DISCUSSION
SJS/TEN is caused by a type IV-c delayed hypersensitivity reaction to infections or drugs7. SJS/TEN is defined as a widespread vesiculobullous rash with epidermal sloughing, necrosis, and mucous membrane involvement, typically in the eyes, oral cavity, and skin. SJS/TEN were classified according to the extent of the detached and detachable epidermis, expressed as a percentage of the total body surface area (TBSA) (SJS: <10% TBSA; SJS-TEN overlap: 10–30% TBSA; and TEN: >30% TBSA)8. Mucosal and eye inflammation are present in 90% and 60% of cases, respectively. Severe cases culminate in corneal scarring, respiratory distress syndrome, pneumonia, and respiratory failure9.
According to the United States Food and Drug Administration Adverse Event Reporting System database, the top five most frequently administered drugs associated with SJS/TEN are valdecoxib, lamotrigine, phenytoin, acetaminophen, and furosemide5. In contrast, allopurinol, loxoprofen, acetaminophen, carbamazepine, and lamotrigine are the frequent causes of SJS in Japan4.
In our case, we initially suspected that it was caused by an infectious agent, such as mycoplasma, or was induced by drugs such as acetaminophen and clarithromycin. However, the LAMP assay of M. pneumoniae was negative, and the DLST against acetaminophen was positive; thus, acetaminophen was considered to be the cause.
SJS caused by acetaminophen tended to be more predominant in the younger groups aged 0–19 years old, with a median time to onset of 2 days4. The time to onset was only 1 day in the present case, which is consistent with a previous report. However, the present case was followed by a more rapid and serious course than that of the previous reports on acetaminophen-related SJS. Therefore, early and aggressive therapeutic interventions are required, as in this case.
A recent review of cases of SJS/TEN associated with acetaminophen summarized a total of 36 patients described in 29 previously published reports6. TEN, SJS, and SJS/TEN overlap were diagnosed in 24 (66.7%), 10 (27.8%), and 2 (5.6%) patients, respectively. Of these 36 patients, 28 (77.8%) received supportive and symptomatic care. Systemic corticosteroids were administered to 25 patients (69.4%), and intravenous immunoglobulin was administered to 16 patients (44.4%). The prognosis of these patients was not poor, as all patients survived according to the reports, although long-term sequelae were available only in five patients (13.9%)6.
Reports in the United States have shown that the SJS mortality rate was 4.8% in adults10 and 0% in children11. Predictors of mortality risk in pediatric SJS include the presence of renal failure, sepsis, epilepsy, bacterial infections, and malignant diseases11. According to this criterion, the mortality risk was not high in our case. Although the patient’s skin and mucosal lesions improved with immunosuppressive therapy, the lung injury did not improve despite intensive treatment. Accordingly, we considered that the severity of lung injury might also affect the prognosis of SJS, with a profound impact on mortality. Additional clinical studies with larger numbers of patients are needed to determine whether a pulmonary impairment is a risk factor.
In adults, 37.8% of patients with SJS/TEN may require mechanical ventilation in the acute phase12. Pathologically, epidermal sloughing of the bronchial epithelium was observed by fiberoptic bronchoscopy in 27% of SJS/TEN cases, and those with positive pathological findings showed early pulmonary complications in the acute phase, with a high rate of fatal outcome13. Although fiberoptic bronchoscopy could not be performed in our case, pathological findings of pulmonary tissue in the lung biopsy revealed DAD. There are few reports of drug-induced lung injury caused by acetaminophen and even fewer reports of DAD caused by acetaminophen. DAD is the most severe type of drug-induced lung injury, requiring high-dose steroid therapy early after diagnosis14. However, there are many unresponsive cases to treatment, and the prognosis of patients with DAD is poor. Our patient was diagnosed with DAD based on CT and pathological findings and was refractory to various drug treatments.
In conclusion, there are cases of acetaminophen-induced SJS in which lung injury progresses rapidly and irreversibly, leading to fatal outcomes.