Pregnancy outcomes after first-trimester treatment with artemisinin derivatives versus non-artemisinin antimalarials: a systematic review and individual patient data meta-analysis.

BACKGROUND: Malaria in the first trimester of pregnancy is associated with adverse pregnancy outcomes. Artemisinin-based combination therapies (ACTs) are a highly effective, first-line treatment for uncomplicated Plasmodium falciparum malaria, except in the first trimester of pregnancy, when quinine with clindamycin is recommended due to concerns about the potential embryotoxicity of artemisinins. We compared adverse pregnancy outcomes after artemisinin-based treatment (ABT) versus non-ABTs in the first trimester of pregnancy. METHODS: For this systematic review and individual patient data (IPD) meta-analysis, we searched MEDLINE, Embase, and the Malaria in Pregnancy Library for prospective cohort studies published between Nov 1, 2015, and Dec 21, 2021, containing data on outcomes of pregnancies exposed to ABT and non-ABT in the first trimester. The results of this search were added to those of a previous systematic review that included publications published up until November, 2015. We included pregnancies enrolled before the pregnancy outcome was known. We excluded pregnancies with missing estimated gestational age or exposure information, multiple gestation pregnancies, and if the fetus was confirmed to be unviable before antimalarial treatment. The primary endpoint was adverse pregnancy outcome, defined as a composite of either miscarriage, stillbirth, or major congenital anomalies. A one-stage IPD meta-analysis was done by use of shared-frailty Cox models. This study is registered with PROSPERO, number CRD42015032371. FINDINGS: We identified seven eligible studies that included 12 cohorts. All 12 cohorts contributed IPD, including 34 178 pregnancies, 737 with confirmed first-trimester exposure to ABTs and 1076 with confirmed first-trimester exposure to non-ABTs. Adverse pregnancy outcomes occurred in 42 (5·7%) of 736 ABT-exposed pregnancies compared with 96 (8·9%) of 1074 non-ABT-exposed pregnancies in the first trimester (adjusted hazard ratio [aHR] 0·71, 95% CI 0·49-1·03). Similar results were seen for the individual components of miscarriage (aHR=0·74, 0·47-1·17), stillbirth (aHR=0·71, 0·32-1·57), and major congenital anomalies (aHR=0·60, 0·13-2·87). The risk of adverse pregnancy outcomes was lower with artemether-lumefantrine than with oral quinine in the first trimester of pregnancy (25 [4·8%] of 524 vs 84 [9·2%] of 915; aHR 0·58, 0·36-0·92). INTERPRETATION: We found no evidence of embryotoxicity or teratogenicity based on the risk of miscarriage, stillbirth, or major congenital anomalies associated with ABT during the first trimester of pregnancy. Given that treatment with artemether-lumefantrine was associated with fewer adverse pregnancy outcomes than quinine, and because of the known superior tolerability and antimalarial effectiveness of ACTs, artemether-lumefantrine should be considered the preferred treatment for uncomplicated P falciparum malaria in the first trimester. If artemether-lumefantrine is unavailable, other ACTs (except artesunate-sulfadoxine-pyrimethamine) should be preferred to quinine. Continued active pharmacovigilance is warranted. FUNDING: Medicines for Malaria Venture, WHO, and the Worldwide Antimalarial Resistance Network funded by the Bill & Melinda Gates Foundation.

A study to validate the Ten-Question-Questionnaire + for the detection of moderate to severe neurological disabilities in older Bangladeshi children.

PURPOSE: Our study validated the Ten Question Questionnaire (TQQ+) for Bangladeshi children between 10 and 16 years. The TQQ + is a rapid screening tool for disability and was previously validated in children below 9 years of age. MATERIALS AND METHODS: The study was carried out in Chattogram, Bangladesh. One hundred children aged 10-16 years, 10 with mild or moderate disabilities, 40 with severe disabilities, and 50 children without a disability were identified. Children with disability (n = 50) had previously undergone Wechsler Intelligence Scale-Revised (WISC-R) assessments by psychologists as a reference standard. Each child was evaluated using Rapid Neurodevelopmental Assessment (RNDA) by physicians and TQQ + was administered by researchers. Sensitivities and specificities of TQQ + were evaluated in comparison with RNDA and WISC-R. RESULTS: The sensitivity of TQQ + was 98% in comparison with either RNDA or WISC-R. The specificity of TQQ was 76.5% compared with RNDA and 78% with WISC-R. TQQ + successfully picked up cognitive (98%) and motor (75%) disabilities as well as behavioural problems (88.9%). Specificity was good to excellent in all other domains. Logistic regression showed that TQQ + could reliably predict disability by RNDA and WISC-R. The area under the Receiver Operating Characteristic Curve (ROC) curve was 0.88 which denoted good diagnostic accuracy of the questionnaire. CONCLUSION: The TQQ + is valid for screening disabilities in 10-16 year old Bangladeshi children.IMPLICATIONS FOR REHABILITATIONIf children with neurodevelopmental disabilities are screened early, the benefit of intervention will be greater.TQQ + is an easy to administer and low-cost tool that has been validated internationally.The TQQ + is now validated and can be used for children aged 10 to 16 years in Bangladesh.

Daily Life and Challenges Faced By Households With Permanent Childhood Developmental Disability in Rural Tanzania - A Qualitative Study.

Severe developmental disability in children affects the life of the child and entire household. We conducted a qualitative study to understand how caregivers manage severe developmental disabilities in children in rural Africa. Families and six children (out of 15 children) who had serious permanent sequelae from a cerebral infection in Handeni, Tanzania, were contacted and invited to a workshop to recount their experience living with severe developmental disabilities. After consent, individual interviews were conducted first through recording of individual digital stories and then through individual semi-structured interviews. Pre-determined key categories were used to analyse the data. Our results showed that developmental disabilities required constant care and reduced the autonomy of the children. Schooling had not been attempted or was halted because of learning problems or inability to meet specialized school costs. Parents were under constant physical, emotional and financial stress. Their occupational earnings decreased. Some families sold their assets to survive. Others began to rely on relatives. Understanding the consequences of developmental disability helps to identify where social support should be focused and improved.

Etiology of severe invasive infections in young infants in rural settings in sub-Saharan Africa.

BACKGROUND: Serious invasive infections in newborns are a major cause of death. Lack of data on etiological causes hampers progress towards reduction of mortality. This study aimed to identify pathogens responsible for such infections in young infants in sub-Saharan Africa and to describe their antibiotics resistance profile. METHODS: Between September 2016 and April 2018 we implemented an observational study in two rural sites in Burkina Faso and Tanzania enrolling young infants aged 0-59 days old with serious invasive infection. Blood samples underwent blood culture and molecular biology. RESULTS: In total 634 infants with clinical diagnosis of serious invasive infection were enrolled and 4.2% of the infants had a positive blood culture. The most frequent pathogens identified by blood culture were Klebsiella pneumonia and Staphylococcus aureus, followed by Escherichia coli. Gram-negative isolates were only partially susceptible to first line WHO recommended treatment for neonatal sepsis at community level. A total of 18.6% of the infants were PCR positive for at least one pathogen and Escherichia coli and Staphylococcus aureus were the most common bacteria detected. Among infants enrolled, 60/634 (9.5%) died. Positive blood culture but not positive PCR was associated with risk of death. For most deaths, no pathogen was identified either by blood culture or molecular testing, and hence a causal agent remained unclear. Mortality was associated with low body temperature, tachycardia, respiratory symptoms, convulsions, history of difficult feeding, movement only when stimulated or reduced level of consciousness, diarrhea and/or vomiting. CONCLUSION: While Klebsiella pneumonia and Staphylococcus aureus, as well as Escherichia coli were pathogens most frequently identified in infants with clinical suspicion of serious invasive infections, most cases remain without definite diagnosis, making more accurate diagnostic tools urgently needed. Antibiotics resistance to first line antibiotics is an increasing challenge even in rural Africa.

Pharmacokinetic Study of Rectal Artesunate in Children with Severe Malaria in Africa.

When severe malaria is suspected in children, the WHO recommends pretreatment with a single rectal dose of artesunate before referral to an appropriate facility. This was an individually randomized, open-label, 2-arm, crossover clinical trial in 82 Congolese children with severe falciparum malaria to characterize the pharmacokinetics of rectal artesunate. At admission, children received a single dose of rectal artesunate (10 mg/kg of body weight) followed 12 h later by intravenous artesunate (2.4 mg/kg) or the reverse order. All children also received standard doses of intravenous quinine. Artesunate and dihydroartemisinin were measured at 11 fixed intervals, following 0- and 12-h drug administrations. Clinical, laboratory, and parasitological parameters were measured. After rectal artesunate, artesunate and dihydroartemisinin showed large interindividual variability (peak concentrations of dihydroartemisinin ranged from 5.63 to 8,090 nM). The majority of patients, however, reached previously suggested in vivo IC50 and IC90 values (98.7% and 92.5%, respectively) of combined concentrations of artesunate and dihydroartemisinin between 15 and 30 min after drug administration. The median (interquartile range [IQR]) time above IC50 and IC90 was 5.68 h (2.90 to 6.08) and 2.74 h (1.52 to 3.75), respectively. The absolute rectal bioavailability (IQR) was 25.6% (11.7 to 54.5) for artesunate and 19.8% (10.3 to 35.3) for dihydroartemisinin. The initial 12-h parasite reduction ratio was comparable between rectal and intravenous artesunate: median (IQR), 84.3% (50.0 to 95.4) versus 69.2% (45.7 to 93.6), respectively (P = 0.49). Despite large interindividual variability, rectal artesunate can initiate and sustain rapid parasiticidal activity in most children with severe falciparum malaria while they are transferred to a facility where parenteral artesunate is available. (This study has been registered at ClinicalTrials.gov under identifier NCT02492178.).

The fidelity of implementation of recommended care for children with malaria by community health workers in Nigeria.

BACKGROUND: In the context of task shifting, a promoted approach to healthcare delivery in resource-poor settings, trained community health workers (CHWs) have been shown to be effective in delivering quality care of malaria for febrile under-5 children. While their effectiveness has been documented, the fidelity of implementation (FOI) has not been adequately studied. By understanding and measuring whether an intervention has been performed with fidelity, researchers and practitioners gain a better understanding of how and why an intervention works, and the extent to which outcomes can be improved. The objective of this study was to assess the FOI of a recommended protocol for malaria care by CHWs in a resource-poor setting in Nigeria. METHODS: Thirty-five female CHWs who participated in a 3-day training on home management of malaria among under-5 children were studied. They managed 1,646 children over the implementation period and then underwent evaluation via a one-time hospital-based observation by the trainers. During the evaluation, a pre-tested standard checklist was used to compute performance scores for CHWs; doctors and nurses were selected to serve as the gold standard for comparison. Performance scores (PS) recorded during the evaluation were used to assess adherence and compliance with the recommended treatment protocol. RESULTS: Of the 4 skill domains assessed, adherence was greatest for compliance with malaria treatment recommendations (94%) and lowest for post-treatment initiation counseling of home-based caregivers (69%). The average overall adherence of 83% was comparable to adherence by gold standard comparators. Mean PS was not found to be significantly associated with CHW demographics. Scores for clinical evaluation among those whose occupation was not healthcare-related were significantly lowered by 0.52 [95% CI (1.05-0.01), p = 0.05]. Compliance with the treatment protocol increased by 23% for every unit increase in total PS (p = 0.07) and doubled for every unit increase in scores for post-treatment initiation counseling of caregivers (p = 0.002). CONCLUSIONS: Studying intervention fidelity stands to identify the shortcomings of implementation and specific areas to target for improvement in future adoption or implementation. This study concludes that future trainings should emphasize clinical evaluation and post-treatment counseling of caregivers by CHWs to ensure the best outcome for children.

Development of Rectodispersible Tablets and Granulate Capsules for the Treatment of Serious Neonatal Sepsis in Developing Countries.

Current pediatric antibiotic therapies often use oral and parenteral routes of administration. Neither are suitable for treating very sick neonates who cannot take oral medication and may be several hours away from hospital in developing countries. Here, we report on the development of rectal forms of ceftriaxone, a third-generation cephalosporin. Rectodispersible tablets and capsules were developed and successfully passed 6-month accelerated stability tests. Rabbit bioavailability showed plasma concentrations above the minimal inhibitory concentrations for 3 formulations of rectodispersible tablets and 2 formulations of hard capsules. Clinical batches are currently being prepared for human evaluation with the prospect of offering therapeutic alternatives for treating critically ill neonates. This proof of concept for efficient rectal delivery of antibiotics could help the development of other rectal antibiotic treatments and increase options for noninvasive drug development for pediatric patients.

Household costs and time to treatment for children with severe febrile illness in rural Burkina Faso: the role of rectal artesunate.

BACKGROUND: Community health workers (CHWs) were trained to identify children with malaria who could not take oral medication, treat them with rectal artesunate (RA) and refer them to the closest healthcare facility to complete management. However, many children with such symptoms did not seek CHWs' care. The hypothesis was that the cost of referral to a health facility was a deterrent. The goal of this study was to compare the out-of-pocket costs and time to seek treatment for children who sought CHW care (and received RA) versus those who did not. METHODS: Children with symptoms of severe malaria receiving RA at CHWs and children with comparable disease symptoms who did not go to a CHW were identified and their parents were interviewed. Household out-of-pocket costs per illness episode and speed of treatment were evaluated and compared between RA-treated children vs. non-RA treated children and by central nervous symptoms (CNS: repeated convulsions, altered consciousness or coma). RESULTS: Among children with CNS symptoms, costs of RA-treated children were similar to those of non-RA treated children ($5.83 vs. $4.65; p = 0.52), despite higher transport costs ($2.74 vs. $0.91; p < 0.0001). However, among children without CNS symptoms, costs of RA-treated children were higher than the costs of non-RA treated children with similar symptoms ($5.62 vs. $2.59; p = 0.0001), and the main driver of the cost difference was transport. After illness onset, CNS children reached CHWs for RA an average of 9.0 h vs. 16.1 h for non-RA treated children reaching first treatment [difference 7.1 h (95% CI - 1.8 to 16.1), p = 0.11]. For non-CNS patients the average time to CHW-delivered RA treatment was 12.2 h vs. 20.1 h for those reaching first treatment [difference 7.9 h (95% CI 0.2-15.6), p = 0.04]. More non-RA treated children developed CNS symptoms before arrival at the health centre but the difference was not statistically significant (6% vs. 4%; p = 0.58). CONCLUSIONS: Community health worker-delivered RA does not affect the total out-of-pocket costs when used in children with CNS symptoms, but is associated with higher total out-of-pocket costs when used in children with less severe symptoms. RA-treated children sought treatment more quickly.

Ceftriaxone Absorption Enhancement for Noninvasive Administration as an Alternative to Injectable Solutions.

Neonatal sepsis is a major cause of infant mortality in developing countries because of delayed injectable treatment, making it urgent to develop noninjectable formulations that can reduce treatment delays in resource-limited settings. Ceftriaxone, available only for injection, needs absorption enhancers to achieve adequate bioavailability via nonparenteral administration. This article presents all available data on the nonparenteral absorption of ceftriaxone in humans and animals, including unpublished work carried out by F. Hoffmann-La Roche (Roche) in the 1980s and new data from preclinical studies with rabbits, and discusses the importance of these data for the development of noninjectable formulations for noninvasive treatment. The combined results indicate that the rectal absorption of ceftriaxone is feasible and likely to lead to a bioavailable formulation that can reduce treatment delays in neonatal sepsis. A bile salt, chenodeoxycholate sodium salt (Na-CDC), used as an absorption enhancer at a 125-mg dose, together with a 500-mg dose of ceftriaxone provided 24% rectal absorption of ceftriaxone and a maximal plasma concentration of 21 µg/ml with good tolerance in human subjects. The rabbit model developed can also be used to screen for the bioavailability of other formulations before assessment in humans.

Safety Profile of Drug Use During Pregnancy at Peripheral Health Centres in Burkina Faso: A Prospective Observational Cohort Study.

PURPOSE: Safety data of many drugs used during pregnancy remain scarce. This is especially true in developing countries characterised by the absence of a robust pharmacovigilance system, high prevalence of different tropical diseases affecting patients and potential for drug-drug interactions. This study aimed to assess the safety profile of drugs used in women at high risk of malaria during pregnancy and delivery in Burkina Faso's health facilities. It also aimed to assess factors associated with the use of potentially risky drugs over the entire course of pregnancy. METHODS: We enrolled pregnant women from their first antenatal care visit and followed them up until delivery, and collected data on drug use. Based on United States Food and Drug Administration (FDA) or Australian Therapeutic Goods Administration (TGA) drug risk classification, drugs were classified into three groups: 'probably safe', 'potentially risky' or 'unclassified'. A modified classification was built to take into account national malaria policy treatment guidelines and World Health Organization Malaria Treatment Guidelines recommending malaria chemoprophylaxis during pregnancy. RESULTS: Out of 2371 pregnant women enrolled, 56.7% used at least one medication during the entire course of the pregnancy (excluding sulphadoxine-pyrimethamine and iron-folic acid). A total of 101 different types of medications were used by study participants and 36.6, 49.5 and 13.9% were, respectively, classified as 'probably safe', 'potentially risky' and 'unclassified'. Antimalarials and antibiotics were the most frequently used drugs. Around 39% of women used a least one medication classified as potentially risky. However, this proportion dropped to 26% with the modified classification. Living in urban areas and attending the first antenatal care within their first trimester of pregnancy (longer health surveillance) were associated with using 'potentially risky' medications. CONCLUSION: This study provides rare and valuable information on the current use of drugs among pregnant women in Burkina Faso. Many pregnant women used medications classified as potentially risky. Our findings suggest the need for rational drug prescription and community education to reduce hazardous drug exposure during pregnancy.

Can we measure cognitive constructs consistently within and across cultures? Evidence from a test battery in Bangladesh, Ghana, and Tanzania.

We developed a test battery for use among children in Bangladesh, Ghana, and Tanzania, assessing general intelligence, executive functioning, and school achievement. The instruments were drawn from previously published materials and tests. The instruments were adapted and translated in a systematic way to meet the needs of the three assessment contexts. The instruments were administered by a total of 43 trained assessors to 786 children in Bangladesh, Ghana, and Tanzania with a mean age of about 13 years (range: 7-18 years). The battery provides a psychometrically solid basis for evaluating intervention studies in multiple settings. Within-group variation was adequate in each group. The expected positive correlations between test performance and age were found and reliability indices yielded adequate values. A confirmatory factor analysis (not including the literacy and numeracy tests) showed a good fit for a model, merging the intelligence and executive tests in a single factor labeled general intelligence. Measurement weights invariance was found, supporting conceptual equivalence across the three country groups, but not supporting full score comparability across the three countries.

Development of rectal self-emulsifying suspension of a moisture-labile water-soluble drug.

Self-emulsifying drug delivery systems, commonly used for oral delivery of poorly soluble compounds, were used to formulate water soluble but moisture labile compounds for rectal application. The objective was to use the oily phase of the system to formulate a liquid, non-aqueous product while obtaining the advantages of self-emulsification, rapid contact with the rectal mucosa and rapid absorption post-administration. Ceftriaxone was used as a model drug and the human bile salt sodium chenodeoxycholate was used as an absorption enhancer. After preliminary screening of 23 excipients, based on their emulsification ability and emulsion fineness in binary and ternary mixtures, a full factorial design was used to screen different formulations of three preselected excipients. The optimal formulation contained 60% of excipients, namely Capryol 90, Kolliphor EL and Kolliphor PS20 in 4 : 6 : 6 ratio and 40% of a powder blend that included 500 mg of ceftriaxone. Characterization of the system showed that it complied with the requirements for rectal administration, in particular rapid emulsification in a small quantity of liquid. Rabbit bioavailability showed rapid absorption of ceftriaxone, achieving 128% bioavailability compared to powder control formulation. These results demonstrated the potential of self-emulsifying formulations for rectal administration of Class 3 BCS drugs.

Ethics review of studies during public health emergencies - the experience of the WHO ethics review committee during the Ebola virus disease epidemic.

BACKGROUND: Between 2013 and 2016, West Africa experienced the largest ever outbreak of Ebola Virus Disease. In the absence of registered treatments or vaccines to control this lethal disease, the World Health Organization coordinated and supported research to expedite identification of interventions that could control the outbreak and improve future control efforts. Consequently, the World Health Organization Research Ethics Review Committee (WHO-ERC) was heavily involved in reviews and ethics discussions. It reviewed 24 new and 22 amended protocols for research studies including interventional (drug, vaccine) and observational studies. WHO-ERC REVIEWS: WHO-ERC provided the reviews within on average 6 working days. The WHO-ERC often could not provide immediate approval of protocols for reasons which were not Ebola Virus Disease specific but related to protocol inconsistencies, missing information and complex informed consents. WHO-ERC considerations on Ebola Virus Disease specific issues (benefit-risk assessment, study design, exclusion of pregnant women and children from interventional studies, data and sample sharing, collaborative partnerships including international and local researchers and communities, community engagement and participant information) are presented. CONCLUSIONS: To accelerate study approval in future public health emergencies, we recommend: (1) internally consistent and complete submissions with information documents in language participants are likely to understand, (2) close collaboration between local and international researchers from research inception, (3) generation of template agreements for data and sample sharing and use during the ongoing global consultations on bio-banks, (4) formation of Joint Scientific Advisory and Data Safety Review Committees for all studies linked to a particular intervention or group of interventions, (5) formation of a Joint Ethics Review Committee with representatives of the Ethics Committees of all institutions and countries involved to strengthen reviews through the different perspectives provided without the 'opportunity costs' for time to final approval of multiple, independent reviews, (6) direct information exchange between the chairs of advisory, safety review and ethics committees, (7) more Ethics Committee support for investigators than is standard and (8) a global consultation on criteria for inclusion of pregnant women and children in interventional studies for conditions which put them at particularly high risk of mortality or other irreversible adverse outcomes under standard-of-care.

Preformulation studies of ceftriaxone for pediatric non-parenteral administration as an alternative to existing injectable formulations.

Ceftriaxone, a third generation cephalosporin, has a wide antibacterial spectrum that has good CNS penetration, which makes it potentially suitable for initial treatment of severe neonatal pediatric infections providing suitable formulation. We evaluated its physicochemical and technical characteristics to assess its potential for development as a non-parenteral dosage form. As ceftriaxone is marked only for injectable use, these data are not available. Using HPLC and Karl Fischer titration, sensitivity of ceftriaxone to water, feasibility and impact of pharmaceutical processes and compatibility with common pharmaceutical excipients were assessed. X-ray diffraction studies gave deeper insight into the mechanisms involved in degradation. Chemometrical analysis of near infrared spectra enabled classification of ceftriaxone powder according to exposure conditions or processes applied. The results showed that ceftriaxone was not highly hygroscopic, could be processed in all climatic zones, but should be packaged protected against humidity. Controlling water presence in formulation was shown critical, as ceftriaxone degraded in the presence of water content above 2.4% w/w. To improve flowability, a critical parameter for dry dosage form development, granulation (wet and dry techniques, providing complete drying and moderate force compaction respectively) was shown feasible. Compression with moderate forces was possible, but grinding and high compression forces significantly affected long term ceftriaxone stability and should be avoided. Based on these results, development of ceftriaxone non-parenteral solid or liquid non-aqueous forms appears feasible.

Protected to death: systematic exclusion of pregnant women from Ebola virus disease trials.

BACKGROUND: For 30 years, women have sought equal opportunity to be included in trials so that drugs are equitably studied in women as well as men; regulatory guidelines have changed accordingly. Pregnant women, however, continue to be excluded from trials for non-obstetric conditions, though they have been included for trials of life-threatening diseases because prospects for maternal survival outweighed potential fetal risks. Ebola virus disease is a life-threatening infection without approved treatments or vaccines. Previous Ebola virus (EBOV) outbreak data showed 89-93% maternal and 100% fetal/neonatal mortality. Early in the 2013-2016 EBOV epidemic, an expert panel pointed to these high mortality rates and the need to prioritize and preferentially allocate unregistered interventions in favor of pregnant women (and children). Despite these recommendations and multiple ethics committee requests for their inclusion on grounds of justice, equity, and medical need, pregnant women were excluded from all drug and vaccine trials in the affected countries, either without justification or on grounds of potential fetal harm. An opportunity to offer pregnant women the same access to potentially life-saving interventions as others, and to obtain data to inform their future use, was lost. Once again, pregnant women were denied autonomy and their right to decide. CONCLUSION: We recommend that, without clear justification for exclusion, pregnant women are included in clinical trials for EBOV and other life-threatening conditions, with lay language on risks and benefits in information documents, so that pregnant women can make their own decision to participate. Their automatic exclusion from trials for other conditions should be questioned.

Feasibility of Malaria Diagnosis and Management in Burkina Faso, Nigeria, and Uganda: A Community-Based Observational Study.

BACKGROUND: Malaria-endemic countries are encouraged to increase, expedite, and standardize care based on parasite diagnosis and treat confirmed malaria using oral artemisinin-based combination therapy (ACT) or rectal artesunate plus referral when patients are unable to take oral medication. METHODS: In 172 villages in 3 African countries, trained community health workers (CHWs) assessed and diagnosed children aged between 6 months and 6 years using rapid histidine-rich protein 2 (HRP2)-based diagnostic tests (RDTs). Patients coming for care who could take oral medication were treated with ACTs, and those who could not were treated with rectal artesunate and referred to hospital. The full combined intervention package lasted 12 months. Changes in access and speed of care and clinical course were determined through 1746 random household interviews before and 3199 during the intervention. RESULTS: A total of 15 932 children were assessed: 6394 in Burkina Faso, 2148 in Nigeria, and 7390 in Uganda. Most children assessed (97.3% [15 495/15 932]) were febrile and most febrile cases (82.1% [12 725/15 495]) tested were RDT positive. Almost half of afebrile episodes (47.6% [204/429]) were RDT positive. Children eligible for rectal artesunate contributed 1.1% of episodes. The odds of using CHWs as the first point of care doubled (odds ratio [OR], 2.15; 95% confidence interval [CI], 1.9-2.4; P < .0001). RDT use changed from 3.2% to 72.9% (OR, 80.8; 95% CI, 51.2-127.3; P < .0001). The mean duration of uncomplicated episodes reduced from 3.69 ± 2.06 days to 3.47 ± 1.61 days, Degrees of freedom (df) = 2960, Student's t (t) = 3.2 (P = .0014), and mean duration of severe episodes reduced from 4.24 ± 2.26 days to 3.7 ± 1.57 days, df = 749, t = 3.8, P = .0001. There was a reduction in children with danger signs from 24.7% before to 18.1% during the intervention (OR, 0.68; 95% CI, .59-.78; P < .0001). CONCLUSIONS: Provision of diagnosis and treatment via trained CHWs increases access to diagnosis and treatment, shortens clinical episode duration, and reduces the number of severe cases. This approach, recommended by the World Health Organization, improves malaria case management. CLINICAL TRIALS REGISTRATION: ISRCTN13858170.