Michael David Shields

Introduction: Congenital lung malformations (CLMs) are often identified on antenatal scanning and malignant transformation is cited as an indication for early resection. Long‐term follow‐up of asymptomatic lesions managed nonoperatively is lacking. Herein, we prospectively follow up children with antenatally identified CLMs and reviewed adult patients diagnosed with adenocarcinoma to look for background CLM changes. Methods: This is a single‐center cohort study of pediatric patients with antenatal or early postnatal diagnosis of CLMs and a retrospective review of adult patients with lung adenocarcinoma. In children, data collected included type or location of CLMs and subsequent follow‐up. In adult patients, we reviewed radiology for background CLMs. Results: One hundred and twenty‐nine pediatric patients diagnosed with CLMs: congenital pulmonary airway malformations ( n = 79; 61%), bronchopulmonary sequestrations ( n = 26; 20%), congenital lobar emphysema ( n = 11; 9%), resolved lesions ( n = 10; 8%), bronchogenic cysts ( n = 2; 2%), and an unknown lesion ( n = 1; 1%). The patients were followed up for 6.7 (IQR: 3.4–10.5; range 0.08–20.6) years. No pediatric patient was subsequently identified on the Northern Ireland Cancer Registry. Three hundred and twenty‐three adult patients were diagnosed with lung carcinoma: 37 (11%) were mucinous adenocarcinomas and 21 (57%) had a KRAS mutation. No CLMs were identified on review of radiological imaging in adult patients presenting with malignancy. Conclusion: In children with CLMs, no resected malignant lesions could be identified on medium‐term follow‐up. Furthermore, no CLMs were identified in adult patients presenting with resected mucinous adenocarcinoma. Prospective collaborative databases are needed to determine true malignancy risk in asymptomatic CLM lesions and CPAMs.

Respiratory syncytial virus (RSV) disease burden is greatest between 6 weeks and 6 months of life, with young age the most common risk factor among hospitalized children. A robust innate immune response in the airway epithelium is crucial for mitigating RSV-associated disease, but early-life immune responses to infection remain largely unexplored. RNA-seq analysis of RSV-infected primary nasal epithelial cell cultures from healthy infants at birth and 1 year revealed diminished expression of interferon epsilon ( IFNE ), a poorly characterized type I IFN, in newborns vs 1 year. We hypothesized, therefore, that IFNE plays an important role during infant RSV infection. We found that IFNE is basally expressed in airway epithelial cell lines. Recombinant human IFNε (rhIFNε) induced an antiviral state against an RSV clinical isolate and related Sendai virus, but not SARS-CoV-2 under the conditions tested. The antiviral potency of rhIFNε was diminished relative to rhIFN beta (rhIFNβ1) or rhIFN lambda-1 (rhIFNλ1), as evidenced by IC ₅₀ data. Importantly, rhIFNε induced similar ISGs as rhIFNβ1 but demonstrated a transient temporal expression profile that differed from both rhIFNβ1 and rhIFNλ1. These results suggest that lower IFNε expression at birth may contribute to increased susceptibility to severe RSV-associated disease, offering insights into potential interventions. IMPORTANCE: Respiratory syncytial virus (RSV) is a major pediatric respiratory pathogen. Despite advances in vaccine development and monoclonal antibody prophylaxis, the immune factors driving RSV-associated disease remain unclear. Notably, severe disease is not limited to recognized high-risk groups; most affected children share only young age as a risk factor. To better understand virus-host interactions in early life, we previously derived primary airway epithelial cell cultures from the same healthy newborns at birth and at 1 year, infected them with a clinical RSV isolate, and performed total RNA sequencing. In this study, we present evidence that the transcriptional expression of interferon epsilon ( IFNE ), a relatively understudied type I interferon, varies with chronological age, coinciding with the period of the greatest burden of severe RSV-associated disease. We also show that recombinant human IFNε exhibits antiviral activity against RSV in airway epithelial cells, although with reduced potency compared to other type I and III interferons. These results expand our understanding of interferon responses during early-life RSV infection and suggest that reduced IFNε expression in newborns may partly explain their increased vulnerability to severe disease.

Introduction: Respiratory syncytial virus (RSV) is the leading cause of severe lower respiratory tract infection in infants globally. Newborns, especially those born prematurely, are at increased risk of severe RSV-related illness, yet the influence of age on early-life airway epithelium innate immune responses remains relatively understudied. Methods: We established ex-vivo/in-vitro well-differentiated paediatric nasal epithelial cell (WD-PNEC) cultures derived from preterm and term infants at birth and again at 1-year old. Infection characteristics and innate immune responses were determined following in vitro RSV infection. Results: RSV growth kinetics and cytopathology were similar irrespective of gestation or age. Secretion of interferon lambda-1 (IFN-λ1), CXCL10, CCL5 and CXCL8 was comparable between RSV-infected preterm-newborn and term-newborn WD-PNECs. Importantly, following RSV infection, secretion of RSV-induced IFN-λ1 (pIFN-alpha inducible protein 6 ( IFI6) (p<0.05) were significantly higher in 1 year- compared with newborn-derived WD-PNECs. Interestingly, secretion of the cell signalling cytokine pleiotrophin increased significantly with longer gestation (p<0.01) and older age (p<0.001). Differential gene expression analysis demonstrated 156 differentially expressed genes (DEGs) with age and revealed transcriptomic changes linked to gestation in newborns that persisted at 1 year. Conclusion: These findings indicate two major conclusions. First, we report transcriptomic differences in airway epithelial cell (AEC) development between term and preterm infants across the first year of life. Second, we demonstrate that RSV infection responses of AECs become more robust with age in early life. Further investigation of identified DEGs and differentially expressed chemokines/cytokines is warranted to clarify their role in increased susceptibility of very young infants to severe RSV disease as well as the significance of these factors in the emergence of wheezing phenotypes and long-term respiratory outcomes.

Respiratory syncytial virus (RSV) disease burden is greatest between six weeks and 6 months of life, with young age the most common risk factor among hospitalised children. A robust innate immune response in the airway epithelium is crucial for mitigating RSV-associated disease, but early-life immune responses to infection remain largely unexplored. RNA-seq analysis of RSV-infected primary nasal epithelial cell cultures from healthy infants at birth and one year revealed diminished expression of interferon epsilon ( IFNE ), a poorly characterised type I IFN, in newborns versus one-year. We hypothesised, therefore, that IFNE plays an important role during infant RSV infection. We found that IFNE is endogenously expressed in airway epithelial cell lines. Recombinant human IFNε (rhIFNε) induced an antiviral state against an RSV clinical isolate and related Sendai virus, but not SARS-CoV-2 under the conditions tested. The antiviral potency of rhIFNε was diminished relative to rhIFN beta (rhIFNβ1) or rhIFN lambda-1 (rhIFNλ1), as evidenced by IC ₅₀ data. Importantly, rhIFNε induced similar ISGs as rhIFNβ1 but demonstrated a transient temporal expression profile that differed from both rhIFNβ1 and rhIFNλ1. These results suggest that lower IFNε expression at birth may contribute to increased susceptibility to severe RSV-associated disease, offering insights into potential therapeutic interventions.

Asthma is the most common chronic disease in childhood. If untreated, asthma can lead to debilitating daily symptoms which affect quality of life, but more importantly can lead to fatal asthma attacks which unfortunately still occur globally. The most effective treatment strategy for controlling asthma is for the patient to follow a personalised asthma action plan (PAAP) which will invariably include regular use of an inhaled corticosteroid. To examine medication adherence in children with asthma, we collated recent evidence from systematic reviews in this area to address the following 5 key questions; What is adherence? Is there evidence that children are not adhering to preventer medication? Why is adherence poor and what are the barriers to adherence? Does good adherence improve outcomes in asthma? And lastly, how can treatment adherence be improved?

Project AimTo retrospectively evaluate a clinical management algorithm for acute wheezers in a UK Pediatric Emergency Department (PED). Overview and RationaleAcute wheezing attacks are a leading cause of PED attendances and inpatient admissions. Prednisolone, a routine treatment, is intolerable in almost one-third of children, requiring repeated dosing, which may prolong length of stay (LOS). To address this problem, we: (1) developed an acute management algorithm (concise, single-sided flow-chart, instructing immediate management); (2) modified the OCS regime from prednisolone (1 mg/kg, 3-day course) to dexamethasone (600 then 300 mcg/kg); (3) and disseminated guidance regionally. Written information-handouts, e-mails, and posters-were followed-up with verbal reinforcement. We implemented the algorithm in 2017 and revised it further in 2018. EvaluationIn 2019, we retrospectively collected data on 100 acute wheeze attendances (those requiring OCS, aged 2-14), between October and December in 2016, 2017, and 2018 (n = 300), and assessed outcomes. ResultsOver a 48-month period, we reduced OCS intolerability by 67.2% and OCS drug costs by 85.8% (saving 41,470.14) pound, while not significantly influencing the other outcomes. ConclusionsReduced intolerability and substantial cost savings can be achieved by implementing a structured acute pediatric wheeze algorithm and modifying the OCS to single-dose dexamethasone (300 mcg/kg).

Incorrect inhaler technique and non-adherence to inhaled preventer therapy often is the cause of poorly controlled asthma. Detecting and correcting non-adherence in asthma therapy has proven difficult. In addition, while patients may be able to demonstrate correct inhaler technique at the clinic recent evidence suggests that critical errors in inhaler technique occur in the home setting. Remote video directly observed therapy (vDOT) has recently been described as a potentially useful tool for addressing non-adherence while also allowing timely correction of inhaler technique errors. In this mini-review we describe the use of vDOT in asthma management.

Background: Many children attend Emergency Departments (ED) and Out of Hours (OoH) frequently for acute asthma. Follow up care is often suboptimal leaving these children at risk of a future attacks. We report on the development, implementation and evaluation of a safe asthma discharge care pathway (SADCP). Methods: This is a retrospective report on the development, implementation and evaluation of outcomes of a SADCP. The pathway was based on the Teach-to-goal educational methodology that supported the mastery correct inhaler technique and ability to action the personalized asthma action plan (PAAP). Children with frequent asthma attacks were entered as they were discharged from the Emergency Department or ward. The first training session occurred within 1–3 weeks of the index asthma attack with 2 further sessions in the following 8 weeks. Children exiting the pathway were discharged either back to primary care or to a hospital clinic. Results: 81 children entered the pathway (median age 5 years) with 72 discharged from the ED and 9 from the medical wards of the Royal Belfast Hospital for Sick Children. At pathway entry 13% had correct inhaler technique, 10% had a Personalized Asthma Action Plan (PAAP), and 5% had >80% (45% >50%) repeat refill evidence of adherence to inhaled corticosteroid over the previous 12 months. On pathway exit all children demonstrated correct inhaler technique and were able to action their PAAP. One year later 51% and 95% had refill evidence of >80% and >50% adherence. Comparisons of the 12 months before and 12 months after exit from the pathway the median number of emergency ED or OoH asthma attendances and courses of oral corticosteroids reduced to zero with >75% having no attacks requiring this level of attention. Similar findings resulted when the SADCP was implemented in a district general hospital pediatric unit. Conclusion: Implementing an asthma care pathway, using Teach-to-Goal skill training methods and frequent early reviews after an index asthma attack can reduce the future risk of asthma attacks in the next 6 to 12 months.

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 ofStreptococcusspecies andCandida. 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/