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The World Health Organization recommends inpatient hospital treatment of young infants up to two months old with any sign of possible serious infection. However, each sign may have a different risk of death. The current study aims to calculate the case fatality ratio for infants with individual or combined signs of possible serious infection, stratified by inpatient or outpatient treatment. We analysed data from the African Neonatal Sepsis Trial conducted in five sites in the Democratic Republic of the Congo, Kenya and Nigeria. Trained study nurses classified sick infants as pneumonia (fast breathing in 7-59 days old), severe pneumonia (fast breathing in 0-6 days old), clinical severe infection [severe chest indrawing, high (> = 38°C) or low body temperature (<35.5°C), stopped feeding well, or movement only when stimulated] or critical illness (convulsions, not able to feed at all, or no movement at all), and referred them to a hospital for inpatient treatment. Infants whose caregivers refused referral received outpatient treatment. The case fatality ratio by day 15 was calculated for individual and combined clinical signs and stratified by place of treatment. An infant with signs of clinical severe infection or severe pneumonia was recategorised as having low- (case fatality ratio ≤2%) or moderate- (case fatality ratio >2%) mortality risk. Of 7129 young infants with a possible serious infection, fast breathing (in 7-59 days old) was the most prevalent sign (26%), followed by high body temperature (20%) and severe chest indrawing (19%). Infants with pneumonia had the lowest case fatality ratio (0.2%), followed by severe pneumonia (2.0%), clinical severe infection (2.3%) and critical illness (16.9%). Infants with clinical severe infection had a wide range of case fatality ratios for individual signs (from 0.8% to 11.0%). Infants with pneumonia had similar case fatality ratio for outpatient and inpatient treatment (0.2% vs. 0.3%, p = 0.74). Infants with clinical severe infection or severe pneumonia had a lower case fatality ratio among those who received outpatient treatment compared to inpatient treatment (1.9% vs. 6.5%, p<0.0001). We recategorised infants into low-mortality risk signs (case fatality ratio ≤2%) of clinical severe infection (high body temperature, or severe chest indrawing) or severe pneumonia and moderate-mortality risk signs (case fatality ratio >2%) (stopped feeding well, movement only when stimulated, low body temperature or multiple signs of clinical severe infection). We found that both categories had four times lower case fatality ratio when treated as outpatient than inpatient treatment, i.e., 1.0% vs. 4.0% (p<0.0001) and 5.3% vs. 22.4% (p<0.0001), respectively. In contrast, infants with signs of critical illness had nearly two times higher case fatality ratio when treated as outpatient versus inpatient treatment (21.7% vs. 12.1%, p = 0.097). The mortality risk differs with clinical signs. Young infants with a possible serious infection can be grouped into those with low-mortality risk signs (high body temperature, or severe chest indrawing or severe pneumonia); moderate-mortality risk signs (stopped feeding well, movement only when stimulated, low body temperature or multiple signs of clinical severe infection), or high-mortality risk signs (signs of critical illness). New treatment strategies that consider differential mortality risks for the place of treatment and duration of inpatient treatment could be developed and evaluated based on these findings. This trial was registered with the Australian New Zealand Clinical Trials Registry under ID ACTRN 12610000286044.

Accurate assessment and monitoring of the Plasmodium falciparum Kelch 13 ( pfk13) gene associated with artemisinin resistance is critical to understand the emergence and spread of drug-resistant parasites in malaria-endemic regions. In this study, we evaluated the genomic profile of the pfk13 gene associated with artemisinin resistance in P . falciparum in Nigerian children by targeted sequencing of the pfk13 gene. Genomic DNA was extracted from 332 dried blood (DBS) spot filter paper samples from three Nigerian States. The pfk13 gene was amplified by nested polymerase chain reaction (PCR), and amplicons were sequenced to detect known and novel polymorphisms across the gene. Consensus sequences of samples were mapped to the reference gene sequence obtained from the National Center for Biotechnology Information (NCBI). Out of the 13 single nucleotide polymorphisms (SNPs) detected in the pfk13 gene, five (F451L, N664I, V487E, V692G and Q661H) have not been reported in other endemic countries to the best of our knowledge. Three of these SNPs (V692G, N664I and Q661H) and a non-novel SNP, C469C, were consistent with late parasitological failure (LPF) in two States (Enugu and Plateau States). There was no validated mutation associated with artemisinin resistance in this study. However, a correlation of our study with in vivo and in vitro phenotypes is needed to establish the functional role of detected mutations as markers of artemisinin resistance in Nigeria. This baseline information will be essential in tracking and monitoring P . falciparum resistance to artemisinin in Nigeria.

Community-based data on the prevalence of clinical signs of possible serious bacterial infection (PSBI) and the mortality associated with them are scarce. The aim was to examine the prevalence for each sign of infection and mortality associated with infants in the first two months of life, using community surveillance through community health workers (CHW). We used population-based surveillance data of infants up to two months of age from the African Neonatal Sepsis Trial (AFRINEST). In this study, CHWs visited infants up to 10 times during the first two months of life at five sites in three sub-Saharan African countries. CHW assessed the infant for signs of infection (local or systemic) and referred infants who presented with any sign of infection to a health facility. We used a longitudinal analysis to calculate the risk of death associated with the presence of a sign of infection at the time of the visit until the subsequent visit. During the first two months of their life, CHWs visited 84,759 live-born infants at least twice. In 11,089 infants (13.1%), one or more signs of infection were identified, of which 237 (2.1%) died. A sign of infection was detected at 2.1% of total visits. In 52% of visits, infants had one or more sign of systemic infection, while 25% had fast breathing in 7-59 days period and 23% had a local infection. All signs of infection, including multiple signs, were more frequently seen in the first week of life. The risk of mortality was very low (0.2%) for local infections and fast breathing in 7-59 days old, it was low for fast breathing 0-6 days old (0.6%), high body temperature (0.7%) and severe chest indrawing (1.0%), moderate for low body temperature (4.9%) and stopped feeding well/not able to feed at all (5.0%) and high for movement only when stimulated or no movement at all (10%) and multiple signs of systemic infection (15.5%). The risk of death associated with most clinical signs was higher (1.5 to 9 times) in the first week of life than at later age, except for low body temperature (4 times lower) as well as high body temperature (2 times lower). Signs of infections are common in the first two months of life. The mortality risk differs with clinical signs and can be grouped as very low (local infections, fast breathing 7-59 days), low (fever, severe chest indrawing and fast breathing 0-6 days), moderate (low body temperature and stopped feeding well/not able to feed at all) and high (for movements only on stimulation or no movements at all and multiple signs of infection). New treatment strategies that consider differential mortality risk could be developed and evaluated based on these findings. The trial was registered with Australian New Zealand Clinical Trials Registry under ID ACTRN 12610000286044.

Neonatal infections are estimated to account for a quarter of the 2·8 million annual neonatal deaths, as well as approximately 3% of all disability-adjusted life-years. Despite this burden, few data are available on incidence, aetiology, and outcomes, particularly regarding impairment. We aimed to develop guidelines for improved scientific reporting of observational neonatal infection studies, to increase comparability and to strengthen research in this area. This checklist, Strengthening the Reporting of Observational Studies in Epidemiology for Newborn Infection (STROBE- NI), is an extension of the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) statement. STROBE-NI was developed following systematic reviews of published literature (1996–2015), compilation of more than 130 potential reporting recommendations, and circulation of a survey to relevant professionals worldwide, eliciting responses from 147 professionals from 37 countries. An international consensus meeting of 18 participants (with expertise in infectious diseases, neonatology, microbiology, epidemiology, and statistics) identified priority recommendations for reporting, additional to the STROBE statement. Implementation of these STROBE-NI recommendations, and linked checklist, aims to improve scientific reporting of neonatal infection studies, increasing data utility and allowing meta-analyses and pathogen-specific burden estimates to inform global policy and new interventions, including maternal vaccines.

WHO recommends hospital-based treatment for young infants aged 0–59 days with clinical signs of possible serious bacterial infection, but most families in resource-poor settings cannot accept referral. We aimed to assess whether use of simplified antibiotic regimens to treat young infants with clinical signs of severe infection was as efficacious as an injectable procaine benzylpenicillin–gentamicin combination for 7 days for situations in which hospital referral was not possible. In a multisite open-label equivalence trial in DR Congo, Kenya, and Nigeria, community health workers visited all newborn babies at home, identifying and referring unwell young infants to a study nurse. We stratified young infants with clinical signs of severe infection whose parents did not accept referral to hospital by age (0–6 days and 7–59 days), and randomly assigned each individual within these strata to receive one of the four treatment regimens. Randomisation was stratified by age group of infants. An age-stratified randomisation scheme with block size of eight was computer-generated off-site at WHO. The outcome assessor was masked. We randomly allocated infants to receive injectable procaine benzylpenicillin–gentamicin for 7 days (group A, reference group); injectable gentamicin and oral amoxicillin for 7 days (group B); injectable procaine benzylpenicillin–gentamicin for 2 days, then oral amoxicillin for 5 days (group C); or injectable gentamicin for 2 days and oral amoxicillin for 7 days (group D). Trained health professionals gave daily injections and the first dose of oral amoxicillin. Our primary outcome was treatment failure by day 8 after enrolment, defined as clinical deterioration, development of a serious adverse event (including death), no improvement by day 4, or not cured by day 8. Independent outcome assessors, who did not know the infant's treatment regimen, assessed study outcomes on days 4, 8, 11, and 15. Primary analysis was per protocol. We used a prespecified similarity margin of 5% to assess equivalence between regimens. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12610000286044. In Kenya and Nigeria, we started enrolment on April 4, 2011, and we enrolled the necessary number of young infants aged 7 days or older from Oct 17, 2011, to April 30, 2012. At these sites, we continued to enrol infants younger than 7 days until March 29, 2013. In DR Congo, we started enrolment on Sept 17, 2012, and continued until June 28, 2013. We randomly assigned 3564 young infants to either group A (n=894), group B (n=884), group C (n=896), or group D (n=890). We excluded 200 randomly assigned infants, who did not fulfil the predefined criteria of adherence to treatment and adequate follow-up. In the per-protocol analysis, 828 infants were included in group A, 826 in group B, 862 in group C, and 848 in group D. 67 (8%) infants failed treatment in group A compared with 51 (6%) infants in group B (risk difference −1·9%, 95% CI −4·4 to 0·1), 65 (8%) in group C (−0·6%, −3·1 to 2·0), and 46 (5%) in group D (−2·7%, −5·1 to 0·3). Treatment failure in groups B, C, and D was within the similarity margin compared with group A. During the 15 days after random allocation, 12 (1%) infants died in group A, compared with ten (1%) infants in group B, 20 (2%) infants in group C, and 11 (1%) infants in group D. An infant in group A had a serious adverse event other than death (injection abscess). The three simplified regimens were as effective as injectable procaine benzylpenicillin–gentamicin for 7 days on an outpatient basis in young infants with clinical signs of severe infection, without signs of critical illness, and whose caregivers did not accept referral for hospital admission. Bill & Melinda Gates Foundation grant to WHO.

Background Nigeria has one of the highest under-five mortality rates in the world. Identifying the causes of these deaths is crucial to inform changes in policy documents, design and implementation of appropriate interventions to reduce these deaths. This study aimed to provide national and zonal-level estimates of the causes of under-five death in Nigeria in the 2013–2018 periods. Methods We conducted retrospective inquiries into the cause of deaths of 948 neonates and 2,127 children aged 1–59 months as identified in the 2018 Nigeria Demographic and Health Survey (NDHS). The verbal autopsy asked about signs and symptoms during the final illness. The Physician Coded Verbal Autopsy (PCVA) and Expert Algorithm Verbal Autopsy (EAVA) methods were employed to assign the immediate and underlying cause of deaths to all cases. Result For the analysis, sampling weights were applied to accommodate non-proportional allocation. Boys accounted for 56 percent of neonatal deaths and 51.5 percent of the 1–59-months old deaths. About one-quarter of under-5 mortality was attributed to neonatal deaths, and 50 percent of these neonatal deaths were recorded within 48 h of delivery. Overall, 84 percent of the under-5 deaths were in the northern geopolitical zones. Based on the two methods for case analysis, neonatal infections (sepsis, pneumonia, and meningitis) were responsible for 44 percent of the neonatal deaths, followed by intrapartum injury (PCVA: 21 percent vs. EAVA: 29 percent). The three main causes of death in children aged 1–59 months were malaria (PCVA: 23 percent vs. EAVA: 35 percent), diarrhoea (PCVA: 17 percent vs. EAVA: 23 percent), and pneumonia (PCVA: 10 percent vs. EAVA: 12 percent). In the North West, where the majority of under-5 (1–59 months) deaths were recorded, diarrhoea was the main cause of death (PCVA: 24.3 percent vs. EAVA: 30 percent). Conclusion The causes of neonatal and children aged 1–59 months deaths vary across the northern and southern regions. By homing on the specific causes of mortality by region, the study provides crucial information that may be useful in planning appropriately tailored interventions to significantly reduce under-five deaths in Nigeria.

Serious bacterial neonatal infections are a major cause of global neonatal mortality. While hospitalized treatment is recommended, families cannot access inpatient treatment in low resource settings. Two parallel randomized control trials were conducted at five sites in three countries (Democratic Republic of Congo, Kenya, and Nigeria) to compare the effectiveness of treatment with experimental regimens requiring fewer injections with a reference regimen A (injection gentamicin plus injection procaine penicillin both once daily for 7 days) on the outpatient basis provided to young infants (0-59 days) with signs of possible serious bacterial infection (PSBI) when the referral was not feasible. Costs were estimated to quantify the financial implications of scaleup, and cost-effectiveness of these regimens. Direct economic costs (including personnel, drugs and consumable costs) were estimated for identification, prenatal and postnatal visits, assessment, classification, treatment and follow-up. Data on time spent by providers on each activity was collected from 83% of providers. Indirect marginal financial costs were estimated for non-consumables/capital, training, transport, communication, administration and supervision by considering only a share of the total research and health system costs considered important for the program. Total economic costs (direct plus indirect) per young infant treated were estimated based on 39% of young infants enrolled in the trial during 2012 and the number of days each treated during one year. The incremental cost-effectiveness ratio was calculated using treatment failure after one week as the outcome indicator. Experimental regimens were compared to the reference regimen and pairwise comparisons were also made. The average costs of treating a young infant with clinical severe infection (a sub-category of PSBI) in 2012 was lowest with regimen D (injection gentamicin once daily for 2 days plus oral amoxicillin twice daily for 7 days) at US$ 20.9 (95% CI US$ 16.4-25.3) or US$ 32.5 (2018 prices). While all experimental regimens B (injection gentamicin once daily plus oral amoxicillin twice daily, both for 7 days), regimen C (once daily of injection gentamicin injection plus injection procaine penicillin for 2 days, thereafter oral amoxicillin twice daily for 5 days) and regimen D were found to be more cost-effective as compared with the reference regimen A; pairwise comparison showed regimen D was more cost-effective than B or C. For fast breathing, the average cost of treatment with regimen E (oral amoxicillin twice daily for 7 days) at US$ 18.3 (95% CI US$ 13.4-23.3) or US$ 29.0 (2018 prices) was more cost-effective than regimen A. Indirect costs were 32% of the total treatment costs. Scaling up of outpatient treatment for PSBI when the referral is not feasible with fewer injections and oral antibiotics is cost-effective for young infants and can lead to increased access to treatment resulting in potential reductions in neonatal mortality. The trial was registered with Australian New Zealand Clinical Trials Registry under ID ACTRN 12610000286044.

Bacterial infection is one of the leading causes of mortality in young infants globally. The standard practice to manage young infants with any sign of possible serious bacterial infection (PSBI) is in a hospital setting with parenteral antibiotics, which may not be feasible for majority of cases in most low resource settings. The World Health Organization developed a guideline on management of PSBI in young infants when referral is not feasible in 2016. We conducted implementation research in selected communities in Zaria Local Government Areas of Kaduna State with an estimated population of 50,000 with the aim of understanding how to implement the WHO PSBI treatment guideline to achieve high coverage with low case fatality and treatment failure rates. Implementation was within the programmatic settings using existing health structure. We conducted policy dialogue with decision makers to adapt the recommendations to their social, cultural and programmatic context in Nigeria, held orientation meetings with program managers, built capacity of the health workers and supported the implementation within the health system. We supported a non-government organization to conduct community sensitization to promote care seeking and adherence to treatment advice. The research team collected data systematically on all young infants identified to have PSBI, the treatment they received and the clinical outcome. Between April 2016 and March 2017, we identified 347 young infants up to 2 months of age with signs of PSBI who received treatment either as an outpatient or in a hospital among 2,154 births in the study population. The coverage of PSBI treatment in the study area was 95.5% assuming that 10% of all births have an episode of PSBI in the first two months of life. Most (89%) sick young infants with PSBI were identified by the community-oriented resource persons and sent to the Primary Health Care Centres (PHCs). Most families (97%) refused referral and were treated at a primary health care centre on outpatient basis. There were 12 deaths (3.5%) and 17 non-death treatment failures (4.9%) in 343 infants in whom an outcome could be ascertained. While non-death treatment failure rate was highest in 0-6-day infants with fast breathing (14.4%), case fatality was highest in those with signs of critical illness (20%). We have demonstrated that outpatient treatment strategy for young infants with PSBI when referral is not feasible is implementable within the programmatic settings, achieving very high population coverage and relatively low treatment failure and case fatality rates. Implementation at scale will require government's commitment to strengthen the health system with trained, motivated health care providers and necessary commodities.

WHO recommends referral to hospital for possible serious bacterial infection in young infants aged 0–59 days. We aimed to assess whether oral amoxicillin treatment for fast breathing, in the absence of other signs, is as efficacious as the combination of injectable procaine benzylpenicillin–gentamicin. In a randomised, open-label, equivalence trial at five sites in DR Congo, Kenya, and Nigeria, community health workers followed up all births in the community, identified unwell young infants, and referred them to study nurses. We randomly assigned infants with fast breathing as a single sign of illness or possible serious bacterial infection, whose parents did not accept referral to hospital, to receive either injectable procaine benzylpenicillin–gentamicin once per day or oral amoxicillin treatment twice per day for 7 days. A person who was off-site generated randomisation lists using computer software. Trained health professionals gave injections, but outcome assessors were masked to group allocations. The primary outcome was treatment failure by day 8 after enrolment, defined as clinical deterioration, development of a serious adverse event including death, persistence of fast breathing on day 4, or recurrence up to day 8. The primary analysis was per protocol and we used a prespecified similarity margin of 5% to assess equivalence between regimens. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12610000286044. From April 4, 2011, to March 29, 2013, we enrolled 2333 infants aged 0–59 days with fast breathing as the only sign of possible serious bacterial infection at the five study sites. We assigned 1170 infants to receive injectable procaine benzylpenicillin–gentamicin and 1163 infants to receive oral amoxicillin. In the per-protocol analysis, from which 137 infants were excluded, we included 1061 (91%) infants who fulfilled predefined criteria of adherence to treatment and adequate follow-up in the injectable procaine benzylpenicillin–gentamicin group and 1145 (98%) infants in the oral amoxicillin group. In the procaine benzylpenicillin–gentamicin group, 234 infants (22%) failed treatment, compared with 221 (19%) infants in the oral amoxicillin group (risk difference −2·6%, 95% CI −6·0 to 0·8). Four infants died within 15 days of follow-up in each group. We detected no drug-related serious adverse events. Young infants with fast breathing alone can be effectively treated with oral amoxicillin on an outpatient basis when referral to a hospital is not possible. Bill & Melinda Gates Foundation grant to WHO.

Background Nigeria’s under-five health outcomes have improved over the years, but the mortality rates remain unacceptably high. The qualitative component of Nigeria’s 2019 verbal and social autopsy (VASA) showed that caregivers’ health beliefs about causes of illnesses and efficacious treatment options contribute to non-use/delay in use of facility-based healthcare for under-five children. This study explored how these health beliefs vary across zones and how they shape how caregivers seek healthcare for their under-five children. Methods Data for this study come from the qualitative component of the 2019 Nigeria VASA, comprising 69 interviews with caregivers of under-five children who died in the five-year period preceding the 2018 Nigeria Demographic and Health Survey (NDHS); and 24 key informants and 48 focus group discussions (FGDs) in 12 states, two from each of the six geo-political zones. The transcripts were coded using predetermined themes on health beliefs from the 2019 VASA (qualitative component) using NVivo. Results The study documented zonal variation in belief in traditional medicine, biomedicine, spiritual causation of illnesses, syncretism, and fatalism, with greater prevalence of beliefs discouraging use of facility-based healthcare in the southern zones. Driven by these beliefs and factors such as availability, affordability, and access to and perceived quality of care in health facilities, caregivers often choose one or a combination of traditional medicines, care from medicine vendors, and faith healing. Most use facility-based care as the last option when other methods fail. Conclusion Caregivers’ health beliefs vary by zones, and these beliefs influence when and whether they will use facility-based healthcare services for their under-five children. In Nigeria’s northern zones, health beliefs are less likely to deter caregivers from using facility-based healthcare services, but they face other barriers to accessing facility-based care. Interventions seeking to reduce under-five deaths in Nigeria need to consider subnational differences in caregivers’ health beliefs and the healthcare options they choose based on those beliefs.