DRESS syndrome is an acute, severe, and life-threatening disease with a mortality rate of about 10%. It is more common in adults and only rarely seen in children, in whom it is frequently associated with systemic organ involvement, such as liver dysfunction, renal impairment, and interstitial pneumonitis. Myocarditis, thyroiditis, encephalitis, and type 1 diabetes mellitus have also been reported as manifestations of this syndrome.
DRESS usually starts abruptly with maculopapular morbilliform exanthema with fever of > 38°C as of 2–3 weeks after the introduction of the culprit drug. Sometimes, there may be an upper-airway infection-like prodrome, suggesting viral infections as a possible trigger for this syndrome.
A diagnosis of DRESS can be made based on the diagnostic criteria established by the RegiSCAR group (Table 1) or those established by the Japanese Research Committee on Severe Cutaneous Adverse Reaction (Table 2), respectively.6–8 Leucocytosis with atypical lymphocytes and eosinophilia of various degrees are unique features of the early phase of DRESS, although leukocytopenia can occasionally precede leucocytosis. Our patient presented with fever and skin rash, and her lab data showed leucocytosis; therefore, mycoplasma pneumonia was suspected initially. However, in tracing back our patient’s past history, it was found that she had a history of epilepsy that been controlled initially under treatment with the anticonvulsant drug sodium valproate, which had subsequently been replaced with lamotrigine, 2 weeks after the initiation of which her skin rash first appeared. This drug history was a very important clue for the diagnosis of DRESS.
According to a review article by Shiohara et al., lamotrigine is the fourth most common culprit among anticonvulsant drugs in terms of inducing DRESS.3 In another study, Brandon et al. reported that among 32 children diagnosed with anticonvulsant hypersensitivity syndrome, 12 of them (37.5%) were taking carbamazepine, 11 of them (34.5%) were taking phenytoin, 5 of them (6.25%) were taking phenobarbital, and 5 of them (6.25%) were taking lamotrigine.10 In still another study, Wang et al. reported that of 57 patients with DRESS induced by lamotrigine, 14 of them (24.6%) were children. This study found a greater predominance of women with lamotrigine-induced DRESS, but in children, we found a greater predominance of lamotrigine-induced DRESS among boys (with a boy-to-girl ratio = 9:7), and we have summarized the characteristics of 16 published cases of paediatric patients with lamotrigine-induced DIHS/DRESS in Table 3.10 Four of them had DRESS when lamotrigine was given concurrently with sodium valproate.
Table 3
Characteristics of children (< 18 year-old) with lamotrigine-induced DIHS/DRESS in published case studies.10–12
Case | Age/Sex | Initial dose (mg/day) | Final dose (mg/day) | Latency time (days) | Concurrent drugs | Treatment | Outcome |
1 | 11/F | NA | NA | NA | NA | Steroid + IVIG | Cured |
2 | 6/M | NA | NA | 10 | VPA | No steroid | Cured |
3 | 14/M | NA | NA | 52 | NA | No steroid | Cured |
4 | 8/M | NA | NA | 21 | None | Steroid | NA |
5 | 16/F | NA | NA | within 56 | NA | NA | NA |
6 | 17/F | 50 | 50 | 21 | None | Steroid | Cured |
7 | 4/F | NA | NA | NA | NA | NA | NA |
8 | 2/F | NA | NA | NA | NA | NA | NA |
9 | 3/M | NA | NA | NA | NA | NA | NA |
10 | 7/M | NA | NA | NA | NA | NA | NA |
11 | 12/M | NA | NA | NA | NA | NA | NA |
12 | 6/M | NA | NA | NA | VPA | No steroid | Cured |
13 | 15/F | 50 | 75 | 30 | VPA 2000mg/d | NA | NA |
14 | 12/M | 25 | 50 | 18 | VPA | Steroid | Cured |
15 | 4/M | NA | NA | 30 | NA | IVIG + plasma exchange | Cured |
16 (Our patient) | 7/F | 50 | 100 | 14 | NA | Steroid + mycophenolate + tacolimus | Cured |
VPA = valproic acid, IVIG = intravenous immunoglobulin, NA = not available |
About 50–60% of cases of DRESS with organ involvement occur in the liver, and such DRESS may progress into fulminant hepatitis or hepatomegaly, with hepatic failure being a common cause of death.11
Systemic corticosteroids have been accepted as the gold standard treatment for ameliorating the clinical symptoms of DRESS. However, they need to be tapered over 6–8 weeks to prevent the relapse of various symptoms.3 The usage of intravenous immunoglobulin (IVIG) for patients with life-threatening signs such as renal failure or respiratory failure has also been recommended.10–13 Meanwhile, some authors have reported beneficial effects of the concomitant use of N-acetyl cysteine because of its detoxifying capabilities.12 Alexander et al. reported a dramatic, sustained clinical response to therapeutic plasma exchange after a steroid treatment failed in a paediatric case of DRESS associated with either lamotrigine or bupropion, leading to multiorgan involvement and life-threatening complications of respiratory failure and cardiac arrest.13 Our patient presented fever and dyspnoea initially, and her symptoms progressed to pulmonary insufficiency requiring non-invasive positive pressure ventilator support. Furthermore, our patient developed jaundice with severe liver dysfunction, and the immunosuppressant drugs of mycophenolate and tacolimus were even prescribed after steroid therapy due to hepatic failure. The use of immunosuppressant drugs for DRESS has never previously been reported in the literature. Our patient may thus be the first patient with a case of DRESS treated with immunosuppressant drugs.
The pathogenesis of DRESS remains a matter of speculation, but several theories have been proposed. On theory is that the anticonvulsants are converted into toxic arene oxide metabolites, which are then metabolized by enzymes within the body.14 Another neoantigen theory speculates that toxic arene oxide reactive metabolites may also alter the cytochrome P450 enzymes, such as those in the liver, skin, kidneys, stomach, intestinal tract, and lungs.15 In short, it is generally regarded, like other severe drug eruptions, as a T-cell mediated hypersensitivity reaction. Therefore, the clinical resolution of DRESS is associated with a shift away from Tregs to Th 17 cell differentiation.3
DRESS should be considered in patients with skin rash and liver function impairment occurring several weeks after the initiation of an anticonvulsant drug. Relatedly, the early recognition and early withdrawal of allergenic drugs is a very important aspect of the management of DRESS. Glucocorticoid therapy is the first choice treatment, and plasma exchange, IVIG, and immunosuppressant drugs should be considered for multiorgan involvement and life-threatening complications.