Drug‐induced hypersensitivity syndrome followed by exacerbation of Crohn's disease

To the Editor:

Drug‐induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) represents a severe T cell–mediated reaction frequently complicated by viral reactivation, including human herpesvirus 6 (HHV‐6). ¹ While autoimmune sequelae such as thyroiditis are recognized, gastrointestinal manifestations are rarely documented. ² We report the first endoscopically and histopathologically confirmed exacerbation of Crohn's disease (CD) following DIHS in a patient with preexisting CD.

A 16‐year‐old boy with a 3‐year history of ileocolonic CD was maintained on mesalazine (5‐aminosalicylic acid) and azathioprine. Because of persistent rectal inflammation (Figure 1A), aminosalicylic acid was substituted with salazosulfapyridine (SASP). After two weeks, he developed pyrexia, independently discontinued SASP, and the fever subsided within four days. One week later, he presented with pyrexia (>38°C); a diffuse, milia‐sized papular eruption with facial edema (Figure 1B–D); and cervical, axillary, and inguinal lymphadenopathies. Marked hepatic involvement and elevated inflammatory markers, including thymus and activation‐regulated chemokines, were observed. Skin biopsy revealed necrotic keratinocytes, spongiosis, and interface dermatitis with lymphocytic infiltration (Figure 1E). Serological testing for Epstein‐Barr virus, human immunodeficiency virus, syphilis, and cytomegalovirus (CMV) was negative. Serum polymerase chain reaction (PCR) detected HHV‐6 DNA, fulfilling the criteria for typical DIHS. ³

FIGURE 1.

Colonoscopic findings of Crohn's disease and clinicopathological features of drug‐induced hypersensitivity syndrome. (A) Sparse mucosal erythema with white plaques in the rectum before the onset of DIHS. Top left: terminal ileum; top center: cecum; top right: transverse colon; bottom left: descending colon; bottom center: sigmoid colon; bottom right: rectum. (B) Facial edema and diffuse scaling in the midface and periorbital region. (C) Multiple milia‐sized erythematous papules on the trunk. (D) Multiple milia‐sized erythematous papules on the upper extremities. (E) Spongiotic dermatitis with keratinocyte necrosis (arrow), vacuolar interface dermatitis with lymphocytic infiltrates (hematoxylin and eosin stain 100×). (F) Granular and edematous mucosa with erythema, bleeding, and white plaques over the whole colorectal region during treatment for DIHS (same orientation as in A). DIHS, drug‐induced hypersensitivity syndrome.

Prednisolone (1 mg/kg/d) achieved prompt cutaneous remission. Tapering prednisolone to 0.5 mg/kg/d triggered the emergence of bloody diarrhea, pyrexia, rash recrudescence, and newly positive thyroid autoantibodies. Colonoscopy demonstrated scattered erosions in the ileum and continuous granular edematous mucosa, hemorrhage, and white plaques. Biopsies of the colon, stomach, and duodenum revealed cryptitis and crypt abscesses consistent with CD flare (Figure 1F). Quantitative PCR for HHV‐6A and HHV‐6B performed on colonic biopsy specimens from CD lesions, obtained pre‐ and post‐DIHS onset, was negative. Immunostaining and peripheral blood DNA testing excluded CMV colitis. The flare was considered a post‐DIHS immune reconstitution phenomenon. Cyclosporine (5 mg/kg/d)‐prednisolone combinatorial treatment controlled both skin and bowel inflammation, but hematochezia recurred with dose reduction. Vedolizumab, indicated for refractory CD, induced sustained remission, and steroids and cyclosporine were withdrawn. The patient remained asymptomatic on vedolizumab monotherapy.

DIHS may trigger comorbidities or exacerbate preexisting autoimmune, autoimmune‐related, and infectious diseases. ² The present case necessitated escalation to vedolizumab to manage complications of underlying CD, suggesting that DIHS may aggravate preexisting inflammatory bowel diseases (IBD), particularly during steroid tapering or intravenous immunoglobulin administration, which may prompt immune reconstitution inflammatory syndrome. Although gastrointestinal involvement in DIHS is infrequently reported, the current case, a systematic review identifying 21 cases of DIHS‐associated colitis (not endoscopically verified), ⁴ and an account of endoscopically verified de novo Crohn’s‐like colitis, ⁵ emphasize the need for heightened awareness of gastrointestinal symptoms in DIHS. Clinicians should monitor gastrointestinal symptoms long‐term in DIHS/DRESS, especially in patients with preexisting IBDs.

CONSENT FOR PUBLICATION

Written informed consent was obtained from the patient's legal guardian.

CONFLICT OF INTEREST

The authors declare no conflict of interest.