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1.  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
2.  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
3.  Respiratory symptoms in adults are related to impaired quality of life, regardless of asthma and COPD: results from the European community respiratory health survey 
Respiratory symptoms are common in the general population, and their presence is related to Health-related quality of life (HRQoL). The objective was to describe the association of respiratory symptoms with HRQoL in subjects with and without asthma or COPD and to investigate the role of atopy, bronchial hyperresponsiveness (BHR), and lung function in HRQoL.
The European Community Respiratory Health Survey (ECRHS) I and II provided data on HRQoL, lung function, respiratory symptoms, asthma, atopy, and BHR from 6009 subjects. Generic HRQoL was assessed through the physical component summary (PCS) score and the mental component summary (MCS) score of the SF-36.
Factor analyses and linear regressions adjusted for age, gender, smoking, occupation, BMI, comorbidity, and study centre were conducted.
Having breathlessness at rest in ECRHS II was associated with mean score (95% CI) impairment in PCS of -8.05 (-11.18, -4.93). Impairment in MCS score in subjects waking up with chest tightness was -4.02 (-5.51, -2.52). The magnitude of HRQoL impairment associated with respiratory symptoms was similar for subjects with and without asthma/COPD. Adjustments for atopy, BHR, and lung function did not explain the association of respiratory symptoms and HRQoL in subjects without asthma and/or COPD.
Subjects with respiratory symptoms had poorer HRQoL; including subjects without a diagnosis of asthma or COPD. These findings suggest that respiratory symptoms in the absence of a medical diagnosis of asthma or COPD are by no means trivial, and that clarifying the nature and natural history of respiratory symptoms is a relevant challenge.
Several community studies have estimated the prevalence of common respiratory symptoms like cough, dyspnoea, and wheeze in adults [1-3]. Although the prevalence varies to a large degree between studies and geographical areas, respiratory symptoms are quite common. The prevalences of respiratory symptoms in the European Community Respiratory Health Study (ECRHS) varied from one percent to 35% [1]. In fact, two studies have reported that more than half of the adult population suffers from one or more respiratory symptoms [4,5].
Respiratory symptoms are important markers of the risk of having or developing disease. Respiratory symptoms have been shown to be predictors for lung function decline [6-8], asthma [9,10], and even all-cause mortality in a general population study [11]. In patients with a known diagnosis of asthma or chronic obstructive pulmonary disease (COPD), respiratory symptoms are important determinants of reduced health related quality of life (HRQoL) [12-15]. The prevalence of respiratory symptoms exceeds the combined prevalences of asthma and COPD, and both asthma and COPD are frequently undiagnosed diseases [16-18]. Thus, the high prevalence of respipratory symptoms may mirror undiagnosed and untreated disease.
The common occurrence of respiratory symptoms calls for attention to how these symptoms affect health also in subjects with no diagnosis of obstructive airways disease. Impaired HRQoL in the presence of respiratory symptoms have been found in two population-based studies [6,19], but no study of respiratory sypmtoms and HRQoL have separate analyses for subjects with and without asthma and COPD, and no study provide information about extensive objective measurements of respiratory health.
The ECRHS is a randomly sampled, multi-cultural, population based cohort study. The ECRHS included measurements of atopy, bronchial hyperresponsiveness (BHR), and lung function, and offers a unique opportunity to investigate how respiratory symptoms affect HRQoL among subjects both with and without obstructive lung disease.
In the present paper we aimed to: 1) Describe the relationship between respiratory symptoms and HRQoL in an international adult general population and: 2) To assess whether this relationship varied with presence of asthma and/or COPD, or presence of objective functional markers like atopy and BHR.
PMCID: PMC2954977  PMID: 20875099
4.  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
5.  Serum concentration of C-reactive protein is not a good marker of bronchial hyperresponsiveness 
Asthmatic inflammation is responsible for vital features of the disease, including bronchial hyperresponsiveness (BHR). At present we do not have precise markers for monitoring asthmatic inflammation. C-reactive protein (CRP), a marker of systemic inflammation, seemed to be a factor which could also reflect the level of asthmatic inflammation expressed by BHR. Therefore the relationship between CRP concentration and BHR was evaluated.
Materials and Methods:
One hundred and two patients entered the study. A skin prick test with a broad spectrum of common aeroallergens as well as baseline spirometry and a histamine bronchoprovocation test were performed in each subject. Blood samples for high-sensitivity CRP (hsCRP) measurement were taken before the bronchial challenge tests.
Serum hsCRP concentrations ranged from 0.20 to 14.5 mg/l (median: 1.2 mg/l, 25–75% quartiles: 0.6–2.4). Positive skin prick tests were found in 26 subjects. Bronchial hyperresponsiveness was confirmed in 42 patients (first subgroup), while 60 subjects did not demonstrate BHR (second subgroup). Among the patients with BHR, asthma was diagnosed in 33 cases and Corrao syndrome in 9. In both subgroups, serum hsCRP concentrations had similar levels (median: 1.4 mg/l, 25–75% quartiles: 0.8–2.4 and median: 0.9 mg/l, 25–75% quartiles: 0.5–2.8, respectively; p=0.297). There was no statistically significant correlation (r= −0.163, p=0.302) between serum hsCRP concentration and the level of BHR expressed as the 20% provocative concentration for histamine. In addition, hsCRP serum concentration, after adjustment for age, atopy, body mass index, and gender, was not a significant predictor of positive histamine bronchoprovocation test results (p=0.22, OR=0.86, 95% CI).
Serum hsCRP concentration is not a good marker of BHR, which is mainly dependent on asthmatic inflammation and is measured during bronchial challenge with histamine. This finding is important for interpreting and discussing results obtained from epidemiological and population-based studies on relationships between either CRP concentration and BHR or local and systemic inflammation.
PMCID: PMC2766458  PMID: 18219765
asthmatic inflammation; asthma; Corrao syndrome; BHR; high-sensitivity CRP; systemic inflammation
6.  Atopy, bronchial hyperresponsiveness, and peak flow variability in children with mild occasional wheezing. 
Thorax  1996;51(3):272-276.
BACKGROUND: Children who suffer from recurrent wheezy episodes are often promptly classified as asthmatic. The aim of this study was to evaluate a population of mild wheezy children with repeatedly normal spirometric tests at rest for atopy, bronchial hyperresponsiveness, and peak expiratory flow variability. METHODS: Thirty nine children aged 6-16 years with 1-12 wheezy attacks during the previous year were recruited from a community paediatric primary health care clinic serving an urban Israeli population. The conditions for inclusion were a physician-diagnosed wheeze on auscultation and normal spirometric tests at rest on at least three occasions. Evaluation included skin prick tests for atopy and a physician-completed questionnaire. In addition, two tests of bronchial hyperresponsiveness (BHR) were performed--namely, exercise-induced bronchospasm and inhaled methacholine hyperresponsiveness--as well as diurnal variability of peak expiratory flow (PV). RESULTS: One or more tests of BHR/PV were positive in 27 (69%) but repeatedly negative in 12 (31%). In terms of frequency of wheezing attacks, atopy, and questionnaire responses, there were no differences between BHR/PV and non-BHR/PV children, with the exception of a history of chest radiography proven pneumonia (only noted in the BHR/PV group). Overall, evidence of atopy (mainly indoor allergens) was noted in 21 (56%) of those tested and parental smoking in 29 (74%) of households. Thirty-two (82%) of the children complained of an exercise-related wheeze, yet exercise-induced bronchospasm was only demonstrated in nine (23%). CONCLUSIONS: This selected group of wheezy children appears to be intermediate between a normal and clearly asthmatic population and, despite the recurrent wheezy attacks, some should probably not be classified as asthmatic by conventional criteria. Important aetiological factors in the symptomatology of these children may include parental smoking and atopy as well as other elements such as viral infections.
PMCID: PMC1090638  PMID: 8779130
7.  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
8.  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
9.  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
10.  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
11.  Relationship between Bronchial Hyperresponsiveness and Impaired Lung Function after Infantile Asthma 
PLoS ONE  2007;2(11):e1180.
Wheezing during infancy has been linked to early loss of pulmonary function. We prospectively investigated the relation between bronchial hyperresponsiveness (BHR) and progressive impairment of pulmonary function in a cohort of asthmatic infants followed until age 9 years. We studied 129 infants who had had at least three episodes of wheezing. Physical examinations, baseline lung function tests and methacholine challenge tests were scheduled at ages 16 months and 5, 7 and 9 years. Eighty-three children completed follow-up. Twenty-four (29%) infants had wheezing that persisted at 9 years of age. Clinical outcome at age 9 years was significantly predicted by symptoms at 5 years of age and by parental atopy. Specific airway resistance (sRaw) was altered in persistent wheezers as early as 5 years of age, and did not change thereafter. Ninety-five per cent of the children still responded to methacholine at the end of follow-up. The degree of BHR at 9 years was significantly related to current clinical status, baseline lung function, and parental atopy. BHR at 16 months and 5 years of age did not predict persistent wheezing between 5 and 9 years of age, or the final degree of BHR, but it did predict altered lung function. Wheezing that persists from infancy to 9 years of age is associated with BHR and to impaired lung function. BHR itself is predictive of impaired lung function in children, strongly pointing to early airway remodeling in infantile asthma.
PMCID: PMC2048663  PMID: 18000551
12.  Methacoline Challenge test as an Evaluator of Response to Statins in Bronchial Hyperresponsiveness 
3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins), are effective serum cholesterol-lowering agents which also have anti-inflammatory properties. The objective of this study was to evaluate the effect of atorvastatin on bronchial hyperresponsiveness.
Adult patients (age 14 to 65 years) with bronchial hyperresponsiveness (BHR) diagnosis based on the spirometry with methacholine challenge test were entered into the study. The study was conducted in the National Research Institute of Tuberculosis and Lung Disease. Patients were randomized to receive either atorvastatin 20 mg/day or placebo for 4 weeks. Spirometric parameters were determined at baseline and at completion of the study. Twenty two patients with the age of 32.95±10.30 years completed the trial.
Changes in airway responsiveness categories (moderate to severe, mild, borderline, normal) after the intervention were not significant in atorvastatin group as in placebo group (p-value= 0.131 for atorvastatin group and p-value = 0.305 for placebo group). Also, changes in methacholine solution number (different concentrations of methacholine) which caused at least 20% decrease in FEV1 were not significant between groups (p-value = 0.089). Although we could not find a significant difference, the patients’ fall in FEV1 in atorvastatin group was observed in higher concentrations of methacholine. Median before treatment versus after treatment in atorvastatin group was 1 versus 4 mg/mL, while those were 2 versus 1 mg/mL in placebo group.
This study showed a better but not significant hyperresponsiveness control in the treatment group. The result might be presented more pronounced, if we could increase the sample size.
PMCID: PMC3813126  PMID: 24250526
Bronchial hyperresponsiveness; Atorvastatin; Methacholine; Clinical Trial; Lung function; Statin
13.  Asymptomatic bronchial hyperreactivity and the development of asthma and other respiratory tract illnesses in children. 
Thorax  1994;49(8):757-761.
BACKGROUND--It is not clear whether asymptomatic bronchial hyperresponsiveness (BHR) in children is a risk factor for the subsequent development of asthma. A longitudinal study was conducted to determine the predictive value of BHR for the development of asthma in a primary care patient population. METHODS--A standard free running asthma screening test (FRAST) was applied to 956 schoolchildren aged between 4 and 11 years in 1985. Peak expiratory flow (PEF) rates were measured before hard running for six minutes and following a three minute rest period. Children with a fall in PEF of more than 15% were labelled as having a positive FRAST. Clinical data from the patients' notes and from symptom questionnaires were compared with age and sex matched controls for children known to have asthma, and for those with a positive FRAST but no asthma (BHR group). Over the ensuing six years to 1991 further clinical data were gathered to compare the development of asthma and other diseases of the airways in both the BHR groups and their controls. RESULTS--Of the 956 children exercised in 1985, 60 who were not known to have asthma had an abnormal test. Of the 55 of these studied in 1991, 32 (58%) had developed asthma. The sensitivity of a positive FRAST for the development of asthma was 58%, its specificity 97%, and positive predictive value 72%. Hay fever, eczema, otitis media, "bronchitis," and family history of atopy also occurred more commonly in this group. CONCLUSIONS--Asymptomatic BHR, as shown by exercise challenge, can predict the development of clinical asthma. This study has also shown a relation between BHR, asthma, and other diseases of the airways, notably upper respiratory tract infection, "bronchitis," and otitis media.
PMCID: PMC475119  PMID: 8091319
14.  Occupational asthma in New Zealanders: a population based study. 
OBJECTIVES: To examine the effect of occupation on respiratory symptoms in a randomly selected adult population aged 20-44 years. METHODS: It is based on the phase II sampling of the New Zealand part of the European Community respiratory health survey. 1609 people (63.9% response rate) completed a detailed respiratory questionnaire. Of those responding, 1174 (73%) underwent skin tests and 1126 (70%) attended to undergo methacholine bronchial challenge. Current occupation was recorded and a previous occupation was also recorded if it had led to respiratory problems. 21 occupational groups were used for analysis for the five definitions of asthma wheezing in the previous 12 months; symptoms related to asthma; bronchial hyperresponsiveness (BHR); BHR with wheezing in the previous 12 months; and BHR with symptoms related to asthma. RESULTS: Prevalence odds ratios (ORs) were significantly increased for farmers and farm workers (OR 4.16, 95% confidence interval (95% CI) 1.33 to 13.1 for the combination of wheezing and BHR). Increased risks of prevalence of asthma were also found for laboratory technicians, food processors (other than bakers), chemical workers, and plastic and rubber workers. Workers had also been divided into high and low risk exposure categories according to relevant publications. The prevalence of wheezing was greater in the high risk group (OR 1.57, 95% CI 0.83 to 2.95) than in the low risk group. Atopy was associated with asthma, but the prevalence of atopy did not differ significantly between occupational exposure groups. The attributable risk of wheezing that occurred after the age of 15 years and that was estimated to be due to occupational exposure (based on the defined high risk group) was 1.9%, but this increased to 3.1% when farmers and food processors (other than bakers) were also included in the high risk group. CONCLUSIONS: This population based study has identified certain occupations significantly associated with combinations of asthmatic symptoms and BHR.
PMCID: PMC1128776  PMID: 9196450
15.  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
16.  Bronchial hyperresponsiveness in lung transplant recipients: lack of correlation with airway inflammation 
Thorax  1997;52(6):551-556.
BACKGROUND: Bronchial hyperresponsiveness (BHR) to methacholine has been reported to occur in most lung transplant recipients. BHR to physical stimuli such as exercise and non-isotonic aerosols has not been as extensively studied in this subject population. This report aims to assess the presence and degree of BHR to methacholine and hypertonic saline in stable lung transplant recipients and to relate it to the presence of airway inflammation. METHODS: Ten patients undergoing bilateral sequential lung transplantation and six heart-lung transplant recipients, all with stable lung function, were recruited 66- 1167 days following transplantation. Subjects underwent a methacholine challenge and bronchoscopy for sampling of bronchoalveolar lavage fluid, transbronchial and endobronchial biopsy tissues. Hypertonic saline challenge was performed six days later. RESULTS: Nine of the 16 transplant recipients had positive methacholine challenges (geometric mean PD20 0.18 mg, interquartile range 0.058-0.509) and three of these subjects also had positive hypertonic saline challenges (PD15 = 2.3, 33.0, and 51.5 ml). No clear relationship was found between BHR to either methacholine or hypertonic saline and levels of mast cells, eosinophils or lymphocytes in samples of biopsy tissue or lavage fluid. CONCLUSIONS: Most of the lung transplant recipients studied were responsive to methacholine and unresponsive to hypertonic saline. BHR was not clearly related to airway inflammation, suggesting an alternative mechanism for BHR following lung transplantation from that usually assumed in asthma. 

PMCID: PMC1758572  PMID: 9227723
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.  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
19.  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
20.  Seasons can influence the results of the methacholine challenge test 
Annals of Thoracic Medicine  2012;7(2):61-68.
This study tried to evaluate whether a methacholine test may be influenced by the seasons.
We considered 4826 consecutive subjects with normal spirometry (50.53% males; age: 35.1±16.2; forced expiratory volume in one second: 99.5±13.0%) who underwent a methacholine test for suspected asthma symptoms between 2000 and 2010. They were subdivided into four groups, like the seasons, according to the test dates.
A total of 1981 (41%) resulted normal (no PD20 was obtained with 2400 μg of methacholine); the others showed a mean LogPD20 of 2.52±0.5 μg. The number of subjects with bronchial hyper-responsiveness (BHR) found in autumn (789, 62.3%) was higher than in summer (583, 56.7%; P=0.03). A higher number of females and overweight/obese subjects showed a BHR in autumn compared with the other seasons. The spring mean LogPD20 value (2.48±0.48 μg) was lower if compared with the one measured in summer (2.59±0.49 μg; P=0.05). LogPD20 value was lower in females and non-smokers in spring compared with summer (P<0.05). Overweight/obese non-smokers showed a lower LogPD20 in spring and autumn compared with that in summer (P<0.05). Autumn was a risk factor (OR: 1.378; P=0.001) for BHR (using a PD20 <2 400 μg as BHR limit), while spring (OR: 1.330; P=0.021) and autumn (OR: 1.331; P=0.020) were risk factors for a more severe BHR (using a PD20 <400 μg as BHR limit).
There was a higher probability of finding BHR in outpatients with suspected asthma in autumn and spring compared with summer. Spring is the season where BHR may be more severe. Females and overweight/obese subjects were those mainly involved in this seasonal variability of BHR.
PMCID: PMC3339205  PMID: 22558009
Airway; asthma; bronchial hyper-responsiveness; methacholine challenge test; season
21.  81 Dose Response Relationship Between Ascaris Sensitisation and Atopy and Bronchial Hyper-Responsiveness but not Allergic Diseases in Black South Africans 
The World Allergy Organization Journal  2012;5(Suppl 2):S43-S44.
The relationship between sensitisation to helminths and atopy, bronchial-hyperresponsiveness and allergic diseases may differ depending on many factors, including the genes of the population studied. We sought to examine this relationship in an African cohort.
Urban Xhosa children were tested for ascaris IgE levels, bronchial hyper-responsiveness (BHR) by methacholine challenge, atopic sensitisation (skin tests to aeroallergens) and allergic disease (asthma, eczema and rhinitis) assessed by questionnaire.
Ascaris sensitisation was strongly associated with BHR but not with asthma, eczema or rhinitis. There was a dose-response relationship between increasing class of ascaris IgE and increased BHR (Prevalence ratio (PR) 1.75; CI 1.09-2.82). Higher levels of ascaris IgE were seen in those with BHR. Ascaris IgE was associated with atopic sensitisation to aeroallergens. There was a dose-response relationship between increasing class of ascaris IgE and sensitisation to one or more allergen (PR 1.65; CI, 1.27-2.13), sensitisation to house dust mites (HDM) (PR 1.79; CI, 1.29-2.46) and grass (PR 2.66; CI, 1.24-5.71) and number of positive skin prick tests (PR 1.78; CI, 1.27-2.49). Presence of any sensitisation to ascaris was associated with more than doubling the prevalence of HDM sensitisation (41.5 vs 18.5%) and almost quadrupling the prevalence of grass sensitisation (10.8 vs 2.8%).
Ascaris sensitisation was strongly associated with BHR and with atopy, but not with allergic diseases. Possible explanations might be that the type of ascaris infection that causes high levels of ascaris IgE in this genetic population may also favour the development of atopy or that atopics in Africa have upregulation of their defence system against parasitic infection. These hypotheses are not mutually exclusive.
PMCID: PMC3512651
22.  Effects of fluticasone propionate in COPD patients with bronchial hyperresponsiveness 
Thorax  2002;57(8):694-700.
Background: Treatment of chronic obstructive pulmonary disease (COPD) with inhaled corticosteroids does not appear to be as effective as similar treatment of asthma. It seems that only certain subgroups of patients with COPD benefit from steroid treatment. A study was undertaken to examine whether inhaled fluticasone propionate (FP) had an effect on lung function and on indices of inflammation in a subgroup of COPD patients with bronchial hyperresponsiveness (BHR).
Methods: Twenty three patients with COPD were studied. Patients had to be persistent current smokers between 40 and 70 years of age. Non-specific BHR was defined as a PC20 for histamine of ≤8 mg/ml. Patients received either 2 x 500 µg FP or placebo for 6 months. Expiratory volumes were measured at monthly visits, BHR was determined at the start of the study and after 3 and 6 months, and bronchial biopsy specimens were taken at the start and after 6 months of treatment. Biopsy specimens from asymptomatic smokers served as controls.
Results: In contrast to asthma, indices of BHR were not significantly influenced by treatment with FP. Forced expiratory volume in 1 second (FEV1) showed a steep decline in the placebo group but remained stable in patients treated with FP. FEV1/FVC, and maximal expiratory flows at 50% and 25% FVC (MEF50, MEF25) were significantly increased in the FP treated patients compared with the placebo group. Biopsy specimens were analysed for the presence of CD3+, CD4+, CD8+, MBP+, CD15+, CD68+, CD1a, and tryptase cells. FP treatment resulted in marginal reductions in these indices of inflammation.
Conclusion: In patients with COPD and BHR, FP has a positive effect on indices of lung function compared with placebo. Bronchial inflammation analysed in bronchial biopsy specimens is only marginally reduced.
PMCID: PMC1746396  PMID: 12149529
23.  Testing bronchial hyper-responsiveness: provocation or peak expiratory flow variability? 
BACKGROUND: Assessing bronchial hyper-responsiveness (BHR) is a main diagnostic criterion of asthma. Provocation testing is not readily available in general practice, but peak expiratory flow (PEF) is. Several guidelines promote the use of PEF variability as a diagnostic tool for BHR. This study tested the agreement between histamine challenge testing and PEF variability, and the consequences for diagnosing asthma. AIM: To investigate the possibility of assessing BHR by PEF variability, using a histamine provocation test as a reference. METHOD: Subjects with signs of symptoms indicating asthma (persistent or recurrent respiratory symptoms or signs of reversible bronchial obstruction) (n = 323) were studied. They had been identified in a population screening for asthma. A histamine provocation test and PEF variability were assessed over a three-week period. Asthma was defined as signs or symptoms together with a reversible airflow obstruction or BHR to the histamine challenge test. BHR was defined as a PC20 histamine of < or = 8 mg/ml or a PEF variability of > or = 15%. Overall correlation between PC20 and PEF variability was calculated using Spearman's rho. Furthermore, a decision tree was constructed to clarify the role of BHR in diagnosing asthma. RESULTS: Thirty-two patients had a reversibility in forced expiratory volume in 1 second (FEV1) of > or = 9% predicted, 131 patients showed a PC20 of < or = 8 and 11 patients had a PEF variability of > or = 15%. Overall correlation was poor at only -0.27 (P < 0.0001). One hundred and fourteen of the 131 patients diagnosed as having asthma when the histamine challenge test was used were not diagnosed by PEF variability. CONCLUSION: PEF variability cannot replace bronchial provocation testing in assessing BHR. This indicates that PEF variability and bronchial provocation do not measure the same aspects of BHR. If BHR testing is required in diagnosing asthma, a bronchial provocation test has to be used in general practice as well.
PMCID: PMC1313077  PMID: 9302787
24.  Exhaled nitric oxide is related to atopy, but not asthma in adolescents with bronchiolitis in infancy 
The fraction of exhaled nitric oxide (FeNO) has been suggested as a non-invasive marker of eosinophilic inflammation in asthma, but lately rather as a biomarker of atopy than of asthma itself. Asthma after bronchiolitis is common up to early adolescence, but the inflammation and pathophysiology may differ from other phenotypes of childhood asthma. We aimed to assess if FeNO was different in children with former hospitalization for bronchiolitis and a control group, and to explore whether the role of FeNO as a marker of asthma, atopy or bronchial hyperresponsiveness (BHR) differed between these two groups of children.
The study included 108 of 131 children (82%) hospitalized for bronchiolitis in 1997–98, of whom 82 (76%) had tested positive for Respiratory syncytial virus, and 90 age matched controls. The follow-up took place in 2008–2009 at 11 years of age. The children answered an ISAAC questionnaire regarding respiratory symptoms and skin prick tests, spirometry, methacholine provocation test and measurement of FeNO were performed.
Analysed by ANOVA, FeNO levels did not differ between the post-bronchiolitis and control groups (p = 0.214). By multivariate regression analyses, atopy, height (p < 0.001 for both) and BHR (p = 0.034), but not asthma (p = 0.805) or hospitalization for bronchiolitis (p = 0.359), were associated with FeNO in the post-bronchiolitis and control groups. The associations for atopy and BHR were similar in the post-bronchiolitis and in the control group.
FeNO did not differ between 11 year old children hospitalized for bronchiolitis and a control group. FeNO was associated with atopy, but not with asthma in both groups.
PMCID: PMC3840648  PMID: 24237793
Children; Eosinophilic inflammation; Respiratory syncytial virus; Wheezing
25.  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

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