Efficacy of oral corticosteroids for acute preschool wheeze: a systematic review and individual participant data meta-analysis of randomised clinical trials.

BACKGROUND: Oral corticosteroids are commonly used for acute preschool wheeze, although there is conflicting evidence of their benefit. We assessed the clinical efficacy of oral corticosteroids by means of a systematic review and individual participant data (IPD) meta-analysis. METHODS: In this systematic review with IPD meta-analysis, we systematically searched eight databases (PubMed, Ovid Embase, CINAHLplus, CENTRAL, ClinicalTrials.gov, EudraCT, EU Clinical Trials Register, WHO Clinical Trials Registry) for randomised clinical trials published from Jan 1, 1994, to June 30, 2020, comparing oral corticosteroids with placebo in children aged 12 to 71 months with acute preschool wheeze in any setting based on the Population, Intervention, Comparison, Outcomes framework. We contacted principal investigators of eligible studies to obtain deidentified individual patient data. The primary outcome was change in wheezing severity score (WSS). A key secondary outcome length of hospital stay. We also calculated a pooled estimate of six commonly reported adverse events in the follow-up period of IPD datasets. One-stage and two-stage meta-analyses employing a random-effects model were used. This study is registered with PROSPERO, CRD42020193958. FINDINGS: We identified 16 102 studies published between Jan 1, 1994, and June 30, 2020, from which there were 12 eligible trials after deduplication and screening. We obtained individual data from seven trials comprising 2172 children, with 1728 children in the eligible IPD age range; 853 (49·4%) received oral corticosteroids (544 [63·8%] male and 309 [36·2%] female) and 875 (50·6%) received placebo (583 [66·6%] male and 292 [33·4%] female). Compared with placebo, a greater change in WSS at 4 h was seen in the oral corticosteroids group (mean difference -0·31 [95% CI -0·38 to -0·24]; p=0·011) but not 12 h (-0·02 [-0·17 to 0·14]; p=0·68), with low heterogeneity between studies (I2=0%; τ2<0·001). Length of hospital stay was significantly reduced in the oral corticosteroids group (-3·18 h [-4·43 to -1·93]; p=0·0021; I2=0%; τ2<0·001). Subgroup analyses showed that this reduction was greatest in those with a history of wheezing or asthma (-4·54 h [-5·57 to -3·52]; pinteraction=0·0007). Adverse events were infrequently reported (four of seven datasets), but oral corticosteroids were associated with an increased risk of vomiting (odds ratio 2·27 [95% CI 0·87 to 5·88]; τ2<0·001). Most datasets (six of seven) had a low risk of bias. INTERPRETATION: Oral corticosteroids reduce WSS at 4 h and length of hospital stay in children with acute preschool wheeze. In those with a history of previous wheeze or asthma, oral corticosteroids provide a potentially clinically relevant effect on length of hospital stay. FUNDING: Asthma UK Centre for Applied Research.

Obstructive and restrictive spirometry from school age to adulthood: three birth cohort studies.

Background: Spirometric obstruction and restriction are two patterns of impaired lung function which are predictive of poor health. We investigated the development of these phenotypes and their transitions through childhood to early adulthood. Methods: In this study, we analysed pooled data from three UK population-based birth cohorts established between 1989 and 1995. We applied descriptive statistics, regression modelling and data-driven modelling to data from three population-based birth cohorts with at least three spirometry measures from childhood to adulthood (mid-school: 8-10 years, n = 8404; adolescence: 15-18, n = 5764; and early adulthood: 20-26, n = 4680). Participants were assigned to normal, restrictive, and obstructive spirometry based on adjusted regression residuals. We considered two transitions: from 8-10 to 15-18 and from 15-18 to 20-26 years. Findings: Obstructive phenotype was observed in ∼10%, and restrictive in ∼9%. A substantial proportion of children with impaired lung function in school age (between one third in obstructive and a half in restricted phenotype) improved and achieved normal and stable lung function to early adulthood. Of those with normal lung function in school-age, <5% declined to adulthood. Underweight restrictive and obese obstructive participants were less likely to transit to normal. Maternal smoking during pregnancy and current asthma diagnosis increased the risk of persistent obstruction and worsening. Significant associate of worsening in restrictive phenotypes was lower BMI at the first lung function assessment. Data-driven methodologies identified similar risk factors for obstructive and restrictive clusters. Interpretation: The worsening and improvement in obstructive and restrictive spirometry were observed at all ages. Maintaining optimal weight during childhood and reducing maternal smoking during pregnancy may reduce spirometry obstruction and restriction and improve lung function. Funding: MRC Grant MR/S025340/1.

Parents underestimate fatigue in younger children aged 5-7 years with asthma but not in older children.

AIM: To assess fatigue in children aged 2-17 years with asthma from both child and parent perspectives and describe associated factors. METHODS: Fatigue scores were self-reported by children aged 5-17 years old and proxy-reported by parents or carers for all children. The Pediatric Quality of Life Inventory Multidimensional Fatigue Scale was used. Fatigue scores ranged from 0 to 100, higher scores meant less fatigue. RESULTS: There were 527 children and parents enrolled. The mean overall fatigue score by self-report was 72.7 ± 15.8 and by proxy report was 75.8 ± 16.3. Self-reported fatigue score was lower in children aged 5-7 years (71.5 ± 15.9) compared to proxy-reported score (76.3 ± 15.5). Proxy and self-reported fatigue scores were similar between parents and older children. Fatigue scores were lower in association with poor asthma control and receipt of social support. Lower self-reported, but not proxy-reported, fatigue score was related to asthma severity. Lower proxy-reported, but not self-reported, fatigue score was related to the child being older and having shortness of breath. CONCLUSION: Parents underestimated the fatigue of younger children aged 5-7 years, but fatigue scores were similar between parents and older children. Both clinical and social factors are associated with fatigue in children with asthma.

ERS technical standard: Global Lung Function Initiative reference values for exhaled nitric oxide fraction (F ENO50 ).

BACKGROUND: Elevated exhaled nitric oxide fraction at a flow rate of 50 mL·s-1 (F ENO50 ) is an important indicator of T-helper 2-driven airway inflammation and may aid clinicians in the diagnosis and monitoring of asthma. This study aimed to derive Global Lung Function Initiative reference equations and the upper limit of normal for F ENO50 . METHODS: Available individual F ENO50 data were collated and harmonised using consensus-derived variables and definitions. Data collected from individuals who met the harmonised definition of "healthy" were analysed using the generalised additive models of location, scale and shape (GAMLSS) technique. RESULTS: Data were retrospectively collated from 34 782 individuals from 34 sites in 15 countries, of whom 8022 met the definition of healthy (19 sites, 11 countries). Overall, height, age and sex only explained 12% of the between-subject variability of F ENO50 (R2=0.12). F ENO device was neccessary as a predictor of F ENO50 , such that the healthy range of values and the upper limit of normal varied depending on which device was used. The range of F ENO50 values observed in healthy individuals was also very wide, and the heterogeneity was partially explained by the device used. When analysing a subset of data in which F ENO50 was measured using the same device and a stricter definition of health (n=1027), between-site heterogeneity remained. CONCLUSION: Available F ENO50 data collected from different sites using different protocols and devices were too variable to develop a single all-age reference equation. Further standardisation of F ENO devices and measurement are required before population reference values might be derived.

Use of exhaled nitric oxide in the diagnosis and monitoring of childhood asthma: myth or maxim?

Asthma is a common condition in children. This review describes the evidence from the literature and international asthma guidelines for using fractional exhaled nitric oxide (FENO) in the diagnosis and monitoring of childhood asthma. The accuracy of FENO measuring devices could be further improved, the difference in FENO results between devices are equivalent to what is considered a clinically important difference. For diagnosing asthma no guideline currently recommends FENO is used as the first test, but many recommend FENO as part of a series of tests. A cut-off of 35 ppb is widely recommended as being supportive of an asthma diagnosis, but evidence from children at risk of asthma suggests that a lower threshold of 25 ppb may be more appropriate. Nine randomised clinical trials including 1885 children have added FENO to usual asthma care and find that exacerbations are reduced when care is guided by FENO (OR for exacerbation compared to usual care 0.77, 95% CI 0.62-0.94). What is not clear is what cut-off(s) of FENO should be used to trigger a change in treatment. After 30 years of intensive research there is not sufficient evidence to recommend FENO for routine diagnosing and monitoring asthma in children. Educational aims: To give the reader an overview of literature that supports and does not support the role of FENO in diagnosing asthma in children.To give the reader an overview of literature that supports and does not support the role of FENO in monitoring asthma in children.To give the reader an understanding of the role of FENO in international guidelines for diagnosing and monitoring asthma in children.

Deriving and validating an asthma diagnosis prediction model for children and young people in primary care.

Introduction: Accurately diagnosing asthma can be challenging. We aimed to derive and validate a prediction model to support primary care clinicians assess the probability of an asthma diagnosis in children and young people. Methods: The derivation dataset was created from the Avon Longitudinal Study of Parents and Children (ALSPAC) linked to electronic health records. Participants with at least three inhaled corticosteroid prescriptions in 12-months and a coded asthma diagnosis were designated as having asthma. Demographics, symptoms, past medical/family history, exposures, investigations, and prescriptions were considered as candidate predictors. Potential candidate predictors were included if data were available in ≥60% of participants. Multiple imputation was used to handle remaining missing data. The prediction model was derived using logistic regression. Internal validation was completed using bootstrap re-sampling. External validation was conducted using health records from the Optimum Patient Care Research Database (OPCRD). Results: Predictors included in the final model were wheeze, cough, breathlessness, hay-fever, eczema, food allergy, social class, maternal asthma, childhood exposure to cigarette smoke, prescription of a short acting beta agonist and the past recording of lung function/reversibility testing. In the derivation dataset, which comprised 11,972 participants aged <25 years (49% female, 8% asthma), model performance as indicated by the C-statistic and calibration slope was 0.86, 95% confidence interval (CI) 0.85-0.87 and 1.00, 95% CI 0.95-1.05 respectively. In the external validation dataset, which included 2,670 participants aged <25 years (50% female, 10% asthma), the C-statistic was 0.85, 95% CI 0.83-0.88, and calibration slope 1.22, 95% CI 1.09-1.35. Conclusions: We derived and validated a prediction model for clinicians to calculate the probability of asthma diagnosis for a child or young person up to 25 years of age presenting to primary care. Following further evaluation of clinical effectiveness, the prediction model could be implemented as a decision support software.

Breastfeeding and impact on childhood hospital admissions: a nationwide birth cohort in South Korea.

Benefits of breastfeeding for both the mother and the child are well established, but a comprehensive and robust study to investigate the protective effect of breastfeeding and attenuated time effect stratified by cause of morbidity are lacking. This study is based on the nationwide birth cohort in Korea that includes data on all infants born from 2009 to 2015. Of 1,608,540 children, the median follow-up period was 8.41 years (interquartile range, 6.76-10.06). When compared to children with fully formula feeding, the hospital admission rate was 12% lower in those with partially breastfeeding and 15% lower in those with exclusive breastfeeding. The apparent protective effect of breastfeeding was reduced with increasing age. Our study provides potential evidence of the beneficial association of breastfeeding on subsequent hospital admissions. The protective effect declined over time as the children grew older. Encouraging any breastfeeding for at least the first 6 months among infants is an important public health strategy to improve overall child health.

Routine FEV1 measurement is essential in diagnosis and monitoring of childhood asthma: myth or maxim?

Childhood asthma is a common condition in children. This review describes the evidence from seven asthma guidelines for using spirometry in the diagnosis and monitoring of childhood asthma. All guidelines recommend spirometry as the primary test to be performed for diagnosing asthma in children aged >5 years. Spirometry is often normal in children with asthma. Guidelines are not consistent with respect to whether forced expiratory volume in 1 s (FEV1) or FEV1/forced vital capacity (FVC) should be measured, or their threshold for "abnormal" spirometry, and we describe the sensitivity and specificity for these different cut-offs. The role of spirometry in monitoring asthma is less clear in the guidelines, and some do not suggest spirometry should be done. There is no consensus on what spirometric measurement should be used, how often it should be measured and what is a minimum clinically important change in spirometry. The role of spirometry in diagnosing asthma is more clearly established when compared to its role in monitoring asthma. The potential of spirometry to aid decision making for asthma diagnosis and monitoring in children remains to be fully evaluated. Educational aims: To provide knowledge of the commonly used guidelines for asthma diagnosis and management.To give insight into the opportunities and challenges in using spirometry to diagnose and monitor asthma in children.To provide an understanding of the precision of spirometry for diagnosing asthma.

Pediatric Hospitalizations and ICU Admissions Due to COVID-19 and Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-2 in England.

Importance: Investigating how the risk of serious illness after SARS-CoV-2 infection in children and adolescents has changed as new variants have emerged is essential to inform public health interventions and clinical guidance. Objective: To examine risk factors associated with hospitalization for COVID-19 or pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) among children and adolescents during the first 2 years of the COVID-19 pandemic and change in risk factors over time. Design, Setting, and Participants: This population-level analysis of hospitalizations after SARS-CoV-2 infection in England among children and adolescents aged 0 to 17 years was conducted from February 1, 2020, to January 31, 2022. National data on hospital activity were linked with data on SARS-CoV-2 testing, SARS-CoV-2 vaccination, pediatric intensive care unit (PICU) admissions, and mortality. Children and adolescents hospitalized with COVID-19 or PIMS-TS during this time were included. Maternal, elective, and injury-related hospitalizations were excluded. Exposures: Previous medical comorbidities, sociodemographic factors, and timing of hospitalization when different SARS-CoV-2 variants (ie, wild type, Alpha, Delta, and Omicron) were dominant in England. Main Outcomes: PICU admission and death within 28 days of hospitalization with COVID-19 or PIMS-TS. Results: A total of 10 540 hospitalizations due to COVID-19 and 997 due to PIMS-TS were identified within 1 125 010 emergency hospitalizations for other causes. The number of hospitalizations due to COVID-19 and PIMS-TS per new SARS-CoV-2 infections in England declined during the second year of the COVID-19 pandemic. Among 10 540 hospitalized children and adolescents, 448 (4.3%) required PICU admission due to COVID-19, declining from 162 of 1635 (9.9%) with wild type, 98 of 1616 (6.1%) with Alpha, and 129 of 3789 (3.4%) with Delta to 59 of 3500 (1.7%) with Omicron. Forty-eight children and adolescents died within 28 days of hospitalization due to COVID-19, and no children died of PIMS-TS (PIMS-S data were limited to November 2020 onward). Risk of severe COVID-19 in children and adolescents was associated with medical comorbidities and neurodisability regardless of SARS-CoV-2 variant. Results were similar when children and adolescents with prior SARS-CoV-2 exposure or vaccination were excluded. Conclusions: In this study of data across the first 2 years of the COVID-19 pandemic, risk of severe disease from SARS-CoV-2 infection in children and adolescents in England remained low. Children and adolescents with multiple medical problems, particularly neurodisability, were at increased risk and should be central to public health measures as further variants emerge.

Antenatal size, early childhood growth, and asthma within a cohort created by data linkage.

INTRODUCTION: The gestation when small for gestational age (SGA) is first associated with asthma is not well understood. Here, we use routinely acquired data from 10 weeks gestation to up to 28 years of age to test the hypothesis that SGA before birth is associated with an increased risk for asthma in a large population born between 1987 and 2015. METHODS: Databases were linked to produce a single database that held antenatal fetal ultrasound measurements; maternal characteristics; birth measurements; childhood anthropometric measurements at age 5 years; hospital admission data (1987-2015); and family doctor prescribing (2009-2015). Asthma admission and receipt of any asthma medications were the outcomes. Analyses related single and then multiple anthropometric measurements to asthma outcomes. RESULTS: Outcome data were available for 63,930 individuals. Increased length in the first-trimester size was associated with a reduced odds ratio (OR) for asthma admission of 0.991 [0.983, 0.998] per mm increase and also a shorter time to first admission, with a hazard ratio risk of 0.987 [0.980, 0.994] per mm increase. Independent of all earlier measurements, increased height at 5 years (available in a subset of 15,760) was associated with reduced OR for an asthma admission, with OR of 0.874 [0.790, 0.967] per z score. Longitudinal measurements of weight were not related to asthma outcomes. CONCLUSIONS: Longer first-trimester length is associated with more favorable asthma outcomes, and subsequently, increased height in childhood is also independently associated with more favorable asthma outcomes. Interventions that reduce SGA and encourage healthy postnatal growth might improve asthma outcomes.

A meta-analysis of genome-wide association studies of childhood wheezing phenotypes identifies ANXA1 as a susceptibility locus for persistent wheezing.

Background: Many genes associated with asthma explain only a fraction of its heritability. Most genome-wide association studies (GWASs) used a broad definition of 'doctor-diagnosed asthma', thereby diluting genetic signals by not considering asthma heterogeneity. The objective of our study was to identify genetic associates of childhood wheezing phenotypes. Methods: We conducted a novel multivariate GWAS meta-analysis of wheezing phenotypes jointly derived using unbiased analysis of data collected from birth to 18 years in 9568 individuals from five UK birth cohorts. Results: Forty-four independent SNPs were associated with early-onset persistent, 25 with pre-school remitting, 33 with mid-childhood remitting, and 32 with late-onset wheeze. We identified a novel locus on chr9q21.13 (close to annexin 1 [ANXA1], p<6.7 × 10-9), associated exclusively with early-onset persistent wheeze. We identified rs75260654 as the most likely causative single nucleotide polymorphism (SNP) using Promoter Capture Hi-C loops, and then showed that the risk allele (T) confers a reduction in ANXA1 expression. Finally, in a murine model of house dust mite (HDM)-induced allergic airway disease, we demonstrated that anxa1 protein expression increased and anxa1 mRNA was significantly induced in lung tissue following HDM exposure. Using anxa1-/- deficient mice, we showed that loss of anxa1 results in heightened airway hyperreactivity and Th2 inflammation upon allergen challenge. Conclusions: Targeting this pathway in persistent disease may represent an exciting therapeutic prospect. Funding: UK Medical Research Council Programme Grant MR/S025340/1 and the Wellcome Trust Strategic Award (108818/15/Z) provided most of the funding for this study.

Three-quarters of children hospitalized for wheezing or asthma symptoms are preschool-aged. Some will continue to experience breathing difficulties through childhood and adulthood. Others will undergo a complete resolution of their symptoms by the time they reach elementary school. The varied trajectories of young children with wheezing suggest that it is not a single disease. There are likely different genetic or environmental causes. Despite these differences, wheezing treatments for young children are 'one size fits all.' Studying the genetic underpinnings of wheezing may lead to more customized treatment options. Granell et al. studied the genetic architecture of different patterns of wheezing from infancy to adolescence. To do so, they used machine learning technology to analyze the genomes of 9,568 individuals, who participated in five studies in the United Kingdom from birth to age 18. The experiments found a new genetic variation in the ANXA1 gene linked with persistent wheezing starting in early childhood. By comparing mice with and without this gene, Granell et al. showed that the protein encoded by ANXA1 controls inflammation in the lungs in response to allergens. Animals lacking the protein develop worse lung inflammation after exposure to dust mite allergens. Identifying a new gene linked to a specific subtype of wheezing might help scientists develop better strategies to diagnose, treat, and prevent asthma. More studies are needed on the role of the protein encoded by ANXA1 in reducing allergen-triggered lung inflammation to determine if this protein or therapies that boost its production may offer relief for chronic lung inflammation.

Past asthma exacerbation in children predicting future exacerbation: a systematic review.

Acute exacerbations are common in children and potentially preventable. Currently, a past exacerbation is the best predictor of a future exacerbation. We undertook a systematic review of the literature describing the relationship between past and future exacerbations. Our analysis considered whether the odds ratios for one exacerbation to predict a recurrence were different across different categories of exacerbation. Four databases were searched systematically (MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health and PsycInfo). Exacerbations were categorised by severity as: presentation to emergency department (ED); hospital admission; paediatric intensive care unit (PICU) admission; and "unspecified severity" (i.e. no distinction between severity categories was made). Meta-analysis was performed for studies where sufficient data were provided for inclusion. There were 26 eligible articles from 9185 identified. There was significant heterogeneity in duration of follow-up, healthcare system and exacerbation definition between studies. For the unspecified severity definition, the odds ratio for an exacerbation after a previous exacerbation was 9.87 (95% CI 5.02-19.39; six studies, 162 583 individuals). PICU admission was also associated with increased risk of future admission (OR 5.87, 95% CI 2.96-11.64; two studies, 730 individuals). Meta-analysis was not possible for ED visits or hospitalisation. The median odds ratio (range) for past ED visit predicting future ED visit was 6.27 (3.3-8.26) and for past hospitalisation predicting future hospitalisation was 3.37 (1.89-5.36). The odds for a second asthma exacerbation do not necessarily increase with increasing severity of an initial exacerbation.

Household income, fetal size and birth weight: an analysis of eight populations.

BACKGROUND: The age at onset of the association between poverty and poor health is not understood. Our hypothesis was that individuals from highest household income (HI), compared to those with lowest HI, will have increased fetal size in the second and third trimester and birth. METHODS: Second and third trimester fetal ultrasound measurements and birth measurements were obtained from eight cohorts. Results were analysed in cross-sectional two-stage individual patient data (IPD) analyses and also a longitudinal one-stage IPD analysis. RESULTS: The eight cohorts included 21 714 individuals. In the two-stage (cross-sectional) IPD analysis, individuals from the highest HI category compared with those from the lowest HI category had larger head size at birth (mean difference 0.22 z score (0.07, 0.36)), in the third trimester (0.25 (0.16, 0.33)) and second trimester (0.11 (0.02, 0.19)). Weight was higher at birth in the highest HI category. In the one-stage (longitudinal) IPD analysis which included data from six cohorts (n=11 062), head size was larger (mean difference 0.13 (0.03, 0.23)) for individuals in the highest HI compared with lowest category, and this difference became greater between the second trimester and birth. Similarly, in the one-stage IPD, weight was heavier in second highest HI category compared with the lowest (mean difference 0.10 (0 .00, 0.20)) and the difference widened as pregnancy progressed. Length was not linked to HI category in the longitudinal model. CONCLUSIONS: The association between HI, an index of poverty, and fetal size is already present in the second trimester.

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.

Uptake of infant and preschool immunisations in Scotland and England during the COVID-19 pandemic: An observational study of routinely collected data.

BACKGROUND: In 2020, the SARS-CoV-2 (COVID-19) pandemic and lockdown control measures threatened to disrupt routine childhood immunisation programmes with early reports suggesting uptake would fall. In response, public health bodies in Scotland and England collected national data for childhood immunisations on a weekly or monthly basis to allow for rapid analysis of trends. The aim of this study was to use these data to assess the impact of different phases of the pandemic on infant and preschool immunisation uptake rates. METHODS AND FINDINGS: We conducted an observational study using routinely collected data for the year prior to the pandemic (2019) and immediately before (22 January to March 2020), during (23 March to 26 July), and after (27 July to 4 October) the first UK "lockdown". Data were obtained for Scotland from the Public Health Scotland "COVID19 wider impacts on the health care system" dashboard and for England from ImmForm. Five vaccinations delivered at different ages were evaluated; 3 doses of "6-in-1" diphtheria, tetanus, pertussis, polio, Haemophilus influenzae type b, and hepatitis B vaccine (DTaP/IPV/Hib/HepB) and 2 doses of measles, mumps, and rubella (MMR) vaccine. This represented 439,754 invitations to be vaccinated in Scotland and 4.1 million for England. Uptake during the 2020 periods was compared to the previous year (2019) using binary logistic regression analysis. For Scotland, uptake within 4 weeks of a child becoming eligible by age was analysed along with geographical region and indices of deprivation. For Scotland and England, we assessed whether immunisations were up-to-date at approximately 6 months (all doses 6-in-1) and 16 to 18 months (first MMR) of age. We found that uptake within 4 weeks of eligibility in Scotland for all the 5 vaccines was higher during lockdown than in 2019. Differences ranged from 1.3% for first dose 6-in-1 vaccine (95.3 versus 94%, odds ratio [OR] compared to 2019 1.28, 95% confidence intervals [CIs] 1.18 to 1.39) to 14.3% for second MMR dose (66.1 versus 51.8%, OR compared to 2019 1.8, 95% CI 1.74 to 1.87). Significant increases in uptake were seen across all deprivation levels. In England, fewer children due to receive their immunisations during the lockdown period were up to date at 6 months (6-in-1) or 18 months (first dose MMR). The fall in percentage uptake ranged from 0.5% for first 6-in-1 (95.8 versus 96.3%, OR compared to 2019 0.89, 95% CI 0.86- to 0.91) to 2.1% for third 6-in-1 (86.6 versus 88.7%, OR compared to 2019 0.82, 95% CI 0.81 to 0.83). The use of routinely collected data used in this study was a limiting factor as detailed information on potential confounding factors were not available and we were unable to eliminate the possibility of seasonal trends in immunisation uptake. CONCLUSIONS: In this study, we observed that the national lockdown in Scotland was associated with an increase in timely childhood immunisation uptake; however, in England, uptake fell slightly. Reasons for the improved uptake in Scotland may include active measures taken to promote immunisation at local and national levels during this period and should be explored further. Promoting immunisation uptake and addressing potential vaccine hesitancy is particularly important given the ongoing pandemic and COVID-19 vaccination campaigns.

Early life inter-kingdom interactions shape the immunological environment of the airways.

BACKGROUND: There is increasing evidence that the airway microbiome plays a key role in the establishment of respiratory health by interacting with the developing immune system early in life. While it has become clear that bacteria are involved in this process, there is a knowledge gap concerning the role of fungi. Moreover, the inter-kingdom interactions that influence immune development remain unknown. In this prospective exploratory human study, we aimed to determine early post-natal microbial and immunological features of the upper airways in 121 healthy newborns. RESULTS: We found that the oropharynx and nasal cavity represent distinct ecological niches for bacteria and fungi. Breastfeeding correlated with changes in microbiota composition of oropharyngeal samples with the greatest impact upon the relative abundance of Streptococcus species and Candida. Host transcriptome profiling revealed that genes with the highest expression variation were immunological in nature. Multi-omics factor analysis of host and microbial data revealed unique co-variation patterns. CONCLUSION: These data provide evidence of a diverse multi-kingdom microbiota linked with local immunological characteristics in the first week of life that could represent distinct trajectories for future respiratory health. TRIAL REGISTRATION: NHS Health Research Authority, IRAS ID 199053. Registered 5 Oct 2016. https://www.hra.nhs.uk/planning-and-improving-research/application-summaries/research-summaries/breathing-together/ Video abstract.