Association between socioeconomic deprivation, ethnicity and health outcomes in preschool children with recurrent wheeze in England: a retrospective cohort study.

BACKGROUND: Preschool-aged children have among the highest burden of acute wheeze. We investigated differences in healthcare use, treatment and outcomes for recurrent wheeze/asthma in preschoolers from different ethno-socioeconomic backgrounds. METHODS: Retrospective cohort study using data from the Clinical Practice Research Datalink linked to Hospital Episode Statistics in England. We reported number of acute presentations and hospitalisations stratified by index of multiple deprivation (IMD) and ethnicity; and factors associated with treatment non-escalation, and hospitalisation rates using multivariable logistic and Poisson regression models. RESULTS: 194 291 preschool children were included. In children not trialled on asthma preventer medications, children from the most deprived IMD quintile (adjusted OR 1.67; 95% CI 1.53 to 1.83) and South Asian (1.77; 1.64 to 1.91) children were more likely to have high reliever usage and where specialist referral had not occurred, the odds of referral being indicated was higher in the most deprived quintile (1.39; 1.28 to 1.52) and South Asian (1.86; 1.72 to 2.01) children compared with the least deprived quintile and white children, respectively.Hospitalisation rates for wheeze/asthma were significantly higher in children from the most deprived quintile (adjusted IRR 1.20; 95% CI 1.13 to 1.27) compared with the least, and in South Asian (1.57; 1.44 to 1.70) and black (1.32; 1.22 to 1.42) compared with white children. CONCLUSIONS: We identified inequalities in wheeze/asthma treatment and morbidity in preschool children from more deprived, and non-white backgrounds. A multifaceted approach to tackle health inequality at both the national and local levels, which includes a more integrated and standardised approach to treatment, is needed to improve health outcomes in children with preschool wheeze/asthma.

Influence of umbilical cord clamping time on cerebral oxygenation and early cardiac function in term infants.

BACKGROUND: Delayed cord clamping is the standard of care for both term and preterm infants worldwide. The aim of this study was to evaluate the effect of 60-second or 180-second delayed cord clamping during labor on cerebral oxygenation and cardiac function. METHODS: Healthy newborns were divided into two groups: a 60-second delay in cord clamping (60-s DCC) and a 180-second delay in cord clamping (180-s DCC) at birth. Pulse oximetry and cerebral near-infrared spectroscopy (cNIRS) probes were placed during postnatal care. A total of 84 healthy newborns were included in this study. Preductal oxygen saturation (SpO2), heart rate, and cNIRS values were recorded at 5 and 10 minutes after delivery. The cardiac function of the infants was assessed by echocardiography at 3-7 days postnatally. RESULTS: There was no significant difference between the groups in SpO2 and cNIRS values at 5 and 10 min. While there was no significant difference in the number of neonates with targeted SpO2 at the 5th and 10th min and targeted cNIRS values at the 10th min, there was a significant difference in the number of neonates with target cNIRS values at the 5th min between groups (p <  0.001). Echocardiographic findings showed that pulmonary flow velocity was increased in the 180-s DCC group; the difference was statistically significant (p = 0.04). CONCLUSION: Our results showed that the number of infants with normal cNIRS values regarding cerebral oxygenation was higher in the 180-s DCC group. The pulmonary flow velocity was significantly increased in the 180-s DCC group in terms of echocardiographic findings.

Prevalence of childhood cough in epidemiological studies depends on the question used: findings from two population-based studies.

BACKGROUND: Epidemiological studies use different questions to assess recurrent cough in children. In two independent population-based studies, we assessed how prevalence estimates of cough vary depending on the questions parents are asked about their child's cough and how answers to the different questions overlap. METHODS: We analysed cross-sectional data from two population-based studies on respiratory health: LuftiBus in the School (LUIS), conducted in 2013-2016 among 6- to 17-year-school children in the Canton of Zurich, Switzerland, and the 1998 Leicester Respiratory Cohort (LRC) study, UK where we used data from 6- to 8-year-old children from the 2003 follow-up survey. Both studies used parental questionnaires that included the same three questions on the child's cough, namely cough without a cold, dry cough at night and coughing more than others. We assessed how the prevalence of cough varied depending on the question and how answers to the different questions on cough overlapped. We also assessed how results were influenced by age, sex, presence of wheeze and parental education. RESULTS: We included 3457 children aged 6-17 years from LUIS and 2100 children aged 6-8 years from LRC. All respiratory outcomes - cough, wheeze and physician-diagnosed asthma - were reported twice as often in the LRC as in LUIS. We found large differences in the prevalence of parent-reported cough between the three cough questions. In LUIS, 880 (25%) parents reported cough without a cold, 394 (11%) dry night cough, and 159 (5%) reported that their child coughed more than other children. In the LRC, these numbers were 1003 (48%), 527 (25%) and 227 (11%). There was only partial overlap of answers, with 89 (3%) answering yes to all questions in LUIS and 168 (8%) in LRC. Prevalence of all types of cough and overlap between the cough questions was higher in children with current wheeze. CONCLUSION: In both population-based studies prevalence estimates of cough depended strongly on the question used to assess cough with only partial overlap of responses to different questions. Epidemiological studies on cough can only be compared if they used exactly the same questions for cough.

Asthma medication adherence and exacerbations and lung function in children managed in Leicester primary care.

Poor adherence to asthma preventer medication is associated with life-threatening asthma attacks. The quality and outcomes framework mandated primary care annual asthma review does not include adherence monitoring and the effect of poor adherence on lung function in paediatric primary care patients is unknown. The aim was to investigate the link between inhaled corticosteroid (ICS) adherence and spirometry, fraction of exhaled nitric oxide (FeNO) and asthma control in asthmatic school-age children in this cross-sectional observational study involving three Leicestershire general practices. Children 5-16 years on the practice's asthma registers, were invited for a routine annual asthma review between August 2018 and August 2019. Prescription and clinical data were extracted from practice databases. Spirometry, bronchodilator reversibility (BDR) and FeNO testing were performed as part of the review. 130 of 205 eligible children (63.4%) attended their review. Mean adherence to ICS was 36.2% (SEM 2.1%) and only 14.6% of children had good adherence (≥75% prescriptions issued). We found no differences in asthma exacerbations in the preceding 12 months between the adherence quartiles. 28.6% of children in the lowest and 5.6% in the highest adherence quartile had BDR ≥ 12% but this was not statistically significant (p = 0.55). A single high FeNO value did not predict adherence to ICS. Adherence to ICS in children with asthma in primary care is poor. The link between adherence to ICS and asthma exacerbations, spirometry and FeNO is complex but knowledge of adherence to ICS is critical in the management of children with asthma.

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.

Development of Core Outcome Measures sets for paediatric and adult Severe Asthma (COMSA).

BACKGROUND: Effectiveness studies with biological therapies for asthma lack standardised outcome measures. The COMSA (Core Outcome Measures sets for paediatric and adult Severe Asthma) Working Group sought to develop Core Outcome Measures (COM) sets to facilitate better synthesis of data and appraisal of biologics in paediatric and adult asthma clinical studies. METHODS: COMSA utilised a multi-stakeholder consensus process among patients with severe asthma, adult and paediatric clinicians, pharmaceutical representatives, and health regulators from across Europe. Evidence included a systematic review of development, validity and reliability of selected outcome measures plus a narrative review and a pan-European survey to better understand patients' and carers' views about outcome measures. It was discussed using a modified GRADE (Grading of Recommendations Assessment, Development and Evaluation) Evidence to Decision framework. Anonymous voting was conducted using predefined consensus criteria. RESULTS: Both adult and paediatric COM sets include forced expiratory volume in 1 s (FEV1) as z-scores, annual frequency of severe exacerbations and maintenance oral corticosteroid use. Additionally, the paediatric COM set includes the Paediatric Asthma Quality of Life Questionnaire and Asthma Control Test or Childhood Asthma Control Test, while the adult COM set includes the Severe Asthma Questionnaire and Asthma Control Questionnaire-6 (symptoms and rescue medication use reported separately). CONCLUSIONS: This patient-centred collaboration has produced two COM sets for paediatric and adult severe asthma. It is expected that they will inform the methodology of future clinical trials, enhance comparability of efficacy and effectiveness of biological therapies, and help assess their socioeconomic value. COMSA will inform definitions of non-response and response to biological therapy for severe asthma.

Visualization of exhaled breath metabolites reveals distinct diagnostic signatures for acute cardiorespiratory breathlessness.

Acute cardiorespiratory breathlessness accounts for one in eight of all emergency hospitalizations. Early, noninvasive diagnostic testing is a clinical priority that allows rapid triage and treatment. Here, we sought to find and replicate diagnostic breath volatile organic compound (VOC) biomarkers of acute cardiorespiratory disease and understand breath metabolite network enrichment in acute disease, with a view to gaining mechanistic insight of breath biochemical derangements. We collected and analyzed exhaled breath samples from 277 participants presenting acute cardiorespiratory exacerbations and aged-matched healthy volunteers. Topological data analysis phenotypes differentiated acute disease from health and acute cardiorespiratory exacerbation subtypes (acute heart failure, acute asthma, acute chronic obstructive pulmonary disease, and community-acquired pneumonia). A multibiomarker score (101 breath biomarkers) demonstrated good diagnostic sensitivity and specificity (≥80%) in both discovery and replication sets and was associated with all-cause mortality at 2 years. In addition, VOC biomarker scores differentiated metabolic subgroups of cardiorespiratory exacerbation. Louvain clustering of VOCs coupled with metabolite enrichment and similarity assessment revealed highly specific enrichment patterns in all acute disease subgroups, for example, selective enrichment of correlated C5-7 hydrocarbons and C3-5 carbonyls in heart failure and selective depletion of correlated aldehydes in acute asthma. This study identified breath VOCs that differentiate acute cardiorespiratory exacerbations and associated subtypes and metabolic clusters of disease-associated VOCs.

Practical approaches to the diagnosis of asthma in school-age children.

INTRODUCTION: Asthma is a chronic airways disease characterized by episodes of wheeze, chest tightness, and evidence of reversible airflow obstruction. Symptoms are frequently triggered by exercise, exposure to aeroallergens, and respiratory viruses. It is the commonest non-communicable respiratory condition in children, affecting over 5.5 million children in the European Union alone. Both over- and under- diagnosis of asthma are common for several reasons. AREAS COVERED: The diagnosis is frequently based on parental or patient reported non-specific symptoms alone. All major asthma guidelines now recommend the use of objective tests, including spirometry, bronchodilator reversibility testing, fraction of exhaled nitric oxide measurements and challenge testing to confirm the diagnosis. Recently, the European Respiratory Society published the first evidence-based international guidelines for diagnosing asthma in school-age children using objective measures. Major barriers to implementation in primary care and less well-resourced healthcare settings are access to relevant objective tests for children and quality assurance to obtain reliable results. EXPERT OPINION: We highlight the importance of diagnosing asthma in school-age children using objective tests and outline a practical approach for the use of widely available tests. We also review challenges and barriers to implementation of objective testing in children managed outside specialist settings.

Rhinovirus persistence during the COVID-19 pandemic-Impact on pediatric acute wheezing presentations.

Rhinoviruses have persisted throughout the COVID-19 pandemic, despite other seasonal respiratory viruses (influenza, parainfluenza, respiratory syncytial virus, adenoviruses, human metapneumovirus) being mostly suppressed by pandemic restrictions, such as masking and other forms of social distancing, especially during the national lockdown periods. Rhinoviruses, as nonenveloped viruses, are known to transmit effectively via the airborne and fomite route, which has allowed infection among children and adults to continue despite pandemic restrictions. Rhinoviruses are also known to cause and exacerbate acute wheezing episodes in children predisposed to this condition. Noninfectious causes such as air pollutants (PM2.5 , PM10 ) can also play a role. In this retrospective ecological study, we demonstrate the correlation between UK national sentinel rhinovirus surveillance, the level of airborne particulates, and the changing patterns of pediatric emergency department presentations for acute wheezing, before and during the COVID-19 pandemic (2018-2021) in a large UK teaching hospital.

Reducing asthma attacks in children using exhaled nitric oxide (RAACENO) as a biomarker to inform treatment strategy: a multicentre, parallel, randomised, controlled, phase 3 trial.

BACKGROUND: The benefit of fractional exhaled nitric oxide (FeNO) in guiding asthma treatment is uncertain. We evaluated the efficacy of adding FeNO to symptom-guided treatment in children with asthma versus only symptom-guided treatment. METHODS: RAACENO was a multicentre, parallel, randomised, controlled, phase 3 trial done in 35 secondary care centres and 17 primary care recruitment sites (only seven primary care sites managed to recruit patients) in the UK. Patients with a confirmed asthma diagnosis, aged 6-15 years, prescribed inhaled corticosteroids, and who received a course of oral corticosteroids for at least one asthma exacerbation during the 12 months before recruitment were included. Participants were randomly assigned to either FeNO plus symptom-guided treatment (intervention) or symptom-guided treatment alone (standard care) using a 24 h in-house, web-based randomisation system. Participants and the clinical and research teams were not masked to the group allocation. A web-based algorithm gave treatment recommendations based on the Asthma Control Test (ACT) or Childhood ACT (CACT) score; current asthma treatment; adherence to study treatment in the past 3 months; and use of FeNO (in the intervention group). Follow-up occurred at 3-month intervals for 12 months. The primary outcome was any asthma exacerbation treated with oral corticosteroids in the 12 months after randomisation, assessed in the intention-to-treat population. This study is registered with the International Standard Randomised Controlled Trial Registry, ISRCTN67875351. FINDINGS: Between June 22, 2017, and Aug 8, 2019, 535 children were assessed for eligibility, 20 were ineligible and six were excluded post-randomisation. 509 children were recruited and at baseline, the mean age of participants was 10·1 years (SD 2·6), and 308 (60·5%) were male. The median FeNO was 21 ppb (IQR 10-48), mean predicted FEV1 was 89·6% (SD 18·0), and median daily dose of inhaled corticosteroids was 400 µg budesonide equivalent (IQR 400-1000). Asthma was partly or fully controlled in 256 (50·3%) of 509 participants. The primary outcome, which was available for 506 (99%) of 509 participants, occurred in 123 (48·2%) of 255 participants in the intervention group and 129 (51·4%) of 251 in the standard care group, the intention-to-treat adjusted odds ratio (OR) was 0·88 (95% CI 0·61 to 1·27; p=0·49). The adjusted difference in the percentage of participants who received the intervention in whom the primary outcome occurred compared with those who received standard care was -3·1% (-11·9% to 5·6%). In 377 (21·3%) of 1771 assessments, the algorithm recommendation was not followed. Adverse events were reported by 27 (5·3%) of 509 participants (15 in the standard care group and 12 in the intervention group). The most common adverse event was itch after skin prick testing (reported by eight participants in each group). INTERPRETATION: We found that the addition of FeNO to symptom-guided asthma treatment did not lead to reduced exacerbations among children prone to asthma exacerbation. Asthma symptoms remain the only tool for guiding treatment decisions. FUNDING: National Institute for Health Research.

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.

Sputum biomarkers during acute severe asthma attacks in children-a case-control study.

AIM: To study sputum mediator profiles pattern in children with acute severe asthma, compared with stable asthma and healthy controls. The mechanisms of acute severe asthma attacks, such as biomarkers cascades and immunological responses, are poorly understood. METHODS: We conducted a prospective observational case-control study of children aged 5 to 17 years, who presented to hospital with an asthma attack. Children with stable asthma were recruited during outpatient asthma clinic visits. Control children without an asthma diagnosis were recruited from surgical wards. Sputum mediator profiles were measured, and sputum leukocyte differential cell counts were generated. RESULTS: Sputum data were available in 48 children (acute asthma; n = 18, stable asthma; n = 17, healthy controls; n = 13). Acute-phase biomarkers and neutrophil attractants such as IL-6 and its receptor, IL-8 and cytokines linked with bacterial signals, including TNF-R1 and TNF-R2, were elevated in asthma attacks versus stable asthma and healthy controls. T-cell attractant cytokines, associated with viral infections, such as CCL-5, CXCL-10 and CXCL-11, and CXCL-9 (secreted from eosinophils after a viral trigger) were also raised. CONCLUSION: Mediator profiles consistent with bacterial and viral respiratory infections, and T2 inflammation markers co-exist in the sputum of children with acute severe asthma attacks.

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.

Assessing the feasibility and acceptability of online measurements of exhaled volatile organic compounds (VOCs) in children with preschool wheeze: a pilot study.

Background: Investigating airway inflammation and pathology in wheezy preschool children is both technically and ethically challenging. Identifying and validating non-invasive tests would be a huge clinical advance. Real-time analysis of exhaled volatile organic compounds (VOCs) in adults is established, however, the feasibility of this non-invasive method in young children remains undetermined. Aim: To determine the feasibility and acceptability of obtaining breath samples from preschool children by means of real-time mass spectrometry analysis of exhaled VOCs. Methods: Breath samples from preschool children were collected and analysed in real time by proton transfer reaction-time of flight-mass spectrometry (PTR-TOF-MS) capturing unique breath profiles. Acetone (mass channel m/z 59) was used as a reference profile to investigate the breath cycle in more detail. Dynamic time warping (DTW) was used to compare VOC profiles from adult breath to those we obtained in preschool children. Results: 16 children were recruited in the study, of which eight had acute doctor-diagnosed wheeze (mean (range) age 3.2 (1.9-4.5) years) and eight had no history of wheezing (age 3.3 (2.2-4.1) years). Fully analysable samples were obtained in 11 (68%). DTW was used to ascertain the distance between the time series of mass channel m/z 59 (acetone) and the other 193 channels. Commonality of 12 channels (15, 31, 33, 41, 43, 51, 53, 55, 57, 60, 63 and 77) was established between adult and preschool child samples despite differences in the breathing patterns. Conclusion: Real-time measurement of exhaled VOCs by means of PTR-MS is feasible and acceptable in preschool children. Commonality in VOC profiles was found between adult and preschool children.

New Perspectives in the Diagnosis and Management of Allergic Fungal Airway Disease.

Allergy to airway-colonising, thermotolerant, filamentous fungi represents a distinct eosinophilic endotype of often severe lung disease. This endotype, which particularly affects adult asthma, but also complicates other airway diseases and sometimes occurs de novo, has a heterogeneous presentation ranging from severe eosinophilic asthma to lobar collapse. Its hallmark is lung damage, characterised by fixed airflow obstruction (FAO), bronchiectasis and lung fibrosis. It has a number of monikers including severe asthma with fungal sensitisation (SAFS) and allergic bronchopulmonary aspergillosis/mycosis (ABPA/M), but these exclusive terms constitute only sub-sets of the condition. In order to capture the full extent of the syndrome we prefer the inclusive term allergic fungal airway disease (AFAD), the criteria for which are IgE sensitisation to relevant fungi in association with airway disease. The primary fungus involved is Aspergillus fumigatus, but a number of other thermotolerant species from several genera have been implicated. The unifying mechanism involves germination of inhaled fungal spores in the lung in the context of IgE sensitisation, leading to a persistent and vigorous eosinophilic inflammatory response in association with release of fungal proteases. Most allergenic fungi, including Alternaria and Cladosporium species, are not thermotolerant and cannot germinate in the airways so only act as aeroallergens and do not cause AFAD. Studies of the airway mycobiome have shown that A. fumigatus colonises the normal as much as the asthmatic airway, suggesting it is the tendency to become IgE-sensitised that is the critical triggering factor for AFAD rather than colonisation per se. Treatment is aimed at preventing exacerbations with glucocorticoids and increasingly by the use of anti-T2 biological therapies. Anti-fungal therapy has a limited place in management, but is an effective treatment for fungal bronchitis which complicates AFAD in about 10% of cases.

Precision Medicine for Paediatric Severe Asthma: Current Status and Future Direction.

Asthma is a heterogeneous disease, characterised by different phenotypes and endotypes. Precision medicine in asthma refers to the implementation of a targeted therapy for each individual child, based on the identification of treatable traits, including environmental, immunological and genetic factors. Severe asthma in children is associated with increased hospitalisation rates, a lower quality of life, increased healthcare costs and an increased mortality. In the era of new molecular biologics treatments, it is essential to improve deep phenotyping of children with severe asthma in order to deliver the most effective treatment to each individual child. In this review, we discuss the personalised approach to the assessment and management of severe asthma. We explore the indications and use of the currently licensed biologics, as well as the potential of other emerging treatments.

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.

European Respiratory Society clinical practice guidelines for the diagnosis of asthma in children aged 5-16†years.

BACKGROUND: Diagnosing asthma in children represents an important clinical challenge. There is no single gold-standard test to confirm the diagnosis. Consequently, over- and under-diagnosis of asthma is frequent in children. METHODS: A task force supported by the European Respiratory Society has developed these evidence-based clinical practice guidelines for the diagnosis of asthma in children aged 5-16 years using nine Population, Intervention, Comparator and Outcome (PICO) questions. The task force conducted systematic literature searches for all PICO questions and screened the outputs from these, including relevant full-text articles. All task force members approved the final decision for inclusion of research papers. The task force assessed the quality of the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. RESULTS: The task force then developed a diagnostic algorithm based on the critical appraisal of the PICO questions, preferences expressed by lay members and test availability. Proposed cut-offs were determined based on the best available evidence. The task force formulated recommendations using the GRADE Evidence to Decision framework. CONCLUSION: Based on the critical appraisal of the evidence and the Evidence to Decision framework, the task force recommends spirometry, bronchodilator reversibility testing and exhaled nitric oxide fraction as first-line diagnostic tests in children under investigation for asthma. The task force recommends against diagnosing asthma in children based on clinical history alone or following a single abnormal objective test. Finally, this guideline also proposes a set of research priorities to improve asthma diagnosis in children in the future.