Optimizing care for children with difficult-to-treat and severe asthma through specialist paediatric asthma centres: expert practical experience and advice.

Severe asthma in children carries an unacceptable treatment burden, yet its rarity means clinical experience in treating it is limited, even among specialists. Practical guidance is needed to support clinical decision-making to optimize treatment for children with this condition.This modified Delphi convened 16 paediatric pulmonologists and allergologists from northern Europe, all experienced in treating children with severe asthma. Informed by interviews with stakeholders involved in the care of children with severe asthma (including paediatricians, nurses and carers), and an analysis of European guidelines, the experts built a consensus focused on the gaps in existing guidance. Explored were considerations for optimizing care for patients needing biologic treatment, and for selecting home or hospital delivery of biologics. This consensus is aimed at clinicians in specialist centres, as well as general paediatricians, paediatric allergologists and paediatric pulmonologists who refer children with the most severe asthma to specialist care. Consensus is based on expert opinion and is intended for use alongside published guidelines.Our discussions revealed three key facets to optimizing care. Firstly, early asthma detection in children presenting with wheezing and/or dyspnoea is vital, with a low threshold for referral from primary to specialist care. Secondly, children who may need biologics should be referred to and managed by specialist paediatric asthma centres; we define principles for the specialist team members, tests, and expertise necessary at such centres, as well as guidance on when homecare biologics delivery is and is not appropriate. Thirdly, shared decision-making is essential at all stages of the patient's journey: clear, concise treatment plans are vital for patient/carer self-management, and structured processes for transition from paediatric to adult services are valuable. The experts identified the potential for specialist paediatric asthma nurses to play a significant role in facilitating multidisciplinary working.Through this project is agreed a framework of practical advice to optimize the care of children with severe asthma. We encourage clinicians and policymakers to implement this practical advice to enhance patient care.

Chest computed tomography in severe bronchopulmonary dysplasia: Comparing quantitative scoring methods.

PURPOSE: Bronchopulmonary dysplasia (BPD) is the most common complication of extreme preterm birth and structural lung abnormalities are frequently found in children with BPD. To quantify lung damage in BPD, three new Hounsfield units (HU) based chest-CT scoring methods were evaluated in terms of 1) intra- and inter-observer variability, 2) correlation with the validated Perth-Rotterdam-Annotated-Grid-Morphometric-Analysis (PRAGMA)-BPD score, and 3) correlation with clinical data. METHODS: Chest CT scans of children with severe BPD were performed at a median of 7 months corrected age. Hyper- and hypo-attenuated regions were quantified using PRAGMA-BPD and three new HU based scoring methods (automated, semi-automated, and manual). Intra- and inter-observer variability was measured using intraclass correlation coefficients (ICC) and Bland-Altman plots. The correlation between the 4 scoring methods and clinical data was assessed using Spearman rank correlation. RESULTS: Thirty-five patients (median gestational age 26.1 weeks) were included. Intra- and inter-observer variability was excellent for hyper- and hypo-attenuation regions for the manual HU method and PRAGMA-BPD (ICCs range 0.80-0.97). ICC values for the semi-automated HU method were poorer, in particular for the inter-observer variability of hypo- (0.22-0.71) and hyper-attenuation (-0.06-0.89). The manual HU method was highly correlated with PRAGMA-BPD score for both hyper- (ρs0.92, p < 0.001) and hypo-attenuation (ρs0.79, p < 0.001), while automated and semi-automated HU methods showed poor correlation for hypo- (ρs < 0.22) and good correlation for hyper-attenuation (ρs0.72-0.74, p < 0.001). Several scores of hyperattenuation correlated with the use of inhaled bronchodilators in the first year of life; two hypoattenuation scores correlated with birth weight. CONCLUSIONS: PRAGMA-BPD and the manual HU method have the best reproducibility for quantification of CT abnormalities in BPD.

Symptomatic treatment of pollen-related allergic rhinoconjunctivitis in children: randomized controlled trial.

BACKGROUND: About 12% of children are affected by allergic rhinoconjunctivitis (AR). Although the main symptomatic treatments are intranasal corticosteroids (INCS) (daily or on demand) and oral antihistamines, it remains unclear which treatment provides the best relief of symptoms. Therefore, this study examines whether daily use of INCS is superior to on-demand use or to oral antihistamines on demand. METHODS: A single-blinded randomized controlled trial in children (aged 6-18 years) with pollen-related AR. Patients received either INCS daily (fluticasone propionate), INCS on demand (fluticasone propionate) or oral antihistamine on demand (levocetirizine) for 3 months during the grass pollen season. A daily online symptom diary on both nose and eye symptoms was completed. The primary outcome was the percentage of symptom-free days. RESULTS: A total of 150 children were randomized. The percentage symptom-free days was in favour of INCS on demand (30%) compared with INCS daily (22%), that is 8% difference (95% CI -5 to +21%; not significant). The antihistamine on-demand group had 15% symptom-free days, that is 7% difference compared to INCS daily (95% CI -6 to +19%;, not significant). Patients in the INCS on-demand group used on average 61% less fluticasone than patients in the INCS daily group during the study period (P < 0.0001). CONCLUSIONS: This trial with three parallel treatment groups shows that INCS daily was not superior to INCS on demand or to antihistamine on demand regarding the number of symptom-free days. An on-demand INCS strategy has the advantage of a lower overall corticosteroid exposure and less costs.

Exhaled breath profiling using broadband quantum cascade laser-based spectroscopy in healthy children and children with asthma and cystic fibrosis.

Exhaled breath analysis is a potential non-invasive tool for diagnosing and monitoring airway diseases. Gas chromatography-mass spectrometry and electrochemical sensor arrays are the main techniques to detect volatile organic compounds (VOC) in exhaled breath. We developed a broadband quantum cascade laser spectroscopy technique for VOC detection and identification. The objective of this study was to assess the repeatability of exhaled breath profiling with broadband quantum cascade laser-based spectroscopy and to explore the clinical applicability by comparing exhaled breath samples from healthy children with those from children with asthma or cystic fibrosis (CF). Healthy children and children with stable asthma or stable CF, aged 6-18 years, were included. Two to four exhaled breath samples were collected in Tedlar bags and analyzed by quantum cascade laser spectroscopy to detect VOCs with an absorption profile in the wavenumber region between 832 and 1262.55 cm(-1). We included 35 healthy children, 39 children with asthma and 15 with CF. Exhaled breath VOC profiles showed poor repeatability (Spearman's rho = 0.36 to 0.46) and agreement of the complete profiles. However, we were able to discriminate healthy children from children with stable asthma or stable CF and identified VOCs that were responsible for this discrimination. Broadband quantum cascade laser-based spectroscopy detected differences in VOC profiles in exhaled breath samples between healthy children and children with asthma or CF. The combination of a relatively easy and fast method and the possibility of molecule identification makes broadband quantum cascade laser-based spectroscopy attractive to investigate the diagnostic and prognostic potential of volatiles in exhaled breath.

Reproducibility and utility of an overnight 0.25 mg dexamethasone suppression test as a marker for glucocorticoid sensitivity in children with asthma.

PURPOSE: Inhaled corticosteroids (ICS) are the cornerstone of asthma treatment in children. However, there is considerable inter-individual variation in glucocorticoid sensitivity, leading to over- as well as undertreatment. A simple and fast test to predict glucocorticoid sensitivity would enable more tailored therapy in children with asthma. AIM: To study reproducibility and utility of an overnight 0.25 mg dexamethasone suppression test (DST) with salivary cortisol levels as marker for glucocorticoid sensitivity in asthmatic children. METHODS: 23 children with atopic asthma were recruited for two overnight 0.25 mg DST's, 1 month apart. RESULTS: Baseline cortisol levels correlated well between both tests. However, cortisol levels, change in cortisol levels or fractional suppression of cortisol levels after dexamethasone did not correlate between the two tests. Bland-Altman plots showed that the difference in salivary cortisol levels between test 1 and 2 of an individual patient could go up to 12 nmol/l, which is a clinically relevant difference. ICS dose did not correlate with baseline cortisol levels, height and BMI SDS. CONCLUSION: The low-dose salivary DST test in its current form is not suitable for use in clinical practice in children with asthma, due to low reproducibility. Therefore, studies using the 0.25 mg salivary DST should be interpreted cautiously.

Asthma control questionnaires in the management of asthma in children: A review.

Several self-administered questionnaires have been developed to assess childhood asthma control in a simple and standardized way. This review discusses the most commonly used questionnaires and explores their usefulness in asthma management in children. We conclude that the use of asthma control questionnaires in daily practice and in research contributes to the standardized evaluation of children with asthma and helps to track asthma symptoms, but validation studies in a wider range of settings are needed.

The analysis of volatile organic compounds in exhaled breath and biomarkers in exhaled breath condensate in children - clinical tools or scientific toys?

Current monitoring strategies for respiratory diseases are mainly based on clinical features, lung function and imaging. As airway inflammation is the hallmark of many respiratory diseases in childhood, noninvasive methods to assess the presence and severity of airway inflammation might be helpful in both diagnosing and monitoring paediatric respiratory diseases. At present, the measurement of fractional exhaled nitric oxide is the only noninvasive method available to assess eosinophilic airway inflammation in clinical practice. We aimed to evaluate whether the analysis of volatile organic compounds (VOCs) in exhaled breath (EB) and biomarkers in exhaled breath condensate (EBC) is helpful in diagnosing and monitoring respiratory diseases in children. An extensive literature search was conducted in Medline, Embase and PubMed on the analysis and applications of VOCs in EB and EBC in children. We retrieved 1165 papers, of which nine contained original data on VOCs in EB and 84 on biomarkers in EBC. These were included in this review. We give an overview of the clinical applications in childhood and summarize the methodological issues. Several VOCs in EB and biomarkers in EBC have the potential to distinguish patients from healthy controls and to monitor treatment responses. Lack of standardization of collection methods and analysis techniques hampers the introduction in clinical practice. The measurement of metabolomic profiles may have important advantages over detecting single markers. There is a lack of longitudinal studies and external validation to reveal whether EB and EBC analysis have added value in the diagnostic process and follow-up of children with respiratory diseases. In conclusion, the use of VOCs in EB and biomarkers in EBC as markers of inflammatory airway diseases in children is still a research tool and not validated for clinical use.

Multicomponent gas analysis using broadband quantum cascade laser spectroscopy.

We present a broadband quantum cascade laser-based spectroscopic system covering the region between 850 and 1250 cm(-1). Its robust multipass cavity ensures a constant interaction length over the entire spectral region. The device enables the detection and identification of numerous molecules present in a complex gas mixture without any pre-treatment in two minutes. We demonstrate that we can detect sub-ppmv concentration of acetone in presence of 2% of water at the same wavenumber region.

Validation of a web-based version of the asthma control test and childhood asthma control test.

RATIONALE: Recent guidelines focus on adjusting asthma treatment to the level of asthma control. The availability of a web-based asthma control questionnaire offers the possibility to assess asthma control without the need of outpatient clinic visits. The aim of this study was to evaluate the agreement between web-based and paper-based versions of the Asthma Control Test (ACT) and Childhood Asthma Control Test (C-ACT), short-term reproducibility and satisfaction with both versions. METHODS: One hundred seventy-three children with stable asthma and a normal lung function were randomized to fill in a web-based or paper-based version of the C-ACT (4-11 years) or ACT (12-18 years). According to a cross-over design, they completed the opposite version after 1 week. Reproducibility was evaluated by repeating the 2nd version (web- or paper-based) 7 days later. RESULTS: Eighty-eight children filled in the C-ACT, 68 children filled in the ACT. Intraclass Correlation Coefficient (ICC) for web-based versus paper-based C-ACT was 0.81 (95% confidence interval [95% CI] 0.72-0.87). For ACT this was 0.84 (95% CI 0.76-0.90). For web-based and paper-based C-ACT the reproducibility ICC was 0.82 (95% CI 0.67-0.90) and 0.75 (95% CI 0.59-0.85), respectively. The reproducibility ICC of the ACT for web- and paper-based versions was 0.93 (95% CI 0.87-0.97) and 0.77 (95% CI 0.59-0.88), respectively. Eighty-six percent of patients preferred the web-based version. CONCLUSION: The web-based version of the C-ACT and ACT is reproducible and comparable with the paper-based version in assessing asthma control. Most children and their parents prefer the web-based version.

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.

Paediatrics in Berlin.

The aim of this report is to describe the highlights of the European Respiratory Society annual congress in Berlin, Germany. The best abstracts in asthma and allergy, cystic fibrosis, respiratory infection, paediatric and neonatal intensive care, paediatric investigative techniques (in particular respiratory physiology and bronchoscopy) and respiratory epidemiology are presented and set in the context of the current literature.

Exhaled nitric oxide in childhood asthma: a review.

As an 'inflammometer', the fraction of nitric oxide in exhaled air (Fe(NO)) is increasingly used in the management of paediatric asthma. Fe(NO) provides us with valuable, additional information regarding the nature of underlying airway inflammation, and complements lung function testing and measurement of airway hyper-reactivity. This review focuses on clinical applications of Fe(NO) in paediatric asthma. First, Fe(NO) provides us with a practical tool to aid in the diagnosis of asthma and distinguish patients who will benefit from inhaled corticosteroids from those who will not. Second, Fe(NO) is helpful in predicting exacerbations, and predicting successful steroid reduction or withdrawal. In atopic asthmatic children Fe(NO) is beneficial in adjusting steroid doses, discerning those patients who require additional therapy from those whose medication dose could feasibly be reduced. In pre-school children Fe(NO) may be of help in the differential diagnosis of respiratory symptoms, and may potentially allow for better targeting and monitoring of anti-inflammatory treatment.

[Airway malacia: not uncommon in children with atypical respiratory symptoms]. / Luchtwegmalacie: niet zeldzaam bij kinderen met atypische luchtwegsymptomen.

OBJECTIVE: To estimate the prevalence of primary airway malacia at birth, determine the predictive value of a clinical diagnosis of airway malacia compared with bronchoscopy results and describe the presenting symptoms. DESIGN: Retrospective descriptive study. METHOD: We reviewed the results of all bronchoscopies performed in the period 1997-2004 at the Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands, and the standardised status assessment of children diagnosed with primary airway malacia. RESULTS: A total of 512 bronchoscopies were performed. Primary airway malacia was diagnosed in 136 children (80 boys) with a median age of 4.3 years (range: 0-17). The prevalence of primary airway malacia at birth was estimated at approximately 1 in 2100. A diagnosis of probable airway malacia based on symptoms, patient history and targeted assessment of pulmonary function proved to be correct in 74% of patients. However, airway malacia was not suspected before bronchoscopy in 52% of patients. The symptoms were atypical and included: cough, recurrent airway infections, dyspnoea, wheezing and reduced exertional tolerance. The peak expiratory flow was more affected than the forced expiratory volume in 1 second value. CONCLUSION: Primary airway malacia occurs in an estimated 1 out of 2100 children and is difficult to recognise based on patient history and symptoms. Bronchoscopy should be considered to rule out airway malacia in patients with unexplained exertional intolerance, recurrent lower airway infections, or with 'atypical' or 'treatment-resistant' asthma.

Exhaled nitric oxide measurements: clinical application and interpretation.

The use of exhaled nitric oxide measurements (F(E)NO) in clinical practice is now coming of age. There are a number of theoretical and practical factors which have brought this about. Firstly, F(E)NO is a good surrogate marker for eosinophilic airway inflammation. High F(E)NO levels may be used to distinguish eosinophilic from non-eosinophilic pathologies. This information complements conventional pulmonary function testing in the assessment of patients with non-specific respiratory symptoms. Secondly, eosinophilic airway inflammation is steroid responsive. There are now sufficient data to justify the claim that F(E)NO measurements may be used successfully to identify and monitor steroid response as well as steroid requirements in the diagnosis and management of airways disease. F(E)NO measurements are also helpful in identifying patients who do/do not require ongoing treatment with inhaled steroids. Thirdly, portable nitric oxide analysers are now available, making routine testing a practical possibility. However, a number of issues still need to be resolved, including the diagnostic role of F(E)NO in preschool children and the use of reference values versus individual F(E)NO profiles in managing patients with difficult or severe asthma.

High fractional concentration of nitric oxide in exhaled air despite steroid treatment in asthmatic children.

BACKGROUND: The fractional concentration of nitric oxide in exhaled air (FENO) is elevated in atopic asthma and typically responds to treatment with inhaled corticosteroids (ICS). However, some patients have persistently high FENO levels despite treatment. OBJECTIVE: We studied how optimizing the inhalation technique and increasing ICS doses would affect FENO in stable atopic asthmatic children who had elevated FENO while using ICS. METHODS: In 41 stable asthmatic children who were treated with ICS (median daily dose 800 microg budesonide equivalent, range 100-1600 microg) and maintained FENO> or =20 p.p.b., we optimized the inhalation technique by thorough instruction and measured FENO 2 weeks later. Then, if FENO remained > or =20 p.p.b., we increased the ICS dose and reassessed FENO 2 weeks later. RESULTS: Improving the inhalation technique did not reduce FENO. Increasing ICS from a daily median dose of 800 to 1200 microg budesonide had no significant effect on FENO. FENO correlated positively with symptom scores in the following 2 and 4 weeks (P=0.001, 0.002) and beta2-agonist use the 2 and 4 weeks following FENO measurement (P=0.02, 0.004). CONCLUSION: We conclude that common steps in asthma treatment, i.e. inhalation instruction and increasing ICS dose, were both ineffective in reducing FENO in atopic asthmatic children with elevated FENO values despite treatment with ICS. This implies that FENO cannot simply be incorporated in current treatment guidelines.

Exhaled nitric oxide predicts asthma relapse in children with clinical asthma remission.

BACKGROUND: Nitric oxide in exhaled air (FE(NO)) is a marker of eosinophilic airway inflammation. A study was undertaken to determine whether FE(NO) predicts asthma relapse in asymptomatic asthmatic children in whom inhaled corticosteroids are discontinued. METHODS: Forty children (21 boys) of mean age 12.2 years on a median dose of 400 mug budesonide or equivalent (range 100-400) were included. FE(NO) was measured before and 2, 4, 12, and 24 weeks after withdrawal of steroids. A relapse was defined as more than one exacerbation per month, or need for beta agonist treatment on 4 days per week for at least 2 weeks, or diurnal peak flow variability of >20%. FE(NO) measurements were performed online with an expiratory flow of 50 ml/s. RESULTS: Nine patients relapsed. Two and 4 weeks after withdrawal of steroids geometric mean FE(NO) in children who were about to relapse was higher than in those who did not relapse: 35.3 ppb v 15.7 ppb at 2 weeks (ratio 2.3; 95% CI 1.2 to 4.1; p = 0.01) and 40.8 ppb v 15.9 ppb at 4 weeks (ratio 2.6; 95% CI 1.3 to 5.1). An FE(NO) value of 49 ppb at 4 weeks after discontinuation of steroids had the best combination of sensitivity (71%) and specificity (93%) for asthma relapse. CONCLUSION: FE(NO) 2 and 4 weeks after discontinuation of steroids in asymptomatic asthmatic children may be an objective predictor of asthma relapse.

Exhaled nitric oxide measurements with dynamic flow restriction in children aged 4-8 yrs.

Fractional exhaled nitric oxide concentration (FENO) depends on exhalation flow; however, children often are unable to perform controlled flow procedures. Therefore, a device was developed for off-line FENO sampling, with dynamic flow restriction (DFR). The authors compared off-line with on-line FENO, assessed feasibility, and obtained normal values for FENO in children aged 4-8 yrs. Subjects inhaled nitric oxide (NO)-free air and exhaled into the device, where DFR kept exhalation flow constant at 50 mL x s(-1). Dead space air was discarded. Exhaled air was collected in a 150 mL mylar balloon. On-line measurements were performed and values compared with off-line FENO in 19 adult volunteers. Seventy-nine children performed off-line sampling. All samples were analysed with a chemiluminescence NO-analyser. Normal values were obtained in 34 healthy children. There was an excellent correlation between on- and off-line values. Bland and Altman plots showed good agreement between on- and off-line FENO. Seventy-four out of 79 children were able to perform a correct off-line procedure. Geometric mean+/-SEM FENO in healthy children was 4.9+/-1.2 parts per billion (ppb) for male children and 7.6+/-1.1 ppb for female children. It can be concluded that off-line fraction of exhaled nitric oxide measurements with dynamic flow restriction are feasible in young children and correspond to on-line values.

['Inflammometry' with nitric oxide in exhaled air: a new test for lung diseases]. / 'Inflammometrie' met stikstofmonoxide in uitademingslucht: een nieuw onderzoek bij longaandoeningen.

The gas nitric oxide (NO) is produced in increased amounts in certain types of inflammatory responses and its presence in exhaled air can be demonstrated. The nitric oxide fraction in exhaled air (FeNO) is elevated in patients with asthma and lowered in the case of several other lung diseases such as cystic fibrosis and primary ciliary dyskinesia. The FeNO can be quickly measured in a non-invasive and reproducible manner: on-line if the patient (adult or child), having taken a deep breath in, breathes out with a low flow rate into the NO measuring device or off-line if the expired air is collected in an NO inert reservoir. Confounding factors are contamination of inhaled air with ambient NO and contamination of exhaled air with NO that has been produced in the paranasal sinuses and the nose. The possible applications of FeNO measurement as a new lung function test include diagnostic tests for chronic respiratory symptoms and the possible guidance of anti-inflammatory therapy for asthma and, perhaps, other respiratory disorders.