Atopic asthma after rhinovirus-induced wheezing is associated with DNA methylation change in the SMAD3 gene promoter.

Children with rhinovirus-induced severe early wheezing have an increased risk of developing asthma later in life. The exact molecular mechanisms for this association are still mostly unknown. To identify potential changes in the transcriptional and epigenetic regulation in rhinovirus-associated atopic or nonatopic asthma, we analyzed a cohort of 5-year-old children (n = 45) according to the virus etiology of the first severe wheezing episode at the mean age of 13 months and to 5-year asthma outcome. The development of atopic asthma in children with early rhinovirus-induced wheezing was associated with DNA methylation changes at several genomic sites in chromosomal regions previously linked to asthma. The strongest changes in atopic asthma were detected in the promoter region of SMAD3 gene at chr 15q22.33 and introns of DDO/METTL24 genes at 6q21. These changes were validated to be present also at the average age of 8 years.

The potential of anti-infectives and immunomodulators as therapies for asthma and asthma exacerbations.

Asthma is responsible for approximately 25,000 deaths annually in Europe despite available medicines that maintain asthma control and reduce asthma exacerbations. Better treatments are urgently needed for the control of chronic asthma and reduction in asthma exacerbations, the major cause of asthma mortality. Much research spanning >20 years shows a strong association between microorganisms including pathogens in asthma onset, severity and exacerbation, yet with the exception of antibiotics, few treatments are available that specifically target the offending pathogens. Recent insights into the microbiome suggest that modulating commensal organisms within the gut or lung may also be a possible way to treat/prevent asthma. The European Academy of Allergy & Clinical Immunology Task Force on Anti-infectives in Asthma was initiated to investigate the potential of anti-infectives and immunomodulators in asthma. This review provides a concise summary of the current literature and aimed to identify and address key questions that concern the use of anti-infectives and both microbe- and host-based immunomodulators and their feasibility for use in asthma.

Determination of avidity of IgG against protein antigens from Streptococcus pneumoniae: assay development and preliminary application in clinical settings.

The measurement of antibody levels is a common test for the diagnosis of Streptococcus pneumoniae infection in research. However, the quality of antibody response, reflected by avidity, has not been adequately evaluated. We aimed to evaluate the role of avidity of IgG against eight pneumococcal proteins in etiologic diagnosis. Eight pneumococcal proteins (Ply, CbpA, PspA1 and 2, PcpA, PhtD, StkP-C, and PcsB-N) were used to develop a multiplex bead-based avidity immunoassay. The assay was tested for effects of the chaotropic agent, multiplexing, and repeatability. The developed assay was applied to paired samples from children with or without pneumococcal disease (n = 38 for each group), determined by either serology, polymerase chain reaction (PCR), or blood culture. We found a good correlation between singleplex and multiplex assays, with r ≥ 0.94.The assay was reproducible, with mean inter-assay variation ≤ 9% and intra-assay variation < 6%. Children with pneumococcal disease had lower median avidity indexes in the acute phase of disease for PspA1 and 2 (p = 0.042), PcpA (p = 0.002), PhtD (p = 0.014), and StkP-C (p < 0.001). When the use of IgG avidity as a diagnostic tool for pneumococcal infection was evaluated, the highest discriminative power was found for StkP-C, followed by PcpA (area under the curve [95% confidence interval, CI]: 0.868 [0.759-0.977] and 0.743 [0.607-879], respectively). The developed assay was robust and had no deleterious influence from multiplexing. Children with pneumococcal disease had lower median avidity against five pneumococcal proteins in the acute phase of disease compared to children without disease.

Distinct regulation of tonsillar immune response in virus infection.

BACKGROUND: The relationships between tonsillar immune responses, and viral infection and allergy are incompletely known. OBJECTIVE: To study intratonsillar/nasopharyngeal virus detections and in vivo expressions of T-cell- and innate immune response-specific cytokines, transcription factors, and type I/II/III interferons in human tonsils. METHODS: Palatine tonsil samples were obtained from 143 elective tonsillectomy patients. Adenovirus, bocavirus-1, coronavirus, enteroviruses, influenza virus, metapneumovirus, parainfluenza virus, rhinovirus, and respiratory syncytial virus were detected using PCR. The mRNA expression levels of IFN-α, IFN-ß, IFN-γ, IL-10, IL-13, IL-17, IL-28, IL-29, IL-37, TGF-ß, FOXP3, GATA3, RORC2, and Tbet were directly analyzed by quantitative RT-PCR. RESULTS: Fifty percentage of subjects reported allergy, 59% had ≥1 nasopharyngeal viruses, and 24% had ≥1 intratonsillar viruses. Tonsillar virus detection showed a strong negative association with age; especially rhinovirus or parainfluenza virus detection showed positive association with IFN-γ and Tbet expressions. IL-37 expression was positively associated with atopic dermatitis, whereas IFN-α, IL-13, IL-28, and Tbet expressions were negatively associated with allergic diseases. Network analyses demonstrated strongly polarized clusters of immune regulatory (IL-10, IL-17, TGF-ß, FOXP3, GATA3, RORC2, Tbet) and antiviral (IFN-α, IFN-ß, IL-28, IL-29) genes. These two clusters became more distinctive in the presence of viral infection or allergy. A negative correlation between antiviral cytokines and IL-10, IL-17, IL-37, FOXP3, and RORC2 was observed only in the presence of viruses, and interestingly, IL-13 strongly correlated with antiviral cytokines. CONCLUSIONS: Tonsillar cytokine expression is closely related to existing viral infections, age, and allergic illnesses and shows distinct clusters between antiviral and immune regulatory genes.

Nasopharyngeal bacterial colonization during the first wheezing episode is associated with longer duration of hospitalization and higher risk of relapse in young children.

The purpose of this study was to examine the association between bacterial colonization/infection and respiratory outcomes in children younger than 3 years old who were hospitalized for their first wheezing episode. This was an observational study. The primary outcome was hospitalization time and the secondary outcomes included relapses within 2 months and time to recurrent wheezing (i.e. three physician confirmed wheezing episodes) within 12 months. Bacterial antibody assays for Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae and Chlamydia pneumoniae were studied as well as nasopharyngeal bacterial culture for the three former and urine pneumococcal antigen. Nasopharyngeal bacterial culture was positive in 31/52 (60%) children, serologic evidence of bacterial infection was found in 17/96 (18%) children, urine pneumococcal antigen was positive in 24/101 (24%), and any bacterial detection method was positive in 53/106 (50%) children. The children with positive nasopharyngeal bacterial culture had longer duration of hospitalization (hazard ratio 2.4) and more often relapsed within two months than those with negative culture (odds ratio 7.3). In this study, half of the first time wheezing children had bacterial colonization or symptomatic or asymptomatic bacterial infection. The bacterial colonization (i.e. positive nasopharyngeal bacterial culture) was associated with longer duration of hospitalization and higher risk of recurrent wheezing.

Allergic sensitization is associated with rhinovirus-, but not other virus-, induced wheezing in children.

BACKGROUND: Data on the link between atopy and viral wheeze are limited. AIM: To evaluate the association between IgE sensitization and viral infection in wheezing children. METHODS: This is an observational study in hospitalized wheezing children (n = 247; median age 1.6 ; interquartile range 1.1, 2.9). Eighteen respiratory viral infections were studied using all available methods. A specific immunoglobulin E (IgE) sensitization for common food and aeroallergens and other atopy-related variables including total IgE, blood and nasal eosinophils, exhaled nitric oxide, eczema and atopic eczema, parental allergy and asthma, number of wheezing episodes, positive asthma predictive index or asthma and use of inhaled corticosteroid were correlated with specific viral etiology. RESULTS: Atopy was closely associated with sole rhinovirus etiology (n = 58) but not with sole respiratory syncytial virus, sole enterovirus, sole human bocavirus, sole other virus, mixed viral, or virus negative etiology. The number of sensitizations was particularly associated with sole rhinovirus etiology (odds ratio 4.59; 95% confidence interval 1.78, 11.8; adjusted to age and sex), followed by aeroallergen sensitization (respectively; 4.18; 2.00, 8.72), total IgE level (2.06; 1.32, 3.21), food allergen sensitization (2.02; 1.08, 3.78), and nasal eosinophil count (1.52; 1.08, 2.13). CONCLUSIONS: According to our data, allergic sensitization is positively linked to rhinovirus-, but not other virus-, associated wheezing and calls attention for studies to test rhinovirus-associated wheezing as a part of asthma risk indices.

Obesity, adipokines and asthma.

BACKGROUND: The prevalence of asthma and obesity is increasing concomitantly, but many aspects of this link are unclear. Our objective was to examine whether obesity is associated with asthma in three time points of life, and whether immunomodulatory adipokines, leptin and adiponectin are linked to overweight-associated asthma. METHODS: We studied the association between obesity and asthma at ages 3-18 years [mean (SD), 10 years (5), n = 3582, year 1980], 9-24 years [16 years (5), n = 2764, 1986] and 24-39 years [32 years (5), n = 2620, 2001] in a prospective cohort study and further tested for associations with serum leptin and adiponectin concentrations. Data on allergy status, smoking and other laboratory values (serum insulin, plasma C-reactive protein and serum lipid values) were also analyzed. RESULTS: Allergy and parental asthma were significantly associated with asthma at all ages. At ages 24-39 years, but not earlier, body mass index (BMI) (odds ratio, OR 1.05; P = 0.019) and female gender (OR 1.56; P = 0.031) were independently associated with asthma. Increase in BMI was also associated with incident asthma during adulthood (OR 1.08; P = 0.030). Levels of leptin, adiponectin or any other obesity-related biomarker were not independently associated with asthma. CONCLUSIONS: Asthma is linked with obesity in adults, but our results do not support a significant role for leptin, adiponectin or any other obesity-related biomarker studied in this association. Other factors should be sought for better understanding the connection between obesity and asthma.

Serial viral infections in infants with recurrent respiratory illnesses.

To better understand the viral aetiology of recurrent and prolonged illnesses, nasal secretions were prospectively collected from 285 infants at increased risk of developing asthma. Of these, 27 infants had recurrent (at least five) moderate-to-severe respiratory illnesses (MSIs). The viral aetiology of the 150 MSIs and 86 scheduled visits was analysed by molecular diagnostics. The demographic and clinical data were compared with infants who had 0-4 MSIs. Frequently ill infants had higher exposure to other children and more wheezing illnesses than less symptomatic children. Viruses were detected in 136 (91%) out of 150 MSIs, 14 (67%) out of 21 mild illnesses and 29 (45%) out of 65 asymptomatic visits. Human rhinovirus was the most common aetiological agent (61, 43 and 35% in MSIs, mild illnesses and asymptomatic visits, respectively). Mixed viral infections were generally associated with more severe illnesses (27, 0 and 5%, respectively). Among the 27 frequently ill infants, only eight (5.3%) out of 150 MSIs were prolonged (> or =2 weeks duration). Considering all samples, detection of the same virus strain > or =2 weeks apart was unusual (5.3% of all 244 positive findings). Human rhinovirus infections occur early, pervasively and repetitively in these high-risk infants. Infants with prolonged or recurrent respiratory illnesses most often have a series of infections rather than persistent infection with one virus strain.

Bacterial coinfections in children with viral wheezing.

Bacterial coinfections occur in respiratory viral infections, but the attack rates and the clinical profile are not clear. The aim of this study was to determine bacterial coinfections in children hospitalized for acute expiratory wheezing with defined viral etiology. A total of 220 children aged 3 months to 16 years were investigated. The viral etiology of wheezing was confirmed by viral culture, antigen detection, serologic investigation, and/or PCR. Specific antibodies to common respiratory bacteria were measured from acute and convalescent serum samples. All children were examined clinically for acute otitis media, and subgroups of children were examined radiologically for sinusitis and pneumonia. Rhinovirus (32%), respiratory syncytial virus (31%), and enteroviruses (31%) were the most common causative viruses. Serologic evidence of bacterial coinfection was found in 18% of the children. Streptococcus pneumoniae (8%) and Mycoplasma pneumoniae (5%) were the most common causative bacteria. Acute otitis media was diagnosed in 44% of the children. Chest radiographs showed alveolar infiltrates in 10%, and paranasal radiographs and clinical signs showed sinusitis in 17% of the older children studied. Leukocyte counts and serum C-reactive protein levels were low in a great majority of patients. Viral lower respiratory tract infection in children is often associated with bacterial-type upper respiratory tract infections. However, coexisting bacterial lower respiratory tract infections that induce systemic inflammatory response are seldom detected.

Effect of cardiac vagal outflow on complexity and fractal correlation properties of heart rate dynamics.

1. Cardiac vagal outflow is the major factor determining the magnitude of heart rate (HR) variability analysed by traditional time and frequency domain methods. New analysis techniques, such as fractal and complexity methods, have been developed to probe non-linear features in HR behaviour that may not be detectable by traditional methods. 2. We investigated the effects of vagal blockade (glycopyrrolate i.v. 5 microg kg-1 h-1 for 2 h, n = 8 vs. unmedicated control group, n = 8) and various breathing patterns (n = 12) on two non-linear measures of HR variability--detrended fluctuation analysis (DFA) and approximate entropy (ApEn)--in healthy male volunteers. 3. Glycopyrrolate decreased the mean (+/-SD) ApEn from 1.46 +/- 0.18 to 0.85 +/- 0.24 (P = 0.001 in comparison with the control group), and increased the short-term (alpha 1) and intermediate-term (alpha 2) fractal scaling exponents of DFA, alpha 1 from 0.96 +/- 0.19 to 1.43 +/- 0.29 (P = 0.003) and alpha 2 from 1.13 +/- 0.10 to 1.34 +/- 0.14 (P < 0.001). 4. Decrease in fixed respiration rate from 15 to 6 breaths min-1 increased alpha 1 from 0.83 +/- 0.25 to 1.18 +/- 0.27 (P < 0.001), but decreased alpha 2 from 0.88 +/- 0.09 to 0.45 +/- 0.17 (P < 0.001) and ApEn from 1.26 +/- 0.12 to 1.10 +/- 0.14 (P = 0.028). Rapid breathing (24 min-1) had no influence on these non-linear measures of HR variability. Hyperventilation (15 min-1, tidal volume increased voluntarily by 0.5 l) decreased alpha 1 from 0.83 +/- 0.25 to 0.66 +/- 0.28 (P = 0.002) but did not affect alpha 2 or ApEn. 5. To conclude, vagal blockade alters the fractal scaling properties of R-R intervals (alpha 1, alpha 2) and reduces the complexity (ApEn) of HR behaviour. Both the fractal and complexity measures of HR variability can also be influenced by changes in the breathing pattern.

Time domain, geometrical and frequency domain analysis of cardiac vagal outflow: effects of various respiratory patterns.

The purpose of this study was to compare the applicability of four different measures of heart rate variability (HRV) in the assessment of cardiac vagal outflow, with special reference to the effect of breathing pattern. The anticholinergic effects of an intravenous glycopyrrolate infusion (5 microg x kg(-1) x h(-1) for 2 h) during spontaneous and controlled (15 min(-1)) breathing rate were investigated in eight volunteers, and the effects of different fixed breathing rates (6-15-24 min(-1)) and hyperventilation in 12 subjects. Cardiac vagal activity was assessed by ECG recordings in which the following measures of HRV were computed: the high-frequency (HF) spectral component, the instantaneous RR interval (RRI) variability (SD1) analysed from the Poincaré plots, the percentage of differences between successive RRIs greater than 50 ms (pNN50), and the square root of the mean squared differences of successive RRIs (RMSSD). On average, glycopyrrolate reduced the HF spectral component by 99.8%, SD1 by 91.3%, pNN50 by 100% and RMSSD by 97.0%. The change of breathing pattern from controlled to spontaneous decreased significantly the HF component and pNN50, but did not affect SD1 or RMSSD. Rapid breathing rate (24 min(-1)) decreased the HF component, but had no effects on the other measures. A controlled breathing rate is needed for a reliable assessment of cardiac vagal outflow by the spectral analysis technique. The quantitative geometrical analysis of short-term RRI variability from the Poincaré plots and the time domain measure RMSSD were not significantly affected by changes in the breathing rate, suggesting that these indices are more suitable for the measurement of cardiac vagal outflow during the 'free-running' ambulatory conditions.

Asthma, asthma medication and autonomic nervous system dysfunction.

Asthma is associated with autonomic nervous imbalance: an increased bronchial sensitivity to cholinergic constrictors and possibly a decreased sensitivity to beta2-adrenergic dilators have been reported in this disease. Also, non-adrenergic and non-cholinergic (NANC) mediators have a small regulatory effect on airway function. These mediators contribute to the pathogenesis of asthma not only by regulating smooth muscle tone in the airways but also by affecting pulmonary blood flow, endothelial permeability and airway secretions. In many studies increased parasympathetic responsiveness has been associated with clinical asthma or the worsening of asthma in adults. However, most of the studies in children have not found association between autonomic dysfunction and asthma. Therefore, the autonomic dysfunction in asthma may be related to more advanced disease or long-term asthma medication in adults. This article briefly reviews the relationships between airway inflammation, beta2-agonist, anticholinergic and glucocorticoid medication as well as autonomic nervous function in asthma.

Cardiac positron emission tomography imaging with [11C]hydroxyephedrine, a specific tracer for sympathetic nerve endings, and its functional correlates in congestive heart failure.

The integrative mechanisms of autonomic dysfunction in congestive heart failure (CHF) remain poorly understood. We sought to study cardiac retention of [11C]hydroxyephedrine (HED), a specific tracer for sympathetic presynaptic innervation, and its functional correlates in CHF. Thirty patients with mild to moderate heart failure underwent resting cardiac HED positron emission tomography imaging, spectrum analysis testing of systolic pressure and heart rate variability in the resting supine and 70 degrees head-up tilt positions, and testing of baroreflex sensitivity. Compared with control subjects, global myocardial HED retention index was reduced by 30% (p <0.01) in patients with CHF. The HED retention index did not correlate significantly with heart rate variability. However, it correlated with baroreflex sensitivity at rest (r = 0.43, p = 0.05) and with systolic pressure low-frequency (0.03 to 0.15 Hz) variability at head-up tilt (r = 0.76, p <0.01), as well as with low-frequency systolic pressure variability response from baseline to tilt (r = 0.75, p <0.01). We conclude that cardiac HED retention is reduced in patients with CHF. This correlates with blunted vascular sympathetic effector responses during posture-induced reflex activation and baroreflex control of heart rate, suggesting an interdependence between cardiac presynaptic innervation abnormalities and neural mechanisms important to blood pressure maintenance in CHF.

Effects of tocolytic treatment with ritodrine on cardiovascular autonomic regulation.

OBJECTIVE: To study the acute effects of tocolytic treatment with intravenous ritodrine on cardiovascular autonomic regulation. DESIGN: Validated methods to assess cardiovascular autonomic nervous function-heart rate and blood pressure variability and vagal cardiac baroreflex sensitivity-were measured before and during ritodrine infusion. SETTING: Turku University Central Hospital, Turku, Finland. SAMPLE: Twelve pregnant women admitted to hospital for threatened preterm labour. METHODS: Electrocardiogram and continuous noninvasive finger blood pressure signals were recorded in each woman, resting in a supine position. Autoregressive spectrum analysis was used to quantify short term heart rate and blood pressure variability. Vagal cardiac baroreflex sensitivity was measured as the bradycardia response to an intravenous bolus injection of phenylephrine. MAIN OUTCOME MEASURES: Vagal cardiac baroreflex sensitivity and spectrum analysis indices of short term heart rate and blood pressure variability. RESULTS: Ritodrine significantly decreased vagal cardiac baroreflex sensitivity as well as total (0.00-0.40 Hz), low frequency (0.04-0.15 Hz) and high frequency (0.15-0.40 Hz) power bands of the heart rate variability spectrum. Ritodrine significantly increased mean heart rate and the low frequency power band of the systolic blood pressure variability spectrum. CONCLUSIONS: In pregnant women with threatened preterm labour intravenous administration of ritodrine decreases vagal cardiac baroreflex sensitivity and vagal modulation of heart rate, and increases sympathetically mediated blood pressure variability. Decreased baroreflex sensitivity and heart rate variability are known to be associated with a poor prognosis in some patient groups, so the effects of ritodrine tocolysis may be unfavourable in women with impaired circulatory homeostasis.

Altered cardiovascular autonomic regulation after salmeterol treatment in asthmatic children.

The effects of therapeutic 4 weeks' inhaled salmeterol treatment on the cardiovascular and respiratory autonomic nervous regulation was studied in 11 asthmatic children using inhaled corticosteroid medication. The study followed a randomized, double-blind, placebo-controlled cross-over design. The salmeterol dose was 50 micrograms twice daily. The 4-week salmeterol treatment increased baseline heart rate, low-frequency/high-frequency (LF/HF) variability ratio of R-R intervals, LF variability of systolic arterial pressure (SAP) and maximum tidal volume during the deep breathing test, as well as morning and evening peak expiratory flow (PEF) values. The 4-week salmeterol treatment decreased baseline HF variability of R-R intervals. As a response to the acute 600 micrograms of salbutamol, the changes in heart rate, HF variability of R-R intervals and diastolic blood pressure were significantly smaller after 4 weeks' salmeterol treatment. In conclusion, 4 weeks' therapeutic salmeterol treatment decreases basal cardiovagal reactivity, increases sympathetic dominance in the cardiovascular autonomic balance and improves pulmonary function. A tolerance develops in the cardiovascular response but not in the bronchodilatory response.

The dose-response effects of terbutaline on the variability, approximate entropy and fractal dimension of heart rate and blood pressure.

AIMS: To study the dose-response effects of intravenous terbutaline on the cardiovascular and respiratory autonomic nervous regulation. METHODS: The study followed a randomized, placebo-controlled crossover design in six healthy adult volunteers. The terbutaline dose ranged from 10 to 30 microg min(-1) We continuously measured electrocardiogram, finger systolic arterial pressure (SAP) and flow-volume spirometry in supine and upright positions at baseline and during 3 h drug infusion. The periodic variability components of R-R intervals (time between successive heart beats) and SAP in relation to respiration were assessed using spectral analysis techniques. The regularity of the time series was assessed by approximate entropy (ApEn) and the convolutedness by fractal dimension (FD). RESULTS: Terbutaline dose-dependently decreased total variability of R-R intervals, low frequency (LF) variability of R-R intervals (10 s waves), high frequency (HF) variability of R-R intervals (respiratory variability), total variability of SAP, HF variability of SAP, baroreflex sensitivity, plasma potassium concentration, approximate entropy of R-R interval and of SAP as well as fractal dimension of R-R interval. Terbutaline dose-dependently increased heart rate, LF/HF ratios of R-R intervals and of SAP, LF variability of SAP, minute ventilation and plasma terbutaline concentration. CONCLUSIONS: Terbutaline infusion decreases parasympathetic cardiovascular reactivity, baroreflex sensitivity, dimensionality of heart rate and plasma potassium concentration; it increases sympathetic dominance in cardiovascular autonomic balance, minute ventilation, and the regularity of heart rate and blood pressure time series.

Altered cardiovascular autonomic regulation after 2-week inhaled salbutamol treatment in asthmatic children.

UNLABELLED: We studied the effects of therapeutic 2-week inhaled salbutamol treatment on the cardiovascular and respiratory autonomic nervous regulation in eight children with asthma. In this randomized, double-blind, placebo-controlled crossover study our test subjects inhaled 200 microg salbutamol or placebo thrice daily for 14 days. After the 14-day treatment we continuously measured electrocardiogram, finger systolic arterial pressure (SAP) and flow-volume spirometry at baseline and the response to a single 600 microg salbutamol inhalation. The periodic variability components of R-R intervals (the time between successive heart beats) and SAP in relation to respiration were assessed using spectral analysis. Two-week salbutamol treatment increased baseline low frequency (LF) variability (P < 0.05) and low frequency/high frequency (LF/HF) variability ratio of R-R intervals (P < 0.05) when compared to the placebo treatment. As a response to the single salbutamol inhalation the increase in LF/HF ratio of R-R intervals was smaller after the 2-week salbutamol treatment (P < 0.01). No significant differences were found in the bronchodilatory response after the treatment period. CONCLUSION: Two-week salbutamol treatment shifts the cardiovascular autonomic regulation to a new level characterized by greater sympathetic responsiveness and slight beta2-receptor tolerance. Because these effects were evident 18 h after cessation of the therapy they are likely to reflect the adaptation of organ responses to regular therapy or altered central autonomic regulation rather than direct drug effect. A slight tolerance developed in the sympathovagal cardiac response but not in the bronchodilatory response.

The acute effects of inhaled salbutamol on the beat-to-beat variability of heart rate and blood pressure assessed by spectral analysis.

AIMS: We wanted to study the effects of a 600 micrograms inhaled salbutamol dose on the cardiovascular and respiratory autonomic nervous regulation in eight children suffering from bronchial asthma. METHODS: In this randomized, double-blind, placebo-controlled, crossover study we continuously measured electrocardiogram, finger systolic arterial pressure (SAP) and flow-volume spirometry at baseline as well as 20 min and 2 h after the drug inhalation. The R-R interval (the time between successive heart beats) and SAP variabilities were assessed by using spectral analysis. Baroreflex sensitivity was assessed by using cross-spectral analysis. RESULTS: Salbutamol significantly decreased the total and low frequency (LF) variability of R-R intervals as well as the high frequency (HF) variability of R-R intervals and of SAP. Salbutamol significantly increased the LF/HF ratio of R-R intervals and of SAP, minute ventilation, heart rate and forced pulmonary function in comparison with placebo. The weight of the subjects significantly correlated positively with baroreflex sensitivity and negatively with heart rate after the salbutamol inhalation. CONCLUSIONS: We conclude that the acute salbutamol inhalation decreases cardiovagal nervous responsiveness, increases sympathetic dominance in the cardiovascular autonomic balance, and has a tendency to decrease baroreflex sensitivity in addition to improved pulmonary function.