Paediatrics (RCH) - Research Publications
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ItemEfficacy of mass drug administration with ivermectin for control of scabies and impetigo, with coadministration of azithromycin: a single-arm community intervention trial(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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ItemSystematic review of the diagnosis of scabies in therapeutic trials(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.
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ItemAdherence to secondary antibiotic prophylaxis for patients with rheumatic heart disease diagnosed through screening in Fiji(WILEY, 2016-12)OBJECTIVES: Echocardiographic screening for rheumatic heart disease (RHD) can detect subclinical cases; however, adequate adherence to secondary antibiotic prophylaxis (SAP) is required to alter disease outcomes. We aimed to investigate the adherence to SAP among young people with RHD diagnosed through echocardiographic screening in Fiji and to investigate factors associated with adherence. METHODS: Patients diagnosed with RHD through echocardiographic screening in Fiji from 2006 to 2014 were included. Dates of benzathine penicillin G injections were collected from 76 health clinics nationally from December 2011 to December 2014. Adherence was measured using the proportion of days covered (PDC). Multivariate logistic regression analysis was used to identify characteristics associated with any adherence (≥1 injection received) and adequate adherence (PDC ≥0.80). RESULTS: Of 494 patients, 268 (54%) were female and the median age was 14 years. Overall, 203 (41%) had no injections recorded and just 33 (7%) had adequate adherence. Multivariate logistic regression showed increasing age (OR 0.93 per year, 95% CI 0.87-0.99) and time since diagnosis ≥1.5 years (OR 0.53, 95% CI 0.37-0.79) to be inversely associated with any adherence. Non-iTaukei ethnicity (OR 2.58, 95%CI 1.04-6.33) and urban residence (OR 3.36, 95% CI 1.54-7.36) were associated with adequate adherence, whereas time since diagnosis ≥1.5 years (OR 0.38, 95%CI 0.17-0.83) was inversely associated with adequate adherence. CONCLUSIONS: Adherence to SAP after screening in Fiji is currently inadequate for individual patient protection or population disease control. Secondary prevention should be strengthened before further screening can be justified.
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ItemInvestigation of group A Streptococcus immune responses in an endemic setting, with a particular focus on J8(ELSEVIER SCI LTD, 2018-11-29)Sustained control of group A Streptococcus (GAS) infections in settings of poverty has proven to be challenging, and an effective vaccine may be the most practical long-term strategy to reduce GAS-related disease burden. Candidate GAS vaccines based on the J8 peptide have demonstrated promising immunogenicity in mice, however, less is known about the role of J8 antibodies in the human immune response to GAS infection. We analysed the stimulation of J8 antibodies in response to infection, and the role of existing J8 antibodies in protection against subsequent infection, using data collected in the Fijian population: (1) cross sectional population serosurvey; (2) paired serum collection for assessment of M-specific and J8 antibody responses; and (3) longitudinal assessment of GAS infection and immunity. Median J8 antibody concentrations peaked in the 5-14 year age group, but there was no sustained increase with age. J8 antibody concentration was neither a significant predictor of time to next infection, nor did it show any relationship to the time since last recorded skin infection. Similarly, J8 antibody fold changes over a defined period were associated neither with the time since last skin infection, nor the number of intervening skin infections. While strong M-specific antibody responses were observed for skin infection, similarly strong J8 antibody responses were not observed. There is no indication that antibodies to the J8 antigen would be useful as either a marker of GAS infection or a measure of population immunity, with J8 antibody responses to infection fleeting, if existent at all.
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ItemPulmonary Mycobacterium abscessus complex in children with cystic fibrosis: A practical management guideline(WILEY, 2019-05)The treatment of Mycobacterium abscessus complex (MABSC) pulmonary infections is an emerging challenge in patients with cystic fibrosis (CF). Multidrug therapy for prolonged durations is required and carries the significant burden of drug-related toxicity, cost and selective pressure for multiresistant bacteria. International guidelines acknowledge that clinical and in vitro data to support treatment regimens are limited, particularly in children. As part of a collaboration between the infectious diseases and respiratory units at our institution, we have developed a modified treatment guideline that aims to balance the aims of MABSC eradication and slowing disease progression with minimising drug toxicity and resistance. The outcomes of this treatment approach will be monitored and reported. In this manuscript, we discuss the available evidence for treatment choices and present our treatment guideline for paediatric patients with CF and MABSC infection.
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ItemInternational survey of paediatric infectious diseases consultants on the management of community-acquired pneumonia complicated by pleural empyema(WILEY, 2019-01)AIM: Community-acquired pneumonia (CAP) complicated by pleural empyema is an important paediatric problem. Antibiotic management decisions are made on the basis of little available data and without strong specific recommendations in guidelines. METHODS: This was an online survey of paediatric infectious diseases (PID) physicians disseminated by major international professional organisations, examining empiric and targeted antibiotic choice, switch to oral antibiotics and duration of treatment for two hypothetical cases of contrasting severity. RESULTS: This study included 183 responses, mostly from North America, Western Europe and Australia/New Zealand. Increased disease severity was significantly associated with broader-spectrum and combination empiric and targeted antibiotic treatment, empiric methicillin-resistant Staphylococcus aureus (MRSA) coverage and both longer intravenous (IV) and total duration of antibiotic treatment. Empirical MRSA coverage was also associated with local prevalence. Clinical progress was most important for determining the timing of the switch from IV to oral antibiotics. Few respondents chose antibiotics with activity against organisms associated with atypical pneumonia (e.g. Mycoplasma, Chlamydia), and most did not choose agents that inhibit protein synthesis (e.g. clindamycin), even in the case of a severe invasive group A streptococcal infection. Some variation in targeted treatment choices reflected areas of uncertainty, such as Streptococcus pneumoniae susceptibility breakpoints, comparative effectiveness of anti-staphylococcal penicillins and first-generation cephalosporins for serious S. aureus infections and linezolid and vancomycin for MRSA pneumonia. CONCLUSIONS: This international survey of PID physicians highlights the priority targets for clinical research to improve antibiotic treatment of CAP complicated by empyema. Interventions that might be studied include empirical antibiotic guidelines stratified by case severity, adjunctive empirical use of agents that inhibit protein synthesis (e.g. clindamycin) and approaches to encourage rapid IV-to-oral switch and shorter total antibiotic treatment.
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ItemRheumatic fever: The rebound phenomenon returns(WILEY, 2018-06)
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ItemImpact of ivermectin administered for scabies treatment on the prevalence of head lice in Atoifi, Solomon Islands.(Public Library of Science (PLoS), 2018-09)BACKGROUND: Scabies and head lice are ubiquitous ectoparasitic infestations that are common across the Pacific Islands. Ivermectin is an effective treatment for both conditions, although the doses used vary. At a community level, mass drug administration (MDA) with ivermectin is an effective strategy to decrease prevalence of scabies. To what extent MDA with ivermectin will also reduce prevalence of head lice is unknown. METHODOLOGY: Head lice prevalence was assessed before and after MDA with oral ivermectin (at a dose of 200 micrograms per kilogram of body weight) administered on day 1 and day 8. The primary outcome was the change in prevalence of head louse infestation at two weeks compared to baseline. Longer term efficacy was assessed three months after MDA. RESULTS: 118 participants were enrolled. Baseline prevalence of active head louse infestation was 25.4% (95% CI 18.4-34.0). At two-week follow-up, prevalence was 2.5% (95% CI 0.9-7.2), a relative reduction of 89.1% (95% CI 72.7-91.4%, p<0.001). At three-month follow-up, prevalence was 7.5% (95% CI 2.7-12.3), a relative reduction of 70.6% (95% CI 72.7%-91.4%, p <0.001). Head louse infestation was associated with younger age (age ≤10 years: prevalence 46.7%; adjusted odds ratio compared to adults of 7.2, 95%CI 2.0-25.9) and with having at least one other member of the household with active head louse infestation (adjusted odds ratio 4.3, 95%CI 1.7-11.1). CONCLUSIONS: Head louse infestation is common in the Solomon Islands. This proof of principle study shows that oral ivermectin at a dose of 200 micrograms per kilogram can reduce the burden of active head louse infestation, offering an additional collateral benefit of MDA with ivermectin for scabies control. TRIAL REGISTRATION: ClinicalTrials.gov NCT03236168.
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ItemNo Preview AvailableThe safety of double- and triple-drug community mass drug administration for lymphatic filariasis: A multicenter, open-label, cluster-randomized study(PUBLIC LIBRARY SCIENCE, 2019-06)BACKGROUND: The Global Programme to Eliminate Lymphatic Filariasis (GPELF) provides antifilarial medications to hundreds of millions of people annually to treat filarial infections and prevent elephantiasis. Recent trials have shown that a single-dose, triple-drug treatment (ivermectin with diethylcarbamazine and albendazole [IDA]) is superior to a two-drug combination (diethylcarbamazine plus albendazole [DA]) that is widely used in LF elimination programs. This study was performed to assess the safety of IDA and DA in a variety of endemic settings. METHODS AND FINDINGS: Large community studies were conducted in five countries between October 2016 and November 2017. Two studies were performed in areas with no prior mass drug administration (MDA) for filariasis (Papua New Guinea and Indonesia), and three studies were performed in areas with persistent LF despite extensive prior MDA (India, Haiti, and Fiji). Participants were treated with a single oral dose of IDA (ivermectin, 200 μg/kg; diethylcarbamazine, 6 mg/kg; plus albendazole, a fixed dose of 400 mg) or with DA alone. Treatment assignment in each study site was randomized by locality of residence. Treatment was offered to residents who were ≥5 years of age and not pregnant. Adverse events (AEs) were assessed by medical teams with active follow-up for 2 days and passive follow-up for an additional 5 days. A total of 26,836 persons were enrolled (13,535 females and 13,300 males). A total of 12,280 participants were treated with DA, and 14,556 were treated with IDA. On day 1 or 2 after treatment, 97.4% of participants were assessed for AEs. The frequency of all AEs was similar after IDA and DA treatment (12% versus 12.1%, adjusted odds ratio for IDA versus DA 1.15, 95% CI 0.87-1.52, P = 0.316); 10.9% of participants experienced mild (grade 1) AEs, 1% experienced moderate (grade 2) AEs, and 0.1% experienced severe (grade 3) AEs. Rates of serious AEs after DA and IDA treatment were 0.04% (95% CI 0.01%-0.1%) and 0.01% (95% CI 0.00%-0.04%), respectively. Severity of AEs was not significantly different after IDA or DA. Five of six serious AEs reported occurred after DA treatment. The most common AEs reported were headache, dizziness, abdominal pain, fever, nausea, and fatigue. AE frequencies varied by country and were higher in adults and in females. AEs were more common in study participants with microfilaremia (33.4% versus 11.1%, P < 0.001) and more common in microfilaremic participants after IDA than after DA (39.4% versus 25.6%, P < 0.001). However, there was no excess of severe or serious AEs after IDA in this subgroup. The main limitation of the study was that it was open-label. Also, aggregation of AE data from multiple study sites tends to obscure variability among study sites. CONCLUSIONS: In this study, we observed that IDA was well tolerated in LF-endemic populations. Posttreatment AE rates and severity did not differ significantly after IDA or DA treatment. Thus, results of this study suggest that IDA should be as safe as DA for use as a MDA regimen for LF elimination in areas that currently receive DA. TRIAL REGISTRATION: Clinicaltrials.gov registration number: NCT02899936.