Liver transplantation after DRESS syndrome: A case report and review of the literature

Abstract This study reports a patient with DRESS syndrome, associated with liver failure, treated with orthotopic liver transplantation.


| INTRODUCTION
Drug reaction with eosinophilia and systemic symptoms is an unusual drug reaction-related condition. A case report of sulfasalazine-induced liver failure is described. The patient required liver transplantation. Liver transplantation is an option when the DRESS syndrome is associated with acute liver failure, but the prognosis remains poor.
Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) is a rare drug reaction-related condition. 1 Several drugs have been linked to DRESS. It is a severe idiosyncratic drug reaction characterized by erythematous or papulopustular skin eruption associated with lymphadenopathy, fever, and visceral involvement (hepatitis, nephritis pneumonitis, pericarditis, myocarditis, and colitis). [2][3][4][5][6] Leukocytosis, eosinophilia (90%), or mononucleosis (40%) may also be identified. 6 Severe acute hepatitis due to sulfasalazine or trimethoprim-sulfamethoxazole is described in the literature, but the occurrence of DRESS syndrome causing liver failure is rare.
In this study, we report a patient with acute liver failure due to sulfasalazine-induced DRESS, treated with a liver transplant.

| CASE REPORT
An 18-year-old male patient was treated with sulfasalazine for toxoplasma retinochoroiditis for one month. The patient had no history of allergies or drug intolerance. He reported to a local hospital with fever, vomiting, cervical and inguinal nodules, abdominal pain, and generalized body macular rash. The patient was transferred to our transplant center after the onset of jaundice and encephalopathy. He was admitted to the intensive care unit with facial edema, generalized scaling exanthema, and acute hepatitis. Serological tests for viral hepatitis and all autoimmune antibodies were negative. Laboratory tests showed a total eosinophil count of 3220/mm 3 (normal < 500 mm 3 ), high level of transaminases (aspartate aminotransferase = 1303 IU/L; alanine aminotransferase = 1768 IU/L, lactate dehydrogenase level of 2274 IU/L (normal, 240-480 IU/L), total bilirubin level of 18.47 mg/dL, direct bilirubin level of 14.81 mg/dL, prothrombin time (PT), international normalized ratio (INR) of 5.18, and factor V 17% (normal, 50%-150%). The MELD score was 43.
An abdominal ultrasound examination identified no chronic liver disease. The RegiSCAR (Registry of Severe Cutaneous Adverse Reaction) 7 system scored 5 points, confirming the DRESS syndrome diagnosis. Skin biopsy observed interface and spongiotic dermatitis, consistent with drug eruption.
Following the Clichy criteria, 8 the patient was worked up for urgent orthotopic liver transplantation (OLT), which was performed 24 hours after admission. At the time, he was under corticosteroids and clinical support, including mechanic ventilation due to progressive encephalopathy and dialysis due to lactic acidosis.
The orthotopic liver transplantation was uneventful. While liver function improved in the postoperative period, the patient developed sepsis requiring high doses of vasopressors. Broad-spectrum antibiotics were introduced (third-generation cephalosporin associated with ampicillin and then switched to carbapenem), but the patient remained hemodynamically unstable. The laboratory test showed progressively increasing acidosis and lactate levels, aspartate aminotransferase = 230 IU/L, alanine aminotransferase = 110 IU/L, total bilirubin level of 2 mg/dL, and INR of 1.5. The patient died on the seventh postoperative day. Blood cultures showed growth of Klebsiella pneumoniae resistant to carbapenems.

| Liver and skin histology
The histological analysis demonstrated massive eosinophilic infiltrates compatible with the diagnosis of DRESS syndrome, and the liver explant showed massive necrosis associated with eosinophilic infiltrate (Figures 1 and 2).

| DISCUSSION
This report describes an adult patient with DRESS syndrome and liver failure treated with OLT. Liver failure in the setting of DRESS syndrome is quite rare. A few case reports recorded in the literature showed DRESS syndrome and significant hepatic injury (Table 1). In these studies, most of the patients were treated with corticosteroids. 9-30 Among patients needing liver transplantation, there was approximately 50% perioperative mortality.
The management of DRESS syndrome is challenging. It is important to withdraw the suspected drug, and the delay is associated with poorer outcomes. [31][32][33] Supportive therapy in the intensive care unit should be provided to stabilize the patient. Early administration of systemic corticosteroid therapy is generally recommended. 34 A systemic corticosteroid helps to improve both clinical symptoms and laboratory abnormalities within days. 34 Most of the case reports of DRESS syndrome with liver dysfunction showed success with corticosteroid treatment (Table 1).
Liver transplantation is an option when the DRESS syndrome is associated with acute fulminant hepatic failure, but the prognosis remains poor (Table 2). 35 Recent studies support the use of Molecular Adsorbents Recirculation System (MARS), which uses albumin dialysis to mainly replace the liver's detoxification function as a rescue for liver failure patients. Roales-Gómez et al 39 described MARS use, although the patient did not respond well, and patients eventually underwent OLT. Ng et al 24 reported a pediatric patient that underwent MARS in the intensive care unit with a satisfactory response.
This study showed a patient with sulfasalazine and trimethoprim-sulfamethoxazole severe reaction.
Sulfasalazine and trimethoprim-sulfamethoxazole carry a significant risk of drug toxicity. Yusuf et al 25 reported the first case of DRESS syndrome in a child treated for toxoplasma retinochoroiditis. Rare cases of immunoallergic reactions to sulfasalazine, including DRESS syndromes, have been reported, such as the classic "3week sulfasalazine syndrome" occurring three weeks after the first administration. 9 The treatment of this reaction with a hefty dose of steroids, which can depress the immune system and can flare infections, most likely impacted the postoperative outcomes in the present case.