Paediatrics (RCH) - Research Publications

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    Diagnostics to support the control of scabies-Development of two target product profiles
    Marks, M ; McVernon, J ; McCarthy, JS ; Enbiale, W ; Hanna, C ; Chosidow, O ; Engelman, D ; Asiedu, K ; Steer, A ; Mumcuoglu, KY (PUBLIC LIBRARY SCIENCE, 2022-08)
    BACKGROUND: Scabies was added to the WHO NTD portfolio in 2017 and targets for the control of scabies were included in the 2021-2030 WHO NTD roadmap. A major component of scabies control efforts a strategy based on mass drug administration (MDA) with ivermectin. Currently diagnosis of scabies relies on clinical examination with a limited role for diagnostic testing. Under the recommendation of the WHO Diagnostic Technical Advisory Group (DTAG) for Neglected Tropical Diseases, a working group was assembled and tasked with agreeing on priority use cases for and developing target product profiles (TPPs) for new diagnostics tools for scabies. METHODOLOGY AND PRINCIPAL FINDINGS: The working group convened three times and established two use cases: establishing if the 10% threshold for mass drug administration had been reached and if the 2% threshold for stopping mass drug administration has been achieved. One subgroup assessed the current diagnostic landscape for scabies and a second subgroup determined the test requirements for both use cases. Draft TPPs were sent out for input from stakeholders and experts. Both TPPs considered the following parameters: product use, design, performance, configuration, cost, access and equity. The group considered the use of the tests as a single step process or as part of a two step process following initial clinical examination. When used a single step test (the ideal scenario) for starting MDA a new diagnostic required a sensitivity of ≥92% and a specificity of ≥98%. When used a single step test (the ideal scenario) for stopping MDA a new diagnostic required a sensitivity of ≥80% and a specificity of ≥99%. CONCLUSIONS: The TPPs developed will provide test developers with guidance to ensure that novel diagnostic tests meet identified public health needs.
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    Comparison of antibody responses to SARS-CoV-2 variants in Australian children
    Toh, ZQ ; Mazarakis, N ; Nguyen, J ; Higgins, RA ; Anderson, J ; Lien, AHD ; Burgner, DP ; Curtis, N ; Steer, AC ; Mulholland, K ; Crawford, NW ; Tosif, S ; Licciardi, P (NATURE PORTFOLIO, 2022-11-23)
    There is limited understanding of antibody responses in children across different SARS-CoV-2 variants. As part of an ongoing household cohort study, we assessed the antibody response among unvaccinated children infected with Wuhan, Delta, or Omicron variants, as well as vaccinated children with breakthrough Omicron infection, using a SARS-CoV-2 S1-specific IgG assay and surrogate virus neutralization test (% inhibition). Most children infected with Delta (100%, 35/35) or Omicron (81.3%, 13/16) variants seroconverted by one month following infection. In contrast, 37.5% (21/56) children infected with Wuhan seroconverted, as previously reported. However, Omicron-infected children (geometric mean concentration 46.4 binding antibody units/ml; % inhibition = 16.3%) mounted a significantly lower antibody response than Delta (435.5 binding antibody untis/mL, % inhibition = 76.9%) or Wuhan (359.0 binding antibody units/mL, % inhibition = 74.0%). Vaccinated children with breakthrough Omicron infection mounted the highest antibody response (2856 binding antibody units/mL, % inhibition = 96.5%). Our findings suggest that despite a high seropositivity rate, Omicron infection in children results in lower antibody levels and function compared with Wuhan or Delta infection or with vaccinated children with breakthrough Omicron infection. Our data have important implications for public health measures and vaccination strategies to protect children.
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    Study protocol for controlled human infection for penicillin G against Streptococcus pyogenes: a double-blinded, placebo-controlled, randomised trial to determine the minimum concentration required to prevent experimental pharyngitis (the CHIPS trial)
    Hla, TK ; Osowicki, J ; Salman, S ; Batty, KT ; Marsh, JA ; Kado, J ; Barr, R ; Enkel, SL ; Snelling, TL ; McCarthy, J ; Steer, AC ; Carapetis, J ; Manning, L (BMJ PUBLISHING GROUP, 2022-12)
    INTRODUCTION: Regular intramuscular benzathine penicillin G injections have been the cornerstone of rheumatic heart disease (RHD) secondary prophylaxis since the 1950s. As the pharmacological correlate of protection remains unknown, it is difficult to recommend changes to this established regimen. Determining the minimum effective penicillin exposure required to prevent Streptococcus pyogenes infection will accelerate development of new long-acting penicillins for RHD prevention as well as inform opportunities to improve existing regimens. The CHIPS trial will address this knowledge gap by directly testing protection afforded by different steady state plasma concentrations of penicillin in an established model of experimental human S. pyogenes pharyngitis. METHODS AND ANALYSIS: This is a double-blinded, placebo-controlled, randomised experimental human infection study. Sixty healthy adult volunteers aged 18-40 years will be recruited and randomised 1:1:1:1:1 to continuous intravenous penicillin infusions targeting five different steady state plasma concentrations of 0 (placebo), 3, 6, 12 and 20 ng/mL via a midline catheter. Each participant's penicillin pharmacokinetic parameters will be established prior to the challenge, to ensure accurate dosing for the continuous infusion. Following the challenge with a well-characterised strain of S. pyogenes, participants will be observed for up to 6 days for the development of pharyngitis and treated with antibiotics prior to discharge. The primary objective is to determine the minimum effective steady-state plasma penicillin concentration required to prevent experimental pharyngitis. Secondary objectives will explore systemic and mucosal immunoinflammatory responses during pharyngitis, bacterial colonisation dynamics, environmental contamination and qualitative evaluation of the participant experience. ETHICS AND DISSEMINATION: Ethical approval has been obtained (Bellberry Human Research Ethics Committee). Findings will be reported in peer-reviewed publications and presented at national/international stakeholder forums. TRIAL REGISTRATION NUMBER: ACTRN12621000751875.
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    Comparison of approaches to determine echocardiographic outcomes for children with latent rheumatic heart disease
    Rwebembera, J ; Beaton, A ; Okello, E ; Engelman, D ; Fall, N ; Mirabel, M ; Nakitto, M ; Nunes, MCP ; Pulle, J ; Sarnacki, R ; Scheel, A ; Zuhlke, L ; Grobler, A ; Steer, AC ; Sable, C (BMJ PUBLISHING GROUP, 2022-12)
    BACKGROUND: Screening programmes using echocardiography offer opportunity for intervention through identification and treatment of early (latent) rheumatic heart disease (RHD). We aimed to compare two methods for classifying progression or regression of latent RHD: serial review method and blinded, side-by-side review. METHODS: A four-member expert panel reviewed 799 enrolment (in 2018) and completion (in 2020) echocardiograms from the GOAL Trial of latent RHD in Uganda to make consensus determination of normal, borderline RHD or definite RHD. Serial interpretations (enrolment and completion echocardiograms read at two different time points, 2 years apart, not beside one another) were compared with blinded side-by-side comparisons (enrolment and completion echocardiograms displayed beside one another in random order on same screen) to determine outcomes according to prespecified definitions of disease progression (worsening), regression (improving) or no change. We calculated inter-rater agreement using Cohen's kappa. RESULTS: There were 799 pairs of echocardiogram assessments included. A higher number, 54 vs 38 (6.8% vs 4.5%), were deemed as progression by serial interpretation compared with side-by-side comparison. There was good inter-rater agreement between the serial interpretation and side-by-side comparison methods (kappa 0.89). Disagreement was most often a result of the difference in classification between borderline RHD and mild definite RHD. Most discrepancies between interpretation methods (46 of 47, 98%) resulted from differences in valvular morphological evaluation, with valves judged to be morphologically similar between enrolment and final echocardiograms when compared side by side but classified differently on serial interpretation. CONCLUSIONS: There was good agreement between the methods of serial and side-by-side interpretation of echocardiograms for change over time, using the World Heart Federation criteria. Side-by-side interpretation has higher specificity for change, with fewer differences in the interpretation of valvular morphology, as compared with serial interpretation.
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    Prevention of young infant infections using oral azithromycin in labour in Fiji (Bulabula MaPei): study protocol of a randomised control trial
    Hume-Nixon, M ; Ratu, T ; Clark, S ; Nguyen, CD ; Neal, EFG ; Pell, CL ; Bright, K ; Watts, E ; Hart, J ; Mulholland, K ; Fong, J ; Rafai, E ; Sakumeni, K ; Tuibeqa, I ; Satzke, C ; Steer, A ; Russell, FM (BMJ PUBLISHING GROUP, 2022-12)
    INTRODUCTION: Infections are a leading cause of neonatal mortality globally and can be transmitted from mother-to-child vertically or horizontally. Fiji has higher rates of serious neonatal infections and infant skin and soft tissue infections (SSTIs) than high-income countries. Research from the Gambia found that a single dose of oral azithromycin in labour decreased bacterial carriage and infections in mothers and infants, particularly infant skin infections. The Bulabula MaPei clinical trial evaluates the safety and efficacy of a single dose of azithromycin in labour in reducing the incidence of maternal and infant SSTIs and other infections and the impact on bacterial carriage. It will also describe the effect of azithromycin on antimicrobial (AMR) resistance, the maternal and infant microbiome, and infant dysbiosis. METHODS AND ANALYSIS: We are conducting a blinded, placebo-controlled randomised clinical trial administering 2 g of oral azithromycin, or placebo, given to healthy, pregnant women (≥18 years) in labour in Suva, Fiji. The primary outcome is the cumulative incidence of SSTIs in infants by 3 months of age. Secondary outcomes include the incidence of other infant and maternal infections, and safety and tolerability of azithromycin in mother and infant. Following informed consent, 2110 pregnant women will be randomised in a 1:1 ratio, with all study staff and participants masked to group allocation. Mother/infant pairs will be followed up for 12 months over six visits collecting clinical data on infections, antimicrobial use, safety and anthropometrics, in addition to nasopharyngeal, oropharyngeal, rectovaginal and vaginal swabs, maternal breastmilk and infant stool samples, in order to compare bacterial carriage, AMR rates and microbiome. Recruitment for Bulabula MaPei started in June 2019. ETHICS AND DISSEMINATION: This trial was approved and is being conducted according to the protocol approved by The Royal Children's Hospital Human Research Ethics Committee, Australia, and the Fiji National Health Research and Ethics Review Committee. The findings of this study will be disseminated in peer-reviewed journals and presented at conferences. TRIAL REGISTRATION NUMBER: NCT03925480.
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    Standardization of Epidemiological Surveillance of Acute Poststreptococcal Glomerulonephritis.
    Miller, KM ; Van Beneden, C ; McDonald, M ; Hla, TK ; Wong, W ; Pedgrift, H ; Kaslow, DC ; Cherian, T ; Carapetis, JR ; Scheel, A ; Seale, A ; Bowen, AC ; Moore, HC ; Lamagni, T ; Rodriguez-Iturbe, B (Oxford University Press (OUP), 2022-09)
    Acute poststreptococcal glomerulonephritis (APSGN) is an immune complex-induced glomerulonephritis that develops as a sequela of streptococcal infections. This article provides guidelines for the surveillance of APSGN due to group A Streptococcus (Strep A). The primary objectives of APSGN surveillance are to monitor trends in age- and sex-specific incidence, describe the demographic and clinical characteristics of patients with APSGN, document accompanying risk factors, then monitor trends in frequency of complications, illness duration, hospitalization rates, and mortality. This document provides surveillance case definitions for APSGN, including clinical and subclinical APSGN based on clinical and laboratory evidence. It also details case classifications that can be used to differentiate between confirmed and probable cases, and it discusses the current investigations used to provide evidence of antecedent Strep A infection. The type of surveillance recommended depends on the burden of APSGN in the community and the objectives of surveillance. Strategies for minimal surveillance and enhanced surveillance of APSGN are provided. Furthermore, a discussion covers the surveillance population and additional APSGN-specific surveillance considerations such as contact testing, active follow up of cases and contacts, frequency of reporting, surveillance visits, period of surveillance, and community engagement. Finally, the document presents core data elements to be collected on case report forms, along with guidance for documenting the course and severity of APSGN.
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    Virology and immune dynamics reveal high household transmission of ancestral SARS-CoV-2 strain
    Tosif, S ; Haycroft, ER ; Sarkar, S ; Toh, ZQ ; Lien, AHD ; Donato, CM ; Selva, KJ ; Hoq, M ; Overmars, I ; Nguyen, J ; Lee, L-Y ; Clifford, V ; Daley, A ; Mordant, FL ; McVernon, J ; Mulholland, K ; Marcato, AJ ; Smith, MZ ; Curtis, N ; McNab, S ; Saffery, R ; Kedzierska, K ; Subarrao, K ; Burgner, D ; Steer, A ; Bines, JE ; Sutton, P ; Licciardi, P ; Chung, AW ; Neeland, MR ; Crawford, NW (WILEY, 2022-07)
    BACKGROUND: Household studies are crucial for understanding the transmission of SARS-CoV-2 infection, which may be underestimated from PCR testing of respiratory samples alone. We aim to combine the assessment of household mitigation measures; nasopharyngeal, saliva, and stool PCR testing; along with mucosal and systemic SARS-CoV-2-specific antibodies, to comprehensively characterize SARS-CoV-2 infection and transmission in households. METHODS: Between March and September 2020, we obtained samples from 92 participants in 26 households in Melbourne, Australia, in a 4-week period following the onset of infection with ancestral SARS-CoV-2 variants. RESULTS: The secondary attack rate was 36% (24/66) when using nasopharyngeal swab (NPS) PCR positivity alone. However, when respiratory and nonrespiratory samples were combined with antibody responses in blood and saliva, the secondary attack rate was 76% (50/66). SARS-CoV-2 viral load of the index case and household isolation measures were key factors that determine secondary transmission. In 27% (7/26) of households, all family members tested positive by NPS for SARS-CoV-2 and were characterized by lower respiratory Ct values than low transmission families (Median 22.62 vs. 32.91; IQR 17.06-28.67 vs. 30.37-34.24). High transmission families were associated with enhanced plasma antibody responses to multiple SARS-CoV-2 antigens and the presence of neutralizing antibodies. Three distinguishing saliva SARS-CoV-2 antibody features were identified according to age (IgA1 to Spike 1, IgA1 to nucleocapsid protein (NP)), suggesting that adults and children generate distinct mucosal antibody responses during the acute phase of infection. CONCLUSION: Utilizing respiratory and nonrespiratory PCR testing, along with the measurement of SARS-CoV-2-specific local and systemic antibodies, provides a more accurate assessment of infection within households and highlights some of the immunological differences in response between children and adults.
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    The Importance of Partnership in the Rollout of Triple-Drug Therapy to Eliminate Lymphatic Filariasis in the Pacific.
    Rainima-Qaniuci, M ; Lepaitai, HB ; Bhagirov, R ; Padmasiri, E ; Naseri, T ; Thomsen, R ; Won, KY ; Brant, TA ; Dodd, E ; Nua, MT ; Utu, F ; Tufa, A ; Chutaro, E ; Camacho, J ; Suiaunoa-Scanlan, L ; Thean, LJ ; Mani, J ; Hardy, M ; Samuela, J ; Romani, L ; Kaldor, J ; Steer, AC ; Faktaufon, D ; Bechu, V ; Naqio, F ; Sosene, V ; Sekihara, M ; Otaki, J ; Buhagiar, TS ; Yajima, A (American Society of Tropical Medicine and Hygiene, 2022-05-11)
    We discuss the experience of some Pacific island countries in introducing the new WHO-recommended treatment protocol for lymphatic filariasis-a triple-drug therapy composed of ivermectin, diethylcarbamazine, and albendazole. The successful rollout of the new treatment protocol was dependent on strong partnerships among these countries' ministries of health, WHO, and other stakeholders. Effective communication among these partners allowed for lessons learned to cross borders and have a positive impact on the experiences of other countries. We also describe various challenges confronted during this process and the ways these countries overcame them.
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    Acute rheumatic fever and rheumatic heart disease in Victoria, 2006-18
    Oliver, J ; Hardy, M ; Osowicki, J ; Engelman, D ; Steer, AC ; Gibney, K (WILEY, 2022-03-07)
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    Paediatric treatment trials for COVID-19 are an ethical imperative
    Gwee, A ; Boast, A ; Osowicki, J ; Steer, AC ; Coghlan, S (BMJ PUBLISHING GROUP, 2021-02)