Cow's milk allergy as a predictor of bronchial hyperresponsiveness and airway inflammation at school age.

BACKGROUND: Cow's milk allergy (CMA) has been found to be associated with an increased incidence of asthma at school age. However, prospective population-based studies of CMA and the development of airway inflammation and bronchial hyperresponsivess (BHR) are lacking. OBJECTIVE: The aims of this study was to evaluate CMA as a risk factor for BHR and airway inflammation presented later in childhood. METHODS: We followed prospectively 118 children with CMA and invited them to a clinical visit at a mean age of 8.6 years including the measurement of exhaled nitric oxide (FE(NO) ) and bronchial challenge with histamine. Ninety-four patients and 80 control subjects from the same cohort participated. RESULTS: At school age, children with a history of CMA had higher FE(NO) levels (P=0.0009) and more pronounced responsiveness to histamine (P=0.027) than their controls. Stratified analysis showed a significant difference only in IgE-positive CMA. Multinomial logistic regression analysis showed that IgE-positive CMA [odds ratio (OR) 3.51; 95% confidence intervals (CI) 1.56-7.90; P=0.002] and a history of wheeze during the first year of life (OR 2.81; 95% CI 1.16-6.84; P=0.023) were independent explanatory factors for increased FE(NO) , and IgE-positive CMA (OR 3.37; 95% CI 1.03-10.97; P=0.044) and parental smoking (OR 3.41; 95% CI 1.14-10.22; P=0.028) for increased BHR, whereas for IgE-negative CMA, no associations with FE(NO) or BHR were found. In the CMA group, those exposed to CM very early at the maternity hospital, had less BHR (P=0.002). CONCLUSIONS: Compared with their controls, children with a history of IgE-positive CMA show signs of airway inflammation, expressed as higher FE(NO) , and more pronounced bronchial responsiveness to histamine at school age. In contrast to IgE-negative CMA, IgE-positive CMA is a significant predictor of increased FE(NO) and BHR at school age. Very early exposure to CM was associated with less BHR.

Clinical findings associated with abnormal lung function in children aged 3-26 months with recurrent respiratory symptoms.

AIM: To evaluate whether there are any associations between parentally reported symptoms, clinical findings and lung function in young children with recurrent lower respiratory tract symptoms. METHODS: In 2000-2003, 148 children, aged 3-26 months, with recurrent lower respiratory tract symptoms underwent physical examination, investigation of a chest radiograph, whole body plethysmography and skin prick testing to common food and inhalant allergens. RESULTS: Lung function was considered abnormal (i.e. functional residual capacity z-score of > or =1.65 and/or specific conductance z-score of < or =-1.65) in 83 (56%) children. Findings of increased work of breathing (p < 0.001) and nonspecific noisy breathing sounds (p < 0.001) in the physical examination, as well as an abnormal chest radiograph (p = 0.028) were independently associated with abnormal lung function, explaining up to 34% of the variation in lung function. In contrast, parentally reported respiratory symptoms, environmental exposures or atopic trait were not associated with lung function abnormalities. CONCLUSION: The results of this study emphasize the importance of the meticulous clinical examination in the evaluation of early childhood respiratory disorders. As physical examination alone cannot predict lung function abnormalities reliably in preschool children with troublesome respiratory symptoms, lung function testing may be considered in such patients to obtain additional objective information.

Bronchial response pattern of antigen presenting cells and regulatory T cells in children less than 2 years of age.

BACKGROUND: In early childhood, the ability to mount protective immune responses in the airways is impaired, with increased risk of allergic sensitisation to inhaled allergens. Antigen presenting cells (APC) and regulatory T cells (Treg) are important modifiers of T cell immunity but little is known about their distribution in bronchial mucosa at this age. Here the subset distribution of APC and the appearance of Foxp3(+) Treg and bronchus associated lymphoid tissue (BALT) were examined immunohistochemically in children less than 2 years of age with chronic asthma-like symptoms of the lower airways. METHODS: Immunophenotyping was performed in situ on bronchial biopsy specimens obtained from 45 infants, 4-23 months of age, under investigation for airway disease. RESULTS: A well developed HLA-DR(+) network of APC was present in all samples, approximately 50% of the cells being CD68(+) macrophages and the remainder various subsets of dendritic cells. The density of HLA-DR(+) cells increased significantly with age but was not related to atopy, clinical symptoms or lung function. Comparing the density of APC subsets and clinical parameters, only the number of intraepithelial CD1a(+) dendritic cells was significantly increased in infants who had recently suffered a respiratory infection. BALT structures were identified in 22 children, with no relation to lung function, atopic status or human rhinovirus positivity. Plasmacytoid dendritic cells and Foxp3(+) Treg were located primarily within these isolated lymphoid follicles. CONCLUSION: A bronchial network of dendritic cells and macrophages develops quite rapidly after birth, apparently independent of clinical symptoms or atopy. The high frequency of BALT structures containing putative tolerogenic dendritic cells and Treg suggests that these lymphoid follicles play an important role in bronchial immune homeostasis during infancy.

Exhaled nitric oxide in healthy nonatopic school-age children: determinants and height-adjusted reference values.

Exhaled nitric oxide (FENO) was proposed as a marker of airway inflammation, but data about FENO in healthy children measured with standardized methods are so far limited. In order to assess the determinants of FENO in healthy children, we investigated a population-based sample of school-age children (n = 276) with a questionnaire, skin-prick tests, spirometry, and the measurement of FENO. The FENO of 114 nonatopic and nonsmoking children considered healthy were analyzed with stepwise multiple regression analysis, which showed significant associations with age, standing height, weight, and body surface area, but not with gender. Height was found to be the best independent variable for the regression equation for FENO, which on average showed an increase in the height range of 120-180 cm from 7 to 14 ppb. In the random sample of children, increased FENO was associated with atopy (odds ratio, 9.0; 95% confidence interval, 3.9-21.1; P < 0.0001), and significantly with allergic rhinitis and atopic dermatitis, but not with asthma. Respiratory symptom-free children with skin-prick test positivity had significantly higher FENO than healthy nonatopic subjects. We conclude that height is the best determinant of FENO in healthy children. Due to the strong effect of atopy, FENO data should not be interpreted without knowing the atopic status of the child. The present reference values of FENO may serve in clinical assessments for measuring airway inflammation in children.

Reference values for respiratory system impedance by using impulse oscillometry in children aged 2-11 years.

The forced oscillation technique makes it possible to evaluate the mechanical properties of the respiratory system with a minimum of cooperation. The method is therefore especially useful in children. Impulse oscillometry (IOS) is a commercially available version of this technique. There is, as yet, limited information on reference values for IOS in children. The aim of this study was to extend the reference values for IOS variables and to study their correlation with height, weight and age in healthy children. A sample (n = 360) of children (age 2.1-11.1 years) was measured by using impulse oscillometry (IOS; Jaeger, Würzburg, Germany). The sample was based on children attending kindergarten in Finland and children attending primary school in Sweden. Measurements of respiratory resistance (Rrs) and reactance (Xrs) at 5, 10, 15 and 20 Hz, total respiratory impedance (Zrs) and the resonance frequency (Fr) were made. All variables were related to body height. Most of them were also weakly related to weight. Reference equations for children (height 90-160 cm) are presented.

Averaged and time-gated spectral analysis of respiratory sounds. Repeatability of spectral parameters in healthy men and in patients with fibrosing alveolitis.

STUDY OBJECTIVE: To obtain a basis for assessment of changes in breath sound spectra in patients with pulmonary diseases, short-term and day-to-day repeatability of spectral parameters was studied. DESIGN: Breath sounds were recorded simultaneously from the trachea and from the chest twice at an interval of 15 min (short-term repeatability) and of 1 to 3 days (day-to-day repeatability). During recordings, air flow at the mouth was controlled, the target inspiratory and expiratory peak flow being 1.25 L/s. Inspiratory and expiratory breath sound spectra were averaged over 7 to 10 successive respiratory cycles. The repeatability of sound intensity (RMS), frequency of maximum intensity (Fmax), and median frequency (F50) was analyzed with analysis of variance. PARTICIPANTS: Short-term repeatability was studied in 10 healthy nonsmoking men (age 25 to 44 years), and day-to-day repeatability was studied in 10 healthy nonsmoking men (age 23 to 41 years) and in 12 patients with clinically stable fibrosing alveolitis (age 35 to 82 years). RESULTS: Short-term coefficient of variation (CoV) of Fmax and F50 was 2.6 to 6.7% when recorded from the chest, and 6.2 to 8.7% when recorded from the trachea. Day-to-day CoV of Fmax and F50 in healthy subjects was 4.7 to 8.5% and 5.0 to 8.7% recorded from the chest or from the trachea, respectively. Inspiratory day-to-day variation in those parameters was higher in patients with fibrosing alveolitis. CoV of RMS was high, ranging from 18 to 47% in different subject groups and sampling situations. CONCLUSIONS: Repeatability of F50 of averaged flow-controlled lung sound spectra is good both in healthy subjects and in patients with fibrosing alveolitis. Thus, F50 of respiratory sound spectra may be useful in monitoring of changes induced by respiratory diseases and interventions. These results emphasize the importance of standardization of recording conditions and of analyzing techniques.

Changes in frequency spectra of breath sounds during histamine challenge test in adult asthmatics and healthy control subjects.

Air-flow standardized breath sounds were recorded at the chest and at the trachea during histamine challenge test and after subsequent bronchodilation in 12 asthmatics and 6 healthy controls for spectral analysis, to be compared with simultaneous changes in spirometric variables. Of all the lung sound variables measured, the changes in median frequency of the power spectrum (F50) of tracheal expiratory sounds were found to correlate best (r = 0.853, p < 0.0001) with changes in FEV1. The increase of F50 during histamine challenge was significantly larger in asthmatics than in healthy control subjects (p < 0.005). The provocative dose of histamine inducing a decrease of 15 percent in FEV1 (PD15FEV1) and the provocative dose causing an increase of 30 percent in tracheal expiratory F50 (PD30F50) were significantly related (r = 0.754, p = 0.012). In asthmatics, the breath sound frequency distribution in terms of median frequency reflected acute changes in airways obstruction with high sensitivity and specificity. The present method for breath sound analysis can be applied for patients with limited cooperation during bronchial challenge tests.

A rapid dosimetric method with controlled tidal breathing for histamine challenge. Repeatability and distribution of bronchial reactivity in a clinical material.

A rapid dosimetric method with controlled tidal breathing for histamine challenge was evaluated by assessment of its repeatability, by comparing to a present nondosimetric standard method, and by application to adult patients with recent asthma (n = 31), chronic asthma (n = 33), chronic cough (n = 71) or chronic rhinitis (n = 41) and to healthy controls (n = 31). An automatic inhalation-synchronized dosimetric jet nebulizer with a known lung deposition of the aerosol was used to administer histamine and to control breathing. The non-cumulative doses of histamine diphosphate were 0.025, 0.1, 0.4 and 1.6 mg, administered during 0.4 s following tidal inspiration of 100 ml of air. The test procedure required 1 inhalation of histamine 4 mg/ml and followed by 1, 4 and 16 inhalations of histamine 16 mg/ml from the device, and its duration was about 30 minutes. The intraindividual correlation coefficient of the histamine dose causing a reduction of 15 percent in FEV1 (PD15FEV1) on 2 consecutive days in 14 asthmatic subjects was 0.937; the standard error of the single determination was 13 percent of the mean PD15 FEV1. A PD15FEV1 value below 0.4 mg was found only in asthmatic subjects; in chronic asthma, below 0.5 mg; in recent asthma, between 0.1 mg and 1.6 mg or more. In patients with chronic cough and chronic rhinitis, 20 and 32 percent, respectively, the PD15FEV1 values between 0.4 and 1.6 mg, the other patients in these groups were non-responsive. In all healthy control subjects, the PD15FEV1 was over 1.0 mg, 80 percent of them were nonresponsive to the maximum 1.6 mg dose. This new test allows rapid, accurate, and quantitative assessment of bronchial responsiveness to histamine.

Acceptability, reproducibility, and sensitivity of forced expiratory volumes and peak expiratory flow during bronchial challenge testing in asthmatic children.

OBJECTIVES: To compare the acceptability, reproducibility, and sensitivity of spirometric outcome measures of airway caliber during challenge testing in children. DESIGN: FEV(1), forced expiratory volume in 0.75 s, forced expiratory volume in 0.5 s, and peak expiratory flow (PEF) were recorded during stepwise dosimetric histamine challenge tests. The responses were compared, and the reproducibility at baseline and from duplicate measurements at each challenge step was determined. PATIENTS: One hundred five children with newly diagnosed asthma, aged 5 to 10 years. RESULTS: Compared to PEF, FEV(1) showed better baseline reproducibility (p = 0.002) and higher sensitivity (p < 0.0001) during challenge testing, determined as the change normalized to the baseline variation, while the forced expiratory volumes were not significantly different in these respects. During challenge testing in subjects with acceptable flow-volume tracings, paired recordings of FEV(1) agreed within 0.1 L in 85% and within 0.2 L in 93% of measurements. During challenge testing, the reproducibility of FEV(1) measurements was not better than that of the other indexes. Failure to exhale long enough precluded the use of FEV(1) in 16 of the children, particularly the youngest children. CONCLUSIONS: The results demonstrated that the recently published guidelines for FEV(1) measurements during challenge tests can be applied to children. During challenge tests in asthmatic children, the advantage of the shorter fractions of forced expiratory volume was that they were more often acceptably recorded than FEV(1), while they showed as good reproducibility and were also equally sensitive in assessing changes in airway obstruction.

Frequency distribution of breath sounds as an indicator of bronchoconstriction during histamine challenge test in asthmatic children.

In order to study changes in respiratory sounds associated with acute bronchoconstriction and -dilatation, breath sounds of 11 children with asthma (age range, 10-14 years) were recorded at the chest and at the trachea during histamine challenge test and after subsequent bronchodilatation. The changes in frequency spectra of breath sounds were compared with simultaneous changes in forced expiratory volume in 1 second (FEV1). In seven children who responded to histamine with a decrease in FEV1 of more than 15%, there was a significant relationship between percentage change in FEV1 (delta FEV1) and percentage change in median frequency (delta F50) of expiratory breath sounds recorded at the chest (r = 0.865; beta = -0.706, P = 0.0001) and at the trachea (r = 0.888; beta = -1.12, P = 0.0001). The association between breath sound intensity and FEV1 was weaker. Based on ANOVA, the increase of F50 during the challenge test was significantly larger in children who responded to histamine than in those who were non-responsive (P = 0.0016). At the chest, a decrease of 15% in FEV1 corresponded to an increase of 8% in expiratory F50. The provocative dose of histamine inducing a decrease of 15% in FEV1 (PD15FEV1) and the provocative dose causing an increase of 8% in F50 (PD8F50) were significantly related (r = 0.927, P = 0.003). We conclude that spectral analysis of breath sounds can be used to indicate airway obstruction during bronchial challenge tests in children, and may be adapted for tests in pre-school children. The results suggest that the same mechanisms that induce airflow limitation due to inhaled histamine may generate an increase in frequency content of breath sounds in children with asthma.

Intraindividual variability of infant whole-body plethysmographic measurements: effects of age and disease.

The intraindividual variability of whole-body plethysmographic measurements was studied in a large series of consecutive infants (N = 144), divided into two groups: a group of infants born very prematurely (PM, N = 63), with (N = 28) or without (N = 35) a history of bronchopulmonary dysplasia (BPD), and a group of infants with persistent respiratory symptoms (PRS, N = 81), i.e., wheezing (N = 53) or cough (N = 28). The intraindividual variability was determined within each test and between tests, separated by a 10-min interval. In both study groups, the between-test variability was significantly larger than that within tests. Expressed as the median coefficient of variation (CV), the between-test repeatabilities in the PRS group were 8.0% for thoracic gas volume (TGV), 17.5% for airway resistance (Raw), and 18.4% for specific airway conductance (sGaw), and in the PM group, 8.9% for TGV, 20.4% for Raw, and 20.7% for sGaw. However, the individual range of CVs was large, ranging from 3 to 19% for TGV and from 5 to 55% for sGaw. With respect to TGV, the difference between the groups was statistically significant (P = 0.03). In infants with a history of BPD, there was also a significant negative age dependency in CVs of sGaw (r = -0.50, P = 0. 009), showing larger variation among younger individuals. The presenting symptom (wheezing or cough) in the PRS group did not influence the measurement variability significantly, and neither did the degree of bronchial obstruction. We conclude that on a group basis, the repeatability of infant body plethysmographic measurements may be satisfactory for scientific studies demonstrating pharmacodynamic effects; however, the intraindividual measurement variability should be reported for each test conditions and for infant groups in each study. Due to the large range in individual variation and the influence of age and disease processes on the variation, for an individual child there is only questionable benefit from a given measurement, unless the intrasubject, between-test variability is assessed individually before interventions, such as a bronchodilation test.

Determinants of respiratory system input impedance and bronchodilator response in healthy Finnish preschool children.

In order to study the determinants of respiratory system impedance and bronchodilator response in preschool children, a sample (n = 109) of healthy children (age 2.1-7.0 years) attending kindergarten was measured by using the impulse oscillometry. Their selection was based on a standardized questionnaire, negative skin prick test results and clinical examination, and sufficient cooperation. Triple measurements of respiratory resistance (Rrs) and reactance (Xrs) at 5, 10, 15 and 20 Hz, total respiratory impedance (Zrs), the resonance frequency (Fr) and the frequency dependence of resistance (dRrs/df) were performed, to determine individual mean values. Measurements were repeated after inhalation of 300 microg salbutamol (n = 89) or placebo (n = 19). At the baseline, Zrs and Rrs5-20 showed negative, and Xrs5-20, Fr and dRrs/df positive correlations with age, height and weight. However, logarithmic transformed height was the best independent variable for the regression equations of all the oscillometric variables. After inhalation of placebo, none of the oscillometric variables changed significantly. In the salbutamol group, the mean (SD) change in Rrs5 was -0.187 (0.124) kPa l(-1) s(-1) and -19.2 (10.2)%, corresponding to a lower reference limit of -36.9%. Both the within-test and between-test repeatabilities for the measurement of respiratory resistance were acceptable, for Rrs5 the coefficients of variation being 6.2 and 6.1%, respectively. As the overall success rate in our sample was high (89%), the forced oscillation technique seems to be a useful method in assessing respiratory function and bronchial lability in preschool children.

Metered dose inhaler add-on devices: is the inhaled mass of drug dependent on the size of the infant?

Limited cooperation and low tidal volumes in infants make aerosol therapy difficult. We measured the amount of drug delivered from two baby spacer devices especially developed for use in infants. Designed as a randomized crossover study, aerolized budesonide from a pressurized metered dose inhaler (pMDI) was collected in the inspiratory filter interposed between the face mask and the spacer in 13 infants aged from 2 to 19 months old. The study was performed in connection with pulmonary function testing with a plethysmograph, and the children were sedated with cloral hydrate. Two small-volume baby spacer devices were used: a Babyhaler spacer (GlaxoWellcome, Hertfordshire, UK) made of polycarbonate with a volume of 350 mL and a built-in dead space of 40 mL and a NebuChamber spacer (AstraZeneca, Lund, Sweden) made of stainless steel with a volume of 250 mL and no dead space. Budesonide delivery from the NebuChamber was significantly higher than from the Babyhaler: 38.2% (range, 28.3%-47.5%) of the nominal dose versus 12% (range, 3.3%-21.25%) of the nominal dose of 400 micrograms of budesonide (P = 0.002). The inhaled mass of budesonide from the Babyhaler correlated significantly with skin surface area (r = 0.68, P = 0.018), weight (r = 0.66, P = 0.019), height (r = 0.69; P = 0.017), tidal volume (r = 0.82; P = 0.004), and minute volume (r = 0.67; P = 0.019). No correlations were found between these variables and the inhaled mass of budesonide from the NebuChamber. The results indicate that the design of the NebuChamber spacer affords stable drug delivery in infants and that a large variability in the inhaled mass of drug may be found when infants are inhaling from different baby spacers.

A new versatile PC-based lung sound analyzer with automatic crackle analysis (HeLSA); repeatability of spectral parameters and sound amplitude in healthy subjects.

A versatile PC-based lung sound analyzer has been developed for short-term recording and analysis of respiratory sounds in research and clinical applications. The system consists of two sound sensors, a flow sensor, a filtering signal amplifier and a PC with a data acquisition card and software for measurement and analysis of the sounds. The analyses include phonopneumography, time expanded waveform analysis, spectral analysis with time averaged Fast Fourier Transform, frequency analysis in time domain (sonogram), and automatic detection and waveform analysis of crackles. Short-term repeatability of spectral parameters of tracheal and lung sounds was studied in 10 healthy subjects. The coefficients of variation (CoV) of the averaged quartile frequencies (F25, F50 and F75) of lung sounds during flow-controlled tidal breathing were 3.7, 4.0 and 8.9% in expiration and 2.7, 3.5 and 4.5% in inspiration, respectively. CoVs of the averaged F25, F50 and F75 of expiratory tracheal sounds were 6.9, 3.0 and 2.4%, and those of inspiratory tracheal sounds 6.3, 2.6 and 3.3%, respectively. Examples of lung sound analysis of samples containing adventitious sounds such as crackles and wheezes are presented. The results indicate that the median frequency has the best repeatability of quartile frequencies of breath sounds and they suggest that the variations of those parameters are low enough for diagnostic purposes. The results also suggest that the analyzer can be a useful new tool for pulmonary research in the fields of physiological and clinical short-term studies of respiratory sounds.

Effect of adenoidectomy on respiratory function: a randomised prospective study.

OBJECTIVE: Risk of childhood asthma is increased in children with recurrent otitis media. This may be associated with recurrent respiratory tract infections in these children, but the role of adenoidectomy, a frequent operation during childhood, is unknown. Therefore, the role of adenoidectomy in the development of atopy and respiratory function changes characteristic of asthma was evaluated. DESIGN: Randomised controlled study. SETTING: Tertiary care centre. PATIENTS: 166 children aged 12-48 months who had recurrent or persistent otitis media and who were followed-up for 3 years after randomisation. INTERVENTION: Randomisation to undergo insertion of tympanostomy tubes with or without adenoidectomy. MAIN OUTCOME MEASURES: The primary outcome measure was exercise-induced bronchoconstriction as evaluated by impulse oscillometry. The secondary outcome measures were bronchial inflammation as evaluated by exhaled nitric oxide and atopy as evaluated by skin prick tests. During the 3-year follow-up period otitis media episodes were documented in patient diaries. RESULTS: Adenoidectomy did not significantly influence baseline lung function, exercise-induced bronchoconstriction, exhaled nitric oxide concentration, the development of positive skin prick tests, or doctor-diagnosed asthma. Adenoidectomy did not significantly prevent otitis media. Recurrent otitis media (>or=4 episodes) during the first follow-up year was associated with an abnormal exercise-induced bronchoconstriction (OR 6.62, 95% CI 1.27 to 34) and an elevated exhaled nitric oxide concentration (OR 3.26, 95% CI 0.98 to 10.8) regardless of adenoidectomy. CONCLUSIONS: Adenoidectomy did not promote asthma or allergy. Recurrent respiratory tract infections during early childhood are associated with the risk of bronchial hyper-reactivity.

Budesonide improves decreased airway conductance in infants with respiratory symptoms.

OBJECTIVE: Inhaled corticosteroids (ICS) are commonly used to treat wheezing disorders in children, but few studies have investigated the effect of ICS on lung function in infants. We evaluated the efficacy of inhaled budesonide for decreased specific airway conductance (sGaw) as an indication of bronchial obstruction in very young children with recurrent cough and/or wheeze. PATIENTS, DESIGN AND INTERVENTIONS: Functional residual capacity (FRC) and sGaw of steroid-naive children aged 3-26 months with respiratory symptoms were measured using an infant whole-body plethysmograph. Clinically indicated bronchoscopy was performed in 79% of the patients to exclude anatomical abnormalities before randomisation. Children with abnormal lung function and respiratory symptoms were randomised into two treatment groups, receiving either inhaled budesonide (400 microg/day) or placebo with NebuChamber for 6 weeks. Inhaled terbutaline 0.25 mg/dose was used as a rescue medication. Lung function measurements were repeated after 6 weeks. MAIN OUTCOME MEASURE: Lung function. RESULTS: 44 children with a median age of 11.3 months (range 3.7-25.9) completed the study. Median sGaw improved from a z score of -3.6 to -1.2 (p<0.001) in the budesonide group and from -3.2 to -2.6 (p = 0.033) in the placebo group; between group difference p = 0.014. Improvement in sGaw was more pronounced in children with atopy (p = 0.017). Symptom-free days increased in both the budesonide and placebo groups with no difference between groups. CONCLUSION: Treatment with inhaled budesonide for 6 weeks improved sGaw in young children with chronic cough or wheeze and bronchial obstruction.

Airway responsiveness: associated features in infants with recurrent respiratory symptoms.

Increased airway responsiveness (AR) is one of the main pathophysiological manifestations of asthma. The present study aimed to define the clinical features associated with increased AR in infants with recurrent lower respiratory tract symptoms. AR was evaluated by performing a novel dosimetric methacholine challenge test. Increased AR to methacholine, defined as a methacholine dose of < or =0.90 mg producing a 40% fall (PD(40)) in the maximal flow at functional residual capacity (V'(max,FRC)), was associated with atopy (odds ratio (OR) 4.1; 95% confidence interval (CI) 1.3-13.3), a history of physician-confirmed wheezing with respiratory syncytial virus (OR 32.9; 95% CI 2.5-428.8) or of a nonspecified aetiology (OR 4.9; 95% CI 1.1-22.5), functional residual capacity z-score > or =2 (OR 36.8; 95% CI 2.9-472.6), and V'(max,FRC) z-score (OR 0.5; 95% CI 0.2-0.9) at baseline, when compared with infants with only mild or no responsiveness to methacholine (PD(40) V'(max,FRC) >0.90 mg). In conclusion, in recurrently symptomatic infants, increased airway responsiveness is associated with reduced baseline lung function, an atopic trait of the child, a history of physician-confirmed wheeze and viral aetiology of wheeze. Future intervention studies are needed to confirm the role of airway responsiveness in respiratory morbidity during infancy.

Formoterol as needed with or without budesonide in patients with intermittent asthma and raised NO levels in exhaled air: A SOMA study.

Patients with mild intermittent asthma sometimes show signs of inflammation, and guidelines suggesting bronchodilator therapy alone as needed may be questioned. The current study compared as-needed use of a rapid-acting beta2-agonist with as-needed use of a beta2-agonist and corticosteroid combination as the only medication in asthma patients with intermittent symptoms. A total of 92 nonsmoking asthma patients (of 187 screened) using only an inhaled beta2-agonist as needed (28 males, 64 females; mean age 37 yrs; mean forced expiratory volume in one second (FEV1) 101% predicted, mean reversibility 6.5% pred and fractional exhaled nitric oxide (FeNO) > or =20 parts per billion (ppb)) were randomised to treatment with formoterol (Oxis Turbuhaler) 4.5 microg as needed (n = 47) or budesonide/formoterol (Symbicort Turbuhaler) 160/4.5 microg as needed (n = 45) in a double-blind, parallel-group 24-week study. The primary variable of efficacy was change in FeNO. Baseline FeNO was 60 ppb and 59 ppb in the budesonide/formoterol and formoterol groups, respectively. Mean reductions in FeNO in the budesonide/formoterol and formoterol groups were 18.2 ppb and 2.8 ppb, respectively (95% confidence interval (CI) 7.5-23.5 ppb). The reduction in the budesonide/formoterol group occurred during the first 4 weeks of treatment and remained at this low level. Mean FEV1 increased by 1.8% pred normal value in the budesonide/formoterol group and decreased by 0.9% pred normal value in the formoterol group (95% CI -4.7- -0.7). In the budesonide/formoterol group, use of > or =4 inhalations x day(-1) of study medication was seen on 21 treatment days compared with 74 in the formoterol group. In conclusion, as-needed use of an inhaled corticosteroid together with a rapid-acting bronchodilator may be more beneficial than a beta2-agonist alone in patients with intermittent asthma and signs of airway inflammation. The long-term benefits are unknown.

Determinants of increased exhaled nitric oxide in patients with suspected asthma.

Exhaled nitric oxide (FENO) has been proposed as a marker of asthmatic inflammation, but it is unclear whether FENO in clinical use selects patients primarily according to their atopic or asthmatic status. The aim of this study was to investigate the determinants of increased FENO in patients with suspected asthma, by means of multinomial logistic regression analysis. The FENO of 132 patients referred because of symptoms suggestive of asthma were studied, and the explanatory factors tested included atopy according to prick skin tests, clinical asthma according to lung function tests, sputum eosinophilia and bronchial hyperresponsiveness (BHR). Slightly elevated FE(NO) levels were significantly explained only by sputum eosinophilia (OR: 3.7; 95% CI: 1.1-13.1; P=0.04), but for high levels of FE(NO) (> or =3 SD of predicted), clinical asthma (OR: 16.3; 95% CI: 5.4-49.7; P <0.0001) and sputum eosinophilia (OR: 12.0; 95% CI: 4.1-35.0; P >0.0001) were the characteristics with the highest prediction, followed by atopy and BHR. A significant interaction between asthma and atopy was observed relating to the effect on high FENO, but further analyses stratified by atopy showed significant associations between asthma and high FENO both in atopic and nonatopic patients. We conclude that in patients with symptoms suggesting asthma, slightly elevated and high levels of FENO are associated with sputum eosinophilia, whereas asthma is significantly associated only with high levels of FENO, irrespective of atopy. The results suggest that FENO is primarily a marker of airway eosinophilia, and that only high values of FENO may be useful to identify patients with atopic or nonatopic asthma.