Small airways targeted treatment with smart nebulizer technology could improve severe asthma in children: a retrospective analysis.

OBJECTIVE: Conventional inhaler devices have a low efficacy in targeting small airways. Smart nebulizers can be used to increase deposition to small airways by adjusting the flow and depth of each inhalation based on patients 'individual inspiratory capacity. We investigated whether targeting of high dose inhaled corticosteroids (ICS) to small airways with a smart nebulizer could reduce exacerbation rate in children with severe asthma (SA). METHODS: We conducted a retrospective study in children with SA using a smart nebulizer (Akita® Jet nebulizer) for the administration of high dose ICS in our outpatient clinic at the Erasmus MC - Sophia Children's Hospital. Clinical data before and after start of treatment were collected. The primary outcome was exacerbation rate, defined as: number of asthma exacerbations for which oral corticosteroid courses (OCS) were prescribed. The exacerbation rate 1 year before treatment was compared with the exacerbation rate 1 year after start of treatment. Secondary outcomes were changes in spirometry parameters, hospital admissions and medication use. RESULTS: Data on OCS use was available for 28/31 patients. Median number of asthma exacerbations requiring OCS courses 1 year before decreased from 2 (interquartile range(IQR) 2) to 0.5 (IQR 3) 1 year after treatment (p = 0.021). Hospital admission decreased from 1 (IQR 3) to 0 (IQR 1)(p = 0.028). FEV1, FEF25-75 and FEF75 were not significantly improved after one year of treatment with the smart nebulizer (p = 0.191; p = 0.248; p = 0.572). CONCLUSION: Targeting small airways with high dose ICS using a smart nebulizer resulted in a significant reduction in exacerbations requiring OCS after one year of treatment.

Genome-wide association studies of exacerbations in children using long-acting beta2-agonists.

BACKGROUND: Some children with asthma experience exacerbations despite long-acting beta2-agonist (LABA) treatment. While this variability is partly caused by genetic variation, no genome-wide study until now has investigated which genetic factors associated with risk of exacerbations despite LABA use in children with asthma. We aimed to assess whether genetic variation was associated with exacerbations in children treated with LABA from a global consortium. METHODS: A meta-analysis of genome-wide association studies (meta-GWAS) was performed in 1,425 children and young adults with asthma (age 6-21 years) with reported regular use of LABA from six studies within the PiCA consortium using a random effects model. The primary outcome of each study was defined as any exacerbation within the past 6 or 12 months, including at least one of the following: 1) hospital admissions for asthma, 2) a course of oral corticosteroids or 3) emergency room visits because of asthma. RESULTS: Genome-wide association results for a total of 82 996 common single nucleotide polymorphisms (SNPs, MAF ≥1%) with high imputation quality were meta-analysed. Eight independent variants were suggestively (P-value threshold ≤5 × 10-6 ) associated with exacerbations despite LABA use. CONCLUSION: No strong effects of single nucleotide polymorphisms (SNPs) on exacerbations during LABA use were identified. We identified two loci (TBX3 and EPHA7) that were previously implicated in the response to short-acting beta2-agonists (SABA). These loci merit further investigation in response to LABA and SABA use.

Children with severe asthma have substantial structural airway changes on computed tomography.

Background: In adults with severe asthma (SA) bronchial wall thickening, bronchiectasis and low attenuation regions (LAR) have been described on chest computed tomography (CT) scans. The extent to which these structural abnormalities are present in children with SA is largely unknown. Our aim was to study the presence and extent of airway abnormalities on chest CT of children with SA. Methods: 161 inspiratory and expiratory CT scans, either spirometer-controlled or technician-controlled, obtained in 131 children with SA (mean±SD age 11.0±3.8 years) were collected retrospectively. Inspiratory scans were analysed manually using a semi-quantitative score and automatically using LungQ (v2.1.0.1; Thirona B.V., Nijmegen, the Netherlands). LungQ segments the bronchial tree, identifies the generation for each bronchus-artery (BA) pair and measures the following BA dimensions: outer bronchial wall diameter (Bout), adjacent artery diameter (A) and bronchial wall thickness (Bwt). Bronchiectasis was defined as Bout/A ≥1.1, bronchial wall thickening as Bwt/A ≥0.14. LAR, reflecting small airways disease (SAD), was measured automatically on inspiratory and expiratory scans and manually on expiratory scans. Functional SAD was defined as FEF25-75 and/or FEF75 z-scores <-1.645. Results are shown as median and interquartile range. Results: Bronchiectasis was present on 95.8% and bronchial wall thickening on all CTs using the automated method. Bronchiectasis was present on 28% and bronchial wall thickening on 88.8% of the CTs using the manual semi-quantitative analysis. The percentage of BA pairs defined as bronchiectasis was 24.62% (12.7-39.3%) and bronchial wall thickening was 41.7% (24.0-79.8%) per CT using the automated method. LAR was observed on all CTs using the automatic analysis and on 82.9% using the manual semi-quantitative analysis. Patients with LAR or functional SAD had more thickened bronchi than patients without. Conclusion: Despite a large discrepancy between the automated and the manual semi-quantitative analysis, bronchiectasis and bronchial wall thickening are present on most CT scans of children with SA. SAD is related to bronchial wall thickening.

Oxygen saturation targets for children with respiratory distress: a systematic review.

Background: In children with respiratory distress, supplemental oxygen is indicated at peripheral oxygen saturation (SpO2) thresholds of 90-94%. However, these thresholds are poorly studied. We conducted a systematic review to summarise the existing evidence for SpO2 thresholds in children with respiratory distress. Methods: Electronic databases and registries were searched for original articles published from 1 January 2010 to 7 January 2022 comparing two or more SpO2 thresholds in children with respiratory distress. Primary outcomes were safety, including mortality, neurocognitive outcomes and readmissions, and effectiveness, including admission rate and length of hospital stay. Methodological appraisal was performed using the Cochrane Risk of Bias 2 (RoB-2) or Risk of Bias in Non-Randomized Studies - of Interventions (ROBINS-I) tools. Results were narratively synthesised. Results: We retrieved 3384 results; seven studies were included. Lower thresholds ranged from 80% to 92% and were compared with higher thresholds ranging from 92% to 94%. Studies were highly heterogeneous in setting, design, population and outcomes. Risk of bias varied from low to high. Lower SpO2 thresholds had equivalent mortality, neurocognitive outcomes and readmissions or re-attendance to healthcare to higher thresholds. Lower SpO2 thresholds showed a significant decrease in admission rates by up to 40% and shortened hospitalisation duration by 10-18 h. Conclusions: The current SpO2 thresholds of 90-94% in children with respiratory distress may be too high, which could lead to unnecessary hospitalisations and prolonged hospitalisation duration. SpO2 thresholds as low as 88% are potentially safe in children with respiratory distress and may reduce hospitalisation rates and length of stay. However, high-quality evidence is needed to support this.

An infant with fever and tachypnoea: diagnosis at first sight?

Complicated pneumonia can resemble an infection in congenital pulmonary abnormalities such as CPAM or sequestration. Both have an increased risk of a complicated course. Imaging can support treatment decisions and may avoid unnecessary surgical intervention. https://bit.ly/3IMU9aL.

Lung structure and function on MRI in preterm born school children with and without BPD: A feasibility study.

BACKGROUND AND OBJECTIVE: The most common respiratory complication of prematurity is bronchopulmonary dysplasia (BPD), leading to structural lung changes and impaired respiratory outcomes. However, also preterm children without BPD may show similar adverse respiratory outcomes. There is a need for a safe imaging modality for preterm children with and without BPD for disease severity assessment and risk stratification. Our objective was to develop a magnetic resonance imaging (MRI) protocol in preterm children with and without BPD at school age. METHODS: Nine healthy volunteers (median age 11.6 [range: 8.8-12.8] years), 11 preterm children with BPD (11.0 [7.2-15.6] years), and 9 without BPD (11.1 [10.7-12.6] years) underwent MRI. Images were scored on hypo- and hyperintense abnormalities, bronchopathy, and architectural distortion. MRI data were correlated to spirometry. Ventilation and perfusion defects were analyzed using Fourier Decomposition (FD) MRI. RESULTS: On MRI, children with BPD had higher %diseased lung (9.1 (interquartile range [IQR] 5.9-11.6)%) compared to preterm children without BPD (3.4 (IQR 2.5-5.4)%, p < 0.001) and healthy volunteers (0.4 (IQR 0.1-0.8)%, p < 0.001). %Diseased lung correlated negatively with %predicted FEV1 (r = -0.40, p = 0.04), FEV1 /FVC (r = -0.49, p = 0.009) and FEF75 (r = -0.63, p < 0.001). Ventilation and perfusion defects on FD sequence corresponded to hypointense regions on expiratory MRI. CONCLUSION: Chest MRI can identify structural and functional lung damage at school age in preterm children with and without BPD, showing a good correlation with spirometry. We propose MRI as a sensitive and safe imaging method (without ionizing radiation, contrast agents, or the use of anesthesia) for the long-term follow-up of preterm children.

Pediatric long-COVID: An overlooked phenomenon?

BACKGROUND: Long-COVID is a well-documented multisystem disease in adults. Far less is known about long-term sequelae of COVID in children. Here, we report on the occurrence of long-COVID in Dutch children. PATIENTS AND METHODS: We conducted a national survey asking Dutch pediatricians to share their experiences on long-COVID in children. We furthermore describe a case series of six children with long-COVID to explore the clinical features in greater detail. RESULTS: With a response rate of 78% of Dutch pediatric departments, we identified 89 children, aged 2-18 years, suspected of long-COVID with various complaints. Of these children, 36% experienced severe limitations in daily function. The most common complaints were fatigue, dyspnea, and concentration difficulties with 87%, 55%, and 45% respectively. Our case series emphasizes the nonspecific and broad clinical manifestations seen in post-COVID complaints. CONCLUSION: Our study shows that long-COVID is also present in the pediatric population. The main symptoms resemble those previously described in adults. This novel condition demands a multidisciplinary approach with international awareness and consensus to aid early detection and effective management.

Airway-artery quantitative assessment on chest computed tomography in paediatric primary ciliary dyskinesia.

Chest computed tomography (CT) is the gold standard for detecting structural abnormalities in patients with primary ciliary dyskinesia (PCD) such as bronchiectasis, bronchial wall thickening and mucus plugging. There are no studies on quantitative assessment of airway and artery abnormalities in children with PCD. The objectives of the present study were to quantify airway and artery dimensions on chest CT in a cohort of children with PCD and compare these with control children to analyse the influence of covariates on airway and artery dimensions. Chest CTs of 13 children with PCD (14 CT scans) and 12 control children were collected retrospectively. The bronchial tree was segmented semi-automatically and reconstructed in a three-dimensional view. All visible airway-artery (AA) pairs were measured perpendicular to the airway centre line, annotating per branch inner and outer airway and adjacent artery diameter and computing inner airway diameter/artery ratio (AinA ratio), outer airway diameter/artery ratio (AoutA ratio), wall thickness (WT), WT/outer airway diameter ratio (Awt ratio) and WT/artery ratio. In the children with PCD (38.5% male, mean age 13.5 years, range 9.8-15.3) 1526 AA pairs were measured versus 1516 in controls (58.3% male, mean age 13.5 years, range 8-14.8). AinA ratio and AoutA ratio were significantly higher in children with PCD than in control children (both p<0.001). Awt ratio was significantly higher in control children than in children with PCD (p<0.001). Our study showed that in children with PCD airways are more dilated than in controls and do not show airway wall thickening.

COVID-19 in children with underlying chronic respiratory diseases: survey results from 174 centres.

BACKGROUND: Early reports suggest that most children infected with severe acute respiratory syndrome coronavirus 2 ("SARS-CoV-2") have mild symptoms. What is not known is whether children with chronic respiratory illnesses have exacerbations associated with SARS-CoV-2 virus. METHODS: An expert panel created a survey, which was circulated twice (in April and May 2020) to members of the Paediatric Assembly of the European Respiratory Society (ERS) and via the social media of the ERS. The survey stratified patients by the following conditions: asthma, cystic fibrosis (CF), bronchopulmonary dysplasia (BPD) and other respiratory conditions. RESULTS: In total 174 centres responded to at least one survey. 80 centres reported no cases, whereas 94 entered data from 945 children with coronavirus disease 2019 (COVID-19). SARS-CoV-2 was isolated from 49 children with asthma of whom 29 required no treatment, 19 needed supplemental oxygen and four children required mechanical ventilation. Of the 14 children with CF and COVID-19, 10 required no treatment and four had only minor symptoms. Among the nine children with BPD and COVID-19, two required no treatment, five required inpatient care and oxygen and two were admitted to a paediatric intensive care unit (PICU) requiring invasive ventilation. Data were available from 33 children with other conditions and SARS-CoV-2 of whom 20 required supplemental oxygen and 11 needed noninvasive or invasive ventilation. CONCLUSIONS: Within the participating centres, in children with asthma and CF, infection with SARS-CoV-2 was well tolerated, but a substantial minority of children with BPD and other conditions required ventilatory support indicating that these latter groups are at risk from SARS-CoV-2 infection.

First analysis of the Severe Paediatric Asthma Collaborative in Europe registry.

New biologics are being continually developed for paediatric asthma, but it is unclear whether there are sufficient numbers of children in Europe with severe asthma and poor control to recruit to trials needed for registration. To address these questions, the European Respiratory Society funded the Severe Paediatric Asthma Collaborative in Europe (SPACE), a severe asthma registry. We report the first analysis of the SPACE registry, which includes data from 10 paediatric respiratory centres across Europe. Data from 80 children with a clinical diagnosis of severe asthma who were receiving both high-dose inhaled corticosteroid and long-acting ß2-agonist were entered into the registry between January 2019 and January 2020. Suboptimal control was defined by either asthma control test, or Global Initiative for Asthma criteria, or ≥2 severe exacerbations in the previous 12 months, or a combination. Overall, 62 out of 80 (77%) children had suboptimal asthma control, of whom 29 were not prescribed a biologic. However, in 24 there was an option for starting a licensed biologic. 33 children with suboptimal control were prescribed a biologic (omalizumab (n=24), or mepolizumab (n=7), or dupilumab (n=2)), and for 29 there was an option to switch to a different biologic. We conclude that the SPACE registry provides data that will support the planning of studies of asthma biologics. Not all children on biologics achieve good asthma control, and there is need for new trial designs addressing biologic switching.

Episodic viral wheeze and multiple-trigger wheeze in preschool children are neither distinct nor constant patterns. A prospective multicenter cohort study in secondary care.

OBJECTIVES: To evaluate whether episodic viral wheeze (EVW) and multiple-trigger wheeze (MTW) are clinically distinguishable and stable preschool wheezing phenotypes. METHODS: Children of age 1 to 4 year with recurrent, pediatrician-confirmed wheeze were recruited from secondary care; 189 were included. Respiratory and viral upper respiratory tract infection (URTI) symptoms were recorded weekly by parents in an electronic diary during 12 months. Every 3 months, diary-based symptoms were classified as EVW or MTW and compared to phenotypes assigned by pediatricians based on clinical history. We collected nasal samples for respiratory virus PCR during URTI, respiratory symptoms and in absence of symptoms. RESULTS: Of 660 3-month periods, the diary-based phenotype was EVW in 11%, MTW in 54% and 35% were free from respiratory episodes. Pediatrician-based classification showed 59% EVW and 26% MTW. The Kappa measure of agreement between diary-based and pediatrician-assigned phenotypes was very low (0.12, 95%CI, 0.07-0.17). Phenotypic instability was observed in 32% of cases. PCR was positive in 71% during URTI symptoms, 66% during respiratory symptoms and 38% in the absence of symptoms. CONCLUSION: This study shows that EVW and MTW are variable over time within patients. Pediatrician classification of these phenotypes based on clinical history does not correspond to prospectively recorded symptom patterns. The applicability of these phenotypes as a basis for therapeutic decisions and prognosis should be questioned.

Severe Paediatric Asthma Collaborative in Europe (SPACE): protocol for a European registry.

The development of new asthma biologics and receptor blockers for the treatment of paediatric severe asthma raises challenges. It is unclear whether there are sufficient children in Europe to recruit into randomised placebo-controlled trials to establish efficacy and safety in this age group. In February 2016, the European Respiratory Society funded a clinical research collaboration entitled "Severe Paediatric Asthma Collaborative in Europe" (SPACE). We now report the SPACE protocol for a prospective pan-European observational study of paediatric severe asthma. Inclusion criteria are: 1) age 6-17 years, 2) severe asthma managed at a specialised centre for ≥6 months, 3)clinical and spirometry evidence of asthma, and 4) reaching a pre-defined treatment threshold. The exclusion criterion is the presence of conditions which mimic asthma symptoms. Eligible children will be prospectively recruited into a registry, recording demographics, comorbidities, quality of life, family history, neonatal history, smoking history, asthma background, investigations, and treatment. Follow-up will provide longitudinal data on asthma control and treatment changes. The SPACE registry, by identifying well-phenotyped children eligible for clinical trials, and the amount of overlap in eligibility criteria, will inform the design of European trials in paediatric severe asthma, and facilitate observational research where data from single centres are limited.

Tracheomalacia and bronchomalacia in children: incidence and patient characteristics.

OBJECTIVE: Congenital airway malacia is one of the few causes of irreversible airways obstruction in children, but the incidence in the general population is unknown. Severe airway malacia or malacia associated with specific syndromes is usually recognized and diagnosed early in infancy, but information about clinical features of children with primary malacia, often diagnosed only later in childhood, is scarce. METHODS: We analyzed all flexible bronchoscopies performed between 1997 and 2004 in the Sophia Children's Hospital, summarized clinical features of children with primary airway malacia, estimated the incidence of primary airway malacia, and calculated the predictive value of a clinical diagnosis of airway malacia by pediatric pulmonologists. RESULTS: In a total of 512 bronchoscopies, airway malacia was diagnosed in 160 children (94 males) at a median age of 4.0 years (range, 0 to 17 years). Airway malacia was classified as primary in 136 children and secondary in 24 children. The incidence of primary airway malacia was estimated to be at least 1 in 2,100. When pediatric pulmonologists expected to find airway malacia (based on symptoms, history, and lung function) prior to bronchoscopy, this was correct in 74% of the cases. In 52% of the airway malacia diagnoses, the diagnosis was not suspected prior to bronchoscopy. Presenting clinical features of children with airway malacia were variable and atypical, showing considerable overlap with features of allergic asthma. Peak expiratory flow was more reduced than FEV(1). CONCLUSION: Primary airway malacia is not rare in the general population, with an estimated incidence of at least 1 in 2,100 children. Airway malacia is difficult to recognize based on clinical features that show overlap with those of more common pulmonary diseases. We recommend bronchoscopy in patients with impaired exercise tolerance, recurrent lower airways infection, and therapy-resistant, irreversible, and/or atypical asthma to rule out airway malacia.

Tidal breathing FeNO measurements: a new algorithm.

OBJECTIVE: International guidelines recommend measuring fractional exhaled nitric oxide (FeNO) during a single slow exhalation with a constant flow of 50 ml/sec. We developed a new algorithm to compute FeNO at 50 ml/sec from tidal breathing measurements. The main objective is to assess the correlation and agreement of this algorithm with the conventional single breath FeNO measurements. METHODS: We recruited children aged 6-18 years, who performed both a single breath and a tidal breathing FeNO measurement in random order. Both maneuvers were performed on the Eco Medics NO-analyser (Eco Physics AG, Duernten, Switzerland). RESULTS: We included 109 patients between January 2011 and April 2011. Geometric mean (95% CI) FeNO values did not differ significantly between single breath and tidal breathing technique: 21.0 (17.7-24.8) ppb and 20.0 (17.0-23.6) ppb (P = 0.18), respectively. We found an excellent intraclass correlation coefficient of 0.96 (0.94-0.97) and moderate agreement with a mean difference of 4% (95% limits of agreement -43% and +90%). CONCLUSION: Tidal breathing FeNO values could be transformed with a new algorithm to match single breath FeNO at a constant flow of 50 ml/sec. This algorithm opens the way to standardized FeNO measurements in preschool children and uncooperative patients.

[Treatment of children with asthma based on exhaled nitrogen monoxide: added value of nitrogen monoxide measurements has not yet been demonstrated]. / Behandeling kinderen met astma op geleide van stikstofmonoxide in de uitademingslucht: meerwaarde stikstofmonoxidemeting nog niet aangetoond.

There is controversy about the effectiveness of monitoring of asthma treatment based on the fraction of exhaled nitric oxide (FeNO). We performed a systematic review of the literature on the effectiveness of FeNO-guided asthma treatment in children. Up to the end of March 2009, four randomised controlled trials were published, but the results of the trials could not be pooled. Their methodological quality was moderate to high. There was no significant effect of FeNO-guided asthma treatment on the number of symptom-free days, asthma exacerbations, hospital admissions, pulmonary function history (except one trial) and quality of life. There was a moderate effect on prednisone use. Children receiving FeNO-guided treatment used prednisone less often than children whose treatment was based on symptoms. However, children receiving FeNO-guided treatment used higher doses of inhaled corticosteroids. At this moment, FeNO-guided asthma treatment cannot be recommended in general practice and paediatric care.

The effect of spirometry and exercise on exhaled nitric oxide in asthmatic children.

American Thoracic Society (ATS) guidelines recommend to refrain from spirometry or exercise before measuring fractional exhaled nitric oxide (FENO) because forced breathing maneuvers might influence FENO values. However the few studies already reported in children have given conflicting results. The aim of the study was to observe to what extent spirometry or exercise could affect FENO in asthmatic children. Twenty-four asthmatic children (mean age 12.8 yr) were enrolled. Measurements of FENO were performed before and 5, 15, 30, 45 and 60 min after spirometry or a 6-min walk test, on two separate days in random order. Geometric mean FENO at baseline was 25.6 parts per billion (ppb) before spirometry and 23.5 ppb before exercise. A small drop of FENO to 24.2 and 23.7 ppb was found 5 and 15 min after spirometry (both p = 0.04). After exercise, FENO values showed a larger drop to 18.5 ppb after 5 min and 20.7 ppb after 15 min (p < 0.001; p = 0.004 respectively). Changes in FENO occurred after exercise irrespective of baseline FENO and values returned to baseline within 30 min. We conclude that both spirometry and exercise affect FENO in asthmatic children. As the changes after exercise may lead to erroneous interpretations, children should refrain from physical exercise during at least 30 min before FENO measurements.

Measurements of exhaled nitric oxide in healthy subjects age 4 to 17 years.

BACKGROUND: Fractional exhaled nitric oxide (FE NO ) is used in monitoring of asthma. OBJECTIVES: The aim of this multicenter study was to establish normal values of FE NO and assess feasibility in children with a standardized method and equipment approved for clinical use. METHODS: FE NO was measured in healthy subjects of 4 to 17 years according to American Thoracic Society guidelines (single breath online, exhalation flow 50 mL/s) with a chemiluminescence analyzer (NIOX Exhaled Nitric Oxide Monitoring System, Aerocrine, Sweden) in 3 European and 2 US centers. Each child performed 3 acceptable nitric oxide measurements within 6 attempts and completed an extended International Study of Asthma and Allergy in Children questionnaire. RESULTS: Measurement of FE NO was attempted in 522 children. Four hundred five children completed the study according to the protocol. Geometric mean FE NO in 405 children was 9.7 ppb, and the upper 95% confidence limit was 25.2 ppb. FE NO increased significantly with age, and higher FE NO was seen in children with self-reported rhinitis/conjunctivitis or hay fever. The success rate was age-dependent and improved from 40% in the children 4 years old to almost 100% from the age of 10 years. The repeatability of 3 approved measurements was 1.6 ppb (95% CI, 1.49-1.64 ppb). CONCLUSION: FE NO in healthy children is below 15 to 25 ppb depending on age and self-reported atopy. Measurement of FE NO by NIOX is simple and safe and has a good repeatability. Feasibility depends on age and may be difficult in the preschool child.

Exhaled nitric oxide in mylar balloons: influence of storage time, humidity and temperature.

BACKGROUND: Mylar balloons are used to collect exhaled air for analysis of fractional nitric oxide concentration (FENO). AIM: We studied the effect of storage conditions on the stability of nitric oxide (NO) in mylar balloons. METHODS: Exhaled air samples and calibration gases were stored in mylar balloons at 4, 21 and 37 degrees C, with or without silica gel. NO was measured after 0, 6, 9, 24 and 48 h. Scheffe F-tests were used to compare NO values. RESULTS: NO remained stable in balloons for 9 h at all temperatures, without silica gel. NO increased between 9 and 48 h, but only with low initial FENO. Silica gel increased variability. CONCLUSIONS: FENO in mylar balloons is stable for at least 9 h. The storage temperature is not critical, but silica gel increases variability.