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Background: Many bacterial components in indoor dust can evoke inflammatory pulmonary diseases. Bacteria secrete nanometre-sized vesicles into the extracellular milieu, but it remains to be determined whether bacteria-derived extracellular vesicles in indoor dust are pathophysiologically related to inflammatory pulmonary diseases., Objective: To evaluate whether extracellular vesicles (EV) in indoor air are related to the pathogenesis of pulmonary inflammation and/or asthma., Methods: Indoor dust was collected from a bed mattress in an apartment. EV were prepared by sequential ultrafiltration and ultracentrifugation. Innate and adaptive immune responses were evaluated after airway exposure of EV., Results: Repeated intranasal application of indoor-dust-induced neutrophilic pulmonary inflammation accompanied by lung infiltration of both Th1 and Th17 cells. EV 50-200 nm in diameter were present (102.5 μg protein concentration/g dust) in indoor dust. These vesicles were internalized by airway epithelial cells and alveolar macrophages, and this process was blocked by treatment of polymyxin B (an antagonist of lipopolysaccharide, an outer-membrane component of Gram-negative bacteria). Intranasal application of 0.1 or 1 μg of these vesicles for 4 weeks elicited neutrophilic pulmonary inflammation. This phenotype was accompanied by lung infiltration of both Th1 and Th17 cells, which were reversed by treatment of polymyxin B. Serum dust EV-reactive IgG1 levels were significantly higher in atopic children with asthma than in atopic healthy children and those with rhinitis or dermatitis., Conclusion & Clinical Relevance: Indoor dust EV, especially derived from Gram-negative bacteria, is a possible causative agent of neutrophilic airway diseases., (© 2013 Blackwell Publishing Ltd.)

Background: Bronchial hyperresponsiveness (BHR) is a characteristic feature of asthma, and is usually measured by bronchial challenges using direct or indirect stimuli. The relationship between atopy and BHR remains to be clarified, particularly in a population selected for asthma. Furthermore, data for young children are limited, although asthma frequently occurs in early childhood., Objective: The aim of this study was to investigate methacholine (direct stimulus) and adenosine 5'-monophosphate (AMP) (indirect stimulus) responsiveness according to the presence and degree of atopy in young children with asthma., Methods: A retrospective analysis of data from 122 preschool children (median age [range]: 5.3 years [4.0-6.8]) presenting with the diagnosis of asthma was performed. These children were characterized by skin-prick tests (SPTs) and bronchial challenges with methacholine and AMP, using a modified auscultation method. The end-point concentration, resulting in audible wheezing and/or oxygen desaturation, was determined for each challenge. Atopy was defined by at least one positive reaction to SPTs, and its degree was assessed using serum total IgE levels, number of positive SPTs, and atopic scores (sum of graded weal size)., Results: Atopic patients (n=97) had a significantly lower AMP end-point concentration than non-atopic patients (n=25), whereas the methacholine end-point concentration was not different between the two groups. Among the atopic patients, there was no association between the methacholine end-point concentration and any of the atopy parameters. By contrast, a significant association was found between the AMP end-point concentration and the degree of atopy reflected in serum total IgE and atopic scores (χ² test for trend, P=0.001, 0.003, respectively)., Conclusion and Clinical Relevance: Young children with atopic asthma had a significantly greater AMP responsiveness than those with non-atopic asthma, whereas methacholine responsiveness was not significantly different between the two groups. The degree of atopy appeared to be an important factor in AMP responsiveness, but not in methacholine responsiveness, and thus might be a marker of airway inflammation in asthma., (© 2011 Blackwell Publishing Ltd.)

Background: Both bronchial responsiveness (BR) and peak expiratory flow (PEF) variability are increased in asthma. PEF variability is presumed to reflect the degree of BR in asthma. BR is commonly assessed by bronchial challenges using direct or indirect stimuli., Objective: The aim of this study was to compare methacholine and adenosine 5'-monophosphate (AMP) responsiveness with regard to their relationships with PEF variability in children with asthma., Methods: Methacholine and AMP challenge tests were performed in 79 children with mild to moderate asthma, and a provocative concentration causing a 20% decline in forced expiratory volume in 1 s (PC(20)) was calculated for each challenge. Subjects recorded PEF each morning and each evening for 14 consecutive days. PEF variability was expressed as amplitude percentage mean (amp%mean; high PEF minus low PEF on each day, expressed as a percentage of their mean, averaged over 14 days), and as the lowest percentage highest (low%high; the lowest PEF expressed as a percentage of the highest PEF recorded over the period)., Results: Methacholine PC(20) correlated significantly but weakly with both indices of PEF variability (amp%mean: r=-0.285, P=0.011; low%high: r=0.238, P=0.034). However, there was a significant and strong correlation between AMP PC(20) and both amp%mean (r=-0.583, P=0.000) and low%high (r=0.496, P=0.000). For AMP PC(20), the correlations were stronger than for methacholine PC(20) (comparison of correlation coefficients with amp%mean: P=0.021; with low%high: P=0.063)., Conclusion: Both methacholine PC(20) and AMP PC(20) correlated significantly with PEF variability. However, the stronger correlations for AMP PC(20) than for methacholine PC(20) suggest that PEF variability may be better reflected by BR assessed by AMP than by methacholine.

Background: It is well known that atopy is a major determinant of bronchial hyper-responsiveness (BHR) in both asymptomatic and asthmatic children. However, the relationship between atopy and BHR has not been well studied in preschool children with wheezing. BHR is usually measured by bronchial challenges using direct and indirect stimuli., Objective: The aim of this study was to investigate whether atopic and non-atopic preschool wheezers display similar or different BHR profiles for direct and indirect stimuli., Methods: Methacholine and adenosine 5'-monophosphate (AMP) bronchial challenges were performed in 4 to 6-year-old children with recurrent wheezing, using a modified auscultation method. The end-point was defined as the appearance of wheezing and/or oxygen desaturation. Atopy was determined to be present when a child had at least one positive reaction to a panel of 13 common airborne allergens in the presence of positive and negative controls., Results: A positive response to methacholine (an end-point concentration < or =8 mg/mL) was observed in 89.3% (50/56) of atopic wheezers and in 83.8% (31/37) of non-atopic wheezers (P=0.44) for the difference. By contrast, the frequency of a positive response to AMP (an end-point concentration < or =200 mg/mL) was significantly higher in the atopic group (47/56, 83.9%) compared with the non-atopic group (12/37, 32.4%; P<0.01)., Conclusion: While a majority of both atopic and non-atopic preschool wheezers were hyper-responsive to methacholine, atopic subjects were more hyper-responsive to AMP than non-atopic subjects. These findings suggest that atopic and non-atopic wheeze in preschool children are related to distinctive pathophysiologic pathways.

Objective: In this study, we measured the levels of eosinophil cationic protein (ECP) and interleukin (IL)-8 in bronchoalveolar lavage (BAL) fluid from patients with acute asthma and acute bronchiolitis, to determine any similarities or dissimilarities in the profiles of these biochemical markers in the two diseases., Methods: BAL fluids were obtained from children with acute asthma (n=16), infants with acute bronchiolitis caused by respiratory syncytial virus (n=18), and control subjects (n=14). Children with asthma were selected to be free of viral infection. BAL cell counts and differentials were determined, and ECP and IL-8 levels were measured by radioimmunoassay and ELISA, respectively., Results: ECP levels in BAL fluids were significantly higher in the asthma group than in the bronchiolitis (P<0.01) or control (P<0.0001) groups. However, IL-8 levels were significantly higher in the bronchiolitis group than in the asthma (P<0.01) or control (P<0.001) groups. IL-8 levels in the asthma group and ECP levels in the bronchiolitis group were similar to those of the control group., Conclusion: This difference in profiles of ECP and IL-8 in acute asthma and acute bronchiolitis, together with a different inflammatory cell pattern, suggests that the nature of the inflammatory process within the lower respiratory tract may be distinctive in these two diseases.

Background: A significant proportion of patients diagnosed with cough-variant asthma eventually manifest classic asthma signs, such as wheezing and dyspnoea. The aim of this study was to investigate whether the percentage of eosinophils and/or concentration of eosinophilic cationic protein (ECP) in sputum induced from patients with cough-variant asthma can predict the development of classic asthma., Methods: Sixty-two children with cough-variant asthma were prospectively studied for 4 years. At the initiation of the study, sputum was induced with hypertonic saline, and the sputum samples were analysed for total and differential cell counts, and for ECP. Each subject was checked clinically at least every 3 months, and details of classic asthma signs experienced during the intervening periods were taken., Results: Twenty-four (47.1%) of the 51 subjects available for follow-up developed signs of classic asthma, while 27 did not. The only significant difference in the sputum parameters between these two groups was a higher percentage of sputum eosinophils in subjects who developed classic asthma. A significant association was found between sputum eosinophil percentage and classic asthma development, but not between the concentration of sputum ECP and classic asthma development., Conclusion: Sputum eosinophilia in cough-variant asthma may be a correlate of the later development of classic asthma. This suggests that sputum differential cell counts may be useful in the clinical management of patients with cough-variant asthma, as they may enable the prediction of the subsequent classic asthma development.

Background: Allergic rhinitis is a known predictor and correlate of asthma incidence. However, it is not clear which patients with allergic rhinitis are at greater risk of the development of asthma., Objective: The aim of this study was to investigate whether airway hypersensitivity and/or increased maximal response on the dose-response curve to methacholine would predict the development of asthma in subjects with allergic rhinitis., Methods: One hundred and forty-one children with allergic rhinitis were prospectively studied for 7 years. At the initiation of the study, bronchial provocation test with methacholine using a stepwise increasing concentration technique was performed to measure PC(20) (provocative concentration causing a 20% fall in FEV(1)) and maximal response. Each subject was evaluated at least every 6 months and details of asthmatic symptoms or signs experienced during the intervening period were taken., Results: Twenty of 122 subjects available for the follow-up developed asthma. Nine (19.6%) of 46 hypersensitive (PC(20) < 18 mg/mL) subjects developed asthma, compared with 11 (14.5%) of 76 normosensitive subjects (P = 0.462). Eight (32%) of 25 subjects without maximal response plateau developed asthma, compared with 12 (12.4%) of 97 subjects with maximal response plateau (P = 0.018). Score test for trend revealed a significant association between the level of maximal response (P = 0.007), but not the degree of methacholine PC(20) (P = 0.123), and the future development of asthma., Conclusion: An increased maximal airway response to methacholine is shown to be a better predictor for the future development of asthma in patients with allergic rhinitis, than airway hypersensitivity to methacholine.

Background: Our previous work on linkage analysis showed that histamine release from basophils to anti-IgE stimuli was linked to the gene marker of chromosome 11q13, where the beta chain of the high-affinity receptor for IgE (FcepsilonRI-beta) is located., Objective: To evaluate the association between FcepsilonRI-mediated histamine release from basophils and four bi-allelic single nucleotide polymorphisms of the FcepsilonRI-beta gene., Methods: Phenotypes of asthma, such as maximal histamine release from basophils and atopy, were measured from 80 randomly recruited asthmatic children. Polymorphisms of the FcepsilonRI-beta gene were determined by PCR-based methods., Results: The polymorphism in exon 7, resulting in Glu to Gly substitution, was significantly associated with histamine release from basophils to anti-IgE stimuli, but not with total IgE levels and skin test responses to aeroallergens., Conclusion: This study supports a role for the FcepsilonRI-beta gene in the expression of high affinity IgE receptor-mediated histamine release from basophils.

Background: Several candidate genes have been reported to be linked to intermediate phenotypes of asthma in Caucasian populations., Objective: To evaluate linkage between phenotypes of asthma and gene markers of high affinity IgE receptor-beta gene (D11S97), IL-4 cytokine gene cluster (IL-4R1), and T-cell receptor alpha/delta gene complex (D14S50) in Korean nuclear families., Methods: Nuclear families (127 probands and their 130 siblings) for the linkage analysis were ascertained through asthmatic children. Linkages between total serum IgE response, skin responses to common aeroallergens, and bronchial responsiveness to methacholine were performed using a sib-pair approach., Results: The square difference of the slope of the dose-response curve (DRS) between sib-pairs with two IL-4R1 identical alleles was smaller than with one or with neither IL-4R1 identical allele (P = 0.004). As for D14S50, the differences of DRS between sib-pairs with two identical alleles and with one identical allele were smaller than with neither identical alleles (P = 0.01). As for D11S97, no significant differences were observed among the groups with identical alleles of two, one or zero. With regard to total serum IgE levels, no significant linkage was found between this phenotype and the above three gene markers. As for skin responses to common aeroallergens, significant evidence was obtained to establish a linkage between this phenotype and the marker IL-4R1 (P = 0.01). However, no significant linkage was found between this phenotype and the markers D11S97 and D14S50., Conclusion: The expression of bronchial responsiveness to methacholine may be influenced by genetic factors in the IL-4 cytokine gene cluster and/or T-cell receptor alpha/delta gene complex, but the genetic influence of the FcepsilonRI-beta gene may be minimal in the expression of bronchial responsiveness in Korean nuclear families.

Background: Bronchial asthma is characterized by airway inflammation, which underlies the phenomenon of bronchial hyperresponsiveness. The concentration of serum haptoglobin (Hp), one of the acute phase reactant proteins, has been reported to correlate with bronchial hyperresponsiveness. The extent to which bronchoconstriction or airway inflammation contributes to airflow obstruction of exacerbation is presumed to determine the responsiveness to the initial bronchodilator therapy., Objective: To see whether the Hp levels vary with the disease status of asthma, and also to test whether the Hp level at an acute exacerbation (AE) is correlated with the degree of response to initial bronchodilator therapy., Methods: We measured serum Hp levels in 50 children with asthma at the times of an AE and a clinical remission(CR), and analysed the data according to the response to the initial bronchodilator therapy at AE., Results: The serum concentration of Hp at AE (228.5 +/- 80.8 mg/dl, mean +/- SD) was significantly (P < 0.01) higher than that at CR (152.3 +/- 49.8 mg/dl) in the total study population. The difference of Hp levels between AE and CR was more marked (101.7 +/- 82.2 mg/dl) in the subjects (n = 19) who responded poorly (post-bronchodilator FEV1 < 75% predicted) to the initial bronchodilator therapy at AE than that (61.0 +/- 56.5 mg/dl) of those (n = 31) who responded well (post-bronchodilator FEV1 > or = 75% predicted). The Hp level at AE correlated with the degree of response to initial bronchodilator therapy (r = (-)0.36, P < 0.05), whereas it had no relationship with the severity of exacerbation (r = 0.04, P = 0.79)., Conclusion: Our results showed that Hp levels may be increased at the time of exacerbation in a given asthma patient. The finding that the elevation of Hp level at AE is more marked in the cases with poor response to initial bronchodilator therapy at AE suggests that the increased Hp level at AE in asthma might reflect the degree of airway inflammation.

The hypothesis that repeated exposure to a specific allergen will further increase bronchial responsiveness to that allergen is supported by indirect evidence. However, it has not been tested as intensely in the laboratory setting, and in some cases, conflicting results are presented. In order to test the hypothesis in the atopic subjects, allergen inhalation challenge tests were performed in 29 house dust mite (Dermatophagoides pteronyssinus) sensitive subjects with allergic rhinitis. Nine subjects displayed early asthmatic responses (EARs) to the first challenge (Group I). Twenty subjects with no significant airway response were submitted to the second challenge 24 h later. Thirteen subjects showed EARs (Group II) and two of these showed late asthmatic responses (LARs) as well. In Group II, there were significant changes between the first and second challenge in post-allergen early phase FEV1 (88.1 +/- 4.2 vs 71.7 +/- 4.2% baseline, P < 0.05) and in post-allergen late phase FEV1 (93.1 +/- 3.4 vs 86.6 +/- 7.8, P < 0.05). After the second challenge, PD20 (provocative dose of methacholine required to produce a 20% fall in FEV1) decreased significantly from the baseline values. When challenged separately with twofold dose of allergen, only three and one of the Group II showed EAR and LAR respectively. PD20 did not change significantly after this challenge. These results indicated that two repeated exposure to allergen dose, which is not enough to cause significant airway responses at a time, may provoke asthmatic airway responses in the subjects with allergic rhinitis and that this effect of priming is not attributed to the cumulative dose but to the consequent effect of repeated allergen exposure.

Cough variant asthma is an occult form of asthma in which the only sign or symptom is chronic cough. It is a common problem amongst all ages that frequently goes unrecognized, leading to underdiagnosis and undertreatment. To characterize the pathophysiological abnormalities in these patients, we performed bronchial provocation tests with methacholine using the stepwise doubling concentration technique, and measured the concentration of methacholine and the severity of airway obstruction when wheezing was first detected. Airway hyperresponsiveness, defined as PC20 in the cough variant asthma group was not significantly different from that of classic asthma. There was a good correlation between the PCW (the concentration of methacholine causing wheezing) and the PC20 with the PCW values higher than PC20 values in both groups. However, in the cough variant asthma group, the PCW:PC20 ratio was greater than that of the classic asthma group. Furthermore, the mean % fall in FEV1 at which wheezing was first detected in the former group was significantly larger than that of the latter group. The results indicated that the mechanism for the manifestation of cough without wheeze in the cough variant asthma may be a higher wheezing threshold, i.e. wheezing becomes audible at the greater degree of airway obstruction than classic asthma. They suggested that patients with cough variant asthma may represent a subset of asthmatic subjects whose airways are less able to produce a wheeze.