20 results on '"Bizzintino, Joelene"'
Search Results
2. Comparison of rhinovirus antibody titers in children with asthma exacerbations and species-specific rhinovirus infection
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Iwasaki, Jua, Smith, Wendy-Anne, Khoo, Siew-Kim, Bizzintino, Joelene, Zhang, Guicheng, Cox, Des W., Laing, Ingrid A., Le Souëf, Peter N., Thomas, Wayne R., and Hales, Belinda J.
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- 2014
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3. Human Rhinovirus Species C Infection in Young Children with Acute Wheeze Is Associated with Increased Acute Respiratory Hospital Admissions
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Cox, Desmond W., Bizzintino, Joelene, Ferrari, Giovanni, Khoo, Siew Kim, Zhang, Guicheng, Whelan, Siobhan, Lee, Wai Ming, Bochkov, Yury A., Geelhoed, Gary C., Goldblatt, Jack, Gern, James E., Laing, Ingrid A., and Le Souëf, Peter N.
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- 2013
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4. Symptomatic Viral Infection is Associated with Impaired Response to Treatment in Children with Acute Asthma
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Rueter, Kristina, Bizzintino, Joelene, Martin, Andrew C., Zhang, Guicheng, Hayden, Catherine M., Geelhoed, Gary C., Goldblatt, Jack, Laing, Ingrid A., and Le Souëf, Peter N.
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- 2012
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5. Defining Age-specific Relationships of Respiratory Syncytial Virus and Rhinovirus Species in Hospitalized Children With Acute Wheeze.
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Oo, Stephen W.C., Khoo, Siew-Kim, Cox, Des W., Chidlow, Glenys, Franks, Kimberley, Prastanti, Franciska, Bochkov, Yury A., Borland, Meredith L., Zhang, Guicheng, Gern, James E., Smith, David W., Bizzintino, Joelene A., Laing, Ingrid A., and Le Souëf, Peter N.
- Published
- 2021
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6. The impact of cytokine levels in young South African children with and without HIV‐associated acute lower respiratory infections.
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Annamalay, Alicia A., Abbott, Salome, Khoo, Siew‐Kim, Hibbert, Julie, Bizzintino, Joelene, Zhang, Guicheng, Laing, Ingrid, Currie, Andrew, Le Souëf, Peter N., and Green, Robin J.
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HEPATOCYTE growth factor ,SOUTH Africans ,CYTOKINES ,RESPIRATORY infections ,EPIDERMAL growth factor - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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- View/download PDF
7. Viral respiratory infections and the oropharyngeal bacterial microbiota in acutely wheezing children.
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Cuthbertson, Leah, Oo, Stephen W. C., Cox, Michael J., Khoo, Siew-Kim, Cox, Des W., Chidlow, Glenys, Franks, Kimberley, Prastanti, Franciska, Borland, Meredith L., Gern, James E., Smith, David W., Bizzintino, Joelene A., Laing, Ingrid A., Le Souëf, Peter N., Moffatt, Miriam F., and Cookson, William O. C.
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RESPIRATORY infections ,VIRUS diseases ,BACTERIAL diseases ,BACTERIAL diversity ,HIV-positive children ,BACTERIAL communities - Abstract
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. [ABSTRACT FROM AUTHOR]
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- 2019
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8. Rhinovirus C is associated with wheezing and rhinovirus A is associated with pneumonia in hospitalized children in Morocco.
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Annamalay, Alicia A., Jroundi, Imane, Bizzintino, Joelene, Khoo, Siew‐Kim, Zhang, Guicheng, Lehmann, Deborah, Laing, Ingrid A., Gern, James, Goldblatt, Jack, Mahraoui, Chafiq, Benmessaoud, Rachid, Moraleda, Cinta, Bassat, Quique, and Le Souëf, Peter
- Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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9. Rhinovirus species and clinical features in children hospitalised with pneumonia from Mozambique.
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Annamalay, Alicia A., Lanaspa, Miguel, Khoo, Siew ‐ Kim, Madrid, Lola, Acácio, Sozinho, Zhang, Guicheng, Laing, Ingrid A., Gern, James, Goldblatt, Jack, Bizzintino, Joelene, Lehmann, Deborah, Le Souëf, Peter N., Bassat, Quique, Khoo, Siew-Kim, Acácio, Sozinho, and Le Souëf, Peter N
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HOSPITAL care of children ,RHINOVIRUSES ,PNEUMONIA in children ,DISEASE prevalence ,RESPIRATORY infections ,HIV-positive children ,POLYMERASE chain reaction ,DIAGNOSIS ,BIOLOGICAL evolution ,HOSPITAL care ,IMMUNITY ,PNEUMONIA ,RNA viruses ,GENOTYPES - Abstract
Copyright of Tropical Medicine & International Health is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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- 2016
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10. Prevalence of and Risk Factors for Human Rhinovirus Infection in Healthy Aboriginal and Non-Aboriginal Western Australian Children.
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Annamalay, Alicia A., Khoo, Siew-Kim, Jacoby, Peter, Bizzintino, Joelene, Zhang, Guicheng, Chidlow, Glenys, Lee, Wai-Ming, Moore, Hannah C., Harnett, Gerry B., Smith, David W., Gern, James E., Lesouef, Peter N., Laing, Ingrid A., and Lehmann, Deborah
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- 2012
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11. The role of GSTP1 polymorphisms and tobacco smoke exposure in children with acute asthma.
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Schultz, En Nee, Devadason, Sunalene G., Khoo, Siew-Kim, Zhang, Guicheng, Bizzintino, Joelene A., Martin, Andrew C., Goldblatt, Jack, Laing, Ingrid A., Le Souëf, Peter N., and Hayden, Catherine M.
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GLUTATHIONE transferase ,TOBACCO smoke pollution ,ASTHMA in children ,POLLUTANTS ,HUMAN genetic variation ,ASTHMA risk factors - Abstract
Background. The glutathione S-transferase enzymes (GSTs) play an important role in the detoxification of environmental tobacco smoke (ETS), which contributes to airway inflammation, a key component of asthma. Genetic variation in GST genes may influence individuals' ability to detoxify environmental pollutants. Objective. To examine the role of polymorphisms in GSTP1 (Ile105Val and Ala114Val), alone and in combination with ETS exposure, on atopy and asthma severity. Methods. GSTP1 Ile105Val and Ala114Val were genotyped and ETS exposure was assessed by parental questionnaire, which was validated by urinary cotinine measurements. Associations between ETS exposure, GSTP1 polymorphisms, and their interaction on atopy and asthma severity were investigated. Results. For the functional GSTP1 105 SNP, those with the Ile/Ile genotype had odds for atopy of 2.77 ( p = .054) when assessed by genotype alone, which increased to 9.02 ( p = .050) when ETS was included, relative to individuals with other genotypes. Likewise, compared to children with other GSTP1 114 genotypes, those with Ala/Ala genotype had a 5.47-fold ( p = .002) increased risk of atopy ( p = .020) when assessed by genotype alone, increasing to 9.17-fold when ETS was included. The 105 Ile/Ile individuals all had the AA (105 Ile/Ile and 114 Ala/Ala) haplotype group; therefore, the odds for atopy were the same. Individuals without any *C haplotype (105 Val and 114 Val allele) who were exposed to ETS had a 9.17-fold increased risk of atopy when compared with individuals with at least one *C haplotype and not exposed to ETS ( p = .020). Conclusion. There were significant interactions between GSTP1 SNPs, atopy, and ETS exposure in this cohort. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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12. Leukotriene pathway polymorphisms are associated with altered cysteinyl leukotriene production in children with acute asthma.
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Bizzintino, Joelene A., Khoo, Siew-Kim, Zhang, Guicheng, Martin, Andrew C., Rueter, Kristina, Geelhoed, Gary C., Goldblatt, Jack, Laing, Ingrid A., Le Souëf, Peter N., and Hayden, Catherine M.
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LEUKOTRIENES ,GENETIC polymorphisms ,ASTHMA in children ,URINALYSIS ,GENETICS of asthma ,GENE frequency ,CONFIDENCE intervals - Abstract
Abstract: Cysteinyl leukotrienes (cysLTs) are pro-inflammatory mediators with increasing evidence for a role in childhood acute asthma. This study examined the influence of polymorphisms in cysLT pathway genes on urinary leukotriene E
4 (uLTE4 ) levels and clinical status in acute asthmatic children. Children aged 2–16 years were recruited during an asthma attack (n=205). Where possible, asthma severity scores were assigned, ALOX5AP G-336A, ALOX5 G-1708A, LTC4S A-444C and G-1072A, GPX4 C718T, and CYSTLTR1 T927C genotypes were determined and uLTE4 was measured in acute and convalescent samples. uLTE4 levels were higher acutely compared with convalescence (acute GM: 115.7pg/mg creatinine; 95% CI 88.6–151.1, convalescence GM: 66.4pg/mg creatinine; 95% CI 51.5–85.6; n=50 paired samples, p=0.003) and paired sample analysis showed genotype-specific effects with significantly increased uLTE4 for LTC4 S-444AA (acute GM: 127.9pg/mg creatinine; 95% CI 91.8–178.3, convalescence GM: 68.2pg/mg creatinine; 95% CI 50.5–92.0; n=32, p=0.002), LTC4 S-1072 GG (acute GM: 126.7pg/mg creatinine; 95% CI 95.4–168.3, convalescence GM: 78.9pg/mg creatinine; 95% CI 59.7–104.1; n=39, p=0.019) and CYSLTR1 927 TT/T_ (acute GM: 96.8pg/mg creatinine; 95% CI 73.8–126.9, convalescence GM: 62.4pg/mg creatinine; 95% CI 46.8–83.3; n=28, p=0.036) but not AC/CC, GA/AA, or TC/CC/C_, respectively. When we compared the allele frequencies of the CYSLTR1 SNP between asthmatics and non-asthmatics, the 927C allele was found to be a risk allele for asthma (OR=2.13, 95% CI: 1.06–4.26, p=0.033). Genotypes were not associated with acute or convalescent uLTE4 levels alone and neither the SNPs nor uLTE4 correlated with acute asthma severity. Leukotriene pathway gene polymorphisms may influence the magnitude of cysLT production during an attack, yet their influence alone may not be substantial enough to alter the severity of exacerbations. [Copyright &y& Elsevier]- Published
- 2009
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13. β2-Adrenoceptor Polymorphisms Predict Response to β2-Agonists in Children with Acute Asthma.
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Martin, Andrew C., Zhang, Guicheng, Rueter, Kristina, Khoo, Siew-Kim, Bizzintino, Joelene, Hayden, Catherine M., Geelhoed, Gary C., Goldblatt, Jack, Laing, Ingrid A., and Le Souëf, Peter N.
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ASTHMA in children ,ASTHMATICS ,GENETIC polymorphisms ,PERSONNEL management ,GENETIC research - Abstract
The aim of this study was to determine the influence of single nucleotide polymorphisms in the β2-adrenoceptor gene, on the response to inhaled β2-agonists in children with acute asthma. We hypothesised that children with polymorphisms that generate enhanced receptor downregulation in vitro, Gly16 and Gln27, would have a slower response to β2-agonist therapy during acute asthma. One hundred and forty-eight children with acute asthma were recruited and genotyped for β2Arg16Gly and β2Gln27Glu. For Gln27Glu, individuals Gln27Gln took longest to stretch out to 1, 2 and 4 hourly β2-agonists, followed by heterozygotes who were intermediate and Glu27Glu who responded most rapidly (1hourly: 2.6hr vs. 2.0 vs. 1.4, p = 0.02; 2 hourly: 10.6hr vs. 10.7 vs. 6.8, p = 0.07; 4 hourly: 29.8hr vs. 28.5 vs. 24.3, p = 0.30). The ability to prospectively identify children who respond less effectively to β 2-agonists during an acute asthma attack has the potential to allow the generation of genotype-specific treatment pathways. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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14. Upper Airway Cell Transcriptomics Identify a Major New Immunological Phenotype with Strong Clinical Correlates in Young Children with Acute Wheezing.
- Author
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Siew-Kim Khoo, Read, James, Franks, Kimberley, Guicheng Zhang, Bizzintino, Joelene, Coleman, Laura, McCrae, Christopher, Öberg, Lisa, Troy, Niamh M., Prastanti, Franciska, Everard, Janet, Oo, Stephen, Borland, Meredith L., Maciewicz, Rose A., Souëf, Peter N. Le, Laing, Ingrid A., and Bosco, Anthony
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WHEEZE , *COUGH , *COMMON cold , *ASTHMA in children , *PHENOTYPES , *AIRWAY (Anatomy) , *GENE regulatory networks - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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15. Respiratory viruses in young South African children with acute lower respiratory infections and interactions with HIV.
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Annamalay, Alicia A., Abbott, Salome, Sikazwe, Chisha, Khoo, Siew-Kim, Bizzintino, Joelene, Zhang, Guicheng, Laing, Ingrid, Chidlow, Glenys R., Smith, David W., Gern, James, Goldblatt, Jack, Lehmann, Deborah, Green, Robin J., and Le Souëf, Peter N.
- Subjects
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RHINOVIRUSES , *RESPIRATORY infections , *HIV-positive children , *DISEASE prevalence , *POLYMERASE chain reaction , *DIAGNOSIS - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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16. Upper Airway Cell Transcriptomics Identify a Major New Immunological Phenotype with Strong Clinical Correlates in Young Children with Acute Wheezing.
- Author
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Khoo SK, Read J, Franks K, Zhang G, Bizzintino J, Coleman L, McCrae C, Öberg L, Troy NM, Prastanti F, Everard J, Oo S, Borland ML, Maciewicz RA, Le Souëf PN, Laing IA, and Bosco A
- Subjects
- Adolescent, Asthma immunology, Case-Control Studies, Child, Child, Preschool, Cluster Analysis, Female, Gene Regulatory Networks, Humans, Infant, Infant, Newborn, Male, Phenotype, Respiratory Sounds immunology, Transcriptome, Asthma genetics, Interferon Regulatory Factor-7 genetics, Respiratory Sounds genetics, Respiratory Tract Infections complications, Respiratory Tract Infections genetics, Respiratory Tract Infections immunology
- Abstract
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 IRF7
hi 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., (Copyright © 2019 by The American Association of Immunologists, Inc.)- Published
- 2019
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17. Rhinovirus is the most common virus and rhinovirus-C is the most common species in paediatric intensive care respiratory admissions.
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Cox DW, Khoo SK, Zhang G, Lindsay K, Keil AD, Knight G, Gern JE, Laing IA, Bizzintino J, and Le Souëf PN
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- Adolescent, Australia, Child, Child, Preschool, Databases, Factual, Female, Hospitalization statistics & numerical data, Humans, Infant, Infant, Newborn, Intensive Care Units, Pediatric statistics & numerical data, Male, Picornaviridae Infections complications, Retrospective Studies, Enterovirus isolation & purification, Picornaviridae Infections diagnosis, Respiratory Tract Infections virology, Rhinovirus isolation & purification
- Abstract
Competing Interests: Conflict of interest: P.N. Le Souëf reports grants from National Health and Medical Research Council Australia (programme grant number APP458513, project grant number APP1031635), during the conduct of the study.
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- 2018
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18. Recurrent rhinovirus detections in children following a rhinovirus-induced wheezing exacerbation: A retrospective study.
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Halmø Hürdum S, Zhang G, Khoo SK, Bizzintino J, Franks KM, Lindsay K, Keil AD, Cox DW, Goldblatt J, Bochkov YA, Gern J, Ulrik CS, Souëf PN, and Laing IA
- Abstract
Introduction: It is unclear if children with a rhinovirus (RV)-induced wheezing exacerbation are more susceptible to viruses longitudinally, and whether a parental history of asthma and/or allergy impacts their susceptibility. The objective of this study was to determine if RV, RV-A and RV-C related wheezing exacerbations in children were associated with prior or subsequent viral detections and investigate the role of parental history of asthma and allergy., Materials and Methods: Children presenting to hospital with acute wheeze were prospectively recruited and tested for respiratory viruses. Data on viruses detected in other respiratory samples (May 1997 to December 2012) were collected from hospital microbiology records and additional RV testing was performed on stored hospital respiratory samples (September 2009 to December 2012). A positive parental history was defined as either parent with self-reported asthma and/or allergy., Results: At recruitment, RV was detected in 69.2% of samples from children with an acute wheezing episode (n=373, 0-16 years of age), with RV-C the most common virus (65.5%). Children with a history of parental asthma and/or allergy and RV at recruitment had a 14-fold increased incidence rate ratio (IRR) of subsequent RV detection (IRR 14.0, 95% CI 1.9-104.1; p=0.01) compared with children without RV at recruitment. Children without this parental history had a reduced incident rate ratio for samples assessed during this time (IRR 0.5, 95% CI 0.3-0.9; p=0.03)., Conclusion: Children with a parental history of asthma and/or allergy may become more susceptible to recurrent symptomatic RV infections.
- Published
- 2015
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19. Interactions between innate antiviral and atopic immunoinflammatory pathways precipitate and sustain asthma exacerbations in children.
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Subrata LS, Bizzintino J, Mamessier E, Bosco A, McKenna KL, Wikström ME, Goldblatt J, Sly PD, Hales BJ, Thomas WR, Laing IA, LeSouëf PN, and Holt PG
- Subjects
- Acute Disease, Adenovirus Infections, Human immunology, Adenovirus Infections, Human metabolism, Adenovirus Infections, Human pathology, Adolescent, Asthma pathology, Child, Child, Preschool, Female, Gene Expression Regulation, Viral immunology, Humans, Hypersensitivity, Immediate pathology, Inflammation Mediators physiology, Influenza, Human immunology, Influenza, Human metabolism, Influenza, Human pathology, Male, Paramyxoviridae Infections immunology, Paramyxoviridae Infections metabolism, Paramyxoviridae Infections pathology, Respiratory Syncytial Virus Infections immunology, Respiratory Syncytial Virus Infections metabolism, Respiratory Syncytial Virus Infections pathology, Signal Transduction genetics, Asthma immunology, Asthma virology, Hypersensitivity, Immediate immunology, Hypersensitivity, Immediate virology, Immunity, Innate genetics, Inflammation Mediators metabolism, Signal Transduction immunology
- Abstract
Severe asthma exacerbations in children requiring hospitalization are typically associated with viral infection and occur almost exclusively among atopics, but the significance of these comorbidities is unknown. We hypothesized that underlying interactions between immunoinflammatory pathways related to responses to aeroallergen and virus are involved, and that evidence of these interactions is detectable in circulating cells during exacerbations. To address this hypothesis we used a genomics-based approach involving profiling of PBMC subpopulations collected during exacerbation vs convalescence by microarray and flow cytometry. We demonstrate that circulating T cells manifest the postactivated "exhausted" phenotype during exacerbations, whereas monocyte/dendritic cell populations display up-regulated CCR2 expression accompanied by phenotypic changes that have strong potential for enhancing local inflammation after their recruitment to the atopic lung. Notably, up-regulation of FcepsilonR1, which is known to markedly amplify capacity for allergen uptake/presentation to Th2 effector cells via IgE-mediated allergen capture, and secondarily programming of IL-4/IL-13-dependent IL-13R(+) alternatively activated macrophages that have been demonstrated in experimental settings to be a potent source of autocrine IL-13 production. We additionally show that this disease-associated activation profile can be reproduced in vitro by cytokine exposure of atopic monocytes, and furthermore that IFN-alpha can exert both positive and negative roles in the process. Our findings suggest that respiratory viral infection in atopic children may initiate an atopy-dependent cascade that amplifies and sustains airway inflammation initiated by innate antiviral immunity via harnessing underlying atopy-associated mechanisms. These interactions may account for the unique susceptibility of atopics to severe viral-induced asthma exacerbations.
- Published
- 2009
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20. Beta2-adrenoceptor polymorphisms predict response to beta2-agonists in children with acute asthma.
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Martin AC, Zhang G, Rueter K, Khoo SK, Bizzintino J, Hayden CM, Geelhoed GC, Goldblatt J, Laing IA, and Le Souëf PN
- Subjects
- Adolescent, Asthma diagnosis, Asthma mortality, Child, Child, Preschool, Cohort Studies, Female, Genetic Predisposition to Disease epidemiology, Humans, Kaplan-Meier Estimate, Male, Predictive Value of Tests, Probability, Receptors, Adrenergic, beta-2 metabolism, Respiratory Function Tests, Retrospective Studies, Risk Assessment, Sensitivity and Specificity, Severity of Illness Index, Survival Analysis, Treatment Outcome, Adrenergic beta-Agonists administration & dosage, Asthma drug therapy, Asthma genetics, Polymorphism, Genetic, Receptors, Adrenergic, beta-2 genetics
- Abstract
The aim of this study was to determine the influence of single nucleotide polymorphisms in the beta(2)-adrenoceptor gene, on the response to inhaled beta(2)-agonists in children with acute asthma. We hypothesised that children with polymorphisms that generate enhanced receptor downregulation in vitro, Gly16 and Gln27, would have a slower response to beta(2)-agonist therapy during acute asthma. One hundred and forty-eight children with acute asthma were recruited and genotyped for beta(2)Arg16Gly and beta(2)Gln27Glu. For Gln27Glu, individuals Gln27Gln took longest to stretch out to 1, 2 and 4 hourly beta(2)-agonists, followed by heterozygotes who were intermediate and Glu27Glu who responded most rapidly (1 hourly: 2.6 hr vs. 2.0 vs. 1.4, p = 0.02; 2 hourly: 10.6 hr vs. 10.7 vs. 6.8, p = 0.07; 4 hourly: 29.8 hr vs. 28.5 vs. 24.3, p = 0.30). The ability to prospectively identify children who respond less effectively to beta (2)-agonists during an acute asthma attack has the potential to allow the generation of genotype-specific treatment pathways.
- Published
- 2008
- Full Text
- View/download PDF
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