Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis Associated with Acetaminophen Use during Viral Infections

Cutaneous adverse drug reactions (ADR) range from trivial manifestations, such as morbilliform eruptions, to severe life-threatening reactions, including Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). SJS/TEN is characterized by severe epithelial detachment of both the skin and mucosal membranes.

SJS/TEN is caused by drugs, infections, vaccination, malignant disorders, and radiotherapy (1, 2). The principal drugs inducing SJS/TEN are antibacterial sulfonamides, beta-lactam antibiotics, anticonvulsants, non-steroidal anti-inflammatory drugs, and allopurinol (1, 2). SJS/TEN can also be developed by interactions between drugs and viral infections.

Viruses interact with the immune system and can trigger severe cutaneous adverse reactions (SCAR) in several ways (3). Viral infections can influence drug metabolism, drug presentation to lymphocytes by dendritic cells, and production of cytokines/chemokines during the course of mounting an effector response by the infected host (3). Cells of the innate immune system (principally dendritic cells) are activated by a variety of signals, including pathogen-associated-molecule patterns and bacterial and viral genomes via Toll-like receptors. Mature antigen-presenting cells activated in this manner effectively initiate T-cell responses (3). The CD137 protein expressed by monocytes co-operates with CD137L of CD8⁺ T-cells to expand the numbers of the latter cell type, which play a major role in the development of SJS/TEN (4).

In the present study, we report six SJS/TEN patients that are suspected to be developed by interaction between acetaminophen and viral infection. The cytokine/chemokine levels of activated T-cells and monocytes were measured in an effort to identify the possible serum biomarker that helps evaluating the therapeutic response or prognosis of SJS/TEN.

Some reports on possible interactions of viruses and drugs in terms of induction of non-immediate cutaneous ADRs have appeared. Ampicillin-induced maculopapular exanthema developing in patients with infectious mononucleosis, and the increased risks of development of SCAR in AIDS patients, are well-known examples of such interactions (7). In the absence of concurrent viral infection, the suspect drugs did not stimulate T-cell proliferation in patients showing SCAR (8). Although drugs are widely accepted to be leading causes of SJS/TEN, acetaminophen is generally recognized to be safe, and rarely associated with development of SCAR (9). Based on the previous studies that noted viral infection can have synergistic immunologic effect on adverse drug reaction and previously reported drug lists with a risk to induce SJS/TEN (9, 10), we report the six cases of SJS/TEN whose major culprit was acetaminophen. Although changes in pharmacokinetics during viral infections and drug- and drug-metabolites-related toxicity has been noted in virally infected cells (7, 10), however, immunological and pharmacological interactions between viruses and drugs remain to be elusive. Considering that flu was epidemic at that time in Korea, marked monocytosis, neutropenia, and a positive influenza PCR observed in their initial laboratory tests suggested that those patients were under viral infection which could make further activate their immune system against the causative drug (11, 12). Typically, mean latent period between the exposure to culprit drugs and onset of the adverse drug reactions is 4~28 days (9, 10, 13). However, the reported latency times of TEN cases are varied depending on the causative drugs, combined medications, and conditions of the patients (10). Kim et al. reported that two cases of TEN associated with acetaminophen ingestion under upper respiratory tract infection (14). Similarly with our cases, TENs were developed within 2 to 3 days after medication with acetaminophen in the previous report (14). Taken together, we can speculate that although the acetaminophen is an unusual offending drug of SJS/TEN, it is prone to cause SJS/TEN when it comes with viral infection.

Cytotoxic T-cells/monocytes play important roles in SJS/TEN development via Fas/Fas ligand, perforin, granzyme, granulysin and soluble apoptosis-inducing factors (e.g. TNF-α, IFN-γ) (4). MIF and IL-2Rα trigger T-cell proliferation (2, 15), in addition, RANTES and MCP-1 exert potent chemotactic effects on T-cells/monocytes (16) and play role in SJS/TEN. In contrast, IL-10 generated by T-regulatory cells plays a predominantly anti-inflammatory role by inhibiting the recognition function of dendritic cells (17). In the previous studies, the levels of TNF-α, IL-2Rα, and IL-10 were increased in the sera of TEN patients (17), in addition, the RANTES level was significantly upregulated in the lesions caused by SCAR (18). MIF was suggested to be used to identify the drug adversely affecting TEN patients (19). In the present study, we found that the IL-2Rα level decreased significantly after treatment. Two patients (Patient 2 and 5) with remarkable decline in IL-2Rα levels visited our hospital 7 days after the onset of their skin lesions, in contrast, the remaining four visited within 2 days. This finding may explain why only two patients showed a greater decline in IL-2Rα levels. Patient 2 admitted to the ICU who stayed for the longest duration (67 days) showed the highest IL-2Rα level at baseline whereas the SJS patient (Patient 1) who stayed for the shortest duration (3 days) had the lowest IL-2Rα level at baseline. Additionally, the baseline MCP-1 levels were found to have strong positive correlations with IL-2Rα and MIF levels (r=0.829, p=0.042, respectively) in the same individuals. These data are consistent with a previous study (17) that reported that more severe forms of SCAR resulted in higher production of inflammatory cytokines. Our data collectively suggest that longer periods before appropriate treatment can increase IL-2Rα levels, thereby prolonging hospital stays. Taken together, measuring the IL-2Rα levels may be helpful to evaluate the therapeutic response and predict the prognosis of SCAR. Although it is possible that viral infections may interact with commonly administered medications or their metabolites to cause SCAR, much larger epidemiologic studies will be needed to prove these associations. Therefore, further studies, including larger numbers of patients, are required to elucidate the exact relationship of IL-2Rα, MCP-1 and MIF levels with clinical prognosis.

In conclusion, although acetaminophen is relatively safe, the drug can trigger SJS/TEN in patients with suspected viral infections. A large scale study regarding the role of measuring inflammatory cytokine/chemokine levels of activated T-cells/monocytes in evaluating therapeutic response and predicting the prognosis of SJS/TEN is warranted.