Carbamazepine-Induced Acute Generalized Exanthematous Pustulosis: A Case Report

Abstract

A 15-year-old adolescent was admitted to the hospital for management of a generalized pruritic skin rash, which had appeared 10 days prior to admission. Carbamazepine (CBZ) and insulin were initiated 44 and 23 days prior to the onset of the skin rash (day 44), respectively. Clinical examination showed bluish lesions on the tongue and bilateral keratoconjunctivitis. His skin was very erythematous and pruritic without edema and covered with hundreds of nonfollicular pustules mainly on the trunk and skin folds. Laboratory assessment revealed leukocytosis, hypereosinophilia, and thrombocytopenia. A sample of superficial pus from a pustule on the trunk showed a significant number of leukocytes as well as a significant number of Staphylococcus aureus and Lancefield Group B β-hemolytic streptococci strains. An abdominal skin biopsy revealed acute to subacute folliculocentric spongiotic dermatitis with subcorneal pustules. All of these observations were consistent with a diagnosis of acute generalized exanthematous pustulosis (AGEP). Although we could not exclude with certainty the role of insulin initiated on day 21 and discontinued on day 55 with substitution to oral metformin and repaglinide, no cases of AGEP have ever been published with insulin, and skin lesions were not related to injection sites. This article describes a probable case of CBZ-induced acute generalized exanthematous pustulosis in a 15-year-old adolescent.

CASE REPORT

A 15-year-old adolescent was admitted to the hospital for management of a generalized pruritic skin rash, which had appeared 10 days prior to admission. His medical history was mainly characterized by pinealoblastoma, secondary panhypopituitarism, type 2 diabetes, cerebral vasculitis, and generalized epilepsy. The patient's drug history included oral levothyroxine, hydrocortisone, acetylsalicylic acid, carbamazepine (CBZ), and subcutaneous somatropine and insulin. CBZ (Tegretol CR, Novartis Pharma, Canada) was begun 44 days and insulin (Novolin and Novorapid, Novo Nordisk, Canada; Humalog and Humulin, Eli Lilly, Canada) was initiated 23 days prior to the onset of the skin rash (Figure). The patient had a past history of drug intolerances with hot flushes observed with naproxen and facial dyskinesia with concomitant administration of metoclopramide and diphenhydramine. He had no personal or family history of psoriasis. He also presented an undetermined minor rash localized on the forearms at day 30. This rash was resolved in 2 days without any specific treatment.

Figure.

Timeline of drugs used and adverse drug reactions

At the time of admission (day 54 post initiation of CBZ), his vital signs were as follows: pulse rate of 101 beats/min, respiration rate of 20 breaths/min, systolic and diastolic blood pressure of 90 and 53 mmHg, respectively, with 100% oxygen saturation. Bluish lesions on the tongue and bilateral keratoconjunctivitis were noted on physical examination. Cardiac, pulmonary, and abdominal auscultations were normal. The ear, nose, and throat examination did not reveal angioedema. His skin was very erythematous and pruritic without edema and covered with hundreds of nonfollicular pustules mainly on the trunk and skin folds. Laboratory assessment revealed leukocytosis 11.37 × 10⁹/L (reference range, 4.5-11 109/L) with normal polynuclear neutrophils 6.2 × 10⁹/L (reference range, 1.8-7.0 10⁹/L), hypereosinophilia 2.6 × 10⁹/L (reference range, 0.0-0.4 10⁹/L), and thrombopenia 119 × 10⁹/L (reference range, 140–440 10⁹/L). The remaining blood cell count and other relevant biological parameters (aspartate aminotransferase, alanine aminotransferase, bilirubin, creatinine, plasma proteins) were normal.

A sample of superficial pus that was obtained from a pustule on the trunk showed a significant number of leukocytes as well as Staphylococcus aureus and Lancefield Group B β-hemolytic streptococci strains. Acute to subacute folliculocentric spongiotic dermatitis with subcorneal pustules was noted on skin biopsy. The papillary structure of the dermis revealed pronounced edema associated with a perivascular lymphohistiocytic inflammatory infiltrate rich in eosinophils within the superficial and deep reticular dermis. All of these observations were consistent with a diagnosis of acute generalized exanthematous pustulosis (AGEP). The serum concentration of CBZ performed 24 hours after the last dose was of 3.1 mg/L (13.1 μmol/L). The last serum concentration was within the therapeutic range.

Based on these findings, CBZ was suspected to have caused AGEP. Following a neurology consult, CBZ was discontinued and oral clobazam (Frisium, Lundbeck Inc, Canada) was initiated. Symptomatic treatment consisted of a single 500-mg dose of intravenous hydrocortisone, 5 doses of 50-mg intravenous diphenydramine over 3 days, ten 20- to 30-mg doses of oral hydroxyzine over several days, and hydration solutions. As a precaution, rapid-acting insulin analogue was also discontinued and replaced with oral metformin and repaglinide. The course of recovery from conjunctival alteration began and the pustules evolved into desquamation after 24 hours.

DISCUSSION

AGEP is an uncommon skin eruption characterized by the rapid appearance of areas of red skin studded with small pustules (small blisters filled with white/yellow fluid). According to the European Study of Serious Cutaneous Adverse Reactions study (EuroSCAR),¹ the incidence ranges from 1 to 5 cases per million per year and the mortality rate approaches 1% to 2%.^1,2 Males and females are equally affected.¹ Bernard et al³ investigated genetic predisposing factors for AGEP and found that human leukocyte antigens (HLA) HLA-B51, HLA-DR11, and HLA-DQ3 are more frequent than in the average population.³ Furthermore, Roujeau et al⁴ provided stereotyped clinical features of AGEP with at least a dozen to a hundred small (<5 mm), nonfollicular, noninfectious, and superficial pustules. The rash occurs suddenly and predominately affects the skin folds, then spreads to the trunk and lower limbs. Skin symptoms are usually accompanied by fever and pronounced hyperleukocytosis. Hypereosinophilia, hepatic cytolysis, and renal failure are found in 30% of the reported cases and mucous membrane involvement occurred in 20%. Pustules usually resolve spontaneously after 7 to 10 days of desquamation.¹

As in Lyell syndrome, Stevens-Johnson syndrome, and fixed pigmented erythema, a drug-induced etiology must be considered first in AGEP. Nearly 90% of the cases in the literature are drug related and antibiotics are the main drug class involved.¹

To our knowledge, 7 cases of CBZ-induced AGEP have been previously described^1,2,5–8 (Table). Four of these cases were published with a relevant imputability score for CBZ.^5–8

Table.

Four Cases of Carbamazepine-Induced* Acute Generalized Exanthematous Pustulosis

Saissi et al² analyzed 207 AGEP cases reported to the French pharmacovigilance centers in 1985–2001. They reported a 3-day median interval between drug initiation and the occurrence of AGEP (range, 3 hours to 21 days).² The authors do not comment about the absence or presence of an AGEP–dose-related relationship. Compared with previously reported drug-induced AGEP cases, our patient's time to onset was much longer than any other reported, as the patient first noted it 44 days postinitiation of CBZ (steady-state plasma CBZ concentrations can be achieved in about 1 week⁹). Although the minor rash observed in our patient does not seem to be related to the AGEP episode and considering its quick resolution without any CBZ dose adjustment, we cannot rule out a shorter delay of onset. Most of the common antiepileptic adverse effects are dose dependent and reversible upon discontinuation of the medication.¹⁰ For instance, lamotrigine is frequently associated with cutaneous adverse reactions.¹¹ The incidence of lamotrigine-induced skin rash varies from 5% with initial doses up to 39% with fixed-dose treatment.^12,13

A causality assessment was performed using an AGEP validation score from the EuroSCAR study¹ and the Naranjo algorithm,¹⁴ both of which provided a score determining the likelihood of whether the adverse drug reaction was due to CBZ rather than the result of other factors. Recovery (day 57) after CBZ discontinuation (day 54) was also indicative of the causal relationship.

Although we could not exclude with certainty the role of insulin, no cases of AGEP have ever been published with insulin. Although insulin-induced skin reactions are usually localized around the point of injection,¹⁵ skin lesions were not related to injection sites in our patient.

Further testing could ascertain a definite causality relationship of CBZ with AGEP in this case. For example, epicutaneous patch testing performed 6 to 10 weeks after reaction improvement on previously affected areas has been described.¹⁶ Although drug rechallenge would definitely be conclusive, it is contraindicated, considering the risk of triggering an even more serious and potentially life-threatening AGEP.

CONCLUSION

This article describes a probable case of CBZ-induced acute generalized exanthematous pustulosis in a 15-year-old adolescent.

Abbreviations

AGEP

acute generalized exanthematous pustulosis

CBZ

carbamazepine

HLA

human leukocyte antigen