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1.  Exhaled nitric oxide levels in atopic children: relation to specific allergic sensitisation, AHR, and respiratory symptoms 
Thorax  2002;57(6):518-523.
Background: Exhaled nitric oxide (eNO), which has been proposed as a measure of airway inflammation, is increased in atopic subjects. This raises the question of whether eNO provides any additional information about airway inflammation in asthmatic subjects, other than as a marker for atopy. A study was undertaken to determine whether eNO levels in a population of atopic children are associated with sensitisation or natural exposure to specific allergens, and to examine the relationship between eNO, airway responsiveness, and current respiratory symptoms.
Methods: Exhaled NO and airway responsiveness to histamine were measured in winter and in summer in 235 children aged 8–14 years who had been classified as atopic by skin prick testing. Current respiratory symptoms, defined as wheeze or cough during the month preceding the test, were measured by a parent completed questionnaire. Airway hyperresponsiveness (AHR) was defined as a dose response ratio (DRR) of >8.1 (% fall in forced expiratory volume in 1 second (FEV1)/µmol + 3).
Results: Sensitisation to house dust mite was associated with raised eNO levels in winter while sensitisation to Cladosporium was associated with raised eNO levels in both winter and summer. Grass pollen sensitisation was not associated with raised eNO levels in either season. Exhaled NO correlated significantly with DRR histamine (r=0.43, p<0.001) independently of whether the children had current symptoms or not. In children with current wheeze, those with AHR had eNO levels 1.53 (95% CI 1.41 to 1.66) times higher than those without AHR (p=0.006). Neither DRR (p=1.0) nor eNO levels (p=0.92) differed significantly between children with or without persistent dry cough in the absence of wheeze.
Conclusions: In atopic children, raised eNO levels are associated with sensitisation to perennial allergens, but not to seasonal allergens such as grass pollen. In this population, an increase in eNO is associated with AHR and current wheezing, suggesting that eNO is more than just a marker for atopy.
PMCID: PMC1746345  PMID: 12037227
2.  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
3.  Validation of novel wheeze phenotypes using longitudinal airway function and atopic sensitisation data in the first 6 years of life: Evidence from the Southampton Women’s Survey. 
Pediatric pulmonology  2013;48(7):683-692.
In 1995 the Tucson Children’s Respiratory Study (TCRS) identified clinically distinct phenotypes amongst early wheezers; the Avon Longitudinal Study of Parents And Children (ALSPAC) has recently re-examined these.
To validate statistically derived ALSPAC phenotypes in the Southampton Women’s Survey (SWS) using infant and 6 year lung function, and allergic sensitisation at 1, 3 and 6 years, comparing these with TCRS phenotypes.
Complete 6 year follow-up data were available for 926 children, selected from 1973 infants born to 12,579 women characterised pre-conception. 95 children had V’maxFRC and FEV0.4 measured age 5-14 weeks using rapid compression/raised volume techniques. At 6 years we performed spirometry (n=791), fractional exhaled nitric oxide (FeNO, n=589) and methacholine challenge (n=234). Skin prick testing was performed at 12m, 3 and 6 years (n=1494, 1255, 699, respectively). Using wheeze status questionnaire data at 6m, 12m, 2, 3 and 6 years we classified children into TCRS (never, transient early, persistent, late-onset) and ALSPAC based groups (never, early, transient, intermediate-onset, late-onset, persistent).
Amongst ALSPAC groups, persistent and late-onset wheeze were associated with atopy at 3 and 6 years, whilst intermediate-onset wheeze showed earlier atopic association at 1 year; all three were associated with FeNO at 6 years. Persistent wheezers had lower infant (V’maxFRC p<0.05) and 6 year lung function (FEV1, FEV1/FVC and FEF25-75, p<0.05), whilst late and intermediate-onset wheezers showed no lung function deficits. Transient wheezers were non-atopic but showed persistent lung function deficits (V’maxFRC in infancy, FEV1 and FEF25-75 at 6 years, all p<0.05). Those who wheezed only in the first year (early phenotype) showed no lung function deficits. No associations were seen with 6 years bronchial hyper-responsiveness or infancy FEV0.4.
SWS cohort data validates the statistically derived ALSPAC 6-class model. In particular, lung function and atopy successfully differentiate persistent, late-onset and intermediate-onset wheeze, whilst the Tucson ‘transient early’ wheeze phenotype can be sub-classified into groups that reflect early lung function. Since the 4-class model fails to adequately differentiate phenotypes based on lung function and atopy, we propose that strong consideration be given to using the 6-class paradigm for longitudinal outcome work in wheezing with onset in early life.
PMCID: PMC3689612  PMID: 23401430
Wheeze; asthma; phenotype; lung function; cohort; atopy
4.  The relationship between air pollution from heavy traffic and allergic sensitization, bronchial hyperresponsiveness, and respiratory symptoms in Dutch schoolchildren. 
Environmental Health Perspectives  2003;111(12):1512-1518.
Studies have suggested that children living close to busy roads may have impaired respiratory health. This study was designed to test the hypothesis that exposure to exhaust from heavy traffic in particular is related to childhood respiratory health. Children attending 24 schools located within 400 m from busy motorways were investigated. The motorways carried between 5,190 and 22,326 trucks per weekday and between 30,399 and 155,656 cars per day. Locations were chosen so that the correlation between truck and car traffic counts was low. Air pollution measurements were performed at the schools for 1 year. Respiratory symptoms were collected by parent-completed questionnaire. Sensitization to common allergens was measured by serum immunoglobulin E and skin prick tests. Bronchial hyperresponsiveness (BHR) was measured with a hypertonic saline challenge. Respiratory symptoms were increased near motorways with high truck but not high car traffic counts. They were also related to air pollutants that increased near motorways with high truck traffic counts. Lung function and BHR were not related to pollution. Sensitization to pollen increased in relation to truck but not car traffic counts. The relation between symptoms and measures of exposure to (truck) traffic-related air pollution were almost entirely restricted to children with BHR and/or sensitization to common allergens, indicating that these are a sensitive subgroup among all children for these effects.
PMCID: PMC1241655  PMID: 12948892
5.  Exhaled nitric oxide levels in non-allergic and allergic mono- or polysensitised children with asthma 
Thorax  2001;56(11):857-862.
BACKGROUND—Increased fractional exhaled NO concentrations (FENO) and blood/tissue eosinophilia are frequently reported in allergic children with mild asthma and are thought to reflect the intensity of the inflammation characterising the disease. The aim of this study was to investigate possible differences in FENO levels or in the intensity of the blood eosinophilia in allergic and non-allergic asthmatic children.
METHODS—112 children with stable, mild, intermittent asthma with a positive bronchial challenge to methacholine were consecutively enrolled in the study; 56 were skin prick test and RAST negative (non-sensitised) while 56 were sensitised to house dust mites (23 only to house dust mites (monosensitised) and 33 were sensitised to mites and at least another class of allergens (pollens, pet danders, or moulds)). Nineteen sex and age matched healthy children formed a control group.
RESULTS—Compared with non-allergic patients, allergic children had a significantly higher rate of blood eosinophilia (p=0.0001) with no differences between mono- and polysensitised individuals. Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), forced expiratory flow at 25-75% of vital capacity (FEF25-75%), and the degree of bronchial reactivity to methacholine were similar in non-atopic and atopic children, with no differences between mono- and polysensitised individuals. FENO levels measured by chemiluminescence analyser were higher in asthmatic children (15.9(14.3) ppb) than in the control group (7.6 (1.6) ppb, p=0.04) and higher in allergic patients (23.9 (2.1) ppb) than in non-allergic patients (7.9 (0.8) ppb, p=0.0001), but there were no differences between mono- and polysensitised individuals (p>0.1). Significant correlations between blood eosinophilia and FENO levels were seen only in allergic (r=0.35, p<0.01) and in polysensitised individuals (r=0.45, p<0.05).
CONCLUSIONS—In children with mild asthma, a similar degree of functional disease severity may be associated with a higher inflammatory component in allergic than in non-allergic subjects.

PMCID: PMC1745945  PMID: 11641510
6.  Obesity is a risk for asthma and wheeze but not airway hyperresponsiveness 
Thorax  2001;56(1):4-8.
BACKGROUND—A study was undertaken to assess whether the recent increases in prevalence of both asthma and obesity are linked and to determine if obesity is a risk factor for diagnosed asthma, symptoms, use of asthma medication, or airway hyperresponsiveness.
METHODS—Data from 1971 white adults aged 17-73 years from three large epidemiological studies performed in NSW were pooled. Doctor diagnosis of asthma ever, history of wheeze, and medication use in the previous 12 months were obtained by questionnaire. Body mass index (BMI) in kg/m2 was used as a measure of obesity. Airway hyperresponsiveness (AHR) was defined as dose of <3.9 µmol histamine required to provoke a fall in forced expiratory volume in one second (FEV1) of 20% or more (PD20FEV1). Adjusted odds ratios (OR) were obtained by logistic regression.
RESULTS—After adjusting for atopy, age, sex, smoking history, and family history, severe obesity was a significant risk factor for recent asthma (OR 2.04, p=0.048), wheeze in the previous 12 months (OR 2.6, p=0.001), and medication use in the previous 12 months (OR 2.83, p=0.005), but not for AHR (OR 0.87, p=0.78). FEV1 and forced vital capacity (FVC) were significantly reduced in the group with severe obesity, but FEV1/FVC ratio, peak expiratory flow (PEF), and mid forced expiratory flow (FEF25-75) were not different from the group with normal BMI. The underweight group (BMI <18.5 kg/m2) had increased symptoms of shortness of breath, increased airway responsiveness, and reduced FEV1, FVC, PEF, and FEF25-75 with similar use of asthma medication as subjects in the normal weight range.
CONCLUSIONS—Although subjects with severe obesity reported more wheeze and shortness of breath which may suggest a diagnosis of asthma, their levels of atopy, airway hyperresponsiveness, and airway obstruction did not support the suggestion of a higher prevalence of asthma in this group. The underweight group appears to have more significant respiratory problems with a higher prevalence of symptoms, reduced lung function, and increased airway responsiveness without an increase in medication usage. This group needs further investigation.

PMCID: PMC1745919  PMID: 11120896
7.  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
8.  Interaction of atopy and smoking on respiratory effects of occupational dust exposure: a general population-based study 
For individual exposures, effect modification by atopy or smoking has been reported on the occurrence of occupational airway disease. It is unclear if effect modification can be studied in a general population by an aggregated exposure measure. Assess relationship between airway obstruction and occupational exposure using a job-exposure-matrix (JEM) classifying jobs into 3 broad types of exposure, and test for effect modification by atopy, and smoking.
Data from 1,906 subjects were analyzed, all participants of the European Community Respiratory Health Survey. Job titles were categorized by an a priori constructed job exposure matrix into three classes of exposure to respectively organic dust, mineral dust, and gases/ fumes. Relationships were assessed for 'current wheeze', bronchial hyperresponsiveness (BHR), 'current asthma' (wheeze+BHR), and 'chronic bronchitis' (morning phlegm or morning cough), and lung function.
Subjects with organic dust exposure in their work environment more frequently had 'current asthma' (OR 1.48, 95% C.I. 0.95;2.30), and a lower FEV1 (-59 mL, 95% C.I. -114;-4). The relationship was only present in asthmatic workers, and their risk was four-fold greater than in subjects with either atopy or exposure alone. Mineral dust exposure was associated with 'chronic bronchitis' (OR 2.22, 95% C.I. 1.16;4.23) and a lower FEV1/FVC ratio (-1.1%, 95% C.I. -1.8;-0.3). We observed an excess risk in smokers, greater than the separate effects of smoking or mineral dust exposure together.
Occupational exposure to organic dust is associated with an increased risk of asthma, particularly in atopics. Chronic bronchitis occurs more frequently among individuals exposed to mineral dust, and smoking doubles this risk.
PMCID: PMC443511  PMID: 15175108
9.  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
10.  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
11.  Exhaled Nitric Oxide is Associated with Allergic Inflammation in Children 
Journal of Korean Medical Science  2011;26(10):1265-1269.
Exhaled nitric oxide (eNO) has been proposed as a noninvasive marker of airway inflammation in asthma. In asthmatic patients, exhaled NO levels have been shown to relate with other markers of eosinophilic recruitment, which are detected in blood, sputum, bronchoalveolar lavage fluid and bronchial biopsy samples. The purpose of this study was to assess the possible relationship between eNO and allergic inflammation or sensitization in childhood asthma and allergic rhinitis. Subjects consisted of 118 asthmatic children, 79 patients with allergic rhinitis, and 74 controls. Their age ranged from 6 to 15 yr old. eNO level, peripheral blood eosinophil count, eosinophil cationic protein (ECP), serum total IgE level and specific IgE levels were measured. Methacholine challenge test and allergic skin prick test for common allergens were performed in all subjects. Atopic group (n = 206, 44.48 ± 30.45 ppb) had higher eNO values than non-atopic group (n = 65, 20.54 ± 16.57 ppb, P < 0.001). eNO level was significantly higher in patients with asthma (42.84 ± 31.92 ppb) and in those with allergic rhinitis (43.59 ± 29.84 ppb) than in healthy controls (27.01 ± 21.34 ppb, P < 0.001) but there was no difference between asthma and allergic rhinitis group. eNO also had significant positive correlations with Dermatophagoides pteronyssinus IgE level (r = 0.348, P < 0.001), Dermatophagoides farinae IgE level (r = 0.376, P < 0.001), and the number of positive allergens in skin prick test (r = 0.329, P = 0.001). eNO had significant positive correlations with peripheral blood eosinophil count (r = 0.356, P < 0.001), serum total IgE level (r = 0.221, P < 0.001), and ECP (r = 0.436, P < 0.001). This study reveals that eNO level is associated with allergic inflammation and the degree of allergic sensitization.
PMCID: PMC3192335  PMID: 22022176
Exhaled Nitric Oxide; Asthma; Allergic Rhinitis; Allergy; Sensitization
12.  Airway hyperresponsiveness, prevalence of chronic respiratory symptoms, and lung function in workers exposed to irritants. 
The association between occupational exposure to airway irritants and the prevalence of chronic respiratory symptoms and level of lung function, and whether these associations were modified by airway hyperresponsiveness, smoking, and a history of allergy were studied in 668 workers from synthetic fibre plants. Respiratory symptoms were recorded with a self administered Dutch version of the British Medical Research Council questionnaire, with additional questions on allergy. Airway responsiveness was measured by a 30 second tidal breathing histamine challenge test. On the basis of job titles and working department, the current state of exposure of all workers was characterised as (1) no exposure, reference group; (2) white collar workers; (3) SO2 HCl, SO4(2); (4) polyester vapour; (5) oil mist and vapour; (6) polyamide and polyester vapour; (7) multiple exposure. Workers exposed to airway irritants were not simultaneously exposed to airborne dust. Airway hyperresponsiveness (AHR), defined as a 20% fall in forced expiratory volume in one second (FEV1) at < or = 32 mg/ml histamine, was present in 23% of the subjects. The association between exposure groups and prevalence of symptoms was estimated by means of multiple logistic regression; the association with level of lung function (forced vital capacity (FVC), FEV1, maximum mid-expiratory flow rate (MMEF)) was estimated by means of multiple linear regression. Both methods allow simultaneous adjustment for potential confounding factors. The exposure groups were associated with a higher prevalence of chronic respiratory symptoms. Lower prevalence of symptoms was found for workers exposed to SO2, HCl, and SO4(2-), most likely due to pre-employment selection procedures. Current smoking, AHR, and a history of allergy were significantly associated with a higher prevalence of chronic respiratory symptoms, independent of each other, and independent of irritant exposure. The association between exposure and prevalence of symptoms was greater in smokers than in ex-smokers and non-smokers. This difference was most clearly seen in the polyester vapour and polyamide and polyester vapour group. No modification of the association between exposure groups and prevalence of symptoms by airway hyperresponsiveness could be shown. The exposure groups were not significantly associated with a lower level of lung function. Adjustment for chronic respiratory symptoms did not change the results. There were no indications of a possible interaction between exposure and AHR, current smoking, or a history of allergy on lung function. Workers of the polyester vapour and the oil mist and vapour group with >10 years of exposure had a lower FEV1 (beta = -295 and -358 ml) and significantly lower MMEF (beta = -1080 and -1247 ml/s; p < 0.05) than the reference group. The number of workers of both group were, however, small (n = 10 and n = 13 respectively). More investigations between low level exposure to irritant and respiratory health.
PMCID: PMC1127893  PMID: 8124460
13.  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
Pediatric pulmonology  2010;45(9):919-926.
The purpose of the study was to check the hypothesis that early wheezing as reported by mothers would be associated with reduced lung function in 4-year-olds. Study participants were recruited prenatally, as part of a prospective cohort study on the respiratory health of young children exposed to various ambient air pollutants. After delivery, infants were followed over four years and the interviewers visited participants at their home to record respiratory symptoms every three months in the child’s first two years of life and every 6 months in the third and fourth years. In the fourth year of follow-up, children were invited for standard lung function testing by spirometry quantified by FVC, FEV1 and FEV05 levels. Out of 258 children attending spirometry testing 139 performed at least two acceptable exhalation efforts. Cohort children with acceptable spirometric measurements did not differ with respect to wheezing experience and exposure characteristics from those without. The study shows that episodic wheeze was reported in 28.1% of 4-year-olds, 6.5% had transient wheeze and 4.3% had recurrent wheeze. There was an increased frequency of wheezing symptoms and their duration in transient and recurrent wheezers. Adjusted multivariable regression models for gender and height showed that children who reported more than 2 episodes of wheezing at any point over the follow-up had FVC values lower by 120.5 mL (p = 0.016) and FEV1 values lower by 98.3 mL (p = 0.034) compared to those who did not report any wheezing; children experiencing more than 10 wheezing days by age 4 showed FVC deficit of 87.4 mL (p = 0.034) and FEV1 values of 65.7 mL (p = 0.066) The ratios of FEV1/FVC% and FEV05/FVC% were neither associated with wheezing episodes nor wheezing days. In recurrent wheezers lung function decrement amounted to 207 mL of FVC, 175 mL of FEV1 and 104 mL of FEV05. In conclusion, our findings show that wheezing experience during early postnatal life may be associated with lung function deficit of restrictive character in preschool children and detailed history of wheeze in early postnatal life, even though not physician-confirmed, may help define the high risk group of children for poor lung function testing.
PMCID: PMC3691468  PMID: 20672363
15.  Quantification of atopy, lung function and airway hypersensitivity in adults 
Studies in children have shown that concentration of specific serum IgE (sIgE) and size of skin tests to inhalant allergens better predict wheezing and reduced lung function than the information on presence or absence of atopy. However, very few studies in adults have investigated the relationship of quantitative atopy with lung function and airway hyperresponsiveness (AHR).
To determine the association between lung function and AHR and quantitative atopy in a large sample of adults from the UK.
FEV1 and FVC (% predicted) were measured using spirometry and airway responsiveness by methacholine challenge (5-breath dosimeter protocol) in 983 subjects (random sample of 800 parents of children enrolled in a population-based birth cohort enriched with 183 patients with physician-diagnosed asthma). Atopic status was assessed by skin prick tests (SPT) and measurement of sIgE (common inhalant allergens). We also measured indoor allergen exposure in subjects' homes.
Spirometry was completed by 792 subjects and 626 underwent methacholine challenge, with 100 (16.0%) having AHR (dose-response slope>25). Using sIgE as a continuous variable in a multiple linear regression analysis, we found that increasing levels of sIgE to mite, cat and dog were significantly associated with lower FEV1 (mite p = 0.001, cat p = 0.0001, dog p = 2.95 × 10-8). Similar findings were observed when using the size of wheal on skin testing as a continuous variable, with significantly poorer lung function with increasing skin test size (mite p = 8.23 × 10-8, cat p = 3.93 × 10-10, dog p = 3.03 × 10-15, grass p = 2.95 × 10-9). The association between quantitative atopy with lung function and AHR remained unchanged when we repeated the analyses amongst subjects defined as sensitised using standard definitions (sIgE>0.35 kUa/l, SPT-3 mm>negative control).
In the studied population, lung function decreased and AHR increased with increasing sIgE levels or SPT wheal diameter to inhalant allergens, suggesting that atopy may not be a dichotomous outcome influencing lung function and AHR.
PMCID: PMC3339334  PMID: 22410099
IgE; atopy; quantitative assay; lung function; airway hyperresponsiveness
16.  Tolerance and rebound with zafirlukast in patients with persistent asthma 
The potential for tolerance to develop to zafirlukast, a cysteinyl leukotriene (CysLT) receptor antagonist (LRA) in persistent asthma, has not been specifically examined.
To look for any evidence of tolerance and potential for short-term clinical worsening on LRA withdrawal. Outcome measures included changes in; airway hyperresponsiveness to inhaled methacholine (PD20FEV1), daily symptoms and peak expiratory flows (PEF), sputum and blood cell profiles, sputum CysLT and prostaglandin (PG)E2 and exhaled nitric oxide (eNO) levels.
A double blind, placebo-controlled study of zafirlukast, 20 mg twice daily over 12 weeks in 21 asthmatics taking β2-agonists only (Group I), and 24 subjects treated with ICS (Group II).
In Group I, zafirlukast significantly improved morning PEF and FEV1compared to placebo (p < 0.01), and reduced morning waking with asthma from baseline after two weeks (p < 0.05). Similarly in Group II, FEV1 improved compared to placebo (p < 0.05), and there were early within-treatment group improvements in morning PEF, β2-agonist use and asthma severity scores (p < 0.05). However, most improvements with zafirlukast in Group I and to a lesser extent in Group II deteriorated toward baseline values over 12 weeks. In both groups, one week following zafirlukast withdrawal there were significant deteriorations in morning and evening PEFs and FEV1 compared with placebo (p ≤ 0.05) and increased nocturnal awakenings in Group II (p < 0.05). There were no changes in PD20FEV1, sputum CysLT concentrations or exhaled nitric oxide (eNO) levels. However, blood neutrophils significantly increased in both groups following zafirlukast withdrawal compared to placebo (p = 0.007).
Tolerance appears to develop to zafirlukast and there is rebound clinical deterioration on drug withdrawal, accompanied by a blood neutrophilia.
PMCID: PMC2426667  PMID: 18489783
17.  The relationship between infant lung function and the risk of wheeze in the preschool years 
Pediatric pulmonology  2010;46(1):75-82.
Premorbid infant lung function predicts childhood wheeze, but it is unclear whether lower infant lung function is most closely associated with atopic or non-atopic preschool wheeze.
To examine the association between premorbid infant lung function and preschool wheeze according to atopic or non-atopic wheeze phenotype. Additionally, to explore the relations of ADAM33 polymorphism with lung function during infancy, preschool wheeze and atopy.
Infant lung function was measured in147 healthy term infants aged 5-14 weeks. Raised volume rapid thoracoabdominal compression was performed to determine FEV0.4. Atopic status was determined by skin prick testing at 3 years and wheeze ascertained from parental questionnaires (1 and 3 years). ADAM33 polymorphisms were examined using haplotype analysis.
Measurements and Main Results
Early infancy V’maxFRC and FEV0.4 were lower in those who wheezed in the first year (p=0.002 and p=0.03), and lower V’maxFRC was associated with wheeze in the third year (p=0.006). Non-atopic children who wheezed in their third year of life had lower FEV0.4, compared to non-atopic children who did not wheeze (p=0.02), whilst atopic children with wheeze did not (p=0.4). No ADAM33 haplotype was associated with infant lung function, preschool wheeze or atopy after correction for multiple testing.
Lower premorbid infant lung function was present in infants who subsequently wheezed during the first and third years of life. Lower FEV0.4 was associated with non-atopic wheeze but not atopic wheeze at 3 years of age. The relation between ADAM33 polymorphism, infant lung function and preschool wheeze requires examination in larger studies.
PMCID: PMC3685268  PMID: 20848581
wheeze; asthma; infant lung function; preschool; ADAM Proteins
18.  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
19.  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
20.  Dissociation between exhaled nitric oxide and hyperresponsiveness in children with mild intermittent asthma 
Thorax  2000;55(6):484-488.
BACKGROUND—Bronchial hyperresponsiveness and airway inflammation are distinctive features of asthma. Evaluation of nitric oxide (NO) levels in expired air have been proposed as a reliable method for assessing the airway inflammatory events in asthmatic subjects. A study was undertaken to evaluate whether airway hyperresponsiveness is related to levels of exhaled NO.
METHODS—Thirty two steroid-naive atopic children with mild intermittent asthma of mean (SD) age 11.8 (2.3) years and 28 age matched healthy controls were studied to investigate whether baseline lung function or airway hyperresponsiveness is related to levels of exhaled NO. Airway responsiveness was assessed as the dose of methacholine causing a 20% decrease in forced expiratory volume in one second (FEV1) from control (PD20 methacholine) and exhaled NO levels were measured by chemiluminescence analysis of exhaled air.
RESULTS—At baseline asthmatic children had significantly higher NO levels than controls (mean difference 25.87 ppb (95% CI 18.91 to 32.83); p<0.0001) but there were no significant differences in lung function parameters (forced vital capacity (FVC), FEV1 (%pred), and forced expiratory flows at 25-75% of vital capacity (FEF25-75%)). In the asthmatic group exhaled NO levels were not significantly correlated with baseline lung function values or PD20 methacholine.
CONCLUSIONS—These results suggest that levels of exhaled NO are not accurate predictors of the degree of airway responsiveness to inhaled methacholine in children with mild intermittent asthma.

PMCID: PMC1745786  PMID: 10817797
21.  Reduced lung function both before bronchiolitis and at 11 years 
Archives of Disease in Childhood  2002;87(5):417-420.
Background and Aims: We have previously shown an association between reduced premorbid lung function (V‘maxFRC) and bronchiolitis. We hypothesised that individuals with bronchiolitis will go on to have reduced lung function and increased respiratory symptoms in childhood.
Methods: V‘maxFRC was measured at 1 month of age; individuals with bronchiolitis were prospectively identified. Annual symptom questionnaires were completed from 3 to 6 years. At 11 years of age, children underwent an assessment including questionnaire, lung function, airway response to histamine (AR), and skin prick testing.
Results: Eighteen individuals with bronchiolitis were ascertained from 253 cohort members. Children with bronchiolitis had increased viral induced wheeze at 3 (OR 5.8, 95% CI 1.4 to 25.2; n = 103) and 5 years (OR 5.3, 95% CI 1.1 to 25.5; n = 101). At 11 years of age, 194 children were assessed including 16 with past bronchiolitis. These 16 individuals had reduced mean z scores for % V‘maxFRC compared with other children (-0.56 and 0.06 respectively) and mean z scores for % FEF25–75 at 11 years (-0.53 and 0.06 respectively). At 11 years, FEV1, FVC PEF, AR, atopy, wheeze, and diagnosed asthma were not different between groups.
Conclusions: Reduced lung function is present before and after bronchiolitis; the level of reduction is comparable. The mechanism for wheeze and reduced lung function after bronchiolitis appears to be related to premorbid lung function and not bronchiolitis per se.
PMCID: PMC1763101  PMID: 12390918
22.  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
23.  Exhaled nitric oxide and asthma: complex interactions between atopy, airway responsiveness, and symptoms in a community population of children 
Thorax  2003;58(12):1048-1052.
Background: Exhaled nitric oxide (FENO) is raised in asthmatic children, but there are inconsistencies in the relationship between FENO and characteristics of asthma, including atopy, increased airway responsiveness (AR), and airway inflammation. The aim of this study was to investigate the relationship between FENO and asthma, atopy, and increased AR in children.
Methods: One hundred and fifty five children (79 boys) of mean age 11.5 years underwent an assessment that included FENO measurements, spirometric tests, inhaled histamine challenge, and a skin prick test. Blood was collected for eosinophil count. Current and past asthma like symptoms were determined by questionnaire.
Results: In multiple linear regression analyses FENO was associated with atopy (p<0.001), level of AR (p = 0.005), blood eosinophil count (p = 0.007), and height (p = 0.002) but not with physician diagnosed asthma (p = 0.1) or reported wheeze in the last 12 months (p = 0.5). Separate regression models were conducted for atopic and non-atopic children and associations between FENO and AR, blood eosinophils and height were only evident in atopic children. Exhaled NO was raised in children with a combination of atopy and increased AR independent of symptoms.
Conclusion: Raised FENO seems to be associated with an underlying mechanism linking atopy and AR but not necessarily respiratory symptoms.
PMCID: PMC1746531  PMID: 14645971
24.  Natural history of asthma in childhood--a birth cohort study. 
Archives of Disease in Childhood  1991;66(9):1050-1053.
A cohort of 67 babies at risk of developing atopic disorders was followed up prospectively for 11 years. Clinical assessment and skin prick allergen sensitivity testing were performed annually over the first five years. At 11 years the cohort was restudied, symptoms were assessed by questionnaire, and bronchial reactivity (BHR) to histamine was measured. On the basis of skin testing, 35 children were atopic and 32 remained non-atopic. The expression of atopy increased with age. The lifetime prevalence of eczema, wheeze, and hay fever were 46%, 63%, and 56% respectively. The yearly period prevalence of hay fever increased with age, that of eczema declined, while that for wheeze showed a bimodal distribution with a peak before the age of 2 years and a gradual increase thereafter. Of the 21 children who wheezed before their second birthday, most never wheezed again and did not show BHR at 11 years. Of the 21 children whose first wheezing was after 2 years of age, 17 were still wheezing at 11 years and 12 showed BHR. Of the children who wheezed before 2 years of age, 10 were or became atopic, compared with 20 of the 23 children who wheezed at 11 years. These findings suggest that childhood asthma is a heterogeneous condition with atopy being strongly associated with the persistence of wheeze.
PMCID: PMC1793050  PMID: 1929511
25.  Prevalence of bronchial hyperresponsiveness and asthma in a rural adult population. 
Thorax  1987;42(5):361-368.
The prevalence of bronchial hyperresponsiveness in adult populations is not known. To document its prevalence and distribution and to determine the factors associated with it, a random sample of the adult population of Busselton, Western Australia, was studied. Spirometric function, bronchial responsiveness to histamine, and atopic responses to skin prick tests were measured. Respiratory symptoms were determined by questionnaire. Data were obtained from 916 subjects. Of these, 876 underwent a histamine inhalation test and bronchial hyperresponsiveness to histamine (defined as a dose of histamine provoking a 20% fall in FEV1 equal to or less than 3.9 mumol) was found in 10.5%. Another 40 subjects with poor lung function were tested with a bronchodilator and 12 were found to have bronchial hyperresponsiveness (defined as a greater than 15% increase in FEV1), making the total prevalence of bronchial hyperresponsiveness 11.4%. The prevalence of current asthma, defined as bronchial hyperresponsiveness plus symptoms consistent with asthma in the last 12 months, was 5.9%. The distribution of bronchial hyperresponsiveness in the studied population was continuous. There was a significant association between it and respiratory symptoms, atopy, smoking, and abnormal lung function (p less than 0.001 for all associations). There was no association with age, sex, or recent respiratory tract infection.
PMCID: PMC460757  PMID: 3660290

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