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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.

© 2018 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd. Background: Significant differences exist in the prevalence, spectrum, and severity of allergic diseases between developing and developed countries and between subpopulations within single countries. These discrepancies likely result from a complex interaction between genetic and environmental factors. However, the precise nature of the contribution of ethnicity to genetic differences in the predisposition to allergic disease is not yet fully understood. In particular, there is a paucity of literature regarding the genetic determinants of allergic disease in people of black African origin with little or no genetic admixture. Objective: We aimed to analyze associations between 27 single nucleotide polymorphisms (SNPs) and allergy phenotypes in the local Xhosa population. Methods: A convenience sample of 213 Xhosa teenagers was enrolled at a local high school. Phenotypic data were collected in the form of a symptom questionnaire, skin prick tests for common food and aeroallergens, total serum IgE, and IgE to Ascaris lumbricoides. In addition, genotyping was performed to establish the prevalence of putative pro-inflammatory alleles. Results: We demonstrated several significant associations between polymorphisms and allergy phenotypes. In particular, 2 polymorphisms in the IL-10 gene (IL10 -592A > C and IL10 -1082A > G) and 1 in the IL-4 gene (IL4 -589C > T) showed multiple associations with allergic sensitization and asthma phenotypes. Other polymorphisms, across a multitude of genes with discrepant fu nctions, showed less consistent associations. Conclusion: This study represents an important first step in genotype/phenotype association in this population. Further research is required to confirm or refute our findings.

© 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.

Background: Hundreds of genetic variants are thought to contribute to variation in asthma risk by modulating gene expression. Methods that increase the power of genome-wide association studies (GWASs) to identify risk-associated variants are needed. Objective: We sought to develop a method that aggregates the evidence for association with disease risk across expression quantitative trait loci (eQTLs) of a gene and use this approach to identify asthma risk genes. Methods: We developed a gene-based test and software package called EUGENE that (1) is applicable to GWAS summary statistics; (2) considers both . cis- and . trans-eQTLs; (3) incorporates eQTLs identified in different tissues; and (4) uses simulations to account for multiple testing. We applied this approach to 2 published asthma GWASs (combined n = 46,044) and used mouse studies to provide initial functional insights into 2 genes with novel genetic associations. Results: We tested the association between asthma and 17,190 genes that were found to have . cis- and/or . trans-eQTLs across 16 published eQTL studies. At an empirical FDR of 5%, 48 genes were associated with asthma risk. Of these, for 37, the association was driven by eQTLs located in established risk loci for allergic disease, including 6 genes not previously implicated in disease cause (eg, . LIMS1, . TINF2, and . SAFB). The remaining 11 significant genes represent potential novel genetic associations with asthma. The association with 4 of these replicated in an independent GWAS: . B4GALT3, . USMG5, . P2RY13, and . P2RY14, which are genes involved in nucleotide synthesis or nucleotide-dependent cell activation. In mouse studies, P2ry13 and P2ry14-purinergic receptors activated by adenosine 5-diphosphate and UDP-sugars, respectively-were upregulated after allergen challenge, notably in airway epithelial cells, eosinophils, and neutrophils. Intranasal exposure with receptor agonists induced the release of IL-33 and subsequent eosinophil infiltrati

BACKGROUND: The major trigger of asthma exacerbations is infection with a respiratory virus, most commonly rhinovirus. Type 2 inflammation is known to be associated with an increased risk of exacerbations in general. Whether type 2 inflammation at baseline increases the risk of future virus-induced exacerbations is unknown.OBJECTIVE: To assess whether type 2 inflammation is associated with an increased risk of virus-induced exacerbations of asthma.METHODS: Stable asthmatics had spirometry, skin prick test, measurement of FeNO and sputum induced for differential cell counts. Patients were followed up for 18 months, during which they were assessed at the research unit when they had symptoms of an exacerbation. Nasal swabs collected at these assessments underwent viral detection by PCR.RESULTS: A total of 81 asthma patients were recruited, of which 22 (27%) experienced an exacerbation during the follow-up period. Of these, 15 (68%) had a respiratory virus detected at exacerbation. Sputum eosinophils >1% at baseline increased the risk of having a subsequent virus-induced exacerbation (HR 7.6 95% CI: 1.6-35.2, P=.010) as did having FeNO >25 ppb (HR 3.4 95% CI: 1.1-10.4, P=.033).CONCLUSION AND CLINICAL RELEVANCE: Established type 2 inflammation during stable disease is a risk factor for virus-induced exacerbations in a real-life setting. Measures of type 2 inflammation, such as sputum eosinophils and FeNO, could be included in the risk assessment of patients with asthma in future studies.

Despite effective measles vaccines, measles still causes severe morbidity and mortality worldwide, particularly in developing countries. The Th2 pathway involving interleukin (IL)-4 and IL-13 cytokines, and their receptor IL-4Ra, play important roles in the Th1/Th2 balance and antibody production. A Th2 skewing of the cytokine milieu may affect vaccine responses. We investigated IL-4, IL-13, and IL-4Ra polymorphisms and their impact on measles IgG responses and measles vaccine failure, in two separate cohorts: 12-month-old Australian children immunized with measles-mumps-rubella vaccine (n?=?137) and a case/control cohort of children aged 6 months-14 years from Mozambique, Africa (n?=?89), some of whom were vaccinated, but still contracted measles (vaccine failure). We found that IL-4Ra haplotypes for Val75Ile, Ser503Pro, and Arg576Gln were associated with measles IgG in Mozambican children (p?=?0.016 and p?=?0.032 for Val.Pro.Arg and Val.Ser.Arg, respectively), but not Australian children. IL-4Ra 503Pro was more prevalent in Mozambique vaccine failure cases compared with controls (p?=?0.008). We showed that the impact of Th2 genes on measles vaccine responses differs between ethnicities and IL-4Ra polymorphisms may work in combination to affect measles antibody responses and vaccine failure in Mozambican children. Studies in this area are particularly important in developing countries like Mozambique where measles is still a major health issue.

Human rhinovirus (RV) is commonly associated with severe acute lower respiratory infections (ALRI) in children. We aimed to describe the distribution of RV species and associations between RV species and clinical features in children hospitalized with clinically severe pneumonia (CSP) in Morocco. Nasopharyngeal aspirates (NPAs) were collected from 700 children, 2-59 months of age, admitted with CSP to the Hôpital d'Enfants de Rabat in Morocco. At least one respiratory virus was identified in 92% of children, of which RV was the most common (53%). PCR assays, sequencing, and phylogenetic tree analyses were carried out on 183 RV-positive NPAs to determine RV species and genotypes. Of 157 successfully genotyped NPAs, 60 (38.2%) were RV-A, 8 (5.1%) were RV-B, and 89 (56.7%) were RV-C. Wheezing and cyanosis were more common in RV-C-positive than RV-A-positive children (80.9% vs. 56.7%; P?=?0.001 for wheezing and 10.1% vs. 0%; P?=?0.011 for cyanosis). Physician's discharge diagnosis of pneumonia was more frequent among RV-A-positive (40.0%) than RV-C-positive children (20.2%; P?=?0.009). RV-A and RV-C showed distinct seasonal patterns. Our findings suggest that RV-C is associated with wheezing illness while RV-A is associated with pneumonia. J. Med. Virol. 89:582-588, 2017. © 2016 Wiley Periodicals, Inc.

Background and objective: Asthma in adults is associated with a persistent reduction in lung function from childhood, but this link has not been assessed back to infancy. Reduced infant lung function (ILF), a measure of antenatal and infant lung growth, is associated with asthma into adolescence. Our aim was to assess whether this link persists into adulthood and whether ILF can predict the remission of asthma symptoms in young adults. Methods: The study cohort was an unselected full-term birth cohort of 253 subjects enrolled antenatally with lung function assessments at 1, 6 and 12months (maximum expiratory flow at functional residual capacity, V'maxFRC), and 6, 11, 18 and 24years (spirometry) of age. Results: Infants with V'maxFRC in the lowest quartile at 1month had an OR of 5.1 (95% CI: 2-13, P=0.001) for asthma at 24years. Subjects with asthma at 24years had a mean V'maxFRC at 1 month of 69% predicted (95% CI: 48-90%) versus 110% (95% CI: 101-119%) in non-asthmatic patients (P=0.001). Subjects with current versus resolved asthma symptoms at 24years had a mean V'maxFRC at 1month of 69% predicted (95% CI: 53-84%) versus 105% (88-123%), respectively (P=0.003). Subjects with current asthma at 24years had persistently lower lung function from infancy with a mean reduction of 16.2% (95% CI: 8.1-24.3%, P<0.0001). Conclusion: Reduced lung function in early infancy is predictive of persistent asthma in young adults and a persistent reduction in lung function, suggesting abnormal lung development and growth in utero or very early in life.

© 2016 John Wiley & Sons Ltd. Objectives: To describe the prevalence of human rhinovirus (RV) species in children hospitalised with pneumonia in Manhiça, Mozambique, and the associations between RV species and demographic, clinical and laboratory features. Methods: Nasopharyngeal aspirates were collected from children 0 to 10 years of age (n = 277) presenting to Manhiça District Hospital with clinical pneumonia. Blood samples were collected for HIV and malaria testing, blood culture and full blood counts, and a chest X-ray was performed. A panel of common respiratory viruses was investigated using two independent multiplex RT-PCR assays with primers specific for each virus and viral type. RV species and genotypes were identified by seminested PCR assays, sequencing and phylogenetic tree analyses. Results: At least one respiratory virus was identified in 206 (74.4%) children hospitalised with clinical pneumonia. RV was the most common virus identified in both HIV-infected (17 of 38, 44.7%) and HIV-uninfected (74 of 237, 31.2%; P = 0.100) children. RV-A was the most common RV species identified (47 of 275, 17.0%), followed by RV-C (35/275, 12.6%) and RV-B (8/275, 2.9%). Clinical presentation of the different RV species was similar and overlapping, with no particular species being associated with specific clinical features. Conclusions: RV-A and RV-C were the most common respiratory viruses identified in children hospitalised with clinical pneumonia in Manhiça. Clinical presentation of RV-A and RV-C was similar and overlapping.

© 2016, Springer-Verlag Berlin Heidelberg. The importance of good device technique to maximise delivery of aerosolised medications is widely recognised. Pressurised metered dose inhaler (pMDI)-spacer technique was investigated in 122 children, aged 2–7 years, w ith asthma. Eight individual steps of device technique were evaluated before and after viewing an instructional video for correct device technique. Video measurements were repeated every three months for nine months. Device technique improved directly after video instruction at the baseline study visit (p < 0.001) but had no immediate effect at subsequent visits. Additionally, pMDI-spacer technique improved with successive visits over one year for the group overall as evidenced by increases in the proportion of children scoring maximal (p = 0.02) and near-maximal (p = 0.04) scores. Conclusion: Repeated video instruction over time improves inhaler technique in young children.What is Known:• Correct device technique is considered essential for sufficient delivery of inhaled medication.• Poor inhaler use is common in young asthmatic children using pressurised metered dose inhalers and spacers.What is New:• Video instruction could be used as a strategy to improve device technique in young children.

© 2016 Elsevier B.V..Background: Human rhinovirus (RV) is the most common respiratory virus and has been associated with frequent and severe acute lower respiratory infections (ALRI). The prevalence of RV species among HIV-infected children in South Africa is unknown. Objectives: To describe the prevalence of respiratory viruses, including RV species, associated with HIV status and other clinical symptoms in children less than two years of age with and without ALRI in Pretoria, South Africa. Study design: Nasopharyngeal aspirates were collected from 105 hospitalized ALRI cases and 53 non-ALRI controls less than two years of age. HIV status was determined. Common respiratory viruses were identified by PCR, and RV species and genotypes were identified by semi-nested PCR, sequencing and phylogenetic tree analyses. Results: Respiratory viruses were more common among ALRI cases than controls (83.8% vs. 69.2%; p = 0.041). RV was the most commonly identified virus in cases with pneumonia (45.6%) or bronchiolitis (52.1%), regardless of HIV status, as well as in controls (39.6%). RV-A was identified in 26.7% of cases and 15.1% of controls while RV-C was identified in 21.0% of cases and 18.9% of controls. HIV-infected children were more likely to be diagnosed with pneumonia than bronchiolitis (p < 0.01). RSV was not identified in any HIV-infected cases (n = 15) compared with 30.6% of HIV-uninfected cases (n = 85, p = 0.013), and was identified more frequently in bronchiolitis than in pneumonia cases (43.8% vs. 12.3%; p < 0.01). Conclusions: RV-A and RV-C are endemic in South African children and HIV infection may be protective against RSV and bronchiolitis.