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Introduction/Aim: Differentiation of preschool wheeze into asthma and non‐asthma would allow targeted treatment for those more likely to benefit. We aimed to use metabolic biochemical profiling to discover novel urinary biomarkers of asthma in school‐age children (6‐10y) and investigate the potential to predict future development of asthma in preschool children (2‐4y). Methods: 211 children were recruited. Healthy preschool(n=25); preschool wheeze (n=87); school‐aged healthy(n=43) and school‐aged asthma(n=56). Urinary metabolic profiles at baseline and during exacerbations were characterized using liquid chromatography mass spectrometry. The utility of each individual metabolite as a biomarker of asthma at school‐age was tested using one‐way ANOVA. Canonical Variate Analysis (CVA), followed by multivariate regression, was performed to identify a specific urinary profile for effectively discriminating school‐age asthma from healthy controls. This model was then mapped to the urinary profiles of the preschool‐wheeze children, collected under identical analytical and data processing protocols. Results: 162 putatively identified metabolites were measured within approved levels of analytical repeatability. There was a significant (p<0.05) disease effect for 34 metabolites. CVA uncovered a strong exacerbation profile correlated to the preschool‐wheeze exacerbation sample. Baseline and exacerbation regression models showed strong discrimination (AUROC=0.91&0.98 respectively). When preschool urinary profiles were projected through these models the proportion of preschool wheeze participants classified as “asthma”(~40%) was in‐line with clinical expectations(~30%). Conclusion: A putative multifactorial urinary biomarker of asthma has shown promise of predicting the onset of childhood asthma. Longitudinal follow‐up is ongoing to determine predictive accuracy of the model. Targeted chemical assay development is underway. Grant Support: Telethon Perth Children's Hospital Resear

Introduction/Aim. Early childhood wheeze is a major risk factor for asthma. However, not all children who wheeze will develop the disease. The airway epithelium (including altered epithelial barrier function) has been shown to be involved in asthma pathogenesis (Looi et al, CEA 2018, 48:513). Despite this, the airway epithelium of children with acute wheeze remains poorly characterized. This study aimed to characterize the airway epithelium in children with acute wheeze. Methods. Nasal epithelial cells (NECs) from children with acute wheeze (n = 11; 6 males; mean age 3.7 _ 1.3 years old) and community controls (n = 8; 4 males; mean age 2.7 _ 0.3 years old), were expanded (Martinovich et al, Sci Rep 2017, 7:17971) andalso differentiated into airliquid interface (ALI) cultures. Markers of epithelial lineage (Cytokeratin (Ck)-5, -19) and vimentin was assessed via qPCR and immunocytochemistry. Inflammatory cytokines (Interleukin (IL)-6, -8 and -1β) were measured using ELISA. Barrier integrity was determined via In-Cell Western assay for tight junction (TJ) expression and transepithelial electrical resistance (RT) measurement and permeability assay for epithelial function. Results. NECs from children with acute wheeze had significantly higher Ck-19 and lower vimentin gene expression compared to community controls (P < 0.05) but Ck-5 was not significantly different. Similar staining intensities of Ck-5 and -19 proteins were observed in both acute wheeze and controls. IL-6 and -8 levels were not significantly different, but IL-1β was increased in NEC cultures of acute wheeze when compared to controls. TJ protein expression of claudin-1, occludin and ZO-1 were significantly lower in acute wheeze cohorts and was concomitant with decreased epithelial RT and increased permeability. Conclusion. Airway epithelium of children experiencing acute wheeze appears abnormal primarily with compromised epithelial barrier integrity and function. Collectively, these data infer potentially

Altered host immune responses are considered to play a key role in the pathogenesis of acute lower respiratory infections (ALRI). The existing literature on cytokine responses in ALRI is largely focussed on adults from developed countries and there are few reports describing the role of cytokines in childhood ALRI, particularly in African or human immunodeficiency virus (HIV)‐infected populations. To measure systemic cytokine levels in blood plasma from young South African children with and without ALRI and with and without HIV to determine associations between cytokine responses and disease status and respiratory viral identification. Blood plasma samples were collected from 106 hospitalized ALRI cases and 54 non‐ALRI controls less than 2 years of age. HIV status was determined. Blood plasma concentrations of 19 cytokines, 7 chemokines, and 4 growth factors (epidermal growth factor, fibroblast growth factor‐basic, hepatocyte growth factor, and vascular endothelial) were measured using The Human Cytokine 30‐Plex Panel. Common respiratory viruses were identified by PCR. Mean cytokine concentrations for G‐CSF, interferon (IFN)‐γ, interleukin (IL)‐5, and MCP‐1 were significantly higher in ALRI cases than in nonrespiratory controls. Within the ALRI cases, several cytokines were higher in children with a virus compared with children without a virus. Mean cytokine concentrations for IFN‐α, IFN‐γ, IL‐4, IL‐5, IL‐13, tumour necrosis factor‐α, and MIP‐1α were significantly lower in HIV‐infected cases than in HIV‐uninfected cases, while IP‐10 and monokine induced by interferon‐γ were significantly higher in HIV‐infected cases than in HIV‐uninfected cases. Certain cytokines are likely to play an important role in the host immune response to ALRI. HIV‐infected children have impaired inflammatory responses to respiratory infections compared with HIV‐uninfected children.

Asthma exacerbations are triggered by rhinovirus infections. We employed a systems biology approach to delineate upper-airway gene network patterns underlying asthma exacerbation phenotypes in children. Cluster analysis unveiled distinct IRF7hi versus IRF7lo molecular phenotypes, the former exhibiting robust upregulation of Th1/type I IFN responses and the latter an alternative signature marked by upregulation of cytokine and growth factor signaling and downregulation of IFN-?. The two phenotypes also produced distinct clinical phenotypes. For IRF7lo children, symptom duration prior to hospital presentation was more than twice as long from initial symptoms (p = 0.011) and nearly three times as long for cough (p < 0.001), the odds ratio of admission to hospital was increased more than 4-fold (p = 0.018), and time to recurrence was shorter (p = 0.015). In summary, our findings demonstrate that asthma exacerbations in children can be divided into IRF7hi versus IRF7lo phenotypes with associated differences in clinical phenotypes.

© 2018 Owens et al. Purpose: The aim of this study was to longitudinally assess the prevalence of allergic sensitization, asthma, eczema and hay fever from infancy to adulthood in a single cohort. Participants and methods: This prospective study is based on a longitudinal birth cohort of 253 participants, with respiratory and immunological assessments at 1, 6, 11, 18 and 24 years of age. Subjects were recruited from an urban maternity hospital. Retention rates varied from 45% to 72% at follow-up assessments. Asthma diagnosis was based on physician diagnosis of asthma and symptoms/medications in the previous 12 months. Allergic sensitization was defined by the positive skin prick test. Hay fever and eczema were based on a questionnaire. Results: The prevalence of allergic sensitization rose from 19% (n=33) at 1 year of age to 71% (n=77) at 24 years of age. The rate of asthma halved from 25% at 6 years of age to 12%–15% between 11 and 24 years of age, but the prevalence of allergic sensitization among those with asthma doubled from 50% at 6 years of age to 100% at 24 years of age. Hay fever rates rose throughout childhood from 7% at 6 years of age to 44% at 24 years of age, while the prevalence of eczema reduced from 25% at 6 years of age to 16% at 24 years of age. Parental atopy doubled the odds of asthma in their offspring by 24 years of age (odds ratio [OR]= 2.63, 95% CI 1.1–6.2, p=0.029). In all, 74% of those with asthma at 24 years of age also reported hay fever. The relationship between eczema and asthma was only significant up to 11 years of age, and the relationship between hay fever and asthma was stronger in adolescence and early adulthood than in early childhood. Conclusion: Patterns of atopic disorders vary throughout childhood. Although the prevalence of allergic sensitization and hay fever rose throughout childhood and the prevalence of asthma reduced, the strength of their relationship with asthma increased with age.

Respiratory virus infections account for a significant proportion of acute admissions to the paediatric intensive care unit (PICU). Recent studies have shown that rhinoviruses (RV) are the most frequent virus detected in severe cases of acute respiratory illnesses (ARI) admitted to a PICU. The aim of this study was to determine the prevalence of different viruses, in particular RV species, in children with ARI admitted to a tertiary PICU. Nasopharyngeal aspirates (NPA) from 229 children admitted to PICU with an ARI were analysed. RV was the most common virus detected, being present in 94 (41.0%) of samples examined, followed by respiratory syncytial virus (RSV) which was identified in 50 (21.8%) samples. A subsection analysis of cases with residual sample available of sufficient quality to allow for RV species typing showed that overall, the percentage of PICU admissions for each RV species was 22.3% for RV-C, 17.5% for RV-A and 1.7% for RV-B. This study demonstrated that RV is the most frequent virus identified in children admitted to a tertiary PICU with an ARI and RV-C is the most common RV species detected. Importantly, in the children admitted to PICU with an ARI, RV-C was by itself as common a pathogen as RSV.

Children born preterm, less than 37 weeks' gestation, are at increased risk of viral respiratory infections and associated complications both during their initial birth hospitalisation and in their first years following discharge. This increased burden of viral respiratory infections is likely to have long term implications for lung health and function in individuals born preterm, particularly those with bronchopulmonary dysplasia. Several hypotheses have been put forward to explain the association between early life viral respiratory infection and development of suboptimal lung health and function later in life following preterm birth. Although preterm infants with diminished lung function, particularly small airways, might be particularly susceptible to asthma and wheezing disorders following viral infection, there is evidence that respiratory viruses can activate number of inflammatory and airway re-modelling pathways. Therefore, the aim of this review is to highlight the perinatal and early life risk factors that may contribute to increased susceptibility to viral respiratory infections among preterm infants during early life and to understand how respiratory viral infection may influence the development of abnormal lung health and function later in life.

Using a well-designed longitudinal cohort, we aimed to identify cytokines that were protective against malaria and to explore how they were influenced by genetic and immunological factors. 349 Mozambican pregnant women and their newborn babies were recruited and followed up for malaria outcomes until 24 months of age. Six Th1 cytokines in cord blood were screened for correlation with malaria incidence, of which IL-12 was selected for further analyses. We genotyped IL-12 polymorphisms in children/mothers and evaluated the genotype-phenotype associations and genetic effects on IL-12 levels. Maternal IL-12 concentrations were also investigated in relation to Plasmodium infections and cord blood IL-12 levels. Our data showed that high background IL-12 levels were prospectively associated with a low incidence of clinical malaria, while IL-12 production after parasite stimulation had the opposite effect on malaria incidence. IL-12 genotypes (IL-12b rs2288831/rs17860508) and the haplotype CGTTAGAG distribution were related to malaria susceptibility and background IL-12 levels. Maternal genotypes also exhibited an evident impact on host genotype-phenotype associations. Finally, a positive correlation in background IL-12 levels between maternal and cord blood was identified. Thus, cord blood background IL-12 concentrations are important for protecting children from clinical malaria, likely mediated by both genotypes (children&mothers) and maternal immunity.

© 2018 Wiley Periodicals, Inc. Introduction: Increasing evidence suggests that poor lung function in adulthood is determined very early in life. Our study aims were: (1) identify factors associated with early infant lung function; (2) quantify the link between early infant lung function and early adult lung function; and (3) identify environmental and inherited factors which predict lung function throughout the post-natal growth period. Methods: In this longitudinal study, 253 individuals were recruited antenatally. Lung function and allergy testing occurred at 1, 6, 12 months, 6, 11, 18, and 24 years of age. The relationship between lung function at 1 month (V'maxFRC) and spirometry variables at each follow-up was evaluated. Early life predictors of spirometry were assessed longitudinally using linear mixed models. Results: V'maxFRC correlated positively with FEF25-75% at every assessment from 6 to 24 years and FEV 1 /FVC at 11 and 24 years and inversely with airway responsiveness at 6 and 18 years. Maternal asthma and smoking in pregnancy were associated with lower FEV 1 from 6 to 24 years (-99mL, P=0.03; -77mL, P=0.045 respectively). Lower V'maxFRC at 1 month was associated with asthma and wheeze through to 24 years. Conclusion: Lung airflow measurements track from birth into early adulthood, suggesting a permanent and stable airway framework is laid down in the antenatal period. Lower infant airway function is associated with respiratory symptoms into adulthood, indicating the link is clinically important. Antenatal and early life exposures must be addressed in order to maximize airway growth and reduce lifelong respiratory compromise.