Stevens–Johnson syndrome (SJS)–like mucocutaneous reactions are commonly attributed to either drug hypersensitivity or infection-related mucositis 1. In clinical practice, however, distinguishing between these entities can be challenging when clinical features overlap 2. We report an SJS-like mucocutaneous reaction in which objective evidence of both active Mycoplasma pneumoniae infection and phenytoin-specific T-cell reactivity was demonstrated within the same disease episode. A 22-year-old man with temporal lobe epilepsy presented with high-grade fever and a rapidly evolving mucocutaneous eruption. He had been receiving levetiracetam, and phenytoin was added because of persistent seizures. Approximately three weeks after phenytoin initiation, he developed upper respiratory symptoms, followed three days later by symptomatic treatment with cough suppressants and amoxicillin. Four days thereafter, he experienced abrupt onset of fever, lip swelling, and progressive mucocutaneous involvement. Cutaneous examination revealed multiple flat atypical target lesions involving the trunk and extremities, accompanied by prominent mucosal disease with severe oral erosions and hemorrhagic crusting of the lips (Figure 1). Bilateral conjunctival injections were present, while genital mucosal involvement was absent. No clinically significant epidermal detachment nor generalized lymphadenopathy was observed. Laboratory investigations demonstrated marked leukocytosis with neutrophil predominance without eosinophilia, significant transaminase elevation in a hepatocellular pattern, and hyperbilirubinemia (total bilirubin 3.88 mg/dL). The patient also developed anemia with laboratory features suggestive of hemolysis, including reticulocytosis and an increased cold agglutinin titer, together with chest radiographic findings compatible with an infectious process (Figure 2). The presence of early hepatocellular injury was atypical for Mycoplasma pneumoniae–associated mucocutaneous syndromes, while phenytoin is a recognized trigger of SJS/TEN with a compatible exposure timeline in this case. Accordingly, diagnostic evaluation was broadened to assess both infectious and drug-related contributors, including Mycoplasma pneumoniae serology, together with interferon-γ enzyme-linked immunospot (ELISpot) testing for phenytoin and other concomitant medications. Microbiological testing supported active Mycoplasma pneumoniae infection, with respiratory polymerase chain reaction (PCR) providing the primary evidence, accompanied by IgM and IgG serology. Additional findings, including respiratory symptoms, radiographic abnormalities, and cold agglutinin–associated hemolysis, further supported active infection. ELISpot assays demonstrated a concentration-dependent interferon-γ response to phenytoin, while testing for other concomitant medications was negative (Figure 2). Repeat ELISpot testing performed three months after clinical recovery and drug discontinuation remained positive, consistent with drug-specific T-cell reactivity rather than nonspecific immune activation 3. A skin biopsy was not performed, as the clinical presentation and laboratory findings were considered sufficient to guide diagnosis and management. Phenytoin was discontinued, and targeted antimicrobial therapy for Mycoplasma pneumoniae was initiated, together with supportive care and topical corticosteroids. The patient's mucocutaneous symptoms gradually improved, with resolution of fever and mucosal inflammation. Liver enzyme levels progressively decreased during follow-up, and no recurrence was observed after recovery. Infection-related mucocutaneous eruptions such as Mycoplasma-induced rash and mucositis (MIRM) typically present with prominent mucositis and limited cutaneous involvement; however, the degree of hepatocellular injury with hyperbilirubinemia observed in these settings is less characteristic of classic MIRM 4. Conversely, although phenytoin-induced SJS/TEN may involve mucocutaneous disease and hepatic dysfunction 5, the predominance of mucositis is atypical for classical SJS/TEN. Features typical of DRESS, such as eosinophilia, were absent, and the mucosal-predominant presentation is not characteristic of DRESS. This case underscores that severe mucocutaneous reactions may arise from concurrent immune drivers that are not adequately captured by rigid diagnostic categorization. Objective evidence of both infection and persistent drug-specific immune reactivity within a single episode is consistent with overlapping infectious and drug-related contributors in this case, rather than establishing dual causation. Early parallel assessment of infectious and drug-related triggers may therefore be required to identify the clinically relevant immune contributors in phenotypically ambiguous cases. The authors thank the clinical and laboratory staff at the Allergy and Clinical Immunology Unit, King Chulalongkorn Memorial Hospital, for their assistance in patient care and sample processing. This work was supported by the Center of Excellence for Skin and Allergy Research, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. This study was approved by the Institutional Review Board of the Faculty of Medicine, Chulalongkorn University (IRB No 0092/69). Written informed consent for publication of clinical details and images was obtained from the patient. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.
Chumsaengchotsakul et al. (Sun,) studied this question.