Paediatrics (RCH) - Research Publications
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ItemNo Preview AvailableUtilising surface-level data to explore surface, tooth, individual and family influence on the aetiology of hypomineralised second primary molars(ELSEVIER SCI LTD, 2021-10)OBJECTIVES: Hypomineralised second primary molars (HSPM) are common developmental enamel defects. The aims of this study were to use surface-level data to explore the clustering of HSPM at four levels (family, child, tooth, surface). METHODS: This study of 172 twin pairs was nested within the Peri/postnatal Epigenetic Twin Study. HSPM was measured by standardised oral examinations at age 6 years. Multilevel logistic regression models were fitted to assess the correlation structure of surface level data and variation in HSPM. The associations between surface level risk factors and HSPM were then explored using the multilevel logistic regression model using the best fitting correlation structure. RESULTS: The prevalence of HSPM was 68 (19.8%) children, with a total of 141 (10.3%) teeth and 264 tooth surfaces (6.3%) affected. Multilevel models revealed that a hierarchical structure accounting for correlation at the family, child and tooth level best accounted for the variation in HSPM. The estimated variances from the best fitting model (Model 3) were largest at the family level (12.27, 95% CI 6.68, 22.51) compared with 5.23 at the child level and 1.93 at the tooth level. Application of regression analysis utilising this three-level correlation structure identified tooth/surface level factors in addition to the previously identified familial and individual risk factors for HSPM. CONCLUSION: In addition to familial (environmental and genetic) and unique child-level factors, the aetiology of HSPM is likely to be influenced by local tooth-level factors.
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ItemNo Preview AvailablePostnatal inflammation in ApoE-/- mice is associated with immune training and atherosclerosis(PORTLAND PRESS LTD, 2021-08)BACKGROUND AND AIMS: Preterm birth is associated with increased risk of cardiovascular disease (CVD). This may reflect a legacy of inflammatory exposures such as chorioamnionitis which complicate pregnancies delivering preterm, or recurrent early-life infections, which are common in preterm infants. We previously reported that experimental chorioamnionitis followed by postnatal inflammation has additive and deleterious effects on atherosclerosis in ApoE-/- mice. Here, we aimed to investigate whether innate immune training is a contributory inflammatory mechanism in this murine model of atherosclerosis. METHODS: Bone marrow-derived macrophages and peritoneal macrophages were isolated from 13-week-old ApoE-/- mice, previously exposed to prenatal intra-amniotic (experimental choriomanionitis) and/or repeated postnatal (peritoneal) lipopolysaccharide (LPS). Innate immune responses were assessed by cytokine responses following ex vivo stimulation with toll-like receptor (TLR) agonists (LPS, Pam3Cys) and RPMI for 24-h. Bone marrow progenitor populations were studied using flow cytometric analysis. RESULTS: Following postnatal LPS exposure, bone marrow-derived macrophages and peritoneal macrophages produced more pro-inflammatory cytokines following TLR stimulation than those from saline-treated controls, characteristic of a trained phenotype. Cytokine production ex vivo correlated with atherosclerosis severity in vivo. Prenatal LPS did not affect cytokine production capacity. Combined prenatal and postnatal LPS exposure was associated with a reduction in populations of myeloid progenitor cells in the bone marrow. CONCLUSIONS: Postnatal inflammation results in a trained phenotype in atherosclerosis-prone mice that is not enhanced by prenatal inflammation. If analogous mechanisms occur in humans, then there may be novel early life opportunities to reduce CVD risk in infants with early life infections.
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ItemThe familial risk of infection-related hospitalization in children: A population-based sibling study(PUBLIC LIBRARY SCIENCE, 2021-04-28)OBJECTIVE: To assess the risk of severe childhood infections within families, we conducted a sibling analysis in a population-based cohort study with genealogical linkage. We investigated the sibling risk of hospitalization with common infections, a marker of severity. We hypothesized that having siblings hospitalized for infection would increase the proband's risk of admission with infection. STUDY DESIGN: We used population data on Western Australian live-born singletons and their siblings between 1980 and 2014. Measures of infection were infection-related hospitalizations from discharge diagnostic codes. Exposure was having a sibling who had an infection-related hospitalization. Outcomes were infection-related hospitalizations in the child/proband. Probands were followed until an infection-related hospitalization admission (up to the first three), death, 18th birthday, or end of 2014, whichever occurred first. Infection risks were estimated by adjusted Cox proportional hazard models for multiple events. RESULTS: Of 512,279 probands, 142,915 (27.9%) had infection-related hospitalizations; 133,322 (26.0%) had a sibling with a previous infection-related hospitalization (i.e. exposed). Median interval between sibling and proband infection-related hospitalizations was 1.4 years (inter-quartile range 0.5-3.7). Probands had a dose-dependent increase in risk if sibling/s had 1, 2, or 3+ infection-related hospitalizations (adjusted hazard ratio, aHR 1.41, 95% CI 1.39-1.43; aHR 1.65, 1.61-1.69; aHR 1.83, 1.77-1.90, respectively). Among siblings with the same clinical infection type, highest sibling risks were for genitourinary (aHR 2.06, 1.68-2.53), gastrointestinal (aHR 2.07, 1.94-2.19), and skin/soft tissue infections (aHR 2.34, 2.15-2.54). Overall risk of infection-related hospitalization was higher in children with more siblings and with older siblings. CONCLUSION: In this population-based study, we observed an increased risk of infection-related hospitalization in children whose siblings were previously hospitalized for infection. Public health interventions may be particularly relevant in families of children hospitalized with infection.
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ItemMaternal prenatal stress exposure and sex-specific risk of severe infection in offspring(PUBLIC LIBRARY SCIENCE, 2021-01-29)BACKGROUND: Maternal stressful life events during pregnancy have been associated with immune dysregulation and increased risk for asthma and atopy in offspring. Few studies have investigated whether prenatal stress is associated with increased overall or specific infectious diseases in childhood, nor explored sex differences. We sought to examine the relationship between the nature and timing of maternal stress in pregnancy and hospitalisation with infection in offspring. METHODS: Between 1989 and 1992, exposure data on stressful life events were collected from pregnant women (Gen1) in the Raine Study at 18 and 34 weeks' gestation and linked to statutory state-wide hospital morbidity data. We examined associations between the number, category and timing of maternal prenatal stress events and overall and clinical groups of offspring (Gen2) infection-related hospitalisation until age 16 years, adjusting for maternal age, education, and smoking in pregnancy in addition to the presence of siblings at birth. RESULTS: Of 2,141 offspring with complete stress in pregnancy data available, 1,089 had at least one infection-related hospitalisation, with upper respiratory tract infections the most common (n = 556). Each additional stressful life event during pregnancy was associated with increased risk in male offspring for hospitalisation with all infection types. There was little evidence of these associations in girls. CONCLUSIONS: Increased exposure to stressful life events in utero is associated with sex-specific infection-related hospitalisations in childhood. Prenatal stress may adversely affect early immune development for boys and increase the risk of more severe infections. Mechanistic understanding would inform preventative interventions.
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ItemA case report describing the immune response of an infant with congenital heart disease and severe COVID-19(SPRINGERNATURE, 2021-11-15)BACKGROUND: Children with SARS-CoV-2 infection generally present with milder symptoms or are asymptomatic in comparison with adults, however severe disease occurs in a subset of children. To date, the immune correlates of severe COVID-19 in young children have been poorly characterised. METHODS: We report the kinetics of immune responses in relation to clinical and virological features in an infant with acute severe COVID-19 using high-dimensional flow cytometry and multiplex cytokine analysis. RESULTS: Systemic cellular and cytokine profiling show an initial increase in neutrophils and monocytes with depletion of lymphoid cell populations (particularly CD8 + T and NK cells) and elevated inflammatory cytokines. Expansion of memory CD4 + T (but not CD8 + T) cells occurred over time, with a predominant Th2 bias. Marked activation of T cell populations observed during the acute infection gradually resolved as the child recovered. Substantial in vitro activation of T-cell populations and robust cytokine production, in response to inactivated SARS-CoV-2 stimulation, was observed 3 months after infection indicating durable, long-lived cellular immune memory. CONCLUSIONS: These findings provide important insights into the immune response of a young infant with severe COVID-19 and will help to inform future research into therapeutic targets for high-risk groups.
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ItemIdentification of novel locus associated with coronary artery aneurysms and validation of loci for susceptibility to Kawasaki disease.(Springer Science and Business Media LLC, 2021-12)Kawasaki disease (KD) is a paediatric vasculitis associated with coronary artery aneurysms (CAA). Genetic variants influencing susceptibility to KD have been previously identified, but no risk alleles have been validated that influence CAA formation. We conducted a genome-wide association study (GWAS) for CAA in KD patients of European descent with 200 cases and 276 controls. A second GWAS for susceptibility pooled KD cases with healthy paediatric controls from vaccine trials in the UK (n = 1609). Logistic regression mixed models were used for both GWASs. The susceptibility GWAS was meta-analysed with 400 KD cases and 6101 controls from a previous European GWAS, these results were further meta-analysed with Japanese GWASs at two putative loci. The CAA GWAS identified an intergenic region of chromosome 20q13 with multiple SNVs showing genome-wide significance. The risk allele of the most associated SNV (rs6017006) was present in 13% of cases and 4% of controls; in East Asian 1000 Genomes data, the allele was absent or rare. Susceptibility GWAS with meta-analysis with previously published European data identified two previously associated loci (ITPKC and FCGR2A). Further meta-analysis with Japanese GWAS summary data from the CASP3 and FAM167A genomic regions validated these loci in Europeans showing consistent effects of the top SNVs in both populations. We identified a novel locus for CAA in KD patients of European descent. The results suggest that different genes determine susceptibility to KD and development of CAA and future work should focus on the function of the intergenic region on chromosome 20q13.
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ItemVariation in the management of Kawasaki disease in Australia and New Zealand: A survey of paediatricians(WILEY, 2021-05)AIM: This study aimed to describe the current management practices for Kawasaki disease (KD) in Australia and New Zealand. METHODS: We performed a secondary analysis on the Australian and New Zealand responses to a large international survey of clinicians' perspectives on KD diagnosis and management. RESULTS: There was general consensus among Australian and New Zealand clinicians regarding the indications for intravenous immunoglobulin and aspirin in the management of acute KD. There was less consensus on the dose of these agents, the definition and management of treatment-resistant KD and the approach to long-term thromboprophylaxis. CONCLUSION: Most clinicians use intravenous immunoglobulin for primary treatment of KD. There is variation regarding other aspects of KD diagnosis and important management issues. Future studies should confirm whether this reported variation occurs in real-world practice and assess potential impacts on patient outcome.
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ItemChildren and Adults in a Household Cohort Study Have Robust Longitudinal Immune Responses Following SARS-CoV-2 Infection or Exposure(FRONTIERS MEDIA SA, 2021-10-13)Children have reduced severity of COVID-19 compared to adults and typically have mild or asymptomatic disease. The immunological mechanisms underlying these age-related differences in clinical outcomes remain unexplained. Here, we quantify 23 immune cell populations in 141 samples from children and adults with mild COVID-19 and their PCR-negative close household contacts at acute and convalescent time points. Children with COVID-19 displayed marked reductions in myeloid cells during infection, most prominent in children under the age of five. Recovery from infection in both children and adults was characterised by the generation of CD8 TCM and CD4 TCM up to 9 weeks post infection. SARS-CoV-2-exposed close contacts also had immunological changes over time despite no evidence of confirmed SARS-CoV-2 infection on PCR testing. This included an increase in low-density neutrophils during convalescence in both exposed children and adults, as well as increases in CD8 TCM and CD4 TCM in exposed adults. In comparison to children with other common respiratory viral infections, those with COVID-19 had a greater change in innate and T cell-mediated immune responses over time. These findings provide new mechanistic insights into the immune response during and after recovery from COVID-19 in both children and adults.
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ItemProspective characterisation of SARS-CoV-2 infections among children presenting to tertiary paediatric hospitals across Australia in 2020: a national cohort study(BMJ PUBLISHING GROUP, 2021-11)OBJECTIVE: To present Australia-wide data on paediatric COVID-19 and multisystem inflammatory syndromes to inform health service provision and vaccination prioritisation. DESIGN: Prospective, multicentre cohort study. SETTING: Eight tertiary paediatric hospitals across six Australian states and territories in an established research surveillance network-Paediatric Active Enhanced Disease (PAEDS). PARTICIPANTS: All children aged <19 years with SARS-CoV-2 infection including COVID-19, Paediatric Inflammatory Multisystem Syndrome Temporally Associated with SARS-CoV-2 (PIMS-TS) and Kawasaki-like disease TS infection (KD-TS) treated at a PAEDS site from 24 March 2020 to 31 December 2020. INTERVENTION: Laboratory-confirmed SARS-CoV-2 infection. MAIN OUTCOME: Incidence of severe disease among children with COVID-19, PIMS-TS and KD-TS. We also compared KD epidemiology before and during the COVID-19 pandemic. RESULTS: Among 386 children with SARS-CoV-2 infection, 381 (98.7%) had COVID-19 (median 6.3 years (IQR 2.1-12.8),53.3% male) and 5 (1.3%) had multisystem inflammatory syndromes (PIMS-TS, n=4; KD-TS, n=1) (median 7.9 years (IQR 7.8-9.8)). Most children with COVID-19 (n=278; 73%) were Australian-born from jurisdictions with highest community transmission. Comorbidities were present in 72 (18.9%); cardiac and respiratory comorbidities were most common (n=32/72;44%). 37 (9.7%) children with COVID-19 were hospitalised, and two (0.5%) required intensive care. Postinfective inflammatory syndromes (PIMS-TS/KD-TS) were uncommon (n=5; 1.3%), all were hospitalised and three (3/5; 60%) required intensive care management. All children recovered and there were no deaths. KD incidence remained stable during the pandemic compared with prepandemic. CONCLUSIONS: Most children with COVID-19 had mild disease. Severe disease was less frequent than reported in high prevalence settings. Preventative strategies, such as vaccination, including children and adolescents, could reduce both the acute and postinfective manifestations of the disease.
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