• Clinical and Experimental Pediatrics
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• v.50 no.6
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• pp.556-564
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• 2007

Purpose : We hypothesized that the persisting bronchial hyperresponsiveness (BHR) of adolescents with asthma remission may be controlled mainly by genetic factors, and the BHR of symptomatic asthma by airway inflammation. ${\beta}_2$-adrenoceptor gene is considered to be a candidate gene in the development of BHR. Thus, ${\beta}_2$-adrenoceptor gene polymorphism may be associated with the BHR of adolescents with asthma remission, but not with the BHR of symptomatic asthma. To evaluate this hypothesis, ${\beta}_2$-adrenoceptor gene polymorphism at 2 sites (Arg16-Gly, Gln27-Glu) were examined. Methods : Two hundred two adolescents with BHR ($PC_{20}<18\;mg/mL$) and long term remission (neither asthma-related symptoms nor medication during the previous 2 years) of their asthma (remission group), 182 adolescents with symptomatic asthma (symptomatic group), and 200 healthy adolescents (control group) were studied. Asthma phenotypes were determined using methacholine bronchial provocation test and skin prick test. Genotypes of ${\beta}_2$-adrenoceptor polymorphism were evaluated by PCR-based methods. Results : Gly/Gly allele and Gly16-Gln27 haplotype were more prevalent in the remission group than in the control group (P=0.01, P=0.02), although there was no difference between the symptomatic group and the control group. In the remission group, there was significant difference in geometric mean of $PC_{20}$ among the 3 groups subdivided by the number of Gly16-Gln27 haplotype, showing that the Gly16-Gln27 haplotype was positively associated with BHR. However, no association was found between Gly16-Gln27 haplotype and BHR in the symptomatic group. Conclusion : This study demonstrates that ${\beta}_2$-adrenoceptor polymorphism at amino acid 16 and 27 was associated with BHR persisting in adolescents with asthma remission.

• Tuberculosis and Respiratory Diseases
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• v.44 no.1
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• pp.146-153
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• 1997

Background : Chronic cough is commomly defined as a persistent or recurrent cough exceeding 3 week's duration. The prevalence of chroinc cough is reported to range from 14% to 23 % for nonsmoking adults. The post nasal drip syndrome has been determined to be the most common cause of chronic cough, followed by asthma, chronic bronchitis, gastroesophageal reflux and bronchiectasis. Cough can be the only manifestation of asthma. Bronchial provocation tests are useful in diagnosing cough variant asthma. We investigated the clinical or laboratory findings and the incidence of airway hyperresponsiveness and evaluated the etiology in patients with chronic cough. Method : We evaluated 46 patients with chronic cough. Methacholine challenge test were done. Results : The results were as follows : 1) Thirty - five percent(16/46) of the chronic cough patients and 44% of the post nasal drip syndrom(7/16) showed the positive responses to methacholine challenge test 2) The underlying causes of chronic cough were post nasal drip syndrome in 35%, bronchitis in 21.7%, cough-variant asthma in 17.4%, and unknown condition in 25.9%. 3) Airway hyperresponsiveness in chronic cough was not related to respiratory symptom, nasal symptom, post nasal drip, smoking, derangement of ventilatory function, atopy, or sinusitis. Conclusion : Airway hyperresponsivenss in patients with chronic cough increased in frequency when compaired with normal control, allergic rhinitis. Cough-variant asthma account for 17.4% of patients with chronic cough.

• Clinical and Experimental Pediatrics
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• v.45 no.12
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• pp.1577-1584
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• 2002

Purpose : Airway inflammation is considered to be a characteristic feature of asthma, and eosinophils are recognized as the most important inflammatory cells. This study aims to assess the importance of blood eosinophil count and serum eosinophil cationic protein(ECP) levels as a noninvasive marker of bronchial hyperresponsiveness(BHR) in children with suspected asthma. Methods : This study used data from 87 subjects with asthma-like symptoms(6-18 years old). The $FEV_1$ and provocative concentration producing a 20% fall in $FEV_1(PC_{20})$ on methacholin inhalation challenge test were measured. Four groups were classified based on $PC_{20}$[Group I : <2 mg/mL; Group II : 2-8 mg/mL; Group III : 8-18 mg/mL; Group IV : (18 mg/mL], and blood eosinophil count and serum ECP levels were analyzed. In addition, subjects were classified based on the cutoff value of $PC_{20}$(BHR positive group : <18 mg/mL; BHR negative group : (18 mg/mL). Then blood eosinophil count and serum ECP level were compared between these two groups. Results : Likelihood ratio test for trends revealed a significant association between the blood eosinophil count or serum ECP level, and the degree of BHR as measured by methacholine $PC_{20}$. Blood eosinophil count or serum ECP level was significantly higher in the BHR(+) group than in the BHR(-) group. Blood eosinophil count had a positive correlation with serum ECP level. Conclusion : Blood eosinophil count and serum ECP level may be a useful non-invasive clinical marker of BHR in subjects with suspected asthma. This supports the hypothesis that BHR in asthma is a consequence of airway eosinophilic inflammation.

• Clinical and Experimental Pediatrics
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• v.46 no.10
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• pp.1013-1018
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• 2003

Purpose : Bronchial hyperresponsiveness(BHR) in asthma is thought to be a consequence of underlying airway inflammation. But the mechanism responsible for persistent BHR in adolescents with long-term asthma remission is poorly understood. The aim of this study was to examine whether BHR in adolescents with asthma remission is associated with peripheral blood eosinophilia and/or increased serum levels of eosinophil cationic protein(ECP). Methods : We studied 35 adolescents with long-term asthma remission(neither symptoms nor medication during the previous two years) who have persistent BHR(remission group) and 35 adolescents with symptomatic asthma(symptomatic group) who were matched for methacholine provocative concentration producing a 20% fall in $FEV_1(PC_{20})$ with subjects in the remission group. The peripheral blood eosinophil counts and serum ECP concentrations were compared between these two groups. Correlations between $PC_{20}$ and peripheral blood eosinophil counts or serum ECP concentrations were assessed in these two groups. Results : Peripheral blood eosinophil counts and serum ECP concentrations were significantly lower in the remission group than in the symptomatic group($273{\pm}108$ vs. $365{\pm}178/{\mu}L$; $16.3{\pm}9.4$ vs. $26.5{\pm}15.1{\mu}g/L$, both, P<0.05). $PC_{20}$ was correlated with peripheral blood eosinophil counts and serum ECP concentrations in the symptomatic group(r=-0.385, P=0.022; r=-0.439, P=0.008), but not in the remission group(r=-0.292, P=0.089; r=-0.243, P=0.159). Conclusion : BHR in adolescents with long-term asthma remission is not associated with peripheral blood eosinophilia or an increase in serum ECP concentration, which suggests that BHR in this clinical setting may not be attributed to airway eosinophilic inflammation. Further studies including direct assessment of airway inflammation are needed to confirm this conclusion.

• Tuberculosis and Respiratory Diseases
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• v.58 no.1
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• pp.25-30
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• 2005

Background : An insertion-deletion polymorphism of angiotensin converting enzyme (ACE) gene has been shown to be associated with enzyme activity levels of ACE. Reported results that have been mutually contradictory about asthmatic hypersensitiveness and occurrence according to ACE gene insertion (I)/deletion (D) polymorphism. Also, the involvement of the ACE genes as the genetic basis of bronchial asthma is currently controversy. We investigated whether there was any association between polymorphisms of the ACE genes and airway hyper-responsiveness in chronic obstructive pulmonary disease (COPD). Methods : A total of 100 patients with COPD were enrolled in this study. The ACE genotypes were determined in all subjects by polymerase chain reaction. Pulmonary function test including bronchodilator response (BDR), methacholine bronchial provocation test (MBPT) were done in those patients. Airway hyper-responsiveness include any findings of positive BDR or MBPT. Results : In COPD patients, the ACE genotype distribution did not differ significantly among groups of patients with severities of COPD, and with or without airway hyper-responsiveness. Conclusions : These results suggest that polymorphisms of the ACE gene may not be associated with airway hyper-responsiveness, development and severity of COPD.

• Tuberculosis and Respiratory Diseases
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• v.60 no.2
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• pp.221-227
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• 2006

Background : Cough may be a consequence of bronchial hyperresponsiveness or inflammation. Empirical treatment is important in this context because it difficult to verify the obvious cause of cough using laboratory tests, Corticosteroid has a nonspecific anti-inflammatory effect, and can be used for cough management. However, its response rate has not yet been fully elucidated. This study investigated the short- term effects of inhaled corticosteroid on chronic cough Methods : Patients with chronic cough with a normal chest radiograph and a pulmonary function test were enrolled. Cases with a prior respiratory infection within 8 weeks, a history of bronchial asthma, objective wheezing on examination, subjective symptoms of gastroesophageal reflux or taking an ACE inhibitor were excluded. On the first visit, a methacholine bronchial provocation test, spontaneous sputum eosinophil count performed twice and a paranasal sinus radiograph were checked, and the patients were treated with budesonide turbuhaler $800{\mu}g/day$ for ten days. The primary outcome measure was a decrease in the cough score after treatment. Results : Sixty nine chronic coughers were finally analyzed. The final diagnoses by the routine tests were as follows: bronchial asthma 13.0%, eosinophilic bronchitis 18.8%, paranasal sinusitis 23.2% and non-diagnostic cases 53.6%. The following responses to the inhaled corticosteroid were observed: definite responders, 76.8%, possible responders, 2.9% and non-responders, 20.3%. The response rate was not affected by the final diagnosis even in the non-diagnostic cases. There were minimal adverse drug related effects during the empirical treatment. Conclusion : Routine objective tests such as methacholine provocation, sputum eosinophil count and simple radiographs were notare not suitable for diagnosing chronic cough Therefore, empirical treatment is important. Short term inhaled corticosteroid is effective and can guide a further treatment plan for chronic cough.

• Tuberculosis and Respiratory Diseases
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• v.45 no.2
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• pp.341-350
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• 1998

Background: Airway hyperreponsiveness is a cardinal feature of asthma. It consists of both an increased sensitivity of the airways, as indicated by a smaller concentration of a constrictor agonist needed to initiate the brochoconstrictor response and an increased reactivity, increments in response induced subsequent doses of constrictor, as manifested by slopes of the dose-response curve. The purpose of this study is to observe the relationship between bronchial sensitivity and reactivity in asthmatic subjects. Method: Inhalation dose-response curves using methacholine were plotted in 56 asthmatic subjects. They were divided into three groups(mild, moderate and severe) according to clinical severity of bronchial asthma. PC20 were determined from the dose-response curve as the provocative concentration of the agonist causing a 20% fall in FEVl. PC40 were presumed or determined from the dose response curve, using the PC20 and the one more dose after PC20. Reactivity was calculated from the dose-response curve regression line, connecting PC20 with PC40. Results: PC20 were 1.83mg/ml in mild group, 0.96mg/ml in moderate, and 0.34mg/ml in severe. PC40 were 7.l7mg/ml in mild group, 2.34mg/ml in moderate, and 0.75mg/ml in severe. Reactivity were $24.7{\pm}17.06$ in mild group, $46.1{\pm}22.l0$ in moderate, and $59.0{\pm}5.82$ in severe. There was significant negative correlation between PC20 and reactivity (r= -0.70, P<0.01). Conclusion: Accordingly, there was significant negative correlation between bronchial sensitivity and brochial reactivity in asthmatic subjects. However, in some cases, there were wide variations in terms of the reactivity among the subjects who have similar sensitivity. So both should be assessed when the bronchial response tor bronchoconstrictor agonists is measured.

• Tuberculosis and Respiratory Diseases
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• v.39 no.6
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• pp.490-501
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• 1992

Background: Isocyanate is the most significant cause of occupational asthma in this country. The mechanism of isocyanate induced bronchoconstriction is unclear. Subjects and Method: To observe its immunologic and clinical findings, we performed methacholine bronchial challenge test (MBCT), toluene diisocyanate (TDI)-bronchoprovocation test (BPT) and RAST to TDI-, diphenylmethane diisocyanate (MDI)-, and hexamethylene diisocyanate (HDI)-human serum albumin (HSA) conjugate in 22 isocyanate-sensitive asthmatic workers. Results: BPT revealed early (11), dual (5), and late only (6) asthmatic responses. Their latent period ranged from 3 to 120 months (mean:45.9 months). Three cases (13.6%)showed a negative response on initial MBCT, but following MBeT performed 24 hours after TDI-BPT revealed the development of airway hyperresponsivenss. Twelve (54.5%) workers had increased specific IgE to TDI-HSA, seven (31.8%) had to MDI-HSA, and nine (40.9%) had to HDI-HSA conjugate. The prevalence of specific IgE was not associated with latent period, type of asthmatic responses, smoking, and atopic status. After 3 months' avoidance from workplace, airway hyperresponsiveness was improved in 10 (38.3%), among 12 followed cases. Conclusion: It is suggested that isocyanate can induce IgE-mediated bronchoconstriction in 59.1% of isocyanate-sensitive asthmatic workers. Isocyanate-induced asthma can occur even though MBeT showed a negative result, and measurement of the changes of airway hyperresponsivenss after isocyanate-BPT could be helpful to diagnose isocyanate-sensitive asthma.

• Tuberculosis and Respiratory Diseases
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• v.45 no.5
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• pp.1012-1021
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• 1998

Background : It is known that airway inflammation is present in most patients with asthma, but the relationship between symptoms and the severity and nature of airway inflammation has not been established. Cough variant asthma is defined as an asthma in which the dominant symptom is cough, and the condition can be successfully treated with inhaled steroids. This study was performed to evaluate the time course of bronchial responsiveness according to an inhaled anti-inflammatory therapy and the factors which affect the resolution of bronchial responsiveness, and an efficacy of nedocromil to cough asthma. Method: A prospective study for the investigation of bronchial responsiveness according to an inhaled anti-inflammatory treatment in sixty-one cough asthmatics was performed. Twenty-three entered budesonide ($400{\mu}g{\times}2/day$), twenty-two entered nedocromil ($4mg{\times}2/day$) and sixteen patients entered combined group. The bronchial hyperresponsiveness (BHR) was estimated by methacholine challenge test using counted breath method. The symptom was estimated by 'symptom score'. Reevaluation of BHR and symptom was performed at 2 month after treatment, and if BHR was not resoluted at this time, regarded as a non-responder, and then follow-up of BHR and symptom was performed at 4- and/or 6 month after treatment. Results: The improvement of BHR and symptom was significant in 2 month (p<0.05), but there was no change of them during follow-up period of 4- and/or 6 month in non-responders. In comparison of allergic markers such as serum total IgE, peripheral eosinophil count and skin test reactivity between responders and non-responders, there was no difference in each other. However, in comparison of other factors such as cumulative pack-years, symptom duration, age, gender, and the initial degree of PC20, there was a significant difference in each other(p<0.05). The percent of patients with the resolution of BHR in 2 month was not different in each group(p=0.95). There was no significant difference in the degree of improvement of BHR and symptom in each group. Conclusion: Bronchial responsiveness and symptom was not significantly improved in non-responders during follow-up period of 4- and/or 6 month. The effect of inhaled nedocromil was equivalent to that of inhaled steroid in cough asthmatics, and the response to combined treatment is not superior to that achieved by either of these agents used alone.

• Clinical and Experimental Pediatrics
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• v.53 no.4
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• pp.481-487
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• 2010

Purpose: Recently many studies show early exposure during childhood growth to endotoxin (lipopolysaccharides, LPS) and/or early exposure to allergens exhibit important role in development of allergy including bronchial asthma. The aim of this study was to evaluate the role of endotoxin and allergen exposure in early life via the airways in the pathogenesis of allergic airways inflammation and airway hyperresposiveness (AHR) in mouse model of asthma. Methods: Less than one week-old Balb/c mice was used. Groups of mice were received either a single intranasal instillation of sterile physiologic saline, 1% ovalbumin (OVA), LPS or $1.0{\mu}g$ LPS in 1% OVA. On 35th day, these animals were sensitized with 1% OVA for 10 consecutive days via the airways. Animals were challenged with ovalbumin for 3 days on 55th days, and airway inflammation, hyperresponsiveness, and cytokine expression were assessed. Measurements of airway function were obtained in unrestrained animals, using whole-body plethysmography. Airway responsiveness was expressed in terms of % enhanced pause (Penh) increase from baseline to aerosolized methacholine. Lung eosinophilia, serum OVA-IgE and bronchoalveolar lavage (BAL) fluid cytokine levels were also assessed. ANOVA was used to determine the levels of difference between all groups. Comparisons for all pairs were performed by Tukey-Kramer honest significant difference test; $P$ values for significance were set to 0.05. Results: Sensitized and challenged mice with OVA showed significant airway eosinophilia and heightened responsiveness to methacholine. Early life exposure of OVA and/or LPS via the airway prevented both development of AHR as well as bronchoalveolar lavage fluid eosinophilia. Exposure with OVA or LPS also resulted in suppression of interleukin (IL)-4, 5 production in BAL fluid and OVA specific IgE in blood. Conclusion: These results indicate that antigen and/or LPS exposure in the early life results in inhibition of allergic responses to OVA in this mouse model of astham. Our data show that early life exposure with OVA and/or LPS may have a protective role in the development of allergic airway inflammation and development of allergen-induced airway responses in mouse model of asthma.