Correction: Burden of disease and risk factors for mortality amongst hospitalized newborns in Nigeria and Kenya.

[This corrects the article DOI: 10.1371/journal.pone.0244109.].

Time to full enteral feeds in hospitalised preterm and very low birth weight infants in Nigeria and Kenya.

BACKGROUND: Preterm (born < 37 weeks' gestation) and very low birthweight (VLBW; <1.5kg) infants are at the greatest risk of morbidity and mortality within the first 28 days of life. Establishing full enteral feeds is a vital aspect of their clinical care. Evidence predominantly from high income countries shows that early and rapid advancement of feeds is safe and reduces length of hospital stay and adverse health outcomes. However, there are limited data on feeding practices and factors that influence the attainment of full enteral feeds among these vulnerable infants in sub-Saharan Africa. AIM: To identify factors that influence the time to full enteral feeds, defined as tolerance of 120ml/kg/day, in hospitalised preterm and VLBW infants in neonatal units in two sub-Saharan African countries. METHODS: Demographic and clinical variables were collected for newborns admitted to 7 neonatal units in Nigeria and Kenya over 6-months. Multiple linear regression analysis was conducted to identify factors independently associated with time to full enteral feeds. RESULTS: Of the 2280 newborn infants admitted, 484 were preterm and VLBW. Overall, 222/484 (45.8%) infants died with over half of the deaths (136/222; 61.7%) occurring before the first feed. The median (inter-quartile range) time to first feed was 46 (27, 72) hours of life and time to full enteral feeds (tFEF) was 8 (4.5,12) days with marked variation between neonatal units. Independent predictors of tFEF were time to first feed (unstandardised coefficient B 1.69; 95% CI 1.11 to 2.26; p value <0.001), gestational age (1.77; 0.72 to 2.81; <0.001), the occurrence of respiratory distress (-1.89; -3.50 to -0.79; <0.002) and necrotising enterocolitis (4.31; 1.00 to 7.62; <0.011). CONCLUSION: The use of standardised feeding guidelines may decrease variations in clinical practice, shorten tFEF and thereby improve preterm and VLBW outcomes.

Derivation and external validation of a clinical prognostic model identifying children at risk of death following presentation for diarrheal care.

Diarrhea continues to be a leading cause of death for children under-five. Amongst children treated for acute diarrhea, mortality risk remains elevated during and after acute medical management. Identification of those at highest risk would enable better targeting of interventions, but available prognostic tools lack validation. We used clinical and demographic data from the Global Enteric Multicenter Study (GEMS) to build clinical prognostic models (CPMs) to predict death (in-treatment, after discharge, or either) in children aged ≤59 months presenting with moderate-to-severe diarrhea (MSD), in Africa and Asia. We screened variables using random forests, and assessed predictive performance with random forest regression and logistic regression using repeated cross-validation. We used data from the Kilifi Health and Demographic Surveillance System (KHDSS) and Kilifi County Hospital (KCH) in Kenya to externally validate our GEMS-derived CPM. Of 8060 MSD cases, 43 (0.5%) children died in treatment and 122 (1.5% of remaining) died after discharge. MUAC at presentation, respiratory rate, age, temperature, number of days with diarrhea at presentation, number of people living in household, number of children <60 months old living in household, and how much the child had been offered to drink since diarrhea started were predictive of death both in treatment and after discharge. Using a parsimonious 2-variable prediction model, we achieved an area under the ROC curve (AUC) of 0.84 (95% CI: 0.82, 0.86) in the derivation dataset, and an AUC = 0.74 (95% CI 0.71, 0.77) in the external dataset. Our findings suggest it is possible to identify children most likely to die after presenting to care for acute diarrhea. This could represent a novel and cost-effective way to target resources for the prevention of childhood mortality.

Derivation and external validation of a clinical prognostic model identifying children at risk of death following presentation for diarrheal care.

Diarrhea continues to be a leading cause of death for children under-five. Amongst children treated for acute diarrhea, mortality risk remains elevated during and after acute medical management. Identification of those at highest risk would enable better targeting of interventions, but available prognostic tools lack validation. We used clinical and demographic data from the Global Enteric Multicenter Study (GEMS) to build predictive models for death (in-treatment, after discharge, or either) in children aged ≤59 months presenting with moderate-to-severe diarrhea (MSD), in Africa and Asia. We screened variables using random forests, and assessed predictive performance with random forest regression and logistic regression using repeated cross-validation. We used data from the Kilifi Health and Demographic Surveillance System (KHDSS) and Kilifi County Hospital (KCH) in Kenya to externally validate our GEMS-derived clinical prognostic model (CPM). Of 8060 MSD cases, 43 (0.5%) children died in treatment and 122 (1.5% of remaining) died after discharge. MUAC at presentation, respiratory rate, age, temperature, number of days with diarrhea at presentation, number of people living in household, number of children <60 months old living in household, and how much the child had been offered to drink since diarrhea started were predictive of death both in treatment and after discharge. Using a parsimonious 2-variable prediction model, we achieve an AUC=0.84 (95% CI: 0.82, 0.86) in the derivation dataset, and an AUC=0.74 (95% CI 0.71, 0.77) in the external dataset. Our findings suggest it is possible to identify children most likely to die after presenting to care for acute diarrhea. This could represent a novel and cost-effective way to target resources for the prevention of childhood mortality.

Trends in inpatient and post-discharge mortality among young infants admitted to Kilifi County Hospital, Kenya: a retrospective cohort study.

OBJECTIVES: To describe admission trends and estimate inpatient and post-discharge mortality and its associated exposures, among young infants (YI) admitted to a county hospital in Kenya. DESIGN: Retrospective cohort study. SETTING: Secondary level hospital. PARTICIPANTS: YI aged less than 60 days admitted to hospital from January 2009 to December 2019: 12 271 admissions in 11 877 individuals. YI who were resident within a Kilifi Health and Demographic Surveillance System (KHDSS): n=3625 with 4421 admissions were followed-up for 1 year after discharge. PRIMARY AND SECONDARY OUTCOME MEASURES: Inpatient and 1-year post-discharge mortality, the latter in KHDSS residents. RESULTS: Of 12 271 YI admissions, 4421 (36%) were KHDSS-resident. Neonatal sepsis, preterm complications and birth asphyxia accounted for 83% of the admissions. The proportion of YI among under-5s admissions increased from 19% in 2009 to 34% in 2019 (Ptrend=0.02). Inpatient case fatality was 16%, with 66% of the deaths occurring within 48 hours of admission. The introduction of free maternity care in 2013 was not associated with a change in admissions or inpatient mortality among YI. During 1-year post-discharge, 208/3625 (5.7%) YI died, 64.3 (95% CI 56.2 to 73.7) per 1000 infant-years. 49% of the post-discharge deaths occurred within 1 month of discharge, and 49% of post-discharge deaths occurred at home. Both inpatient and post-discharge deaths were associated with low admission weight. Inpatient mortality was associated with clinical signs of disease severity, while post-discharge mortality was associated with the length of hospitalisation, leaving against advice and referral to a specialised hospital. CONCLUSIONS: YIs accounted for an increasing proportion of paediatric admissions and their overall mortality remains high. Post-discharge mortality accounts for a lower proportion of deaths but mortality rate is higher than among children aged 2-59 months. Services to address post-discharge mortality are needed and should focus on infants at higher risk.

Enteral Feeding Practices for Very Preterm and Very Low Birth Weight Infants in Nigeria and Kenya.

Background: Optimizing nutrition in very preterm (28-32 weeks gestation) and very low birth weight (VLBW; 1,000 g to <1,500 g) infants has potential to improve their survival, growth, and long-term health outcomes. Aim: To assess feeding practices in Nigeria and Kenya for very preterm and VLBW newborn infants. Methods: This was a cross-sectional study where convenience sampling was used. A standard questionnaire was sent to doctors working in neonatal units in Nigeria and Kenya. Results: Of 50 respondents, 37 (74.0%) were from Nigeria and 13 (26.0%) from Kenya. All initiated enteral feeds with breastmilk, with 24 (48.0%) initiating within 24 h. Only 28 (56.0%) used written feeding guidelines. Starting volumes ranged between 10 and 80 ml/kg/day. Median volume advancement of feeds was 20 ml/kg/day (IQR 10-20) with infants reaching full feeds in 8 days (IQR 6-12). 26 (52.0%) of the units fed the infants 2 hourly. Breastmilk fortification was practiced in 7 (14.0%) units, while folate, iron, calcium, and phosphorus were prescribed in 42 (84.0%), 36 (72.0%), 22 (44.0%), 5 (10.0%) of these units, respectively. No unit had access to donor breastmilk, and only 18 (36.0%) had storage facilities for expressed breastmilk. Twelve (24.0%) used wet nurses whilst 30 (60.0%) used formula feeds. Conclusion: Feeding practices for very preterm and VLBW infants vary widely within Nigeria and Kenya, likely because of lack of locally generated evidence. High quality research that informs the feeding of these infants in the context of limited human resources, technology, and consumables, is urgently needed.

Prospective observational study of the challenges in diagnosing common neonatal conditions in Nigeria and Kenya.

OBJECTIVES: Accurate and timely diagnosis of common neonatal conditions is crucial for reducing neonatal deaths. In low/middle-income countries with limited resources, there is sparse information on how neonatal diagnoses are made. The aim of this study was to describe the diagnostic criteria used for common conditions in neonatal units (NNUs) in Nigeria and Kenya. DESIGN: Prospective observational study. Standard case report forms for suspected sepsis, respiratory disorders, birth asphyxia and abdominal conditions were co-developed by the Neonatal Nutrition Network (https://www.lstmed.ac.uk/nnu) collaborators. Clinicians completed forms for all admissions to their NNUs. Key data were displayed using heatmaps. SETTING: Five NNUs in Nigeria and two in Kenya comprising the Neonatal Nutrition Network. PARTICIPANTS: 2851 neonates, which included all neonates admitted to the seven NNUs over a 6-month period. RESULTS: 1230 (43.1%) neonates had suspected sepsis, 874 (30.6%) respiratory conditions, 587 (20.6%) birth asphyxia and 71 (2.5%) abdominal conditions. For all conditions and across all NNUs, clinical criteria were used consistently with sparse use of laboratory and radiological criteria. CONCLUSION: Our findings highlight the reliance on clinical criteria and extremely limited use of diagnostic technologies for common conditions in NNUs in sub-Saharan Africa. This has implications for the management of neonatal conditions which often have overlapping clinical features. Strategies for implementation of diagnostic pathways and investment in affordable and sustainable diagnostics are needed to improve care for these vulnerable infants.

Burden of disease and risk factors for mortality amongst hospitalized newborns in Nigeria and Kenya.

OBJECTIVE: To describe the patient population, priority diseases and outcomes in newborns admitted <48 hours old to neonatal units in both Kenya and Nigeria. STUDY DESIGN: In a network of seven secondary and tertiary level neonatal units in Nigeria and Kenya, we captured anonymised data on all admissions <48 hours of age over a 6-month period. RESULTS: 2280 newborns were admitted. Mean birthweight was 2.3 kg (SD 0.9); 57.0% (1214/2128) infants were low birthweight (LBW; <2.5kg) and 22.6% (480/2128) were very LBW (VLBW; <1.5 kg). Median gestation was 36 weeks (interquartile range 32, 39) and 21.6% (483/2236) infants were very preterm (gestation <32 weeks). The most common morbidities were jaundice (987/2262, 43.6%), suspected sepsis (955/2280, 41.9%), respiratory conditions (817/2280, 35.8%) and birth asphyxia (547/2280, 24.0%). 18.7% (423/2262) newborns died; mortality was very high amongst VLBW (222/472, 47%) and very preterm infants (197/483, 40.8%). Factors independently associated with mortality were gestation <28 weeks (adjusted odds ratio 11.58; 95% confidence interval 4.73-28.39), VLBW (6.92; 4.06-11.79), congenital anomaly (4.93; 2.42-10.05), abdominal condition (2.86; 1.40-5.83), birth asphyxia (2.44; 1.52-3.92), respiratory condition (1.46; 1.08-2.28) and maternal antibiotics within 24 hours before or after birth (1.91; 1.28-2.85). Mortality was reduced if mothers received a partial (0.51; 0.28-0.93) or full treatment course (0.44; 0.21-0.92) of dexamethasone before preterm delivery. CONCLUSION: Greater efforts are needed to address the very high burden of illnesses and mortality in hospitalized newborns in sub-Saharan Africa. Interventions need to address priority issues during pregnancy and delivery as well as in the newborn.

Evidence that informs feeding practices in very low birthweight and very preterm infants in sub-Saharan Africa: an overview of systematic reviews.

BACKGROUND: Optimal feeding of very low birthweight (VLBW <1500 g)/very preterm (gestation <32 weeks) infants in resource-limited settings in sub-Saharan Africa (sSA) is critical to reducing high mortality and poor outcomes. OBJECTIVE: To review evidence on feeding of VLBW/very preterm infants relevant to sSA. METHODS: We searched the Cochrane Database of Systematic Reviews, Embase, PubMed and Cumulative Index to Nursing and Allied Health Literature (CINAHL) from inception to July 2019 to identify reviews of randomised and quasi-randomised controlled trials of feeding VLBW/very preterm infants. We focused on interventions that are readily available in sSA. Primary outcomes were weight gain during hospital stay and time to achieve full enteral feeds (120 mL/kg/day). Secondary outcomes were growth, common morbidities, mortality, duration of hospital stay and cognitive development. Quality of evidence (QOE) was assessed using the Measurement Tool to Assess Systematic Reviews (AMSTAR2). RESULTS: Eight systematic reviews were included. Higher feed volume of day 1 (80 mL/kg) reduced late-onset sepsis and time to full enteral feeds, and higher feed volume (up to 300 mL/kg/day) improved weight gain without adverse events (QOE: low-moderate). Rapid advancement of feeds (30-40 mL/kg/day) was not associated with harm. Breast milk fortification with energy and protein increased growth and with prebiotics increased growth and reduced duration of admission (QOE: low-very low) and did not result in harm. Evidence regarding feeding tube placement and continuous versus bolus feeds was insufficient to draw conclusions. We found no reviews meeting our selection criteria regarding when to start feeds, use of preterm formula, cup-and-spoon feeding or gravity versus push feeds and none of the reviews included trials from low-income countries of sSA. CONCLUSIONS: The evidence base informing feeding of VLBW/very preterm babies in resource-limited settings in sSA is extremely limited. Pragmatic studies are needed to generate evidence to guide management and improve outcomes for these highly vulnerable infants. PROSPERO REGISTRATION NUMBER: CRD42019140204.

Exclusive breastfeeding in first-time mothers in rural Kenya: a longitudinal observational study of feeding patterns in the first six months of life.

BACKGROUND: Exclusive breastfeeding up to 6 months of age is recommended by the World Health Organization as the optimal mode of infant feeding, providing adequate nutrition for the baby and protection against infectious diseases. Breastfeeding can be adversely affected by individual, cultural and socio-economic factors. The study aimed to explore barriers of exclusive breastfeeding in the first 6 months of life among first-time mothers in rural Kenya. METHODS: An observational longitudinal design aimed to provide rich data on breastfeeding behaviour. Twenty pregnant first-time mothers were recruited through antenatal clinics and snowballing. Mothers were visited nine times at home from late pregnancy, at 1 week and 2 weeks post-delivery, then monthly until the baby was aged 6 months. Visits were conducted between November 2016 and April 2018. At the first visit, participants were asked about breastfeeding intentions and infant feeding education received. At each postnatal visit, direct observation of breastfeeding, a recorded semi-structured interview on feeding, mother's and baby's health was performed. Interviews were transcribed, checked, content was grouped into categories and analyzed using a qualitative descriptive approach. RESULTS: Most participants were adolescent (75%) and unmarried (65%). All 20 mothers intended to and did breastfeed, however additional fluids and semi-solids were commonly given. Only two mothers exclusively breastfed from birth up to 6 months of age. Prelacteal feeds, home remedies and traditional medicine were given by over a third of mothers in the first week of life. Concern over babies' bowel habits and persistent crying perceived as abdominal colic led to several mothers receiving advice to give gripe water and traditional remedies. Early introduction of maize porridge from 3 months of age because of perceived hunger of the child was recommended by other family members. Breastfeeding observation showed persistent problems with positioning and attachment of infants. CONCLUSIONS: Exclusive breastfeeding from birth to 6 months was uncommon. Prioritization of capacity to detect mothers with breastfeeding problems and provide breastfeeding education and support is necessary, particularly during the antenatal and early postnatal period. It is important to engage with other women resident in the household who may offer conflicting feeding advice.

Individualized breastfeeding support for acutely ill, malnourished infants under 6 months old.

Reestablishing exclusive breastfeeding is the cornerstone of the 2013 World Health Organization (WHO) treatment guidelines for acute malnutrition in infants less than 6 months. However, no studies have investigated guideline implementation and subsequent outcomes in a public hospital setting in Africa. To facilitate implementation of the WHO 2013 guidelines in Kilifi County Hospital, Kenya, we developed standard operating procedure, recruited, and trained three breastfeeding peer supporters (BFPS). Between September 2016 and January 2018, the BFPS provided individual breastfeeding support to mothers of infants aged 4 weeks to 4 months admitted to Kilifi County Hospital with an illness and acute malnutrition (mid-upper-arm circumference < 11.0 cm OR weight-for-age z score < -2 OR weight-for-length z score < -2). Infants were followed daily while in hospital then every 2 weeks for 6 weeks after discharge with data collected on breastfeeding, infant growth, morbidity, and mortality. Of 106 infants with acute malnutrition at admission, 51 met the inclusion criteria for the study. Most enrolled mothers had multiple breastfeeding challenges, which were predominantly technique based. Exclusive breastfeeding was 55% at admission and 81% at discharge; at discharge 67% of infants had attained a weight velocity of >5 g/kg/day for three consecutive days on breastmilk alone. Gains in weight-for-length z score and weight-for-age z score were generally not sustained beyond 2 weeks after discharge. BFPS operated effectively in an inpatient setting, applying the 2013 updated WHO guidelines and increasing rates of exclusive breastfeeding at discharge. However, lack of continued increase in anthropometric Z scores after discharge suggests the need for more sustained interventions.

Mortality after inpatient treatment for diarrhea in children: a cohort study.

BACKGROUND: There is an increasing recognition that children remain at elevated risk of death following discharge from health facilities in resource-poor settings. Diarrhea has previously been highlighted as a risk factor for post-discharge mortality. METHODS: A retrospective cohort study was conducted to estimate the incidence and demographic, clinical, and biochemical features associated with inpatient and 1-year post-discharge mortality amongst children aged 2-59 months admitted with diarrhea from 2007 to 2015 at Kilifi County Hospital and who were residents of Kilifi Health and Demographic Surveillance System (KHDSS). Log-binomial regression was used to identify risk factors for inpatient mortality. Time at risk was from the date of discharge to the date of death, out-migration, or 365 days later. Post-discharge mortality rate was computed per 1000 child-years of observation, and Cox proportion regression used to identify risk factors for mortality. RESULTS: Two thousand six hundred twenty-six child KHDSS residents were admitted with diarrhea, median age 13 (IQR 8-21) months, of which 415 (16%) were severely malnourished and 130 (5.0%) had a positive HIV test. One hundred twenty-one (4.6%) died in the hospital, and of 2505 children discharged alive, 49 (2.1%) died after discharge: 21.4 (95% CI 16.1-28.3) deaths per 1000 child-years. Admission with signs of both diarrhea and severe pneumonia or severe pneumonia alone had a higher risk of both inpatient and post-discharge mortality than admission for diarrhea alone. There was no significant difference in inpatient and post-discharge mortality between children admitted with diarrhea alone and those with other diagnoses excluding severe pneumonia. HIV, low mid-upper arm circumference (MUAC), and bacteremia were associated with both inpatient and post-discharge mortality. Signs of circulatory impairment, sepsis, and abnormal electrolytes were associated with inpatient but not post-discharge mortality. Prior admission and lower chest wall indrawing were associated with post-discharge mortality but not inpatient mortality. Age, stuntedness, and persistent or bloody diarrhea were not associated with mortality before or after discharge. CONCLUSIONS: Our results accentuate the need for research to improve the uptake and outcomes of services for malnutrition and HIV as well as to elucidate causal pathways and test interventions to mitigate these risks.

Knowledge of, and attitudes to giving expressed breastmilk to infants in rural coastal Kenya; focus group discussions of first time mothers and their advisers.

BACKGROUND: The World Health Organization (WHO)/UNICEF Baby-Friendly Hospital Initiative step number five of the "Ten steps to successful breastfeeding" states "Show mothers how to breastfeed and how to maintain lactation even if they should be separated from their infants." Urban mothers in Nairobi have low rates of exclusive breastfeeding after returning to work but there are no published data on rural Kenya mothers' infant feeding practices when working or schooling away from home. METHODS: We explored knowledge of, and attitudes to, the practice of giving expressed breastmilk in a mixed methods observational study of breastfeeding in rural Kenyan mothers. Fifty mothers with newborns, identified by nurses and community health workers, were asked questions about their experiences of breastfeeding and who they had sought or received advice from on breastfeeding. Focus group discussions, one with community health workers, and four each with mothers and their named advisers were held. Recordings were analyzed using a thematic framework approach. RESULTS: The main themes were: the baby's right to feed from the breast, lack of knowledge about expressing and giving breastmilk, negative attitudes towards expressed breastmilk, and traditional customs for disposing of expressed breast milk. Most participants did not have any experience of giving expressed breastmilk to infants. They described practices of expressing and discarding milk when the mother or baby was ill, to relieve discomfort from engorgement or after the baby had died. CONCLUSIONS: Feeding expressed breastmilk to infants is a new concept in this context. Promotion of, and training in this practice would help mothers to maintain their milk supply when away from their babies and benefit the infants of working and schoolgirl mothers.

"When you give birth you will not be without your mother" A mixed methods study of advice on breastfeeding for first-time mothers in rural coastal Kenya.

BACKGROUND: Exclusive breastfeeding for the first 6 months of life is currently recommended by the World Health Organization, but mixed feeding earlier than this commonly occurs in rural coastal Kenya. Mothers may receive conflicting advice on breastfeeding from various sources including health workers, relatives and community members. We aimed to find out how first-time mothers learn to breastfeed, who advises them on infant feeding and what advice they obtain in case of any breastfeeding problems. METHODS: To identify advisers, a questionnaire on socio-demographic status, place of delivery, household members, education and help received on breastfeeding, breastfeeding problems, name of advisers and their relationship to the mothers was administered to 50 new first-time mothers in Jaribuni, Kilifi (population approximately 18,000). Summary statistics were obtained using frequencies, medians and interquartile ranges (IQR). Focus group discussions (FGDs) were held amongst 4 groups of mothers who had answered questionnaires; 4 groups of their named advisers; and 1 group of community health workers in order to explore breastfeeding practices, problems and advice given. FGDs were analysed by thematic framework analysis. RESULTS: First-time mothers were young (median age 18, IQR 17-21, range 14-26 years) and 42 % were single. Living in extended families was the norm and married women lived with their husband's family. All had a female family member or neighbour helping with childcare in the perinatal period. The main advisers on breastfeeding were their mother or older female members of their husband's family. Married first-time mothers felt obliged to follow their mother-in-law's advice to maintain good relationships and show respect within the household. Breastfeeding problems were reported by 80 % of respondents. Nipple pain (56 %) was the most reported problem, then breast engorgement (48 %) and insufficient milk supply (38 %). Most problems were treated at home without consultation with health workers. Concerns were raised about co-sleeping, breastfeeding whilst lying down, and insufficient milk supply. Advisers would like more information on breastfeeding in order to help mothers. CONCLUSIONS: Interventions to increase knowledge of, and facilitate optimal breastfeeding practices in first-time mothers should include those family members who advise and assist with childcare around the time of delivery.

Ready-to-use therapeutic food with elevated n-3 polyunsaturated fatty acid content, with or without fish oil, to treat severe acute malnutrition: a randomized controlled trial.

BACKGROUND: Ready-to-use therapeutic foods (RUTF) are lipid-based pastes widely used in the treatment of acute malnutrition. Current specifications for RUTF permit a high n-6 polyunsaturated fatty acid (PUFA) content and low n-3 PUFA, with no stipulated requirements for preformed long-chain n-3 PUFA. The objective of this study was to develop an RUTF with elevated short-chain n-3 PUFA and measure its impact, with and without fish oil supplementation, on children's PUFA status during treatment of severe acute malnutrition. METHODS: This randomized controlled trial in children with severe acute malnutrition in rural Kenya included 60 children aged 6 to 50 months who were randomized to receive i) RUTF with standard composition; ii) RUTF with elevated short chain n-3 PUFA; or iii) RUTF with elevated short chain n-3 PUFA plus fish oil capsules. Participants were followed-up for 3 months. The primary outcome was erythrocyte PUFA composition. RESULTS: Erythrocyte docosahexaenoic acid (DHA) content declined from baseline in the two arms not receiving fish oil. Erythrocyte long-chain n-3 PUFA content following treatment was significantly higher for participants in the arm receiving fish oil than for those in the arms receiving RUTF with elevated short chain n-3 PUFA or standard RUTF alone: 3 months after enrollment, DHA content was 6.3% (interquartile range 6.0-7.3), 4.5% (3.9-4.9), and 3.9% (2.4-5.7) of total erythrocyte fatty acids (P <0.001), respectively, while eicosapentaenoic acid (EPA) content was 2.0% (1.5-2.6), 0.7% (0.6-0.8), and 0.4% (0.3-0.5) (P <0.001). RUTF with elevated short chain n-3 PUFA and fish oil capsules were acceptable to participants and carers, and there were no significant differences in safety outcomes. CONCLUSIONS: PUFA requirements of children with SAM are not met by current formulations of RUTF, or by an RUTF with elevated short-chain n-3 PUFA without additional preformed long-chain n-3 PUFA. Clinical and growth implications of revised formulations need to be addressed in large clinical trials. TRIAL REGISTRATION: Clinicaltrials.gov NCT01593969. Registered 4 May 2012.

Endotoxaemia is common in children with Plasmodium falciparum malaria.

BACKGROUND: Children presenting to hospital with recent or current Plasmodium falciparum malaria are at increased the risk of invasive bacterial disease, largely enteric gram-negative organisms (ENGO), which is associated with increased mortality and recurrent morbidity. Although incompletely understood, the most likely source of EGNO is the bowel. We hypothesised that as a result of impaired gut-barrier function endotoxin (lipopolysaccharide), present in the cell-wall of EGNO and in substantial quantities in the gut, is translocated into the bloodstream, and contributes to the pathophysiology of children with severe malaria. METHODS: We conducted a prospective study in 257 children presenting with malaria to two hospitals in Kenya and Uganda. We analysed the clinical presentation, endotoxin and cytokine concentration. RESULTS: Endotoxaemia (endotoxin activity ≥0.4 EAA Units) was observed in 71 (27.6%) children but its presence was independent of both disease severity and outcome. Endotoxaemia was more frequent in children with severe anaemia but not specifically associated with other complications of malaria. Endotoxaemia was associated with a depressed inflammatory and anti-inflammatory cytokine response. Plasma endotoxin levels in severe malaria negatively correlated with IL6, IL10 and TGFß (Spearman rho: TNFα: r=-0.122, p=0.121; IL6: r=-0.330, p<0.0001; IL10: r=-0.461, p<0.0001; TGFß: r=-0.173, p<0.027). CONCLUSIONS: Endotoxaemia is common in malaria and results in temporary immune paralysis, similar to that observed in patients with sepsis and experimentally-induced endotoxaemia. Intense sequestration of P. falciparum-infected erythrocytes within the endothelial bed of the gut has been observed in pathological studies and may lead to gut-barrier dysfuction. The association of endotoxaemia with the anaemia phenotype implies that it may contribute to the dyserythropoesis accompanying malaria through inflammation. Both of these factors feasibly underpin the susceptibility to EGNO co-infection. Further research is required to investigate this initial finding, with a view to future treatment trials targeting mechanism and appropriate antimicrobial treatment.

Diarrhoea complicating severe acute malnutrition in Kenyan children: a prospective descriptive study of risk factors and outcome.

BACKGROUND: Severe acute malnutrition (SAM) accounts for two million deaths worldwide annually. In those hospitalised with SAM, concomitant infections and diarrhoea are frequent complications resulting in adverse outcome. We examined the clinical and laboratory features on admission and outcome of children with SAM and diarrhoea at a Kenyan district hospital. METHODS: A 4-year prospective descriptive study involving 1,206 children aged 6 months to 12 years, hospitalized with SAM and managed in accordance with WHO guidelines. Data on clinical features, haematological, biochemical and microbiological findings for children with diarrhoea (≥ 3 watery stools/day) were systematically collected and analyzed to identify risk factors associated with poor outcome. RESULTS: At admission 592 children (49%) had diarrhoea of which 122 (21%) died compared to 72/614 (12%) deaths in those without diarrhoea at admission (Χ(2) = 17.6 p<0.001). A further 187 (16%) children developed diarrhoea after 48 hours of admission and 33 died (18%). Any diarrhoea during admission resulted in a significantly higher mortality 161/852 (19%) than those uncomplicated by diarrhoea 33/351 (9%) (Χ(2) = 16.6 p<0.001). Features associated with a fatal outcome in children presenting with diarrhoea included bacteraemia, hyponatraemia, low mid-upper arm circumference <10 cm, hypoxia, hypokalaemia and oedema. Bacteraemia had the highest risk of death (adjusted OR 6.1; 95% C.I 2.3, 16.3 p<0.001); and complicated 24 (20%) of fatalities. Positive HIV antibody status was more frequent in cases with diarrhoea at admission (23%) than those without (15%, Χ(2) = 12.0 p = 0.001) but did not increase the risk of death in diarrhoea cases. CONCLUSION: Children with SAM complicated by diarrhoea had a higher risk of death than those who did not have diarrhoea during their hospital stay. Further operational and clinical research is needed to reduce mortality in children with SAM in the given setting.

Clinical indicators of bacterial meningitis among neonates and young infants in rural Kenya.

BACKGROUND: Meningitis is notoriously difficult to diagnose in infancy because its clinical features are non-specific. World Health Organization (WHO) guidelines suggest several indicative signs, based on limited data. We aimed to identify indicators of bacterial meningitis in young infants in Kenya, and compared their performance to the WHO guidelines. We also examined the feasibility of developing a scoring system for meningitis. METHODS: We studied all admissions aged < 60 days to Kilifi District Hospital, 2001 through 2005. We evaluated clinical indicators against microbiological findings using likelihood ratios. We prospectively validated our findings 2006 through 2007. RESULTS: We studied 2,411 and 1,512 young infants during the derivation and validation periods respectively. During derivation, 31/1,031 (3.0%) neonates aged < 7 days and 67/1,380 (4.8%) young infants aged 7-59 days (p < 0.001) had meningitis. 90% of cases could be diagnosed macroscopically (turbidity) or by microscopic leukocyte counting. Independent indicators of meningitis were: fever, convulsions, irritability, bulging fontanel and temperature ≥ 39°C. Areas under the receiver operating characteristic curve in the validation period were 0.62 [95%CI: 0.49-0.75] age < 7 days and 0.76 [95%CI: 0.68-0.85] thereafter (P = 0.07), and using the WHO signs, 0.50 [95%CI 0.35-0.65] age < 7 days and 0.82 [95%CI: 0.75-0.89] thereafter (P = 0.0001). The number needed to LP to identify one case was 21 [95%CI: 15-35] for our signs, and 28 [95%CI: 18-61] for WHO signs. With a scoring system, a cut-off of ≥ 1 sign offered the best compromise on sensitivity and specificity. CONCLUSION: Simple clinical signs at admission identify two thirds of meningitis cases in neonates and young infants. Lumbar puncture is essential to diagnosis and avoidance of unnecessary treatment, and is worthwhile without CSF biochemistry or bacterial culture. The signs of Meningitis suggested by the WHO perform poorly in the first week of life. A scoring system for meningitis in this age group is not helpful.

Congenital and neonatal malaria in a rural Kenyan district hospital: an eight-year analysis.

BACKGROUND: Malaria remains a significant burden in sub-Saharan Africa. However, data on burden of congenital and neonatal malaria is scarce and contradictory, with some recent studies reporting a high burden. Using prospectively collected data on neonatal admissions to a rural district hospital in a region of stable malaria endemicity in Kenya, the prevalence of congenital and neonatal malaria was described. METHODS: From 1st January 2002 to 31st December 2009, admission and discharge information on all neonates admitted to Kilifi District Hospital was collected. At admission, blood was also drawn for routine investigations, which included a full blood count, blood culture and blood slide for malaria parasites. RESULTS: Of the 5,114 neonates admitted during the eight-year surveillance period, blood slide for malaria parasites was performed in 4,790 (93.7%). 18 (0.35%) neonates with Plasmodium falciparum malaria parasitaemia, of whom 11 were admitted within the first week of life and thus classified as congenital parasitaemia, were identified. 7/18 (39%) had fever. Parasite densities were low, ≤50 per µl in 14 cases. The presence of parasitaemia was associated with low haemoglobin (Hb) of <10 g/dl (χ² 10.9 P = 0.001). The case fatality rate of those with and without parasitaemia was similar. Plasmodium falciparum parasitaemia was identified as the cause of symptoms in four neonates. CONCLUSION: Congenital and neonatal malaria are rare in this malaria endemic region. Performing a blood slide for malaria parasites among sick neonates in malaria endemic regions is advisable. This study does not support routine treatment with anti-malarial drugs among admitted neonates with or without fever even in a malaria endemic region.

Invasive bacterial infections in neonates and young infants born outside hospital admitted to a rural hospital in Kenya.

BACKGROUND: Bacterial sepsis is thought to be a major cause of young infant deaths in low-income countries, but there are few precise estimates of its burden or causes. We studied invasive bacterial infections (IBIs) in young infants, born at home or in first-level health units ("outborn") who were admitted to a Kenyan rural district hospital during an 8-year period. METHODS: Clinical and microbiologic data, from admission blood cultures and cerebrospinal fluid cultures on all outborn infants aged less than 60 days admitted from 2001 to 2009, were examined to determine etiology of IBI and antimicrobial susceptibilities. RESULTS: Of the 4467 outborn young infants admitted, 748 (17%) died. Five hundred five (11%) had IBI (10% bacteremia and 3% bacterial meningitis), with a case fatality of 33%. The commonest organisms were Klebsiella spp., Staphylococcus aureus, Streptococcus pneumoniae, Group B Streptococcus, Acinetobacter spp., Escherichia coli, and Group A Streptococcus. Notably, some blood culture isolates were seen in outborn neonates in the first week of life but not in inborns: Salmonella, Aeromonas, and Vibrio spp. Eighty-one percent of isolates were susceptible to penicillin and/or gentamicin and 84% to ampicillin and/or gentamicin. There was a trend to increasing in vitro antimicrobial resistance to these combinations from 2008 but without a worse outcome. CONCLUSIONS: IBI is common in outborn young infants admitted to rural African hospitals with a high mortality. Presumptive antimicrobial use is justified for all young infants admitted to the hospital.