Prevalence and risk factors of neonatal hyperbilirubinemia in a semi-rural area of the Democratic Republic of Congo: a cohort study

Neonatal hyperbilirubinemia (NH) is a frequent condition that, if left untreated, can lead to neurological disability and death. We assessed the prevalence of NH and associated neonatal and maternal risk factors in 362 mothers and 365 newborns in a semi-rural area of the Democratic Republic of Congo. In addition, we explored the knowledge and practices of mothers regarding this condition. We collected demographic data, anthropometric data, and obstetric and medical anamneses. We examined newborns at birth and at 24, 48, and 72 hours and measured bilirubin at birth in umbilical cord and capillary blood and thereafter in capillary blood. Hemoglobin, hematocrit, ABO group, Rhesus factor, glucose-6-phosphate dehydrogenase (G6PD) deficiency, Hemoglobin S (HbS), and malaria were assessed in mothers and newborns. Among 296 newborns (all time points available), 5.7% developed NH (95% CI: 3.4–9.0) between 24 and 72 hours according to National Institute for Health and Care Excellence (NICE) UK guidelines. There was a significantly higher risk in newborns with G6PD deficiency (homo- and hemizygous adjusted Odd Ratio [aOR]: 21.0, 95% CI: 4.1–105.9), preterm births (aOR: 6.1, 95% CI: 1.4–26.9), newborns with excessive birth weight loss (aOR: 5.8, 95% CI: 1.4–23.2), and hyperbilirubinemia at birth (aOR: 14.8, 95% CI: 2.7–79.6). Newborns with feto-maternal ABO incompatibility and G6PD deficiency had significantly higher bilirubin at birth than others. More than 60% of mothers had adequate knowledge of NH, but compliance with phototherapy in the absence of symptoms was low. Although risk factors for NH are common in this area, prevalence was not high, suggesting a need for better case definition. Implementation of point-of-care devices for diagnosis and awareness programs on risk prevention could help reduce neonatal morbidity and mortality associated with hyperbilirubinemia in these areas

Social, ethical and behavioural aspects of COVID-19.

Introduction: Vaccines and drugs for the treatment and prevention of COVID-19 require robust evidence generated from clinical trials before they can be used. Decisions on how to apply non-pharmaceutical interventions such as quarantine, self-isolation, social distancing and travel restrictions should also be based on evidence. There are some experiential and mathematical modelling data for these interventions, but there is a lack of data on the social, ethical and behavioural aspects of these interventions in the literature. Therefore, our study aims to produce evidence to inform (non-pharmaceutical) interventions such as communications, quarantine, self-isolation, social distancing, travel restrictions and other public health measures for the COVID-19 pandemic. Methods: The study will be conducted in the United Kingdom, Italy, Malaysia, Slovenia and Thailand. We propose to conduct 600-1000 quantitative surveys and 25-35 qualitative interviews per country. Data collection will follow the following four themes: (1) Quarantine and self-isolation (2) social distancing and travel restrictions (3) wellbeing and mental health (4) information, misinformation and rumours. In light of limitations of travel and holding in-person meetings, we will primarily use online/remote methods for collecting data. Study participants will be adults who have provided informed consent from different demographic, socio-economic and risk groups. Discussion: At the time of the inception of the study, United Kingdom, Italy, Malaysia, Slovenia and Thailand have initiated strict public health measures and varying degrees of "lockdowns" to curb the pandemic. These public health measures will change in the coming weeks and months depending on the number of cases of COVID-19 in the respective countries. The data generated from our study could inform these strategies in real time

Study protocol: an open-label individually randomised controlled trial to assess the efficacy of artemether-lumefantrine prophylaxis for malaria among forest goers in Cambodia

Introduction In the Greater Mekong Subregion, adults are at highest risk for malaria. The most relevant disease vectors bite during daytime and outdoors which makes forest work a high-risk activity for malaria. The absence of effective vector control strategies and limited periods of exposure during forest visits suggest that chemoprophylaxis could be an appropriate strategy to protect forest goers against malaria. Methods and analysis The protocol describes an open-label randomised controlled trial of artemether-lumefantrine (AL) versus multivitamin as prophylaxis against malaria among forest goers aged 16–65 years in rural northeast Cambodia. The primary objective is to compare the efficacy of the artemisinin combination therapy AL versus a multivitamin preparation as defined by the 28-day PCR parasite positivity rate and incidence of confirmed clinical malaria of any species. The sample size is 2200 patient-episodes of duration 1 month in each arm. The duration of follow-up and prophylaxis for each participant is 1, 2 or 3 consecutive 28-day periods, followed by a further 28 days of post-exposure prophylaxis, depending on whether they continue to visit the forest. Analysis will be done both by intention to treat and per protocol. Ethics and dissemination All participants will provide written, informed consent. Ethical approval was obtained from the Oxford Tropical Research Ethics Committee and the Cambodia National Ethics Committee for Health Research. Results will be disseminated by peer-reviewed open access publication together with open data

Antimalarial Chemoprophylaxis for Forest Goers in Southeast Asia: An Open-Label, Individually Randomised Controlled Trial

Summary Background Malaria in the eastern Greater Mekong subregion has declined to historic lows. Countries in the Greater Mekong subregion are accelerating malaria elimination in the context of increasing antimalarial drug resistance. Infections are now increasingly concentrated in remote, forested foci. No intervention has yet shown satisfactory efficacy against forest-acquired malaria. The aim of this study was to assess the efficacy of malaria chemoprophylaxis among forest goers in Cambodia. Methods We conducted an open-label, individually randomized controlled trial in Cambodia, which recruited participants aged 16–65 years staying overnight in forests. Participants were randomly allocated 1:1 to antimalarial chemoprophylaxis, a 3-day course of twice-daily artemether–lumefantrine followed by the same daily dosing once a week while travelling in the forest and for a further 4 weeks after leaving the forest (four tablets per dose; 20 mg of artemether and 120 mg of lumefantrine per tablet), or a multivitamin with no antimalarial activity. Allocations were done according to a computer-generated randomization schedule, and randomization was in permuted blocks of size ten and stratified by village. Investigators and participants were not masked to drug allocation, but laboratory investigations were done without knowledge of allocation. The primary outcome was a composite endpoint of either clinical malaria with any Plasmodium species within 1–28, 29–56, or 57–84 days, or subclinical infection detected by PCR on days 28, 56, or 84 using complete-case analysis of the intention-to-treat population. Adherence to study drug was assessed primarily by self-reporting during follow-up visits. Adverse events were assessed in the intention-to-treat population as a secondary endpoint from self-reporting at any time, plus a physical examination and symptom questionnaire at follow-up. This trial is registered at ClinicalTrials.gov (NCT04041973) and is complete. Findings Between March 11 and November 20, 2020, 1,480 individuals were enrolled, of whom 738 were randomly assigned to artemether–lumefantrine and 742 to the multivitamin. 713 participants in the artemether–lumefantrine group and 714 in the multivitamin group had a PCR result or confirmed clinical malaria by rapid diagnostic test during follow-up. During follow-up, 19 (3%, 95% CI 2–4) of 713 participants had parasitaemia or clinical malaria in the artemether– lumefantrine group and 123 (17%, 15–20) of 714 in the multivitamin group (absolute risk difference 15%, 95% CI 12–18; p \u3c 0·0001). During follow-up, there were 166 malaria episodes caused by Plasmodium vivax, 14 by Plasmodium falciparum, and five with other or mixed species infections. The numbers of participants with P. vivax were 18 (3%, 95% CI 2–4) in the artemether–lumefantrine group versus 112 (16%, 13–19) in the multivitamin group (absolute risk difference 13%, 95% CI 10–16; p \u3c 0.0001). The numbers of participants with P. falciparum were two (0.3%, 95% CI 0.03–1.01) in the artemether–lumefantrine group versus 12 (1·7%, 0.9–2.9) in the multivitamin group (absolute risk difference 1·4%, 95% CI 0.4–2·4; p = 0.013). Overall reported adherence to the full course of medication was 97% (95% CI 96–98; 1,797 completed courses out of 1,854 courses started) in the artemether–lumefantrine group and 98% (97–98; 1,842 completed courses in 1,885 courses started) in the multivitamin group. Overall prevalence of adverse events was 1.9% (355 events in 18,806 doses) in the artemether–lumefantrine group and 1.1% (207 events in 19,132 doses) in the multivitamin group (p \u3c 0.0001). Interpretation Antimalarial chemoprophylaxis with artemether–lumefantrine was acceptable and well tolerated and substantially reduced the risk of malaria. Malaria chemoprophylaxis among high-risk groups such as forest workers could be a valuable tool for accelerating elimination in the Greater Mekong subregion

Effect of point-of-care C-reactive protein testing on antibiotic prescription in febrile patients attending primary care in Thailand and Myanmar : an open-label, randomised, controlled trial

Background In southeast Asia, antibiotic prescription in febrile patients attending primary care is common, and a probable contributor to the high burden of antimicrobial resistance. The objective of this trial was to explore whether C-reactive protein (CRP) testing at point of care could rationalise antibiotic prescription in primary care, comparing two proposed thresholds to classify CRP concentrations as low or high to guide antibiotic treatment. Methods We did a multicentre, open-label, randomised, controlled trial in participants aged at least 1 year with a documented fever or a chief complaint of fever (regardless of previous antibiotic intake and comorbidities other than malignancies) recruited from six public primary care units in Thailand and three primary care clinics and one outpatient department in Myanmar. Individuals were randomly assigned using a computer-based randomisation system at a ratio of 1:1:1 to either the control group or one of two CRP testing groups, which used thresholds of 20 mg/L (group A) or 40 mg/L CRP (group B) to guide antibiotic prescription. Health-care providers were masked to allocation between the two intervention groups but not to the control group. The primary outcome was the prescription of any antibiotic from day 0 to day 5 and the proportion of patients who were prescribed an antibiotic when CRP concentrations were above and below the 20 mg/L or 40 mg/L thresholds. The primary outcome was analysed in the intention-to-treat and per-protocol populations. The trial is registered with ClinicalTrials.gov, number NCT02758821, and is now completed. Findings Between June 8, 2016, and Aug 25, 2017, we recruited 2410 patients, of whom 803 patients were randomly assigned to CRP group A, 800 to CRP group B, and 807 to the control group. 598 patients in CRP group A, 593 in CRP group B, and 767 in the control group had follow-up data for both day 5 and day 14 and had been prescribed antibiotics (or not) in accordance with test results (per-protocol population). During the trial, 318 (39%) of 807 patients in the control group were prescribed an antibiotic by day 5, compared with 290 (36%) of 803 patients in CRP group A and 275 (34%) of 800 in CRP group B. The adjusted odds ratio (aOR) of 0·80 (95% CI 0·65–0·98) and risk difference of −5·0 percentage points (95% CI −9·7 to −0·3) between group B and the control group were significant, although lower than anticipated, whereas the reduction in prescribing in group A compared with the control group was not significant (aOR 0·86 [0·70–1·06]; risk difference −3·3 percentage points [–8·0 to 1·4]). Patients with high CRP concentrations in both intervention groups were more likely to be prescribed an antibiotic than in the control group (CRP ≥20 mg/L: group A vs control group, p<0·0001; CRP ≥40 mg/L: group B vs control group, p<0·0001), and those with low CRP concentrations were more likely to have an antibiotic withheld (CRP <20 mg/L: group A vs control group, p<0·0001; CRP <40 mg/L: group B vs control group, p<0·0001). 24 serious adverse events were recorded, consisting of 23 hospital admissions and one death, which occurred in CRP group A. Only one serious adverse event was thought to be possibly related to the study (a hospital admission in CRP group A). Interpretation In febrile patients attending primary care, testing for CRP at point of care with a threshold of 40 mg/L resulted in a modest but significant reduction in antibiotic prescribing, with patients with high CRP being more likely to be prescribed an antibiotic, and no evidence of a difference in clinical outcomes. This study extends the evidence base from lower-income settings supporting the use of CRP tests to rationalise antibiotic use in primary care patients with an acute febrile illness. A key limitation of this study is the individual rather than cluster randomised study design which might have resulted in contamination between the study groups, reducing the effect size of the intervention

Weekly primaquine for radical cure of patients with Plasmodium vivax malaria and glucose-6-phosphate dehydrogenase deficiency

Background The World Health Organization recommends that primaquine should be given once weekly for 8-weeks to patients with Plasmodium vivax malaria and glucose-6-phosphate dehydrogenase (G6PD) deficiency, but data on its antirelapse efficacy and safety are limited. Methods Within the context of a multicentre, randomised clinical trial of two primaquine regimens in P. vivax malaria, patients with G6PD deficiency were excluded and enrolled into a separate 12-month observational study. They were treated with a weekly dose of 0.75 mg/kg primaquine for 8 weeks (PQ8W) plus dihydroartemisinin piperaquine (Indonesia) or chloroquine (Afghanistan, Ethiopia, Vietnam). G6PD status was diagnosed using the fluorescent spot test and confirmed by genotyping for locally prevalent G6PD variants. The risk of P. vivax recurrence following PQ8W and the consequent haematological recovery were characterized in all patients and in patients with genotypically confirmed G6PD variants, and compared with the patients enrolled in the main randomised control trial. Results Between July 2014 and November 2017, 42 male and 8 female patients were enrolled in Afghanistan (6), Ethiopia (5), Indonesia (19), and Vietnam (20). G6PD deficiency was confirmed by genotyping in 31 patients: Viangchan (14), Mediterranean (4), 357A-G (3), Canton (2), Kaiping (2), and one each for A-, Chatham, Gaohe, Ludhiana, Orissa, and Vanua Lava. Two patients had recurrent P. vivax parasitaemia (days 68 and 207). The overall 12-month cumulative risk of recurrent P. vivax malaria was 5.1% (95% CI: 1.3–18.9) and the incidence rate of recurrence was 46.8 per 1000 person-years (95% CI: 11.7–187.1). The risk of P. vivax recurrence was lower in G6PD deficient patients treated with PQ8W compared to G6PD normal patients in all treatment arms of the randomised controlled trial. Two of the 26 confirmed hemizygous males had a significant fall in haemoglobin (>5g/dl) after the first dose but were able to complete their 8 week regimen. Conclusions PQ8W was highly effective in preventing P. vivax recurrences. Whilst PQ8W was well tolerated in most patients across a range of different G6PD variants, significant falls in haemoglobin may occur after the first dose and require clinical monitoring. Trial registration This trial is registered at ClinicalTrials.gov (NCT01814683)

Pharmacokinetics of single low dose primaquine in Ugandan and Congolese children with falciparum malaria

Background: There are no pharmacokinetic data of single low dose primaquine (SLDPQ) as transmission blocking in African children with acute Plasmodium falciparum and glucose-6-phosphate dehydrogenase deficiency (G6PDd). Methods: Primaquine pharmacokinetics of age-dosed SLDPQ (shown previously to be gametocytocidal with similar tolerability as placebo) were characterised in falciparum-infected Ugandan and Congolese children aged 6 months to 11 years, treated on admission with standard 3-day dihydroartemisinin-piperaquine or artemether-lumefantrine plus SLDPQ: 6 m–<1 y: 1.25 mg, 1–5 y: 2.5 mg, 6–9 y: 5 mg, 10–11 y: 7.5 mg. LC-MS/MS-measured plasma primaquine and carboxyprimaquine (baseline, 1, 1.5, 2, 4, 8, 12, 24 h) were analysed by noncompartmental analysis. Multivariable linear regression modelled associations between covariates, including cytochrome-P450 2D6 metaboliser status, and outcomes. Findings: 258 children (median age 5 [interquartile range (IQR) 3–7]) were sampled; 8 (3.1%) with early vomiting were excluded. Primaquine doses of 0.10–0.40 (median 0.21, IQR 0.16–0.25) mg base/kg resulted in primaquine maximum plasma concentrations (Cmax) of 2.3–447 (median 103.0, IQR 72.1–140.0) ng/mL between 1.0 and 8.0 (median 2) hours (Tmax) and median areas under the drug concentration curves (AUC0-last) 730.2 (6 m–<1 y, n = 12), 582.8 (1–5 y, n = 126), 871.1 (6–9 y, n = 80), and 931.0 (10–11 y, n = 32) ng∗h/mL. Median elimination half-live (T½) was 4.7 (IQR 3.8–5.6) hours. Primaquine clearance/kg peaked at 18 months, plateauing at 4 y. Increasing CYP2D6 metaboliser activity score [poor (3/250), intermediate (52/250), normal (150/250), ultrarapid (5/250), indeterminate (40/250)] and baseline haemoglobin were significantly associated with a lower primaquine AUC0-last,which increased with increasing mg/kg dose and age but was independent of the artemisinin treatment used. Interpretation: Age-dosed SLDPQ resulted in variable primaquine exposure that depended on bodyweight-adjusted dose, age, baseline haemoglobin and CYP2D6 metaboliser status, but not on dihydroartemisinin-piperaquine or artemether-lumefantrine. These data support age-dosed SLDPQ for transmission blocking in sub-Saharan Africa. Funding: This work was cofunded by the UK Medical Research Council, Wellcome Trust, and UK Aid through the Global Health Trials (grant reference MR/P006973/1). The funders had no role in the study design, execution, and analysis and decisions regarding publication

Intravenous doxycycline, azithromycin, or both for severe scrub typhus

BACKGROUND: The appropriate antibiotic treatment for severe scrub typhus, a neglected but widespread reemerging zoonotic infection, is unclear. METHODS: In this multicenter, double-blind, randomized, controlled trial, we compared the efficacy of intravenous doxycycline, azithromycin, or a combination of both in treating severe scrub typhus. Patients who were 15 years of age or older with severe scrub typhus with at least one organ involvement were enrolled. The patients were assigned to receive a 7-day course of intravenous doxycycline, azithromycin, or both (combination therapy). The primary outcome was a composite of death from any cause at day 28, persistent complications at day 7, and persistent fever at day 5. RESULTS: Among 794 patients (median age, 48 years) who were included in the modified intention-to-treat analysis, complications included those that were respiratory (in 62%), hepatic (in 54%), cardiovascular (in 42%), renal (in 30%), and neurologic (in 20%). The use of combination therapy resulted in a lower incidence of the composite primary outcome than the use of doxycycline (33% and 47%, respectively), for a risk difference of −13.3 percentage points (95% confidence interval [CI], (21.6 to −5.1; P=0.002). The incidence with combination therapy was also lower than that with azithromycin (48%), for a risk difference of −14.8 percentage points (95% CI, −23.1 to −6.5; P<0.001). No significant difference was seen between the azithromycin and doxycycline groups (risk difference, 1.5 percentage points; 95% CI, −7.0 to 10.0; P=0.73). The results in the per-protocol analysis were similar to those in the primary analysis. Adverse events and 28-day mortality were similar in the three groups. CONCLUSIONS: Combination therapy with intravenous doxycycline and azithromycin was a better therapeutic option for the treatment of severe scrub typhus than monotherapy with either drug alone. (Funded by the India Alliance and Wellcome Trust; INTREST Clinical Trials Registry–India number, CTRI/2018/08/015159.

A Clinically Oriented antimicrobial Resistance surveillance Network (ACORN): pilot implementation in three countries in Southeast Asia, 2019-2020

Background: Case-based surveillance of antimicrobial resistance (AMR) provides more actionable data than isolate- or sample-based surveillance. We developed A Clinically Oriented antimicrobial Resistance surveillance Network (ACORN) as a lightweight but comprehensive platform, in which we combine clinical data collection with diagnostic stewardship, microbiological data collection and visualisation of the linked clinical-microbiology dataset. Data are compatible with WHO GLASS surveillance and can be stratified by syndrome and other metadata. Summary metrics can be visualised and fed back directly for clinical decision-making and to inform local treatment guidelines and national policy. Methods: An ACORN pilot was implemented in three hospitals in Southeast Asia (1 paediatric, 2 general) to collect clinical and microbiological data from patients with community- or hospital-acquired pneumonia, sepsis, or meningitis. The implementation package included tools to capture site and laboratory capacity information, guidelines on diagnostic stewardship, and a web-based data visualisation and analysis platform. Results: Between December 2019 and October 2020, 2294 patients were enrolled with 2464 discrete infection episodes (1786 community-acquired, 518 healthcare-associated and 160 hospital-acquired). Overall, 28-day mortality was 8.7%. Third generation cephalosporin resistance was identified in 54.2% (39/72) of E. coli and 38.7% (12/31) of K. pneumoniae isolates. Almost a quarter of S. aureus isolates were methicillin resistant (23.0%, 14/61). 290/2464 episodes could be linked to a pathogen, highlighting the level of enrolment required to achieve an acceptable volume of isolate data. However, the combination with clinical metadata allowed for more nuanced interpretation and immediate feedback of results. Conclusions: ACORN was technically feasible to implement and acceptable at site level. With minor changes from lessons learned during the pilot ACORN is now being scaled up and implemented in 15 hospitals in 9 low- and middle-income countries to generate sufficient case-based data to determine incidence, outcomes, and susceptibility of target pathogens among patients with infectious syndromes

Evaluation of hydroxychloroquine or chloroquine for the prevention of COVID-19 (COPCOV): A double-blind, randomised, placebo-controlled trial

Background: Hydroxychloroquine (HCQ) has proved ineffective in treating patients hospitalised with Coronavirus Disease 2019 (COVID-19), but uncertainty remains over its safety and efficacy in chemoprevention. Previous chemoprevention randomised controlled trials (RCTs) did not individually show benefit of HCQ against COVID-19 and, although meta-analysis did suggest clinical benefit, guidelines recommend against its use. Methods and findings: Healthy adult participants from the healthcare setting, and later from the community, were enrolled in 26 centres in 11 countries to a double-blind, placebo-controlled, randomised trial of COVID-19 chemoprevention. HCQ was evaluated in Europe and Africa, and chloroquine (CQ) was evaluated in Asia, (both base equivalent of 155 mg once daily). The primary endpoint was symptomatic COVID-19, confirmed by PCR or seroconversion during the 3-month follow-up period. The secondary and tertiary endpoints were: asymptomatic laboratory-confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection; severity of COVID-19 symptoms; all-cause PCR-confirmed symptomatic acute respiratory illness (including SARS-CoV-2 infection); participant reported number of workdays lost; genetic and baseline biochemical markers associated with symptomatic COVID-19, respiratory illness and disease severity (not reported here); and health economic analyses of HCQ and CQ prophylaxis on costs and quality of life measures (not reported here). The primary and safety analyses were conducted in the intention-to-treat (ITT) population. Recruitment of 40,000 (20,000 HCQ arm, 20,000 CQ arm) participants was planned but was not possible because of protracted delays resulting from controversies over efficacy and adverse events with HCQ use, vaccine rollout in some countries, and other factors. Between 29 April 2020 and 10 March 2022, 4,652 participants (46% females) were enrolled (HCQ/CQ n = 2,320; placebo n = 2,332). The median (IQR) age was 29 (23 to 39) years. SARS-CoV-2 infections (symptomatic and asymptomatic) occurred in 1,071 (23%) participants. For the primary endpoint the incidence of symptomatic COVID-19 was 240/2,320 in the HCQ/CQ versus 284/2,332 in the placebo arms (risk ratio (RR) 0.85 [95% confidence interval, 0.72 to 1.00; p = 0.05]). For the secondary and tertiary outcomes asymptomatic SARS-CoV-2 infections occurred in 11.5% of HCQ/CQ recipients and 12.0% of placebo recipients: RR: 0.96 (95% CI, 0.82 to 1.12; p = 0.6). There were no differences in the severity of symptoms between the groups and no severe illnesses. HCQ/CQ chemoprevention was associated with fewer PCR-confirmed all-cause respiratory infections (predominantly SARS-CoV-2): RR 0.61 (95% CI, 0.42 to 0.88; p = 0.009) and fewer days lost to work because of illness: 104 days per 1,000 participants over 90 days (95% CI, 12 to 199 days; p < 0.001). The prespecified meta-analysis of all published pre-exposure RCTs indicates that HCQ/CQ prophylaxis provided a moderate protective benefit against symptomatic COVID-19: RR 0.80 (95% CI, 0.71 to 0.91). Both drugs were well tolerated with no drug-related serious adverse events (SAEs). Study limitations include the smaller than planned study size, the relatively low number of PCR-confirmed infections, and the lower comparative accuracy of serology endpoints (in particular, the adapted dried blood spot method) compared to the PCR endpoint. The COPCOV trial was registered with ClinicalTrials.gov; number NCT04303507. Interpretation: In this large placebo-controlled, double-blind randomised trial, HCQ and CQ were safe and well tolerated in COVID-19 chemoprevention, and there was evidence of moderate protective benefit in a meta-analysis including this trial and similar RCTs. Trial registration: ClinicalTrials.gov NCT04303507; ISRCTN Registry ISRCTN10207947