Ventilation heterogeneity in children with severe asthma.

Small airway disease, characterised by ventilation heterogeneity (VH), is present in a subgroup of patients with asthma. Ventilation heterogeneity can be measured using multiple breath washout testing. Few studies have been reported in children. We studied the relationship between VH, asthma severity, and spirometry in a cross-sectional observational cohort study involving children with stable mild-moderate and severe asthma by GINA classification and a group of healthy controls. Thirty-seven participants aged 5-16 years completed multiple breath nitrogen washout (MBNW) testing (seven controls, seven mild-moderate asthma, 23 severe asthma). The lung clearance index (LCI) was normal in control and mild-moderate asthmatics. LCI was abnormal in 5/23 (21%) of severe asthmatics. The LCI negatively correlated with FEV1 z-score.Conclusion: VH is present in asthmatic children and appears to be more common in severe asthma. The LCI was significantly higher in the cohort of children with severe asthma, despite no difference in FEV1 between the groups. This supports previous evidence that LCI is a more sensitive marker of airway disease than FEV1. MBNW shows potential as a useful tool to assess children with severe asthma and may help inform clinical decisions. What is Known: • Increased ventilation heterogeneity is present in some children with asthma • Spirometry is not sensitive enough to detect small airway involvement in asthma What is New • Lung clearance index is abnormal in a significant subgroup of children with severe asthma but rarely in children with mild-moderate asthma • Our data suggests that LCI monitoring should be considered in children with severe asthma.

LabPipe: an extensible bioinformatics toolkit to manage experimental data and metadata.

BACKGROUND: Data handling in clinical bioinformatics is often inadequate. No freely available tools provide straightforward approaches for consistent, flexible metadata collection and linkage of related experimental data generated locally by vendor software. RESULTS: To address this problem, we created LabPipe, a flexible toolkit which is driven through a local client that runs alongside vendor software and connects to a light-weight server. The toolkit allows re-usable configurations to be defined for experiment metadata and local data collection, and handles metadata entry and linkage of data. LabPipe was piloted in a multi-site clinical breathomics study. CONCLUSIONS: LabPipe provided a consistent, controlled approach for handling metadata and experimental data collection, collation and linkage in the exemplar study and was flexible enough to deal effectively with different data handling challenges.

Lung function and asthma control in school-age children managed in UK primary care: a cohort study.

BACKGROUND: Spirometry and fraction of exhaled nitric oxide (FeNO) are commonly used in specialist centres to monitor children with asthma. The National Institute for Health and Care Excellence recommends spirometry for asthma monitoring from 5 years in all healthcare settings. There is little spirometry and FeNO data in children managed for asthma in UK primary care to support their use. OBJECTIVES: To study the prevalence of abnormal spirometry and FeNO in children with asthma managed in primary care and to explore their relationship with asthma control and unplanned healthcare attendances (UHA). METHODS: Prospective observational cohort study in children aged 5-16 years with suspected or doctor-diagnosed asthma attending an asthma review in UK general practice. Spirometry, FeNO, asthma control test (ACT) scores and number of UHAs were studied. RESULTS: Of 612 children from 10 general practices, 23.5% had abnormal spirometry, 36.0% had raised FeNO ≥35 parts per billion and 41.8% reported poor control. Fifty-four per cent of children reporting good asthma control had abnormal spirometry and/or raised FeNO. At follow-up, the mean number of UHAs fell from 0.31/child in the 6 months preceding review to 0.20/child over the 6 months following review (p=0.0004). Median ACT scores improved from 20 to 22 (p=0.032), and children's ACT from 21 to 23 (p<0.0001). CONCLUSIONS: Abnormal lung function and FeNO are common in children attending for asthma review in primary care and relate poorly to symptom scores. A symptoms-based approach to asthma monitoring without objective testing is likely to miss children at high risk of future severe asthma attacks.

Longitudinal Associations Between Respiratory Infections and Asthma in Young Children.

We examined temporal dependencies between repeated assessments of respiratory tract infections (RTIs) and asthma in children in the Leicester Respiratory Cohort, Leicestershire, United Kingdom. Information associated with asthma (i.e., doctor diagnosis, health care visits, wheeze frequency) and RTIs (i.e., cold duration and frequency, cough with colds, ear infections) in the previous 12 months was assessed repeatedly at ages 1, 4, and 6 years for children born between April 1996 and April 1997. We determined associations between contemporaneous and lagged measures of asthma and RTIs, using structural equation modelling. In 1,995 children, asthma was positively associated with contemporaneous infections. Asthma at age 6 years was positively associated with asthma at age 4 years (regression coefficient = 0.87; 95% confidence interval (CI): 0.76, 0.97), but not with asthma at age 1 year (regression coefficient = -0.01; 95% CI: -0.14, 0.11). We found no evidence for direct protective effect of infections at age 1 year on asthma either at age 4 (regression coefficient = -0.20; 95% CI: -0.51, 0.10) or 6 (regression coefficient = 0.24; 95% CI: -0.04, 0.52) years. Adjusting for potential confounders did not qualitatively change those relationships. Based on our findings, we suggest that asthma at age 6 years is directly influenced by asthma history and only indirectly, if at all, by earlier infection episodes. We found little support for a protective effect of preschool infections on asthma at early school age.

Early growth characteristics and the risk of reduced lung function and asthma: A meta-analysis of 25,000 children.

BACKGROUND: Children born preterm or with a small size for gestational age are at increased risk for childhood asthma. OBJECTIVE: We sought to assess the hypothesis that these associations are explained by reduced airway patency. METHODS: We used individual participant data of 24,938 children from 24 birth cohorts to examine and meta-analyze the associations of gestational age, size for gestational age, and infant weight gain with childhood lung function and asthma (age range, 3.9-19.1 years). Second, we explored whether these lung function outcomes mediated the associations of early growth characteristics with childhood asthma. RESULTS: Children born with a younger gestational age had a lower FEV1, FEV1/forced vital capacity (FVC) ratio, and forced expiratory volume after exhaling 75% of vital capacity (FEF75), whereas those born with a smaller size for gestational age at birth had a lower FEV1 but higher FEV1/FVC ratio (P < .05). Greater infant weight gain was associated with higher FEV1 but lower FEV1/FVC ratio and FEF75 in childhood (P < .05). All associations were present across the full range and independent of other early-life growth characteristics. Preterm birth, low birth weight, and greater infant weight gain were associated with an increased risk of childhood asthma (pooled odds ratio, 1.34 [95% CI, 1.15-1.57], 1.32 [95% CI, 1.07-1.62], and 1.27 [95% CI, 1.21-1.34], respectively). Mediation analyses suggested that FEV1, FEV1/FVC ratio, and FEF75 might explain 7% (95% CI, 2% to 10%) to 45% (95% CI, 15% to 81%) of the associations between early growth characteristics and asthma. CONCLUSIONS: Younger gestational age, smaller size for gestational age, and greater infant weight gain were across the full ranges associated with childhood lung function. These associations explain the risk of childhood asthma to a substantial extent.

Catch-up alveolarization in ex-preterm children: evidence from (3)He magnetic resonance.

RATIONALE: Histologic data from fatal cases suggest that extreme prematurity results in persisting alveolar damage. However, there is new evidence that human alveolarization might continue throughout childhood and could contribute to alveolar repair. OBJECTIVES: To examine whether alveolar damage in extreme-preterm survivors persists into late childhood, we compared alveolar dimensions between schoolchildren born term and preterm, using hyperpolarized helium-3 magnetic resonance. METHODS: We recruited schoolchildren aged 10-14 years stratified by gestational age at birth (weeks) to four groups: (1) term-born (37-42 wk; n = 61); (2) mild preterm (32-36 wk; n = 21); (3) extreme preterm (<32 wk, not oxygen dependent at 4 wk; n = 19); and (4) extreme preterm with chronic lung disease (<32 wk and oxygen dependent beyond 4 wk; n = 18). We measured lung function using spirometry and plethysmography. Apparent diffusion coefficient, a surrogate for average alveolar dimensions, was measured by helium-3 magnetic resonance. MEASUREMENTS AND MAIN RESULTS: The two extreme preterm groups had a lower FEV1 (P = 0.017) compared with term-born and mild preterm children. Apparent diffusion coefficient was 0.092 cm(2)/second (95% confidence interval, 0.089-0.095) in the term group. Corresponding values were 0.096 (0.091-0.101), 0.090 (0085-0.095), and 0.089 (0.083-0.094) in the mild preterm and two extreme preterm groups, respectively, implying comparable alveolar dimensions across all groups. Results did not change after controlling for anthropometric variables and potential confounders. CONCLUSIONS: Alveolar size at school age was similar in survivors of extreme prematurity and term-born children. Because extreme preterm birth is associated with deranged alveolar structure in infancy, the most likely explanation for our finding is catch-up alveolarization.

Comparison of phenotypes of childhood wheeze and cough in 2 independent cohorts.

BACKGROUND: Among children with wheeze and recurrent cough there is great variation in clinical presentation and time course of the disease. We previously distinguished 5 phenotypes of wheeze and cough in early childhood by applying latent class analysis to longitudinal data from a population-based cohort (original cohort). OBJECTIVE: To validate previously identified phenotypes of childhood cough and wheeze in an independent cohort. METHODS: We included 903 children reporting wheeze or recurrent cough from an independent population-based cohort (validation cohort). As in the original cohort, we used latent class analysis to identify phenotypes on the basis of symptoms of wheeze and cough at 2 time points (preschool and school age) and objective measurements of atopy, lung function, and airway responsiveness (school age). Prognostic outcomes (wheeze, bronchodilator use, cough apart from colds) 5 years later were compared across phenotypes. RESULTS: When using a 5-phenotype model, the analysis distinguished 3 phenotypes of wheeze and 2 of cough as in the original cohort. Two phenotypes were closely similar in both cohorts: Atopic persistent wheeze (persistent multiple trigger wheeze and chronic cough, atopy and reduced lung function, poor prognosis) and transient viral wheeze (early-onset transient wheeze with viral triggers, favorable prognosis). The other phenotypes differed more between cohorts. These differences might be explained by differences in age at measurements. CONCLUSIONS: Applying the same method to 2 different cohorts, we consistently identified 2 phenotypes of wheeze (atopic persistent wheeze, transient viral wheeze), suggesting that these represent distinct disease processes. Differences found in other phenotypes suggest that the age when features are assessed is critical and should be considered carefully when defining phenotypes.

Breastfeeding and lung function at school age: does maternal asthma modify the effect?

RATIONALE: The evidence for an effect of breastfeeding on lung function is conflicting, in particular whether the effect is modified by maternal asthma. OBJECTIVES: To explore the association between breastfeeding and school-age lung function. METHODS: In the Leicestershire Cohort Studies we assessed duration of breastfeeding (not breastfed, ≤3 months, 4-6 months, and >6 months), other exposures, and respiratory symptoms by repeated questionnaires. Post-bronchodilator FVC, FEV(1), peak expiratory flow (PEF), forced midexpiratory flow (FEF(50)), and skin prick tests were measured at age 12 years. We performed multivariable linear regression and tested potential causal pathways (N = 1,458). MEASUREMENTS AND MAIN RESULTS: In the entire sample, FEF(50) was higher by 130 and 164 ml in children breastfed for 4 to 6 months and longer than 6 months, respectively, compared with those not breastfed (P = 0.048 and 0.041), with larger effects if the mother had asthma. FVC and FEV(1) were associated with breastfeeding only in children of mothers with asthma (P for interaction, 0.018 and 0.008): FVC was increased by 123 and 164 ml for those breastfed 4 to 6 months or longer than 6 months, respectively (P = 0.177 and 0.040) and FEV(1) was increased by 148 and 167 ml, respectively (P = 0.050 and 0.016). Results were unchanged after adjustment for respiratory infections in infancy and asthma and atopy in the child. CONCLUSIONS: In this cohort, breastfeeding for more than 4 months was associated with increased FEF(50) and, in children of mothers with asthma, with increased FEV(1) and FVC. It seems that the effect is not mediated via avoidance of early infections or atopy but rather through a direct effect on lung growth.

Alveolarization continues during childhood and adolescence: new evidence from helium-3 magnetic resonance.

RATIONALE: The current hypothesis that human pulmonary alveolarization is complete by 3 years is contradicted by new evidence of alveolarization throughout adolescence in mammals. OBJECTIVES: We reexamined the current hypothesis using helium-3 ((3)He) magnetic resonance (MR) to assess alveolar size noninvasively between 7 and 21 years, during which lung volume nearly quadruples. If new alveolarization does not occur, alveolar size should increase to the same extent. METHODS: Lung volumes were measured by spirometry and plethysmography in 109 healthy subjects aged 7-21 years. Using (3)HeMR we determined two independent measures of peripheral airspace dimensions: apparent diffusion coefficient (ADC) of (3)He at FRC (n = 109), and average diffusion distance of helium (X(rms)) by q-space analysis (n = 46). We compared the change in these parameters with lung growth against a model of lung expansion with no new alveolarization. MEASUREMENTS AND MAIN RESULTS: ADC increased by 0.19% for every 1% increment in FRC (95% confidence interval [CI], 0.13-0.25), whereas the expected change in the absence of neoalveolarization is 0.41% (95% CI, 0.31-0.52). Similarly, increase of (X(rms)) with FRC was significantly less than the predicted increase in the absence of neoalveolarization. The number of alveoli is estimated to increase 1.94-fold (95% CI, 1.64-2.30) across the age range studied. CONCLUSIONS: Our observations are best explained by postulating that the lungs grow partly by neoalveolarization throughout childhood and adolescence. This has important implications: developing lungs have the potential to recover from early life insults and respond to emerging alveolar therapies. Conversely, drugs, diseases, or environmental exposures could adversely affect alveolarization throughout childhood.

Differences in respiratory oscillometry measurements using mouthpiece, mouth, and nasal mask in healthy adults.

Airway resistance measurements using oscillometry provide a potential alternative to spirometry in assessing airway obstruction and dynamics due to measurements taken during tidal breathing. Oscillometry typically requires participants to form a tight seal around a mouthpiece that can prove challenging for some people. To address this challenge, we conducted a prospective study to evaluate the effect of different interfaces like mouthpiece, mouth mask, and nasal mask on respiratory impedance results from oscillometry in a cohort of healthy adults. Ten healthy adults [7 females; mean age: 38.9 yr (SD ±15.5)] underwent oscillometry using each of the three interfaces. We measured resistance at 5 Hz (Rrs5), frequency dependence of resistance at 5-20 Hz (Rrs5-20), and reactance area (Ax). Rrs5 was not different when using the mouthpiece compared with the mouth mask [mean 2.98 cmH2O/L/s (SD ±0.68) vs. mean 3.2 cmH2O/L/s (SD ±0.81); P = 0.92; 95% CI -0.82 to +0.38], respectively. Nasal mask Rrs5 measurements were significantly higher than mouthpiece measurements (mean 7.31 cmH2O/L/s; SD ±2.62; P < 0.01; 95%CI -6.91 to -1.75). With Ax5, we found a mean of 4.01 cmH2O/L (SD ±2.04) with the mouth mask compared with a mean of 4.02 cmH2O/L (SD ±1.87; P = 1.0 95% CI -1.86 to +1.87) for the mouthpiece, however, we found a significant difference between the mouthpiece and nasal mask for Ax (mean = 10.71; SD ±7.0 H2O/L; P = 0.04, 95% CI -12.96 to -0.43). Our findings show that oscillometry using a mouth mask may be just as effective as using a mouthpiece in assessing airway dynamics and resistance.NEW & NOTEWORTHY This is the first study to compare the use of different interfaces: mouthpiece, mouth mask, and nasal mask, for oscillometry in an adult population. We report that using a mouth mask in oscillometry may provide a valid alternative to a mouthpiece in cohorts who may struggle to form the required tight seal that is typically required in oscillometry or spirometry.

Risk factors for asthma attacks and poor control in children: a prospective observational study in UK primary care.

OBJECTIVE: To identify risk factors for asthma attacks and poor asthma control in children aged 5-16 years. METHODS: Prospective observational cohort study of 460 children with asthma or suspected asthma from 10 UK general practices.Gender, age, ethnicity, body mass index, practice deprivation decile, spirometry and fraction of exhaled nitric oxide (FeNO) were recorded at baseline. Asthma control scores, asthma medication ratio (AMR) and the number of asthma attacks were recorded at baseline and at 6 months.The above independent variables were included in binary multiple logistic regression analyses for the dependent variables of: (1) poor symptom control and (2) asthma attacks during follow-up. RESULTS: Poor symptom control at baseline predicted poor symptom control at 6 months (OR 4.4, p=0.001), while an increase in deprivation decile (less deprived) was negatively associated with poor symptom control at 6 months (OR 0.79, p=0.003). Higher FeNO levels (OR 1.02, p<0.001) and a recent history of asthma attacks (OR 2.03, p=0.02) predicted asthma attacks during follow-up. Asian ethnicity was associated with a lower OR for a future attack (OR 0.32, p=0.02).A decrease in AMR was also associated with an increased OR for future asthma attacks (OR 2.99, p=0.003) when included as an independent variable. CONCLUSIONS: We identified risk factors for poor symptom control and asthma attacks in children. Routine assessment of these factors should form part of the asthma review to identify children at an increased risk of adverse asthma-related events.

Implementing spirometry and fractional exhaled nitric oxide testing in childhood asthma management in UK primary care: an observational study to examine training and implementation cost and impact on patient's health use and outcome.

OBJECTIVES: Implementation of guidelines into clinical practice is challenging and complex. This study aims to (1) identify the training needs and capacity requirements, and (2) explore the impact on healthcare utilisation and asthma-related quality of life of implementing both spirometry and fraction of exhaled nitric oxide in diagnosis of asthma among children in the UK primary care. METHODS: Ten UK general practitioner practices and a total of 612 children (5-16 years) with diagnosed or suspected asthma were invited to participate in this prospective observational study. The total times that the trainer and trainee clinical staff spent on developing the training package, providing and receiving, and performing and interpreting the two tests as part of routine child asthma review were collected, and costs were calculated. We compared healthcare utilisation and asthma-related and general health-related quality of life data between the 6 months before and after the asthma review guided by objective tests. RESULTS: The average training cost for the 27 primary care clinical members was £1395. The average cost to implement and deliver the test-guided asthma review among the 612 included children was £22. In the 6 months following the tests-guided asthma review, both unplanned primary care attendance, and hospital admissions were reduced, and the asthma-related health status increased significantly. CONCLUSION: This study provides robust cost estimates of the resources needed to implement the National Institute for Health and Care Excellence asthma guideline. It also demonstrates the potential to save healthcare costs and improve health status among asthmatic children by implementing this guideline.

The variability of volatile organic compounds in the indoor air of clinical environments.

The development of clinical breath-analysis is confounded by the variability of background volatile organic compounds (VOCs). Reliable interpretation of clinical breath-analysis at individual, and cohort levels requires characterisation of clinical-VOC levels and exposures. Active-sampling with thermal-desorption/gas chromatography-mass spectrometry recorded and evaluated VOC concentrations in 245 samples of indoor air from three sites in a large National Health Service (NHS) provider trust in the UK over 27 months. Data deconvolution, alignment and clustering isolated 7344 features attributable to VOC and described the variability (composition and concentration) of respirable clinical VOC. 328 VOC were observed in more than 5% of the samples and 68 VOC appeared in more than 30% of samples. Common VOC were associated with exogenous and endogenous sources and 17 VOC were identified as seasonal differentiators. The presence of metabolites from the anaesthetic sevoflurane, and putative-disease biomarkers in room air, indicated that exhaled VOC were a source of background-pollution in clinical breath-testing activity. With the exception of solvents, and waxes associated with personal protective equipment (PPE), exhaled VOC concentrations above 3µg m-3are unlikely to arise from room air contamination, and in the absence of extensive survey-data, this level could be applied as a threshold for inclusion in studies, removing a potential environmental confounding-factor in developing breath-based diagnostics.

Spirometry and FeNO testing for asthma in children in UK primary care: a prospective observational cohort study of feasibility and acceptability.

BACKGROUND: The National Institute for Health and Care Excellence recommends the use of spirometry and measuring the fraction of exhaled nitric oxide (FeNO) as part of the diagnostic work-up for children with suspected asthma, and spirometry for asthma monitoring, across all care settings. However, the feasibility and acceptability of these tests within primary care are not known. AIM: To investigate the feasibility, acceptability, training, and capacity requirements of performing spirometry and FeNO testing in children managed for asthma in UK primary care. DESIGN AND SETTING: Prospective observational study involving 10 general practices in the East Midlands, UK, and 612 children between 2016 and 2017. METHOD: Training and support to perform spirometry and FeNO in children aged 5 to 16 years were provided to participating practices. Children on the practice's asthma registers, and those with suspected asthma, were invited for a routine asthma review. Time for general practice staff to achieve competencies in performing and/or interpreting both tests, time to perform the tests, number of children able to perform the tests, and feedback on acceptability were recorded. RESULTS: A total of 27 general practice staff were trained in a mean time of 10.3 (standard deviation 2.7) hours. Usable spirometry and FeNO results were obtained in 575 (94%) and 472 (77%) children respectively. Spirometry is achievable in the majority of children aged ≥5 years, and FeNO in children aged ≥7 years. All of the staff and 97% of families surveyed provided positive feedback for the tests. CONCLUSION: After training, general practice staff obtained quality spirometry and FeNO data from most children tested. Testing was acceptable to staff and families. The majority of general practice staff reported that spirometry helped them to manage children's asthma better.

Use of the ReCIVA device in breath sampling of patients with acute breathlessness: a feasibility study.

INTRODUCTION: Investigating acute multifactorial undifferentiated breathlessness and understanding the driving inflammatory processes can be technically challenging in both adults and children. Being able to validate noninvasive methods such as breath analysis would be a huge clinical advance. The ReCIVA® device allows breath samples to be collected directly onto sorbent tubes at the bedside for analysis of exhaled volatile organic compounds (eVOCs). We aimed to assess the feasibility of using this device in acutely breathless patients. METHODS: Adults hospitalised with acute breathlessness and children aged 5-16 years with acute asthma or chronic stable asthma, as well as healthy adult and child volunteers, were recruited. Breath samples were collected onto sorbent tubes using the ReCIVA® device and sent for analysis by means of two-dimensional gas chromatography-mass spectrometry (GCxGC-MS). The NASA Task Load Index (NASA-TLX) was used to assess the perceived task workload of undertaking sampling from the patient's perspective. RESULTS: Data were available for 65 adults and 61 children recruited. In total, 98.4% of adults and 75.4% of children were able to provide the full target breath sample using the ReCIVA® device. NASA-TLX measurements were available in the adult population with mean values of 3.37 for effort, 2.34 for frustration, 3.8 for mental demand, 2.8 for performance, 3.9 for physical demand and 2.8 for temporal demand. DISCUSSION: This feasibility study demonstrates it is possible and acceptable to collect breath samples from both adults and children at the bedside for breathomics analysis using the ReCIVA® device.

Lung clearance index: assessment and utility in children with asthma.

There is increasing evidence that ventilation heterogeneity and small airway disease are significant factors in asthma, with evidence suggesting that the small airways are involved from an early stage in childhood asthma. Spirometry is commonly used to monitor lung function in asthmatics; however, it is not sensitive to small airway disease. There has been renewed interest in multibreath washout (MBW) tests, with recognition of the lung clearance index (LCI) as a global index of abnormality in gas mixing of the lungs that therefore also reflects small airway disease. This review summarises the technical and practical aspects of the MBW/LCI in children, and the differences between commercially available equipment. Children with severe asthma are more likely to have an abnormal LCI, whereas most children with mild-to-moderate asthma have an LCI within the normal range, but slightly higher than age-matched healthy controls. Monitoring children with asthma with MBW alongside standard spirometry may provide useful additional information.