Peter Merkus

Classification and pharmacological treatment of preschool wheezing: changes since 2008

Since the publication of the European Respiratory Society Task Force report in 2008, significant new evidence has become available on the classification and management of preschool wheezing disorders. In this report, an international consensus group reviews this new evidence and proposes some modifications to the recommendations made in 2008. Specifically, the consensus group acknowledges that wheeze patterns in young children vary over time and with treatment, rendering the distinction between episodic viral wheeze and multiple-trigger wheeze unclear in many patients. Inhaled corticosteroids remain first-line treatment for multiple-trigger wheeze, but may also be considered in patients with episodic viral wheeze with frequent or severe episodes, or when the clinician suspects that interval symptoms are being under reported. Any controller therapy should be viewed as a treatment trial, with scheduled close follow-up to monitor treatment effect. The group recommends discontinuing treatment if there is no benefit and taking favourable natural history into account when making decisions about long-term therapy. Oral corticosteroids are not indicated in mild-to-moderate acute wheeze episodes and should be reserved for severe exacerbations in hospitalised patients. Future research should focus on better clinical and genetic markers, as well as biomarkers, of disease severity. The distinction between episodic viral and multiple-trigger wheeze is unclear in many preschool children http://ow.ly/sKYZF

An Official American Thoracic Society Workshop Report: Optimal Lung Function Tests for Monitoring Cystic Fibrosis, Bronchopulmonary Dysplasia, and Recurrent Wheezing in Children Less Than 6 Years of Age

Although pulmonary function testing plays a key role in the diagnosis and management of chronic pulmonary conditions in children under 6 years of age, objective physiologic assessment is limited in the clinical care of infants and children less than 6 years old, due to the challenges of measuring lung function in this age range. Ongoing research in lung function testing in infants, toddlers, and preschoolers has resulted in techniques that show promise as safe, feasible, and potentially clinically useful tests. Official American Thoracic Society workshops were convened in 2009 and 2010 to review six lung function tests based on a comprehensive review of the literature (infant raised-volume rapid thoracic compression and plethysmography, preschool spirometry, specific airway resistance, forced oscillation, the interrupter technique, and multiple-breath washout). In these proceedings, the current state of the art for each of these tests is reviewed as it applies to the clinical management of infants and children under 6 years of age with cystic fibrosis, bronchopulmonary dysplasia, and recurrent wheeze, using a standardized format that allows easy comparison between the measures. Although insufficient evidence exists to recommend incorporation of these tests into the routine diagnostic evaluation and clinical monitoring of infants and young children with cystic fibrosis, bronchopulmonary dysplasia, or recurrent wheeze, they may be valuable tools with which to address specific concerns, such as ongoing symptoms or monitoring response to treatment, and as outcome measures in clinical research studies.

Comparing Global Initiative for Asthma (GINA) criteria with the Childhood Asthma Control Test (C-ACT) and Asthma Control Test (ACT)

Several tools are useful in detecting uncontrolled asthma in children. The aim of this study was to compare Global Initiative for Asthma (GINA) guidelines with the Childhood Asthma Control Test (C-ACT) and the Asthma Control Test (ACT) in detecting uncontrolled asthma in children. 145 children with asthma filled in a web-based daily diary card for 4 weeks on symptoms, use of rescue medication and limitations of activities, followed by either the C-ACT or ACT. For predicting uncontrolled asthma, score cut-off points of 19 were used for C-ACT and ACT. According to GINA guidelines, asthma was uncontrolled in 71 (51%) children and completely controlled in 19 (14%) children. The area under the curve in the receiver operating characteristic curves for C-ACT and ACT versus GINA guidelines were 0.89 and 0.92, respectively. Cut-off points of 19 for C-ACT and ACT resulted in a sensitivity of 33% and 66% in predicting uncontrolled asthma, respectively. C-ACT and ACT correlate well with GINA criteria in predicting uncontrolled asthma, but commonly used cut-off points for C-ACT and ACT seem to underestimate the proportion of children with uncontrolled asthma as defined by GINA.

Exhaled Nitric Oxide Differentiates Airway Diseases in the First Two Years of Life

Fractional exhaled nitric oxide (FENO) levels are increased in children and adults with asthma, whereas low levels have been found in cystic fibrosis and primary ciliary dyskinesia. The aim of this study was to investigate whether FENO measurements could distinguish between children below the age of 2 with different airway diseases. FENO measurements were performed in 118 infants aged between 4.6 and 25.2 mo: 74 infants with recurrent wheezing (RW), 24 with bronchopulmonary dysplasia (BPD), and 20 with cystic fibrosis (CF). FENO was measured also in 100 healthy controls aged between 1.1 and 7.7 mo. Geometric mean (95% confidence interval) FENO values were 10.4 (9.1–12.0) parts per billion (ppb) in healthy infants, 18.6 (15.6–22.2) ppb in wheezy infants, 11.7 (8.2–16.8) ppb in BPD infants and 5.9 (3.4–10.1) ppb in CF infants. FENO in wheezers was higher than in controls, BPD, and CF (p = 0.009, p = 0.038, and p < 0.001, respectively). Atopic wheezers showed higher FENO than nonatopic wheezers (p = 0.04). CF infants had lower FENO than healthy controls and BPD infants (p = 0.003 and p = 0.043, respectively). FENO values in BPD and control infants were not different. We conclude that FENO is helpful to differentiate various airway diseases already in the first 2 y of life.

DNase and atelectasis in non-cystic fibrosis pediatric patients

IntroductionNo evidence based treatment is available for atelectasis. We aimed to evaluate the clinical and radiologic changes in pediatric patients who received DNase for persistent atelectasis that could not be attributed to cardiovascular causes, and who were unresponsive to treatment with inhaled bronchodilators and physiotherapy.MethodsAll non-cystic fibrosis pediatric patients who received nebulised or endotracheally instilled DNase for atelectasis between 1998 and 2002, with and without mechanical ventilation, were analysed in a retrospective descriptive study. The endpoints were the blood pCO2, the heart rate, the respiratory rate, the FiO2 and the chest X-ray scores before and after treatment.ResultsIn 25 of 30 patients (median [range] age, 1.6 [0.1–11] years) who met inclusion criteria, paired data of at least three endpoints were available. All clinical parameters improved significantly within 2 hours (P < 0.01), except for the heart rate (P = 0.06). Chest X-ray scores improved significantly within 24 hours after DNase treatment (P < 0.001). Individual improvement was observed in 17 patients and no clinical change was observed in five patients. Temporary deterioration (n = 3) was associated with increased airway obstruction and desaturations. No other complications were observed.ConclusionAfter treatment with DNase for atelectasis of presumably infectious origin in non-cystic fibrosis pediatric patients, rapid clinical improvement was observed within 2 hours and radiologic improvement was documented within 24 hours in the large majority of children, and increased airway obstruction and ventilation–perfusion mismatch occurred in three children, possibly due to rapid mobilisation of mucus. DNase may be an effective treatment for infectious atelectasis in non-cystic fibrosis pediatric patients.

Reference ranges for interrupter resistance technique: the Asthma UK Initiative

Measuring interrupter resistance (Rint) is an increasingly popular lung function technique and especially suitable for preschool children because it is simple, quick and requires only passive cooperation. A European Respiratory Society (ERS)/American Thoracic Society (ATS) Task Force recently published empirical recommendations related to procedures, limitations and interpretation of the technique. However, for valid interpretation, high-quality reference equations are required and these have been lacking. The aim of the present study was to collate Rint data from healthy children in order to produce more robust reference equations. A further aim was to examine the influence of methodological differences on predicted Rint values. Rint data from healthy children were collected from published and unpublished sources. Reference equations for expiratory and inspiratory Rint were developed using the LMS (lambda, mu, sigma) method. Data from 1,090 children (51% males) aged 3–13 yrs were collated to construct sex-specific reference equations for expiratory Rint and data from 629 children (51% males) were collated for inspiratory Rint. Height was the best independent predictor of both expiratory and inspiratory Rint. Differences between centres were clinically irrelevant, and differences between ethnic groups could not be examined. The availability of a large and generalisable sample and the use of modern statistical techniques enabled the development of more appropriate reference equations for Rint in young children.

Cross-sectional and Longitudinal Spirometry in Children and Adolescents Interpretative Strategies

RATIONALE Single and serial spirometric data are commonly compared with predicted values to assess pulmonary function and normal lung growth. OBJECTIVES Do reference equations adequately describe pulmonary function in a population and in growing individuals? METHODS We applied five sets of reference equations with appropriate age ranges to cross-sectional data of FEV(1), FVC, and FEV(1)/FVC from the United States, Estonia, and The Netherlands (1,487 boys and 1,340 girls, 6 to 18 years of age), and to serial measurements in Dutch (430 girls and 769 boys, 6 to 19 years of age) and in German and Austrian children (1,305 girls and 1,303 boys, 6 to 13 years of age). MEASUREMENTS AND MAIN RESULTS Compared with reference equations from Polgar and Zapletal, cross-sectional FEV(1) and FVC declined between the ages of 6 and 12 and then increased, leading to a spurious change of up to 25% predicted; this pattern was most pronounced in boys. In cross-sectional data this trend was much weaker when using reference equations from Hankinson, Quanjer, and Stanojevic, and these equations provided a good fit from the age of 12 upward. In longitudinal data (i.e., within individuals), the trend was more pronounced for FEV(1) in boys than in girls. No set of equations provided a satisfactory fit in the lower limits of normal, but Hankinson and Stanojevic equations performed best. CONCLUSIONS Spirometric reference equations that use only height for predicting pulmonary function are unsuitable for describing the progression of pulmonary function. Those that incorporate height and age demonstrate some discrepancy with longitudinal data. Failure to take these spurious trends into account leads to significant errors in estimating the natural course of respiratory disease, in allocating patients to treatment groups, or in assessing long-term effects of drug intervention in school children and adolescents.

Aerosol Therapy and the Fighting Toddler: Is Administration During Sleep an Alternative?

Insufficient cooperation during administration of aerosols by pressurized metered dose inhaler (pMDI)/spacers is a problem in nearly 50% of treated children younger than 2 years. For these children, administration during sleep might be more efficient. However, it is unknown how much aerosol reaches the lungs during sleep. The aim of this study was to determine in vitro the lung dose in young children from a pMDI/spacer during sleep and while being awake. Breathing patterns were recorded by a pneumotachograph in 18 children (age 11 +/- 5.1 months) during sleep and wakefulness. Next, breathing patterns were replayed by a computer-controlled breathing simulator to which an anatomically correct nose-throat model of a 9-month-old child was attached. One puff of budesonide (200 microg) was administered to the model via a metal spacer. Aerosol was trapped in a filter placed between model and breathing simulator. The amount of budesonide on the filter (5 lung dose) was analyzed by HPLC. For each of the 36 breathing patterns, lung dose was measured in triplicate. The sleep breathing patterns had significantly lower respiratory rate and peak inspiratory flows, and smaller variability in respiratory rate, tidal volume, and peak inspiratory flows. Lung dose (mean +/- SD) was 6.5 +/- 3.2 and 11.3 +/- 3.9 microg (p = 0.004) for the wake and sleep breathing pattern, respectively. This infant model-study shows that the lung dose of budesonide by pMDI/spacer is significantly higher during sleep compared to inhalation during wake breathing. Administration of aerosols during sleep might, therefore, be an efficient alternative for uncooperative toddlers.

Inhaled corticosteroids and growth of airway function in asthmatic children

Airway inflammation and remodelling play an important role in the pathophysiology of asthma. Remodelling may affect childhood lung function, and this process may be reversed by anti-inflammatory treatment. The current study assessed longitudinally whether asthma affects growth of airway function relative to airspaces, and if so whether this is redressed by inhaled corticosteroids (ICS). Every 4 months for up to 3 yrs, lung function was assessed in 54 asthmatic children (initial age 7–16 yrs), who inhaled 0.2 mg salbutamol t.i.d. and 0.2 mg budesonide t.i.d. (β2‐agonist (BA)+ICS), or placebo (PL) t.i.d. (BA+PL) in a randomised, double-blind design. Measurements were carried out before and after maximal bronchodilation. Airway growth was assessed from the change of forced expiratory volume in one second and of maximal expiratory flows (at 60% and 40% of total lung capacity (TLC) remaining in the lung) relative to TLC, as measures of more central, intermediate and more peripheral airways. Growth patterns were compared with the longitudinal findings in 376 healthy children. Airway patency after maximal bronchodilation in patients on BA+PL remained reduced compared to healthy subjects, whereas in patients on BA+ICS a marked improvement was observed to subnormal. No differences between patients and controls could be demonstrated for growth patterns of central and intermediate airway function. Compliance with BA+ICS was 75% of the prescribed dose, resulting in significant, sustained improvement of symptoms and postbronchodilator calibre of central and intermediate airways to subnormal within 2 months, but postbronchodilator small airway patency remained reduced, though improved compared to patients on BA+PL. Anti-inflammatory treatment of asthmatic children is associated with normal functional development of central and intermediate airways. The persistently reduced postbronchodilator patency of peripheral airways may reflect remodelling, or insufficient anti-inflammatory treatment.

Exhaled nitric oxide monitoring by quantum cascade laser: comparison with chemiluminescent and electrochemical sensors.

Fractional exhaled nitric oxide (F(E)NO) is considered an indicator in the diagnostics and management of asthma. In this study we present a laser-based sensor for measuring F(E)NO. It consists of a quantum cascade laser (QCL) combined with a multi-pass cell and wavelength modulation spectroscopy for the detection of NO at the sub-part-per-billion by volume (ppbv, 110(-9)) level. The characteristics and diagnostic performance of the sensor were assessed. A detection limit of 0.5 ppbv was demonstrated with a relatively simple design. The QCL-based sensor was compared with two market sensors, a chemiluminescent analyzer (NOA 280, Sievers) and a portable hand-held electrochemical analyzer (MINO, Aerocrine AB, Sweden). F(E)NO from 20 children diagnosed with asthma and treated with inhaled corticosteroids were measured. Data were found to be clinically acceptable within 1.1 ppbv between the QCL-based sensor and chemiluminescent sensor and within 1.7 ppbv when compared to the electrochemical sensor. The QCL-based sensor was tested on healthy subjects at various expiratory flow rates for both online and offline sampling procedures. The extended NO parameters, i.e. the alveolar region, airway wall, diffusing capacity, and flux were calculated and showed a good agreement with the previously reported values.