Exhaled nitric oxide in symptomatic children at preschool age predicts later asthma.

BACKGROUND: Prediction of asthma in young children with respiratory symptoms is hampered by the lack of objective measures applicable in clinical routine. In this prospective study in a preschool children cohort, we assessed whether the fraction of exhaled nitric oxide (FeNO), a biomarker of airway inflammation, is associated with asthma at school age. METHODS: At baseline, IgE and eosinophils were measured in the blood, and FeNO was measured offline in 391 children aged 3-47 months with lower airway symptoms. We developed an asthma predictive index (API) including high FeNO as major criterion. At follow-up, primary outcome was physician-diagnosed asthma based on standardized interviews in those children reaching school age (n = 166). RESULTS: FeNO was significantly elevated in those children with later asthma (68/166) as compared to children not developing asthma. Median (IQR) FeNO was 10.5 (6.6-17.2) vs. 7.4 (5.3-10.3) ppb. Per 5 ppb FeNO increase, the odds ratio (95% CI) for asthma increased by 2.44 (1.61-3.70) without changing when adjusting for confounders. Using the new API, children scored at risk had 58.0% probability for later asthma, whereas the negative predictive value was 78.2%, which was comparable to the classical API. CONCLUSIONS: In this cohort of high-risk preschool children, elevated FeNO is associated with increased risk for school-age asthma. The new API including FeNO identifies children at risk of later asthma comparably to the classical API, but does not require blood sampling.

[Intermittent or persistent rhinitis in children and adolescents with Asthma: «the Swiss LARA paediatrics survey¼]. / Intermittierende oder Persistierende Rhinitis bei Kindern und Jugendlichen mit Asthma: «The Swiss LARA paediatrics survey¼

Asthma and allergic rhinitis are chronic inflammatory airway diseases which often occur concomitantly. The objective of the LARA program was to identify the comorbidities and characteristics of asthma (A), intermittent or persistent rhinitis (IPR) and physician defined atopic dermatitis (AD) in 6- to 16-year old asthmatic Swiss children and adolescents. Overall, 126 general practitioners and paediatricians collected the data of 670 asthmatics. Approximately one third of the asthmatic children in Switzerland had well-controlled asthma. Almost two thirds of these asthmatics suffered from concomitant IPR. The latter presented with significantly less symptoms while the treatment rates with inhaled corticosteroids (approximately 90%) and leukotriene-receptorantagonists (approximately 50%) were comparable. However, there were almost twice as many passive smokers in the less well-controlled group. The prevalence of AD was similar in both groups. IPR and AD may play an important role as risk factors in the future development of asthma.

Predictors of asthma control in everyday clinical practice in Switzerland.

OBJECTIVE: To identify predictors of improved asthma control under conditions of everyday practice in Switzerland. RESEARCH DESIGN AND METHODS: A subgroup of 1380 patients with initially inadequately controlled asthma was defined from a cohort of 1893 asthmatic patients (mean age 45.3 + or - 19.2 years) recruited by 281 office-based physicians who participated in a previously-conducted asthma control survey in Switzerland. Multiple regression techniques were used to identify predictors of improved asthma control, defined as an absolute decrease of 0.5 points or more in the Asthma Control Questionnaire between the baseline (V1) and follow-up visit (V2). RESULTS: Asthma control between V1 and V2 improved in 85.7%. Add-on treatment with montelukast was reported in 82.9% of the patients. Patients with worse asthma control at V1 and patients with good self-reported adherence to therapy had significantly higher chances of improved asthma control (OR = 1.24 and 1.73, 95% CI 1.18-1.29 and 1.20-2.50, respectively). Compared to adding montelukast and continuing the same inhaled corticosteroid/fixed combination (ICS/FC) dose, the addition of montelukast to an increased ICS/FC dose yielded a 4 times higher chance of improved asthma control (OR = 3.84, 95% CI 1.58-9.29). Significantly, withholding montelukast halved the probability of achieving improved asthma control (OR = 0.51, 95% CI = 0.33-078). The probability of improved asthma control was almost 5 times lower among patients in whom FEV(1) was measured compared to those in whom it was not (OR = 0.23, 95% CI = 0.09-0.55). Patients with severe persistent asthma also had a significantly lower probability of improved control (OR = 0.15, 95% CI = 0.07-0.32), as did older patients (OR = 0.98, 95% CI = 0.97-0.99). Subgroup analyses which excluded patients whose asthma may have been misdiagnosed and might in reality have been chronic obstructive pulmonary disease (COPD) showed comparable results. CONCLUSIONS: Under conditions of everyday clinical practice, the addition of montelukast to ICS/FC and good adherence to therapy increased the likelihood of achieving better asthma control at the follow-up visit, while older age and more severe asthma significantly decreased it.

Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach.

There is poor agreement on definitions of different phenotypes of preschool wheezing disorders. The present Task Force proposes to use the terms episodic (viral) wheeze to describe children who wheeze intermittently and are well between episodes, and multiple-trigger wheeze for children who wheeze both during and outside discrete episodes. Investigations are only needed when in doubt about the diagnosis. Based on the limited evidence available, inhaled short-acting beta(2)-agonists by metered-dose inhaler/spacer combination are recommended for symptomatic relief. Educating parents regarding causative factors and treatment is useful. Exposure to tobacco smoke should be avoided; allergen avoidance may be considered when sensitisation has been established. Maintenance treatment with inhaled corticosteroids is recommended for multiple-trigger wheeze; benefits are often small. Montelukast is recommended for the treatment of episodic (viral) wheeze and can be started when symptoms of a viral cold develop. Given the large overlap in phenotypes, and the fact that patients can move from one phenotype to another, inhaled corticosteroids and montelukast may be considered on a trial basis in almost any preschool child with recurrent wheeze, but should be discontinued if there is no clear clinical benefit. Large well-designed randomised controlled trials with clear descriptions of patients are needed to improve the present recommendations on the treatment of these common syndromes.

Longitudinal monitoring of pediatric cystic fibrosis lung disease using nitrite in exhaled breath condensate.

Cystic fibrosis (CF) lung disease is characterized by airway inflammation and airway infection. Nitrites in exhaled breath condensate (EBC-NO(2)(-)) have been shown to be increased in children and adults with CF compared to healthy controls suggesting its use as a measure of airway inflammation. This longitudinal study aimed to evaluate if repeated measurements of EBC-NO(2)(-) are helpful in monitoring CF lung disease activity in children. Thirty-two children with mild CF lung disease (age 10.6 +/- 3.3 years) were recruited in two study centers. Follow-up visits occurred every 3 months over a period of 1 year with a total of five visits. Each visit included a clinical assessment incorporating a modified Shwachman-Kulczycki (SK) score, spirometry, an oropharyngeal swab, or sputum sample for bacterial analysis and an EBC sample analyzed for NO(2)(-) using a spectrophotometric assay. Furthermore at the first and the last visit a chest radiograph was done and scored (Chrispin-Norman (CN) score). There was no correlation of EBC-NO(2)(-) and parameters of spirometry, SK-score, or CN-score. Furthermore, increased EBC-NO(2)(-) levels did not predict subsequent pulmonary exacerbations. We conclude that repeated measurements of EBC-NO(2)(-) are not helpful in the longitudinal monitoring of mild CF lung disease in children.

Inducible NO synthase expression is low in airway epithelium from young children with cystic fibrosis.

BACKGROUND: This is the first study to measure inducible nitric oxide synthase (iNOS) gene and protein expression quantitatively in primary epithelial cells from very young children with cystic fibrosis (CF). Low levels of exhaled nitric oxide (NO) in CF suggest dysregulation of NO production in the airway. Due to the importance of NO in cell homeostasis and innate immunity, any defect in the pathway associated with CF would be a potential target for treatment. METHODS: Cells were obtained by tracheobronchial brushing from 40 children with CF of mean (SD) age 2.1 (1.5) years and from 12 healthy non-atopic children aged 3.4 (1.2) years. Expression of iNOS mRNA was measured using quantitative PCR and iNOS protein by immunofluorescence and Western blot analysis. RESULTS: Inducible NOS mRNA expression was significantly lower in CF patients with and without bacterial infection than in healthy children (0.22 and 0.23 v 0.76; p=0.002 and p=0.01, respectively). Low levels of iNOS gene expression were accompanied by low levels of iNOS protein expression as detected by Western blot analysis. CONCLUSIONS: These results support the findings of previous studies in adult patients with advanced disease, cell lines, and animal models. Our findings reflect the situation in children with mild lung disease. They indicate that low iNOS expression may be an innate defect in CF with potential consequences for local antimicrobial defence and epithelial cell function and provide evidence for an approach to treatment based on increasing epithelial NO production or the sensitivity of NO dependent cellular processes.

The effect of montelukast on lung function and exhaled nitric oxide in infants with early childhood asthma.

Effective treatment of respiratory symptoms, airway inflammation and impairment of lung function is the goal of any asthma therapy. Although montelukast has been shown to be a possible add-on therapy for anti-inflammatory treatment in older children, its efficacy in infants and young children is not well known. The aim of this study was to investigate its effect in infants and young children with early childhood asthma. In a prospective randomised double-blind placebo-controlled study, 24 young children (10-26 months) with wheeze, allergy and a positive family history of asthma consistent with the diagnosis of early childhood asthma were randomised to receive montelukast 4 mg or placebo. The forced expiratory volume in 0.5 seconds (FEV0.5) was measured using the raised volume rapid thoracic compression technique, and fractional exhaled nitric oxide (FeNO) and symptom scores were determined. No change was noted in FEV0.5, FeNO or symptom score in the placebo group following the treatment period. In contrast, significant improvements in mean+/-SD FEV0.5 (189.0+/-37.8 and 214.4+/-44.9 mL before and after treatment, respectively), FeNO (29.8+/-10.0 and 19.0+/-8.5 ppb) and median symptom score (5.5 and 1.5) were noted following treatment with montelukast. In conclusion, montelukast has a positive effect on lung function, airway inflammation and symptom scores in very young children with early childhood asthma.

Measurement of lung volume and ventilation distribution with an ultrasonic flow meter in healthy infants.

Small airway disease in infants is characterised by abnormal lung volume and uneven ventilation distribution. An inert tracer gas washin/washout technique using a pulsed ultrasonic flow meter is presented to measure functional residual capacity (FRC) and ventilation distribution in spontaneously breathing and unsedated infants. With a pulsed ultrasound sent through the main stream of the flow meter, flow, volume and MM of the breathing gas can be calculated. Sulphur hexafluoride was used as a tracer gas. In a mechanical lung model (volume range 53-188 mL) and in 12 healthy infants (aged 38.3+/-9.2 days; mean+/-SD) accuracy and reproducibility of the technique was assessed. Indices of ventilation distribution such as alveolar-based mean dilution number (AMDN) and pulmonary clearance delay (PCD) were calculated. Mean error of volume measurement in the lung model was 0.58% (coefficient of variance (CV) 1.3%). FRC was in the low predicted range for normal infants (18.0+/-2.0 mL x kg(-1)) and highly reproducible (5.5+/-1.7% intra-subject CV). AMDN was 1.63+/-0.15 and PCD was 52.9+/-11.1%. Measurement of functional residual capacity and ventilation distribution using a sulphur hexafluoride washin/washout and an ultrasonic flow meter proved to be highly accurate and reproducible in a lung model and in healthy, spontaneously breathing and unsedated infants.

Dosage regimens for inhaled therapy in children should be reconsidered.

In current asthma guidelines, dosage regimens for inhalation therapy in children are based on adult doses and are generally titrated per kilogram of bodyweight or per square metre of body surface area. However, these recommendations do not correspond well with current knowledge of aerosol therapy in childhood. Lung deposition of the aerosolised drug is the key determinant for clinical efficacy and for systemic side effects of inhalation therapy. Lung deposition increases with age, whereas lung deposition expressed as a percentage per kilogram bodyweight is age-independent. This finding is explained by the self-regulating effect of age-dependent airway anatomy on lung deposition. Therefore, it is more likely that adult doses translate into paediatric doses only by virtue of the differences in self-limiting pulmonary deposition when using the same absolute nominal doses of the medication. Adapting the adult dose to a paediatric dose calculated on body size might be unnecessary and could lead to insufficient pulmonary deposition of medication. These findings suggest that dosage regimens for inhalation therapy for children may have to be reconsidered, and should be determined from dose-ranging studies rather than calculated from adult doses based on body size.

Contribution of nasal pathways to low frequency respiratory impedance in infants.

BACKGROUND: In infants the impedance of the nasal pathways (Zn) is a significant proportion of the total respiratory impedance (Zrs). METHODS: In 11 infants Zrs was partitioned into Zn and lower respiratory system impedance (Zlrs) using a nasal catheter. A low frequency oscillatory signal (0.5-20 Hz) was applied during a pause in breathing to obtain the impedance spectra. A model of the respiratory system containing an airway and tissue compartment was then fitted to Zrs and Zlrs. The airway compartment consisted of a frequency independent resistance (R) and inertance (I), while the tissue compartment was described by coefficients of tissue damping (G) and elastance (H). RESULTS: Zrs could be reliably partitioned into Zn and Zlrs. The nasal pathway acted as a purely resistive-inertive impedance and contributed approximately half of the airway resistance (mean (SE) 44.6 (4.9)%) and most of the respiratory system inertance (71.7 (3.5)%). CONCLUSIONS: In studies investigating changes in airway resistance in nasally breathing infants, the separation of nasal and lower respiratory system mechanics will increase the sensitivity of the tests.

Elevated nitrite in breath condensates of children with respiratory disease.

The aim of the study was to determine the differences in nitrite, in the exhaled breath condensates of healthy children and those children with asthma, cystic fibrosis (CF) and nonasthmatic, episodic cough. Breath condensates were obtained from 66 children (43 males:23 females, 3.1-16 yrs) and included 29 asthmatics, 12 clinically stable CF patients, 12 children with cough but not asthma and 13 healthy volunteers. The collected condensate was assayed colourimetrically using the Griess reaction to determine nitrite concentrations. Patients with CF (median: 5-95% percentiles; 2.02: 0.43-6.37 microM) or asthma (2.10: 0.63-5.45 microM) had significantly higher levels of nitrite compared to healthy subjects (0.41: 0.13-1.83 microM; p<0.05) or subjects with cough (0.75: 0.03-1.75 microM; p<0.05). Airway inflammation, as assessed by the nitrite in breath condensates, is present in children with asthma and cystic fibrosis, but not those children with nonasthmatic, episodic cough. Nitrite can be conveniently, cheaply and rapidly measured in breath condensates of children as young as 3 yrs of age, and may prove useful for the assessment of airway inflammation in children with respiratory disease.

Wearing a noseclip improves nebulised aerosol delivery.

OBJECTIVE: The efficiency of nebulised aerosol delivery is limited due to drug retained within the nebuliser, and due to a poor ratio between inspiratory drug delivery and expiratory drug loss. Several technical approaches have improved the ratio between inspiratory aerosol delivery and expiratory aerosol loss. In our pilot study we aimed to investigate if wearing a noseclip during inhalation therapy improves the inspiratory versus expiratory ratio and hence, improves nebulised aerosol delivery. METHODS: Drug delivery was measured in thirteen subjects (7 males; age range 23-36 years) inhaling in random order nebulised aerosol through a mouthpiece once while wearing a noseclip and once without. RESULTS: Wearing a noseclip leads to an increase of 113% (SEM 23.5) in drug delivery and improves the inspiratory versus expiratory ratio (ratio 2.07 versus 0.75). CONCLUSIONS: We have shown that aerosol delivery is increased due to an improved inspiratory versus expiratory ratio when wearing a noseclip.

Factors affecting the efficiency of aerosol therapy with pressurised metered-dose inhalers through plastic spacers.

AIM: The main objective of this study was to compare the in vitro delivery of salbutamol from a chlorofluorocarbon(CFC)-propelled pressurised metered-dose inhaler (pMDI) versus a newly developed hydrofluoroalkane(HFA)-propelled pMDI through various spacers. In addition, we aimed to study the effect on bronchodilator response when using an optimal pMDI/spacer combination for aerosol delivery compared to a suboptimal combination. METHODS: Particle size distribution and output from salbutamol pMDIs containing either CFC propellants (Ventolin) or HFA propellants (Airomir) were measured using a multistage liquid impinger (MSLI) and compared to that through both detergent-coated (non-static) or untreated (static) large volume (Nebuhaler, Volumatic) and small volume (Aerochamber) plastic spacers. Flow-volume curves (FEV1) were obtained from twelve asthmatic children with known significant bronchodilator response (8 males), aged 13-17 years, randomly inhaling salbutamol from a CFC-pMDI through a static spacer (Nebuhaler) and from an HFA-pMDI through a non-static spacer (Nebuhaler). RESULTS: In vitro output of particles in the respirable range (< 6.8 microns) from HFA-pMDIs was significantly higher than that from CFC-pMDIs using various spacers. Removal of electrostatic charge increased output from CFC- and HFA-pMDIs through all spacers by 17-82%. The mean (SD) bronchodilator response after inhalation of salbutamol from a CFC-pMDI through a static spacer was 7.1% (6.3%) compared to 17.5% (7.9%) after inhalation from an HFA-pMDI through a non-static spacer (p = 0.002). CONCLUSIONS: Use of a newly developed HFA-propelled pMDI greatly improves drug delivery through spacers compared to a CFC-propelled pMDI. However, electrostatic charge in plastic spacers remains the key determinant limiting delivery of salbutamol from a pMDI through spacers, and can be reduced by soaking the spacer in a household detergent. Using an optimal pMDI/spacer combination leads to a significantly improved bronchodilator response.

Methacholine responsiveness in infants assessed with low frequency forced oscillation and forced expiration techniques.

BACKGROUND: The contribution of the pulmonary tissues to the mechanical behaviour of the respiratory system is well recognised. This study was undertaken to detect airway and lung tissue responses to inhaled methacholine (Mch) using the low frequency forced oscillation technique (LFOT). METHODS: The respiratory system impedance (Zrs, 0.5-20 Hz) was determined in 17 asymptomatic infants. A model containing airway resistance (Raw) and inertance (Iaw) and a constant phase tissue damping (G) and elastance (H) was fitted to Zrs data. Tissue hysteresivity (eta) was calculated as eta=G/H. The raised volume rapid thoracic compression technique (RVRTC) was used to generate forced expiratory volume in 0.5 seconds (FEV(0.5)). Lung function was determined at baseline and following inhaled Mch in doubling doses (0.25-16 mg/ml) until the maximal dose was reached or a fall of 15% in FEV(0.5) was achieved (PC(15)FEV(0.5)). The response to Mch was defined in terms of the concentration of Mch provoking a change in lung function parameters of more than two standard deviation units (threshold concentration). RESULTS: At PC(15)FEV(0.5) a response in Raw, Iaw, G, and eta, but not H, was detected (mean (SE) 61.28 (12.22)%, 95.43 (34.31)%, 46.28 (22.36)%, 44.26 (25.83)%, and -6.48 (4.94)%, respectively). No significant differences were found between threshold concentrations of LFOT parameters and FEV(0.5). CONCLUSIONS: Inhaled Mch alters both airway and respiratory tissue mechanics in infants.

Evaluation of the interrupter technique in healthy, unsedated infants.

The interrupter technique may be used to monitor respiratory resistance and does not require active patient cooperation, but has yet to be applied in unsedated, spontaneously breathing infants. The aim of this study was to determine if the interrupter technique is feasible in spontaneously breathing infants and to investigate the influence of facemask types and analysis techniques on the interrupter resistance (Rint). Rint was measured in 14 healthy, unsedated, sleeping infants (aged 38.4 (31-56) days (mean (range)). Paired measurements were made using large volume, compliant (Mcomp) and small volume, rigid (Mrigid) facemasks. Flow and pressure were measured at the airway opening prior to- and following a brief airway occlusion (500 ms). Rint was calculated using four previously reported analysis techniques. Rint could be measured in all infants. Mcomp, independent of the analysis method significantly underestimated Rint (p<0.001). The variability and magnitude of Rint were significantly influenced by the choice of analysis method. The conclusion is that the interrupter technique is feasible in spontaneously breathing, unsedated infants. Equipment design and analysis method significantly influences interrupter resistance. Studies standardizing equipment and identifying the most appropriate analysis technique in this age group are needed.

Airway and respiratory tissue mechanics in normal infants.

Low-frequency respiratory impedance (Zrs) was measured by applying a forcing signal, between 0.5 and 21 Hz at a transrespiratory pressure of 20 cm H(2)O, in a cross-sectional study of 37 normal infants. A model containing an airway resistance (Raw) and inertance (Iaw) and a tissue damping (G) and elastance (H) was fitted to the individual Zrs. Forced expiratory volume in 0.5 second (FEV(0.5)) was determined using the raised volume rapid thoracic compression technique. Multivariate regression analysis was used to analyze the relationships between the lung function parameters and length. Both airway and tissue parameters showed a decreasing quadratic relationship with increasing length. FEV(0.5) showed an increasing cubic relationship with length. A family history of asthma was found to have a negative effect on Raw, H, and FEV(0.5).

Reducing electrostatic charge on spacer devices and bronchodilator response.

AIMS: Plastic spacers are widely used with pressurized metered dose inhalers (pMDI). Reducing electrostatic charge by washing spacers with detergent has been shown to greatly improve in vitro and in vivo drug delivery. We assessed whether this finding is associated with an improved bronchodilator response in adult asthmatics. METHODS: Twenty subjects (age 18-65 years) with a known bronchodilator response inhaled in random order salbutamol from a pMDI (Ventolin) through an untreated new spacer (Volumatic) and through a detergent washed spacer. Patients received the following doses of salbutamol via pMDI at 20 min intervals: 100 microg, 100 microg, 200 microg, 400 microg, 800 microg. Spirometry, heart rate and blood pressure were checked prior to each dose and 20 min after the last dose. RESULTS: There were no differences between baseline forced expiratory volume in 1 s (FEV1) using either spacer (2.61+/-0.56 and 2.52+/-0.45 l, untreated and treated with detergent, respectively; mean +/- s.d.). The provocation dose required to cause a clinically significant improvement of 10% in FEV1 (PD10) was significantly lower when the detergent treated spacer was used (1505 +/-1335 and 430+/-732 microg, untreated and treated, respectively, P<0.002). CONCLUSIONS: We have demonstrated an improvement in bronchodilator response, in adult asthmatics, after reducing the electrostatic charge in a spacer device by washing it with ordinary household detergent. This finding stresses the importance of an optimal choice of delivery device for asthma medication.

High-percentage lung delivery in children from detergent-treated spacers.

Pressurized metered-dose inhalers attached to spacers are now the most common form of delivery of anti-asthma medication in children. However, no reliable data are available of how much drug reaches the lungs in children of different ages. This information is crucial, as it determines the efficacy of therapy. In this study, we present information on the amount of drug reaching the lungs in children from a pressurized metered-dose inhaler attached to a detergent-coated spacer. We studied 18 asthmatic children inhaling radiolabeled salbutamol through detergent treated spacers to minimize electrostatic charge on the spacer wall. Lung deposition was much higher than expected when using detergent-coated spacers. Mean (SD) lung deposition, expressed as a percentage of the total actuated dose (five actuations), was 16.4% (5.5) in younger children inhaling through a small volume spacer, and 28.2% (6.7) and 41.8% (3. 8) in older children inhaling with different breathing patterns through a large volume spacer. These findings have major implications for dosage regimens for inhaled anti-asthma medication in children. Lower doses may be sufficient for adequate drugs delivered through spacers treated for static to achieve a desired clinical response.

Pulmonary vascular congestion selectively potentiates airway responsiveness in piglets.

The influence of pulmonary vascular congestion on the response of the airways and lung tissue to low doses of inhaled methacholine (MCh) was studied by inflating a balloon catheter in the left atrium of the heart in six piglets, with an additional five piglets serving as control animals. Congestion alone resulted in small increased in baseline airway (Raw) (14.6 +/- 3.7%) and tissue (Rti) resistance (8. 1 +/- 6.5%). Low-dose inhaled MCh (0.3 mg/ml) increased Raw and Rti in the control group by 10.8 +/- 10.3% and 42.2 +/- 29.5%, respectively. The increase in Raw with MCh in the presence of vascular engorgement was significantly greater (67.8 +/- 18.9%) but the increase in Rti (38.1 +/- 13.2%) was similar to that seen in the control group. Morphometric measurements were performed on transverse sections of large and small airways from nine additional piglets (three congested only, three MCh only, and three congestion plus MCh). The thickness of the inner airway wall was similar in all groups. Compared with MCh only piglets, the thickness of the outer airway wall (between the outer border of the smooth muscle and the surrounding lung parenchyma) was increased (p < 0.05) in engorged only and engorged plus MCh piglets. Compared with MCh only and engorgement only, the amount of airway smooth muscle shortening was greater (p < 0.05) in all airway size groups in piglets that underwent engorgement plus MCh challenge. The results of this study demonstrate that pulmonary vascular engorgement, induced by increased left atrial pressure, selectively enhances the airway, but not the parenchymal, response to inhaled MCh. These changes are associated with increased thickness of the outer airway wall in response to vascular congestion, suggesting that uncoupling of the mechanical interdependence between the airway smooth muscle and the lung parenchyma may have occurred. Mechanical uncoupling may reduce the load opposing smooth muscle shortening resulting in increased airway narrowing in response to low doses of inhaled methacholine.