Paediatrics (RCH) - Research Publications

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    Using quantitative PCR to identify opportunities to strengthen soil-transmitted helminth control in Solomon Islands: A cross-sectional epidemiological survey.
    Le, B ; Clarke, N ; Hii, SF ; Byrne, A ; Zendejas-Heredia, PA ; Lake, S ; Sokana, O ; Khattak, A ; Romani, L ; Engelman, D ; Nasi, T ; Boara, D ; Kaldor, J ; Steer, A ; Traub, R ; Nery, SV ; Mitreva, M (Public Library of Science (PLoS), 2022-05)
    BACKGROUND: The Kato-Katz microscopy technique is the global standard for assessment of soil-transmitted helminth (STH) burden. However, major limitations include its poor sensitivity, requirement for rapid sample processing, and inability to differentiate hookworm species nor detect Strongyloides spp. infections. We assessed the prevalence and intensity of STH species in Solomon Islands by conducting a province-wide survey using quantitative PCR (qPCR) for diagnosis, which can provide much better characterisation of STH burden than microscopy. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a cross-sectional survey in 18 villages in Western Province to detect infections with six STH species and quantify intensity with three. We used linear mixed model regression to identify potential water, sanitation, and hygiene (WASH) and environmental risk factors for infection. We collected stool specimens from 830 village residents. Overall STH prevalence was 63.3% (range 27.5 to 91.5% across villages), led by Necator americanus (54.5% [range 17.5-89.4%]), followed by Ancylostoma ceylanicum (15.5% [range 2.8-45.8%]), Trichuris trichiura (9.1% [range 0-79.2%]), and Strongyloides spp. (3.2% [range 0-29.2%]). Most infections were of light intensity for N. americanus (85.7%) and T. trichiura (90.7%). Owning a household latrine was associated with a lower risk of N. americanus infection (AOR 0.41, 95% CI 0.24-0.68) while greater precipitation was linked to more common T. trichiura infection (AOR 1.14, 95% CI 1.04-1.25). CONCLUSION/SIGNIFICANCE: In this first large-scale population survey of STH in the Pacific using qPCR, we found evidence that ivermectin should be incorporated into STH control programmes because of the presence of T. trichiura and Strongyloides spp., both of which are poorly responsive to albendazole. Furthermore, One Health strategies are needed for improved A. ceylanicum and Strongyloides spp. control, WASH access and use should be improved to complement deworming programmes, and control efforts should ideally be expanded to entire communities. TRIAL REGISTRATION: ClinicalTrials.gov Australian and New Zealand Clinical Trials Registry ACTRN12618001086257.
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    Individual Efficacy and Community Impact of Ivermectin, Diethylcarbamazine, and Albendazole Mass Drug Administration for Lymphatic Filariasis Control in Fiji: A Cluster Randomized Trial
    Hardy, M ; Samuela, J ; Kama, M ; Tuicakau, M ; Romani, L ; Whitfeld, MJ ; King, CL ; Weil, GJ ; Grobler, AC ; Robinson, LJ ; Kaldor, JM ; Steer, AC (OXFORD UNIV PRESS INC, 2021-03-16)
    BACKGROUND: Bancroftian filariasis remains endemic in Fiji despite >10 years of mass drug administration (MDA) using diethylcarbamazine and albendazole (DA). The addition of ivermectin to this combination (IDA) has improved efficacy of microfilarial clearance at 12 months in individually randomized trials in nocturnal transmission settings, but impact in a setting of diurnally subperiodic filarial transmission has not been evaluated. METHODS: This cluster randomized study compared the individual efficacy and community impact of IDA vs DA as MDA for lymphatic filariasis in 35 villages on 2 islands of Fiji. Participants were tested at enrollment for circulating filarial antigen and, if positive, for microfilariae. Weight-dosed treatment was offered according to village randomization. Communities were visited at 12 months and retested for lymphatic filariasis. Infected individuals from Rotuma were retested at 24 months. RESULTS: A total of 3816 participants were enrolled and 3616 were treated. At 12 months, microfilariae clearance was achieved in 72 of 111 participants detected with infection at baseline, with no difference in efficacy between treatment groups: DA, 69.2% (95% confidence interval [CI], 57.2%-79.1%) vs IDA, 62.5% (95% CI, 43.6%-78.2%); risk difference, 11.3 % (95% CI, -10% to 32.7%); P = .30. There was no difference between treatment groups in community prevalence of microfilariae at 12 months or individual clearance at 24 months. CONCLUSIONS: We found no difference between IDA and DA in individual clearance or community prevalence of lymphatic filariasis at 12 months, and no improved efficacy following a second annual round of IDA. Possible explanations for the apparent lack of benefit of IDA compared to DA include drug and parasite factors affecting clearance, and higher than expected reinfection rates. Clinical Trials Registration: NCT03177993 and Australian New Zealand Clinical Trial Registry: N12617000738325.
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    Invasive group A streptococcal disease in pregnant women and young children: a systematic review and meta-analysis.
    Sherwood, E ; Vergnano, S ; Kakuchi, I ; Bruce, MG ; Chaurasia, S ; David, S ; Dramowski, A ; Georges, S ; Guy, R ; Lamagni, T ; Levy-Bruhl, D ; Lyytikäinen, O ; Naus, M ; Okaro, JO ; Oppegaard, O ; Vestrheim, DF ; Zulz, T ; Steer, AC ; Van Beneden, CA ; Seale, AC (Elsevier BV, 2022-07)
    BACKGROUND: The incidence of invasive disease caused by group A streptococcus (GAS) has increased in multiple countries in the past 15 years. However, despite these reports, to the best of our knowledge, no systematic reviews and combined estimates of the incidence of invasive GAS have been done in key high-risk groups. To address this, we estimated the incidence of invasive GAS disease, including death and disability outcomes, among two high-risk groups-namely, pregnant women and children younger than 5 years. METHODS: We did a systematic review and meta-analyses on invasive GAS outcomes, including incidence, case fatality risks, and neurodevelopmental impairment risk, among pregnant women, neonates (younger than 28 days), infants (younger than 1 year), and children (younger than 5 years) worldwide and by income region. We searched several databases for articles published from Jan 1, 2000, to June 3, 2020, for publications that reported invasive GAS outcomes, and we sought unpublished data from an investigator group of collaborators. We included studies with data on invasive GAS cases, defined as laboratory isolation of Streptococcus pyogenes from any normally sterile site, or isolation of S pyogenes from a non-sterile site in a patient with necrotising fasciitis or streptococcal toxic shock syndrome. For inclusion in pooled incidence estimates, studies had to report a population denominator, and for inclusion in pooled estimates of case fatality risk, studies had to report aggregate data on the outcome of interest and the total number of cases included as a denominator. We excluded studies focusing on groups at very high risk (eg, only preterm infants). We assessed heterogeneity with I2. FINDINGS: Of the 950 published articles and 29 unpublished datasets identified, 20 studies (seven unpublished; 3829 cases of invasive GAS) from 12 countries provided sufficient data to be included in pooled estimates of outcomes. We did not identify studies reporting invasive GAS incidence among pregnant women in low-income and middle-income countries (LMICs) nor any reporting neurodevelopmental impairment after invasive GAS in LMICs. In nine studies from high-income countries (HICs) that reported invasive GAS in pregnancy and the post-partum period, invasive GAS incidence was 0·12 per 1000 livebirths (95% CI 0·11 to 0·14; I2=100%). Invasive GAS incidence was 0·04 per 1000 livebirths (0·03 to 0·05; I2=100%; 11 studies) for neonates, 0·13 per 1000 livebirths (0·10 to 0·16; I2=100%; ten studies) for infants, and 0·09 per 1000 person-years (95% CI 0·07 to 0·10; I2=100%; nine studies) for children worldwide; 0·12 per 1000 livebirths (95% CI 0·00 to 0·24; I2=100%; three studies) in neonates, 0·33 per 1000 livebirths (-0·22 to 0·88; I2=100%; two studies) in infants, and 0·22 per 1000 person-years (0·13 to 0·31; I2=100%; two studies) in children in LMICs; and 0·02 per 1000 livebirths (0·00 to 0·03; I2=100%; eight studies) in neonates, 0·08 per 1000 livebirths (0·05 to 0·11; I2=100%; eight studies) in infants, and 0·05 per 1000 person-years (0·03 to 0·06; I2=100%; seven studies) in children for HICs. Case fatality risks were high, particularly among neonates in LMICs (61% [95% CI 33 to 89]; I2=54%; two studies). INTERPRETATION: We found a substantial burden of invasive GAS among young children. In LMICs, little data were available for neonates and children and no data were available for pregnant women. Incidences of invasive GAS are likely to be underestimates, particularly in LMICs, due to low GAS surveillance. It is essential to improve available data to inform development of prevention and management strategies for invasive GAS. FUNDING: Wellcome Trust.
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    Community perceptions and acceptability of mass drug administration for the control of neglected tropical diseases in Asia-Pacific countries: A systematic scoping review of qualitative research
    Mitchell, E ; Kelly-Hanku, A ; Krentel, A ; Romani, L ; Robinson, LJ ; Vaz Nery, S ; Kaldor, J ; Steer, AC ; Bell, S ; Horstick, O (PUBLIC LIBRARY SCIENCE, 2022-03-01)
    BACKGROUND: Preventative chemotherapy and mass drug administration have been identified as effective strategies for the prevention, treatment, control and elimination of several NTDs in the Asia-Pacific region. Qualitative research can provide in-depth insight into the social dynamics and processes underlying effective implementation of and adherence to mass drug administration programs. This scoping review examines published qualitative literature to examine factors influencing community perceptions and acceptability of mass drug administration approaches to control NTDs in the Asia-Pacific region. METHODOLOGY: Twenty-four peer reviewed published papers reporting qualitative data from community members and stakeholders engaged in the implementation of mass drug administration programs were identified as eligible for inclusion. FINDINGS: This systematic scoping review presents available data from studies focussing on lymphatic filariasis, soil-transmitted helminths and scabies in eight national settings (India, Indonesia, Philippines, Bangladesh, Laos, American Samoa, Papua New Guinea, Fiji). The review highlights the profoundly social nature of individual, interpersonal and institutional influences on community perceptions of willingness to participate in mass drug administration programs for control of neglected tropical diseases (NTD). Future NTD research and control efforts would benefit from a stronger qualitative social science lens to mass drug administration implementation, a commitment to understanding and addressing the social and structural determinants of NTDs and NTD control in complex settings, and efforts to engage local communities as equal partners and experts in the co-design of mass drug administration and other efforts to prevent, treat, control and eliminate NTDs. CONCLUSION: For many countries in the Asia-Pacific region, the "low hanging fruit has been picked" in terms of where mass drug administration has worked and transmission has been stopped. The settings that remain-such as remote areas of Fiji and Papua New Guinea, or large, highly populated, multi-cultural urban settings in India and Indonesia-present huge challenges going forward.
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    The cost of care for children hospitalised with Invasive Group A Streptococcal Disease in Australia
    Brusco, NK ; Oliver, J ; McMinn, A ; Steer, A ; Crawford, N (BMC, 2021-12-14)
    BACKGROUND: Invasive Group A Streptococcal (iGAS) disease exerts an important burden among Australian children. No Australian hospitalisation cost estimates for treating children with iGAS disease exist, so the financial impact of this condition is unknown. AIM: To determine the minimum annual healthcare cost for children (< 18 years) hospitalised with iGAS disease in Australia from a healthcare sector perspective. METHODS: A cost analysis including children with laboratory-confirmed iGAS disease hospitalised at the Royal Children's Hospital (Victoria, Australia; July 2016 to June 2019) was performed. Results were extrapolated against the national minimum iGAS disease incidence. This analysis included healthcare cost from the 7 days prior to the index admission via General Practitioner (GP) and Emergency Department (ED) consultations; the index admission itself; and the 6 months post index admission via rehabilitation admissions, acute re-admissions and outpatient consultations. Additional extrapolations of national cost data by age group, Aboriginal and Torres Strait Islander ethnicity and jurisdiction were performed. RESULTS: Of the 65 included children, 35% (n = 23) were female, 5% (n = 3) were Aboriginal and Torres Strait Islander, and the average age was 4.4 years (SD 4.6; 65% aged 0-4). The iGAS disease related healthcare cost per child was $67,799 (SD $92,410). These costs were distributed across the 7 days prior to the index admission via GP and ED consultations (0.2 and 1.1% of total costs, respectively), the index admission itself (88.7% of the total costs); and the 6 months post index admission via rehabilitation admissions, acute re-admissions and outpatient consultations (5.3, 4.5 and 0.1% of total costs, respectively). Based on a national minimum paediatric incidence estimation of 1.63 per 100,000 children aged < 18 (95%CI: 1.11-2.32), the total annual healthcare cost for children with iGAS in 2019 was $6,200,862. The financial burden reflects the overrepresentation of Aboriginal and Torres Strait Islander people in the occurrence of iGAS disease. Costs were concentrated among children aged 0-4 years (62%). CONCLUSION: As these cost estimations were based on a minimum incidence, true costs may be higher. Strengthening of surveillance and control of iGAS disease, including a mandate for national notification of iGAS disease, is warranted. TRIAL REGISTRATION: The current study is a part of ongoing iGAS surveillance work across seven paediatric health services in Australia. As this is not a clinical trial, it has not undergone trial registration.
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    Immune signature of acute pharyngitis in a Streptococcus pyogenes human challenge trial
    Anderson, J ; Imran, S ; Frost, HR ; Azzopardi, K ; Jalali, S ; Novakovic, B ; Osowicki, J ; Steer, AC ; Licciardi, P ; Pellicci, DG (NATURE PORTFOLIO, 2022-02-09)
    Streptococcus pyogenes causes at least 750 million infections and more than 500,000 deaths each year. No vaccine is currently available for S. pyogenes and the use of human challenge models offer unique and exciting opportunities to interrogate the immune response to infectious diseases. Here, we use high-dimensional flow cytometric analysis and multiplex cytokine and chemokine assays to study serial blood and saliva samples collected during the early immune response in human participants following challenge with S. pyogenes. We find an immune signature of experimental human pharyngitis characterised by: 1) elevation of serum IL-1Ra, IL-6, IFN-γ, IP-10 and IL-18; 2) increases in peripheral blood innate dendritic cell and monocyte populations; 3) reduced circulation of B cells and CD4+ T cell subsets (Th1, Th17, Treg, TFH) during the acute phase; and 4) activation of unconventional T cell subsets, γδTCR + Vδ2+ T cells and MAIT cells. These findings demonstrate that S. pyogenes infection generates a robust early immune response, which may be important for host protection. Together, these data will help advance research to establish correlates of immune protection and focus the evaluation of vaccines.
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    Mass Drug Administration for the Control of Scabies: A Systematic Review and Meta-analysis
    Lake, SJ ; Kaldor, JM ; Hardy, M ; Engelman, D ; Steer, AC ; Romani, L (OXFORD UNIV PRESS INC, 2022-01-28)
    BACKGROUND: Scabies is a neglected tropical disease of the skin that can lead to impetigo, serious secondary bacterial infections and immune-mediated diseases. Mass drug administration (MDA) has been reported in several studies to reduce the prevalence of scabies and impetigo. We aimed to assess the efficacy of MDA for scabies on scabies and impetigo. METHODS: We conducted a systematic review and meta-analysis of reports on the impact of MDA on scabies and impetigo. We included randomised control trials and observational evaluations reported from January 1970 to April 2021 and involving human participants. We searched PubMed, Ovid Medline, Embase and Cochrane. We considered MDA as treatment intended for the whole population, regardless of individual infection status or symptoms. The main outcome assessed was the change in scabies and impetigo prevalence following MDA. This review is registered with PROSPERO (CRD42020169839). RESULTS: We identified 1110 records, of which 11 met inclusion criteria for the review and 9 were deemed suitable for meta-analysis for scabies and four for impetigo. Most studies were in small populations. There was a high degree of heterogeneity between studies (I 2 value 96·19%). The overall relative reduction of the impact of MDA on scabies prevalence was 79%. The effect size was comparable for MDA based on ivermectin and permethrin. MDA for scabies also led to a reduction in impetigo prevalence with a relative reduction of 66%. CONCLUSIONS: MDA for scabies is highly effective in reducing the prevalence of scabies and impetigo. Further research is needed to determine the durability of impact, and the effectiveness of MDA regimens in larger populations.
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    A case report describing the immune response of an infant with congenital heart disease and severe COVID-19.
    Wurzel, D ; Neeland, MR ; Anderson, J ; Abo, Y-N ; Do, LAH ; Donato, CM ; Bines, JE ; Toh, ZQ ; Higgins, RA ; Jalali, S ; Cole, T ; Subbarao, K ; McMinn, A ; Dohle, K ; Haeusler, GM ; McNab, S ; Alafaci, A ; Overmars, I ; Clifford, V ; Lee, L-Y ; Daley, AJ ; Buttery, J ; Bryant, PA ; Burgner, D ; Steer, A ; Tosif, S ; Konstantinov, IE ; Duke, T ; Licciardi, PV ; Pellicci, DG ; Crawford, NW (Springer Science and Business Media LLC, 2021)
    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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    Comparison of Seroconversion in Children and Adults With Mild COVID-19
    Toh, ZQ ; Anderson, J ; Mazarakis, N ; Neeland, M ; Higgins, RA ; Rautenbacher, K ; Dohle, K ; Nguyen, J ; Overmars, I ; Donato, C ; Sarkar, S ; Clifford, V ; Daley, A ; Nicholson, S ; Mordant, FL ; Subbarao, K ; Burgner, DP ; Curtis, N ; Bines, JE ; McNab, S ; Steer, AC ; Mulholland, K ; Tosif, S ; Crawford, NW ; Pellicci, DG ; Do, LAH ; Licciardi, P (AMER MEDICAL ASSOC, 2022-03-09)
    Importance: The immune response in children with SARS-CoV-2 infection is not well understood. Objective: To compare seroconversion in nonhospitalized children and adults with mild SARS-CoV-2 infection and identify factors that are associated with seroconversion. Design, Setting, and Participants: This household cohort study of SARS-CoV-2 infection collected weekly nasopharyngeal and throat swabs and blood samples during the acute (median, 7 days for children and 12 days for adults [IQR, 4-13] days) and convalescent (median, 41 [IQR, 31-49] days) periods after polymerase chain reaction (PCR) diagnosis for analysis. Participants were recruited at The Royal Children's Hospital, Melbourne, Australia, from May 10 to October 28, 2020. Participants included patients who had a SARS-CoV-2-positive nasopharyngeal or oropharyngeal swab specimen using PCR analysis. Main Outcomes and Measures: SARS-CoV-2 immunoglobulin G (IgG) and cellular (T cell and B cell) responses in children and adults. Seroconversion was defined by seropositivity in all 3 (an in-house enzyme-linked immunosorbent assay [ELISA] and 2 commercial assays: a SARS-CoV-2 S1/S2 IgG assay and a SARS-CoV-2 antibody ELISA) serological assays. Results: Among 108 participants with SARS-CoV-2-positive PCR findings, 57 were children (35 boys [61.4%]; median age, 4 [IQR, 2-10] years) and 51 were adults (28 women [54.9%]; median age, 37 [IQR, 34-45] years). Using the 3 established serological assays, a lower proportion of children had seroconversion to IgG compared with adults (20 of 54 [37.0%] vs 32 of 42 [76.2%]; P < .001). This result was not associated with viral load, which was similar in children and adults (mean [SD] cycle threshold [Ct] value, 28.58 [6.83] vs 24.14 [8.47]; P = .09). In addition, age and sex were not associated with seroconversion within children (median age, 4 [IQR, 2-14] years for both seropositive and seronegative groups; seroconversion by sex, 10 of 21 girls [47.6%] vs 10 of 33 boys [30.3%]) or adults (median ages, 37 years for seropositive and 40 years for seronegative adults [IQR, 34-39 years]; seroconversion by sex, 18 of 24 women [75.0%] vs 14 of 18 men [77.8%]) (P > .05 for all comparisons between seronegative and seropositive groups). Symptomatic adults had 3-fold higher SARS-CoV-2 IgG levels than asymptomatic adults (median, 227.5 [IQR, 133.7-521.6] vs 75.3 [IQR, 36.9-113.6] IU/mL), whereas no differences were observed in children regardless of symptoms. Moreover, differences in cellular immune responses were observed in adults compared with children with seroconversion. Conclusions and Relevance: The findings of this cohort study suggest that among patients with mild COVID-19, children may be less likely to have seroconversion than adults despite similar viral loads. This finding has implications for future protection after SARS-CoV-2 infection in children and for interpretation of serosurveys that involve children. Further research to understand why seroconversion and development of symptoms are potentially less likely in children after SARS-CoV-2 infection and to compare vaccine responses may be of clinical and scientific importance.
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    Innovative vaccine approaches-a Keystone Symposia report
    Cable, J ; Rappuoli, R ; Klemm, EJ ; Kang, G ; Mutreja, A ; Wright, GJ ; Pizza, M ; Castro, SA ; Hoffmann, JP ; Alter, G ; Carfi, A ; Pollard, AJ ; Krammer, F ; Gupta, RK ; Wagner, CE ; Machado, V ; Modjarrad, K ; Corey, L ; Gilbert, PB ; Dougan, G ; Lurie, N ; Bjorkman, PJ ; Chiu, C ; Nemes, E ; Gordon, SB ; Steer, AC ; Rudel, T ; Blish, CA ; Sandberg, JT ; Brennan, K ; Klugman, KP ; Stuart, LM ; Madhi, SA ; Karp, CL (WILEY, 2022-01-14)
    The rapid development of COVID-19 vaccines was the result of decades of research to establish flexible vaccine platforms and understand pathogens with pandemic potential, as well as several novel changes to the vaccine discovery and development processes that partnered industry and governments. And while vaccines offer the potential to drastically improve global health, low-and-middle-income countries around the world often experience reduced access to vaccines and reduced vaccine efficacy. Addressing these issues will require novel vaccine approaches and platforms, deeper insight how vaccines mediate protection, and innovative trial designs and models. On June 28-30, 2021, experts in vaccine research, development, manufacturing, and deployment met virtually for the Keystone eSymposium "Innovative Vaccine Approaches" to discuss advances in vaccine research and development.