Extensive use of praziquantel for treatment and control of schistosomiasis requires a comprehensive understanding of efficacy and safety of various doses for different Schistosoma species.
A ...systematic review and meta-analysis of comparative and non-comparative trials of praziquantel at any dose for any Schistosoma species assessed within two months post-treatment. Of 273 studies identified, 55 were eligible (19,499 subjects treated with praziquantel, control treatment or placebo). Most studied were in school-aged children (64%), S. mansoni (58%), and the 40 mg/kg dose (56%); 68% of subjects were in Africa. Efficacy was assessed as cure rate (CR, n=17,017) and egg reduction rate (ERR, n=13,007); safety as adverse events (AE) incidence. The WHO-recommended dose of praziquantel 40 mg/kg achieved CRs of 94.7% (95%CI 92.2-98.0) for S. japonicum, 77.1% (68.4-85.1) for S. haematobium, 76.7% (95%CI 71.9-81.2) for S. mansoni, and 63.5% (95%CI 48.2-77.0) for mixed S. haematobium/S. mansoni infections. Using a random-effect meta-analysis regression model, a dose-effect for CR was found up to 40 mg/kg for S. mansoni and 30 mg/kg for S. haematobium. The mean ERR was 95% for S. japonicum, 94.1% for S. haematobium, and 86.3% for S. mansoni. No significant relationship between dose and ERR was detected. Tolerability was assessed in 40 studies (12,435 subjects). On average, 56.9% (95%CI 47.4-67.9) of the subjects receiving praziquantel 40 mg/kg experienced an AE. The incidence of AEs ranged from 2.3% for urticaria to 31.1% for abdominal pain.
The large number of subjects allows generalizable conclusions despite the inherent limitations of aggregated-data meta-analyses. The choice of praziquantel dose of 40 mg/kg is justified as a reasonable compromise for all species and ages, although in a proportion of sites efficacy may be lower than expected and age effects could not be fully explored.
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WHO recommends a minimum of 80% sensitivity and 97% specificity for antigen-detection rapid diagnostic tests (Ag-RDTs), which can be used for patients with symptoms consistent with COVID-19. However, ...after the acute phase when viral load decreases, use of Ag-RDTs might lead to high rates of false negatives, suggesting that the tests should be replaced by a combination of molecular and serological tests. When the likelihood of having COVID-19 is low, such as for asymptomatic individuals in low prevalence settings, for travel, return to schools, workplaces, and mass gatherings, Ag-RDTs with high negative predictive values can be used with confidence to rule out infection. For those who test positive in low prevalence settings, the high false positive rate means that mitigation strategies, such as molecular testing to confirm positive results, are needed. Ag-RDTs, when used appropriately, are promising tools for scaling up testing and ensuring that patient management and public health measures can be implemented without delay.
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In this Collection Review for the Novel Treatments for Tuberculosis Collection, Piero Olliaro and Michael Vaillant discuss the considerations when choosing a non-inferiority margin that is meaningful ...from statistical, ethical, clinical, and health standpoint.
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Summary The Ebola virus disease outbreak in West Africa was unprecedented in both its scale and impact. Out of this human calamity has come renewed attention to global health security—its definition, ...meaning, and the practical implications for programmes and policy. For example, how does a government begin to strengthen its core public health capacities, as demanded by the International Health Regulations? What counts as a global health security concern? In the context of the governance of global health, including WHO reform, it will be important to distil lessons learned from the Ebola outbreak. The Lancet invited a group of respected global health practitioners to reflect on these lessons, to explore the idea of global health security, and to offer suggestions for next steps. Their contributions describe some of the major threats to individual and collective human health, as well as the values and recommendations that should be considered to counteract such threats in the future. Many different perspectives are proposed. Their common goal is a more sustainable and resilient society for human health and wellbeing.
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Research is urgently needed to reduce the morbidity and mortality of Lassa fever (LF), including clinical trials to test new therapies and to verify the efficacy and safety of the only current ...treatment recommendation, ribavirin, which has a weak clinical evidence base. To help establish a basis for the development of an adaptable, standardised clinical trial methodology, we conducted a systematic review to identify the clinical characteristics and outcomes of LF and describe how LF has historically been defined and assessed in the scientific literature.
Primary clinical studies and reports of patients with suspected and confirmed diagnosis of LF published in the peer-reviewed literature before 15 April 2021 were included. Publications were selected following a two-stage screening of abstracts, then full-texts, by two independent reviewers at each stage. Data were extracted, verified, and summarised using descriptive statistics.
147 publications were included, primarily case reports (36%), case series (28%), and cohort studies (20%); only 2 quasi-randomised studies (1%) were found. Data are mostly from Nigeria (52% of individuals, 41% of publications) and Sierra Leone (42% of individuals, 31% of publications). The results corroborate the World Health Organisation characterisation of LF presentation. However, a broader spectrum of presenting symptoms is evident, such as gastrointestinal illness and other nervous system and musculoskeletal disorders that are not commonly included as indicators of LF. The overall case fatality ratio was 30% in laboratory-confirmed cases (1896/6373 reported in 109 publications).
Systematic review is an important tool in the clinical characterisation of diseases with limited publications. The results herein provide a more complete understanding of the spectrum of disease which is relevant to clinical trial design. This review demonstrates the need for coordination across the LF research community to generate harmonised research methods that can contribute to building a strong evidence base for new treatments and foster confidence in their integration into clinical care.
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The appropriate use of diagnostics is important as misdiagnosis may have serious consequences. Confidence in a diagnostic test result depends on the test’s accuracy (sensitivity and specificity) in ...the context of the use-case (who is tested and why) and the prevalence of the condition investigated. Here, we offer an approach to diagnostics focused on the risks and effects of making the wrong diagnosis. We propose ‘fitness brackets’ for a given test to define the range within which the test is fit-for-purpose, based on the use-case and risk-management principles. We use as exemplars tests for dengue pre-vaccination screening and tests for diagnosing Covid-19 in different settings.
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Background
The World Health Organization (WHO) recommends Artemisinin‐based Combination Therapy (ACT) for treating uncomplicated Plasmodium falciparum malaria. This review aims to assist the ...decision‐making of malaria control programmes by providing an overview of the relative effects of dihydroartemisinin‐piperaquine (DHA‐P) versus other recommended ACTs.
Objectives
To evaluate the effectiveness and safety of DHA‐P compared to other ACTs for treating uncomplicated P. falciparum malaria in adults and children.
Search methods
We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL) published in The Cochrane Library; MEDLINE; EMBASE; LILACS, and the metaRegister of Controlled Trials (mRCT) up to July 2013.
Selection criteria
Randomized controlled trials comparing a three‐day course of DHA‐P to a three‐day course of an alternative WHO recommended ACT in uncomplicated P. falciparum malaria.
Data collection and analysis
Two authors independently assessed trials for eligibility and risk of bias, and extracted data. We analysed primary outcomes in line with the WHO 'Protocol for assessing and monitoring antimalarial drug efficacy’ and compared drugs using risk ratios (RR) and 95% confidence intervals (CI). Secondary outcomes were effects on gametocytes, haemoglobin, and adverse events. We assessed the quality of evidence using the GRADE approach.
Main results
We included 27 trials, enrolling 16,382 adults and children, and conducted between 2002 and 2010. Most trials excluded infants aged less than six months and pregnant women.
DHA‐P versus artemether‐lumefantrine
In Africa, over 28 days follow‐up, DHA‐P is superior to artemether‐lumefantrine at preventing further parasitaemia (PCR‐unadjusted treatment failure: RR 0.34, 95% CI 0.30 to 0.39, nine trials, 6200 participants, high quality evidence), and although PCR‐adjusted treatment failure was below 5% for both ACTs, it was consistently lower with DHA‐P (PCR‐adjusted treatment failure: RR 0.42, 95% CI 0.29 to 0.62, nine trials, 5417 participants, high quality evidence). DHA‐P has a longer prophylactic effect on new infections which may last for up to 63 days (PCR‐unadjusted treatment failure: RR 0.71, 95% CI 0.65 to 0.78, two trials, 3200 participants, high quality evidence).
In Asia and Oceania, no differences have been shown at day 28 (four trials, 1143 participants, moderate quality evidence), or day 63 (one trial, 323 participants, low quality evidence).
Compared to artemether‐lumefantrine, no difference was seen in prolonged QTc (low quality evidence), and no cardiac arrhythmias were reported. The frequency of other adverse events is probably similar with both combinations (moderate quality evidence).
DHA‐P versus artesunate plus mefloquine
In Asia, over 28 days follow‐up, DHA‐P is as effective as artesunate plus mefloquine at preventing further parasitaemia (PCR‐unadjusted treatment failure: eight trials, 3487 participants, high quality evidence). Once adjusted by PCR to exclude new infections, treatment failure at day 28 was below 5% for both ACTs in all eight trials, but lower with DHA‐P in two trials (PCR‐adjusted treatment failure: RR 0.41 95% CI 0.21 to 0.80, eight trials, 3482 participants, high quality evidence). Both combinations contain partner drugs with very long half‐lives and no consistent benefit in preventing new infections has been seen over 63 days follow‐up (PCR‐unadjusted treatment failure: five trials, 2715 participants, moderate quality evidence).
In the only trial from South America, there were fewer recurrent parastaemias over 63 days with artesunate plus mefloquine (PCR‐unadjusted treatment failure: RR 6.19, 95% CI 1.40 to 27.35, one trial, 445 participants, low quality evidence), but no differences were seen once adjusted for new infections (PCR‐adjusted treatment failure: one trial, 435 participants, low quality evidence).
DHA‐P is associated with less nausea, vomiting, dizziness, sleeplessness, and palpitations compared to artesunate plus mefloquine (moderate quality evidence). DHA‐P was associated with more frequent prolongation of the QTc interval (low quality evidence), but no cardiac arrhythmias were reported.
Authors' conclusions
In Africa, dihydroartemisinin‐piperaquine reduces overall treatment failure compared to artemether‐lumefantrine, although both drugs have PCR‐adjusted failure rates of less than 5%. In Asia, dihydroartemisinin‐piperaquine is as effective as artesunate plus mefloquine, and is better tolerated.
11 April 2019
No update planned
Other
There is high‐certainty evidence that dihydroartemisinin‐piperaquine is effective, meaning further research is unlikely to change our confidence in the estimate of effect. All eligible published studies found in the last search (29 Jul, 2013) were included and one ongoing study was identified (see 'Characteristics of ongoing studies' section).
A higher caseload of visceral leishmaniasis (VL) has been observed among males in community-based surveys. We carried out this review to investigate how the observed disparity in gender distribution ...is reflected in clinical trials of antileishmanial therapies.
We identified relevant studies by searching a database of all published clinical trials in VL from 1980 through 2019 indexed in the Infectious Diseases Data Observatory (IDDO) VL clinical trials library. The proportion of male participants enrolled in studies eligible for inclusion in this review were extracted and combined using random effects meta-analysis of proportion. Results were expressed as percentages and presented with respective 95% confidence intervals (95% CIs). Heterogeneity was quantified using I2 statistics and sub-group meta-analyses were carried out to explore the sources of heterogeneity.
We identified 135 published studies (1980-2019; 32,177 patients) with 68.0% 95% CI: 65.9%-70.0%; I2 = 92.6% of the enrolled participants being males. The corresponding estimates were 67.6% 95% CI: 65.5%-69.7%; n = 91 trials; I2 = 90.5%; 24,218 patients in studies conducted in the Indian sub-continent and 74.1% 95% CI: 68.4%-79.1%; n = 24 trials; I2 = 94.4%; 6,716 patients in studies from Eastern Africa. The proportion of male participants was 57.9% 95% CI: 54.2%-61.5% in studies enrolling children aged <15 years, 78.2% 95% CI: 66.0%-86.9% in studies that enrolled adults (≥15 years), and 68.1% 95% CI: 65.9%-70.0% in studies that enrolled patients of all ages. There was a trend for decreased proportions of males enrolled over time: 77.1% 95% CI: 70.2%-82.8%; 1356 patients in studies published prior to the 1990s whereas 64.3% 95% CI: 60.3%-68.2%; 15,611 patients in studies published on or after 2010. In studies that allowed the inclusion of patients with HIV co-infections, 76.5% 95% CI: 63.8%-85.9%; 5,123 patients were males and the corresponding estimate was 64.0% 95% CI: 61.4%-66.5% 17,500 patients in studies which excluded patients with HIV co-infections.
Two-thirds of the participants enrolled in clinical studies in VL conducted in the past 40 years were males, though the imbalance was less in children and in more recent trials. VL treatment guidelines are informed by the knowledge of treatment outcomes from a population that is heavily skewed towards adult males. Investigators planning future studies should consider this fact and ensure approaches for more gender-balanced inclusion.
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AbstractObjectiveTo characterise the clinical features of children and young people admitted to hospital with laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ...infection in the UK and explore factors associated with admission to critical care, mortality, and development of multisystem inflammatory syndrome in children and adolescents temporarily related to coronavirus disease 2019 (covid-19) (MIS-C).DesignProspective observational cohort study with rapid data gathering and near real time analysis.Setting260 hospitals in England, Wales, and Scotland between 17 January and 3 July 2020, with a minimum follow-up time of two weeks (to 17 July 2020).Participants651 children and young people aged less than 19 years admitted to 138 hospitals and enrolled into the International Severe Acute Respiratory and emergency Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK study with laboratory confirmed SARS-CoV-2.Main outcome measuresAdmission to critical care (high dependency or intensive care), in-hospital mortality, or meeting the WHO preliminary case definition for MIS-C.ResultsMedian age was 4.6 (interquartile range 0.3-13.7) years, 35% (225/651) were under 12 months old, and 56% (367/650) were male. 57% (330/576) were white, 12% (67/576) South Asian, and 10% (56/576) black. 42% (276/651) had at least one recorded comorbidity. A systemic mucocutaneous-enteric cluster of symptoms was identified, which encompassed the symptoms for the WHO MIS-C criteria. 18% (116/632) of children were admitted to critical care. On multivariable analysis, this was associated with age under 1 month (odds ratio 3.21, 95% confidence interval 1.36 to 7.66; P=0.008), age 10-14 years (3.23, 1.55 to 6.99; P=0.002), and black ethnicity (2.82, 1.41 to 5.57; P=0.003). Six (1%) of 627 patients died in hospital, all of whom had profound comorbidity. 11% (52/456) met the WHO MIS-C criteria, with the first patient developing symptoms in mid-March. Children meeting MIS-C criteria were older (median age 10.7 (8.3-14.1) v 1.6 (0.2-12.9) years; P<0.001) and more likely to be of non-white ethnicity (64% (29/45) v 42% (148/355); P=0.004). Children with MIS-C were five times more likely to be admitted to critical care (73% (38/52) v 15% (62/404); P<0.001). In addition to the WHO criteria, children with MIS-C were more likely to present with fatigue (51% (24/47) v 28% (86/302); P=0.004), headache (34% (16/47) v 10% (26/263); P<0.001), myalgia (34% (15/44) v 8% (21/270); P<0.001), sore throat (30% (14/47) v (12% (34/284); P=0.003), and lymphadenopathy (20% (9/46) v 3% (10/318); P<0.001) and to have a platelet count of less than 150 × 109/L (32% (16/50) v 11% (38/348); P<0.001) than children who did not have MIS-C. No deaths occurred in the MIS-C group.ConclusionsChildren and young people have less severe acute covid-19 than adults. A systemic mucocutaneous-enteric symptom cluster was also identified in acute cases that shares features with MIS-C. This study provides additional evidence for refining the WHO MIS-C preliminary case definition. Children meeting the MIS-C criteria have different demographic and clinical features depending on whether they have acute SARS-CoV-2 infection (polymerase chain reaction positive) or are post-acute (antibody positive).Study registrationISRCTN66726260.
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