Early-life respiratory infections and developmental immunity determine lifelong lung health.

Respiratory infections are common in infants and young children. However, the immune system develops and matures as the child grows, thus the effects of infection during this time of dynamic change may have long-term consequences. The infant immune system develops in conjunction with the seeding of the microbiome at the respiratory mucosal surface, at a time that the lungs themselves are maturing. We are now recognizing that any disturbance of this developmental trajectory can have implications for lifelong lung health. Here, we outline our current understanding of the molecular mechanisms underlying relationships between immune and structural cells in the lung with the local microorganisms. We highlight the importance of gaining greater clarity as to what constitutes a healthy respiratory ecosystem and how environmental exposures influencing this network will aid efforts to mitigate harmful effects and restore lung immune health.

Asthma Inception: Epidemiologic Risk Factors and Natural History Across the Life-Course.

Asthma is a descriptive label for an obstructive, inflammatory disease in the lower airways manifesting with symptoms including breathlessness, cough, difficulty in breathing and wheezing. From a clinician's point of view, asthma symptoms can commence at any age although most asthma patients - regardless of their age of onset - seem to have had some form of airway problems during childhood. Asthma inception and related pathophysiologic processes are therefore very likely to occur early in life, further evidenced by recent lung physiologic and mechanistic research. Herein, we present state-of-the-art updates on the role of genetics and epigenetics, early viral and bacterial infections, immune response and pathophysiology as well as lifestyle and environmental exposures in asthma across the life-course. We conclude early environmental insults in genetically vulnerable individuals to induce an abnormal, pre-asthmatic airway response as key events in asthma inception and highlight disease heterogeneity - across ages - and the potential shortness of treating all patients with asthma using the same treatments. Although there are no interventions that, at present, can modify long-term outcomes, a precision-medicine approach should be implemented to optimize treatment and tailor follow-up for all patients with asthma.

Influence of age on clinical characteristics, pharmacological management and exacerbations in children with asthma.

BACKGROUND: Asthma trials and guidelines often do not distinguish between adolescents and younger children. Using a large English data set, we evaluated the impact of age on asthma characteristics, management and exacerbations. METHODS: Primary care medical records, 2004-2021, were linked to hospital records. Children were categorised by age at diagnosis and followed until the next age bracket. Ages (based on management guidelines) were 5-8 years, 9-11 years and adolescents (12-16 years). Characteristics evaluated included body mass index, allergies and events before and after diagnosis (symptoms, medication). Exacerbation incidence was calculated. Multivariable Cox proportional hazards determined associations with exacerbations. RESULTS: 119 611 children were eligible: 61 940 (51.8%) 5-8 years, 32 316 (27.7%) 9-11 years and 25 355 (21.2%) adolescents. Several characteristics differed by age; children aged 5-8 years had the highest proportion with eczema, food/drug allergy and cough, but adolescents had the highest proportion with overweight/obesity, aeroallergen sensitisation, dyspnoea and short-acting-beta-agonist only use. Exacerbation rates were highest in the youngest children (per 100 person-years (95% CI): 5-8 years =13.7 (13.4-13.9), 9-11 years =10.0 (9.8-10.4), adolescents =6.7 (6.5-7.0)). Exacerbation risk factors also differed by age; 5-8 years: male, eczema and food/drug allergy were strongly associated, but for children ≥9 years old, obesity and aeroallergen sensitisation were strongly associated. For all children, higher socioeconomic deprivation was significantly associated with having an exacerbation. Delayed diagnosis was most common in children aged 5-8 years and was associated with increased exacerbations across all ages. CONCLUSION: Children's baseline characteristics and exacerbation rates varied according to their age group. Clinical guidelines should consider age at time of diagnosis more discretely than the broad range, 5-16 years, as this appears to impact on asthma severity and management.

Immunoregulation of asthma by type 2 cytokine therapies: Treatments for all ages?

Asthma is classically considered to be a disease of type 2 immune dysfunction, since many patients exhibit the consequences of excess secretion of cytokines such as IL-4, IL-5, and IL-13 concomitant with inflammation typified by eosinophils. Mouse and human disease models have determined that many of the canonical pathophysiologic features of asthma may be caused by these disordered type 2 immune pathways. As such considerable efforts have been made to develop specific drugs targeting key cytokines. There are currently available multiple biologic agents that successfully reduce the functions of IL-4, IL-5, and IL-13 in patients, and many improve the course of severe asthma. However, none are curative and do not always minimize the key features of disease, such as airway hyperresponsiveness. Here, we review the current therapeutic landscape targeting type 2 immune cytokines and discuss evidence of efficacy and limitations of their use in adults and children with asthma.

European Respiratory Society Statement on preschool wheezing disorders: updated definitions, knowledge gaps, and proposed future research directions.

Since the publication of the European Respiratory Society (ERS) Task Force reports on the management of preschool wheezing in 2008 and 2014, a large body of evidence has accumulated suggesting the clinical phenotypes that were proposed, episodic (viral) wheezing and multiple-trigger wheezing, do not relate to underlying airway pathology and may not help determine response to treatment. Specifically, using clinical phenotypes alone may no longer be appropriate, and new approaches that can be used to inform clinical care are needed for future research. This ERS Task Force reviewed the literature published after 2008 related to preschool wheezing and has suggested the criteria used to define wheezing disorders in preschool children should include age of diagnosis (0 to <6 years), confirmation of wheezing on at least one occasion, and more than one episode of wheezing ever.Furthermore, diagnosis and management may be improved by identifying treatable traits, including inflammatory biomarkers (blood eosinophils, aeroallergen sensitisation) associated with type-2 immunity and differential response to inhaled corticosteroids, lung function parameters, and airway infection. However, more comprehensive use of biomarkers/treatable traits in predicting the response to treatment requires prospective validation. There is evidence that specific genetic traits may help guide management, but these must be adequately tested. In addition, the Task Force identified an absence of caregiver-reported outcomes, caregiver/self-management options, and features that should prompt specialist referral for this age group. Priorities for future research include a focus on identifying i) mechanisms driving preschool wheezing, ii) biomarkers of treatable traits and efficacy of interventions in those without allergic sensitisation/eosinophilia, iii) the need to include both objective outcomes and caregiver-reported outcomes in clinical trials, iv) the need for a suitable action plan for children with preschool wheezing and v) a definition of severe/difficult-to-treat preschool wheezing.

Role of epithelial barrier function in inducing type 2 immunity following early-life viral infection.

BACKGROUND: Preschool wheeze attacks triggered by recurrent viral infections, including respiratory syncytial virus (RSV), are associated with an increased risk of childhood asthma. However, mechanisms that lead to asthma following early-life viral wheezing remain uncertain. METHODS: To investigate a causal relationship between early-life RSV infections and onset of type 2 immunity, we developed a neonatal murine model of recurrent RSV infection, in vivo and in silico, and evaluated the dynamical changes of altered airway barrier function and downstream immune responses, including eosinophilia, mucus secretion and type 2 immunity. RESULTS: RSV infection of neonatal BALB/c mice at 5 and 15 days of age induced robust airway eosinophilia, increased pulmonary CD4+ IL-13+ and CD4+ IL-5+ cells, elevated levels of IL-13 and IL-5 and increased airway mucus at 20 days of age. Increased bronchoalveolar lavage albumin levels, suggesting epithelial barrier damage, were present and persisted following the second RSV infection. Computational in silico simulations demonstrated that recurrent RSV infection resulted in severe damage of the airway barrier (epithelium), triggering the onset of type 2 immunity. The in silico results also demonstrated that recurrent infection is not always necessary for the development of type 2 immunity, which could also be triggered with single infection of high viral load or when the epithelial barrier repair is compromised. CONCLUSIONS: The neonatal murine model demonstrated that recurrent RSV infection in early life alters airway barrier function and promotes type 2 immunity. A causal relationship between airway barrier function and type 2 immunity was suggested using in silico model simulations.

Preventing progression of preschool wheezing to asthma: Opportunities for intervention.

Recurrent wheezing in preschool children is heterogeneous and results from numerous genetic and environmental risk factors, which result in the same final clinical manifestation of acute episodes of wheezing but have distinct underlying mechanisms. Effective disease-modifying approaches, therefore, need to target the pathways driving the symptoms. We have good evidence to show that targeting airway eosinophilia alone in early-life preschool wheezing and using inhaled corticosteroids is not disease-modifying. Although airway remodelling develops early in preschool wheezing, the challenge is identifying suitable treatments for structural airway changes. There is increasing evidence for the role of lower airway bacterial infection contributing to wheeze episodes, but clinical trials investigating the impact of targeted antibiotic treatment on disease modification are needed. There is also increasing data supporting an association between lower airway neutrophilia and wheezing in a subgroup of preschool children, but direct causation and the role of neutrophil function remain unknown. Finally, there is encouraging preliminary data for the role of inactivated mixed bacterial lysates in children with non-allergic, infection-associated wheeze episodes, but the impact on longer-term outcomes and their mechanism of action is unknown. This review outlines a range of potential novel targets and approaches that may enable secondary prevention of asthma from preschool wheezing. In parallel, the potential for harm when interventions are introduced indiscriminately is highlighted. Some of the challenges that need to be addressed, including trial designs allowing tailored interventions, the need for non-invasive biomarkers for targeted interventions, and ensuring extended and long-term follow-up after intervention, are highlighted.

WITHDRAWN: Update in Asthma 2021.

Ahead of Print article withdrawn by publisher.

Considering biomarkers in asthma disease severity.

Among patients with asthma, reliance on the type/dose of prescribed medication and symptom control does not adequately capture those at risk of adverse outcomes, and we need biomarkers for risk and treatment stratification that are consistently accurate, readily quantifiable, and reproducible. Most patients with severe asthma, regardless of age, have predominant type-2 inflammation-mediated disease, making airway/blood eosinophils, fractional exhaled nitric oxide, periostin, and/or allergic sensitization potentially important biomarkers for severe disease. In both adult and pediatric asthma, there is scope to improve prediction of severe attacks by using a composite type-2 biomarker of blood eosinophils and fractional exhaled nitric oxide. Technological advances in component-resolved diagnostics microarray technologies coupled with the development of interpretation software offer a possibility to use component-resolved diagnostics as biomarkers of asthma severity among sensitized patients with asthma. Genetic predisposition and polygenic risk scores of relevant traits (eg, lung function, host immune responses, biomarkers of exposure from the indoor and outdoor environment, infection, and microbial dysbiosis) may also contribute to prediction algorithms. We challenge the idea that asthma can be accurately defined in an individual patient by a discrete and static "endotype" (eg, type-2-high asthma). As we traverse the new era of molecular endotyping in asthma, we need to understand how relevant mechanisms impact patient outcomes, and in parallel develop new tools and approaches to stratify therapies and define individual patient trajectories.

Airway inflammation in severe asthmatics with acid gastro-oesophageal reflux.

The relationship between childhood asthma and gastro-oesophageal reflux (GOR) is contentious. Recent studies in adult asthmatics suggest that GOR is associated with worse control and differences in sputum proteomics related to epithelial integrity, systemic inflammation and host defence. We assessed 127 children with severe asthma undergoing bronchoscopy and pH study. There were no differences in asthma control or measures of airway inflammation or remodelling when those with acid GOR were compared with those without. These results suggest that acid GOR is not an important comorbidity in paediatric severe asthma.

Disadvantage in early-life and persistent asthma in adolescents: a UK cohort study.

OBJECTIVE: To determine how early-life risk factors explain socioeconomic inequalities in persistent asthma in adolescence. METHODS: We did a causal mediation analysis using data from 7487 children and young people in the UK Millennium Cohort Study. Persistent asthma was defined as having a diagnosis reported at any two or more time points at 7, 11 or 14 years. The main exposure was maternal education, a measure of early-life socioeconomic circumstances (SECs), used to calculate the relative index of inequality. We assessed how blocks of perinatal (maternal health behaviours, infant characteristics and duration of breastfeeding, measured at 9 months) and environmental risk factors (family housing conditions; potential exposure to infections through childcare type and sibling number, and neighbourhood characteristics, measured at 3 years) mediated the total effect of childhood SECs on persistent asthma risk, calculating the proportion mediated and natural indirect effect (NIE) via blocks of mediators. RESULTS: At age 14 the overall prevalence of persistent asthma was 15%. Children of mothers with lower educational qualifications were more likely to have persistent asthma, with a clear social gradient (degree plus: 12.8% vs no qualifications: 20.3%). The NIE gives the effect of SECs acting only via the mediators and shows a 31% increased odds of persistent asthma when SECs are fixed at the highest level, and mediators at the level which would naturally occur at the lowest SECs versus highest SECs (NIE OR 1.31, 95% CI 1.04 to 1.65). Overall, 58.9% (95% CI 52.9 to 63.7) of the total effect (OR 1.70, 95% CI 1.20 to 2.40) of SECs on risk of persistent asthma in adolescence was mediated by perinatal and environmental characteristics. CONCLUSIONS: Perinatal characteristics and the home environment in early life are more important in explaining socioeconomic inequalities in persistent asthma in British adolescents than more distal environmental exposures outside the home.

Childhood asthma: pathogenesis and phenotypes.

In the pathogenesis of asthma in children there is a pivotal role for a type 2 inflammatory response to early life exposures or events. Interactions between infections, atopy, genetic susceptibility and environmental exposures (such as farmyard environment, air pollution and tobacco smoke exposure) influence the development of wheezing illness and the risk of progression to asthma. The immune system, lung function and the microbiome in gut and airways develop in parallel, and dysbiosis of the microbiome may be a critical factor in asthma development. Increased infant weight gain and preterm birth are other risk factors for development of asthma and reduced lung function. The complex interplay between these factors explains the heterogeneity of asthma in children. Subgroups of patients can be identified as phenotypes, based on clinical parameters, or endotypes, based on a specific pathophysiological mechanism. Paediatric asthma phenotypes and endotypes may ultimately help to improve diagnosis of asthma, prediction of asthma development and treatment of individual children, based on clinical, temporal, developmental or inflammatory characteristics. Unbiased, data-driven clustering, using a multidimensional or systems biology approach may be needed to better define phenotypes. The present knowledge on inflammatory phenotypes of childhood asthma has now been successfully applied in the treatment with biologicals of children with severe therapy-resistant asthma, and it is to be expected that more personalised treatment options may become available.

Opening the Window of Immune Opportunity: Treating Childhood Asthma.

Asthma is an increasingly common childhood disease and although most patients can control their symptoms with medication, a proportion experience life-threatening symptoms. The advent of novel biologic therapies represents a giant leap forward for asthma treatment, but efficacy is rarely tested in children. Recent mechanistic work in mice suggests that early life is a key period for immune development and, therefore, allergen sensitization. Although children with severe asthma experience significant comorbidities and are at increased risk for serious diseases such as chronic obstructive pulmonary disease as adults, no specific investigation into tailored treatment for young children with severe asthma exists. Here, we propose how new information regarding early life immunity could be used to inform modified treatments for children.

Blood eosinophils in managing preschool wheeze: Lessons learnt from a proof-of-concept trial.

BACKGROUND: Management of preschool wheeze is based predominantly on symptom patterns. OBJECTIVE: To determine whether personalizing therapy using blood eosinophils or airway bacterial infection results in fewer attacks compared with standard care. METHODS: A proof-of-concept, randomized trial to investigate whether the prescription of inhaled corticosteroids (ICS) guided by blood eosinophils, or targeted antibiotics for airway bacterial infection, results in fewer unscheduled healthcare visits (UHCVs) compared with standard care. Children aged 1-5 years with ≥2 wheeze attacks in the previous year were categorized as episodic viral wheeze (EVW) or multiple trigger wheeze (MTW). The intervention group was prescribed ICS if blood eosinophils ≥3%, or targeted antibiotics if there is positive culture on induced sputum/cough swab. The control group received standard care. The primary outcome was UHCV at 4 months. RESULTS: 60 children, with a median age of 36.5 (range 14-61) months, were randomized. Median blood eosinophils were 5.2 (range 0-21)%, 27 of 60 (45%) children were atopic, and 8 of 60 (13%) had airway bacterial infection. There was no relationship between EVW, MTW and either blood eosinophils, atopic status or infection. 67% in each group were prescribed ICS. 15 of 30 control subjects and 16 of 30 patients in the intervention group had UHCV over 4 months (p = .8). The time to first UHCV was similar. 50% returned adherence monitors; in those, median ICS adherence was 67%. There were no differences in any parameter between those who did and did not have an UHCV. CONCLUSION: Clinical phenotype was unrelated to allergen sensitization or blood eosinophils. ICS treatment determined by blood eosinophils did not impact UHCV, but ICS adherence was poor.

Growth of the airway smooth muscle layer from late gestation to childhood is mediated initially by hypertrophy and subsequently hyperplasia.

BACKGROUND AND OBJECTIVE: The airway smooth muscle (ASM) layer thickens during development. Identifying the mechanism(s) for normal structural maturation of the ASM reveals pathways susceptible to disease processes. This study characterized thickening of the ASM layer from foetal life to childhood and elucidated the underlying mechanism in terms of hypertrophy, hyperplasia and extracellular matrix (ECM) deposition. METHODS: Airways from post-mortem cases were examined from seven different age groups: 22-24 weeks gestation, 25-31 weeks gestation, term (37-41 weeks gestation), <0.5 year, 0.5-1 year, 2-5 years and 6-10 years. The ASM layer area (thickness), the number and size of ASM cells and the volume fraction of ECM were assessed by planimetry and stereology. RESULTS: From late gestation to the first year of life, normalized ASM thickness more than doubled as a result of ASM hypertrophy. Thereafter, until childhood, the ASM layer grew in proportion to airway size, which was mediated by ASM hyperplasia. Hypertrophy and hyperplasia of ASM were accompanied by a proportional change in ECM such that the broad composition of the ASM layer was constant across age groups. CONCLUSION: These data suggest that the mechanisms of ASM growth from late gestation to childhood are temporally decoupled, with early hypertrophy and subsequent proliferation. We speculate that the developing airway is highly susceptible to ASM thickening in the first year of life and that the timing of an adverse event will determine structural phenotype.

Recurrent Severe Preschool Wheeze: From Prespecified Diagnostic Labels to Underlying Endotypes.

Rationale: Preschool wheezing is heterogeneous, but the underlying mechanisms are poorly understood.Objectives: To investigate lower airway inflammation and infection in preschool children with different clinical diagnoses undergoing elective bronchoscopy and BAL.Methods: We recruited 136 children aged 1-5 years (105 with recurrent severe wheeze [RSW]; 31 with nonwheezing respiratory disease [NWRD]). Children with RSW were assigned as having episodic viral wheeze (EVW) or multiple-trigger wheeze (MTW). We compared lower airway inflammation and infection in different clinical diagnoses and undertook data-driven analyses to determine clusters of pathophysiological features, and we investigated their relationships with prespecified diagnostic labels.Measurements and Main Results: Blood eosinophil counts and percentages and allergic sensitization were significantly higher in children with RSW than in children with a NWRD. Blood neutrophil counts and percentages, BAL eosinophil and neutrophil percentages, and positive bacterial culture and virus detection rates were similar between groups. However, pathogen distribution differed significantly, with higher detection of rhinovirus in children with RSW and higher detection of Moraxella in sensitized children with RSW. Children with EVW and children with MTW did not differ in terms of blood or BAL-sample inflammation, or bacteria or virus detection. The Partition around Medoids algorithm revealed four clusters of pathophysiological features: 1) atopic (17.9%), 2) nonatopic with a low infection rate and high use of inhaled corticosteroids (31.3%), 3) nonatopic with a high infection rate (23.1%), and 4) nonatopic with a low infection rate and no use of inhaled corticosteroids (27.6%). Cluster allocation differed significantly between the RSW and NWRD groups (RSW was evenly distributed across clusters, and 60% of the NWRD group was assigned to cluster 4; P < 0.001). There was no difference in cluster membership between the EVW and MTW groups. Cluster 1 was dominated by Moraxella detection (P = 0.04), and cluster 3 was dominated by Haemophilus or Staphylococcus or Streptococcus detection (P = 0.02).Conclusions: We identified four clusters of severe preschool wheeze, which were distinguished by using sensitization, peripheral eosinophilia, lower airway neutrophilia, and bacteriology.

Burden of preschool wheeze and progression to asthma in the UK: Population-based cohort 2007 to 2017.

BACKGROUND: Wheeze is one of the most common symptoms of preschool children (age 1-5 years), yet we have little understanding of the burden in the United Kingdom. OBJECTIVES: We sought to determine prevalence and pattern of physician-confirmed preschool wheeze, related health care utilization, and factors associated with progression to school-age asthma. METHODS: We used nationally representative primary and secondary care electronic medical records between 2007 and 2017 to identify preschool children with wheeze. Factors associated with asthma progression were identified in a nested cohort of children with follow-up from age 1 to 2 years, until at least age 8 years. RESULTS: From 1,021,624 preschool children, 69,261 were identified with wheeze. Prevalence of preschool wheeze was 7.7% in 2017. Wheeze events were lowest in August and highest in late-autumn/early-winter. During median follow-up of 2 years (interquartile range, 1.2-4.0 years), 15.8% attended an emergency department, and 13.9% had a hospital admission, for a respiratory disorder. The nested cohort with prolonged follow-up identified 15,085 children; 35.5% progressed to asthma between age 5 and 8 years. Of children with preschool wheeze, without an asthma diagnosis, 34.9% were prescribed inhaled corticosteroids and 15.6% oral corticosteroids. The factors most strongly associated with progression to asthma were wheeze frequency and severity, atopy, prematurity, maternal asthma severity, and first reported wheeze event occurring in September. CONCLUSIONS: Preschool wheeze causes considerable health care burden, and a large number of children are prescribed asthma medication and have unplanned secondary care visits. Multiple factors influence progression to asthma, including first wheeze event occurring in September.

Airway macrophage-intrinsic TGF-ß1 regulates pulmonary immunity during early-life allergen exposure.

BACKGROUND: Early life represents a major risk window for asthma development. However, the mechanisms controlling the threshold for establishment of allergic airway inflammation in early life are incompletely understood. Airway macrophages (AMs) regulate pulmonary allergic responses and undergo TGF-ß-dependent postnatal development, but the role of AM maturation factors such as TGF-ß in controlling the threshold for pathogenic immune responses to inhaled allergens remains unclear. OBJECTIVE: Our aim was to test the hypothesis that AM-derived TGF-ß1 regulates pathogenic immunity to inhaled allergen in early life. METHODS: Conditional knockout (Tgfb1ΔCD11c) mice, with TGF-ß1 deficiency in AMs and other CD11c+ cells, were analyzed throughout early life and following neonatal house dust mite (HDM) inhalation. The roles of specific chemokine receptors were determined by using in vivo blocking antibodies. RESULTS: AM-intrinsic TGF-ß1 was redundant for initial population of the neonatal lung with AMs, but AMs from Tgfb1ΔCD11c mice failed to adopt a mature homeostatic AM phenotype in the first weeks of life. Evidence of constitutive TGF-ß1 signaling was also observed in pediatric human AMs. TGF-ß1-deficient AMs expressed enhanced levels of monocyte-attractant chemokines, and accordingly, Tgfb1ΔCD11c mice exposed to HDM throughout early life accumulated CCR2-dependent inflammatory CD11c+ mononuclear phagocytes into the airway niche that expressed the proallergic chemokine CCL8. Tgfb1ΔCD11c mice displayed augmented TH2, group 2 innate lymphoid cell, and airway remodeling responses to HDM, which were ameliorated by blockade of the CCL8 receptor CCR8. CONCLUSION: Our results highlight a causal relationship between AM maturity, chemokines, and pathogenic immunity to environmental stimuli in early life and identify TGF-ß1 as a key regulator of this.

Pediatric problematic severe asthma: Recent advances in management.

Problematic severe asthma remains a significant challenge to manage, accounting for the majority of healthcare utilization among children with asthma. The heterogeneity is recognized and the clinical phenotypes of "difficult-to-treat" asthma (DA) and "severe therapy-resistant asthma" (STRA) help to guide management. Recent evidence supports molecular distinctions between these phenotypes and shows poor correlations between peripheral and airway markers of inflammation, especially in STRA. Airway neutrophils in the context of childhood severe asthma have been explored, but their role in disease causation, protection, or as bystanders remain unknown, and thus, treatment implications are unclear. Several novel management strategies, including once-daily maintenance therapy, single-device maintenance and reliever therapy, and novel biological treatments are being increasingly used for DA and STRA. However, pediatric data for efficacy of novel treatments is scarce, and when available, is restricted to adolescents. The aim of this review is to highlight recent advances in objective biomarkers that aid stratification and management of childhood severe asthma and to highlight gaps in pediatric evidence. Specifically, the urgent need for efficacy studies to improve the management of problematic severe asthma in children younger than 12 years.

Safety of live attenuated influenza vaccine (LAIV) in children with moderate to severe asthma.

BACKGROUND: Live attenuated influenza vaccine (LAIV) is recommended for annual influenza vaccination in children from age 2 years. However, some guidelines recommend against its use in children with asthma or recurrent wheeze due to concerns over its potential to induce wheezing. OBJECTIVE: We sought to assess the safety of LAIV in children with moderate to severe asthma, and in preschool children with recurrent wheeze. METHODS: Prospective, multicenter, open-label, phase IV intervention study in 14 specialist UK clinics. LAIV was administered under medical supervision, with follow-up of asthma symptoms 72 hours and 4 weeks late, using validated questionnaires. RESULTS: A total of 478 young people (median, 9.3; range, 2-18 years) with physician-diagnosed asthma or recurrent wheeze were recruited, including 208 (44%) prescribed high-dose inhaled corticosteroids and 122 (31%) with severe asthma. There was no significant change in asthma symptoms in the 4 weeks after administration (median change, 0; P = .26, McNemar test), with no impact of level of baseline asthma control/symptoms in predicting either a worsening of asthma or exacerbation after LAIV using a regression model. A total of 47 subjects (14.7%; 95% CI, 11%-19.1%) reported a severe asthma exacerbation in the 4 weeks after immunization, requiring a short course of systemic corticosteroids; in 4 cases, this occurred within 72 hours of vaccination. No association with asthma severity, baseline lung function, or asthma control was identified. CONCLUSIONS: LAIV appears to be well tolerated in the vast majority of children with asthma or recurrent wheeze, including those whose asthma is categorized as severe or poorly controlled.