Direct costs of severe cutaneous adverse reactions in a tertiary hospital in Korea

BACKGROUND/AIMS: There are only a few reports on the direct costs of severe cutaneous adverse reactions (SCARs), including drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), despite the tremendous negative impact these reactions can have on patients. We estimated the direct costs of treating SCARs. METHODS: Patients admitted to a tertiary teaching hospital for the treatment of SCARs from January 1, 2005 to December 31, 2010 were included. Patients who had experienced SCARs during their admission for other medical conditions were excluded. The direct costs of hospitalization and outpatient department visits were collected. Inpatient and outpatient care costs were calculated, and factors affecting inpatient care costs were analyzed. RESULTS: The total healthcare cost for the management of 73 SCAR patients (36 with DRESS, 21 with SJS, and 16 with TEN) was 752,067 US dollars (USD). Most of the costs were spent on inpatient care (703,832 USD). The median inpatient care cost per person was 3,720 (range, 1,133 to 107,490) USD for DRESS, 4,457 (range, 1,224 to 21,428) USD for SJS, and 8,061 (range, 1,127 to 52,220) USD for TEN. Longer hospitalization significantly increased the inpatient care costs of the patients with DRESS (by 428 USD [range, 395 to 461] per day). Longer hospitalization and death significantly increased the inpatient care costs of the patients with SJS/TEN (179 USD [range, 148 to 210] per day and an additional 14,425 USD [range, 9,513 to 19,337] for the deceased). CONCLUSIONS: The management of SCARs required considerable direct medical costs. SCARs are not only a health problem but also a significant financial burden for the affected individuals.

The Fas Signaling Pathway Is a Common Genetic Risk Factor for Severe Cutaneous Drug Adverse Reactions Across Diverse Drugs

PURPOSE: Human leukocyte antigen (HLA) has been recognized as the most important genetic risk factor for severe cutaneous adverse drug reactions (SCARs) caused by certain drugs. However, cumulated observations suggest the presence of genetic risk factors for SCARs other than drug-specific HLA. We aimed to identify a common genetic risk factor of SCARs across multiple drugs. METHODS: We performed 2 independent genome-wide association studies (GWASs). A total of 68 and 38 subjects with a diagnosis of SCAR were enrolled in each GWAS. Their allele frequencies were compared to those of healthy subjects in Korea. RESULTS: No single nucleotide polymorphism (SNP) with genome-wide significance was found in either GWAS. We next selected and annotated the 200 top-ranked SNPs from each GWAS. These 2 sets of annotated genes were then entered into the web interface of ConsensusPathDB for a pathway-level analysis. The Fas signaling pathway was significantly over-represented in each gene set from the 2 GWASs. CONCLUSIONS: Our observations suggest that the Fas signaling pathway may be a common genetic risk factor for SCARs across multiple drugs.

The virtual asthma guideline e-learning program: learning effectiveness and user satisfaction

BACKGROUND/AIMS: Effective educational tools are important for increasing adherence to asthma guidelines and clinical improvement of asthma patients. We developed a computer-based interactive education program for asthma guideline named the Virtual Learning Center for Asthma Management (VLCAM). We evaluated the usefulness of program in terms of its effects on user awareness of asthma guideline and level of satisfaction. METHODS: Physicians-in-training at tertiary hospitals in Korea were enrolled in a cross-sectional questionnaire survey. The e-learning program on asthma guideline was conducted over a 2-week period. We investigated changes in the awareness of asthma guideline using 35-item self-administered questionnaire aiming at assessing physicians' knowledge, attitude, and practice. Satisfaction with the program was scored on 4-point Likert scales. RESULTS: A total of 158 physicians-in-training at six tertiary hospitals completed the survey. Compared with baseline, the overall awareness obtained from the scores of knowledge, attitude, and practice was improved significantly. Participants were satisfied with the VLCAM program in the following aspects: helpfulness, convenience, motivation, effectiveness, physicians' confidence, improvement of asthma management, and willingness to recommend. All items in user satisfaction questionnaires received high scores over 3 points. Moreover, the problem-based learning with a virtual patient received the highest user satisfaction among all parts of the program. CONCLUSIONS: Our computer-based e-learning program is useful for improving awareness of asthma management. It could improve adherence to asthma guidelines and enhance the quality of asthma care.

Electronic Consultation Support System for Radiocontrast Media Hypersensitivity Changes Clinicians' Behavior

PURPOSE: Patients with a history of radiocontrast media (RCM) hypersensitivity can be overlooked, resulting in repeated reactions. Therefore, a consultation support system for RCM hypersensitivity has been in operation at Seoul National University Bundang Hospital since December 2011. We analyzed the effect of this system on physicians' practice. METHODS: A retrospective study was conducted on patients with previous RCM reactions (December 1, 2010 to November 30, 2012). The control period was December 2010 to November 2011, and the intervention period was December 2011 to November 2012. The primary outcome was the composite outcome of premedication and consultation. Premedication was defined as preventive medication prescribed by the physician who ordered RCM-enhanced computed tomography (CT) at the same time. The secondary outcome was the recurrence rate after using the consultation support system. RESULTS: A total of 189 clinicians prescribed 913 CT scans during the control period and 225 clinicians performed 1,153 examinations during the intervention period. The odds ratio (OR) of achieving the composite outcome increased significantly after use of the consultation support system (OR, 1.54; 95% confidence interval [CI], 1.15–2.05). Clinicians in both medical (OR, 1.48; 95% CI, 1.06–2.07) and surgical (OR, 2.07; 95% CI, 1.24–3.46) departments showed significant changes in their behavior, whereas those in the emergency department did not (OR, 1.07; 95% CI, 0.41–2.78). Professors (OR, 1.47; 95% CI, 1.06–2.04) and trainees (OR, 1.97, 95% CI, 1.22–3.18) showed significant changes in their behavior toward patients with previous RCM reactions. The behavior of 86 clinicians who ordered CT scans during both the control and intervention periods was unchanged. CONCLUSIONS: The consultation support system for those with previous RCM hypersensitivity reactions changed physicians' practice patterns and decreased recurrent RCM hypersensitivity reactions as well.

Fixed Food Eruption Caused by Actinidia arguta (Hardy Kiwi): A Case Report and Literature Review

Fixed drug eruption (FDE) is a common hypersensitivity reaction characterized by recurrent, well-circumscribed, erythematous patches that arise at the same site as a result of systemic drug exposure. However, fixed food eruption (FFE), a lesion triggered by food ingestion, is a rare allergy that was first defined in 1996. Based on their anti-inflammatory and anti-oxidant properties, the fruit and leaves of Actinidia arguta, the hardy kiwi, are widely consumed across Korea, Japan, and China. This report describes the first case of FFE caused by hardy kiwi leaves, known as Daraesun in Korean, confirmed by oral provocation tests and skin biopsy.

A case of oral desensitization for hypersensitivity to exogenous progesterone

Hypersensitivity reaction to progesterone is a rare pathologic condition which consists of autoimmune response to endogenous progesterone, known as autoimmune progesterone dermatitis, and hypersensitivity reaction to exogenous progestogen. We report the case of a 31-year-old woman with a history of whole body urticaria during exogenous progesterone supplementation for in vitro fertilization (IVF). She was admitted to the hospital for the diagnosis and management of progestogen hypersensitivity. An intradermal test with progesterone revealed positivity to 5 mg/mL of progesterone. For her next IVF, progesterone desensitization was performed in a method combining oral and intramuscular progesterone administration. After successfully achieving a target dose of 100 mg per day, the route of progesterone administration was converted to intravaginal tablet (90 mg twice a day) without any hypersensitivity reactions.

Feasibility of a smartphone application based action plan and monitoring in asthma

BACKGROUND: Asthma patients may experience acute episodic exacerbation. The guidelines recommend that written action plan should be given to asthma patients. However, no one can predict when and where acute exacerbation will happen. As people carry smart phone almost anytime and anywhere, smartphone application could be a useful tool in asthma care. We evaluated the feasibility of the ubiquitous healthcare system of asthma care using a smartphone application (snuCare) based on the self-management guideline or action plan. METHODS: Forty-four patients including fragile asthmatics were enrolled from Seoul National University Bundang Hospital between December 2011 and February 2012. They were randomly assigned into application user (n = 22) or application nonuser group (n = 22). We evaluated user-satisfaction, and clinical parameters such as asthma control, Quality of Life Questionnaire for Adult Korean Asthmatics, and the adherence of patients. RESULTS: The characteristics were similar at baseline between the 2 groups except those who treated with short-term systemic steroid or increased dose of systemic steroid during previous 8 weeks (user vs. nonuser: 31.8% vs. 4.5%, p = 0.020). Total of 2,226 signals was generated during 8 weeks including 5 risky states. After eight weeks, the users answered that it was very easy to use the application, which was shown in highest scores in terms of satisfaction (mean ± standard deviation, 4.3 ± 0.56). Seventy-three percent of patients answered that the application was very useful for asthma care. User group showed improved the adherence scores (p = 0.017). One patient in application user group could avoid Emergency Department visit owing to the application while a patient in nonuser group visited Emergency Department. CONCLUSION: The ubiquitous healthcare system using a smartphone application (snuCare) based on the self-management guideline or action plan could be helpful in the monitoring and the management of asthma.

Successful sequential desensitization in a patient with drug hypersensitivity to three kinds of antiplatelet agents

Antiplatelet agents, such as aspirin, clopidogrel, and cilostazol, are essential for the treatment and prevention of cardiovascular, cerebrovascular, and peripheral vascular diseases. A 53-year-old male with aspirin hypersensitivity developed dizziness, which was caused by severe stenosis of the left vertebral artery. Clopidogrel was administerted, but discontinued due to generalized urticaria and angioedema. As an alternative drug, cilostazol was administered, but discontinued again because of the same adverse reactions. Desensitization was planned as other alternative antiplatelet agents were not available. Initially, aspirin desensitization was successfully performed. One day after aspirin desensitization, clopidogrel desensitization was sequentially done successfully. After a few months, cilostazole desensitization was performed. During the follow-up period, he had to stop aspirin and cilostazol twice to prevent the risk of bleeding after a procedure and an operation. After discontinuing medicines, sequential desensitization of aspirin and cilostazol was successfully performed. Physicians should be aware that drug hypersensitivity could be induced by various kinds of antiplatelet agents and that desensitization could be the treatment of choice unless alternative medicines are available.

ERRATUM: Correction of explanation for footnote in Table 3. Clinical experience in managing patients with hereditary angioedema in Korea: questionnaire survey and a literature review

This erratum is being published to correct of footnote in Table 3.

Validation of the Korean version of the European Community Respiratory Health Survey screening questionnaire for use in epidemiologic studies for adult asthma

BACKGROUND: Standardized questionnaire is one of key instruments for general population surveys. OBJECTIVE: The present study aimed to develop and validate the Korean version of the European Community Respiratory Health Survey (ECRHS) screening questionnaire for adult asthma surveys. METHODS: The ECRHS screening questionnaire was translated into Korean language according to the international criteria. Study participants were prospectively recruited from six referral hospitals and one health check-up center. Comprehensibility of the translation was tested in a pilot study of 10 patients. The reliability was evaluated by internal consistency and test-retest repeatability. Validity was assess with regard to physician-diagnosed asthma. RESULTS: A total of 100 adult asthma patients and 134 volunteers were recruited. Reliability was examined for 10 items in 100 asthmatics; Cronbach α coefficients were 0.84, and test-retest repeatability was good (Cohen κ coefficient, 0.71-1.00). Validity was assessed for 8 items in 234 participants; in particular, 'recent wheeze' showed a high sensitivity (0.89) for physician-diagnosed asthma. 'Recent asthma attack' and 'current asthma medication' showed high specificity (0.96-0.98). CONCLUSION: The present study demonstrated that the Korean version of the ECRHS screening questionnaire was comprehensible, reliable and valid. We suggest the questionnaire to be utilized in further epidemiological studies for asthma in Korean adult populations.

Eosinophils Modulate CD4+ T Cell Responses via High Mobility Group Box-1 in the Pathogenesis of Asthma

Eosinophils have been reported to modulate T cell responses. Previously, we reported that high-mobility group box 1 protein (HMGB1) played a key role in the pathogenesis of asthma. This study was conducted to test our hypothesis that eosinophils could modulate T cell responses via HMGB1 in the pathogenesis of asthma characterized by eosinophilic airway inflammation. We performed in vitro experiments using eosinophils, dendritic cells (DCs), and CD4+ T cells obtained from a murine model of asthma. The supernatant of the eosinophil culture was found to significantly increase the levels of interleukin (IL)-4 and IL-5 in the supernatant of CD4+ T cells co-cultured with DCs. HMGB1 levels increased in the supernatant of the eosinophil culture stimulated with IL-5. Anti-HMGB1 antibodies significantly attenuated increases of IL-4 and IL-5 levels in the supernatant of CD4+ T cells co-cultured with DCs that were induced by the supernatant of the eosinophil culture. In addition, anti-HMGB1 antibodies significantly attenuated the expressions of activation markers (CD44 and CD69) on CD4+ T cells. Our data suggest that eosinophils modulate CD4+ T cell responses via HMGB1 in the pathogenesis of asthma.

The impact of sinusitis on the long-term clinical outcomes of asthma

BACKGROUND: Upper respiratory diseases have been linked with lower respiratory diseases. However, the long-term effect of sinusitis on the clinical outcomes of asthma has not been fully evaluated. OBJECTIVE: The aim of this study was to investigate the impact of sinusitis on the disease progression of asthma. METHODS: Seventy-five asthmatic patients confirmed with the methacholine bronchial provocation test or bronchodilator response were included. The study patients underwent paranasal sinus x-ray upon their asthma evaluation and they visited the hospital at least 3 years or longer. We retrospectively reviewed their medical records and compared data according to the presence of comorbid sinusitis. RESULTS: Among the 75 asthmatic subjects, 38 subjects (50.7%) had radiologic evidence of sinusitis. Asthmatics with sinusitis had significantly lower forced expiratory volume in 1 second (FEV₁; 79.2% vs. 88.2%) and PC20 values (5.2 mg/mL vs. 8.9 mg/mL) compared to asthmatics without sinusitis at the time of diagnosis. This difference in FEV₁ disappeared (82.6% vs. 87.2%) in the 3-year follow-up, although FEV₁ was more variable (31.7% vs. 23.5%) and worst FEV₁ was also significantly lower in patients with sinusitis compared to those without (70.9% vs. 79.0%). There were no significant differences in the number of hospital visits, acute exacerbations, and scores for the asthma control test. CONCLUSION: Although sinusitis was associated with lower baseline lung function and higher hyperreactivity, sinusitis was not related with significant deterioration in lung function over 3 years of follow-up. Asthmatics with sinusitis showed more variability in lung function during the follow-up period. Healthcare utilization was not different except antibiotics use.

Lamotrigine-induced toxic epidermal necrolysis confirmed by in vitro granulysin and cytokine assays

Lamotrigine is a recent medication which is prescribed for various neuropsychiatric conditions. It is generally well-tolerated, but recent pharmacoepidemiological evidence suggests that lamotrigine is associated with risks of developing severe cutaneous drug reactions like toxic epidermal necrolysis (TEN). However, there still remains the diagnostic challenge regarding how to confirm the drug causality in suspected cases. In most cases so far, lamotrigine causality has not been objectively demonstrated, which was possibly due to high risk of oral challenge tests or the lack of useful in vitro drug assays. Here we report a case of lamotrigine-induced TEN, of which the drug causality was confirmed by in vitro granulysin and cytokine assays.

Reference ranges for induced sputum eosinophil counts in Korean adult population

BACKGROUND: Induced sputum analyses are widely utilized to evaluate airway inflammation in asthmatics. However, the values have not been examined in Korean adults. OBJECTIVE: The purpose of this study is to determine reference ranges for induced sputum eosinophils and their influencing factors in Korean adults. METHODS: A total of 208 healthy nonasthmatic adults were recruited. Sputum induction and processing followed the international standard protocols. RESULTS: Adequate sputum samples were successfully collected from 81 subjects (38.9%). The upper 90 percentile for sputum eosinophil was calculated as 3.5%. The median value of eosinophil count percentage was significantly higher in subjects with atopy than those without atopy (median, 1.6%; range, 0-11.0% vs. median, 0%; range 0-3.6%, p=0.030). However, no significant correlations were found with age, gender, body mass index, smoking status, blood eosinophil, or fractional exhaled nitric oxide levels. CONCLUSION: Current study was the first attempt to determine the reference ranges of induced sputum eosinophils in Korean adults. The cutoff value for sputum eosinophilia was 3.5%, and was significantly associated with atopy.

Association of insulin resistance with bronchial hyperreactivity

BACKGROUND: Several epidemiologic studies showed the significant association of insulin resistance with asthma. OBJECTIVE: The aim of this study was to evaluate the association of insulin resistance with airway hyperresponsiveness (AHR) in adult population. METHODS: 1,058 subjects who visited to the Seoul National University Hospital Gangnam Center from October 2007 to January 2009 for a routine health check-up were enrolled. All subjects completed a questionnaire, anthropometric measurements such as body mass index (BMI) and waist circumference, blood tests, pulmonary function test, and methacholine bronchial provocation test (MBPT). Insulin resistance was estimated from the homeostasis model of assessment of insulin resistance (HOMA-IR).

Analysis of Drugs Causing Severe Cutaneous Adverse Reactions, Based on the Korean Database of Spontaneously Reported Adverse Drug Reactions / 대한내과학회지

BACKGROUND/AIMS: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) are severe cutaneous adverse reactions (SCARs) that also affect the internal organs with high mortality. However, there has been no previous nationwide study of SCARs in Korea. METHODS: Cases of SCARs were recruited from the nationwide Korean Pharmacovigilance Research Network database, collected from June 2009 to December 2010, by a spontaneous reporting system. We analyzed age, gender, route of administration and the causative agents. We also reviewed previously published cases of SCARs in Korea. RESULTS: In total, 100 cases of SJS (66 cases), TEN (7 cases), and DRESS (27 cases) were reported. The mean age of the patients was 54.1 +/- 19.8 years and the proportion of males to females was 1:0.88. In total, 81 drugs were reported as causative agents: SJS (61 drugs), TEN (15 drugs), and DRESS (29 drugs). The most commonly reported causative drug was allopurinol (12 cases). Allopurinol (8 cases) and levofloxacin (2 cases) were the most commonly reported causative drugs for SJS and TEN, respectively. In DRESS, allopurinol (4 cases) and vancomycin (4 cases) were the two most common causative drugs. Anti-infective drugs were the most common drug category (75 cases). Carbamazepine was the most commonly reported causative drug according to published cases in Korea. CONCLUSIONS: Allopurinol in the spontaneous reporting system and carbamazepine in the published cases were the most common single causative drugs in SCARs in Korea. Anti-infectives were the most common drug category in the spontaneous reporting system.

Successful desensitization of trimethoprim-sulfamethoxazole in Stenostrophomonas maltophilia osteomyelitis

Stenotrophomonas maltophilia is an emerging pathogen associated with morbidity and mortality in hospitalized patients. The treatment of S. maltophilia infection is challenging because clinical isolates are frequently resistant to most antimicrobial agents except trimethoprim-sulfamethoxazole (TMP-SMX). S. maltophilia osteomyelitis is a rare disease and requires a prolonged treatment with TMP-SMX. Here, we report an interesting case of a patient with S. maltophilia osteomyelitis who developed a delayed hypersensitivity reaction during TMP-SMX treatment and successfully treated after desensitization. TMP-SMX desensitization should be considered in patients with hypersensitivity to TMP-SMX, especially when there are no effective alternative drugs in S. maltophilia infection.

The Interaction Between Allelic Variants of CD86 and CD40LG: A Common Risk Factor of Allergic Asthma and Rheumatoid Arthritis

PURPOSE: Allergic asthma (AA) and rheumatoid arthritis (RA) are immune tolerance-related diseases, and immune tolerance is known to be influenced by costimulatory molecules. In this study, we sought to identify common genetic susceptibility in AA and RA. METHODS: Two hundred cases of AA, 184 cases of RA, and 182 healthy controls were recruited at the Seoul National University Hospital, Seoul, Korea. Eight single nucleotide polymorphisms (SNPs) in five genes coding costimulatory molecules, namely, -318C>T, +49A>G, and 6230G>A in CTLA4, IVS3+17T>C in CD28, -3479T>G and I179V in CD86, -1C>T in CD40, and -3458A>G in CD40LG were scored, and genetic interactions were evaluated by multifactor dimensionality reduction (MDR) analysis. RESULTS: MDR analysis revealed a significant gene-gene interaction between -3479T>G CD86 and -3458A>G CD40LG for AA. Subjects with the T/T genotype of -3479T>G CD86 and the A/A genotype of -3458A>G CD40LG were found to be significantly more likely to develop AA than those with the T/T genotype of -3479T>G CD86 and A/- genotype of -3458A>G CD40LG (adjusted OR, 6.09; 95% CI, 2.89-12.98; logistic regression analysis controlled by age). Similarly those subjects showed a significant risk of developing RA (adjusted OR, 39.35; 95% CI, 15.01-107.00, logistic regression analysis controlled by age). CONCLUSIONS: Our findings suggest that a genetic interaction between CD86 and CD40LG favors the development of both AA and RA.

Cross-reactivity to Acetaminophen and Celecoxib According to the Type of Nonsteroidal Anti-inflammatory Drug Hypersensitivity

PURPOSE: Identification of tolerable alternative analgesics is crucial for management in nonsteroidal anti-inflammatory drug (NSAID)-sensitive patients. We investigated cross-reactivity of acetaminophen and celecoxib according to the type of aspirin/NSAID hypersensitivity and aimed to determine the risk factors for cross-intolerance. METHODS: We retrospectively reviewed the medical records of patients intolerant to aspirin and NSAIDs who had undergone an acetaminophen and/or celecoxib oral provocation test. Aspirin/NSAID hypersensitivity was classified into 4 types according to a recently proposed classification: aspirin-exacerbated respiratory disease (AERD), aspirin-exacerbated chronic urticaria (AECU), aspirin-induced acute urticaria/angioedema (AIAU), and NSAID-induced blended reaction (NIRD). RESULTS: A total of 180 patients with hypersensitivity to aspirin and NSAIDs were enrolled; 149 acetaminophen provocation test results and 145 celecoxib provocation test results were analyzed. The overall cross-reaction rates to acetaminophen and celecoxib were 24.8% and 10.3%, respectively. There was a significant difference in the cross-reactivity to acetaminophen according to the type of NSAID hypersensitivity. Cross-reactivity to acetaminophen was highest in the AECU group (43.9%), followed by the AERD (33.3%), NIBR (16.7%), and AIAU (12.5%) groups. Underlying chronic urticaria was more prevalent in patients with cross-intolerance to both acetaminophen (P=0.001) and celecoxib (P=0.033). Intolerance to acetaminophen was associated with intolerance to celecoxib (P<0.001). CONCLUSIONS: Acetaminophen and celecoxib may induce adverse reactions in a non-negligible portion of aspirin/NSAID-sensitive patients. Physicians should be aware of the possible cross-reactions of these alternative drugs and consider an oral challenge test to confirm their tolerability.

Clinical experience in managing patients with hereditary angioedema in Korea: questionnaire survey and a literature review

PURPOSE: Hereditary angioedema is a familial disease which is caused by a genetic deficiency or functional defect of the C1 inhibitor, and it features episodic swelling that can affect any part of the body. A great number of patients are estimated not to have an accurate diagnosis after the onset of symptoms, and close attention is required because sudden hereditary angioedema attacks can result in even death. METHODS: We sent an e-mail questionnaire to 975 members of the Korean Academy of Asthma, Allergy and Clinical Immunology. A total of 82 members replied. The questionnaire, including 15 questions about the diagnosis and management of hereditary angioedema, was developed by the anaphylaxis/urticaria, angioedema workgroup of the Korean Academy of Asthma, Allergy and Clinical Immunology. RESULTS: Forty-two percent of the respondents had experience with treatment of a suspected case of hereditary angioedema, and 15.9% made a confirmed diagnosis of hereditary angioedema. When the respondents suspected of cases, 91.4% of them performed tests for C3 and C4 concentrations and C1 inhibitor level. For maintenance treatment, most of the respondents used androgen, and only 22% found that C1 inhibitor concentrates can be prescribed through the Korea Orphan Drug Center in Korea. CONCLUSION: Allergy physicians in Korea substantially recognized the correct diagnosis and treatment of hereditary angioedema. However, there was a lack of awareness for the latest treatments, such as C1 inhibitor concentrates. Education of doctors and the public is needed.