A Case of Sulfasalazine-Induced Hypersensitivity Syndrome Confirmed by Enzyme-Linked Immunospot Assay
A 24-year-old Thai male presented with high fever and abdominal pain for 4 days. The patient first noticed his fever accompanied with fatigue and a bitemporal throbbing pain without organ-specific symptoms, 2 weeks prior to admission when attending an outpatient clinic. Viral infection was the presumptive diagnosis. His low-grade fever remained for several weeks until 4 days prior to admission, when high fever and a progressive maculopapular rash developed. He also experienced epigastric pain, which brought him to our hospital again seeking medical attention.\nThe patient was diagnosed with bilateral chronic uveitis 2 years ago, when topical steroids had been prescribed. Low-dose oral prednisolone (15 mg/day) was subsequently added before tapering off within 11 months. Two months later, a diagnosis of spondyloarthropathy was suspected by the rheumatologist, when Achilles tenosynovitis, plantar fasciitis, and tenderness over the sacroiliac joints developed. Sulfasalazine was then prescribed starting at 1 g/day, gradually increasing to 2 g/day for 2 weeks prior to the development of fever.\nPhysical examination revealed high fever (38.5℃), cervical lymphadenopathy, pharyngitis with whitish patches on soft palate and buccal mucosa. The patient had a scattered maculopapular rash over his trunk and extremities and abdominal examination revealed mild epigastrium tenderness. A complete blood count revealed marked leukocytosis with a total white blood cell count of 23,740/µL, 50% neutrophils, 16% lymphocytes, 31% monocytes, and 3% eosinophils. Atypical lymphocytes were detected in peripheral blood smears. Blood culture and anti-viral antibody profiles were investigated; sulfasalazine was promptly discontinued.\nOn the third day of admission, the patient developed severe abdominal pain and mild icteric sclera was noted. Liver function tests showed direct hyperbilirubinemia with total bilirubin 3.34 mg/dL and direct bilirubin 2.94 mg/dL. ASL and ALT levels were 536 and 734 U/mL, respectively, and serum alkaline phosphatase was 301 IU/mL. Upper abdominal ultrasonography revealed gallbladder wall thickening with pericholecystic fluid collection and positive sonographic Murphy's sign. Intravenous ceftriaxone was then administered. On the ninth day of admission, he developed hypotension (blood pressure of 70/40 mmHg) before being rescued with 1,500-mL intravenous fluid. Abdominal computed tomography scans showed a collapsed gallbladder with a moderate amount of pericholecystic fluid, but no gallstones could be demonstrated (); hepatosplenomegaly and minimal ascites were also noticed. Dexamethasone (5 mg) was administered every 12 h intravenously for six doses, resulting in cessation of the fever and abdominal pain, after the third dose.\nThe viral studies yielded negative results for IgM and IgG against Epstein-Barr virus, cytomegalovirus, and Dengue virus. Blood culture results showed no bacterial growth. Anti-HIV and anti-human herpes virus 6 (HHV-6) IgM antibodies were also negative, but anti-HHV-6 IgG was positive (17.05 units with a cut-off value of 11 units). Two days after the initiation of steroids, the numbers of IFN-γ-releasing cells in the peripheral blood were measured by ELISPOT assay (Mabtech, Stockholm, Sweden) upon stimulation with four drugs as described previously. Significant numbers of IFN-γ-secreting cells were demonstrated (1,048 spots forming cells/106 PBMCs) upon incubation with 100 µg/mL sulfasalazine, but not with other drugs administered concurrently (ceftriaxone), previously (amoxicillin), or never (ceftazidime) (). Dexamethasone was then replaced with prednisolone 1 mg/kg/day before being tapered off over 3 weeks. His liver function tests returned to normal levels in 1 month; no complications were noted after 2 years of follow-up. His symptoms are now well controlled with NSAIDs and methotrexate.