Relationships between Fraction of Nitric Oxide, Airway Hyperresponsiveness, Blood Eoshinophil Counts and Serum Eosinophil Cationic Protein in Asthmatic Children / 소아알레르기및호흡기학회지

PURPOSE: The measurement of fraction of nitric oxide (FeNO) is a noticeable tool that reflects airway inflammation in asthmatic patients. We wanted to find out the relationship between pulmonary function, bronchial hyperresponsiveness (AHR), blood eosinophilic inflammatory markers and FeNO level before and after methacholine bronchoprovocation test in asthmatic patients. METHODS: Fifty-five children, who visited the Allergy Clinic of Korea University Anam Hospital from March 2011 to February 2012, due to asthmatic symptoms, such as history of episodic wheezing or dyspnea during the previous year and resolved after using bronchodilators, were enrolled. We performed the baseline pulmonary function and methacholine bronchoprovocation test in the enrolled patients. Blood eosinophil counts and blood eosinophil cationic protein (ECP) were measured. FeNO levels were measured before and after the methacholine bronchoprovocation test. RESULTS: The mean FeNO levels (36.3 ppb) fell after methacholine bronchoprovocation test (25.7 ppb). Forced expiratory volume in one second (FEV1) %pred inversely correlated both with FeNO level before (R2=0.07, P=0.029) and after (R2=0.059, P=0.01) methacholine bronchoprovocation test. The provocative concentration, causing a 20% decrease in FEV1 to methacholine (methacholine PC20) inversely correlated both with FeNO levels before (R2=0.086, P=0.001) and after (R2=0.141, P=0.001) the challenge. FeNO level measured at bronchoconstriction state significantly correlated with blood eosinophil counts (R2=0.112, P=0.028). Serum ECP levels correlated FeNO level, neither before nor after bronchoprovocation. CONCLUSION: The baseline FeNO levels were higher in asthmatic children. However, FeNO levels rather decreased after methacholine induced bronchoconstriction. Repeated spirometry maneuver was considered to have an effect on reducing FeNO levels. FeNO correlated with pulmonary function, airway AHR and blood eosinophil counts.

Acute and Chronic Changes of Vascular Endothelial Growth Factor (VEGF)in Induced Sputum of Toluene Diisocyanate (TDI)-induced Asthma Patients

Vascular endothelial growth factor (VEGF) is a multi-functional cytokine involved in inflammation, repair and angiogenesis in asthmatic airway. This study aimed to evaluate the role of VEGF in immediate bronchoconstriction induced by TDI inhalation, and in chronic TDI-asthma patients. 11 newly diagnosed TDI-asthma patients (group I), 12 chronic TDI-asthma patients with persistent asthma symptoms followed for >4 yr and 15 unexposed healthy controls were enrolled. In group I, induced sputum and serum were collected before and 7 hr after placebo- and TDI-bronchoprovocation test (BPT). In group II, induced sputum and serum were collected every 2 yr. VEGF levels were measured by ELISA. There were no significant differences in sputum and serum VEGF levels between patients and controls. Before and after placebo and TDI-BPT, no significant changes were noted in sputum and serum VEGF levels of group I. In group II patients, sputum VEGF showed variable changes at 1-yr, then decreased significantly at 2-yr (p<0.05), while serum VEGF showed variable changes at 2-yr, which decreased significantly at 4-yr (p<0.05). These results suggest that VEGF may play a minor role in immediate bronchoconstriction after TDI-BPT. In chronic TDI-asthma, VEGF may be involved to 2 yr after the diagnosis and the contribution may decrease after then.

Teste de provocação brônquica: comparação de um protocolo encurtado recomendado pela european respiratory society com um protocolo padronizado / Bronchoprovocation test: comparison of a shortened protocol recommended for european respiratory society with one standard protocol

Introdução: o objetivo deste estudo foi testar o protocolo encurtado de provocação brônquica, modificado, recomendado pela European Respiratory Society, comparando-o com outro considerado padrão. Métodos: foram estudados 20 pacientes com sintomas respiratórios de tosse e/ou dispnéia nos quais o teste doi indicado. A técnica de provocação brônquica foi a de inalação de solução de metacolina, em etapas com concentrações crescentes, durante respiração espontânea. As concentrações de metacolina, no protocolo padrão, iniciam com 0,3mg/ml, dobrando-se, segudamente, até 16mg/ml. No protocolo encurtado, a diferença foi na dose inicial, de 0,25 à 1,0 mg/ml, na dependência das drogas usadas para controle dos sintomas. Resultados: a incidência e a intensidade dos efeitos colaterais, assim como os resultados de PC20, foram iguais em ambos os protocolos. Valores médios de PC20 foram de 3,24 e 3,47 mg/ml respectivamente nos protocolos padrão e encurtado. O tempo total gasto para a realização do teste foi significamente inferior no encurtado, reduzindo o número de etapas. Conclusão: concluímos que os protocolos, encurtado e padrão, mostraram resultados equivalentes, sendo o protocolo encurtado mais rápido.

Clinical usefulness of checking wheezing and flow volume loop in methacholine bronchoprovocation test / 천식및알레르기

BACKGROUND: In methacholine bronchoprovocation test, lung function is traditionally measured by using forced vital capacity maneuver which depends on patient's effort. And insufficient breath may result in a false positive test. OBJECTIVE: To evaluate the additional indices of airflow obstruction in the interpretation of methacholine bronchoprovocation test. METHOD: FEV1/FVC, configuration index of flow-volume loop (Slope-Ratio), modified Borg dyspnea score, and wheezing in addition to FEV1 were measured before and after methacholine challenge. RESULTS: The changes of the measurements after methacholine challenge were significantly greater in patients with airway hyperresponsiveness (AHR). However, only 9 out of 29 (31.0%) patients with AHR developed all of indices and 6.9% did not show any evidence of obstruction except dyspnea. On the contrary, 40% of patients without AHR showed positive in two or more indices and 2 of them were hyperresponsive to histamine. Among patients with AHR, those without dyspnea and wheezing on challenge showed significantly lower baseline Borg score, FEV1, FEV1/FVC, and PC20, and were older than those with them (p<0.05). CONCLUSION: Methacholine-induced deltaFEV1 is related to, but not concordant with other indices of airflow obstruction. Development of dyspnea and wheezing depends on age, etc. For an accurate interpretation of methacholine bronchoprovocation test, it maybe necessary to consider these variables.

Methacholine airway hyperresponsiveness measured just after control of acute severe asthma / 천식및알레르기

BACKGROUND: It has been shown that severe asthmatic attacks are related to airway hyperresponsiveness (AHR). However, there has been no study on AHR measured just after control of acute severe asthma. OBJECTIVE: To determine the degree of AHR following acute severe asthma and to evaluate the safety of AHR measurement in patients just recovering from a severe attack. METHOD: In 23 consecutive asthma patients just recovering from a severe attack (10 severe, 13 near-fatal), all medications except inhaled or systemic steroids were withdrawn temporarily for more than each action time. Then a methacholine bronchoprovocation test was performed in patients with FEV1 > or = 75% of predicted or personal best value. RESULTS: Mean duration required to control asthma was 5.6+/-3.6 days, and methacholine provo- cation test was performed at 12.6+/-5.2 hospital days. The patients showed significantly lower methacholine-PC20 (geometric mean: 0.54 vs 1.64 mg/ml, p<0.05) and steeper slope of dose-response curve (p<0.01) compared to 62 outpatients. Initial FEV1 (r=0.470, p<0.05) and the duration required to control asthma (r=-0.623, p<0.01) were significantly related to methacholine-PC20. However, only 9 patients (39.1%) showed severe AHR, which was not significantly different from outpatients (25.8%). CONCLUSION: These results suggest that AHR is a risk factor of severe asthmatic attack and methacholine challenge just after control of acute asthma is relatively safe.

Clinical significance of specific IgG and IgE antibodies to toluene diisocyanate ( TDi ) - human - serum albumin ( HSA ) conjugate in TDI - induceed occupational asthma / 천식및알레르기

BACKGROUND AND OBJECTIVE: TDI is known to be the most prevalent cause of occupational asthma ( OA ) in Korea. However, the pathogenesis of TDI - induced occupational asthma still remains to be further clarified. So, we evaluated clinical significance of serum specific IgG and IgE antibodies to TDI - HSA conjugate in TDI - induced occupational asthma. Subjects and METHODS: Serum specific IgG and IgE antibodies to TDI - HSA conjugate were measured by enzyme linked immunosorbent assay. Serum was collected from 50 TDI- induced OA patients ( classified as group I ), and was compared with that from 13 asthmatic subjects with negative TDI - bronchoprovocation test ( BPT, group II ), allergic asthmatics ( group III ), and unexposed healthy controls ( group IV ). RESULTS: The prevalence of specific IgG was significantly higher in group I than in group II (p = 0.01) or group III (p 0.05). However, the prevalence of specific IgE was not different between group I and group II (p> 0.05 ) or group II and group III( p> 0.05 ). There was no significant difference in prevalence of specific IgG according to the asthmatic response during TDI bronchoprovocation test ( p> 0.05 ). No statistical significance was noted between specific IgG and IgE antibodies in group I subjects ( p> 0.05 ). CONCLUSION: These findings demonstrate that presence of specific IgG to TDI - HSA conjugate is closely related to TDI - BPT results and it may contribute to the development of TDI - induced asthma.

Occupational asthma induced by tobacco leaf / 천식및알레르기

We experienced a cose of occupational asthma induced by the tobacco leaf in 49-year old man. He has worked at the Korean Tobacco and Ginseng company for 23 years but suffered from the intermittent mild wheezing and dyspnea since 6 years ago. He has not involved in the process making the tobacco directly, but just managed it at the storage barn. He showed a whole negative reaction to 55 inhalant allergens(Bencard, UK) and the allergen extracted from the yellow Korean tobacco leaf, but showed the dual asthmatic respose to the allergen bronchial provocation test with it. His basal PC is 6.35 mg/ml with methacholine inhalation challenge. Now he changed the workplace far away from the barn at the same company and is treated with bronchodilator and anti-asthmatic inhaler.

Revival of Hop Japanese pollinosis in asthmatic subjects in Kyungki area / 천식및알레르기

BACKGROUND: Hop Japanese (Hop J) pollens are abundant in the air of Korea during the autumn season. Their significances as a source of allergenic sensitization have been underestimated in this country. MATERIAL AND METHOD: In other to observe clinical features of Hop J-sensitive asthmatic patients in this country, skin prick test with Hop J pollen was performed. The serum specific IgE antibodies to Hop J pollen antigen were detected by enzyme linked immunosorbent assay (ELISA) in positive responders (>2+ of A/H ratio) on skin prick test. To confirm the respiratory sensitization, bronchoprovocation test was performed in 17 asthmatic patients sensitive to this pollen. RESULT: Ten asthmatic subjects showed a significant bronchoconstriction following the inhalation of Hop J pollen extract (6 early and 4 dual astmatic responses) and all of them had high serum specific IgE bindings, with minimal bindings in negative responders. They have suffered from seasonal aggravation of asthmatic symptoms with or without rhinitis, and/or conjunctivitis symptoms. The skin reactivity to Hop J had more than 5+ of A/H ratio on skin prick test in nine positive responders, whlie negative responders showed from 1+ to 3+ response. Moreover, four (40%) asthmatic subjects showed a positive response to only the Hop J pollen on skin prick test and an isolated positive asthmatic response to the Hop J bronchoprovocation test. CONCLUSION: We believe that the Hop J pollen should be considered as an allergen during the Autumn season, and thus included in skin test batteries in this area. Some labelled having intrinsic asthma or rhinitis might be sensitized to this pollen or other unknown allergens.

Isocyanate-induced occupational asthma: challenge and immunologic studies

Isocyanate is the most prevalent agent in occupational asthma(OA) in Korea. We analyzed 43 toluene diisocyanate(TDI) induced OA patients of whom 81% were found to be spray painters. The bronchial sensitivity of all subjects was confirmed by TDI-bronchial challenge test. Serum-specific IgE antibodies to isocyanate-human serum albumin(HSA) conjugate were detected by RAST technique(Pharmacia, Sweden). Bronchial challenge test results revealed 21(57%) early, 5 late only, 4 dual, and 12 atypical responders(5 prolonged immediate, 6 square-shaped, 1 progressive). Four(9%) subjects had negative results on the methacholine bronchial challenge test. High levels of serum specific IgE antibody to isocyanate-HSA were found in 17(40%) patients. The prevalence of a specific IgE antibody was not associated with a type of TDI-bronchial challenge test response, smoking and atopic status, presence of rhino-sinusitis and systemic symptoms, or a degree of airway hyperresponsiveness to methacholine(p> 0.05). The period of latency, ranging from 3 to 132 months, was significantly longer in high specific IgE responders (p< 0.05). These data suggest that 40% of isocyanate-induced occupational asthma patients had high specific IgE antibody to isocyanate-HSA conjugate. The presence of specific IgE antibody does not seem to correlate with clinical parameters.

Correlation of Exercise-Induced Bronchoconstriction to PC20 and Maximal AirwayNarrowing on the Dose-Response Curve to Methacholine / 결핵

BACKGROUND: Exercise is one of the most common precipitants of acute asthma encountered in clinical practice. The development of airflow limitation that occurs several minutes after vigorous exercise, i. g. exercise-induced bronchoconstriction(EIB), has been shown to be closely correlated with the nonspecific bronchial hyperresponsiveness, which is the hallmark of bronchial asthma. All previous reports that assessed the correlation of EIB to nonspecific bronchial hyperresponsiveness have focused on airway sensitivity(PC20) to inhaled bronchoconstrictor such as methacholine or histamine. However, maximal airway narrowing(MAN), reflecting the extent to which the airways can narrow, when being exposed to high dose of inhaled stimuli, has not been studied in relation to the degree of EIB. METHODS: Fifty-six children with mild asthma(41 boys and 15 girls), aged 6 to 15 years(mean +/- SD, 9.9 +/- 2.5 years) completed this study. Subjects attended the laboratory on two consecutive days. Each subject performed the high-dose methacholine inhalation test at 4 p.m. on the first day. The dose-response curves were characterized by their position(PC20) and MAN, which was defined as maximal response plateau(MRP: when two or three data points of the highest concentrations fell within a 5% response range) or the last of the data points(when a plateau could not be measured). On the next day, exercise challenge, free running outdoors for ten minutes, was performed at 9 a.m.. FEV1 was measured at graduated intervals, 3 to 10 minutes apart, until 60 minutes after exercise. Response(the maximal DeltaFEV1 from the pre-exercise value) was classified arbitrarily into three groups; no response ((-) EIB: DeltaFEV1 20%). RESULTS: 1) When geometric mean PC20 of the three groups were compared, PC20 of (+) EIB group was significantly lower than that of (-)EIB group. 2) There was a close correlation between PC20 and the severity of EIB in the whole group(r= -0.568, p<0.01). 3) Of the total 56 subjects, MRP could be measured in 36 subjects, and the MRP of these subjects correlated fairly with the severity of EIB(r= 0.355, p<0.05) 4) The MAN of (+) EIB group was significantly higher than that of (-)EIB group(p<0.01). 5) The MAN correlated well with the severity of EIB in the whole group(r=0.546, p<0.01). CONCLUSION: The degree of MAN as well as bronchial sensitivity (PC2o) to methacholine is correlated well with the severity of EIB. The results suggest that the two main components of airway hyperresponsiveness may be equally important determinants of exercise reactivity, although the mechanism may be different from each other. The present study also provides further evidence that EIB is a manifestation of the increased airway reactivity characteristic of bronchial asthma.

Airway Responses to Bronchoprovocation Using High-Resolution Computed Tomography in Patients with Bronchial Asthma / 결핵

BACKGROUND: Bronchial hyperresponsiveness and abnormal response such as a loss of distensi- bility are pathophysiologic characteristics if bronchial asthma. The only means of direct in vivo measurement of airway size had been a tantalium bronchography, until high-resolution computed tomography(HRCT) enabled to measure noninvasively two dimensional airway area more accurately and reliably. METHOD: To investigate airway area responses to bronchial provocation with methacholine and evaluate the major sites of bronchial constriction in patients with bronchial asthma. We examined HRCT scans in five patients with bronchial asthma who had significant bronchoconstriction(20% or more decrease in FEV1) using CT scanner(5,000T CT, Shimadzu Co, Japan) before and in 3~5 min. after methacholine inhalation. Airways which were matched by parenchymal anatomic landmarks in each patient before and after methacholine inhalation were measured using film scanner(TZ-3X scanner; Truvel Co. Chatsworth CA, USA) and a semiautomated region growing method. RESULTS: 1) We identified 9 to 12 airways in each patient which were matched by parenchymal anatomic landmarks before and after methacholine inhalation. 2) Airway responses to methacholine are quite different even in a patient. 3) The constriction of small airways(average diameter 2 mm; area >3.14 mm2), 53.8% (4.4;SEM, n=10), but not significantly different(p>0.05). 4) There was no significant difference in the degree of constriction between upper(44.3% +5.8; mean + SEM, n=30) and lower lung regions(56.7% +4.5, n=23). CONCLUSIONS: Thus airway responses to methacholine bronchoprovocation is quite variable in a patient with bronchial asthma and has no typical pattern in patients with bronchial asthma.

Bronchial challenge responses in asthmatic patients sensitized to Artemisia spp. pollen

To characterize the patients whose asthma may be caused by Artemisia pollen extracts, we studied the bronchoprovocation test with Korean Artemisia pollen extracts (1:20 w/v), methacholine bronchial challenge test and wormwood-RAST in 32 asthmatic patients sensitized to Artemisia pollen. Twenty-six(81%) developed a 15% or greater decrease in FEVI after the inhalation of Artemisia pollen extracts and 13 patients showed early responses, 8 dual, and 5 late only. Thirteen(50%) out of 26 positive responders complained of seasonal aggravation of their asthmatic symptoms. Seven(53.8%) of the 13 seasonal type patients, 10(76.9%) of the 13 perennial type and 5(100%) of the 5 negative responders showed concurrent positive responses in the house dust bronchoprovocation test. The bronchial responsiveness to allergen(PD15) was more dependent upon the specific IgE level(bound radioactivity on wormwood-RAST) and multiple regression analysis revealed that the specific IgE level and methacholine PC20 may be contributory to allergen PD15. These results suggested that specific IgE to Artemisia pollen appears to be the major contributor to susceptibility to Artemisia bronchial challenges and this pollen may be considered as one of the important allergenic etiologies of atopic asthma in this country.

The significance of specific IgE and IgG to dermatophagoides farinae according to the types of asthmatic reaction in house dust asthmatics

To investigate the role of specific IgE and IgG in the various types of asthmatic reaction, we measured specific IgE and IgG levels to Dermatophagoides farinae (D.farinae) using the D. farinae-radioallergosorbent test (RAST) and Phadebas IgG-RAST in 39 house dust asthmatics (11 early responders, 21 dual responders and 7 isolated late responders) and 12 negative responders on house dust bronchoprovocation. There were significant differences in the D. farinae-specific IgE level and skin reactivity to D. farinae and house dust among the 4 groups (p less than 0.05) and the specific IgE level of dual asthmatic responders was the highest and was significantly higher than that of early responders (p less than 0.05). The specific IgG level showed no differences among the 4 groups. These results suggested that the types of asthmatic reaction in house dust asthmatics were closely related to specific IgE level to D. farinae and the specific IgG level seemed not to be related to an isolated late response.