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Rationale: Lung ultrasound is useful in critically ill patients with acute respiratory failure. Given its characteristics, it could also be useful in extremely preterm infants with evolving chronic respiratory failure, as we lack accurate imaging tools to monitor them. Objectives: To verify if lung ultrasound can monitor lung aeration and function and has good reliability to predict bronchopulmonary dysplasia in extremely preterm neonates. Methods: A multicenter, international, prospective, longitudinal, cohort, diagnostic accuracy study consecutively enrolling inborn neonates with gestational age 30 +6 weeks or younger. Lung ultrasound was performed on the 1, 7, 14, and 28 days of life, and lung ultrasound scores were calculated and correlated with simultaneous blood gases and work of breathing score. Gestational age-adjusted lung ultrasound scores were created, verified in multivariate models, and subjected to receiver operator characteristics (ROC) analyses to predict bronchopulmonary dysplasia at 36 weeks postmenstrual age. Measurements and Main Results: Mean lung ultrasound scores are different between infants developing ( n  = 72) or not developing ( n  = 75) bronchopulmonary dysplasia ( P  < 0.001 at any time point). Lung ultrasound scores significantly correlate with oxygenation metrics and work of breathing at any time point ( P always < 0.0001). Gestational age-adjusted lung ultrasound scores significantly predict bronchopulmonary dysplasia at 7 (area under ROC curve, 0.826-0.833; P  < 0.0001) and 14 (area under ROC curve, 0.834-0.858; P  < 0.0001) days of life. Bronchopulmonary dysplasia severity and gestational age-adjusted lung ultrasound scores are significantly correlated at 7 and 14 days ( P always < 0.0001). Conclusions: Lung ultrasound scores allow monitoring of lung aeration and function in extremely preterm infants. Gestational age-adjusted scores significantly predict the occurrence of bronchopulmonary dysplasia, starting from the seventh day of life.

Rationale: Asthma treatment might improve when inhaled steroids are titrated on airway inflammation. Fractional exhaled nitric oxide (FeNO0.05), a marker of eosinophilic airway inflammation, can be measured at home., Objectives: We assessed daily FeNO0.05 telemonitoring in the management of childhood asthma., Methods: Children with atopic asthma (n = 151) were randomly assigned to two groups: FeNO0.05 plus symptom monitoring, or monitoring of symptoms only. All patients scored asthma symptoms in an electronic diary over 30 weeks; 77 received a portable nitric oxide (NO) analyzer. Data were transmitted daily to the coordinating centers. Patients were phoned every 3 weeks and their steroid dose was adapted according to FeNO0.05 and symptoms, or according to symptoms. Children were seen at 3, 12, 21, and 30 weeks for examination and lung function testing. The primary end point was the proportion of symptom-free days in the last 12 study weeks., Measurements and Main Results: Telemonitoring was feasible with reliable FeNO0.05 data for 86% of days, and valid diary entries for 79% of days. Both groups showed an increase in symptom-free days, improvement of FEV1 and quality of life, and a reduction in steroid dose. None of the changes from baseline differed between groups. The difference in symptom-free days over the last 12 weeks was 0.3% (P = 0.95; 95% confidence interval, -10 to 11%). There was a trend for fewer exacerbations in the FeNO0.05 group., Conclusions: Thirty weeks of daily FeNO0.05 and symptom telemonitoring was associated with improved asthma control and a lower steroid dose. We found no added value of daily FeNO0.05 monitoring compared with daily symptom monitoring only.

Rationale: Metabolomic analysis provides biochemical profiles of low-molecular-weight endogenous metabolites in biological fluids., Objectives: The aim of this study was to assess the feasibility of nuclear magnetic resonance (NMR)-based metabolomic analysis applied to exhaled breath condensate ("breathomics"). Information coming from NMR spectra was analyzed with a view to establish the NMR variables that best discriminate between children with asthma and healthy children., Methods: Twenty-five children with asthma (17 with persistent asthma treated with inhaled corticosteroids, 8 with intermittent asthma inhaled corticosteroid naive; age, 7-15 yr) and 11 healthy age-matched control subjects were enrolled. Every child performed exhaled nitric oxide measurement, spirometry, and condensate collection. Condensate samples were analyzed by means of NMR spectroscopy. Linear and partial least squares discriminant analyses were applied to data obtained from the NMR spectra., Measurements and Main Results: The combination of exhaled nitric oxide and FEV(1) discriminates children with asthma and healthy children with a success rate of approximately 81%, whereas selected signals from NMR spectra offer a slightly better discrimination (approximately 86%). The selected NMR variables derive from the region of 3.2 to 3.4 ppm, indicative of oxidized compounds, and from the region of 1.7 to 2.2 ppm, indicative of acetylated compounds., Conclusions: Metabolomics can be applied to exhaled breath condensate, leading to the characterization of airway biochemical fingerprints. The presence of acetylated compounds suggests new metabolic pathways that may have a role in asthma pathophysiology.

Rationale: Acute exposure to chlorine gas results in respiratory impairment, but few data are available on the pathobiology of the underlying lung damage., Objectives: To assess lung function and potential lung damage pathways in the acute phase and longitudinally over a 15-mo follow-up after acute chlorine exposure., Methods: Ten previously healthy children were accidentally exposed to chlorine gas at a swimming pool because of an erroneous servicing procedure. The fraction of nitric oxide in exhaled air (Fe(NO)), exhaled breath condensate compounds, and serum Clara cell-specific protein CC16 were repeatedly measured., Main Results: In the acute phase, all patients had respiratory distress (one child required mechanical ventilation) and reduced lung function (median and interquartile range: FVC, 51 [43-60]% predicted; FEV(1), 51 [46-60]% predicted). This was accompanied by low Fe(NO) (4.7 [3.9-7.9] ppb), high exhaled breath condensate leukotriene B(4) (LTB(4)) levels (24.4 [22.5-24.9] pg/ml), and increased serum CC16 levels (mean +/- SEM, 23.4 +/- 2.5 microg/L). Lung function returned to normal in 15 d (FVC, 97% predicted [82-108], and FEV(1), 92% predicted [77-102]). Fe(NO) reached normal values after 2 mo (12.6 [11.4-15] ppb), whereas LTB(4) levels were still increased (12 [9.3-17.1] pg/ml)., Conclusion: Children acutely exposed to chlorine in a swimming pool presented a substantial lung function impairment associated with biochemical exhaled breath alterations, represented mainly by an increase in LTB(4) and a reduction in Fe(NO). Although lung function and Fe(NO) improved within a few weeks, the increased levels of exhaled LTB(4) persisted for several months.

Bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, may be associated with long-term airflow limitation. Survivors of BPD may develop asthma-like symptoms in childhood, with a variable response to beta(2)-agonists. However, the pathologic pathways underlying these respiratory manifestations are still unknown. The aim of this study was to measure exhaled nitric oxide (FE(NO)) and lung function in a group of 31 school-age survivors of BPD. They showed variable degrees of airflow obstruction (mean FEV(1) 77.8 +/- 2.3% predicted) unresponsive to beta(2)-agonists in 72% of the subjects. Their FE(NO) values (geometric mean [95% confidence interval]: 7.7 [+/- 1.1] ppb) were significantly lower than in a group of healthy matched control subjects born at term (10.7 [+/- 1.1] ppb, p < 0.05) and a group of preterm children without BPD (9.9 [+/- 1.1] ppb, p < 0.05). The children with BPD were also compared with a group of 31 patients with asthma with a comparable airflow limitation (FEV(1) 80.2 +/- 2.1% predicted) and showed FE(NO) values four times lower than in those with asthma (24.9 [+/- 1.2] ppb, p < 0.001). In conclusion, unlike children with asthma, school-age survivors of BPD have airflow limitation associated with low FE(NO) values and lack of reversibility to beta(2)-agonists, probably as a result of mechanisms related to early life structural changes in the airways.

Oxidative stress is implicated in the pathogenesis of asthma, and clinical studies show an imbalance in the level of oxidants to the level of antioxidants in subjects with asthma. Aldehydes and glutathione are examples of biomarkers of oxidant-induced damage and antioxidant status in asthma, respectively. In the study, we applied analytical techniques based on liquid chromatography for the assessment of aldehydes and glutathione in the exhaled breath condensate of children with asthma and in control subjects without asthma. Twelve subjects with asthma were evaluated at exacerbation and after 5 days of therapy with prednisone. At exacerbation, malondialdehyde levels were higher in patients with asthma (30.2 +/- 2.4 nM) than in control subjects (19.4 +/- 1.9 nM, p = 0.002) and were reduced after steroid therapy (18.5 +/- 1.6 nM, p = 0.001). At exacerbation, glutathione levels were lower in subjects with asthma (5.96 +/- 0.6 nM) than in control subjects (14.1 +/- 0.8 nM, p < 0.0001) and were increased after the therapy (8.44 +/- 1.2 nM, p = 0.04). Malondialdehyde and glutathione both in subjects with asthma and control subjects were negatively correlated (r = -0.5, p = 0.001). The study shows that aldehydes and glutathione are detectable in the exhaled breath condensate of children with asthma and healthy children and that their levels are modified during asthma exacerbation and after a 5-day course of therapy with oral prednisone.

NO is increased in exhaled air of asthmatic patients, and may be used as a marker of airway inflammation. The online method is a standardized technique for measuring exhaled nitric oxide (ENO). However, this method has proven difficult for some children, who may have trouble maintaining a constant expiratory flow. The aim of this study was to validate a modified technique for online ENO measurement that utilizes a flow regulator to overcome the patient problem of having to actively maintain a constant expiratory flow. We measured ENO levels with two methods in 105 asthmatic and 10 healthy subjects, comparing the standardized (ST) single-breath method with a modified single-breath, flow-driven (FD) method. With the ST method and visual monitoring, the subjects inhaled NO-free air to TLC, and exhaled with a target flow of 50 ml/s. With the FD method, the subjects exhaled from TLC and flow was kept constant (50 ml/s) by the operator, using a flow regulator. The subjects were divided into two groups, one consisting of children aged 4 to 8 yr (n = 74) and the other of children aged 9 to 16 yr (n = 41). In the group aged 4 to 8 yr, 38 children (51%) were unable to perform the ST method, whereas only five children (7%) failed to perform the FD technique. In the group aged 9 to 16 yr, only four children (10%) were unable to perform the ST maneuver, and all successfully performed the FD maneuver. The mean concentrations of ENO in the 73 children who performed both types of maneuver were similar (36.1 +/- 3.4 [mean +/- SEM] ppb with the ST method and 33.8 +/- 3.3 ppb with the FD technique, p = NS) and were highly correlated with one another (r = 0.99, p < 0.0001). ENO values were significantly higher in steroid-naive than in steroid-treated asthmatic children. In conclusion, we describe a modified online method for measuring ENO that is simple, does not require active cooperation to maintain a constant expiratory flow, and can be easily performed by children from 4 to 5 yr of age onward.

Flow-volume loop evaluation yields considerable diagnostic information about adult patients with upper airway obstruction. No conclusive data support the reliability of this method in young children with noisy breathing. We used analysis of flow-volume loops at tidal breathing (TB-FV) as a first diagnostic approach to young children presenting with persistent noisy breathing (chronic stridor and/or wheezing). Flexible fiberoptic bronchoscopy was performed to establish a conclusive diagnosis and was used to verify the accuracy of the preliminary functional localization of the airway obstruction causing noisy breathing. The physician conducting pneumotachography was blinded to the bronchoscopic findings in the study, and the investigators conducting bronchoscopy were blinded to the pneumotachographic findings. Through a 6-yr period, 113 consecutive young children (ranging in age from 15 to 48 mo) with noisy breathing were enrolled in the study. Three morphologically abnormal TB-FV patterns, as compared with the normal round-shaped TB-FV loops obtained with 15 healthy children, were identified in 110 patients. A TB-FV pattern of inspiratory fluttering was found in 26 subjects and in the first 3 yr of the study was always associated with an endoscopic diagnosis of isolated laryngomalacia. Subsequently, this pattern was used to diagnose isolated laryngomalacia in 18 other infants, in whom endoscopy was avoided. Of infants with endoscopic evidence of airway obstruction ranging from the glottis to the mainstem bronchi (49 subjects), all but three showed a TB-FV loop pattern characterized by expiratory-limb flattening. A concave expiratory loop, with early expiratory peak flow and low flow at low volume, was invariably associated with peripheral bronchoconstriction, without endoscopic evidence of anatomic abnormalities (20 cases). In conclusion, TB- FV loop analysis is a noninvasive, accurate method of establishing the site of airway obstruction in young children with recurrent stridor and/or wheezing. Clinical use of this method may provide interesting pathophysiologic information and may be useful in addressing the diagnostic management of such children.

It is known that exhaled nitric oxide (ENO) is increased in asthmatic individuals, probably as an expression of airway inflammation, but no studies have been reported of ENO and exercise-induced bronchoconstriction (EIB). We assessed the effect of a treadmill exercise challenge on ENO concentration in 24 asthmatic children aged 11.2 +/- 0.4 yr (mean +/- SEM). According to the presence or absence of EIB, the children were divided into an EIB group (n = 10) and a non-EIB group (n = 14). ENO was measured with a single-breath reservoir technique. FEV(1), ENO, and heart rate were measured at baseline and 1, 6, 12, and 18 min after the end of exercise. We also measured ENO in 18 healthy control children aged 10.8 +/- 0.6 yr, of whom nine underwent an exercise challenge identical to that of the asthmatic children. After the exercise test, the mean decrease in FEV(1) was 34% in the EIB group and 5% in the non-EIB group. The EIB group had higher baseline ENO values (12.3 +/- 1.6 ppb) than the healthy children (6.1 +/- 0.2 ppb) (p < 0.01). The time course of ENO was similar in the EIB, non-EIB, and control groups, with no significant changes after exercise (p = NS). In the overall group of asthmatic children there was a significant correlation (r = 0.61, p < 0.01) between baseline (preexercise) ENO and magnitude of the maximal decrease in FEV(1) after exercise. In conclusion, our study shows that ENO levels do not change during acute airway obstruction induced by exercise challenge in asthmatic children. In addition, baseline ENO values correlate with the magnitude of postexercise bronchoconstriction, suggesting that NO may be a predictor of airway hyperresponsiveness to exercise.

While it is known that exhaled nitric oxide (ENO) is increased in adults and school children with asthma exacerbation probably as an expression of disease activity, no studies have investigated whether this phenomenon also occurs in infants and young children with recurrent wheeze exacerbation. We measured ENO in 13 young children (mean age 20.2 mo) with recurrent wheeze (Group 1) during an acute episode and after 5 d of oral prednisone therapy. ENO was measured also in nine healthy control subjects (Group 2) (mean age 16.9 mo) and in six children with a first-time viral wheezy episode (Group 3) (mean age 11 mo). To measure ENO, infants inhaled NO-free air via a face mask from a reservoir and, through a nonrebreathing valve, exhaled in a collecting bag that was analyzed by chemiluminescence. To address the question of whether the levels of ENO collected in the bag are a reflection of the pulmonary airway, ENO determinations were performed in two healthy infants before and after tracheal intubation for elective surgery. During the acute episode of wheezing the mean (+/- SEM) value of ENO in children with recurrent wheeze (Group 1) was 14.1 +/- 1.8 ppb, almost threefold higher than in healthy control subjects (5.6 +/- 0.5 ppb, p < 0.001). After steroid therapy we found a mean fall of 52% in ENO (5.9 +/- 0.7 ppb, p < 0.01) compared with baseline values. ENO values measured before and after intubation in two infants were 6 ppb and 5 ppb in one child and 7 ppb and 6 ppb in the other one. The mean value of ENO of children with first-time wheeze (Group 3) was 8.3 +/- 1.3 ppb, significantly lower (p < 0.05) than the value of children with recurrent wheeze (Group 1). In conclusion, we describe a method to measure ENO in young children and show that infants with recurrent wheeze have elevated levels of ENO during exacerbation that rapidly decrease after steroid therapy. This suggests that, in these children, airway inflammation could be present at a very early stage.

Exhaled nitiric oxide (NO) is increased in exhaled breath of asthmatic patients. The aim of this study was to investigate the longitudinal changes of exhaled NO outside and during the pollen season in pollen-allergic asthmatic children. Twenty-one children (age 6 to 16 yr), with a seasonal allergic asthma sensitive to grass pollen, underwent measurements of exhaled NO and pulmonary function before (March), during (May), and after (November) the pollen season. Exhaled NO was measured by a tidal breathing method with a chemiluminescence analyzer and NO steady-state levels were recorded. The timing of the measurements during the pollen season was based on the atmospheric pollen count. Exhaled NO values of asthmatic children were compared with those of 21 sex- and age-matched healthy children. Pulmonary function and symptoms of asthma were also evaluated at each visit. The mean value of exhaled NO before the grass season was 12.7 +/- 5.1 ppb (mean +/- SD), significantly higher when compared with controls (7.8 +/- 2.7 ppb, p < 0.001). In the pollen season there was a significant (p < 0.001) twofold increase in exhaled NO (21.4 +/- 7.6 ppb) that, after the season, returned to values similar (12.8 +/- 5.8 ppb, p = NS) to those found before the season. There were no significant changes in FEV1 before and during the season (98.6% predicted versus 101% predicted, p = NS). We conclude that natural allergen exposure is related to an increase of exhaled NO in asthmatic grass pollen-allergic children even in absence of significant changes in airways function. We speculate that measurement of exhaled NO could be a sensitive noninvasive marker of asthma disease activity.