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BACKGROUND: Impaired interferon response and allergic sensitization may contribute to virus-induced wheeze and asthma development in young children. Plasmacytoid dendritic cells (pDCs) play a key role in antiviral immunity as critical producers of type I interferons. pDCs also express the high-affinity IgE receptor through which type I interferon production may be negatively regulated. Whether antiviral function of pDCs is associated with recurrent episodes of wheeze in young children is not well understood. OBJECTIVE: We sought to evaluate the phenotype and function of circulating pDCs in children with a longitudinally defined wheezing phenotype. METHODS: We performed multiparameter flow cytometry on PBMCs from 38 children presenting to the emergency department with an acute episode of respiratory wheeze and 19 controls. RNA sequencing on isolated pDCs from the same individuals was also performed. For each subject, their longitudinal exacerbation phenotype was determined using the Western Australia public hospital database. RESULTS: We observed a significant depletion of circulating pDCs in young children with a persistent phenotype of wheeze. The same individuals also displayed upregulation of the FcεRI on their pDCs. Based on transcriptomic analysis, pDCs from these individuals did not mount a robust systemic antiviral response as observed in children who displayed a nonrecurrent wheezing phenotype. CONCLUSIONS: Our data suggest that circulating pDC phenotype and function are altered in young children with a persistent longitudinal exacerbation phenotype. Expression of high-affinity IgE receptor is increased and their function as major interferon producers is impaired during acute exacerbations of wheeze.
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Asma , Interferón Tipo I , Niño , Humanos , Preescolar , Receptores de IgE , Ruidos Respiratorios , Interferón Tipo I/metabolismo , Células DendríticasRESUMEN
Rhinoviruses (RVs) can cause severe wheezing illnesses in young children and patients with asthma. Vaccine development has been hampered by the multitude of RV types with little information about cross-neutralization. We previously showed that neutralizing antibody (nAb) responses to RV-C are detected twofold to threefold more often than those to RV-A throughout childhood. Based on those findings, we hypothesized that RV-C infections are more likely to induce either cross-neutralizing or longer-lasting antibody responses compared with RV-A infections. We pooled RV diagnostic data from multiple studies of children with respiratory illnesses and compared the expected versus observed frequencies of sequential infections with RV-A or RV-C types using log-linear regression models. We tested longitudinally collected plasma samples from children to compare the duration of RV-A versus RV-C nAb responses. Our models identified limited reciprocal cross-neutralizing relationships for RV-A (A12-A75, A12-A78, A20-A78, and A75-A78) and only one for RV-C (C2-C40). Serologic analysis using reference mouse sera and banked human plasma samples confirmed that C40 infections induced nAb responses with modest heterotypic activity against RV-C2. Mixed-effects regression modeling of longitudinal human plasma samples collected from ages 2 to 18 years demonstrated that RV-A and RV-C illnesses induced nAb responses of similar duration. These results indicate that both RV-A and RV-C nAb responses have only modest cross-reactivity that is limited to genetically similar types. Contrary to our initial hypothesis, RV-C species may include even fewer cross-neutralizing types than RV-A, whereas the duration of nAb responses during childhood is similar between the two species. The modest heterotypic responses suggest that RV vaccines must have a broad representation of prevalent types.
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Asma , Rhinovirus , Niño , Humanos , Animales , Ratones , Preescolar , Formación de Anticuerpos , Anticuerpos Neutralizantes , Reacciones CruzadasRESUMEN
Asthma exacerbations in children are associated with respiratory viral infection and atopy, resulting in systemic immune activation and infiltration of immune cells into the airways. The gene networks driving the immune activation and subsequent migration of immune cells into the airways remains incompletely understood. Cellular and molecular profiling of PBMC was employed on paired samples obtained from atopic asthmatic children (n = 19) during acute virus-associated exacerbations and later during convalescence. Systems level analyses were employed to identify coexpression networks and infer the drivers of these networks, and validation was subsequently obtained via independent samples from asthmatic children. During exacerbations, PBMC exhibited significant changes in immune cell abundance and upregulation of complex interlinked networks of coexpressed genes. These were associated with priming of innate immunity, inflammatory and remodelling functions. We identified activation signatures downstream of bacterial LPS, glucocorticoids and TGFB1. We also confirmed that LPS binding protein was upregulated at the protein-level in plasma. Multiple gene networks known to be involved positively or negatively in asthma pathogenesis, are upregulated in circulating PBMC during acute exacerbations, supporting the hypothesis that systemic pre-programming of potentially pathogenic as well as protective functions of circulating immune cells preceeds migration into the airways. Enhanced sensitivity to LPS is likely to modulate the severity of acute asthma exacerbations through exposure to environmental LPS.
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Asma , Hipersensibilidad Inmediata , Humanos , Niño , Lipopolisacáridos , Leucocitos Mononucleares , Asma/diagnóstico , Asma/genética , Movimiento Celular , ConvalecenciaRESUMEN
BACKGROUND: Malaria is a deadly disease caused by Plasmodium spp. Several blood phenotypes have been associated with malarial resistance, which suggests a genetic component to immune protection. METHODS: One hundred and eighty-seven single nucleotide polymorphisms (SNPs) in 37 candidate genes were genotyped and investigated for associations with clinical malaria in a longitudinal cohort of 349 infants from Manhiça, Mozambique, in a randomized controlled clinical trial (RCT) (AgeMal, NCT00231452). Malaria candidate genes were selected according to involvement in known malarial haemoglobinopathies, immune, and pathogenesis pathways. RESULTS: Statistically significant evidence was found for the association of TLR4 and related genes with the incidence of clinical malaria (p = 0.0005). These additional genes include ABO, CAT, CD14, CD36, CR1, G6PD, GCLM, HP, IFNG, IFNGR1, IL13, IL1A, IL1B, IL4R, IL4, IL6, IL13, MBL, MNSOD, and TLR2. Of specific interest, the previously identified TLR4 SNP rs4986790 and the novel finding of TRL4 SNP rs5030719 were associated with primary cases of clinical malaria. CONCLUSIONS: These findings highlight a potential central role of TLR4 in clinical malarial pathogenesis. This supports the current literature and suggests that further research into the role of TLR4, as well as associated genes, in clinical malaria may provide insight into treatment and drug development.
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Malaria , Receptor Toll-Like 4 , Humanos , Receptor Toll-Like 4/genética , Interleucina-13/genética , Predisposición Genética a la Enfermedad , Malaria/epidemiología , Genotipo , Polimorfismo de Nucleótido SimpleRESUMEN
Human rhinovirus (RV)-induced exacerbations of asthma and wheeze are a major cause of emergency room presentations and hospital admissions among children. Previous studies have shown that immune response patterns during these exacerbations are heterogeneous and are characterized by the presence or absence of robust interferon responses. Molecular phenotypes of asthma are usually identified by cluster analysis of gene expression levels. This approach however is limited, since genes do not exist in isolation, but rather work together in networks. Here, we employed personal network inference to characterize exacerbation response patterns and unveil molecular phenotypes based on variations in network structure. We found that personal gene network patterns were dominated by two major network structures, consisting of interferon-response versus FCER1G-associated networks. Cluster analysis of these structures divided children into subgroups, differing in the prevalence of atopy but not RV species. These network structures were also observed in an independent cohort of children with virus-induced asthma exacerbations sampled over a time course, where we showed that the FCER1G-associated networks were mainly observed at late time points (days four-six) during the acute illness. The ratio of interferon- and FCER1G-associated gene network responses was able to predict recurrence, with low interferon being associated with increased risk of readmission. These findings demonstrate the applicability of personal network inference for biomarker discovery and therapeutic target identification in the context of acute asthma which focuses on variations in network structure.
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The epithelium is integral to the protection of many different biological systems and for the maintenance of biochemical homeostasis. Emerging evidence suggests that particular children have epithelial vulnerabilities leading to dysregulated barrier function and integrity, that resultantly contributes to disease pathogenesis. These epithelial vulnerabilities likely develop in utero or in early life due to various genetic, epigenetic and environmental factors. Although various epithelia are uniquely structured with specific function, prevalent allergic-type epithelial diseases in children potentially have common or parallel disease processes. These include inflammation and immune response dysregulation stemming from atypical epithelial barrier function and integrity. Two diseases where aetiology and pathogenesis are potentially linked to epithelial vulnerabilities include Paediatric Asthma and Eosinophilic Oesophagitis (EoE). For example, rhinovirus C (RV-C) is a known risk factor for paediatric asthma development and is known to disrupt respiratory epithelial barrier function causing acute inflammation. In addition, EoE, a prevalent atopic condition of the oesophageal epithelium, is characterised by similar innate immune and epithelial responses to viral injury. This review examines the current literature and identifies the gaps in the field defining viral-induced effects on a vulnerable respiratory epithelium and resulting chronic inflammation, drawing from knowledge generated in acute wheezing illness, paediatric asthma and EoE. Besides highlighting the importance of epithelial structure and barrier function in allergic disease pathogenesis regardless of specific epithelial sub-types, this review focuses on the importance of examining other parallel allergic-type disease processes that may uncover commonalities driving disease pathogenesis. This in turn may be beneficial in the development of common therapeutics for current clinical management and disease prevention in the future.
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Asma/virología , Esofagitis Eosinofílica/virología , Infecciones por Picornaviridae , Mucosa Respiratoria/virología , Rhinovirus , Niño , Humanos , Ruidos RespiratoriosRESUMEN
BACKGROUND: Acute wheezing is one of the most common hospital presentations for young children. Respiratory syncytial virus (RSV) and rhinovirus (RV) species A, B and the more recently described species C are implicated in the majority of these presentations. However, the relative importance and age-specificities of these viruses have not been defined. Hence, this study aimed to establish these relationships in a large cohort of prospectively recruited hospitalized children. METHODS: The study cohort was 390 children 0-16 years of age presenting with acute wheezing to a children's emergency department, 96.4% being admitted. A nonwheezing control population of 190 was also recruited. Nasal samples were analyzed for viruses. RESULTS: For the first 6 months of life, RSV was the dominant virus associated with wheezing (P < 0.001). From 6 months to 2 years, RSV, RV-A and RV-C were all common but none predominated. From 2 to 6 years, RV-C was the dominant virus detected (50-60% of cases), 2-3 times more common than RV-A and RSV, RSV decreasing to be absent from 4 to 7 years. RV-B was rare at all ages. RV-C was no longer dominant in children more than 10 years of age. Overall, RV-C was associated with lower mean oxygen saturation than any other virus (P < 0.001). Controls had no clear age distribution of viruses. CONCLUSION: This study establishes a clear profile of age specificity of virus infections causing moderate to severe wheezing in children: RSV as the dominant cause in the first 6 months and RV-C in preschool-age children.
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Hospitalización/estadística & datos numéricos , Ruidos Respiratorios/etiología , Virus Sincitial Respiratorio Humano/patogenicidad , Rhinovirus/patogenicidad , Enfermedad Aguda , Adolescente , Factores de Edad , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Nariz/virología , Saturación de Oxígeno , Infecciones por Picornaviridae/complicaciones , Infecciones por Picornaviridae/virología , Estudios Prospectivos , Infecciones por Virus Sincitial Respiratorio/complicaciones , Infecciones por Virus Sincitial Respiratorio/virologíaRESUMEN
BACKGROUND: Chinese immigrants living in Australia experience increased allergic conditions: asthma, eczema, hay fever and wheeze. Recently we reported diminished innate cytokine responses in long-term immigrants, potentially increasing their pathogenic viral load and microbial carriage. We hypothesise that a Western environment changes the nasal microbiome profile, and this altered profile may be associated with the development of allergic conditions. In this cross-sectional study, we aimed to examine the loading of viral and microbial respiratory pathogens in the upper airway. METHODS: Adult Chinese immigrants were grouped depending on time spent in Australia: short-term (<6 years) or long-term (≥6 years). First, age- and gender-matched immigrants were selected for an initial screen using quantitative polymerase chain reaction (qPCR) micro-array panels. Then based on initial results the viruses, human parainfluenza 3 and rhinovirus, and the bacteria, Burkholderia spp., Staphylococcus aureus and Streptococcus pneumoniae, were validated using qPCR in the population. Associations for bacterial prevalence with atopic phenotypes were investigated. RESULTS: Pooling the initial screen and validation subjects, S. aureus and S. pneumoniae had higher prevalence in long-term compared with short-term subjects (25.0% vs 8.1%, P = 0.012; and 76.8% vs 48.4%, P = 0.002). Those immigrants with nasal S. pneumoniae presence resided longer (average time 90.4 months) in Australia than immigrants without S. pneumoniae (52.7 months; P = 0.001). After adjusting for confounders, Chinese immigrants with S. pneumoniae carriage have a five-fold increased risk of doctor-diagnosed eczema (odds ratio, OR 5.36, 95% CI: 1.10-26.14; P = 0.038) compared to immigrants without S. pneumoniae carriage. There was a trend of S. pneumoniae abundance correlating with reduced host Toll-like receptor gene expression. CONCLUSION: Our findings suggest that nasal S. pneumoniae may play a role in the development of allergic conditions in Chinese immigrants in a Western environment.
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Emigrantes e Inmigrantes , Hipersensibilidad , China/epidemiología , Estudios Transversales , Humanos , Staphylococcus aureus , Streptococcus pneumoniaeRESUMEN
Rationale: Rhinovirus (RV) C can cause asymptomatic infection and respiratory illnesses ranging from the common cold to severe wheezing.Objectives: To identify how age and other individual-level factors are associated with susceptibility to RV-C illnesses.Methods: Longitudinal data from the COAST (Childhood Origins of Asthma) birth cohort study were analyzed to determine relationships between age and RV-C infections. Neutralizing antibodies specific for RV-A and RV-C (three types each) were determined using a novel PCR-based assay. Data were pooled from 14 study cohorts in the United States, Finland, and Australia, and mixed-effects logistic regression was used to identify factors related to the proportion of RV-C versus RV-A detection.Measurements and Main Results: In COAST, RV-A and RV-C infections were similarly common in infancy, whereas RV-C was detected much less often than RV-A during both respiratory illnesses and scheduled surveillance visits (P < 0.001, χ2) in older children. The prevalence of neutralizing antibodies to RV-A or RV-C types was low (5-27%) at the age of 2 years, but by the age of 16 years, RV-C seropositivity was more prevalent (78% vs. 18% for RV-A; P < 0.0001). In the pooled analysis, the RV-C to RV-A detection ratio during illnesses was significantly related to age (P < 0.0001), CDHR3 genotype (P < 0.05), and wheezing illnesses (P < 0.05). Furthermore, certain RV types (e.g., C2, C11, A78, and A12) were consistently more virulent and prevalent over time.Conclusions: Knowledge of prevalent RV types, antibody responses, and populations at risk based on age and genetics may guide the development of vaccines or other novel therapies against this important respiratory pathogen.
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Anticuerpos Neutralizantes/sangre , Asma/fisiopatología , Susceptibilidad a Enfermedades , Infecciones por Picornaviridae/fisiopatología , Ruidos Respiratorios/fisiopatología , Rhinovirus/genética , Rhinovirus/patogenicidad , Adolescente , Factores de Edad , Asma/epidemiología , Asma/virología , Australia/epidemiología , Niño , Preescolar , Estudios de Cohortes , Femenino , Finlandia/epidemiología , Variación Genética , Genotipo , Humanos , Lactante , Recién Nacido , Estudios Longitudinales , Masculino , Infecciones por Picornaviridae/epidemiología , Infecciones por Picornaviridae/inmunología , Estados Unidos/epidemiologíaRESUMEN
Single nucleotide polymorphisms (SNPs) of the vitamin D receptor (VDR) gene have shown linkage and association with asthma development in multiple cohort studies. However, the majority of investigations have focused on asthma phenotypes in cohorts with stable disease. We investigated the relationship between VDR SNPs and the frequency and severity of acute episodes of wheeze/asthma in a cohort of Australian children, as the ability to identify children at risk of more severe exacerbations could lead to personalized and improved genotype-specific treatment pathways. We successfully genotyped five SNPs of the VDR gene (rs2525046, rs9729, rs1544410 (BsmI), rs22239179, and rs2228570 (FokI)) in 657 children presenting to a tertiary children's hospital with acute asthma, bronchiolitis, or a wheezing illness. The relationships between VDR SNPs and exacerbation severity scores, ß2-agonist use, and frequency of respiratory exacerbations were analysed using multiple regression. The rs2525046 (FokI) CT genotype was associated with higher VDR mRNA intensity levels (p = 0.007) compared to the CC genotype. A trend towards significance (p=0.056) was identified between the rs2525046 TT genotype and higher VDR mRNA intensity levels compared to the CC genotype. Children with rs2228570 AA genotype had higher exacerbation severity scores (p=0.001) and poorer ß2-agonist treatment response (doses at 6 h: p = 0.009 and 12 h: p=0.033) compared to those with the GG genotype. Children with rs1544410 (BsmI) TT genotype had lower exacerbation severity scores (p = 0.005) compared to those with the CC genotype. Children with rs2228570 GA genotype presented to and/or were admitted to hospital more times since birth with respiratory (p = 0.011) and wheezing (p = 0.021) illnesses than children with the GG genotype. No associations were identified between rs9729, rs2525046 and r2239179 polymorphisms and acute wheezing/asthma variables. These findings suggest that genetic variants at the VDR locus may play a role in acute wheeze/asthma severity in children.
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Asma/genética , Receptores de Calcitriol/genética , Ruidos Respiratorios/genética , Adolescente , Niño , Preescolar , Femenino , Genotipo , Humanos , Lactante , Recién Nacido , Masculino , Polimorfismo de Nucleótido Simple , Índice de Severidad de la Enfermedad , Brote de los SíntomasRESUMEN
Rationale: Individuals with asthma have heightened antibody responses to rhinoviruses (RVs), although those specific for RV-C are lower than responses specific for RV-A, suggesting poor immunity to this species.Objectives: To ascertain and compare T-cell memory responses induced by RV-A and RV-C in children with and without asthma.Methods: Peripheral blood mononuclear cells from 17 children with asthma and 19 control subjects without asthma were stimulated in vitro with peptide formulations to induce representative species-specific responses to RV-A and RV-C. Molecular profiling (RNA sequencing) was used to identify enriched pathways and upstream regulators.Measurements and Main Results: Responses to RV-A showed higher expression of IFNG and STAT1 compared with RV-C, and significant expression of CXCL9, 10, and 11 was not found for RV-C. There was no reciprocal increase of T-helper cell type 2 (Th2) cytokine genes or the Th2 chemokine genes CCL11, CCL17, and CCL22. RV-C induced higher expression of CCL24 (eotaxin-2) than RV-A in the responses of children with and without asthma. Upstream regulator analysis showed both RV-A and, although to a lesser extent, RV-C induced predominant Th1 and inflammatory cytokine expression. The responses of children with asthma compared with those without asthma were lower for both RV-A and RV-C while retaining the pattern of gene expression and upstream regulators characteristic of each species. All groups showed activation of the IL-17A pathway.Conclusions: RV-C induced memory cells with a lower IFN-γ-type response than RV-A without T-helper cell type 2 (Th2) upregulation. Children with asthma had lower recall responses than those without asthma while largely retaining the same gene activation profile for each species. RV-A and RV-C, therefore, induce qualitatively different T-cell responses.
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Asma/genética , Asma/inmunología , Enterovirus/inmunología , Linfocitos/inmunología , Linfocitos/virología , Infecciones por Picornaviridae/genética , Infecciones por Picornaviridae/inmunología , Adolescente , Células Cultivadas , Niño , Preescolar , Femenino , Regulación Viral de la Expresión Génica , Voluntarios Sanos , Humanos , Masculino , Células Th2/inmunologíaRESUMEN
Abnormal wound repair has been observed in the airway epithelium of patients with chronic respiratory diseases, including asthma. Therapies focusing on repairing vulnerable airways, particularly in early life, present a potentially novel treatment strategy. We report defective lower airway epithelial cell repair to strongly associate with common pre-school-aged and school-aged wheezing phenotypes, characterized by aberrant migration patterns and reduced integrin α5ß1 expression. Next generation sequencing identified the PI3K/Akt pathway as the top upstream transcriptional regulator of integrin α5ß1, where Akt activation enhanced repair and integrin α5ß1 expression in primary cultures from children with wheeze. Conversely, inhibition of PI3K/Akt signaling in primary cultures from children without wheeze reduced α5ß1 expression and attenuated repair. Importantly, the FDA-approved drug celecoxib - and its non-COX2-inhibiting analogue, dimethyl-celecoxib - stimulated the PI3K/Akt-integrin α5ß1 axis and restored airway epithelial repair in cells from children with wheeze. When compared with published clinical data sets, the identified transcriptomic signature was also associated with viral-induced wheeze exacerbations highlighting the clinical potential of such therapy. Collectively, these results identify airway epithelial restitution via targeting the PI3K-integrin α5ß1 axis as a potentially novel therapeutic avenue for childhood wheeze and asthma. We propose that the next step in the therapeutic development process should be a proof-of-concept clinical trial, since relevant animal models to test the crucial underlying premise are unavailable.
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Asma/metabolismo , Movimiento Celular , Mucosa Respiratoria/metabolismo , Ruidos Respiratorios , Transducción de Señal , Adolescente , Asma/patología , Línea Celular , Niño , Preescolar , Femenino , Humanos , Lactante , Integrina alfa5beta1/metabolismo , Masculino , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Mucosa Respiratoria/patologíaRESUMEN
BACKGROUND: Rhinovirus C is an important pathogen of asthmatic and non-asthmatic children hospitalised with episodic wheeze. Previous studies on other respiratory viruses have shown that several host cytokines correlate with duration of hospitalisation, but this has yet to be investigated in children with RV-C infection. We determined the nasal cytokine profiles of these children and investigated their relationship with RV-C load and clinical outcome. Flocked nasal swabs were collected from children aged 24-72 months presenting to the Emergency Department at Princess Margaret Hospital with a clinical diagnosis of acute wheeze and an acute upper respiratory tract viral infection. RV-C load was determined by quantitative RT-PCR and cytokine profiles were characterised by a commercial human cytokine 34-plex panel. RV-C was the most commonly detected virus in pre-school-aged children hospitalised with an episodic wheeze. RV-C load did not significantly differ between asthmatic and non-asthmatic patients. Both groups showed a Th2-based cytokine profile. However, Th17 response cytokines IL-17 and IL-1ß were only elevated in RV-C-infected children with pre-existing asthma. Neither RV-C load nor any specific cytokines were associated illness severity in this study. Medically attended RV-C-induced wheeze is characterised by a Th2 inflammatory pattern, independent of viral load. Any therapeutic interventions should be aimed at modulating the host response following infection.
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Asma/complicaciones , Citocinas/metabolismo , Enterovirus , Niño , Preescolar , Enterovirus/inmunología , Enterovirus/aislamiento & purificación , Enterovirus/patogenicidad , Infecciones por Enterovirus/inmunología , Femenino , Humanos , Interleucina-17/metabolismo , Interleucina-1beta/metabolismo , Masculino , Nariz/inmunología , Nariz/virología , Ruidos Respiratorios , Infecciones del Sistema Respiratorio/virología , Rhinovirus/inmunología , Rhinovirus/aislamiento & purificación , Rhinovirus/patogenicidad , Células Th17/metabolismo , Células Th2/metabolismo , Carga Viral/inmunologíaRESUMEN
Acute viral wheeze in children is a major cause of hospitalisation and a major risk factor for the development of asthma. However, the role of the respiratory tract microbiome in the development of acute wheeze is unclear. To investigate whether severe wheezing episodes in children are associated with bacterial dysbiosis in the respiratory tract, oropharyngeal swabs were collected from 109 children with acute wheezing attending the only tertiary paediatric hospital in Perth, Australia. The bacterial community from these samples was explored using next generation sequencing and compared to samples from 75 non-wheezing controls. No significant difference in bacterial diversity was observed between samples from those with wheeze and healthy controls. Within the wheezing group, attendance at kindergarten or preschool was however, associated with increased bacterial diversity. Rhinovirus (RV) infection did not have a significant effect on bacterial community composition. A significant difference in bacterial richness was observed between children with RV-A and RV-C infection, however this is likely due to the differences in age group between the patient cohorts. The bacterial community within the oropharynx was found to be diverse and heterogeneous. Age and attendance at day care or kindergarten were important factors in driving bacterial diversity. However, wheeze and viral infection were not found to significantly relate to the bacterial community. Bacterial airway microbiome is highly variable in early life and its role in wheeze remains less clear than viral influences.
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Bacterias/clasificación , Disbiosis/diagnóstico , Orofaringe/microbiología , Infecciones del Sistema Respiratorio/virología , Virosis/complicaciones , Adolescente , Australia , Bacterias/genética , Niño , Preescolar , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Hospitales Pediátricos , Humanos , Lactante , Recién Nacido , Masculino , ARN Ribosómico 16S/genética , Ruidos Respiratorios , Infecciones del Sistema Respiratorio/complicaciones , Centros de Atención TerciariaRESUMEN
BACKGROUND: Antigen-specific IgE binds the Fcε receptor I (FcεRI) expressed on several types of immune cells, including dendritic cells (DCs). Activation of FcεRI on DCs in atopics has been shown to modulate immune responses that potentially contribute to asthma development. However, the extent to which DC subsets differ in FcεRI expression between atopic children with or without asthma is currently not clear. This study aimed to analyse the expression of FcεRI on peripheral blood mononuclear cells (PBMCs) from atopic children with and without asthma, and non-atopic/non-asthmatic age-matched healthy controls. METHODS: We performed multiparameter flow cytometry on PBMC from 391 children across three community cohorts and one clinical cohort based in Western Australia. RESULTS: We confirmed expression of FcεRI on basophils, monocytes, plasmacytoid and conventional DCs, with higher proportions of all cell populations expressing FcεRI in atopic compared to non-atopic children. Further, we observed that levels of FcεRI expression were elevated across plasmacytoid and conventional DC as well as basophils in atopic asthmatic compared to atopic non-asthmatic children also after adjusting for serum IgE levels. CONCLUSION: Our data suggest that the expression pattern of FcεRI on DC and basophils differentiates asthmatic from non-asthmatic atopic children. Given the significant immune modulatory effects observed as a consequence of FcεRI expression, this altered expression pattern is likely to contribute to asthma pathology in children.
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Asma/metabolismo , Basófilos/fisiología , Células Dendríticas/fisiología , Hipersensibilidad Inmediata/metabolismo , Leucocitos Mononucleares/fisiología , Receptores de IgE/metabolismo , Adolescente , Asma/genética , Australia , Niño , Preescolar , Estudios de Cohortes , Femenino , Citometría de Flujo , Humanos , Hipersensibilidad Inmediata/genética , Inmunoglobulina E/sangre , Inmunomodulación , Masculino , Receptores de IgE/genética , Regulación hacia ArribaAsunto(s)
Contaminantes Ambientales , Enfermedades Pulmonares , Adulto , Biomarcadores , Humanos , Recién Nacido , Dióxido de Nitrógeno , UteroglobinaRESUMEN
Rationale:In utero tobacco exposure is associated with reduced lung function from infancy. Antioxidant enzymes from the glutathione S-transferase (GST) family may protect against these lung function deficits.Objectives: To assess the long-term effect of in utero smoke exposure on lung function into adulthood, and to assess whether GSTT1 and GSTM1 active genotypes have long-term protective effects on lung function.Methods: In this longitudinal study based on a general population (n = 253), lung function was measured during infancy and at 6, 11, 18, and 24 years. GSTM1 and GSTT1 genotype was analyzed in a subgroup (n = 179). Lung function was assessed longitudinally from 6 to 24 years (n = 199).Measurements and Main Results: Exposure to maternal in utero tobacco was associated with lower FEV1 and FVC longitudinally from 6 to 24 years (mean difference, -3.87% predicted, P = 0.021; -3.35% predicted, P = 0.035, respectively). Among those homozygous for the GSTM1-null genotype, in utero tobacco exposure was associated with lower FEV1 and FVC compared with those with no in utero tobacco exposure (mean difference, -6.2% predicted, P = 0.01; -4.7% predicted, P = 0.043, respectively). For those with GSTM1 active genotype, there was no difference in lung function whether exposed to maternal in utero tobacco or not. In utero tobacco exposure was associated with deficits in lung function among those with both GSTT1-null and GSTT1-active genotypes.Conclusions: Certain GST genotypes may have protective effects against the long-term deficits in lung function associated with in utero tobacco exposure. This offers potential preventative targets in antioxidant pathways for at-risk infants of smoking mothers.
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Glutatión Transferasa/genética , Pulmón/fisiopatología , Efectos Tardíos de la Exposición Prenatal/genética , Contaminación por Humo de Tabaco , Fumar Tabaco , Adolescente , Niño , Femenino , Volumen Espiratorio Forzado , Interacción Gen-Ambiente , Genotipo , Humanos , Lactante , Masculino , Exposición Materna , Flujo Espiratorio Medio Máximo , Embarazo , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Factores Protectores , Pruebas de Función Respiratoria , Capacidad Vital , Adulto JovenRESUMEN
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-γ. 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.
Asunto(s)
Asma/genética , Factor 7 Regulador del Interferón/genética , Ruidos Respiratorios/genética , Infecciones del Sistema Respiratorio , Adolescente , Asma/inmunología , Estudios de Casos y Controles , Niño , Preescolar , Análisis por Conglomerados , Femenino , Redes Reguladoras de Genes , Humanos , Lactante , Recién Nacido , Masculino , Fenotipo , Ruidos Respiratorios/inmunología , Infecciones del Sistema Respiratorio/complicaciones , Infecciones del Sistema Respiratorio/genética , Infecciones del Sistema Respiratorio/inmunología , TranscriptomaRESUMEN
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.
RESUMEN
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.