began to resolve. In the second case, a 5-year-old girl was admitted Carbamazepine and Oxcarbazepine with a history of fever, rash, and Buyuktiryaki and colleagues described DRESS lymphadenopathy for 2 weeks. She subsequently in an 8-year-old girl taking carbamazepine.12 developed hepatosplenomegaly and severe The patient initially presented to an emergency respiratory distress with a parahilar infiltrate. department with fever, lymphadenopathy, and a Laboratory values indicated leukocytosis, rash on her trunk. She was given amoxicillin- eosinophilia, thrombocytopenia, increased clavulanic acid, acetaminophen, and transaminase levels, and an increased ESR. hydroxyzine. Ten days later, she returned with After a patient history revealed the use of no improvement. A detailed medication history phenytoin for the previous 1.5 months, a revealed that the patient had been prescribed diagnosis of presumed DRESS was made and carbamazepine 5 weeks earlier. During her phenytoin was discontinued. Although hospitalization, she developed cervical administration of intravenous immune globulin lymphadenopathy, a desquamating rash on the early during her admission failed to produce face, trunk, and extremities, and improvement, treatment with methylprednisolone hepatosplenomegaly. Laboratory values at the time when phenytoin was stopped resulted included a leukocyte count of 6,200/μL with 22% in significant benefit. Her fever, rash, and eosinophils, 41% neutrophils, 29% lymphocytes, respiratory distress resolved within a week. and 7% monocytes. Serum transaminases were within the normal range, but γ-glutamyl Two more pediatric cases of phenytoin- transferase was elevated at 296 IU/L. Her C- associated DRESS were published earlier this reactive protein was 7.5 mg/dL (normal < 0.8 year. Gupta and colleagues described the case of mg/dL). Immunoglobulin and complement levels a 16-year-old boy in BMJ Case Reports.10 The were normal. Bone marrow aspiration revealed patient had been taking phenytoin 300 mg/day dysplastic changes with 24% eosinophils. and folic acid 5 mg/day for 6 weeks. He presented with a high-grade fever, jaundice, and After the patient failed to respond to antibiotics, an erythematous rash that had been present for 15 a hypersensitivity reaction to carbamazepine was days. The rash began as a maculopapular suspected. Skin biopsy revealed acanthosis, eruption, but progressed to an exfoliative parakeratosis, and spongiosis in the epidermis, dermatitis. Upon examination, he had edema, and eosinophilic infiltration in the generalized lymphadenopathy and tender dermis. After meeting the RegiSCAR criteria for hepatomegaly. Laboratory values included a DRESS, the patient’s carbamazepine was hemoglobin of 12 g/dL and a leukocyte count of replaced with levetiracetam and a short course of 15,700/mm3, with 15% eosinophils, 52% systemic corticosteroids and an antihistamine polymorphs, 28% lymphocytes, and 5% were started. Symptoms resolved within 4 monocytes. Serum transaminases were greater weeks. Six weeks after her recovery, the patient than 5 times the upper limit of normal, with a underwent patch testing to compare her reaction serum bilirubin of 7.6 mg/dL. A biopsy of the to carbamazepine, levetiracetam, and petroleum rash revealed spongiosis with intraepidermal as a control. Carbamazepine produced a positive response within 48 hours at both 5 and 10% for an upper respiratory tract infection.16 The concentrations. Levetiracetam and the control patient presented with a pruritic rash, fever, and produced no response. periorbital and perioral edema. She had been prescribed oral penicillin V for Oxcarbazepine, the keto homologue of tonsillopharyngitis 15 days earlier. After failing carbamazepine, has been linked to DRESS in a to improve, she was hospitalized and given IV single case report. In a 2004 issue of Archives of penicillin for 2 days, followed by ceftriaxone