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 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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    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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    Efficacy of mass drug administration with ivermectin for control of scabies and impetigo, with coadministration of azithromycin: a single-arm community intervention trial
    Romani, L ; Marks, M ; Sokana, O ; Nasi, T ; Kamoriki, B ; Cordell, B ; Wand, H ; Whitfeld, MJ ; Engelman, D ; Solomon, AW ; Kaldor, JM ; Steer, AC (ELSEVIER SCI LTD, 2019-05)
    BACKGROUND: In small community-based trials, mass drug administration of ivermectin has been shown to substantially decrease the prevalence of both scabies and secondary impetigo; however, their effect at large scale is untested. Additionally, combined mass administration of drugs for two or more neglected diseases has potential practical advantages, but efficacy of potential combinations should be confirmed. METHODS: The azithromycin ivermectin mass drug administration (AIM) trial was a prospective, single-arm, before-and-after, community intervention study to assess the efficacy of mass drug administration of ivermectin for scabies and impetigo, with coadministration of azithromycin for trachoma. Mass drug administration was offered to the entire population of Choiseul Province, Solomon Islands, and of this population we randomly selected two sets of ten sentinel villages for monitoring, one at baseline and the other at 12 months. Participants were offered a single dose of 20 mg/kg azithromycin, using weight-based bands. Children weighing less than 12·5 kg received azithromycin oral suspension (20 mg/kg), and infants younger than 6 months received topical 1% tetracycline ointment. For ivermectin, participants were offered two doses of oral ivermectin 200 μg/kg 7-14 days apart using weight-based bands, or 5% permethrin cream 7-14 days apart if ivermectin was contraindicated. Our study had the primary outcomes of safety and feasibility of large-scale mass coadministration of oral ivermectin and azithromycin, which have been previously reported. We report here the prevalence of scabies and impetigo in residents of the ten baseline villages compared with those in the ten 12-month villages, as measured by examination of the skin, which was a secondary outcome of the trial. Further outcomes were comparison of the number of all-cause outpatient attendances at government clinics in Choiseul Province at various timepoints before and after mass drug administration. The trial was registered with the Australian and New Zealand Trials Registry (ACTRN12615001199505). FINDINGS: During September, 2015, over 4 weeks, 26 188 people (99·3% of the estimated population of Choiseul [n=26 372] as determined at the 2009 census) were treated. At baseline, 1399 (84·2%) of 1662 people living in the first ten villages had their skin examined, of whom 261 (18·7%) had scabies and 347 (24·8%) had impetigo. At 12 months after mass drug administration, 1261 (77·6%) of 1625 people in the second set of ten villages had their skin examined, of whom 29 (2·3%) had scabies (relative reduction 88%, 95% CI 76·5-99·3) and 81 (6·4%) had impetigo (relative reduction 74%, 63·4-84·7). In the 3 months after mass drug administration, 10 614 attended outpatient clinics for any reason compared with 16 602 in the 3 months before administration (decrease of 36·1%, 95% CI 34·7-37·6), and during this period attendance for skin sores, boils, and abscesses decreased by 50·9% (95% CI 48·6-53·1). INTERPRETATION: Ivermectin-based mass drug administration can be scaled to a population of over 25 000 with high efficacy and this level of efficacy can be achieved when mass drug administration for scabies is integrated with mass drug administration of azithromycin for trachoma. These findings will contribute to development of population-level control strategies. Further research is needed to assess durability and scalability of mass drug administration in larger, non-island populations, and to assess its effect on the severe bacterial complications of scabies. FUNDING: International Trachoma Initiative, Murdoch Children's Research Institute, Scobie and Claire Mackinnon Trust, and the Wellcome Trust.
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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, 2022-09-29)
    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 randomized 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 4 for impetigo. Most studies were in small populations. There was a high degree of heterogeneity between studies (I2 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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    Costs of mass drug administration for scabies in Fiji
    Mow, M ; Thean, LJ ; Parnaby, M ; Mani, J ; Rafai, E ; Sahukhan, A ; Kama, M ; Tuicakau, M ; Kado, J ; Romani, L ; Engelman, D ; Whitfeld, M ; Kaldor, J ; Steer, A ; Carvalho, N ; Turner, HC (PUBLIC LIBRARY SCIENCE, 2022-02)
    In 2019, the Murdoch Children's Research Institute in partnership with the Fiji Ministry of Health and Medical Services carried out an integrated mass drug administration (MDA) for the treatment of scabies and lymphatic filariasis in the Northern Division of Fiji (population estimate 131,914). We conducted a retrospective micro-costing exercise focused on the cost of scabies control in order to inform budgeting and policy decision making in an endemic setting. We collected detailed information on financial and economic costs incurred by both parties during the course of the MDA campaign (April 2018 to July 2019). We also conducted interviews with personnel involved in the financial administration of the MDA campaign. The economic cost of delivering two doses of ivermectin was US$4.88 per person. The cost of donated drugs accounted for 36.3% of total MDA costs. In this first large-scale MDA for the public health control of scabies, the estimated cost of delivering MDA per person for scabies was considerably more expensive than the costs reported for other neglected tropical diseases. The important cost drivers included the remuneration of health care workers who were extensively involved in the campaign, coverage of hard-to-reach, mainly rural populations and the two-dose regimen of ivermectin. These results highlight the importance of these cost determinants and can be used to plan current and future MDA programs.
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    Prevention of bacterial complications of scabies using mass drug administration: A population-based, before-after trial in Fiji, 2018-2020
    Thean, LJ ; Romani, L ; Engelman, D ; Wand, H ; Jenney, A ; Mani, J ; Paka, J ; Cua, T ; Taole, S ; Silai, M ; Ashwini, K ; Sahukhan, A ; Kama, M ; Tuicakau, M ; Kado, J ; Parnaby, M ; Carvalho, N ; Whitfeld, M ; Kaldor, J ; Steer, AC (ELSEVIER, 2022-05)
    BACKGROUND: Scabies is an important predisposing factor of impetigo which can lead to serious bacterial complications. Ivermectin-based mass drug administration can substantially reduce scabies and impetigo prevalence in endemic settings, but the impact on serious bacterial complications is not known. METHODS: We conducted a before-after trial in the Northern Division of Fiji (population: 131,914) of mass drug administration for scabies control. Prospective surveillance was conducted from 2018 to 2020. Mass drug administration took place in 2019, involving two doses of oral ivermectin or topical permethrin, delivered alongside diethylcarbamazine and albendazole for lymphatic filariasis. The primary outcomes were incidence of hospitalisations with skin and soft tissue infections, and childhood invasive infections and post-streptococcal sequelae. Secondary outcomes included presentations to primary healthcare with skin infections and community prevalence of scabies and impetigo. FINDINGS: The incidence of hospitalisations with skin and soft tissue infections was 17% lower after the intervention compared to baseline (388 vs 467 per 100,000 person-years; incidence rate ratio 0.83, 95% CI, 0.74 to 0.94; P = 0.002). There was no difference in incidence of childhood invasive infections and post-streptococcal sequelae. Incidence of primary healthcare presentations with scabies and skin infections was 21% lower (89.2 vs 108 per 1000 person-years, incidence rate ratio, IRR 0.79, 95% CI, 0.78 to 0.82). Crude community prevalence of scabies declined from 14.2% to 7.7% (cluster-adjusted prevalence 12.5% to 8.9%; prevalence ratio 0.71, 95% CI, 0.28 to 1.17). Cluster-adjusted prevalence of impetigo declined from 15.3% to 6.1% (prevalence ratio 0.4, 95% CI, 0.18 to 0.86). INTERPRETATION: Mass drug administration for scabies control was associated with a substantial reduction in hospitalisations for skin and soft tissue infections. FUNDING: National Health and Medical Research Council of Australia and Scobie and Claire Mackinnon Trust.
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    Community control strategies for scabies: A cluster randomised noninferiority trial
    Hardy, M ; Samuela, JJ ; Kama, ML ; Tuicakau, MJ ; Romani, L ; Whitfeld, MC ; King, C ; Weil, GJ ; Schuster, TM ; Grobler, AC ; Engelman, D ; Robinson, L ; Kaldor, J ; Steer, A ; von Seidlein, L (PUBLIC LIBRARY SCIENCE, 2021-11)
    BACKGROUND: Scabies is a neglected tropical disease hyperendemic to many low- and middle-income countries. Scabies can be successfully controlled using mass drug administration (MDA) using 2 doses of ivermectin-based treatment. If effective, a strategy of 1-dose ivermectin-based MDA would have substantial advantages for implementing MDA for scabies at large scale. METHODS AND FINDINGS: We did a cluster randomised, noninferiority, open-label, 3-group unblinded study comparing the effectiveness of control strategies on community prevalence of scabies at 12 months. All residents from 35 villages on 2 Fijian islands were eligible to participate. Villages were randomised 1:1:1 to 2-dose ivermectin-based MDA (IVM-2), 1-dose ivermectin-based MDA (IVM-1), or screen and treat with topical permethrin 5% for individuals with scabies and their household contacts (SAT). All groups also received diethylcarbamazine and albendazole for lymphatic filariasis control. For IVM-2 and IVM-1, oral ivermectin was dosed at 200 μg/kg and when contraindicated substituted with permethrin. We designated a noninferiority margin of 5%. We enrolled 3,812 participants at baseline (July to November 2017) from the 35 villages with median village size of 108 (range 18 to 298). Age and sex of participants were representative of the population with 51.6% male and median age of 25 years (interquartile range 10 to 47). We enrolled 3,898 at 12 months (July to November 2018). At baseline, scabies prevalence was similar in all groups: IVM-2: 11.7% (95% confidence interval (CI) 8.5 to 16.0); IVM-1: 15.2% (95% CI 9.4 to 23.8); SAT: 13.6% (95% CI 7.9 to 22.4). At 12 months, scabies decreased substantially in all groups: IVM-2: 1.3% (95% CI 0.6 to 2.5); IVM-1: 2.7% (95% CI 1.1 to 6.5); SAT: 1.1% (95% CI 0.6 to 2.0). The risk difference in scabies prevalence at 12 months between the IVM-1 and IVM-2 groups was 1.2% (95% CI -0.2 to 2.7, p = 0.10). Limitations of the study included the method of scabies diagnosis by nonexperts, a lower baseline prevalence than anticipated, and the addition of diethylcarbamazine and albendazole to scabies treatment. CONCLUSIONS: All 3 strategies substantially reduced prevalence. One-dose was noninferior to 2-dose ivermectin-based MDA, as was a screen and treat approach, for community control of scabies. Further trials comparing these approaches in varied settings are warranted to inform global scabies control strategies. TRIAL REGISTRATION: Clinitrials.gov NCT03177993 and ANZCTR N12617000738325.
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    Estimation of scabies prevalence using simplified criteria and mapping procedures in three Pacific and southeast Asian countries
    Tsoi, SK ; Lake, SJ ; Thean, LJ ; Matthews, A ; Sokana, O ; Kama, M ; Amaral, S ; Romani, L ; Whitfeld, M ; Francis, JR ; Nery, SV ; Marks, M ; Kaldor, JM ; Steer, AC ; Engelman, D (BMC, 2021-11-10)
    BACKGROUND: Scabies causes considerable morbidity in disadvantaged populations. The International Alliance for the Control of Scabies (IACS) published consensus criteria in 2020 to standardize scabies diagnosis. However, these criteria are complex, and a WHO informal consultation proposed simplified criteria for mapping, to identify regions of high prevalence as targets for mass drug administration. We aimed to investigate the accuracy of simplified criteria in determining scabies prevalence, compared to the 2020 IACS criteria. METHODS: We obtained data relating to demographics, relevant history and skin lesions from all-age prevalence surveys from Fiji (n = 3365) and Solomon Islands (n = 5239), as well as school-aged children in Timor-Leste (n = 1043). We calculated prevalence using the 2020 IACS criteria and simplified criteria and compared these disease estimates. RESULTS: There was no significant difference in the pooled prevalence using the two methods (2020 IACS criteria: 16.6%; simplified criteria: 15.6%; difference = 0.9, [95% CI -0.1, 2.0]). In Timor-Leste, the prevalence using simplified criteria was lower (26.5% vs 33.8%). Simplified criteria had a sensitivity of 82.3% (95% CI 80.2, 84.2) and specificity of 97.6% (95% CI 97.2, 97.9) compared to the 2020 IACS criteria. CONCLUSIONS: The scabies prevalence estimation using simplified criteria was similar to using the 2020 IACS criteria in high prevalence, tropical countries. The prevalence estimation was lower in the school-based survey in Timor-Leste. Mapping using simplified criteria may be a feasible and effective public health tool to identify priority regions for scabies control. Further work assessing use of simplified criteria for mapping in a field setting should be conducted.
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    Systematic review of the diagnosis of scabies in therapeutic trials
    Thompson, MJ ; Engelman, D ; Gholam, K ; Fuller, LC ; Steer, AC (OXFORD UNIV PRESS, 2017-07)
    Human scabies (infestation with the mite Sarcoptes scabiei var hominis) causes a significant disease burden worldwide, yet there are no agreed diagnostic guidelines. We aimed to determine whether a consistent approach to diagnosing scabies has been used for published scabies therapeutic trials. The data sources used were the MEDLINE, Embase and Cochrane databases, from 1946 to 29 August 2013. Eligible studies were trials of therapeutic interventions against scabies in human subjects, published in English, enrolling patients with scabies, and using various therapeutic interventions. Language was a limitation of this study as some relevant trials published in languages other than English may have been excluded. Each study was reviewed by two independent authors, who assessed the clinical examination and testing approaches used for scabies diagnosis in the included studies. We found that of 71 included trials, 40 (56%) specified which clinical findings were used for diagnosis, which were predominantly rash, rash distribution, pruritus and mite burrows. Parasitological testing was used in 63% of trials (n = 45) and was used more frequently in clinic-based than in field studies. Nearly one-quarter of trials (24%, n = 17) did not define the diagnostic method used. Overall, the diagnostic approaches were poorly described, prohibiting accurate comparison of existing studies. This review further supports the need for consensus diagnostic guidelines for scabies.