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1.  Influence of intranasal steroids during the grass pollen season on bronchial responsiveness in children and young adults with asthma and hay fever 
Thorax  2000;55(10):826-832.
BACKGROUND—It has been reported that intranasal corticosteroids can influence bronchial hyperresponsiveness (BHR) in asthmatic subjects with seasonal rhinitis. The purpose of the present study was to evaluate the effect of intranasal fluticasone propionate and beclomethasone dipropionate on BHR and bronchial calibre (forced expiratory volume in one second, FEV1) in children and young adults with seasonal rhinitis and mild asthma during two consecutive grass pollen seasons.
METHODS—In the first pollen season 25 patients aged 8-28 years were included in a double blind, placebo controlled study. The active treatment group used fluticasone aqueous spray 200 µg once daily. In the second pollen season 72 patients aged 8-28 years participated in a double blind, placebo controlled study of a similar design to that of the previous year except that an additional treatment group of patients using beclomethasone 200 µg twice daily was included. FEV1 was measured before and after three and six weeks of treatment; BHR to methacholine (PD20) was measured before and after six weeks of treatment.
RESULTS—In the first season the mean (SD) logPD20 of the patients decreased significantly both in the fluticasone group (from 2.43(0.8) µg to 1.86 (0.85) µg) and in the placebo group (from 2.41(0.42) µg to 1.87 (0.78) µg) without any intergroup difference in the change in logPD20. In the second pollen season the mean logPD20 in the fluticasone, beclomethasone, and placebo groups did not change significantly.
CONCLUSIONS—Intranasal steroids did not influence BHR during two grass pollen seasons in children and young adults with seasonal rhinitis and mild asthma.

PMCID: PMC1745622  PMID: 10992533
2.  Comparison of mannitol and methacholine to predict exercise-induced bronchoconstriction and a clinical diagnosis of asthma 
Respiratory Research  2009;10(1):4.
Asthma can be difficult to diagnose, but bronchial provocation with methacholine, exercise or mannitol is helpful when used to identify bronchial hyperresponsiveness (BHR), a key feature of the disease. The utility of these tests in subjects with signs and symptoms of asthma but without a clear diagnosis has not been investigated. We investigated the sensitivity and specificity of mannitol to identify exercise-induced bronchoconstriction (EIB) as a manifestation of BHR; compared this with methacholine; and compared the sensitivity and specificity of mannitol and methacholine for a clinician diagnosis of asthma.
509 people (6–50 yr) were enrolled, 78% were atopic, median FEV1 92.5% predicted, and a low NAEPPII asthma score of 1.2. Subjects with symptoms of seasonal allergy were excluded. BHR to exercise was defined as a ≥ 10% fall in FEV1 on at least one of two tests, to methacholine a PC20 ≤ 16 mg/ml and to mannitol a 15% fall in FEV1 at ≤ 635 mg or a 10% fall between doses. The clinician diagnosis of asthma was made on examination, history, skin tests, questionnaire and response to exercise but they were blind to the mannitol and methacholine results.
Mannitol and methacholine were therapeutically equivalent to identify EIB, a clinician diagnosis of asthma, and prevalence of BHR. The sensitivity/specificity of mannitol to identify EIB was 59%/65% and for methacholine it was 56%/69%. The BHR was mild. Mean EIB % fall in FEV1 in subjects positive to exercise was 19%, (SD 9.2), mannitol PD15 158 (CI:129,193) mg, and methacholine PC20 2.1(CI:1.7, 2.6)mg/ml. The prevalence of BHR was the same: for exercise (43.5%), mannitol (44.8%), and methacholine (41.6%) with a test agreement between 62 & 69%. The sensitivity and specificity for a clinician diagnosis of asthma was 56%/73% for mannitol and 51%/75% for methacholine. The sensitivity increased to 73% and 72% for mannitol and methacholine when two exercise tests were positive.
In this group with normal FEV1, mild symptoms, and mild BHR, the sensitivity and specificity for both mannitol and methacholine to identify EIB and a clinician diagnosis of asthma were equivalent, but lower than previously documented in well-defined populations.
Trial registration
This was a multi-center trial comprising 25 sites across the United States of America. (NCT0025229).
PMCID: PMC2644668  PMID: 19161635
3.  Fractional Exhaled Nitric Oxide and Impulse Oscillometry in Children With Allergic Rhinitis 
Airway inflammation, bronchial hyper-responsiveness (BHR), and bronchodilator response (BDR) are representative characteristics of asthma. Because allergic rhinitis (AR) is a risk factor for asthma development, we evaluated these 3 characteristics in AR using measurement of fractional exhaled nitric oxide (FeNO), a methacholine challenge test (MCT), and impulse oscillometry (IOS).
This study included 112 children with asthma (asthma group), 196 children with AR (AR group), and 32 control subjects (control group). We compared pulmonary function parameters and FeNO levels among the 3 groups. The AR group was subdivided into 2 categories: the AR group with BHR and the AR group without, and again pulmonary function and FeNO levels were compared between the 2 subgroups.
FeNO levels were more increased in the AR and asthma groups than in the control group; within the AR group, FeNO was higher in the AR group with BHR than in the AR group without. The BDR was more increased in the AR group than in the control group when percent changes in reactance at 5 Hz (Δ X5) and reactance area (Δ AX) were compared. In the AR group, however, there was no difference in Δ X5 and Δ AX between the AR group with BHR and the AR group without.
Reversible airway obstruction on IOS and elevated FeNO levels were observed in children with AR. Because elevated FeNO levels can indicate airway inflammation and because chronic inflammation may lead to BHR, FeNO levels may be associated with BHR in AR. IOS can be a useful tool for detecting lower airway involvement of AR independent of BHR assessed in the MCT.
PMCID: PMC3881396  PMID: 24404390
Asthma; allergic rhinitis; bronchial hyper-responsiveness; bronchodilator effect; child; nitric oxide
4.  Nasal eosinophilic inflammation contributes to bronchial hyperresponsiveness in patients with allergic rhinitis. 
Journal of Korean Medical Science  2002;17(6):761-764.
There are increasing evidences that allergic rhinitis (AR) may influence the clinical course of asthma. We conducted methacholine challenge test and nasal eosinophils on nasal smear to patients with allergic rhinitis in order to investigate the mechanism of connecting upper and lower airway inflammation in 35 patients with AR during exacerbation. The methacholine concentration causing a 20% fall in FEV1 (PC20) was used as thresholds of bronchial hyperresponsiveness (BHR). Thresholds of 25 mg/dL or less were assumed to indicate BHR. All patients had normal pulmonary function. Significant differences in BHR were detected in the comparison of patients with cough or postnasal drip and without cough or postnasal drip. There were significant differences of PC20 between patients with cough or postnasal drip and those without cough or postnasal drip (3.41+/-3.59 mg/mL vs 10.2+/-1.2 mg/mL, p=0.001). The levels of total IgE were higher in patients with seasonal AR than in patients with perennial AR with exacerbation (472.5+/-132.5 IU/L vs. 389.0+/-70.9 IU/L, p<0.05). Nasal eosinophils were closely related to log PC20 (r=-0.65, p<0.01). These findings demonstrated that nasal eosinophilic inflammation might contribute to BHR in patients with AR.
PMCID: PMC3054952  PMID: 12482998
5.  Bronchial hyperresponsiveness and the development of asthma and COPD in asymptomatic individuals: SAPALDIA Cohort Study 
Thorax  2006;61(8):671-677.
Bronchial hyperresponsiveness (BHR) is a common feature of asthma. However, BHR is also present in asymptomatic individuals and its clinical and prognostic significance is unclear. We hypothesised that BHR might play a role in the development of chronic obstructive pulmonary disease (COPD) as well as asthma.
In 1991 respiratory symptoms and BHR to methacholine were evaluated in 7126 of the 9651 participants in the SAPALDIA cohort study. Eleven years later 5825 of these participants were re‐evaluated, of whom 4852 performed spirometric tests. COPD was defined as an FEV1/FVC ratio of <0.70.
In 1991 17% of participants had BHR, of whom 51% were asymptomatic. Eleven years later the prevalence of asthma, wheeze, and shortness of breath in formerly asymptomatic subjects with or without BHR was, respectively, 5.7% v 2.0%, 8.3% v 3.4%, and 19.1% v 11.9% (all p<0.001). Similar differences were observed for chronic cough (5.9% v 2.3%; p = 0.002) and COPD (37.9% v 14.3%; p<0.001). BHR conferred an adjusted odds ratio (OR) of 2.9 (95% CI 1.8 to 4.5) for wheezing at follow up among asymptomatic participants. The adjusted OR for COPD was 4.5 (95% CI 3.3 to 6.0). Silent BHR was associated with a significantly accelerated decline in FEV1 by 12 (5–18), 11 (5–16), and 4 (2–8) ml/year in current smokers, former smokers and never smokers, respectively, at SAPALDIA 2.
BHR is a risk factor for an accelerated decline in FEV1 and the development of asthma and COPD, irrespective of atopic status. Current smokers with BHR have a particularly high loss of FEV1.
PMCID: PMC2104688  PMID: 16670173
bronchial hyperresponsiveness; asthma; chronic obstructive pulmonary disease; smoking; epidemiological study
6.  Relation of bronchial responsiveness to body mass index in the ECRHS 
Thorax  2002;57(12):1028-1033.
Background: There is substantial evidence for an association between symptoms of asthma and overweight or obesity. However, a study that reported no association between bronchial responsiveness (BHR) and body mass index (BMI) suggested that the relation of symptoms to obesity was due to increased diagnosis of asthma. The relation of BHR to BMI was therefore investigated in a large multicentre study.
Methods: Data were obtained for 11 277 participants in stage II of the European Community Respiratory Health Survey (ECRHS). BHR to methacholine was analysed in relation to BMI adjusted for a number of factors known to be associated with BHR, including baseline lung function and allergen sensitisation, and combined across 34 centres using random effects meta-analysis.
Results: BHR increased with increasing BMI in men (ECRHS slope changed by –0.027 for each unit increase in BMI, 95% confidence interval –0.044 to –0.010, p=0.002), but the relation in women was weak (–0.014, 95% CI –0.033 to 0.005, p=0.14). There was no evidence for an interaction of sex with BMI (p=0.41).
Conclusions: BHR is related to BMI in the ECRHS. This suggests that the association is not due to greater diagnosis or perception of symptoms in obese people compared with those of normal weight. The data do not support the finding by some studies of a relation between asthma and obesity in women but not in men.
PMCID: PMC1758811  PMID: 12454296
7.  Bronchial hyperreactivity and spirometric impairment in polysensitized patients with allergic rhinitis 
We previously demonstrated in a group of patients with perennial allergic rhinitis alone impairment of spirometric parameters and high percentage of subjects with bronchial hyperreactivity (BHR). The present study aimed at evaluating a group of polysensitized subjects suffering from allergic rhinitis alone to investigate the presence of spirometric impairment and BHR during the pollen season.
One hundred rhinitics sensitized both to pollen and perennial allergens were evaluated during the pollen season. Spirometry and methacholine bronchial challenge were performed.
Six rhinitics showed impaired values of FEV1 without referred symptoms of asthma. FEF 25–75 values were impaired in 28 rhinitics. Sixty-six patients showed positive methacholine bronchial challenge. FEF 25–75 values were impaired only in BHR positive patients (p < 0.001). A significant difference was observed both for FEV1 (p < 0.05) and FEF 25–75 (p < 0.001) considering BHR severity.
This study evidences that an impairment of spirometric parameters may be observed in polysensitized patients with allergic rhinitis alone during the pollen season. A high percentage of these patients had BHR. A close relationship between upper and lower airways is confirmed.
PMCID: PMC385251  PMID: 15018619
allergic rhinitis; polysensitization; bronchial hyperreactivity; methacholine challenge; FEF 25–75
8.  Bronchial Responsiveness to Dry Air Hyperventilation in Smokers May Predict Decline in Airway Status Using Indirect Methods 
Lung  2013;191(2):183-190.
Disabling respiratory symptoms and rapid decline of lung function may occur in susceptible tobacco smokers. Bronchial hyperresponsiveness (BHR) elicited by direct challenge methods predicts worse lung function outcomes. The aim of this study was to evaluate whether BHR to isocapnic hyperventilation of dry air (IHDA) was associated with rapid deterioration in airway status and respiratory symptoms.
One hundred twenty-eight smokers and 26 age- and sex-matched healthy individuals with no history of smoking were investigated. All subjects completed a questionnaire. Spirometry and impulse oscillometry (IOS) measurements were recorded before and after 4 min of IHDA. The tests were repeated after 3 years in 102 smokers and 11 controls.
Eighty-five smokers (66 %) responded to the challenge with a ≥2.4-Hz increase in resonant frequency (Fres), the cutoff limit defining BHR, as recorded by IOS. They had higher Fres at baseline compared to nonresponding smokers [12.8 ± 3.2 vs. 11.5 ± 3.4 Hz (p < 0.05)] and lower FEV1 [83 ± 13 vs. 89 ± 13 % predicted (p < 0.05)]. Multivariable logistic regression analysis indicated that wheezing (odds ratio = 3.7, p < 0.01) and coughing (odds ratio = 8.1, p < 0.05) were significantly associated with hyperresponsiveness. An increase in Fres was recorded after 3 years in responding smokers but not in nonresponders or controls. The difference remained when subjects with COPD were excluded.
The proportion of hyperresponsive smokers was unexpectedly high and there was a close association between wheezing and coughing and BHR. Only BHR could discriminate smokers with rapid deterioration of airway status from others.
PMCID: PMC3605489  PMID: 23355083
Bronchial hyperresponsiveness; Impulse oscillometry; Isocapnic hyperventilation of dry air; Resonant frequency; Tobacco smoke
9.  AB 22. Study of IL-1, IL-4 and TNFα polymorphisms in extrinsic and intrinsic asthma in a Greek population 
Journal of Thoracic Disease  2012;4(Suppl 1):AB22.
The aim of present study was the definition of the IL-1, IL-4 and TNFα polymorphisms in asthmatic patients and their association with allergy and bronchial hyperresponsiveness (BHR).
Materials and methods
Thirty patients with allergic asthma, mean age 35.2±14.51 years (Group A) and 22 patients with non-allergic asthma, mean age 47.1±16.3 years (Group B) were included in the study. All patients were recruited from the Asthma Clinic of Pulmonary Department, University of Thessaloniki. 21 healthy control subjects of mean age 36.6±10.5 years were also included (Group C). All patients were subjected to skin prick tests and methacholine challenge. DNA was extracted from the patients’ peripheral blood samples. Determination of IL1α -889(T/C), IL1β-511(T/C), IL1β+3962(C/T), IL1R1970(C/T), IL1RA mspa111100(C/T), IL4-1098(T/G), IL4-590(C/T), IL4-33(C/T), TNFα-308(G/A) and TNFα-238(G/A) polymorphisms were performed by PCR using the INVITROGEN kit (C: cytokine, T: thymine, G: Guanine και A: Adenine).
Analysis of IL-1 polymorphisms and in particular IL-1β (+3962) showed statistically significant differences between Group A-B (P=0.029) and Group B-C (P=0.024) respectively. Furthermore, analysis for IL-1 receptor (IL1R) showed statistically significant differences between Group B and C, where C/T showed an increased frequency in Group B and C/C in Group C (P=0.003). Besides, analysis of IL-1 receptor antagonist (IL-1RA) in C/T and Τ/Τ genotypes showed increased frequencies in Group A and C respectively (P=0.03). Analysis of IL4 -1098 polymorphisms showed an increased frequency of guanine in Group A (P=0.036) when compared to Group C whereas for IL4-590, C/C genotype showed an increased frequency in Group C and C/T in Group A (P=0.003), suggesting possible association between thymine and risk of asthma development. Analysis of TNFα-238 in G/G and A/G genotypes showed statistically significant differences between the Group A-C, (P=0.008) and Group B-C (P=0.001). G/G showed an increased frequency in Group C and A/G in Groups A and B. Moreover C/T genotype for IL-4 showed positive association with high concentrations of methacholine (P=0.022) and subsequently low BHR. On the contrary, G/G genotype in TNFα gene were positively associated with lower concentrations of methacholine (P: 0.033) and high BHR.
IL-1, IL-4 and TNFα polymorphisms showed significant differences between patients with allergic and non-allergic asthma and healthy control subjects, which are possibly associated with risk of asthma development. BHR was associated with IL-1, IL-4 and TNFα polymorphisms.
PMCID: PMC3537442
10.  320 Development of a Questionnaire for the Assessment of Bronchial Hyperresponsiveness in Korea 
Bronchial hyperresponsiveness (BHR) is an important pathophysiological feature of asthma. In addition to the diagnostic significance, BHR is associated with the severity of airway inflammation and BHR- based treatment approaches has been shown to be effective. Nevertheless, challenge tests are time consuming, inconvenient to patients, and are not accessible in every primary care physicians. We aimed to develop a questionnaire for the assessment of BHR in Korean subjects.
From the 24 University-affiliated hospitals, we recruited 149 adults between age 20 and 40 years with more than one asthmatic symptom (cough, sputum or dyspnea) and who had bronchial provocation test. A list of 33 symptoms, past history of allergy or smoking and 10 provoking stimuli were selected for the BHR questionnaire. After a methacholine challenge test patients were asked to complete each questionnaire. For each item of questionnaire, diagnostic odds ratios for the presence of BHR were calculated and multiple logistic regression analysis was performed to select final questionnaire items. Receiver operating characteristic (ROC) curve analysis was used to evaluate the sensitivity and specificity of the selected questionnaire items.
Methacholine challenge test was positive in 36 patients (24.2%). Eleven symptoms and 2 provoking stimuli items were statistically significant by the results of diagnostic odds ratio. According to the result of multiple logistic regression analysis, 4 items were finally selected for the significant BHR questionnaire: the presence of wheezing episode, past history of physician-diagnosed asthma, family history of asthma. The psychiatric stress was negatively associated provoking stimuli item for the presence of BHR. The area under the ROC curve was 0.80 (95% CI, 0.72-0.86). Sensitivity was 84.9% (95% CI, 68.1-94.9) and specificity was 65.5% (95% CI, 55.8-74.3).
Four BHR questionnaire items including wheezing episode, past history of physician-diagnosed asthma, family history of asthma and psyachiatric stress stimuli were able to assess the presence of BHR in Korean adults.
PMCID: PMC3512762
11.  Association of bronchial hyperresponsiveness and lung function with C-reactive protein (CRP): a population based study 
Thorax  2004;59(10):892-896.
Background: C-reactive protein (CRP), a marker of systemic inflammation, is a powerful predictor of adverse cardiovascular events. Respiratory impairment is also associated with cardiovascular risk. Although some studies have found an inverse relationship between lung function and markers of systemic inflammation, only one study has reported a relationship between lung function and CRP levels. In contrast, little is known about the relationship between bronchial hyperresponsiveness (BHR) and systemic inflammation. The association between lung function and CRP and between BHR and CRP has been investigated.
Methods: As part of the European Community Respiratory Health Survey follow up study serum CRP levels, forced expiratory volume in 1 second (FEV1), and BHR to methacholine (⩾20% decrease in FEV1 to <4 mg methacholine) were measured in 259 adults aged 28–56 years free of cardiovascular disease or respiratory infection.
Results: Mean (SD) FEV1 (adjusted for age, sex, height, and smoking status) was lower in subjects with a high CRP level (high tertile) (3.29 (0.44) l/s v 3.50 (0.44) l/s; p<0.001) and BHR was more frequent (41.9% v 24.9%; p = 0.005) than in subjects with lower CRP levels (low+middle tertiles). Similar results were obtained when the potential confounding factors were taken into account. Similar patterns of results were found in non-smokers and in non-asthmatic subjects.
Conclusions: Increased CRP levels are strongly and independently associated with respiratory impairment and more frequent BHR. These results suggest that both respiratory impairment and BHR are associated with a systemic inflammatory process.
PMCID: PMC1746828  PMID: 15454657
12.  Bronchial Hyperresponsiveness to Methacholine and AMP in Children With Atopic Asthma 
Bronchial hyperresponsiveness (BHR) is typically measured by bronchial challenge tests that employ direct stimulation by methacholine or indirect stimulation by adenosine 5'-monophosphate (AMP). Some studies have shown that the AMP challenge test provides a better reflection of airway inflammation, but few studies have examined the relationship between the AMP and methacholine challenge tests in children with asthma. We investigated the relationship between AMP and methacholine testing in children and adolescents with atopic asthma.
The medical records of 130 children with atopic asthma (mean age, 10.63 years) were reviewed retrospectively. Methacholine and AMP test results, spirometry, skin prick test results, and blood tests for inflammatory markers (total IgE, eosinophils [total count, percent of white blood cells]) were analyzed.
The concentration of AMP that induces a 20% decline in forced expiratory volume in 1 second [FEV1] (PC20) of methacholine correlated with the PC20 of AMP (r2=0.189, P<0.001). No significant differences were observed in the levels of inflammatory markers (total eosinophil count, eosinophil percentage, and total IgE) between groups that were positive and negative for BHR to methacholine. However, significant differences in inflammatory markers were observed in groups that were positive and negative for BHR to AMP (log total eosinophil count, P=0.023; log total IgE, P=0.020, eosinophil percentage, P<0.001). In contrast, body mass index (BMI) was significantly different in the methacholine positive and negative groups (P=0.027), but not in the AMP positive and negative groups (P=0.62). The PC20 of methacholine correlated with FEV1, FEV1/forced vital capacity (FVC), and maximum mid-expiratory flow (MMEF) (P=0.001, 0.011, 0.001, respectively), and the PC20 of AMP correlated with FEV1, FEV1/FVC, and MMEF (P=0.008, 0.046, 0.001, respectively).
Our results suggest that the AMP and methacholine challenge test results correlated well with respect to determining BHR. The BHR to AMP more likely implicated airway inflammation in children with atopic asthma. In contrast, the BHR to methacholine was related to BMI.
PMCID: PMC3479227  PMID: 23115730
AMP; atopic asthma; bronchial hyper-responsiveness; methacholine
13.  Physical activity and bronchial hyperresponsiveness: European Community Respiratory Health Survey II 
Thorax  2006;62(5):403-410.
Identification of the risk factors for bronchial hyperresponsiveness (BHR) would increase the understanding of the causes of asthma. The relationship between physical activity and BHR in men and women aged 28.0–56.5 years randomly selected from 24 centres in 11 countries participating in the European Community Respiratory Health Survey II was investigated.
5158 subjects answered questionnaires about physical activity and performed BHR tests. Participants were asked about the frequency and duration of usual weekly exercise resulting in breathlessness or sweating. BHR was defined as a decrease in forced expiratory volume in 1 s of at least 20% of its post‐saline value for a maximum methacholine dose of 2 mg.
Both frequency and duration of physical activity were inversely related to BHR. The prevalence of BHR in subjects exercising ⩽1, 2–3 and ⩾4 times a week was 14.5%, 11.6% and 10.9%, respectively (p<0.001). The corresponding odds ratios were 1.00, 0.78 (95% CI 0.62 to 0.99) and 0.69 (95% CI 0.50 to 0.94) after controlling for potential confounding factors. The frequency of BHR in subjects exercising <1 h, 1–3 h and ⩾4 h a week was 15.9%, 10.9% and 10.7%, respectively (p<0.001). The corresponding adjusted odds ratios were 1.00, 0.70 (95% CI 0.57 to 0.87) and 0.67 (95% CI 0.50 to 0.90). Physical activity was associated with BHR in all studied subgroups.
These results suggest that BHR is strongly and independently associated with decreased physical activity. Further studies are needed to determine the mechanisms underlying this association.
PMCID: PMC2117184  PMID: 17121869
14.  Respiratory Effects of Environmental Tobacco Exposure Are Enhanced by Bronchial Hyperreactivity 
Rationale: Exposure to environmental tobacco smoke (ETS) is associated with increased reports of respiratory symptoms and reduced lung function, but the long-term effects of ETS are unclear, notably in healthy individuals with bronchial hyperresponsiveness (BHR).
Objective: To assess the longitudinal effects of ETS exposure on the development of respiratory symptoms and spirometry in subjects with BHR.
Methods: The study population included 1,661 never-smokers from the SAPALDIA (Swiss Study on Air Pollution and Lung Diseases in Adults) cohort, assessed in 1991 (baseline) and 11 yr later, who were symptom-free at baseline. Incident reports of respiratory symptoms and results of spirometry were assessed at the follow-up survey.
Main Results: Exposure to ETS reported in the two surveys was strongly associated with the development of cough (odds ratio, 2.1; 95% confidence interval, 1.2–3.7; p = 0.01). In subjects with BHR exposed to ETS at both surveys, a trend for strong associations were observed for wheeze, cough, dyspnea, and chronic bronchitis; however, the association reached statistical significance only for the symptom of dyspnea (p < 0.01). Lower FEV1/FVC (mean ± SD, 72.9 ± 7.7 vs. 76.8 ± 6.1%; p < 0.01) and FEF25–75 (forced expiratory flow, midexpiratory phase)/FVC (mean ± SD, 56.1 ± 22.5 vs. 68.1 ± 21.6%; p < 0.01) were observed in subjects with BHR exposed to ETS compared with nonexposed subjects without BHR. Lower values were found in subjects continuing exposure by the follow-up survey.
Conclusion: Exposure to ETS was strongly associated with the development of respiratory symptoms in previously asymptomatic subjects with BHR within 11 yr. Furthermore, subjects with underlying BHR had reduced lung function at follow-up, thus suggesting a higher risk for the development of chronic respiratory disease in this subset of the population.
PMCID: PMC2648112  PMID: 16931633
bronchial hyperreactivity; cohort studies; environmental tobacco smoke; lung function; respiratory symptoms
15.  Interaction Between Bronchiolitis Diagnosed Before 2 Years of Age and Socio-Economic Status for Bronchial Hyperreactivity 
The prevalence of asthma has increased in recent decades globally. The objective of the present study is to elucidate whether hospitalization for bronchiolitis in infancy and low socioeconomic status interact for bronchial hyperreactivity during teenage years.
We studied 522 children age 13-14 years attending schools in rural and urban areas to investigate the risk factors for bronchial hyperreactivity (BHR), defined as a provocation concentration of methacholine that causes a decrease of 20% (PC20) in forced expiratory volume within 1 second. Clinical examination, skin prick test, spirometry, and methacholine challenge were performed on all study subjects, who provided written consent. We used multivariate logistic regression to investigate the risk factors for BHR, and analyze the interaction between hospitalization for bronchiolitis in infancy and low socioeconomic status.
Forty-six (10.3%) positive BHR cases were identified. In the multivariate logistic analysis, as independent predictors of BHR, adjusted odds ratio of bronchiolitis diagnosed before 2 years of age in low income families was 13.7 (95% confidence interval, 1.4 to 135.0), compared to reference group, controlling for age, gender, parental allergy history, skin prick test, and environmental tobacco smoke (ETS) exposure. Interaction was observed between bronchiolitis before 2 years old and low socioeconomic status on children's bronchial hyperreactivity (p-interaction=0.025).
This study showed that bronchiolitis diagnosed before 2 years of age and low socioeconomic status interacted on children's bronchial hyperreactivity. Prevention of acute respiratory infection in early childhood in low socioeconomic status is important to prevent BHR as a precursor of asthma.
PMCID: PMC3214987  PMID: 22125773
Asthma; Bronchial hyperreactivity (BHR); Bronchiolitis; Children; Socioeconomic status
16.  Seasonal variation in the behaviour of a short-lived rodent 
BMC Ecology  2013;13:43.
Short lived, iteroparous animals in seasonal environments experience variable social and environmental conditions over their lifetime. Animals can be divided into those with a “young-of-the-year” life history (YY, reproducing and dying in the summer of birth) and an “overwinter” life history (OW, overwintering in a subadult state before reproducing next spring).
We investigated how behavioural patterns across the population were affected by season and sex, and whether variation in behaviour reflects the variation in life history patterns of each season. Applications of pace-of-life (POL) theory would suggest that long-lived OW animals are shyer in order to increase survival, and YY are bolder in order to increase reproduction. Therefore, we expected that in winter and spring samples, when only OW can be sampled, the animals should be shyer than in summer and autumn, when both OW and YY animals can be sampled.
We studied common vole (Microtus arvalis) populations, which express typical, intra-annual density fluctuation. We captured a total of 492 voles at different months over 3 years and examined boldness and activity level with two standardised behavioural experiments.
Behavioural variables of the two tests were correlated with each other. Boldness, measured as short latencies in both tests, was extremely high in spring compared to other seasons. Activity level was highest in spring and summer, and higher in males than in females.
Being bold in laboratory tests may translate into higher risk-taking in nature by being more mobile while seeking out partners or valuable territories. Possible explanations include asset-protection, with OW animals being rather old with low residual reproductive value in spring. Therefore, OW may take higher risks during this season. Offspring born in spring encounter a lower population density and may have higher reproductive value than offspring of later cohorts. A constant connection between life history and animal personality, as suggested by the POL theory, however, was not found. Nevertheless, correlations of traits suggest the existence of animal personalities. In conclusion, complex patterns of population dynamics, seasonal variation in life histories, and variability of behaviour due to asset-protection may cause complex seasonal behavioural dynamics in a population.
PMCID: PMC3870992  PMID: 24238069
Animal personalities; Boldness; Life history; Pace-of-life; POL; Phenotypic plasticity; Common vole
17.  Predictors for Asthma at Age 7 Years for Low-Income Children Enrolled in the Childhood Asthma Prevention Study 
The Journal of pediatrics  2012;162(3):536-542.e2.
To identify the predictive factors of early childhood wheezing in children of low socioeconomic status.
Study design
The Childhood Asthma Prevention Study (CAPS) enrolled 177 low-income children (9–24 months old) with frequent wheezing. At age 7 years, presence of asthma was assessed through caregiver reports of physician diagnosis of asthma (CRPDA) and corroborated by assessment of bronchial hyperresponsiveness (BHR). Lung function, inflammatory markers, and asthma symptom severity were compared for children with ±CRPDA, ±BHR, and asthma. Baseline predictors for CRPDA, BHR and asthma at 7 years of age were examined.
Maternal symptom report strongly differentiated children with +CRPDA (50%) despite comparable airflow measurements (p<0.0001), and spirometric lung function measurements were different for +BHR (65%) vs. −BHR (p<0.005). Univariate analyses revealed different baseline predictors of +CRPDA and +BHR for children at age 7 years. Higher levels of maternal psychological resources were associated with +CRPDA, but not +BHR. Only 39% of children with a history of frequent wheezing met the conservative definition of asthma at age 7 years, with the following significant predictors found: low birth weight, baseline symptom severity and maternal psychological resources.
This low-income, multi-ethnic group of wheezing infants represents a unique population of children with distinct characteristics and risks for persistent asthma. Determination of asthma status at 7 years of age required objective measurement of BHR in addition to CRPDA. The association of maternal psychological resources with +CRPDA may represent a previously unrecognized factor in determination of asthma status among low-income groups.
PMCID: PMC3582795  PMID: 23036483
18.  Seasonality Modifies Methylation Profiles in Healthy People 
PLoS ONE  2014;9(9):e106846.
DNA methylation is a well-characterized epigenetic modification that plays an important role in the regulation of gene expression. There is growing evidence on the involvement of epigenetic mechanisms in disease onset, including cancer. Environmental factors seem to induce changes in DNA methylation affecting human health. However, little is known about basal methylation levels in healthy people and about the correlation between environmental factors and different methylation profiles. We investigated the effect of seasonality on basal methylation by testing methylation levels in the long interspersed nucleotide element-1 (LINE-1) and in two cancer-related genes (RASSF1A and MGMT) of 88 healthy male heavy smokers involved in an Italian randomized study; at enrolment the subjects donated a blood sample collected in different months. Methylation analyses were performed by pyrosequencing. Mean methylation percentage was higher in spring and summer for the LINE1, RASSF1A and MGMT genes (68.26%, 2.35%, and 9.52% respectively) compared with autumn and winter (67.43%, 2.17%, and 8.60% respectively). In particular, LINE-1 was significantly hypomethylated (p = 0.04 or 0.05 depending on the CpG island involved) in autumn and winter compared with spring and summer. Seasonality seems to be a modifier of methylation levels and this observation should be taken into account in future analyses.
PMCID: PMC4161384  PMID: 25210735
19.  Bronchial hyperresponsiveness in women with chronic obstructive pulmonary disease related to wood smoke 
Chronic obstructive pulmonary disease (COPD) related to wood smoke exposure is characterized by important inflammation of the central and peripheral airways without significant emphysema. The objective of this study is to describe the bronchial hyperresponsiveness (BHR) level in women with COPD related to wood smoke exposure and to compare it with the BHR in women with COPD related to tobacco smoking.
Materials and methods
Two groups of women with stable COPD were studied: (1) wood smoke exposed (WS-COPD); and (2) tobacco smoke exposed (TS-COPD). A methacholine challenge test (MCT) was performed in all patients according to American Thoracic Society criteria. BHR levels were compared using the methacholine concentration, which caused a 20% fall in the FEV1 (PC20).
Thirty-one patients, 19 with WS-COPD and 12 with TS-COPD, were included. There were no significant differences between the groups in baseline FVC, FEV1, IC, FEF25–75, and FEF25–75/FVC. All 31 patients had a positive MCT (PC20 < 16 mg/mL) and the fall in the FEV1 and IC was similar in both groups. The severity of BHR was significantly higher in the WS-COPD patients (PC20: 0.39 mg/mL) than in the TS-COPD patients (PC20: 1.24 mg/mL) (P = 0.028). The presence of cough, phlegm, and dyspnea during the test were similar in both groups.
We found moderate to severe BHR in women with WS-COPD, which was more severe than in the TS-COPD women with similar age and airflow obstruction. This paper suggests that the structural and inflammatory changes induced by the chronic exposure to wood smoke, described in other studies, can explain the differences with TS-COPD patients. Future studies may clarify our understanding of the impact of BHR on COPD physiopathology, phenotypes, and treatment strategies.
PMCID: PMC3393338  PMID: 22791990
biomass fuels; indoor air pollution; wood smoke; COPD; methacholine challenge test
20.  AB 86. Validation of a questionnaire for the assessment of bronchial hyperresponsiveness in a Greek population 
Journal of Thoracic Disease  2012;4(Suppl 1):AB86.
The assessment of bronchial hyperresponsiveness (BHR) is considered essential for determining asthma diagnosis and asthma control. Recently a specific-condition questionnaire was developed on this purpose for asthma patients in primary care practice (Riemersa et al., 2009). The aim of the present study is to validate the BHR questionnaire in a Greek population.
Patients and methods
A cross-sectional study was conducted at the Asthma Outpatient clinic of the Pulmonary Department, Aristotle University of Thessaloniki, Greece. Inclusion criteria were males and females, age 14 to 75, with recent history of asthma symptoms and without any other known respiratory/systemic disease that might affect BHR. During patient assessment, translated copies of the BHR questionnaire (BHRQ) were delivered to eligible subjects who had given informed consent. The gold standard method selected to validate the BHRQ was the mannitol challenge test.
Sixty-two patients in total (21 males and 41 females) were recruited: mean age 34±14.9 years, mean total score of the questionnaire 54.39±40.88 years and mean subscores for symptoms and stimuli 28.29±19.97 and 26.10±24.07 years respectively. During mannitol challenge subjects showed a mean fall of FEV1 of 13.41±6.97% from baseline and a mean provocative dose of mannitol, PD15 of 373.11±240.92 mg. Spearman’s rank correlations among variables have shown significant positive correlations among all score variables and negative correlations among the scores and the mannitol test variables. Construct validity was assessed with principal component analysis and managed to identify one underlying factor that explains 42.4% of the variance. The reliability of the questionnaire, as estimated with Cronbach’s alpha, was 0.957, which is considered to be a very good reliability regarding the internal consistency of the questionnaire items. Receiver Operating Curve (ROC) analysis has determined a cut off value of 26 of the total score for BHR response with sensitivity of 78.6% and specificity of 55%.
It is the first time that a BHR questionnaire was validated in a Greek population and it has been shown to be a usable and valid tool for assessing BHR in primary care practice.
PMCID: PMC3537360
21.  In search of childhood asthma: questionnaire, tests of bronchial hyperresponsiveness, and clinical evaluation 
Thorax  2002;57(2):120-126.
Background: The definition or diagnosis of asthma is a challenge for both clinicians and epidemiologists. Symptom history is usually supplemented with tests of bronchial hyperresponsiveness (BHR) in spite of their uncertainty in improving diagnostic accuracy.
Methods: To assess the interrelationship between respiratory symptoms, BHR, and clinical diagnosis of asthma, the respiratory symptoms of 1633 schoolchildren were screened using a questionnaire (response rate 81.2%) and a clinical study was conducted in a subsample of 247 children. Data from a free running test and a methacholine inhalation challenge test were available in 218 children. The diagnosis of asthma was confirmed by a paediatric allergist.
Results: Despite their high specificity (>0.97), BHR tests did not significantly improve the diagnostic accuracy after the symptom history: area under the receiver operator characteristic (ROC) curve was 0.90 for a logistic regression model with four symptoms and 0.94 for the symptoms with free running test and methacholine inhalation challenge results. On the other hand, BHR tests had low sensitivity (0.35–0.47), whereas several symptoms had both high specificity (>0.97) and sensitivity (>0.7) in relation to clinical asthma, which makes them a better tool for asthma epidemiology than BHR.
Conclusions: Symptom history still forms the basis for defining asthma in both clinical and epidemiological settings. BHR tests only marginally increased the diagnostic accuracy after symptom history had been taken into account. The diagnosis of childhood asthma should not therefore be overlooked in symptomatic cases with no objective evidence of BHR. Moreover, BHR should not be required for defining asthma in epidemiological studies.
PMCID: PMC1746240  PMID: 11828040
22.  Seasonal Factors Influencing Exercise-Induced Asthma 
Exercise-induced bronchoconstriction (EIB) in patients with asthma occurs more frequently in winter than in summer. The concentration of house dust mite (HDM) allergens in beds also shows seasonal variation. This study examined the relationship between seasonal differences in the prevalence of EIB and sensitization to HDMs in patients with asthma.
The medical records of 74 young adult male patients with asthma-like symptoms who underwent bronchial challenge with methacholine, 4.5% saline and exercise, and allergen skin prick tests, were reviewed. The subjects were divided into summer (n=27), spring/fall (n=26) and winter (n=21) groups according to the season during which they underwent testing.
The positive responses to exercise differed according to season (48.1% in summer, 73.1% in spring/fall, and 90.5% in winter; P<0.01). In addition, the prevalence of positive responses to HDM (70.4%, 88.5%, and 95.2%, respectively; P<0.05) and pollen skin tests (37.0%, 19.2%, and 0%, respectively; P<0.01) also showed significant seasonal differences. Severe responses to 4.5% saline showed a similar trend, although it was not statistically significant (44.4%, 50.0%, and 71.4%, respectively; P=0.07). Skin test reactivity to HDMs was significantly related to maximal fall in forced expiratory volume in one second (FEV1) following exercise (r=0.302, P<0.01) and the index of airway hyperresponsiveness (AHR) to 4.5% saline (r=-0.232, P<0.05), but not methacholine (r=-0.125, P>0.05).
Positive skin test reactions to HDMs and EIB occurred in winter, spring/fall, and summer in decreasing order of frequency. Seasonal variation in the prevalence of EIB may be related to seasonal variation in sensitization to HDMs, accompanied by differences in indirect, but not direct, AHR.
PMCID: PMC3378925  PMID: 22754712
Asthma; bronchoconstriction; exercise; house dust mite; season
23.  Influence of Rabbit Sire Genetic Origin, Season of Birth and Parity Order on Doe and Litter Performance in an Organic Production System 
The aim of this study was to compare both the performance of litters derived from two sire genetic origins (SGO), Vienna Blue (VB) and Burgundy Fawn (BF), along successive seasons of birth (SB; winter, spring, summer and autumn), and doe reproductive performance in an organic production system. A total of fifty-eight does consisting of a mixture of crosses of several medium-large size breeds at different parity order (P, 1 = nulliparous; 2 = primiparous; ≥3 = multiparous) and twelve males (6 VB and 6 BF) were housed indoors at environmental conditions that followed seasonality. An extensive reproductive rhythm was used and kits were weaned at 46±6 d of age. Doe reproductive performance and the data of 105 litters (55 from VB and 50 from BF SGO) were recorded throughout the SB. No statistically significant differences related to SGO effect were observed. As regards parity order, multiparous does showed higher live weights (LW) (p<0.05), total born (p<0.01), total born alive (p<0.05) per delivery, and litter weight of born alive (p<0.05), but lower milk output at 21st d than primiparous does (p<0.05). The extensive reproductive rhythm mainly increased litter performance at birth in multiparous does but was not sufficient to permit a complete recovery of body reserves lost during lactation. Autumn SB negatively affected doe LW variation between deliveries. The number of pups born and born alive per delivery (p<0.05) and litter size at 21 d of age and at weaning (p<0.01) were lower during hot SB. Due to the lower litter size of pups born in summer and autumn, their individual weight at 21st d of age and daily individual growth rate 0 to 21 d were higher than those of pups born in winter (p<0.001). Litter performance at 21st d of age and individual pup pre-weaning growth rate were poorer for those born in spring than in other seasons due to the harmful effects of increased environmental temperatures. SB affected most of the performance traits of does and young rabbits reared under the organic farming system. The rabbits seemed better suited to organic rearing conditions during winter than in other seasons. The worst results overall were obtained in the spring SB, whereas the hot SB negatively affected both doe energy balance and prolificacy. In conclusion, the pups of the 2 SGO showed good pre-weaning performance and seemed suited to the organic rabbit production system.
PMCID: PMC4093054  PMID: 25049704
Rabbit; Organic Production System; Reproduction; Genetic Origin
24.  Associations of airway inflammation and responsiveness markers in non asthmatic subjects at start of apprenticeship 
Bronchial Hyperresponsiveness (BHR) is considered a hallmark of asthma. Other methods are helpful in epidemiological respiratory health studies including Fractional Exhaled Nitric Oxide (FENO) and Eosinophils Percentage (EP) in nasal lavage fluid measuring markers for airway inflammation along with the Forced Oscillatory Technique measuring Airway resistance (AR). Can their outcomes discriminate profiles of respiratory health in healthy subjects starting apprenticeship in occupations with a risk of asthma?
Rhinoconjunctivitis, asthma-like symptoms, FEV1 and AR post-Methacholine Bronchial Challenge (MBC) test results, FENO measurements and EP were all investigated in apprentice bakers, pastry-makers and hairdressers not suffering from asthma. Multiple Correspondence Analysis (MCA) was simultaneously conducted in relation to these groups and this generated a synthetic partition (EI). Associations between groups of subjects based on BHR and EI respectively, as well as risk factors, symptoms and investigations were also assessed.
Among the 441 apprentice subjects, 45 (10%) declared rhinoconjunctivitis-like symptoms, 18 (4%) declared asthma-like symptoms and 26 (6%) suffered from BHR. The mean increase in AR post-MBC test was 21% (sd = 20.8%). The median of FENO values was 12.6 ppb (2.6-132 range). Twenty-six subjects (6.7%) had EP exceeding 14%. BHR was associated with atopy (p < 0.01) and highest FENO values (p = 0.09). EI identified 39 subjects with eosinophilic inflammation (highest values of FENO and eosinophils), which was associated with BHR and atopy.
Are any of the identified markers predictive of increased inflammatory responsiveness or of development of symptoms caused by occupational exposures? Analysis of population follow-up will attempt to answer this question.
PMCID: PMC2913998  PMID: 20604945
25.  Seasonal Variations in Voluntary Intake and Apparent Digestibility of Forages in Goats Grazing on Introduced Leymus chinensis Pasture 
The nutrient composition of pasture, voluntary intake and digestibility of diet ingested by goats grazing on an introduced Leymus chinensis pasture were measured across spring (May), summer (July), autumn (October) and winter (March). In each season, 12 Inner Mongolian Cashmere goats (6 wethers and 6 does with an average live weight of 22.2±1.3 kg and 19.5±0.8 kg, respectively) were used to graze on a 2 hectares size paddock. Diet selection was observed and the plant parts selected by grazing goats and whole plant L. chinensis were sampled simultaneously. The alkane pair C32:C33 and C36 were used to estimate intake and digestibility, respectively. The results showed that the plant parts selected by goats had higher crude protein (CP) and lower acid detergent fiber (ADF) and neutral detergent fiber (NDF) than the whole plant, especially in the autumn and winter. The voluntary intake of dry matter (DM), CP, ADF, NDF, and metabolizable energy (ME) by goats was highest in summer (p<0.05). The goats ingested more CP, ME, and less ADF in spring than in autumn (p<0.05). The intakes of DM, CP, and ME were lowest in winter (p<0.05). There were significant differences in nutrient intake between wethers and does in each season, except for the ADF and ME intake per metabolic weight (LW0.75). The nutrient digestibilities were higher in spring and summer, and decreased significantly during the autumn and winter (p<0.05). Goats, especially wethers, had a relative constant NDF digestibility across seasons, however, the apparent digestibility of CP in both wethers and does, decreased to negative values in winter. The grazing goats experienced relatively sufficient nutrients supply in spring and summer, and a severe deficiency of CP and ME in winter.
PMCID: PMC4093176  PMID: 25050019
Leymus chinensis; n-Alkanes; Intake; Digestibility; Goat

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