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author:("Kang, Hye-run")
1.  The impact of sinusitis on the long-term clinical outcomes of asthma 
Asia Pacific Allergy  2014;4(4):222-229.
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.
doi:10.5415/apallergy.2014.4.4.222
PMCID: PMC4215430  PMID: 25379482
Sinusitis; Asthma; Disease progression; Forced expiratory volume
2.  Clinical Features of Fixed Drug Eruption at a Tertiary Hospital in Korea 
Purpose
Fixed drug eruption (FDE) is characterized by a well-defined erythematous patch, plaque, or bullous eruption that recurs at the same site as the result of systemic exposure to a causative drug, and resolves with or without hyperpigmentation. This study was carried out to identify the common causative drugs and clinical features of FDE in Korea.
Methods
We reviewed electronic medical records of all patients diagnosed with FDE from January 2000 to December 2010 at a tertiary hospital in Korea.
Results
A total of 134 cases were diagnosed as FDE. The mean age was 35.9 years (range, 0-82 years) and 69 (51.5%) of the patients were male. The mean duration from the first event to attending hospital was 1.9 years (range, 1-20 years). The mean number of recurrences was 2.6 (1-10), and 72.6% of patients sought medical care after experiencing symptoms twice or more. Four patients (3.1%) needed hospitalization. The most common sites were the upper extremities (47.7%), followed by the lower extremities, face, abdomen, chest, buttocks and perineum. Clear documentation on the causative drugs was available for 38 patients (28.4%), and among these, non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen accounted for 71.1% of cases, and antibiotics accounted for 15.8%. Eighty patients (59.7%) underwent active treatment for FDE, and topical steroids were most frequently prescribed (43.3%), with systemic steroids used in 11.2% of patients.
Conclusions
NSAIDs and acetaminophen were the main causative agents of FDE, however, the causative agents were not assessed in 25% of patients.
doi:10.4168/aair.2014.6.5.415
PMCID: PMC4161682  PMID: 25228998
Fixed drug eruption; non-steroidal anti-inflammatory drug
3.  Clinical features and prognostic factors of Churg-Strauss syndrome 
Background/Aims
Churg-Strauss syndrome (CSS) is a rare systemic necrotizing small-vessel vasculitis, with accompanying bronchial asthma, eosinophilia, and eosinophilic infiltration of various tissues. The purposes of our study were to characterize the clinical features of CSS and to identify factors associated with CSS prognosis in Koreans.
Methods
Medical records were reviewed retrospectively for all physician-diagnosed CSS patients in the Seoul National University Hospital between January 1990 and March 2011.
Results
Data from 52 CSS patients were analyzed. The respiratory tract was the most commonly involved organ (90.4%). Renal involvement was less frequent in antineutrophilic cytoplasmic antibody (ANCA)(-) patients than in ANCA(+) patients (p = 0.048). Clinical remission occurred in 95.3% of patients, but 16.3% of them relapsed. Patients who maintained remission for more than 6 months were relatively older (median, 51 years) at diagnosis (p = 0.004), had been diagnosed in earlier stages (p = 0.027), showed more frequent respiratory involvement (p = 0.024) and generalized symptoms (p = 0.039), and showed less frequent cutaneous involvement (p = 0.030) than those who did not achieve persistent (> 6 months) remission. Patients who achieved persistent remission also showed higher C-reactive protein (CRP) levels (p = 0.031) than those who did not.
Conclusions
ANCA(-) CSS patients showed less frequent renal involvement. Characteristics of good responders were older age, diagnosis at earlier stages, less cutaneous involvement, more respiratory involvement, high CRP values, and more generalized symptoms.
doi:10.3904/kjim.2014.29.1.85
PMCID: PMC3932399  PMID: 24574837
Churg-Strauss syndrome; Antibodies, antineutrophil cytoplasmic; Prognosis
4.  Lost to Follow-Up in Asthmatics Does Not Mean Treatment Failure: Causes and Clinical Outcomes of Non-Adherence To Outpatient Treatment In Adult Asthma 
Purpose
Long-term asthma management is recommended to asthmatics; however, many patients do not adhere to follow-up treatment. It is unclear why many asthmatics do not adhere to follow-up treatment and long-term clinical course after discontinuation of asthma management. This study investigates the factors associated with loss to follow-up and observes the clinical course in asthmatics who discontinued asthma treatment.
Methods
A retrospective investigation was conducted after reviewing medical records of adult patients who were newly diagnosed with asthma at a university hospital in Seoul, South Korea from January 2005 to March 2007. We compared baseline demographics and the clinical and laboratory profiles of patients to see if they successfully adhered to the treatment at an outpatient clinic for at least 3 years. The clinical course and asthma control status were surveyed by telephone for patients who were lost to follow-up within 3 years.
Results
A total of 351 (73.9%) out of 475 patients were lost to follow-up within 3 years of asthma diagnosis. Patients lost to follow-up were younger and had clinical features of less severe asthma at time of diagnosis (higher FEV1 and PC20, and lower grade treatments) compared to patients who adhered to the follow-up for longer than 3 years (all P<0.05). Among the 198 responders to the telephone survey, 124 responders (62.6%) answered that they eventually discontinued asthma medication. A significantly higher proportion of the 124 responders who discontinued asthma treatment maintained symptom improvement compared to the 74 responders who continued asthma medication (77.4% vs. 55.4%, P=0.003).
Conclusions
Almost three quarters of newly diagnosed asthmatics discontinued asthma medication within 3 years despite a medical recommendation. There are considerable numbers of asthmatics who can maintain long-term asthma control status without medication.
doi:10.4168/aair.2013.5.6.357
PMCID: PMC3810541  PMID: 24179681
Asthma; medication adherence; lost to follow-up; surveys; telephone; questionnaires
5.  Gastrointestinal tuberculosis is not associated with proton pump inhibitors: A retrospective cohort study 
AIM: To evaluate the effect of proton pump inhibitors (PPIs) on the development of gastrointestinal tuberculosis.
METHODS: All patients who were more than 20 years old and who had received a prescription for PPIs among those who visited Seoul National University Hospital from January 1, 2005 to December 31, 2009 were identified. Due to the low sensitivity of the microbiologic test and the nonspecific pathologic findings, the diagnosis of gastrointestinal tuberculosis was confirmed through the presence of active ulcerations and the responses to anti-tuberculosis medications. The patients were divided into two groups according to treatment duration (group 1: ≤ 3 mo; group 2: > 3 mo) and were followed up from the time they took the first prescription of PPIs until their last visit. Logistic regression analysis was used to calculate the relative risks (RR) and 95%CI, adjusting for covariates.
RESULTS: Among the 61  834 patients exposed to PPIs (50  534 in group 1; 11  300 in group 2), 21 patients were diagnosed with PPI-associated gastrointestinal tuberculosis during 124  274 person-years of follow-up. Of 21 patients, the 12 who revealed only scar changes in the colonoscopy were excluded from the statistical analyses. Of those who remained, 2 were excluded because they underwent gastrointestinal endoscopy within 4 wk of the first prescription for PPIs. Longer exposure to PPI was associated with a higher mean age (55.0 ± 14.5 in group 1 vs 58.2 ± 13.3 in group 2, P < 0.001) and a higher Charlson co-morbidity index (0.50 ± 0.93 in group 1 vs 0.77 ± 1.14 in group 2, P < 0.001). The true incidence of active gastrointestinal tuberculosis was 0.65 per 1000 person-years in group 1 and 0.03 per 1 000 person-years in group 2. Like the less-than-three-month PPI treatment period in group 1, the over-three-month PPI therapy period in group 2 was not associated with increased risk of acquiring gastrointestinal tuberculosis, after adjusting for age and co-morbidities, whereas the Charlson co-morbidity index was associated with increased risk of acquiring gastrointestinal tuberculosis based on the score [RR: (reference 1) in group 1 vs 1.518 in group 2; 95% CI: 1.040-2.216, P = 0.03].
CONCLUSION: Long-term PPI therapy does not seem to be associated with increased risk of acquiring gastrointestinal tuberculosis, but a higher Charlson co-morbidity index is associated with such.
doi:10.3748/wjg.v19.i2.258
PMCID: PMC3547571  PMID: 23345949
Proton pump inhibitor; Acid suppression; Tuberculosis; Gastrointestinal tuberculosis; Tuberculous colitis
6.  A Case of Allopurinol-Induced Fixed Drug Eruption Confirmed With a Lymphocyte Transformation Test 
Allopurinol is one of the causative drugs that induce fixed drug eruption (FDE). The lymphocyte transformation test (LTT) is a safe and reliable diagnostic procedure for drug allergy, but is reported to be rarely positive in patients with FDE. In the current case, we performed an LTT and successfully confirmed allopurinol as the offending drug. This case report suggests that an LTT should be an optional diagnostic tool for FDE or delayed reaction due to allopurinol.
doi:10.4168/aair.2012.4.5.309
PMCID: PMC3423606  PMID: 22950038
Allopurinol; fixed drug eruption; lymphocyte transformation test
7.  Therapeutic Effects of Fermented Red Ginseng in Allergic Rhinitis: A Randomized, Double-Blind, Placebo-Controlled Study 
Purpose
Allergic rhinitis is clinically defined as a disorder of the nose induced by IgE mediated inflammation after allergen exposure of the nasal mucosa. Many reports have stated that Panax ginseng and fermented red ginseng have anti-inflammatory effects, especially against Th2-type inflammation. This study was conducted to evaluate the therapeutic effects of fermented red ginseng in allergic rhinitis.
Methods
In this 4-week, double-blind, placebo-controlled study, 59 patients with persistent perennial allergic rhinitis were randomly divided into two groups: those receiving fermented red ginseng tablets (experimental group) and those receiving placebo (control group). The primary efficacy variable was the total nasal symptom score (TNSS; rhinorrhea, sneezing, itchy nose, and nasal congestion). Secondary efficacy variables were the Rhinitis Quality of Life (RQoL) score and skin reactivity to inhalant allergens, as determined by the skin prick test.
Results
There was no significant difference in the TNSS score and TNSS duration score between the experimental and placebo groups in weeks 1, 2, 3, or 4. For nasal congestion, fermented red ginseng was significantly effective (P<0.005), while placebo caused no change. The activity and emotion of RQoL improved markedly secondary to treatment with fermented red ginseng (P<0.05), while placebo caused no change. Additionally, fermented red ginseng reduced skin reactivity to sensitized perennial allergens (P<0.05). Fermented red ginseng was well tolerated.
Conclusions
Fermented red ginseng improved nasal congestion symptoms and RQoL in patients with perennial allergic rhinitis.
doi:10.4168/aair.2011.3.2.103
PMCID: PMC3062788  PMID: 21461249
Allergic rhinitis; alternative medicine; fermented ginseng; ginsenoside
8.  Predictors of the Severity and Serious Outcomes of Anaphylaxis in Korean Adults: A Multicenter Retrospective Case Study 
Purpose
Differences in definitions of the condition, relevant triggers, and the geographical locations of study centers, cause estimates of the prevalence of anaphylaxis to vary. Recent epidemiological data indicate that the incidence of anaphylaxis is rising.
Methods
To investigate the causes and clinical features of anaphylaxis in Korean adults, factors associated with the severity of the condition, and serious outcomes, a retrospective medical record review was performed on adult patients diagnosed with anaphylaxis between 2007 and 2011 in 15 University Hospitals of South Korea.
Results
A total of 1,806 cases (52% male, age 16-86 years) were reported. Cutaneous symptoms (84.0%), combined with respiratory (53.9%) and/or cardiovascular (55.4%) symptoms, were the most frequent presentations. Using a recognized grading system, 1,776 cases could be classified as either mild, 340; moderate, 690; or severe, 746. Although eliciting factors varied significantly by age, gender, and regional and seasonal factors, drugs (46.5%; including nonsteroidal anti-inflammatory drugs, antibiotics, and radiocontrast media) were the most common cause of anaphylaxis, followed by foods (24.2%), insect stings (16.4%), exercise (5.9%), and unknown etiology (7.0%). All of age, multi-organ involvement, a history of allergic disease, and drug-induced anaphylaxis, were significant predictors of serious outcomes requiring hospital admission or prolongation of hospital stay. Epinephrine auto-injectors were prescribed for 7.4% of reported cases.
Conclusions
The principal causes of anaphylaxis in Korean adults were drugs, food, and insect stings. Drug-associated anaphylaxis, a history of allergic disease, multi-organ involvement, and older age, were identified as predictors of serious outcomes.
doi:10.4168/aair.2015.7.1.22
PMCID: PMC4274465  PMID: 25553259
Anaphylaxis; adult; epidemiology; multicenter study; severity; serious outcomes
9.  Airway Smooth Muscle Sensitivity to Methacholine in Precision-Cut Lung Slices (PCLS) from Ovalbumin-induced Asthmatic Mice 
Asthma is a chronic inflammatory disease characterized by airway hyperresponsiveness (AHR) and reversible airway obstruction. Methacholine (MCh) is widely used in broncho-provocation test to evaluate airway resistance. For experimental investigation, ovalbumin-induced sensitization is frequently used in rodents (Ova-asthma). However, albeit the inflammatory histology and AHR in vivo, it remains unclear whether the MCh sensitivity of airway smooth muscle isolated from Ova-asthma is persistently changed. In this study, the contractions of airways in precision-cut lung slices (PCLS) from control, Ova-asthma, and IL-13 overexpressed transgenic mice (IL-13TG) were compared by analyzing the airway lumen space (AW). The airway resistance in vivo was measured using plethysmograph. AHR and increased inflammatory cells in BAL fluid were confirmed in Ova-asthma and IL-13TG mice. In the PCLS from all three groups, MCh concentration-dependent narrowing of airway lumen (ΔAW) was observed. In contrast to the AHR in vivo, the EC50 of MCh for ΔAW from Ova-asthma and IL-13TG were not different from control, indicating unchanged sensitivity to MCh. Although the AW recovery upon MCh-washout showed sluggish tendency in Ova-asthma, the change was also statistically insignificant. Membrane depolarization-induced ΔAW by 60 mM K+ (60K-contraction) was larger in IL-13TG than control, whereas 60K-contraction of Ova-asthma was unaffected. Furthermore, serotonin-induced ΔAW of Ova-asthma was smaller than control and IL-13TG. Taken together, the AHR in Ova-asthma and IL-13TG are not reflected in the contractility of isolated airways from PCLS. The AHR of the model animals seems to require intrinsic agonists or inflammatory microenvironment that is washable during tissue preparation.
doi:10.4196/kjpp.2015.19.1.65
PMCID: PMC4297764  PMID: 25605999
Airway; Asthma; Lung slice; Smooth muscle
10.  Validation of the Korean version of the European Community Respiratory Health Survey screening questionnaire for use in epidemiologic studies for adult asthma 
Asia Pacific Allergy  2015;5(1):25-31.
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.
doi:10.5415/apallergy.2015.5.1.25
PMCID: PMC4313752  PMID: 25653917
Asthma; Epidemiology; Questionnaires
11.  Chronic Low Dose Chlorine Exposure Aggravates Allergic Inflammation and Airway Hyperresponsiveness and Activates Inflammasome Pathway 
PLoS ONE  2014;9(9):e106861.
Background
Epidemiologic clinical studies suggested that chronic exposure to chlorine products is associated with development of asthma and aggravation of asthmatic symptoms. However, its underlying mechanism was not clearly understood. Studies were undertaken to define the effects and mechanisms of chronic low-dose chlorine exposure in the pathogenesis of airway inflammation and airway hyperresponsiveness (AHR).
Methods
Six week-old female BALB/c mice were sensitized and challenged with OVA in the presence and absence of chronic low dose chlorine exposure of naturally vaporized gas of 5% sodium hypochlorite solution. Airway inflammation and AHR were evaluated by bronchoalveolar lavage (BAL) cell recovery and non-invasive phlethysmography, respectively. Real-time qPCR, Western blot assay, and ELISA were used to evaluate the mRNA and protein expressions of cytokines and other inflammatory mediators. Human A549 and murine epithelial (A549 and MLE12) and macrophage (AMJ2-C11) cells were used to define the responses to low dose chlorine exposure in vitro.
Results
Chronic low dose chlorine exposure significantly augmented airway inflammation and AHR in OVA-sensitized and challenged mice. The expression of Th2 cytokines IL-4 and IL-5 and proinflammatory cytokine IL-1β and IL-33 were significantly increased in OVA/Cl group compared with OVA group. The chlorine exposure also activates the major molecules associated with inflammasome pathway in the macrophages with increased expression of epithelial alarmins IL-33 and TSLP in vitro.
Conclusion
Chronic low dose exposure of chlorine aggravates allergic Th2 inflammation and AHR potentially through activation of inflammasome danger signaling pathways.
doi:10.1371/journal.pone.0106861
PMCID: PMC4159271  PMID: 25202911
12.  Capsaicin cough sensitivity is related to the older female predominant feature in chronic cough patients 
Purpose
The present study aimed to examine the age and gender distributions among chronic cough patients referred to a tertiary cough clinic in Korea, and to investigate clinical factors related to the demographic findings.
Methods
Study participants were unselectively recruited from adult chronic cough patients who attended the cough clinic for the first time during one year. To validate their representativeness, their age and gender distributions were compared to the entire chronic cough population, or with those presenting with other chronic disease. Data from the baseline investigations were analyzed to identify clinical factors related to the demographic findings.
Results
A total of 272 chronic cough patients were included. They had a middle-aged female predominant feature (mean age: 52.8±15.7 years and female 69.1%). Their age and gender distributions were almost identical to the entire chronic cough population, but were distinct from patients with hypertension. Among clinical factors, the older female predominance was associated with enhanced capsaicin cough sensitivity, and also with the presence of 'cough by cold air' symptom. Allotussia and laryngeal paresthesia were highly common in chronic cough patients, affecting 94.8% and 86.8% of them, respectively.
Conclusions
The present study demonstrated older female predominance among adult chronic cough patients attending a referral cough clinic in Korea. The demographic features were significantly associated with the capsaicin cough responses and also potentially with allotussia (particularly cold air as the trigger). These findings suggest a role of cough reflex sensitization in the pathophysiology of chronic cough in adults.
doi:10.4168/aair.2014.6.5.401
PMCID: PMC4161680  PMID: 25228996
Cough; respiratory hypersensitivity
15.  Influence of Chronic Sinusitis and Nasal Polyp on the Lower Airway of Subjects Without Lower Airway Diseases 
Purpose
Upper and lower respiratory tract pathologies are believed to be interrelated; however, the impact of upper airway inflammation on lung function in subjects without lung disease has not been evaluated. This study investigated the association of CT finding suggesting chronic sinusitis and lung function in healthy subjects without lung disease.
Methods
This was a retrospective study of prospectively collected data from 284 subjects who underwent a pulmonary function test, bronchial provocation test, rhinoscopy, and osteomeatal unit computed tomography offered as a private health check-up option.
Results
CT findings showed that the sinusitis group had a significantly lower FEV1/FVC ratio than subjects without sinusitis finding (78.62% vs 84.19%, P=0.019). Among the sinusitis group, subjects classified by CT findings as the extensive disease group had a slightly lower FEV1/FVC than those of the limited disease group (76.6% vs 79.5%, P=0.014) and the associations were independent of the presence of airway hyperresponsiveness. The subjects with nasal polyp had also lower FEV1 and FEV1/FVC than subjects without nasal polyp (FEV1: 100.0% vs 103.6%, P=0.045, FEV1/FVC: 77.4% vs 80.0%, P=0.005).
Conclusions
CT findings suggesting chronic sinusitis and nasal polyp were associated with subclinical lower airway flow limitation even in the absence of underlying lung disease.
doi:10.4168/aair.2014.6.4.310
PMCID: PMC4077957  PMID: 24991454
Bronchial hyperresponsiveness; computed tomography; nasal polyp; pulmonary function test; sinusitis
16.  Anaphylaxis to Iodinated Contrast Media: Clinical Characteristics Related with Development of Anaphylactic Shock 
PLoS ONE  2014;9(6):e100154.
Objective
Anaphylaxis is the most severe form of radiocontrast media (RCM) induced hypersensitivity and can be life-threatening if profound hypotension is combined. With increased use of iodine based RCM, related hypersensitivity is rapidly growing. However, the clinical characteristics and risk factors of RCM induced anaphylaxis accompanied by hypotension (anaphylactic shock) are not clearly defined. This study was performed to investigate the risk factors of RCM induced anaphylactic shock and the clinical value of RCM skin testing to identify causative agents in affected patients.
Methods
We analyzed the data of RCM induced anaphylaxis monitored by an inhospital pharmacovigilance center at a tertiary teaching hospital from January 2005 to December 2012 and compared the clinical features and skin test results according to the accompanying hypotension.
Results
Among total of 104 cases of RCM induced anaphylaxis, 34.6% of patients, developed anaphylaxis on their first exposure to RCM. Anaphylactic patients presenting with shock were older (57.4 vs. 50.1 years, p = 0.026) and had a history of more frequently exposure to RCM (5.1±7.8 vs. 1.9±3.3, p = 0.004) compared to those without hypotension. Among RCMs, hypotension was more frequent in anaphylaxis related to iopromide compared to other agents (85.0% vs. 61.4%, p = 0.011). Skin tests were performed in 51 patients after development of RCM induced anaphylaxis. Overall skin test positivity to RCM was 64.7% and 81.8% in patients with anaphylactic shock.
Conclusion
RCM induced anaphylactic shock is related to multiple exposures to RCM and most patients showed skin test positivity to RCM.
doi:10.1371/journal.pone.0100154
PMCID: PMC4059752  PMID: 24932635
17.  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.
doi:10.4168/aair.2014.6.2.156
PMCID: PMC3936045  PMID: 24587953
Acetaminophen; celecoxib; cross reactions; hypersensitivity; intolerance; anti-inflammatory agents; non-steroidal
18.  What Makes a Difference in Exercise-Induced Bronchoconstriction: An 8 Year Retrospective Analysis 
PLoS ONE  2014;9(1):e87155.
Background
Exercise-induced bronchoconstriction (EIB) was recently classified into EIB alone and EIB with asthma, based on the presence of concurrent asthma.
Objective
Differences between EIB alone and EIB with asthma have not been fully described.
Methods
We retrospectively reviewed who visited an allergy clinic for respiratory symptoms after exercise and underwent exercise bronchial provocation testing. More than a 15% decrease of forced expiratory volume in 1 second (FEV1) from baseline to the end of a 6 min free-running challenge test was interpreted as positive EIB.
Results
EIB was observed in 66.9% of the study subjects (89/133). EIB-positive subjects showed higher positivity to methacholine provocation testing (61.4% vs. 18.9%, p<0.001) compared with EIB-negative subjects. In addition, sputum eosinophilia was more frequently observed in EIB-positive subjects than in EIB-negative subjects (56% vs. 23.5%, p = 0.037). The temperature and relative humidity on exercise test day were significantly related with the EIB-positive rate. Positive EIB status was correlated with both temperature (p = 0.001) and relative humidity (p = 0.038) in the methacholine-negative EIB group while such a correlation was not observed in the methacholine-positive EIB group. In the methacholine-positive EIB group the time to reach a 15% decrease in FEV1 during exercise was significantly shorter than that in the methacholine-negative EIB group (3.2±0.7 min vs. 8.6±1.6 min, p = 0.004).
Conclusions
EIB alone may be a distinct clinical entity from EIB with asthma. Conditions such as temperature and humidity should be considered when performing exercise tests, especially in subjects with EIB alone.
doi:10.1371/journal.pone.0087155
PMCID: PMC3907485  PMID: 24498034
19.  Eosinophilic Airway Inflammation and Airway Hyperresponsiveness According to Aeroallergen Sensitization Pattern in Patients With Lower Airway Symptoms 
Purpose
Sensitization to specific allergens may be important in the development of allergic airway inflammation and airway hyperresponsiveness (AHR). We evaluated the effect of specific aeroallergen sensitization on eosinophilic airway inflammation and AHR.
Methods
We reviewed retrospectively the clinical data of subjects who underwent skin prick tests to aeroallergens, induced sputum analysis, and methacholine bronchial provocation tests to evaluate lower airway symptoms as well as analyzed the associations between the pattern of aeroallergen sensitization and sputum eosinophilia or AHR.
Results
Of the 1,202 subjects be enrolled, 534 (44.4%) were sensitized to at least one aeroallergen in skin tests. AHR was demonstrated in 23.5% and sputum eosinophilia in 38.8%. Sputum eosinophilia was significantly associated with sensitization to perennial allergens (OR, 1.9; 95% CI, 1.4-2.5), house dust mite (OR, 1.7; 95% CI, 1.3-2.3), dog (OR, 1.9; 95% CI, 1.1-3.3), and cat (OR, 2.1; 95% CI, 1.4-3.4). AHR was associated with sensitization to perennial allergens (OR, 2.7; 95% CI, 2.0-3.7), house dust mite (OR, 2.2; 95% CI, 1.6 3.2), Alternaria (OR, 2.3; 95% CI, 1.2-4.7), and cat (OR, 2.7; 95% CI, 1.7-4.3). Sensitization to more perennial allergens increased the risk for sputum eosinophilia and AHR. There was no relationship with individual seasonal allergens.
Conclusion
The development of airway eosinophilic inflammation and AHR in an adult Korean population was associated with sensitization to perennial allergens rather than seasonal allergens.
doi:10.4168/aair.2014.6.1.39
PMCID: PMC3881399  PMID: 24404392
Aeroallergen; airway eosinophilia; airway hyperresponsiveness
20.  CYP1A2 polymorphism and theophylline clearance in Korean non-smoking asthmatics 
Asia Pacific Allergy  2013;3(4):231-240.
Background
Theophylline is mainly metabolized by cytochrome P450 (CYP) 1A2 and CYP2E1 which show inter-individual variations. However, the underlying mechanism remains unknown in humans. We investigated the relationship between differences in theophylline clearance and genetic polymorphisms in the CYP1A2 and CYP2E1 gene in 89 Korean asthmatic patients.
Methods
Polymerase chain reaction (PCR) was performed on the 5'-flanking region of those genes. PCR products were directly sequenced and confirmed using the SNaP shot method. We determined whether the detected SNPs affected gene transcription using electrophoretic mobility shift assay (EMSA). Theophylline clearance (mL/kg/h) was assessed by using a Bayesian approach.
Results
Genetic polymorphisms were identified at 7 sites in the CYP1A2 gene and at 10 sites in the CYP2E1. Among them, subjects with genotypes (GA+AA) of the -3860G>A polymorphism were found to show higher theophylline clearance than those with genotypes GG (29.11 ± 0.91 mL/kg/h vs. 26.12 ± 0.80 mL/kg/h, p = 0.014). This polymorphic site was revealed to be a protein binding site by conducting EMSA on nuclear hepatocyte extracts.
Conclusion
In conclusion, increased theophylline clearance was significantly related to the -3860G>A polymorphism, which could be associated with increased CYP1A2 inducibility in Korean non-smoking asthmatics.
doi:10.5415/apallergy.2013.3.4.231
PMCID: PMC3826610  PMID: 24260728
Theophylline; Cytochrome P450; CYP1A2; Polymorphism; Clearance; Electrophoretic mobility shift assay
21.  Staphylococcal enterotoxin specific IgE and asthma: a systematic review and meta-analysis 
Asia Pacific Allergy  2013;3(2):120-126.
Background
Recent literature suggests that Staphylococcal enterotoxin specific IgE may be a risk factor for asthma.
Objective
To investigate the associations between Staphylococcal enterotoxin sensitization and asthma.
Methods
A systematic review and meta-analysis was performed for relevant case-control or population-based studies, published in the peer-reviewed journals until February 2013. Data were extracted on study designs, subjects, definitions and the prevalence of Staphylococcal enterotoxin sensitization.
Results
A total of 683 studies were initially identified, of which 7 studies finally met the inclusion criteria (5 case-control and 2 population-based studies). All the included studies reported higher prevalence of the sensitization in asthmatics than in controls, despite clinical and methodological heterogeneity. In a meta-analysis, the pooled odds ratio of the sensitization for asthma was 2.95 (95% confidence intervals 2.28-3.82).
Conclusion
Staphylococcal enterotoxin sensitization was significantly associated with asthma. The mechanisms of associations warrant further elucidation.
doi:10.5415/apallergy.2013.3.2.120
PMCID: PMC3643054  PMID: 23667836
Asthma; Staphylococcus; Meta-analysis
22.  Airway epithelial cells initiate the allergen response through transglutaminase 2 by inducing IL-33 expression and a subsequent Th2 response 
Respiratory Research  2013;14(1):35.
Background
Transglutaminase 2 (TG2) is a post-translational protein-modifying enzyme that catalyzes the transamidation reaction, producing crosslinked or polyaminated proteins. Increased TG2 expression and activity have been reported in various inflammatory conditions, such as rheumatoid arthritis, inflammation-associated pulmonary fibrosis, and autoimmune encephalitis. In particular, TG2 from epithelial cells is important during the initial inflammatory response in the lung. In this study, we evaluated the role of TG2 in the pathogenesis of allergic asthma, particularly whether TG2 affects initial activation signaling leading to Th2 differentiation against antigens.
Methods
We induced allergic asthma by ovalbumin sensitization and intranasal challenge in wild-type (WT) BALB/c and TG2-deficient mice. Broncheoalveolar lavage fluid cells and intracellular cytokine production were analyzed by flow cytometry. Interleukin (IL)-33 and TG2 expression in lung epithelial cells was detected by confocal microscopy.
Results
Airway responsiveness was attenuated in TG2-deficient mice compared to that in the WT control. In addition, recruitment of eosinophils and Th2 and Th17 differentiation decreased in TG2-deficient mice. Treatment with cysteamine, a transglutaminase inhibitor, also reduced airway hypersensitivity, inflammatory cell recruitment, and T helper cell differentiation. TG2-deficient mice showed reduced IL-33 expression following induction of allergic asthma compared to those in the WT control.
Conclusions
We found that pulmonary epithelial cells damaged by allergens triggered TG2-mediated IL-33 expression leading to type 2 responses by recruiting both innate and adaptive arms of the immune system.
doi:10.1186/1465-9921-14-35
PMCID: PMC3602182  PMID: 23496815
Epithelium; IL-33; Transglutaminase 2; Asthma; Animal models
23.  Spontaneously Reported Hepatic Adverse Drug Events in Korea: Multicenter Study 
Journal of Korean Medical Science  2012;27(3):268-273.
Hepatic adverse drug reactions (ADRs) to certain drugs may differ within each country, reflecting different patterns of prescription, socioeconomic status, and culture. The purpose of this study was to assess the suspected cause of hepatic ADRs using the spontaneously reported pharmacovigilance data from Korea. A total of 9,360 spontaneously reported adverse drug events (ADEs) from nine Pharmacovigilance Centers were analyzed. Risk of hepatic ADEs was assessed by calculating the reporting odds ratio (ROR). Of the 9,360 cases, 567 hepatic ADEs were reported. The most frequently prescribed drug classes inducing hepatic ADEs were anti-tuberculotics, cephalosporins, valproic acids, penicillins, quinolones, non-steroidal anti-inflammatory drugs (NSAIDs), anti-viral agents, and statins. ROR values were especially high in anti-tuberculosis drugs, systemic antifungal drugs for systemic use, anti-epileptics, propylthiouracil, and herbal medicines. Underlying diseases such as tuberculosis (6.9% vs 0.9%), pneumonia (4.9% vs 1.7%), intracranial injury including skull fracture (4.5% vs 0.9%), HIV (3.4% vs 0.4%), subarachnoid hemorrhage (2.8% vs 0.5%), and osteoporosis (2.4% vs 1.4%) were significantly more common in hepatic ADE group. In conclusion, anti-infective drugs, anti-epileptics, NSAIDs and statins are the most common suspects of the spontaneously reported hepatic ADEs, in Korea. Careful monitoring for such reactions is needed for the prescription of these drugs.
doi:10.3346/jkms.2012.27.3.268
PMCID: PMC3286773  PMID: 22379337
Drug-Induced Hepatitis; Etiology; Spontaneous Pharmacovigilance
24.  294 Reference Values and Influencing Factors of Exhaled Nitric Oxide in Healthy Korean Adults 
The World Allergy Organization Journal  2012;5(Suppl 2):S112-S113.
Background
Fractional exhaled nitric oxide (FeNO) is widely used as an inflammatory marker for asthma. However, reference values and influencing factors of FeNO using Niox Mino, which is the only device achieving US FDA approval, are not well described in healthy Asian adults. This study aimed to suggest the reference values and influencing factors of FeNO in healthy Korean adults.
Methods
Subjects who were over 19 years old and did not have any history of rhinitis, asthma or recent respiratory symptoms were enrolled. FeNO levels were measured using Niox Mino. Age, gender, body mass index (BMI), smoking status and lung function were also measured to analyze factors associated with FeNO levels.
Results
The mean value of FeNO was 16.14 ± 10.04 ppb. The reference value of FeNO, which was defined as the value of 95% in distribution curve, was same or less than 34 ppb. In a univariate analysis, FeNO levels were not associated with age, BMI and smoking history. However, atopy status (18.2 ± 11.8 for atopy and 15.1 ± 8.5 for nonatopy groups, P = 0.008) and gender (17.8 ± 10.2 for male and 14.8 ± 9.8 for female groups, P < 0.001) were positively associated with FeNO levels. In stratified analysis, the significance of both variables remained unchanged (P < 0.001).
Conclusions
Our data suggested that the reference value of FeNO in healthy Korean adults seemed to be same or less than 34 ppb. Reference values of FeNO in Korean adults are influenced by gender and atopy status.
doi:10.1097/01.WOX.0000412051.20565.61
PMCID: PMC3512963
25.  248 HLA-B58 Does not Increase Allopurinol Hypersensitivity among Patients with Hematologic Malignancy 
Background
HLA-B58 is a very strong marker of allopurinol-induced severe cutaneous adverse reactions (SCARs), especially in population with high frequency of HLA-B58, such as Chinese, Thai, and Korean. Although allopurinol is frequently prescribed to patients receiving chemotherapy for the prevention of tumor lysis syndrome, the risk of allopurinol-related SCARs in patients with hematologic malignancies is not evaluated. This study was conducted to find out the incidence of allopurinol-induced hypersensitivity in patients with hematologic malignancy during chemotherapy according to HLA-B58 and clinical usefulness of HLA-B58 as a risk marker for the development of allopurinol-induced hypersensitivity.
Methods
We retrospectively reviewed the medical records of patients with hematologic malignancy who ever took allopurinol and underwent serologic HLA typing for bone marrow transplantation from January 2000 to May 2010.
Results
Among total 463 patients, 13 (2.8%) patients experienced allopurinol hypersensitivity reactions which were simple maculopapular rash and none of those were compatible with SCARs. The mean duration of allopurinol exposure in total patients was 26.46 days (1∼2,173) and the mean duration until development of rash was 5.54 ± 1.20 days. Fifty patients (10.8%) had HLA-B58. However, the incidence of allopurinol induced rash was not different according to HLA-B58 (4% (2/50) and 2.66% (11/413) in B58 (+) and B58 (-) patients, respectively). Frequency of B58 was slightly higher in patients with rash (15.4%) compared with tolerant patients (10.7%) but the difference was statistically insignificant (P > 0.05).
Conclusions
The results of this study that HLA-B58 does not increase the risk of allopurinol induced SCARs as well as simple rash among patients with hematologic malignancy. Allopurinol can be used safely in most patients with hematologic malignancy during chemotherapy and HLA typing does not give additional advantage for clinical decision.
doi:10.1097/01.WOX.0000412005.38490.43
PMCID: PMC3513174

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