Adverse drug reactions (ADRs) refer to noxious and unintended drug effects that occur at doses used in humans for prophylaxis, diagnosis, or therapy [1]. ADRs are one of the leading causes of death in United States hospitals [2] and can necessitate hospital admission or prolong the length of hospital stay, which can eventually lead to increased health care costs. In a meta-analysis of 39 prospective studies from the United States over a period of 32 years (1966 to 1996), the overall incidence of ADRs in hospitalized patients was 15.1%, and that of serious ADRs was 6.7% [2]. The incidence was calculated as the sum of both ADRs that resulted in hospitalization and those that occurred during hospitalization for other diseases. Several reports on the costs associated with ADRs have shown that they are substantially high [3-5]. However, the estimation of costs can be difficult because of the heterogeneity of ADRs, and indeed, the costs were found to be quite variable and dependent on the type of ADR and culprit agent involved [6].

Severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) are rare but potentially fatal diseases. Due to their unexpected drastic progression and serious outcomes, SCARs can be a considerable financial burden to the affected patients and their families. Moreover, standard treatments other than supportive care are not well established, and costly experimental treatments such as intravenous immunoglobulin (IVIG) have often been used, adding to the costs. However, despite its potentially negative impact, the financial burden of SCARs on patients has been overlooked because of the rarity of these diseases [5-7]. In this study, the authors aimed to determine the direct costs of SCARs in a tertiary hospital in Korea.

Seventy-three patients with SCARs (36 DRESS, 21 SJS, and 16 TEN cases) admitted to the Seoul National University Hospital from January 1, 2005 to December 31, 2010 were selected by International Classification of Diseases 10 (ICD-10) diagnostic code and retrospective review of medical records [8]. The diagnostic criteria proposed by the RegiSCAR study group were used to define the individual cases [9,10]. In short, SJS and TEN were diagnosed when there were typical skin lesions such as widespread erythematous or purpuric macules or flat atypical targets. SJS and TEN were diagnosed when the area of skin detachment was less than 10% and greater than 30% of the total body surface area, respectively. There was no case of SJS-TEN overlap among our subjects [9]. DRESS was diagnosed according to the presence of typical skin lesions, fever, enlarged lymph nodes, hematologic abnormality, and organ involvement [10]. The causative agents were assessed based on the WHO-UMC (World Health Organization-Uppsala Monitoring Centre) causality assessment system. Patients who had been admitted for other medical conditions before the onset of SCARs were excluded. Clinical characteristics regarded as relevant to treatment costs, such as duration of hospitalization, admission to an intensive care unit (ICU), use of IVIG, and the presence of ocular involvement, were collected.

Data on the direct costs of SCARs were extracted from a hospital accounting system and divided into two categories: inpatient care costs and outpatient care costs. Inpatient care costs included expenses during a hospital stay such as costs for room and board, physician services, laboratory tests, imaging tests, procedures, and medications. Inpatient care costs were further divided into reimbursed and out-of-pocket costs.

Outpatient care costs consisted of the total payment for problems related to SCARs. Emergency department visits that did not result in readmission were also considered as outpatient visits. The terms related to direct costs used in this article are summarized in Table 1.

This is the first study on the direct medical costs associated with treating SCARs in Korea. In the present study, the median inpatient care cost per person was 3,720 USD for DRESS, 4,457 USD for SJS, and 8,061 USD for TEN. Most of the costs were spent on inpatient care. The length of hospitalization increased the inpatient care cost by 428 USD for DRESS. The inpatient care cost for SJS/TEN increased by 179 USD per day, and the survivors paid less than the deceased.

The findings from this study show that the cost of managing SCARs was quite high. There have been only a few reports on this specific topic. Schlienger et al. [11] determined the direct cost of inpatient care in 13 Canadian patients with severe adverse reactions to AEDs treated at one institution to be a median 3,128 Canadian dollars (2,283 USD). They estimated that the average annual direct cost for severe ADRs due to AEDs was 11,003 Canadian dollars (~8,032 USD). In India, Barvaliya and et al. [7] determined the direct costs of managing SJS and TEN for 11 SJS, 15 TEN, and 6 SJS–TEN overlap patients to be 2,460 Rupees (~39 USD), 7,910 Rupees (~27 USD), and 4,857 Rupees (~77 USD), respectively. The direct costs of managing SCARs in India were lower than expected. This may be because the authors estimated the costs for drugs, investigations, and consumables during the entire hospital stay, but costs for nursing and room, which could account for a substantial proportion of total medical costs, were not included. The differences between our results and those of the other reports may be explained by the different patient populations and different items included in the medical cost estimation. They may also be explained by the different economic conditions and insurance systems of each country. For example, the total medical expenditure per person in Korea is approximately 1,700 USD, whereas that in Canada is 4,000 USD [12]. The direct cost of managing SCARs in Canada per person is approximately 8,000 USD, which is double the total medical expenditure per person. In Korea, the direct cost of managing SCARs was approximately 4,400 USD, which was more than double the total medical expenditure per person. Thus, the cost of managing SCARs in Korea can be considered relatively more burdensome than that in Canada.

A considerable portion of the inpatient care costs for managing SJS and TEN was not covered by insurance. Patients with SJS, TEN, and DRESS paid approximately 55%, 43%, and 41% of their inpatient care costs, respectively. In particular, the cost for IVIG, which accounted for approximately one-third of the cost of medication for SJS/TEN patients, caused a considerable burden to the patients. The length of hospitalization was the single most important factor that affected the inpatient care cost for both DRESS and SJS/TEN. Fatality greatly increased the inpatient care costs for SJS/TEN. Other factors such as ICU admission and ocular involvement did not affect inpatient care cost.

According to Statistics Korea, chronic renal disease is the most expensive disease to treat, requiring an annual expense per capita of more than 8,500 USD, followed by lung and liver/biliary cancers (~6,700 USD), intracranial hemorrhage (~4,800 USD), and breast cancer (~3,800 USD). The inpatient care costs for TEN, SJS, and DRESS from our study were 8,061 USD, 4,457 USD, and 3,720 USD, respectively. Although it is not possible to compare these costs directly, it can be inferred that costs for treating one SCAR case were comparable with those for treating the national top five most expensive common medical conditions.

This study has some limitations. First, due to the retrospective design, we could only estimate the direct costs of SCARs and could not assess the indirect or intangible costs. Second, because this study was conducted in one tertiary hospital, the results do not accurately represent situations in other hospitals; the patient-care patterns may be very dependent on the physicians. To compensate for this, we analyzed national data for all Korean SJS/TEN patients. Finally, the results cannot be generalized to other countries because of differences in medical service systems. Nonetheless, this study may increase awareness of the seriousness of the financial aspect associated with management of SCARs.

In conclusion, SCARs are not only serious health problems but also significant financial burdens accounting for considerable direct medical costs.