Publications by authors named "Andrew C Steer"

149 Publications

Prospective Surveillance of Primary Healthcare Presentations for Scabies and Bacterial Skin Infections in Fiji, 2018-2019.

Am J Trop Med Hyg 2021 May 24. Epub 2021 May 24.

1Tropical Diseases Group, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.

Scabies, impetigo, and other skin and soft tissue infections (SSTIs) are highly prevalent in many tropical, low-middle income settings, but information regarding their burden of disease is scarce. We conducted a surveillance of presentations of scabies and SSTIs, including impetigo, abscesses, cellulitis, and severe SSTI, to primary health facilities in Fiji. We established a monthly reporting system over the course of 50 weeks (July 2018-June 2019) for scabies and SSTIs at all 42 public primary health facilities in the Northern Division of Fiji (population, ≈131,914). For each case, information was collected regarding demographics, diagnosis, and treatment. There were 13,736 individual primary healthcare presentations with scabies, SSTI, or both (108.3 presentations per 1000 person-years; 95% confidence interval [CI], 106.6-110 presentations). The incidence was higher for males than for females (incidence rate ratio [IRR], 1.15; 95% CI, 1.11-1.19). Children younger than 5 years had the highest incidence among all age groups (339.1 per 1000 person-years). The incidence was higher among the iTaukei (indigenous) population (159.9 per 1000 person-years) compared with Fijians of Indian descent (30.1 per 1000 person-years; IRR, 5.32; 95% CI, 5.03-5.61). Abscesses had the highest incidence (63.5 per 1,000 person-years), followed by scabies (28.7 per 1,000 person-years) and impetigo (21.6 per 1,000 person-years). Scabies and SSTIs impose a substantial burden in Fiji and represent a high incidence of primary health presentations in this population. The incidence in low-middle income settings is up to 10-times higher than that in high-income settings. New public health strategies and further research are needed to address these conditions.
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http://dx.doi.org/10.4269/ajtmh.20-1459DOI Listing
May 2021

Prospective surveillance for invasive Staphylococcus aureus and group A Streptococcus infections in a setting with high community burden of scabies and impetigo.

Int J Infect Dis 2021 May 19. Epub 2021 May 19.

Tropical Diseases Group, Murdoch Children's Research Institute, Parkville, 3052 Victoria, Australia; Department of Paediatrics, University of Melbourne, Parkville, 3052, Victoria, Australia; Melbourne Children's Global Health, Melbourne Children's Campus, The Royal Children's Hospital, Parkville, 3052, Australia.

Background: Invasive Staphylococcus aureus (iSA) and group A Streptococcus (iGAS) infections impose significant health burdens globally. Both bacteria commonly cause skin and soft tissue infection (SSTI), which can result in invasive disease. Understanding of iSA and iGAS incidence remains limited in settings with high SSTI burden.

Methods: Prospective surveillance for admissions with iSA or iGAS was conducted at the referral hospital in Fiji's Northern Division over 48 weeks between July 2018-June 2019.

Results: There were 55 admissions for iSA and 15 for iGAS, (incidence; 45.2 and 12.3 per 100,000 person-years respectively). Highest incidence was found in those aged ≥65 years s (59.6 per 100,000 person-years for both). Indigenous Fijians (iTaukei) had higher iSA incidence (71.1 per 100,000 person-years) compared to other ethnicities (incidence risk ratio 9.7, 95% CI 3.5-36.9). SSTIs were found in the majority of iSA (75%) and iGAS (53.3%) cases. Thirteen out of the 14 iGAS strains isolated belonged to emm-cluster D (n = 5) or E (n = 8). Case fatality rate was high for iSA (10.9%) and iGAS (33.3%).

Conclusions: The incidence of iSA and iGAS in Fiji is very high. SSTIs are common clinical foci for iSA and iGAS. Both diseases carry a substantial risk of death. Improved control strategies are needed to reduce the burden of these diseases in Fiji.
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http://dx.doi.org/10.1016/j.ijid.2021.05.041DOI Listing
May 2021

An emm-type specific qPCR to track bacterial load during experimental human Streptococcus pyogenes pharyngitis.

BMC Infect Dis 2021 May 21;21(1):463. Epub 2021 May 21.

Tropical Diseases Research Group, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.

Background: Streptococcus pyogenes causes a profound global burden of morbidity and mortality across its diverse clinical spectrum. To support a new controlled human infection ('challenge') model seeking to accelerate S. pyogenes vaccine development, we aimed to develop an accurate and reliable molecular method for quantifying bacterial load from pharyngeal swabs collected during experimental human pharyngitis.

Methods: Combined sequential RNA + DNA extraction from throat swabs was compared to traditional separate RNA-only and DNA-only extractions. An emm-type specific qPCR was developed to detect the emm75 challenge strain. Results from the qPCR were compared to culture, using throat swab samples collected in a human challenge study.

Results: The qPCR was 100% specific for the emm75 challenge strain when tested against a panel of S. pyogenes emm-types and other respiratory pathogens. Combined RNA + DNA extraction had similar yield to traditional separate extractions. The combined extraction method and emm75 qPCR had 98.8% sensitivity compared to culture for throat swabs collected from challenge study participants.

Conclusions: We have developed a reliable molecular method for measuring S. pyogenes bacterial load from throat swabs collected in a controlled human infection model of S. pyogenes pharyngitis.

Trial Registration: NCT03361163 on 4th December 2017.
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http://dx.doi.org/10.1186/s12879-021-06173-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138111PMC
May 2021

Persistence of SARS-CoV-2-Specific IgG in Children 6 Months After Infection, Australia.

Emerg Infect Dis 2021 May 20;27(8). Epub 2021 May 20.

The duration of the humoral immune response in children infected with severe acute respiratory syndrome coronavirus 2 is unknown. We detected specific IgG 6 months after infection in children who were asymptomatic or had mild symptoms of coronavirus disease. These findings will inform vaccination strategies and other prevention measures.
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http://dx.doi.org/10.3201/eid2708.210965DOI Listing
May 2021

A systematic review and an individual patient data meta-analysis of ivermectin use in children weighing less than fifteen kilograms: Is it time to reconsider the current contraindication?

PLoS Negl Trop Dis 2021 Mar 17;15(3):e0009144. Epub 2021 Mar 17.

WorldWide Antimalarial Resistance Network (WWARN), Oxford, United Kingdom.

Background: Oral ivermectin is a safe broad spectrum anthelminthic used for treating several neglected tropical diseases (NTDs). Currently, ivermectin use is contraindicated in children weighing less than 15 kg, restricting access to this drug for the treatment of NTDs. Here we provide an updated systematic review of the literature and we conducted an individual-level patient data (IPD) meta-analysis describing the safety of ivermectin in children weighing less than 15 kg.

Methodology/principal Findings: A systematic review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) for IPD guidelines by searching MEDLINE via PubMed, Web of Science, Ovid Embase, LILACS, Cochrane Database of Systematic Reviews, TOXLINE for all clinical trials, case series, case reports, and database entries for reports on the use of ivermectin in children weighing less than 15 kg that were published between 1 January 1980 to 25 October 2019. The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO): CRD42017056515. A total of 3,730 publications were identified, 97 were selected for potential inclusion, but only 17 sources describing 15 studies met the minimum criteria which consisted of known weights of children less than 15 kg linked to possible adverse events, and provided comprehensive IPD. A total of 1,088 children weighing less than 15 kg were administered oral ivermectin for one of the following indications: scabies, mass drug administration for scabies control, crusted scabies, cutaneous larva migrans, myiasis, pthiriasis, strongyloidiasis, trichuriasis, and parasitic disease of unknown origin. Overall a total of 1.4% (15/1,088) of children experienced 18 adverse events all of which were mild and self-limiting. No serious adverse events were reported.

Conclusions/significance: Existing limited data suggest that oral ivermectin in children weighing less than 15 kilograms is safe. Data from well-designed clinical trials are needed to provide further assurance.
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http://dx.doi.org/10.1371/journal.pntd.0009144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968658PMC
March 2021

Individual efficacy and community impact of ivermectin, diethylcarbamazine and albendazole mass drug administration for lymphatic filariasis control in Fiji: a cluster randomised trial.

Clin Infect Dis 2021 Mar 17. Epub 2021 Mar 17.

Tropical Diseases Research Group, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.

Background: Bancroftian filariasis remains endemic in Fiji despite over 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 randomised trials in nocturnal transmission settings, but impact in a setting of diurnally subperiodic filarial transmission has not been evaluated.

Methods: This cluster randomised study compared the individual efficacy and community impact of IDA versus DA as MDA for lymphatic filariasis in 35 villages on two islands of Fiji. Participants were tested at enrolment for circulating filarial antigen and, if positive, for microfilariae (Mf). Weight-dosed treatment was offered according to village randomisation. Communities were visited at 12 months and retested for lymphatic filariasis. Infected individuals from Rotuma retested at 24 months.

Results: 3816 participants were enrolled and 3616 treated. At 12 months, Mf 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% CI 57.2-79.1% versus IDA 62.5%, 43.6-78.2%, risk difference 11.3 %, 95% CI -10-32.7%, P = 0.30. There was no difference between treatment groups in community prevalence of Mf 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 re-infection rates.
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http://dx.doi.org/10.1093/cid/ciab202DOI Listing
March 2021

Prevalence of scabies and impetigo in school-age children in Timor-Leste.

Parasit Vectors 2021 Mar 15;14(1):156. Epub 2021 Mar 15.

The Kirby Institute, University of New South Wales, Sydney, Australia.

Background: Scabies and impetigo are endemic in many tropical, low- and middle-income countries. Mass drug administration (MDA) with ivermectin has emerged as a control strategy for these conditions. In 2019, Timor-Leste Ministry of Health planned to implement MDA including ivermectin for the control of lymphatic filariasis, so we undertook a baseline assessment of scabies and impetigo to better understand local epidemiology and contribute to future surveys assessing the impact of MDA.

Methods: A cross-sectional school survey was conducted in April-May 2019 at six primary schools in a semi-urban (Dili) and two rural (Ermera and Manufahi) settings. Children under 19 years of age present at school on survey days were eligible to participate, of whom we enrolled 1183. Trained health workers interviewed and examined 1043 participants to clinically diagnose scabies using the 2020 International Alliance for the Control of Scabies (IACS) diagnostic criteria, as well as impetigo. Prevalence was adjusted for age and sex. Mixed-effects logistic regression models were used to analyse odds of scabies and impetigo infection. All models accounted for clustering at the school level through the use of random effect terms. Population attributable risk of scabies as a cause of impetigo was also estimated.

Results: The overall weighted prevalence of scabies was 30.6%. Children in rural Manufahi were more likely to have scabies than those in semi-urban Dili (53.6% vs 28.2%, adjusted odds ratio [AOR] 3.5). Most cases of scabies were mild (3 to 10 lesions), and lesions were usually distributed on more than one body region. Scabies prevalence was lower among 10 to 14 year olds compared to 5 to 9 year olds. Overall weighted prevalence of impetigo was 11.3%. Relative to Dili, children in rural Ermera and Manufahi were twice as likely to have impetigo. Impetigo was twice as common in children with scabies than in those without, corresponding to an attributable risk of scabies as a cause of impetigo of 22.7%.

Conclusions: Scabies and impetigo prevalence in Timor-Leste is among the highest reported globally, particularly in rural areas. Scabies infestation was strongly associated with impetigo. Comprehensive control strategies are urgently needed in Timor-Leste.
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http://dx.doi.org/10.1186/s13071-021-04645-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962383PMC
March 2021

A multicenter, community-based, mixed methods assessment of the acceptability of a triple drug regimen for elimination of lymphatic filariasis.

PLoS Negl Trop Dis 2021 Mar 3;15(3):e0009002. Epub 2021 Mar 3.

Washington University, St. Louis, Missouri, United States of America.

Background: Many countries will not reach elimination targets for lymphatic filariasis in 2020 using the two-drug treatment regimen (diethylcarbamazine citrate [DEC] and albendazole [DA]). A cluster-randomized, community-based safety study performed in Fiji, Haiti, India, Indonesia and Papua New Guinea tested the safety and efficacy of a new regimen of ivermectin, DEC and albendazole (IDA).

Methodology/principal Findings: To assess acceptability of IDA and DA, a mixed methods study was embedded within this community-based safety study. The study objective was to assess the acceptability of IDA versus DA. Community surveys were performed in each country with randomly selected participants (>14 years) from the safety study participant list in both DA and IDA arms. In depth interviews (IDI) and focus group discussions (FGD) assessed acceptability-related themes. In 1919 individuals, distribution of sex, microfilariae (Mf) presence and circulating filarial antigenemia (CFA), adverse events (AE) and age were similar across arms. A composite acceptability score summed the values from nine indicators (range 9-36). The median (22.5) score indicated threshold of acceptability. There was no difference in scores for IDA and DA regimens. Mean acceptability scores across both treatment arms were: Fiji 33.7 (95% CI: 33.1-34.3); Papua New Guinea 32.9 (95% CI: 31.9-33.8); Indonesia 30.6 (95% CI: 29.8-31.3); Haiti 28.6 (95% CI: 27.8-29.4); India 26.8 (95% CI: 25.6-28) (P<0.001). AE, Mf or CFA were not associated with acceptability. Qualitative research (27 FGD; 42 IDI) highlighted professionalism and appreciation for AE support. No major concerns were detected about number of tablets. Increased uptake of LF treatment by individuals who had never complied with MDA was observed.

Conclusions/significance: IDA and DA regimens for LF elimination were highly and equally acceptable in individuals participating in the community-based safety study in Fiji, Haiti, India, Indonesia, and Papua New Guinea. Country variation in acceptability was significant. Acceptability of the professionalism of the treatment delivery was highlighted.
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http://dx.doi.org/10.1371/journal.pntd.0009002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928496PMC
March 2021

Defining the need for public health control of scabies in Solomon Islands.

PLoS Negl Trop Dis 2021 02 22;15(2):e0009142. Epub 2021 Feb 22.

Tropical Diseases Research Group, Murdoch Children's Research Institute, Melbourne, Australia.

Pacific Island countries have a high burden of scabies and impetigo. Understanding of the epidemiology of these diseases is needed to target public health interventions such as mass drug administration (MDA). The aim of this study is to determine the prevalence of scabies and impetigo in Solomon Islands as well as the relationship between them and their distribution. We conducted a prevalence study in 20 villages in Western Province in Solomon Islands. All residents of the village were eligible to participate. Nurses conducted clinical assessments including history features and skin examination. Diagnosis of scabies was made using the 2020 International Alliance for the Control of Scabies diagnostic criteria. Assessments were completed on 5239 participants across 20 villages. Overall scabies prevalence was 15.0% (95%CI 11.8-19.1). There was considerable variation by village with a range of 3.3% to 42.6%. There was a higher prevalence of scabies in males (16.7%) than females (13.5%, adjusted relative risk 1.2, 95%CI 1.1-1.4). Children aged under two years had the highest prevalence (27%). Overall impetigo prevalence was 5.6% (95%CI 4.2-7.3), ranging from 1.4% to 19% by village. The population attributable risk of impetigo associated with scabies was 16.1% (95% CI 9.8-22.4). The prevalence of scabies in our study is comparable to previous studies in Solomon Islands, highlighting a persistent high burden of disease in the country, and the need for public health strategies for disease control.
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http://dx.doi.org/10.1371/journal.pntd.0009142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932527PMC
February 2021

Innate cell profiles during the acute and convalescent phase of SARS-CoV-2 infection in children.

Nat Commun 2021 02 17;12(1):1084. Epub 2021 Feb 17.

Infection and Immunity Theme, Murdoch Children's Research Institute, Parkville, VIC, Australia.

Children have mild severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) confirmed disease (COVID-19) compared to adults and the immunological mechanisms underlying this difference remain unclear. Here, we report acute and convalescent innate immune responses in 48 children and 70 adults infected with, or exposed to, SARS-CoV-2. We find clinically mild SARS-CoV-2 infection in children is characterised by reduced circulating subsets of monocytes (classical, intermediate, non-classical), dendritic cells and natural killer cells during the acute phase. In contrast, SARS-CoV-2-infected adults show reduced proportions of non-classical monocytes only. We also observe increased proportions of CD63+ activated neutrophils during the acute phase to SARS-CoV-2 in infected children. Children and adults exposed to SARS-CoV-2 but negative on PCR testing display increased proportions of low-density neutrophils that we observe up to 7 weeks post exposure. This study characterises the innate immune response during SARS-CoV-2 infection and household exposure in children.
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http://dx.doi.org/10.1038/s41467-021-21414-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889848PMC
February 2021

An 11-Month-Old Fijian Girl With Down Syndrome, Malnutrition, and Hyperkeratotic Skin Lesions.

Clin Infect Dis 2021 01;72(2):357-359

Tropical Diseases Research Group, Murdoch Children's Research Institute, Melbourne, Australia.

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http://dx.doi.org/10.1093/cid/ciaa650DOI Listing
January 2021

A systematic review and meta-analysis of upper airways swab collection for detection of viral and bacterial pathogens by individuals or caregivers compared to healthcare workers.

J Clin Microbiol 2021 Jan 19. Epub 2021 Jan 19.

Tropical Diseases Research Group, Murdoch Children's Research Institute, Melbourne, Australia

Self- or caregiver-collection of upper airway swabs reduces infectious exposures of healthcare workers (HCW) and the need to redeploy clinical staff to testing roles. We aimed to determine whether self- or caregiver-collection has adequate diagnostic performance for detection of viral and bacterial upper airways pathogens. We did a systematic review and meta-analysis of studies comparing diagnostic accuracy of self- or caregiver-collected upper airway swabs collected by patients or caregivers compared to HCW. All study types except case reports and series were included if sufficient data were presented to calculate sensitivity, specificity and Cohen's kappa. Studies published from 1946 to 17 August 2020 were included in the search. We did a meta-analysis to assess pooled sensitivity and specificity. Twenty studies were included in the systematic review and 15 in the meta-analysis. Overall sensitivity of swabs collected by patients or caregivers compared to HCW was 91% (95% CI: 87-94) and specificity was 98% (95% CI: 96-99). Sensitivity ranged from 65% to 100% and specificity from 73% to 100% across the studies. All but one study concluded that self- or caregiver-collected swabs were acceptable for detection of upper airway pathogens. Self- and caregiver-collection of upper airway swabs had reassuring diagnostic performance for multiple pathogens. There are numerous potential benefits of self- and caregiver-collected swabs for patients, families, researchers, and health systems. Further research to optimize implementation of sample collection by patients and caregivers is warranted.
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http://dx.doi.org/10.1128/JCM.02304-20DOI Listing
January 2021

Hospital admissions for skin and soft tissue infections in a population with endemic scabies: A prospective study in Fiji, 2018-2019.

PLoS Negl Trop Dis 2020 12 9;14(12):e0008887. Epub 2020 Dec 9.

Tropical Diseases Group, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.

Scabies is an important predisposing factor for impetigo but its role in more serious skin and soft tissue infections (SSTIs) is not well understood. Information is limited on incidence of SSTIs in the presence of endemic scabies. We conducted a prospective study of hospital admissions for SSTIs in the Northern Division of Fiji (population: 131,914). Prospective surveillance for admissions with impetigo, abscess, cellulitis, wound infection, pyomyositis, necrotizing fasciitis, infected scabies, and crusted scabies was conducted at the Division's referral hospital between 2018 to 2019. Information was collected on demographic characteristics, clinical features, microbiology, treatment and outcomes. Over the study period, 788 SSTI admissions were recorded corresponding to a population incidence 647 per 100,000 person-years (95%CI 571-660). Incidence was highest at the extremes of age with peak incidence in children aged <5 years (908 per 100,000) and those aged ≥65 years (1127 per 100,000). Incidence was 1.7 times higher among the Indigenous Fijian population (753 per 100,000) compared to other ethnicities (442 per 100,000). Overall case fatality rate was 3.3%, and 10.8% for those aged ≥65 years. Scabies was diagnosed concurrently in 7.6% of all patients and in 24.6% of admitted children <5 years. There is a very high burden of hospital admissions for SSTIs in Fiji compared to high-income settings especially among the youngest, oldest and indigenous population which is concordant with scabies and impetigo distribution in this population. Our findings highlight the need for strategies to reduce the burden of SSTIs in Fiji and similar settings.
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http://dx.doi.org/10.1371/journal.pntd.0008887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752096PMC
December 2020

Population pharmacokinetics of ivermectin for the treatment of scabies in Indigenous Australian children.

PLoS Negl Trop Dis 2020 12 7;14(12):e0008886. Epub 2020 Dec 7.

Department of General Medicine, The Royal Children's Hospital Melbourne, Parkville, Victoria, Australia.

Ivermectin is a broad-spectrum antiparasitic agent used for the treatment and control of neglected tropical diseases. In Australia, ivermectin is primarily used for scabies and is licensed in children aged ≥5 years weighing >15 kg. However, young children, aged <5 years, are particularly vulnerable to scabies and its secondary complications. Therefore, this study aimed to determine an appropriate ivermectin dose for children aged 2 to 4 years and weighing ≤15 kg. We conducted a prospective, pharmacokinetic study of ivermectin in Indigenous Australian children aged between 5 and 15 years and weighing >15 kg. Doses of 200 μg/kg rounded to the nearest whole or half 3 mg tablet were given to children with scabies and ivermectin concentrations determined at two time points after dosing. A population pharmacokinetic model was developed using non-linear mixed effects modelling. A separate covariate database of children aged 2 to 4 years and weighing <15 kg was used to generate 1000 virtual patients and simulate the dose required to achieve equivalent drug exposure in young children as those aged ≥5 years. Overall, 26 children who had 48 ivermectin concentrations determined were included, 11 (42%) were male, the median age was 10.9 years and median body weight 37.6 kg. The final model was a two-compartment model with first-order absorption and linear elimination. For simulated children aged 2 to 4 years, a dose of 3 mg in children weighing 10-15 kg produced similar drug exposures to those >5 years. The median simulated area under the concentration-time curve was 976 μg∙h/L. Using modelling, we have identified a dosing strategy for ivermectin in children aged 2 to 4 years and weighing less than 15 kg that can be prospectively evaluated for safety and efficacy.
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http://dx.doi.org/10.1371/journal.pntd.0008886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746298PMC
December 2020

Lessons from the field: integrated programmes for neglected tropical diseases.

Trans R Soc Trop Med Hyg 2021 01;115(2):127-128

Clinical Research Department, London School of Hygiene & Tropical Medicine, London, UK.

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http://dx.doi.org/10.1093/trstmh/traa149DOI Listing
January 2021

The inter-rater reliability and individual reviewer performance of the 2012 world heart federation guidelines for the echocardiographic diagnosis of latent rheumatic heart disease.

Int J Cardiol 2021 04 10;328:146-151. Epub 2020 Nov 10.

Cincinnati Children's Hospital Medical Center, The Heart Institute, 3333 Burnet Ave, Cincinnati, 45229, OH, USA; Department of Pediatrics, University of Cincinnati College of Medicine, 3230 Eden Ave, Cincinnati, OH 45229, USA. Electronic address:

Background: In 2012, the World Heart Federation (WHF) published guidelines for the echocardiographic diagnosis of rheumatic heart disease (RHD). This study assesses individual reviewer performance and inter-rater agreement and reliability on the presence of any RHD, as well classification of RHD based on the 2012 WHF criteria.

Methods: Four cardiologists individually reviewed echocardiograms in the context of a randomized clinical trial (ClinicalTrials.gov:NCT03346525) and participated in a blinded adjudication panel. Panel decision was the reference standard for diagnosis. Performance of individual reviewers to panel adjudication was compared through sensitivity and specificity analyses and inter-rater reliability was assessed between individual panelists using Fleiss free marginal multirater kappa.

Results: Echocardiograms from 784 children had two independent reports and panel adjudication. The accuracy of independent reviewers for any RHD had high sensitivity (94%, 95% CI 93-95%) and moderate specificity (62%, 95% CI 53-70%). Sensitivity and specificity for definite RHD was 61.3 (95% CI, 55.3-67.1) and 93.1 (95% CI, 91.6-94.4), with 86.8 (84.7-88.7) and 65.8 (61.0-70.4) for borderline RHD. There was moderate inter-rater agreement (κ = 0.66) on the presence of any RHD while agreement for specific 2012 WHF classification was only fair (κ = 0.51).

Conclusions: The 2012 WHF guidelines are moderately reproducible when used by expert cardiologists. More cases of RHD were diagnosed by an consensus panel than by individual reviewers. A revision to the criteria is now warranted to further increase the reliability of the WHF criteria.
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http://dx.doi.org/10.1016/j.ijcard.2020.11.013DOI Listing
April 2021

COVID-19 in health-care workers: Testing and outcomes at a Victorian tertiary children's hospital.

J Paediatr Child Health 2020 10 1;56(10):1642-1644. Epub 2020 Sep 1.

Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1111/jpc.15143DOI Listing
October 2020

Pharmacokinetic considerations on the repurposing of ivermectin for treatment of COVID-19.

Br J Clin Pharmacol 2021 03 17;87(3):1589-1590. Epub 2020 Jul 17.

Otago Pharmacometrics Group, School of Pharmacy, University of Otago, Dunedin, New Zealand.

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http://dx.doi.org/10.1111/bcp.14476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404744PMC
March 2021

Incidence of acute rheumatic fever and rheumatic heart disease in Melbourne, Australia from 1937 to 2013.

J Paediatr Child Health 2020 Sep 8;56(9):1408-1413. Epub 2020 Jul 8.

Tropical Diseases Research Group, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.

Aim: Acute rheumatic fever (ARF) most commonly presents in children aged 5-14 years old. Lifelong rheumatic heart disease (RHD) can result. This study investigated time trends in ARF and RHD using inpatient data from the Royal Children's Hospital, Melbourne (RCH).

Methods: A retrospective cohort study covering the period 1937-2013 was conducted using records from RCH, a quaternary paediatric hospital in Melbourne, Victoria, Australia. Patient data were identified using RCH classification of diseases coding for ARF or RHD for years <1952. For the period 1952-1987, this system was used in addition to identifying International Classification of Disease (ICD) discharge codes that corresponded to ARF or RHD. From 1988-2013, only ICD codes were used to identify patient data. Descriptive epidemiological analyses were performed, including incidence rate calculations using historical census population denominator data. Analyses focussed on children in the peak age group.

Results: Among children aged five to 14 years, a total of 4337 RCH admissions with ARF/RHD occurred for 3015 patients. A sharp decline in first ARF/RHD hospitalisations at RCH occurred from 1959, following a peak mean annual incidence rate during 1944-1947 of 40.1/100 000 children (95% confidence interval (CI): 36.6-43.9; P < 0.05). Over 1996-2013, the mean annual incidence rate was 1.6/100 000 (95% CI: 1.3-1.8) and reached 2.3/100 000 (95% CI: 1.3-3.7) in 2005.

Conclusion: The burden of ARF and RHD treated at RCH declined following the 1940s, mirroring changes seen in North America and Europe. Despite this, inpatient treatment for these conditions continued to be provided right up until the end of the study period.
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http://dx.doi.org/10.1111/jpc.14950DOI Listing
September 2020

Diagnosis of rheumatic fever: the need for a better test.

Arch Dis Child 2020 09 29;105(9):813-814. Epub 2020 Jun 29.

Tropical Diseases Research Group, Murdoch Children's Research Institute, The Royal Children's Hospital Melbourne, Parkville, Victoria, Australia

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http://dx.doi.org/10.1136/archdischild-2020-318970DOI Listing
September 2020

Paediatric treatment trials for COVID-19 are an ethical imperative.

Arch Dis Child 2021 02 9;106(2):e4. Epub 2020 Jun 9.

Centre for AI and Digital Ethics (CAIDE), Melbourne School of Engineering, The University of Melbourne, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1136/archdischild-2020-319701DOI Listing
February 2021

The Human Leukocyte Antigen Locus and Rheumatic Heart Disease Susceptibility in South Asians and Europeans.

Sci Rep 2020 06 2;10(1):9004. Epub 2020 Jun 2.

The Wellcome Centre for Human Genetics, University of Oxford, Oxford, Oxfordshire, OX3 7BN, UK.

Rheumatic heart disease (RHD), an autoinflammatory heart disease, was recently declared a global health priority by the World Health Organization. Here we report a genome-wide association study (GWAS) of RHD susceptibility in 1,163 South Asians (672 cases; 491 controls) recruited in India and Fiji. We analysed directly obtained and imputed genotypes, and followed-up associated loci in 1,459 Europeans (150 cases; 1,309 controls) from the UK Biobank study. We identify a novel susceptibility signal in the class III region of the human leukocyte antigen (HLA) complex in the South Asian dataset that clearly replicates in the Europeans (rs201026476; combined odds ratio 1.81, 95% confidence intervals 1.51-2.18, P = 3.48×10). Importantly, this signal remains despite conditioning on the lead class I and class II variants (P = 0.00033). These findings suggest the class III region is a key determinant of RHD susceptibility offering important new insight into pathogenesis while partly explaining the inconsistency of earlier reports.
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http://dx.doi.org/10.1038/s41598-020-65855-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265443PMC
June 2020

Impact of Community Treatment With Ivermectin for the Control of Scabies on the Prevalence of Antibodies to Strongyloides stercoralis in Children.

Clin Infect Dis 2020 12;71(12):3226-3228

Division of Parasitic Diseases and Malaria, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

The prevalence of antibodies to Strongyloides stercoralis was measured in 0-12-year-olds using a bead-based immunoassay before and after ivermectin mass drug administration (MDA) for scabies in the Solomon Islands. Seroprevalence was 9.3% before and 5.1% after MDA (P = .019), demonstrating collateral benefits of ivermectin MDA in this setting.
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http://dx.doi.org/10.1093/cid/ciaa584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819519PMC
December 2020

SARS-CoV-2 testing and outcomes in the first 30 days after the first case of COVID-19 at an Australian children's hospital.

Emerg Med Australas 2020 10 23;32(5):801-808. Epub 2020 Jun 23.

Department of Paediatrics, The University of Melbourne, Melbourne, Victoria, Australia.

Objective: International studies describing COVID-19 in children have shown low proportions of paediatric cases and generally a mild clinical course. We aimed to present early data on children tested for SARS-CoV-2 at a large Australian tertiary children's hospital according to the state health department guidelines, which varied over time.

Methods: We conducted a retrospective cohort study at The Royal Children's Hospital, Melbourne, Australia. It included all paediatric patients (aged 0-18 years) who presented to the ED or the Respiratory Infection Clinic (RIC) and were tested for SARS-CoV-2. The 30-day study period commenced after the first confirmed positive case was detected at the hospital on 21 March 2020, until 19 April 2020. We recorded epidemiological and clinical data.

Results: There were 433 patients in whom SARS-CoV-2 testing was performed in ED (331 [76%]) or RIC (102 [24%]). There were four (0.9%) who had positive SARS-CoV-2 detected, none of whom were admitted to hospital or developed severe disease. Of these SARS-CoV-2 positive patients, 1/4 (25%) had a comorbidity, which was asthma. Of the SARS-CoV-2 negative patients, 196/429 (46%) had comorbidities. Risk factors for COVID-19 were identified in 4/4 SARS-CoV-2 positive patients and 47/429 (11%) SARS-CoV-2 negative patients.

Conclusion: Our study identified a very low rate of SARS-CoV-2 positive cases in children presenting to a tertiary ED or RIC, none of whom were admitted to hospital. A high proportion of patients who were SARS-CoV-2 negative had comorbidities.
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http://dx.doi.org/10.1111/1742-6723.13550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273066PMC
October 2020

The cost-of-illness due to rheumatic heart disease: national estimates for Fiji.

Trans R Soc Trop Med Hyg 2020 07;114(7):483-491

Centre for International Child Health, University of Melbourne, Royal Children's Hospital, Parkville 3052, Australia.

Background: Rheumatic heart disease (RHD) is a chronic valvular heart disease that is responsible for a heavy burden of premature mortality in low- and middle-income countries. The total costs of RHD are important to health policy and research investment decisions. We estimate for the first time the total cost of RHD for Fiji (2008-2012) using a cost-of-illness approach and novel primary data on RHD disease burden and costs.

Methods: RHD cases were identified using probabilistic record linkage across four routine data sources: (1) the Fiji RHD Control Program, (2) national hospital admissions records, (3) the Ministry of Health database of cause-specific deaths and (4) hospital ECG clinic registers. For each individual with RHD, we obtained information on RHD hospital admissions, treatment and death. We conducted a prevalence-based cost-of-illness analysis, including bottom-up assessment of indirect and direct (healthcare) costs.

Results: The estimated cost of RHD in Fiji for 2008-2012 was year-2010 $FJ91.6 million (approximately US$47.7 million). Productivity losses from premature mortality constituted the majority of costs (71.4%). Indirect costs were 27-fold larger than the direct costs.

Conclusions: RHD leads to a heavy economic burden in Fiji. Improved prevention strategies for RHD will likely confer substantial economic benefits to the country.
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http://dx.doi.org/10.1093/trstmh/trz118DOI Listing
July 2020

The safety of combined triple drug therapy with ivermectin, diethylcarbamazine and albendazole in the neglected tropical diseases co-endemic setting of Fiji: A cluster randomised trial.

PLoS Negl Trop Dis 2020 03 16;14(3):e0008106. Epub 2020 Mar 16.

Tropical Diseases Research Group, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.

Lymphatic filariasis has remained endemic in Fiji despite repeated mass drug administration using the well-established and safe combination of diethylcarbamazine and albendazole (DA) since 2002. In certain settings the addition of ivermectin to this combination (IDA) remains a safe strategy and is more efficacious. However, the safety has yet to be described in scabies and soil-transmitted helminth endemic settings like Fiji. Villages of Rotuma and Gau islands were randomised to either DA or IDA. Residents received weight-based treatment unblinded with standard exclusions. Participants were actively found and asked by a nurse about their health daily for the first two days and then asked to seek review for the next five days if unwell. Anyone with severe symptoms were reviewed by a doctor and any serious adverse event was reported to the Medical Monitor and Data Safety Monitoring Board. Of 3612 enrolled and eligible participants, 1216 were randomised to DA and 2396 to IDA. Age and sex in both groups were representative of the population. Over 99% (3598) of participants completed 7 days follow-up. Adverse events were reported by 600 participants (16.7%), distributed equally between treatment groups, with most graded as mild (93.2%). There were three serious adverse events, all judged not attributable to treatment by an independent medical monitor. Fatigue was the most common symptom reported by 8.5%, with headache, dizziness, nausea and arthralgia being the next four most common symptoms. Adverse events were more likely in participants with microfilaremia (43.2% versus 15.7%), but adverse event frequency was not related to the presence of scabies or soil-transmitted helminth infection. IDA has comparable safety to DA with the same frequency of adverse events experienced following community mass drug administration. The presence of co-endemic infections did not increase adverse events. IDA can be used in community programs where preventative chemotherapy is needed for control of lymphatic filariasis and other neglected tropical diseases.
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http://dx.doi.org/10.1371/journal.pntd.0008106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098623PMC
March 2020

Clinical Description and Outcomes of Australian Children With Invasive Group A Streptococcal Disease.

Pediatr Infect Dis J 2020 05;39(5):379-384

Paediatric Department, Université Libre de Bruxelles, Bruxelles, Belgium.

Background: Invasive group A streptococcal disease is a severe infection with a high case fatality rate, estimated to cause more than 150,000 deaths per year worldwide. The clinical presentation of this infection is variable, and early diagnosis can be challenging. There are few data on its short- and longer-term outcomes, especially in children. The aim of this study was to assess the clinical presentation, management and short- and longer-term outcomes of invasive group A streptococcal disease in children in Australia.

Methods: We undertook a prospective surveillance study of children with laboratory-confirmed invasive group A streptococcus disease admitted to 7 sentinel tertiary and quaternary pediatric hospitals in Australia between July 2016 and June 2018. We collected demographic and clinical data and contacted patients 6 months after discharge to assess longer-term outcomes.

Results: We enrolled 181 children, 7 days to 16 years of age. The principal site of invasive infection was blood (126 children, 69.6%), and the most frequent clinical presentation was pneumonia in 46 children (25.4%). Twenty-six children developed streptococcal toxic shock syndrome (14.4%), and 74 had severe disease (40.9%), including 71 admitted to the intensive care unit. Five children died (2.8%). At discharge and 6 months, 29.3% and 15.2% of the children had persisting health problems, respectively.

Conclusions: Invasive group A streptococcal infection in Australian children is frequently severe and has a high long-term morbidity burden, highlighting the need for strengthened clinical care pathways, epidemiologic surveillance and prevention strategies.
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http://dx.doi.org/10.1097/INF.0000000000002596DOI Listing
May 2020

Analysis of Global Collection of Group A Genomes Reveals that the Majority Encode a Trio of M and M-Like Proteins.

mSphere 2020 01 8;5(1). Epub 2020 Jan 8.

Molecular Bacteriology Laboratory, Université Libre de Bruxelles, Brussels, Belgium

The core Mga (multiple gene activator) regulon of group A (GAS) contains genes encoding proteins involved in adhesion and immune evasion. While all GAS genomes contain genes for Mga and C5a peptidase, the intervening genes encoding M and M-like proteins vary between strains. The genetic make-up of the Mga regulon of GAS was characterized by utilizing a collection of 1,688 GAS genomes that are representative of the global GAS population. Sequence variations were examined with multiple alignments, and the expression of all core Mga regulon genes was examined by quantitative reverse transcription-PCR in a representative strain collection. In 85.2% of the sampled genomes, the Mga locus contained genes encoding Mga, Mrp, M, Enn, and C5a peptidase proteins. These isolates account for 53% of global infections. Only 9.1% of genomes did not contain either an or an gene. The pairwise identity within Enn (68.6%) and Mrp (83.2%) protein sequences was higher than within M proteins (44.7%). Gene expression varied between strains tested, but high expression was recorded for all genes in at least one strain. Previous nomenclature issues were clarified with molecular gene definitions. Our findings support a shift in focus in the GAS research field to further consider the role of Mrp and Enn in virulence and vaccine development. While the GAS M protein has been the leading vaccine target for decades, the bacteria encode many other virulence factors of interest for vaccine development. In this work, we show that -like genes are encoded in a remarkable majority of GAS genomes and expressed at a level similar to that for the gene. In collaboration with the U.S. Centers for Disease Control, we developed molecular definitions of the different and -like gene families. This clarification should abrogate mistyping of strains, especially in the area of whole-genome typing. We have also updated the -typing collection by removing -like gene sequences and provided in-depth analysis of Mrp and Enn protein sequence structure and diversity.
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http://dx.doi.org/10.1128/mSphere.00806-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952200PMC
January 2020

Invasive group A Streptococcus disease in Australian children: 2016 to 2018 - a descriptive cohort study.

BMC Public Health 2019 Dec 30;19(1):1750. Epub 2019 Dec 30.

Murdoch Children's Research Institute, Royal Children's Hospital, Flemington Rd, Parkville, Victoria, 3052, Australia.

Objectives: Invasive group A Streptococcus (iGAS) disease is serious and sometimes life-threatening. The Paediatric Active Enhanced Disease Surveillance (PAEDS) Network collects voluntary notifications from seven major Australian paediatric hospitals on patients with certain conditions, including iGAS disease. Our aims were to: 1) Describe the epidemiological distribution of paediatric iGAS disease in Australia and correlate this with influenza notifications, 2) Identify GAS strains commonly associated with invasive disease in children.

Methods: IGAS and influenza notification data were obtained (from the PAEDS Network and the Australian Institute of Health and Welfare, respectively, for the period 1 July 2016 to 30 June 2018). Included iGAS patients had GAS isolated from a normally sterile body site. Data were described according to selected clinical and demographic characteristics, including by age group and Australian State, with proportions and minimum incidence rates estimated.

Results: A total of 181 patients were identified, with most (115, 63.5%) <5 years old. The mean annual minimum incidence rate was 1.6 (95% confidence interval: 1.1-2.3) per 100,000 children across the study period. An epidemiological correlation with the seasonal burden of influenza was noted. Contact prophylaxis was not consistently offered. Of 96 patients with emm-typing results available, 72.9% showed emm-1, -4 or - 12.

Conclusions: Robust surveillance systems and cohesive patient management guidelines are needed. Making iGAS disease nationally notifiable would help facilitate this. Influenza vaccination may contribute to reducing seasonal increases in iGAS incidence. The burden of disease emphasises the need for ongoing progress in GAS vaccine development.
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http://dx.doi.org/10.1186/s12889-019-8085-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937995PMC
December 2019