Professor James A Berkley

Research Area: Global Health
Technology Exchange: Medical statistics
Scientific Themes: Tropical Medicine & Global Health and Clinical Trials & Epidemiology
Keywords: Epidemiology, clinical trials, malnutrition, infection, inflammation, perinatal, Africa, Antimicrobials, Antimicrobial Resistance, Severe Acute Malnutrition, Randomised Clinical Trial, Neonatal sepsis and Kilifi
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My research career has primarily been within the KEMRI/Wellcome Trust Research Programme in Kilifi, Kenya. My early research career focussed on large epidemiological studies addressing the aetiology, clinical features and risks for mortality of serious infections in infants and children. Major achievements include the largest and most comprehensive study of invasive bacterial infection worldwide; the first comprehensive study of viral causes of pneumonia in Africa; and studies identifying risks for failing pneumonia treatment; diagnostic strategies for meningitis and the performance of clinical syndromes in targeting of antimicrobial treatment. These have been major contributors to the introduction of conjugate vaccines in Africa, and have directly informed WHO and national management guidelines.

The main focus of my research group is serious infection and survival in highly vulnerable groups of infants and children in Africa:

Malnutrition, infection & survival

We recently completed a large multicentre randomised clinical trial of long-term daily antimicrobial prophylaxis to prevent mortality in severely malnourished children; and several proof-of principle trials of gut immunomodulation in growth failure, and polyunsaturated fatty acids within therapeutic feeds for severe malnutrition.

Ongoing, is a large multicentre trial in Kenya and Uganda is examining alternative first-line antimicrobials in severely malnourished children to prevent mortality (FLACSAM). In phase I, we are determining pharmacokinetics in malnourished children, and the presence and acquisition of ESBL and other forms of antimicrobial resistance influencing antimicrobial choices. Phase II examines efficacy on mortality, nutritional recovery, costs to health services and families, and consequences of antimicrobial resistance. Funding is by the MRC/DfID/Wellcome Global Health Trials scheme.

Work on inflammatory activation and functional immune responses to ex vivo pathogen challenge in severely malnourished children is ongoing (Kelsey Jones Wellcome fellowship).

A longitudinal birth cohort is ongoing to study the onset of environmental enteric dysfunction and small intestinal bacterial overgrowth in relation to mode of feeding, acquisition of intestinal pathogens, diarrhoea episodes and antimicrobial usage is ongoing (Rosie Crane Wellcome fellowship)

We are using spatial and temporal Bayesian models to examine proximate and environmental determinants of malnutrition in Kenya on a national scale to maps how determinants may differ in different places (e.g. rural/urban), in collaboration with UNICEF. Funded by Wellcome.

CHAIN: the Childhood Acute Illness & Nutrition Network

I am the Director of the CHAIN Network studying acute illness and recovery in relation to nutritional status at sites in Africa and South Asia. CHAIN aims to better understand infectious, immune, metabolic, nutritional and social factors that could be modified to reduce mortality in hospital and after discharge amongst the most vulnerable children under 2 years old. CHAIN is funded by the Bill & Melinda Gates Foundation and is in collaboration with the University of Washington.

Neonates and infants in resource-poor settings

The Kilifi Perinatal and Maternal Health (KIPMAT) study is examining background, maternal and delivery-associated risk factors for adverse birth outcomes and neonatal infection. KIPMAT has built detailed surveillance into routine maternity care pathways in Kilifi and provides the umbrella for several studies.

A major focus of the group is invasive newborn infection. We recently completed the largest study of the clinical and molecular epidemiology of group B Streptococcus (GBS) carriage and invasive disease across different demographies, providing insight into the evolution of GBS with socio-economic development and informing vaccine design (Anna Seale WT fellowship). We are currently collaborating with the University of Witwatersrand on an international network on GBS, leading up to maternal vaccine trials.  

Following our studies using conventional microbiology, we are now investigating the aetiology of neonatal sepsis in the first 48 hours of life using multiplex molecular methods, taking advantage of surveillance and archived maternal and cord from KIPMAT. Funded by WHO/TDR.

In development are studies of legacy and novel antimicrobial regimens to treat community or hospital acquired neonatal sepsis. This will involve PK studies, re-evaluating the MIC of archived bacterial isolates to alternative antimicrobial combinations, and substantive clinical trials.

On breastfeeding, a pilot trial is ongoing which exploits approaches known to be successful in neonates to optimize the lactation for infants under 6 months old with acute malnutrition. We will determine determine if exclusive breastfeeding can be attained and retained after discharge; and if breastmilk alone is sufficient for recovery of acutely malnourished infants. Funding is from a MRC/DfID/Wellcome Global Health Trials trial development grant (Martha Mwangome). Other work on breastfeeding is investigating the roles of families and community peers in influencing breastfeeding and complimentary feeding in the community.

 

Name Department Institution Country
Associate Professor Judd Walson Global Health University of Washington United States
Associate Professor Robert H Bandsma Division of Gastroenterology, Hepatology, and Nutrition University of Toronto Canada
Professor Holm Uhlig Experimental Medicine Division Oxford University, John Radcliffe Hospital United Kingdom
Professor Mike English Tropical Medicine Oxford University, Nairobi Kenya
Professor Kathryn Maitland Imperial College Kenya
Dr Anna C Seale London School of Hygiene & Tropical Medicine United Kingdom
Professor Andrew Prentice London School of Hygiene and Tropical Medicine United Kingdom
Prof Stephen Kennedy (MPLS) Oxford University,
Dr Mohammed J Chisti Clinical Research International Centre for Diarrhoeal Disease Research, Bangladesh Bangladesh
Associate Professor Christina Lancioni Department of Pediatrics Oregon Health & Science University United States
Dr Ali Saleem Aga Khan University Pakistan
Wieger Voskuijl Paediatrics College of Medicine, Blantyre Malawi
Dr Ezekiel Mupere Departament of Paediatrics and Child Health Makerere University, Kampala, Uganda Uganda
Dr Etienne de Villiers Tropical Medicine Oxford University, Kilifi Kenya
Dr George M Warimwe MRCVS Tropical Medicine Oxford University, Kilifi Kenya
Professor (Ann) Sarah Walker Experimental Medicine Division Oxford University, John Radcliffe Hospital United Kingdom
Professor Catherine (Sassy) Molyneux Tropical Medicine Oxford University, Kilifi Kenya
Professor Caroline Jones Tropical Medicine Oxford University, Kilifi Kenya
Professor Vicki Marsh Tropical Medicine Oxford University, Kilifi Kenya
Dr Abdisalan Noor Tropical Medicine Oxford University, Nairobi Kenya
Professor Derrick Crook Experimental Medicine Division Oxford University, John Radcliffe Hospital United Kingdom
Professor Samuel Kariuki Tropical Medicine Oxford University, Nairobi Kenya
Associate Professor Maureen Kelley Ethox Centre in the Nuffield Department of Population Health University of Oxford United Kingdom
Seale AC, Blencowe H, Bianchi-Jassir F, Embleton N, Bassat Q, Ordi J, Menéndez C, Cutland C, Briner C, Berkley JA et al. 2017. Stillbirth With Group B Streptococcus Disease Worldwide: Systematic Review and Meta-analyses. Clin Infect Dis, 65 (suppl_2), pp. S125-S132. | Show Abstract | Read more

Background: There are an estimated 2.6 million stillbirths each year, many of which are due to infections, especially in low- and middle-income contexts. This paper, the eighth in a series on the burden of group B streptococcal (GBS) disease, aims to estimate the percentage of stillbirths associated with GBS disease. Methods: We conducted systematic literature reviews (PubMed/Medline, Embase, Literatura Latino-Americana e do Caribe em Ciências da Saúde, World Health Organization Library Information System, and Scopus) and sought unpublished data from investigator groups. Studies were included if they reported original data on stillbirths (predominantly ≥28 weeks' gestation or ≥1000 g, with GBS isolated from a sterile site) as a percentage of total stillbirths. We did meta-analyses to derive pooled estimates of the percentage of GBS-associated stillbirths, regionally and worldwide for recent datasets. Results: We included 14 studies from any period, 5 with recent data (after 2000). There were no data from Asia. We estimated that 1% (95% confidence interval [CI], 0-2%) of all stillbirths in developed countries and 4% (95% CI, 2%-6%) in Africa were associated with GBS. Conclusions: GBS is likely an important cause of stillbirth, especially in Africa. However, data are limited in terms of geographic spread, with no data from Asia, and cases worldwide are probably underestimated due to incomplete case ascertainment. More data, using standardized, systematic methods, are critical, particularly from low- and middle-income contexts where the highest burden of stillbirths occurs. These data are essential to inform interventions, such as maternal GBS vaccination.

Williams PCM, Isaacs D, Berkley JA. 2017. Antimicrobial resistance among children in sub-Saharan Africa The Lancet Infectious Diseases, | Show Abstract | Read more

© 2017 Elsevier Ltd. Antimicrobial resistance is an important threat to international health. Therapeutic guidelines for empirical treatment of common life-threatening infections depend on available information regarding microbial aetiology and antimicrobial susceptibility, but sub-Saharan Africa lacks diagnostic capacity and antimicrobial resistance surveillance. We systematically reviewed studies of antimicrobial resistance among children in sub-Saharan Africa since 2005. 18 of 1075 articles reviewed met inclusion criteria, providing data from 67 451 invasive bacterial isolates from inconsistently defined populations in predominantly urban tertiary settings. Among neonates, Gram-negative organisms were the predominant cause of early-onset neonatal sepsis, with a high prevalence of extended-spectrum β-lactamase-producing organisms. Gram-positive bacteria were responsible for a high proportion of infections among children beyond the neon atal period, with high reported prevalence of non-susceptibility to treatment advocated by the WHO therapeutic guidelines. There are few up-to-date or representative studies given the magnitude of the problem of antimicrobial resistance, especially regarding community-acquired infections. Research should focus on differentiating resistance in community-acquired versus hospital-acquired infections, implementation of standardised reporting systems, and pragmatic clinical trials to assess the efficacy of alternative treatment regimens.

Bhutta ZA, Berkley JA, Bandsma RHJ, Kerac M, Trehan I, Briend A. 2017. Severe childhood malnutrition NATURE REVIEWS DISEASE PRIMERS, 3 pp. 17067-17067. | Read more

Obiero CW, Seale AC, Jones K, Ngari M, Bendon CL, Morpeth S, Mohammed S, Mturi N, Fegan G, Berkley JA. 2017. Should first-line empiric treatment strategies cover coagulase-negative staphylococcal infections in severely malnourished or HIV-infected children in Kenya? PLoS One, 12 (8), pp. e0182354. | Show Abstract | Read more

BACKGROUND: Bloodstream infection is a common cause of morbidity in children aged <5 years in developing countries. In studies reporting bacteremia in Africa, coagulase-negative Staphylococci (CoNS) are commonly isolated. However, it is currently unclear whether children who are highly susceptible to infection because of severe acute malnutrition (SAM) or HIV should be treated with antimicrobials specifically to cover CoNS. We aimed to determine the clinical significance of CoNS amongst children admitted to a rural hospital in Kenya in relation to nutritional and HIV status. METHODS: Systematically collected clinical and microbiological surveillance data from children aged 6-59 months admitted to Kilifi County Hospital (2007-2013) were analysed. Multivariable regression was used to test associations between CoNS isolation from blood cultures and SAM (MUAC <11.5cm or nutritional oedema (kwashiorkor)), and HIV serostatus; and among children with SAM or HIV, associations between CoNS isolation and mortality, duration of hospitalization and clinical features. RESULTS: CoNS were isolated from blood culture in 906/13,315 (6.8%) children, of whom 135/906 (14.9%) had SAM and 54/906 (6.0%) were HIV antibody positive. CoNS isolation was not associated with SAM (MUAC<11.5cm (aOR 1.11, 95% CI 0.88-1.40) or kwashiorkor (aOR 0.84, 95% CI 0.48-1.49)), or a positive HIV antibody test (aOR 1.25, 95% CI 0.92-1.71). Among children with SAM or a positive HIV antibody test, CoNS isolation was not associated with mortality or prolonged hospitalization. CONCLUSION: In a large, systematic study, there was no evidence that antimicrobial therapy should specifically target CoNS amongst children with SAM or HIV-infection or exposure.

Mramba L, Ngari M, Mwangome M, Muchai L, Bauni E, Walker AS, Gibb DM, Fegan G, Berkley JA. 2017. A growth reference for mid upper arm circumference for age among school age children and adolescents, and validation for mortality: growth curve construction and longitudinal cohort study. BMJ, 358 pp. j3423. | Show Abstract | Read more

Objectives To construct growth curves for mid-upper-arm circumference (MUAC)-for-age z score for 5-19 year olds that accord with the World Health Organization growth standards, and to evaluate their discriminatory performance for subsequent mortality.Design Growth curve construction and longitudinal cohort study.Setting United States and international growth data, and cohorts in Kenya, Uganda, and Zimbabwe.Participants The Health Examination Survey (HES)/National Health and Nutrition Examination Survey (NHANES) US population datasets (age 5-25 years), which were used to construct the 2007 WHO growth reference for body mass index in this age group, were merged with an imputed dataset matching the distribution of the WHO 2006 growth standards age 2-6 years. Validation data were from 685 HIV infected children aged 5-17 years participating in the Antiretroviral Research for Watoto (ARROW) trial in Uganda and Zimbabwe; and 1741 children aged 5-13 years discharged from a rural Kenyan hospital (3.8% HIV infected). Both cohorts were followed-up for survival during one year.Main outcome measures Concordance with WHO 2006 growth standards at age 60 months and survival during one year according to MUAC-for-age and body mass index-for-age z scores.Results The new growth curves transitioned smoothly with WHO growth standards at age 5 years. MUAC-for-age z scores of -2 to -3 and less than-3, compared with -2 or more, was associated with hazard ratios for death within one year of 3.63 (95% confidence interval 0.90 to 14.7; P=0.07) and 11.1 (3.40 to 36.0; P<0.001), respectively, among ARROW trial participants; and 2.22 (1.01 to 4.9; P=0.04) and 5.15 (2.49 to 10.7; P<0.001), respectively, among Kenyan children after discharge from hospital. The AUCs for MUAC-for-age and body mass index-for-age z scores for discriminating subsequent mortality were 0.81 (95% confidence interval 0.70 to 0.92) and 0.75 (0.63 to 0.86) in the ARROW trial (absolute difference 0.06, 95% confidence interval -0.032 to 0.16; P=0.2) and 0.73 (0.65 to 0.80) and 0.58 (0.49 to 0.67), respectively, in Kenya (absolute difference in AUC 0.15, 0.07 to 0.23; P=0.0002).Conclusions The MUAC-for-age z score is at least as effective as the body mass index-for-age z score for assessing mortality risks associated with undernutrition among African school aged children and adolescents. MUAC can provide simplified screening and diagnosis within nutrition and HIV programmes, and in research.

Seale AC, Obiero CW, Jones KD, Barsosio HC, Thitiri J, Ngari M, Morpeth S, Mohammed S, Fegan G, Mturi N, Berkley JA. 2017. Should First-line Empiric Treatment Strategies for Neonates Cover Coagulase-negative Staphylococcal Infections in Kenya? Pediatr Infect Dis J, 36 (11), pp. 1073-1078. | Show Abstract | Read more

BACKGROUND: Neonatal mortality remains high in sub-Saharan Africa, and a third of deaths are estimated to result from infection. While coagulase-negative staphylococci (CoNS) are leading neonatal pathogens in resource-rich settings, their role, and the need for early anti-Staphylococcal treatment in empiric antibiotic guidelines, is unknown in sub-Saharan Africa. METHODS: We examined systematic clinical and microbiologic surveillance data from all neonatal admissions to Kilifi County Hospital (1998-2013) to determine associated case fatality and/or prolonged duration of admission associated with CoNS in neonates treated according to standard World Health Organization guidelines. RESULTS: CoNS was isolated from blood culture in 995 of 9552 (10%) neonates. Case fatality among neonates with CoNS isolated from blood did not differ from other neonatal admissions (P = 0.2), and duration of admission was not prolonged [odds ratio (OR) = 0.9 (0.7-1.0), P = 0.040]. Neonates with CoNS were more likely to have convulsions [OR = 1.4 (1.0-1.8), P = 0.031] but less likely to have impaired consciousness or severe indrawing [OR = 0.8 (0.7-0.9), P = 0.025; OR = 0.9 (0.7-1.0), P = 0.065]. CONCLUSIONS: CoNS isolation in blood cultures at admission was not associated with adverse clinical outcomes in neonates treated according to standard World Health Organization guidelines for hospital care in this setting. There is no evidence that first-line antimicrobial treatment guidelines should be altered to increase cover for CoNS infections in neonates in this setting.

Nabwera HM, Jepkosgei J, Muraya KW, Hassan AS, Molyneux CS, Ali R, Prentice AM, Berkley JA, Mwangome MK. 2017. What influences feeding decisions for HIV-exposed infants in rural Kenya? International Breastfeeding Journal, 12 (1), | Read more

Njunge JM, Oyaro IN, Kibinge NK, Rono MK, Kariuki SM, Newton CR, Berkley JA, Gitau EN. 2017. Cerebrospinal fluid markers to distinguish bacterial meningitis from cerebral malaria in children. Wellcome Open Res, 2 pp. 47. | Show Abstract | Read more

Background. Few hospitals in high malaria endemic countries in Africa have the diagnostic capacity for clinically distinguishing acute bacterial meningitis (ABM) from cerebral malaria (CM). As a result, empirical use of antibiotics is necessary. A biochemical marker of ABM would facilitate precise clinical diagnosis and management of these infections and enable rational use of antibiotics. Methods. We used label-free protein quantification by mass spectrometry to identify cerebrospinal fluid (CSF) markers that distinguish ABM (n=37) from CM (n=22) in Kenyan children. Fold change (FC) and false discovery rates (FDR) were used to identify differentially expressed proteins. Subsequently, potential biomarkers were assessed for their ability to discriminate between ABM and CM using receiver operating characteristic (ROC) curves. Results. The host CSF proteome response to ABM ( Haemophilusinfluenza and Streptococcuspneumoniae) is significantly different to CM. Fifty two proteins were differentially expressed (FDR<0.01, Log FC≥2), of which 83% (43/52) were upregulated in ABM compared to CM. Myeloperoxidase and lactotransferrin were present in 37 (100%) and 36 (97%) of ABM cases, respectively, but absent in CM (n=22). Area under the ROC curve (AUC), sensitivity, and specificity were assessed for myeloperoxidase (1, 1, and 1; 95% CI, 1-1) and lactotransferrin (0.98, 0.97, and 1; 95% CI, 0.96-1). Conclusion. Myeloperoxidase and lactotransferrin have a high potential to distinguish ABM from CM and thereby improve clinical management. Their validation requires a larger cohort of samples that includes other bacterial aetiologies of ABM.

Garcia-Knight MA, Nduati E, Hassan AS, Nkumama I, Etyang TJ, Hajj NJ, Gambo F, Odera D, Berkley JA, Rowland-Jones SL, Urban B. 2017. Cytomegalovirus viraemia is associated with poor growth and T-cell activation with an increased burden in HIV-exposed uninfected infants. AIDS, 31 (13), pp. 1809-1818. | Show Abstract | Read more

OBJECTIVE: Factors associated with poor health in HIV-exposed-uninfected (HEU) infants are poorly defined. We describe the prevalence and correlates of cytomegalovirus (CMV) viraemia in HEU and HIV-unexposed-uninfected (HUU) infants, and quantify associations with anthropometric, haematological, and immunological outcomes. DESIGN: Cross-sectional, including HEU and HUU infants from rural coastal Kenya. METHODS: Infants aged 2-8 months were studied. The primary outcome was CMV viraemia and viral load, determined by quantitative PCR. Correlates were tested by logistic and linear regression; coefficients were used to describe associations between CMV viraemia and clinical/immunological parameters. RESULTS: In total, 42 of 65 (64.6%) infants had CMV viraemia [median viral load, 3.0 (interquartile ranges: 2.7-3.5) log10 IU/ml]. Compared to community controls, HEU infants had six-fold increased odds of being viraemic (adjusted odds ratio 5.95 [95% confidence interval: 1.82-19.36], P = 0.003). Age, but not HEU/HUU status, was a strong correlate of CMV viral load (coefficient = -0.15, P = 0.009). CMV viral load associated negatively with weight-for-age (WAZ) Z-score (coefficient =  -1.06, P = 0.008) and head circumference-for-age Z-score (coefficient =  -1.47, P = 0.012) and positively with CD8 T-cell coexpression of CD38/human leucocyte antigen DR (coefficient = 15.05, P = 0.003). CONCLUSION: The odds of having CMV viraemia was six-fold greater in HEU than HUU infants when adjusted for age. CMV viral load was associated with adverse growth and heightened CD8 T-cell immune activation. Longitudinal assessments of the clinical effects of primary CMV infection and associated immunomodulation in early life in HEU and HUU populations are warranted.

Gitaka J, Ogwang C, Ngari M, Akoo P, Olotu A, Kerubo C, Fegan G, Njuguna P, Nyakaya G, Otieno T et al. 2017. Clinical laboratory reference values amongst children aged 4 weeks to 17 months in Kilifi, Kenya: A cross sectional observational study. PLoS One, 12 (5), pp. e0177382. | Show Abstract | Read more

Reference intervals for clinical laboratory parameters are important for assessing eligibility, toxicity grading and management of adverse events in clinical trials. Nonetheless, haematological and biochemical parameters used for clinical trials in sub-Saharan Africa are typically derived from industrialized countries, or from WHO references that are not region-specific. We set out to establish community reference values for haematological and biochemical parameters amongst children aged 4 weeks to 17 months in Kilifi, Kenya. We conducted a cross sectional study nested within phase II and III trials of RTS, S malaria vaccine candidate. We analysed 10 haematological and 2 biochemical parameters from 1,070 and 423 community children without illness prior to experimental vaccine administration. Statistical analysis followed Clinical and Laboratory Standards Institute EP28-A3c guidelines. 95% reference ranges and their respective 90% confidence intervals were determined using non-parametric methods. Findings were compared with published ranges from Tanzania, Europe and The United States. We determined the reference ranges within the following age partitions: 4 weeks to <6 months, 6 months to less than <12 months, and 12 months to 17 months for the haematological parameters; and 4 weeks to 17 months for the biochemical parameters. There were no gender differences for all haematological and biochemical parameters in all age groups. Hb, MCV and platelets 95% reference ranges in infants largely overlapped with those from United States or Europe, except for the lower limit for Hb, Hct and platelets (lower); and upper limit for platelets (higher) and haematocrit(lower). Community norms for common haematological and biochemical parameters differ from developed countries. This reaffirms the need in clinical trials for locally derived reference values to detect deviation from what is usual in typical children in low and middle income countries.

Jones KDJ, Hachmeister CU, Khasira M, Cox L, Schoenmakers I, Munyi C, Nassir HS, Hünten-Kirsch B, Prentice A, Berkley JA. 2017. Vitamin D deficiency causes rickets in an urban informal settlement in Kenya and is associated with malnutrition Maternal & Child Nutrition, pp. e12452-e12452. | Show Abstract | Read more

© 2017 John Wiley & Sons Ltd. The commonest cause of rickets worldwide is vitamin D deficiency, but studies from sub-Saharan Africa describe an endemic vitamin D-independent form that responds to dietary calcium enrichment. The extent to which calcium-deficiency rickets is the dominant form across sub-Saharan Africa and in other low-latitude areas is unknown. We aimed to characterise the clinical and biochemical features of young children with rickets in a densely populated urban informal settlement in Kenya. Because malnutrition may mask the clinical features of rickets, we also looked for biochemical indices of risk in children with varying degrees of acute malnutrition. Twenty one children with rickets, aged 3 to 24 months, were identified on the basis of clinical and radiologic features, along with 22 community controls, and 41 children with either severe or moderate acute malnutrition. Most children with rickets had wrist widening (100%) and rachitic rosary (90%), as opposed to lower limb features (19%). Developmental delay (52%), acute malnutrition (71%), and stunting (62%) were common. Compared to controls, there were no differences in calcium intake, but most (71%) had serum 25-hydroxyvitamin D levels below 30 nmol/L. These results suggest that rickets in young children in urban Kenya is usually driven by vitamin D deficiency, and vitamin D supplementation is likely to be required for full recovery. Wasting was associated with lower calcium (p = .001), phosphate (p < .001), 25-hydroxyvitamin D (p = .049), and 1,25-dihydroxyvitamin D (p = 0.022) levels, the clinical significance of which remain unclear.

Kinyoki DK, Moloney GM, Uthman OA, Kandala N-B, Odundo EO, Noor AM, Berkley JA. 2017. Conflict in Somalia: impact on child undernutrition BMJ Global Health, 2 (2), pp. e000262-e000262. | Read more

Muema DM, Macharia GN, Olusola BA, Hassan AS, Fegan GW, Berkley JA, Urban BC, Nduati EW. 2017. Proportions of circulating follicular helper T cells are reduced and correlate with memory B cells in HIV-infected children. PLoS One, 12 (4), pp. e0175570. | Show Abstract | Read more

INTRODUCTION: HIV causes defects in memory B cells in children, but the mechanisms of those defects have not been fully elucidated. One possible mechanism is the lack of T-cell help to B cells during immune reactions. However, few studies have assessed the effect of HIV on follicular helper T cells (TFH cells) in children. METHODS: In this study, follicular-homing CD4 T cells and memory B cells were assessed in HIV-infected children and compared with children from the community. CXCR5 and CD45RO were used as markers of follicular-homing T cells and memory T cells, respectively. Memory TFH cells were identified as CD3+CD8-CD4+CXCR5+CD45RO+PD1+. Central memory T cells were identified based on CCR7 expression. Relationship between the proportions of follicular-homing CD4 T cells and memory B cells were determined in multivariable regression models. RESULTS: Highly viremic HIV-infected children had lower proportions of memory TFH cells when compared with community control children. In multivariable analyses, high proportions of memory TFH cells were associated with increased percentages of resting memory B cells after adjusting for other covariates. CONCLUSION: The impact of HIV on follicular helper T cells could influence the accumulation of memory B cells in HIV-infected children.

Mwangome M, Ngari M, Fegan G, Mturi N, Shebe M, Bauni E, Berkley JA. 2017. Diagnostic criteria for severe acute malnutrition among infants aged under 6 mo. Am J Clin Nutr, 105 (6), pp. 1415-1423. | Show Abstract | Read more

Background: There is an increasing recognition of malnutrition among infants under 6 mo of age (U6M). Current diagnosis criteria use weight-for-length z scores (WLZs), but the 2006 WHO standards exclude infants shorter than 45 cm. In older children, midupper arm circumference (MUAC) predicts mortality better than does WLZ. Outcomes may also be influenced by exposure to HIV and size or gestational age at birth. Diagnostic thresholds for WLZ, MUAC, and other indexes have not been fully evaluated against mortality risk among U6M infants.Objective: The aim was to determine the association of anthropometric indexes with risks of inpatient and postdischarge mortality among U6M infants recruited at the time of hospitalization.Design: We analyzed data from a cohort of U6M infants admitted to Kilifi County Hospital (2007-2013), Kenya. The primary outcomes were inpatient death and death during follow-up over 1 y after discharge. We calculated adjusted RRs for inpatient mortality and HRs for postdischarge mortality for different anthropometric measures and thresholds. Discriminatory value was assessed by using receiver operating characteristic curves.Results: A total of 2882 infants were admitted: 140 (4.9%) died in the hospital and 1405 infants were followed up after discharge. Of these, 75 (5.3%) died within 1 y during 1318 child-years of observation. MUAC and weight-for-age z score (WAZ) predicted inpatient and postdischarge mortality better than did WLZ (P < 0.0001). A single MUAC threshold of <11.0 cm performed similarly to MUAC thresholds that varied with age (all P > 0.05) and performed better than WLZ <-3 for both inpatient and postdischarge mortality (both P < 0.001). Reported small size at birth did not reduce the risk of death associated with anthropometric indexes.Conclusions: U6M infants at the highest risk of death are best targeted by using MUAC or WAZ. Further research into the effectiveness of potential interventions is required.

Crane RJ, Berkley JA. 2017. Progress on growth faltering. Lancet Glob Health, 5 (2), pp. e125-e126. | Read more

Kinyoki DK, Manda SO, Moloney GM, Odundo EO, Berkley JA, Noor AM, Kandala N-B. 2017. Modelling the Ecological Comorbidity of Acute Respiratory Infection, Diarrhoea and Stunting among Children Under the Age of 5 Years in Somalia. Int Stat Rev, 85 (1), pp. 164-176. | Show Abstract | Read more

The aim of this study was to assess spatial co-occurrence of acute respiratory infections (ARI), diarrhoea and stunting among children of the age between 6 and 59 months in Somalia. Data were obtained from routine biannual nutrition surveys conducted by the Food and Agriculture Organization 2007-2010. A Bayesian hierarchical geostatistical shared component model was fitted to the residual spatial components of the three health conditions. Risk maps of the common spatial effects at 1×1 km resolution were derived. The empirical correlations of the enumeration area proportion were 0.37, 0.63 and 0.66 for ARI and stunting, diarrhoea and stunting and ARI and diarrhoea, respectively. Spatially, the posterior residual effects ranged 0.03-20.98, 0.16-6.37 and 0.08-9.66 for shared component between ARI and stunting, diarrhoea and stunting and ARI and diarrhoea, respectively. The analysis showed clearly that the spatial shared component between ARI, diarrhoea and stunting was higher in the southern part of the country. Interventions aimed at controlling and mitigating the adverse effects of these three childhood health conditions should focus on their common putative risk factors, particularly in the South in Somalia.

Ngari MM, Fegan G, Mwangome MK, Ngama MJ, Mturi N, Scott JAG, Bauni E, Nokes DJ, Berkley JA. 2017. Mortality after Inpatient Treatment for Severe Pneumonia in Children: a Cohort Study. Paediatr Perinat Epidemiol, 31 (3), pp. 233-242. | Show Abstract | Read more

BACKGROUND: Although pneumonia is a leading cause of inpatient mortality, deaths may also occur after discharge from hospital. However, prior studies have been small, in selected groups or did not fully evaluate risk factors, particularly malnutrition and HIV. We determined 1-year post-discharge mortality and risk factors among children diagnosed with severe pneumonia. METHODS: A cohort study of children aged 1-59 months admitted to Kilifi County Hospital with severe pneumonia (2007-12). The primary outcome was death <1 year after discharge, determined through Kilifi Health and Demographic Surveillance System (KHDSS) quarterly census rounds. RESULTS: Of 4184 children (median age 9 months) admitted with severe pneumonia, 1041 (25%) had severe acute malnutrition (SAM), 267 (6.4%) had a positive HIV antibody test, and 364 (8.7%) died in hospital. After discharge, 2279 KHDSS-resident children were followed up; 70 (3.1%) died during 2163 child-years: 32 (95% confidence interval (CI) 26, 41) deaths per 1000 child years. Post-discharge mortality was greater after admission for severe pneumonia than for other diagnoses, hazard ratio 2.5 (95% CI 1.2, 5.3). Malnutrition, HIV status, age and prolonged hospitalisation, but not signs of pneumonia severity, were associated with post-discharge mortality. Fifty-two per cent (95% CI 37%, 63%) of post-discharge deaths were attributable to low mid-upper arm circumference and 11% (95% CI 3.3%, 18%) to a positive HIV test. CONCLUSIONS: Admission with severe pneumonia is an important marker of vulnerability. Risk stratification and better understanding of the mechanisms underlying post-discharge mortality, especially for undernourished children, are needed to reduce mortality after treatment for pneumonia.

Lo Vecchio A, Liguoro I, Dias JA, Berkley JA, Boey C, Cohen MB, Cruchet S, Salazar-Lindo E, Podder S, Sandhu B et al. 2017. Rotavirus immunization: Global coverage and local barriers for implementation. Vaccine, 35 (12), pp. 1637-1644. | Show Abstract | Read more

BACKGROUND: Rotavirus (RV) is a major agent of gastroenteritis and an important cause of child death worldwide. Immunization (RVI) has been available since 2006, and the Federation of International Societies of Gastroenterology Hepatology and Nutrition (FISPGHAN) identified RVI as a top priority for the control of diarrheal illness. A FISPGHAN working group on acute diarrhea aimed at estimating the current RVI coverage worldwide and identifying barriers to implementation at local level. METHODS: A survey was distributed to national experts in infectious diseases and health-care authorities (March 2015-April 2016), collecting information on local recommendations, costs and perception of barriers for implementation. RESULTS: Forty-nine of the 79 contacted countries (62% response rate) provided a complete analyzable data. RVI was recommended in 27/49 countries (55%). Although five countries have recommended RVI since 2006, a large number (16, 33%) included RVI in a National Immunization Schedule between 2012 and 2014. The costs of vaccination are covered by the government (39%), by the GAVI Alliance (10%) or public and private insurance (8%) in some countries. However, in most cases, immunization is paid by families (43%). Elevated cost of vaccine (49%) is the main barrier for implementation of RVI. High costs of vaccination (rs=-0.39, p=0.02) and coverage of expenses by families (rs=0.5, p=0.002) significantly correlate with a lower immunization rate. Limited perception of RV illness severity by the families (47%), public-health authorities (37%) or physicians (24%) and the timing of administration (16%) are further major barriers to large- scale RVI programs. CONCLUSIONS: After 10years since its introduction, the implementation of RVI is still unacceptably low and should remain a major target for global public health. Barriers to implementation vary according to setting. Nevertheless, public health authorities should promote education for caregivers and health-care providers and interact with local health authorities in order to implement RVI.

Stirnemann J, Villar J, Salomon LJ, Ohuma E, Ruyan P, Altman DG, Nosten F, Craik R, Munim S, Cheikh Ismail L et al. 2017. International estimated fetal weight standards of the INTERGROWTH-21st Project. Ultrasound Obstet Gynecol, 49 (4), pp. 478-486. | Show Abstract | Read more

OBJECTIVE: Estimated fetal weight (EFW) and fetal biometry are complementary measures used to screen for fetal growth disturbances. Our aim was to provide international EFW standards to complement the INTERGROWTH-21st Fetal Growth Standards that are available for use worldwide. METHODS: Women with an accurate gestational-age assessment, who were enrolled in the prospective, international, multicenter, population-based Fetal Growth Longitudinal Study (FGLS) and INTERBIO-21st Fetal Study (FS), two components of the INTERGROWTH-21st Project, had ultrasound scans every 5 weeks from 9-14 weeks' until 40 weeks' gestation. At each visit, measurements of fetal head circumference (HC), biparietal diameter, occipitofrontal diameter, abdominal circumference (AC) and femur length (FL) were obtained blindly by dedicated research sonographers using standardized methods and identical ultrasound machines. Birth weight was measured within 12 h of delivery by dedicated research anthropometrists using standardized methods and identical electronic scales. Live babies without any congenital abnormality, who were born within 14 days of the last ultrasound scan, were selected for inclusion. As most births occurred at around 40 weeks' gestation, we constructed a bootstrap model selection and estimation procedure based on resampling of the complete dataset under an approximately uniform distribution of birth weight, thus enriching the sample size at extremes of fetal sizes, to achieve consistent estimates across the full range of fetal weight. We constructed reference centiles using second-degree fractional polynomial models. RESULTS: Of the overall population, 2404 babies were born within 14 days of the last ultrasound scan. Mean time between the last scan and birth was 7.7 (range, 0-14) days and was uniformly distributed. Birth weight was best estimated as a function of AC and HC (without FL) as log(EFW) = 5.084820 - 54.06633 × (AC/100)3  - 95.80076 × (AC/100)3  × log(AC/100) + 3.136370 × (HC/100), where EFW is in g and AC and HC are in cm. All other measures, gestational age, symphysis-fundus height, amniotic fluid indices and interactions between biometric measures and gestational age, were not retained in the selection process because they did not improve the prediction of EFW. Applying the formula to FGLS biometric data (n = 4231) enabled gestational age-specific EFW tables to be constructed. At term, the EFW centiles matched those of the INTERGROWTH-21st Newborn Size Standards but, at < 37 weeks' gestation, the EFW centiles were, as expected, higher than those of babies born preterm. Comparing EFW cross-sectional values with the INTERGROWTH-21st Preterm Postnatal Growth Standards confirmed that preterm postnatal growth is a different biological process from intrauterine growth. CONCLUSIONS: We provide an assessment of EFW, as an adjunct to routine ultrasound biometry, from 22 to 40 weeks' gestation. However, we strongly encourage clinicians to evaluate fetal growth using separate biometric measures such as HC and AC, as well as EFW, to avoid the minimalist approach of focusing on a single value. © 2016 Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Attia S, Versloot CJ, Voskuijl W, van Vliet SJ, Di Giovanni V, Zhang L, Richardson S, Bourdon C, Netea MG, Berkley JA et al. 2016. Mortality in children with complicated severe acute malnutrition is related to intestinal and systemic inflammation: an observational cohort study. Am J Clin Nutr, 104 (5), pp. 1441-1449. | Show Abstract | Read more

BACKGROUND: Diarrhea affects a large proportion of children with severe acute malnutrition (SAM). However, its etiology and clinical consequences remain unclear. OBJECTIVE: We investigated diarrhea, enteropathogens, and systemic and intestinal inflammation for their interrelation and their associations with mortality in children with SAM. DESIGN: Intestinal pathogens (n = 15), cytokines (n = 29), fecal calprotectin, and the short-chain fatty acids (SCFAs) butyrate and propionate were determined in children aged 6-59 mo (n = 79) hospitalized in Malawi for complicated SAM. The relation between variables, diarrhea, and death was assessed with partial least squares (PLS) path modeling. RESULTS: Fatal subjects (n = 14; 18%) were younger (mean ± SD age: 17 ± 11 compared with 25 ± 11 mo; P = 0.01) with higher prevalence of diarrhea (46% compared with 18%, P = 0.03). Intestinal pathogens Shigella (36%), Giardia (33%), and Campylobacter (30%) predominated, but their presence was not associated with death or diarrhea. Calprotectin was significantly higher in children who died [median (IQR): 1360 mg/kg feces (2443-535 mg/kg feces) compared with 698 mg/kg feces (1438-244 mg/kg feces), P = 0.03]. Butyrate [median (IQR): 31 ng/mL (112-22 ng/mL) compared with 2036 ng/mL (5800-149 ng/mL), P = 0.02] and propionate [median (IQR): 167 ng/mL (831-131 ng/mL) compared with 3174 ng/mL (5819-357 ng/mL), P = 0.04] were lower in those who died. Mortality was directly related to high systemic inflammation (path coefficient = 0.49), whereas diarrhea, high calprotectin, and low SCFA production related to death indirectly via their more direct association with systemic inflammation. CONCLUSIONS: Diarrhea, high intestinal inflammation, low concentrations of fecal SCFAs, and high systemic inflammation are significantly related to mortality in SAM. However, these relations were not mediated by the presence of intestinal pathogens. These findings offer an important understanding of inflammatory changes in SAM, which may lead to improved therapies. This trial was registered at www.controlled-trials.com as ISRCTN13916953.

Muraya KW, Jones C, Berkley JA, Molyneux S. 2016. Perceptions of childhood undernutrition among rural households on the Kenyan coast - a qualitative study. BMC Public Health, 16 (1), pp. 693. | Show Abstract | Read more

BACKGROUND: Nutrition plays an important role in child survival and development. Treatment action in the management of child health and nutrition is influenced by perceptions of illness, and gender plays an important role. However, little is known about if and how moderate undernutrition is recognised among lay populations, or how local social norms and intra-household dynamics affect decisions to seek biomedical assistance for nutritional concerns. In this paper we describe how childhood nutritional problems are recognised and understood within rural households. We demonstrate how context influences local constructs of 'normal', and suggest the centrality of gender in the management of child health and nutrition in our research context. METHODS: This qualitative study was undertaken in Kilifi County on the Kenyan Coast. A set of 15 households whose children were engaged in a community-based nutrition intervention were followed up over a period of twelve months. Over a total of 54 household visits, group and individual in-depth interviews were conducted with a range of respondents, supplemented by non-participant observations. Eight in-depth interviews with community representatives were also conducted. RESULTS: Local taxonomies of childhood undernutrition were found to overlap with, but differ from, biomedical categories. In particular, moderate undernutrition was generally not recognised as a health problem requiring treatment action, but rather as routine and manageable, typically seasonal, weight-loss. Where symptoms were considered more serious and requiring remedial action, household management strategies were typically based on perceived aetiology of the illness. Additionally, gender emerged as a potentially central theme in childhood nutrition problems and related management. Women reported that they have primary responsibility for ensuring children's good health and nutritional status, and that they are often held accountable when their children are of sub-optimal health. CONCLUSION: Perceptions of child nutrition and illness and gendered roles within households influence treatment action, and engagement with nutrition interventions. Community-based nutrition interventions must recognise these complex realities.

Kinyoki DK, Berkley JA, Moloney GM, Odundo EO, Kandala N-B, Noor AM. 2016. Environmental predictors of stunting among children under-five in Somalia: cross-sectional studies from 2007 to 2010. BMC Public Health, 16 (1), pp. 654. | Show Abstract | Read more

BACKGROUND: Stunting among children under five years old is associated with long-term effects on cognitive development, school achievement, economic productivity in adulthood and maternal reproductive outcomes. Accurate estimation of stunting and tools to forecast risk are key to planning interventions. We estimated the prevalence and distribution of stunting among children under five years in Somalia from 2007 to 2010 and explored the role of environmental covariates in its forecasting. METHODS: Data from household nutritional surveys in Somalia from 2007 to 2010 with a total of 1,066 clusters covering 73,778 children were included. We developed a Bayesian hierarchical space-time model to forecast stunting by using the relationship between observed stunting and environmental covariates in the preceding years. We then applied the model coefficients to environmental covariates in subsequent years. To determine the accuracy of the forecasting, we compared this model with a model that used data from all the years with the corresponding environmental covariates. RESULTS: Rainfall (OR = 0.994, 95 % Credible interval (CrI): 0.993, 0.995) and vegetation cover (OR = 0.719, 95 % CrI: 0.603, 0.858) were significant in forecasting stunting. The difference in estimates of stunting using the two approaches was less than 3 % in all the regions for all forecast years. CONCLUSION: Stunting in Somalia is spatially and temporally heterogeneous. Rainfall and vegetation are major drivers of these variations. The use of environmental covariates for forecasting of stunting is a potentially useful and affordable tool for planning interventions to reduce the high burden of malnutrition in Somalia.

Briend A, Berkley JA. 2016. Long term health status of children recovering from severe acute malnutrition. Lancet Glob Health, 4 (9), pp. e590-e591. | Read more

Nduati EW, Nkumama IN, Gambo FK, Muema DM, Knight MG, Hassan AS, Jahangir MN, Etyang TJ, Berkley JA, Urban BC. 2016. HIV-Exposed Uninfected Infants Show Robust Memory B-Cell Responses in Spite of a Delayed Accumulation of Memory B Cells: an Observational Study in the First 2 Years of Life. Clin Vaccine Immunol, 23 (7), pp. 576-585. | Show Abstract | Read more

Improved HIV care has led to an increase in the number of HIV-exposed uninfected (HEU) infants born to HIV-infected women. Although they are uninfected, these infants experience increased morbidity and mortality. One explanation may be that their developing immune system is altered by HIV exposure, predisposing them to increased postnatal infections. We explored the impact of HIV exposure on the B-cell compartment by determining the B-cell subset distribution, the frequency of common vaccine antigen-specific memory B cells (MBCs), and the levels of antibodies to the respective antigens in HEU and HIV-unexposed uninfected (HUU) infants born to uninfected mothers, using flow cytometry, a B-cell enzyme-linked immunosorbent spot assay, and an enzyme-linked immunosorbent assay, respectively, during the first 2 years of life. For the majority of the B-cell subsets, there were no differences between HEU and HUU infants. However, HIV exposure was associated with a lower proportion of B cells in general and MBCs in particular, largely due to a lower proportion of unswitched memory B cells. This reduction was maintained even after correcting for age. These phenotypic differences in the MBC compartment did not affect the ability of HEU infants to generate recall responses to previously encountered antigens or reduce the antigen-specific antibody levels at 18 months of life. Although HIV exposure was associated with a transient reduction in the proportion of MBCs, we found that the ability of HEU infants to mount robust MBC and serological responses was unaffected.

Mogeni P, Williams TN, Fegan G, Nyundo C, Bauni E, Mwai K, Omedo I, Njuguna P, Newton CR, Osier F et al. 2016. Age, Spatial, and Temporal Variations in Hospital Admissions with Malaria in Kilifi County, Kenya: A 25-Year Longitudinal Observational Study. PLoS Med, 13 (6), pp. e1002047. | Show Abstract | Read more

BACKGROUND: Encouraging progress has been seen with reductions in Plasmodium falciparum malaria transmission in some parts of Africa. Reduced transmission might lead to increasing susceptibility to malaria among older children due to lower acquired immunity, and this has implications for ongoing control strategies. METHODS AND FINDINGS: We conducted a longitudinal observational study of children admitted to Kilifi County Hospital in Kenya and linked it to data on residence and insecticide-treated net (ITN) use. This included data from 69,104 children aged from 3 mo to 13 y admitted to Kilifi County Hospital between 1 January 1990 and 31 December 2014. The variation in malaria slide positivity among admissions was examined in logistic regression models using the following predictors: location of the residence, calendar time, the child's age, ITN use, and the enhanced vegetation index (a proxy for soil moisture). The proportion of malaria slide-positive admissions declined from 0.56 (95% confidence interval [CI] 0.54-0.58) in 1998 to 0.07 (95% CI 0.06-0.08) in 2009 but then increased again through to 0.24 (95% CI 0.22-0.25) in 2014. Older children accounted for most of the increase after 2009 (0.035 [95% CI 0.030-0.040] among young children compared to 0.22 [95% CI 0.21-0.23] in older children). There was a nonlinear relationship between malaria risk and prevalence of ITN use within a 2 km radius of an admitted child's residence such that the predicted malaria positive fraction varied from ~0.4 to <0.1 as the prevalence of ITN use varied from 20% to 80%. In this observational analysis, we were unable to determine the cause of the decline in malaria between 1998 and 2009, which pre-dated the dramatic scale-up in ITN distribution and use. CONCLUSION: Following a period of reduced transmission, a cohort of older children emerged who have increased susceptibility to malaria. Further reductions in malaria transmission are needed to mitigate the increasing burden among older children, and universal ITN coverage is a promising strategy to achieve this goal.

Berkley JA, Ngari M, Thitiri J, Mwalekwa L, Timbwa M, Hamid F, Ali R, Shangala J, Mturi N, Jones KDJ et al. 2016. Daily co-trimoxazole prophylaxis to prevent mortality in children with complicated severe acute malnutrition: a multicentre, double-blind, randomised placebo-controlled trial. Lancet Glob Health, 4 (7), pp. e464-e473. | Show Abstract | Read more

BACKGROUND: Children with complicated severe acute malnutrition (SAM) have a greatly increased risk of mortality from infections while in hospital and after discharge. In HIV-infected children, mortality and admission to hospital are prevented by daily co-trimoxazole prophylaxis, despite locally reported bacterial resistance to co-trimoxazole. We aimed to assess the efficacy of daily co-trimoxazole prophylaxis on survival in children without HIV being treated for complicated SAM. METHODS: We did a multicentre, double-blind, randomised, placebo-controlled study in four hospitals in Kenya (two rural hospitals in Kilifi and Malindi, and two urban hospitals in Mombasa and Nairobi) with children aged 60 days to 59 months without HIV admitted to hospital and diagnosed with SAM. We randomly assigned eligible participants (1:1) to 6 months of either daily oral co-trimoxazole prophylaxis (given as water-dispersible tablets; 120 mg per day for age <6 months, 240 mg per day for age 6 months to 5 years) or matching placebo. Assignment was done with computer-generated randomisation in permuted blocks of 20, stratified by centre and age younger or older than 6 months. Treatment allocation was concealed in opaque, sealed envelopes and patients, their families, and all trial staff were masked to treatment assignment. Children were given recommended medical care and feeding, and followed up for 12 months. The primary endpoint was mortality, assessed each month for the first 6 months, then every 2 months for the second 6 months. Secondary endpoints were nutritional recovery, readmission to hospital, and illness episodes treated as an outpatient. Analysis was by intention to treat. This trial was registered at ClinicalTrials.gov, number NCT00934492. FINDINGS: Between Nov 20, 2009, and March 14, 2013, we recruited and assigned 1778 eligible children to treatment (887 to co-trimoxazole prophylaxis and 891 to placebo). Median age was 11 months (IQR 7-16 months), 306 (17%) were younger than 6 months, 300 (17%) had oedematous malnutrition (kwashiorkor), and 1221 (69%) were stunted (length-for-age Z score <-2). During 1527 child-years of observation, 122 (14%) of 887 children in the co-trimoxazole group died, compared with 135 (15%) of 891 in the placebo group (unadjusted hazard ratio [HR] 0·90, 95% CI 0·71-1·16, p=0·429; 16·0 vs 17·7 events per 100 child-years observed (CYO); difference -1·7 events per 100 CYO, 95% CI -5·8 to 2·4]). In the first 6 months of the study (while participants received study medication), 63 suspected grade 3 or 4 associated adverse events were recorded among 57 (3%) children; 31 (2%) in the co-trimoxazole group and 32 (2%) in the placebo group (incidence rate ratio 0·98, 95% CI 0·58-1·65). The most common adverse events of these grades were urticarial rash (grade 3, equally common in both groups), neutropenia (grade 4, more common in the co-trimoxazole group), and anaemia (both grades equally common in both groups). One child in the placebo group had fatal toxic epidermal necrolysis with concurrent Pseudomonas aeruginosa bacteraemia. INTERPRETATION: Daily co-trimoxazole prophylaxis did not reduce mortality in children with complicated SAM without HIV. Other strategies need to be tested in clinical trials to reduce deaths in this population. FUNDING: Wellcome Trust, UK.

Bourke CD, Berkley JA, Prendergast AJ. 2016. Immune Dysfunction as a Cause one Consecuence of Malnutrition TRENDS IN IMMUNOLOGY, 37 (6), pp. 386-398. | Read more

Kenyan Bacteraemia Study Group, Wellcome Trust Case Control Consortium 2 (WTCCC2), Rautanen A, Pirinen M, Mills TC, Rockett KA, Strange A, Ndungu AW, Naranbhai V, Gilchrist JJ et al. 2016. Polymorphism in a lincRNA Associates with a Doubled Risk of Pneumococcal Bacteremia in Kenyan Children. Am J Hum Genet, 98 (6), pp. 1092-1100. | Show Abstract | Read more

Bacteremia (bacterial bloodstream infection) is a major cause of illness and death in sub-Saharan Africa but little is known about the role of human genetics in susceptibility. We conducted a genome-wide association study of bacteremia susceptibility in more than 5,000 Kenyan children as part of the Wellcome Trust Case Control Consortium 2 (WTCCC2). Both the blood-culture-proven bacteremia case subjects and healthy infants as controls were recruited from Kilifi, on the east coast of Kenya. Streptococcus pneumoniae is the most common cause of bacteremia in Kilifi and was thus the focus of this study. We identified an association between polymorphisms in a long intergenic non-coding RNA (lincRNA) gene (AC011288.2) and pneumococcal bacteremia and replicated the results in the same population (p combined = 1.69 × 10(-9); OR = 2.47, 95% CI = 1.84-3.31). The susceptibility allele is African specific, derived rather than ancestral, and occurs at low frequency (2.7% in control subjects and 6.4% in case subjects). Our further studies showed AC011288.2 expression only in neutrophils, a cell type that is known to play a major role in pneumococcal clearance. Identification of this novel association will further focus research on the role of lincRNAs in human infectious disease.

Seale AC, Koech AC, Sheppard AE, Barsosio HC, Langat J, Anyango E, Mwakio S, Mwarumba S, Morpeth SC, Anampiu K et al. Maternal colonization with Streptococcus agalactiae and associated stillbirth and neonatal disease in coastal Kenya. Nat Microbiol, 1 (7), pp. 16067. | Show Abstract | Read more

Streptococcus agalactiae (group B streptococcus, GBS) causes neonatal disease and stillbirth, but its burden in sub-Saharan Africa is uncertain. We assessed maternal recto-vaginal GBS colonization (7,967 women), stillbirth and neonatal disease. Whole-genome sequencing was used to determine serotypes, sequence types and phylogeny. We found low maternal GBS colonization prevalence (934/7,967, 12%), but comparatively high incidence of GBS-associated stillbirth and early onset neonatal disease (EOD) in hospital (0.91 (0.25-2.3)/1,000 births and 0.76 (0.25-1.77)/1,000 live births, respectively). However, using a population denominator, EOD incidence was considerably reduced (0.13 (0.07-0.21)/1,000 live births). Treated cases of EOD had very high case fatality (17/36, 47%), especially within 24 h of birth, making under-ascertainment of community-born cases highly likely, both here and in similar facility-based studies. Maternal GBS colonization was less common in women with low socio-economic status, HIV infection and undernutrition, but when GBS-colonized, they were more probably colonized by the most virulent clone, CC17. CC17 accounted for 267/915 (29%) of maternal colonizing (265/267 (99%) serotype III; 2/267 (0.7%) serotype IV) and 51/73 (70%) of neonatal disease cases (all serotype III). Trivalent (Ia/II/III) and pentavalent (Ia/Ib/II/III/V) vaccines would cover 71/73 (97%) and 72/73 (99%) of disease-causing serotypes, respectively. Serotype IV should be considered for inclusion, with evidence of capsular switching in CC17 strains.

Seale AC, Koech AC, Sheppard AE, Barsosio HC, Langat J, Anyango E, Mwakio S, Mwarumba S, Morpeth SC, Anampiu K et al. 2016. Maternal colonisation with Streptococcus agalactiae, and associated stillbirth and neonatal disease in coastal Kenya. Nat Microbiol, 1 (7), pp. 16067-16067. | Show Abstract | Read more

Streptococcus agalactiae (Group B Streptococcus, GBS) causes neonatal disease and stillbirth, but its burden in sub-Saharan Africa is uncertain. We assessed maternal recto-vaginal GBS colonisation (7967 women), stillbirth and neonatal disease. Whole genome sequencing was used to determine serotypes, sequence types (ST), and phylogeny. We found low maternal GBS colonisation prevalence (934/7967, 12%), but comparatively high incidence of GBS-associated stillbirth and early onset neonatal disease (EOD) in hospital (0.91(0.25-2.3)/1000 births; 0.76(0.25-1.77)/1000 live-births respectively). However, using a population denominator, EOD incidence was considerably reduced (0.13(0.07-0.21)/1000 live-births). Treated cases of EOD had very high case fatality (17/36, 47%), especially within 24 hours of birth, making under-ascertainment of community-born cases highly likely, both here and in similar facility-based studies. Maternal GBS colonisation was less common in women with low socio-economic status, HIV infection and undernutrition, but when GBS-colonised, they were more likely colonised by the most virulent clone, CC17. CC17 accounted for 267/915(29%) of maternal colonising (265/267(99%) serotype III, 2/267(0.7%) serotype IV), and 51/73(70%) of neonatal disease cases (all serotype III). Trivalent (Ia/II/III) and pentavalent (Ia/Ib/II/III/V) vaccines would cover 71/73(97%) and 72/73(99%) of disease-causing serotypes respectively. Serotype IV should be considered for inclusion, with evidence of capsular switching in CC17 strains.

Sinha A, Russell LB, Tomczyk S, Verani JR, Schrag SJ, Berkley JA, Mohammed M, Sigauque B, Kim S-Y, GBS Vaccine Cost-Effectiveness Analysis in Sub-Saharan Africa Working Group. 2016. Disease Burden of Group B Streptococcus Among Infants in Sub-Saharan Africa: A Systematic Literature Review and Meta-analysis. Pediatr Infect Dis J, 35 (9), pp. 933-942. | Show Abstract | Read more

BACKGROUND: Group B streptococcus (GBS) is a leading neonatal sepsis pathogen globally. Investment in GBS disease prevention, such as maternal vaccination, requires evidence of disease burden, particularly in high infant mortality regions like sub-Saharan Africa. We aimed to provide such evidence by conducting a systematic literature review and meta-analysis to estimate maternal colonization proportion, GBS disease incidence and GBS serotype distribution. METHODS: MEDLINE, MEDLINE in process and Cochrane Library were searched for studies published during 1990-2014, pertaining to sub-Saharan Africa. Eligible studies were used to estimate the proportion of pregnant women colonized with GBS, early-onset GBS disease incidence, late-onset GBS disease incidence and respective serotype distributions. Random effects meta-analysis was conducted to estimate weighted means and confidence intervals (CIs). RESULTS: We identified 17 studies of colonization, 9 of disease incidence, and 6 of serotype distribution meeting inclusion criteria. 21.8% (95% CI: 18.3, 25.5) of expectant women were colonized with GBS. The incidence of early-onset GBS disease was 1.3 per 1000 births (95% CI: 0.81, 1.9), that of late-onset GBS disease 0.73 per 1000 births (95% CI: 0.48, 1.0). The most common disease-causing serotype was 3, followed by 1a. Serotypes 1b, 2 and 5 were next most common in frequency. CONCLUSION: Despite methodological factors leading to underestimation, GBS disease incidence appears high in sub-Saharan Africa. A small number of GBS serotypes cause almost all disease. GBS disease burden in sub-Saharan Africa suggests that safe, effective and affordable GBS disease prevention is needed.

Angood C, Khara T, Dolan C, Berkley JA, WaSt Technical Interest Group. 2016. Research Priorities on the Relationship between Wasting and Stunting. PLoS One, 11 (5), pp. e0153221. | Show Abstract | Read more

BACKGROUND: Wasting and stunting are global public health problems that frequently co-exist. However, they are usually separated in terms of policy, guidance, programming and financing. Though both wasting and stunting are manifestations of undernutrition caused by disease and poor diet, there are critical gaps in our understanding of the physiological relationship between them, and how interventions for one may affect the other. The aim of this exercise was to establish research priorities in the relationships between wasting and stunting to guide future research investments. METHODS AND FINDINGS: We used the CHNRI (Child Health and Nutrition Research Initiative) methodology for setting research priorities in health. We utilised a group of experts in nutrition, growth and child health to prioritise 30 research questions against three criteria (answerability, usefulness and impact) using an online survey. Eighteen of 25 (72%) experts took part and prioritised research directly related to programming, particularly at the public health level. The highest-rated questions were: "Can interventions outside of the 1000 days, e.g. pre-school, school age and adolescence, lead to catch-up in height and in other developmental markers?"; "What timely interventions work to mitigate seasonal peaks in both wasting and stunting?"; and "What is the optimal formulation of ready-to-use foods to promote optimal ponderal growth and also support linear growth during and after recovery from severe acute malnutrition?" There was a high level of agreement between experts, particularly for the highest ranking questions. CONCLUSIONS: Increased commitment to rigorous evaluations of treatment and prevention interventions at the public health level, addressing questions of the timing of intervention, and the extent to which impacts for both wasting and stunting can be achieved, is needed to inform global efforts to tackle undernutrition and its consequences.

Bourke CD, Berkley JA, Prendergast AJ. 2016. Immune Dysfunction as a Cause and Consequence of Malnutrition. Trends Immunol, 37 (6), pp. 386-398. | Show Abstract | Read more

Malnutrition, which encompasses under- and overnutrition, is responsible for an enormous morbidity and mortality burden globally. Malnutrition results from disordered nutrient assimilation but is also characterized by recurrent infections and chronic inflammation, implying an underlying immune defect. Defects emerge before birth via modifications in the immunoepigenome of malnourished parents, and these may contribute to intergenerational cycles of malnutrition. This review summarizes key recent studies from experimental animals, in vitro models, and human cohorts, and proposes that immune dysfunction is both a cause and a consequence of malnutrition. Focusing on childhood undernutrition, we highlight gaps in current understanding of immune dysfunction in malnutrition, with a view to therapeutically targeting immune pathways as a novel means to reduce morbidity and mortality.

Talbert AW, Ngari M, Tsofa B, Mramba L, Mumbo E, Berkley JA, Mwangome M. 2016. "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. Int Breastfeed J, 11 (1), pp. 10. | Show Abstract | Read more

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.

Sheppard AE, Vaughan A, Jones N, Turner P, Turner C, Efstratiou A, Patel D, Modernising Medical Microbiology Informatics Group, Walker AS, Berkley JA et al. 2016. Capsular Typing Method for Streptococcus agalactiae Using Whole-Genome Sequence Data. J Clin Microbiol, 54 (5), pp. 1388-1390. | Show Abstract | Read more

Group B streptococcus (GBS) capsular serotypes are major determinants of virulence and affect potential vaccine coverage. Here we report a whole-genome-sequencing-based method for GBS serotype assignment. This method shows strong agreement (kappa of 0.92) with conventional methods and increased serotype assignment (100%) to all 10 capsular types.

Lafond KE, Nair H, Rasooly MH, Valente F, Booy R, Rahman M, Kitsutani P, Yu H, Guzman G, Coulibaly D et al. 2016. Global Role and Burden of Influenza in Pediatric Respiratory Hospitalizations, 1982-2012: A Systematic Analysis. PLoS Med, 13 (3), pp. e1001977. | Show Abstract | Read more

BACKGROUND: The global burden of pediatric severe respiratory illness is substantial, and influenza viruses contribute to this burden. Systematic surveillance and testing for influenza among hospitalized children has expanded globally over the past decade. However, only a fraction of the data has been used to estimate influenza burden. In this analysis, we use surveillance data to provide an estimate of influenza-associated hospitalizations among children worldwide. METHODS AND FINDINGS: We aggregated data from a systematic review (n = 108) and surveillance platforms (n = 37) to calculate a pooled estimate of the proportion of samples collected from children hospitalized with respiratory illnesses and positive for influenza by age group (<6 mo, <1 y, <2 y, <5 y, 5-17 y, and <18 y). We applied this proportion to global estimates of acute lower respiratory infection hospitalizations among children aged <1 y and <5 y, to obtain the number and per capita rate of influenza-associated hospitalizations by geographic region and socio-economic status. Influenza was associated with 10% (95% CI 8%-11%) of respiratory hospitalizations in children <18 y worldwide, ranging from 5% (95% CI 3%-7%) among children <6 mo to 16% (95% CI 14%-20%) among children 5-17 y. On average, we estimated that influenza results in approximately 374,000 (95% CI 264,000 to 539,000) hospitalizations in children <1 y-of which 228,000 (95% CI 150,000 to 344,000) occur in children <6 mo-and 870,000 (95% CI 610,000 to 1,237,000) hospitalizations in children <5 y annually. Influenza-associated hospitalization rates were more than three times higher in developing countries than in industrialized countries (150/100,000 children/year versus 48/100,000). However, differences in hospitalization practices between settings are an important limitation in interpreting these findings. CONCLUSIONS: Influenza is an important contributor to respiratory hospitalizations among young children worldwide. Increasing influenza vaccination coverage among young children and pregnant women could reduce this burden and protect infants <6 mo.

Seale AC, Davies MR, Anampiu K, Morpeth SC, Nyongesa S, Mwarumba S, Smeesters PR, Efstratiou A, Karugutu R, Mturi N et al. 2016. Invasive Group A Streptococcus Infection among Children, Rural Kenya. Emerg Infect Dis, 22 (2), pp. 224-232. | Show Abstract | Read more

To determine the extent of group A Streptococcus (GAS) infections in sub-Saharan Africa and the serotypes that cause disease, we analyzed surveillance data for 64,741 hospital admissions in Kilifi, Kenya, during 1998-2011. We evaluated incidence, clinical presentations, and emm types that cause invasive GAS infection. We detected 370 cases; of the 369 for which we had data, most were skin and soft tissue infections (70%), severe pneumonia (23%), and primary bacteremia (14%). Overall case-fatality risk was 12%. Incidence of invasive GAS infection was 0.6 cases/1,000 live births among neonates, 101/100,000 person-years among children <1 year of age, and 35/100,000 among children <5 years of age. Genome sequencing identified 88 emm types. GAS causes serious disease in children in rural Kenya, especially neonates, and the causative organisms have considerable genotypic diversity. Benefit from the most advanced GAS type-specific vaccines may be limited, and efforts must be directed to protect against disease in regions of high incidence.

Lo Vecchio A, Dias JA, Berkley JA, Boey C, Cohen MB, Cruchet S, Liguoro I, Salazar Lindo E, Sandhu B, Sherman P et al. 2016. Comparison of Recommendations in Clinical Practice Guidelines for Acute Gastroenteritis in Children. J Pediatr Gastroenterol Nutr, 63 (2), pp. 226-235. | Show Abstract | Read more

OBJECTIVE: Acute gastroenteritis (AGE) is a major cause of child mortality and morbidity. This study aimed at systematically reviewing clinical practice guidelines (CPGs) on AGE to compare recommendations and provide the basis for developing single universal guidelines. METHODS: CPGs were identified by searching MEDLINE, Cochrane-Library, National Guideline Clearinghouse and Web sites of relevant societies/organizations producing and/or endorsing CPGs. RESULTS: The definition of AGE varies among the 15 CPGs identified. The parameters most frequently recommended to assess dehydration are skin turgor and sunken eyes (11/15, 73.3%), general appearance (11/15, 66.6%), capillary refill time, and mucous membranes appearance (9/15, 60%). Oral rehydration solution is universally recognized as first-line treatment. The majority of CPGs recommend hypo-osmolar (Na 45-60 mmol/L, 11/15, 66.6 %) or low-osmolality (Na 75 mmol/L, 9/15, 60%) solutions. In children who fail oral rehydration, most CPGs suggest intravenous rehydration (66.6%). However, nasogastric tube insertion for fluid administration is preferred according by 5/15 CPGs (33.3%). Changes in diet and withdrawal of food are discouraged by all CPGs, and early refeeding is strongly recommended in 13 of 15 (86.7%). Zinc is recommended as an adjunct to ORS by 10 of 15 (66.6%) CPGs, most of them from low-income countries. Probiotics are considered by 9 of 15 (60%) CPGs, 5 from high-income countries. Antiemetics are not recommended in 9 of 15 (60%) CPGs. Routine use of antibiotics is discouraged. CONCLUSIONS: Key recommendations for the management of AGE in children are similar in CPGs. Together with accurate review of evidence-base this may represent a starting point for developing universal recommendations for the management of children with AGE worldwide.

Kinyoki DK, Kandala N-B, Manda SO, Krainski ET, Fuglstad G-A, Moloney GM, Berkley JA, Noor AM. 2016. Assessing comorbidity and correlates of wasting and stunting among children in Somalia using cross-sectional household surveys: 2007 to 2010. BMJ Open, 6 (3), pp. e009854. | Show Abstract | Read more

OBJECTIVE: Wasting and stunting may occur together at the individual child level; however, their shared geographic distribution and correlates remain unexplored. Understanding shared and separate correlates may inform interventions. We aimed to assess the spatial codistribution of wasting, stunting and underweight and investigate their shared correlates among children aged 6-59 months in Somalia. SETTING: Cross-sectional nutritional assessments surveys were conducted using structured interviews among communities in Somalia biannually from 2007 to 2010. A two-stage cluster sampling methodology was used to select children aged 6-59 months from households across three livelihood zones (pastoral, agropastoral and riverine). Using these data and environmental covariates, we implemented a multivariate spatial technique to estimate the codistribution and divergence of the risks and correlates of wasting and stunting at the 1 × 1 km spatial resolution. PARTICIPANTS: 73,778 children aged 6-59 months from 1066 survey clusters in Somalia. RESULTS: Observed pairwise child level empirical correlations were 0.30, 0.70 and 0.73 between weight-for-height and height-for-age; height-for-age and weight-for-age, and weight-for-height and weight-for-age, respectively. Access to foods with high protein content and vegetation cover, a proxy of rainfall or drought, were associated with lower risk of wasting and stunting. Age, gender, illness, access to carbohydrates and temperature were correlates of all three indicators. The spatial codistribution was highest between stunting and underweight with relative risk values ranging between 0.15 and 6.20, followed by wasting and underweight (range: 0.18-5.18) and lowest between wasting and stunting (range: 0.26-4.32). CONCLUSIONS: The determinants of wasting and stunting are largely shared, but their correlation is relatively variable in space. Significant hotspots of different forms of malnutrition occurred in the South Central regions of the country. Although nutrition response in Somalia has traditionally focused on wasting rather than stunting, integrated programming and interventions can effectively target both conditions to alleviate common risk factors.

Kvissberg MA, Dalvi PS, Kerac M, Voskuijl W, Berkley JA, Priebe MG, Bandsma RHJ. 2016. Carbohydrate malabsorption in acutely malnourished children and infants: a systematic review. Nutr Rev, 74 (1), pp. 48-58. | Show Abstract | Read more

CONTEXT: Severe acute malnutrition (SAM) accounts for approximately 1 million child deaths per year. High mortality is linked with comorbidities, such as diarrhea and pneumonia. OBJECTIVE: The aim of this systematic review was to determine the extent to which carbohydrate malabsorption occurs in children with SAM. DATA SOURCES: The PubMed and Embase databases were searched. Reference lists of selected articles were checked. DATA EXTRACTION: All observational and controlled intervention studies involving children with SAM in which direct or indirect measures of carbohydrate absorption were analyzed were eligible for inclusion. A total of 20 articles were selected for this review. DATA SYNTHESIS: Most studies reported carbohydrate malabsorption, particularly lactose malabsorption, and suggested an increase in diarrhea and reduced weight gain in children on a lactose-containing diet. As most studies reviewed were observational, there was no conclusive scientific evidence of a causal relationship between lactose malabsorption and a worse clinical outcome among malnourished children. CONCLUSION: The combined data indicate that carbohydrate malabsorption is prevalent in children with SAM. Additional well-designed intervention studies are needed to determine whether outcomes of SAM complicated by carbohydrate malabsorption could be improved by altering the carbohydrate/lactose content of therapeutic feeds and to elucidate the precise mechanisms involved.

Garcia-Knight MA, Nduati E, Hassan AS, Gambo F, Odera D, Etyang TJ, Hajj NJ, Berkley JA, Urban BC, Rowland-Jones SL. 2015. Altered Memory T-Cell Responses to Bacillus Calmette-Guerin and Tetanus Toxoid Vaccination and Altered Cytokine Responses to Polyclonal Stimulation in HIV-Exposed Uninfected Kenyan Infants. PLoS One, 10 (11), pp. e0143043. | Show Abstract | Read more

Implementation of successful prevention of mother-to-child transmission of HIV strategies has resulted in an increased population of HIV-exposed uninfected (HEU) infants. HEU infants have higher rates of morbidity and mortality than HIV-unexposed (HU) infants. Numerous factors may contribute to poor health in HEU infants including immunological alterations. The present study assessed T-cell phenotype and function in HEU infants with a focus on memory Th1 responses to vaccination. We compared cross-sectionally selected parameters at 3 and 12 months of age in HIV-exposed (n = 42) and HU (n = 28) Kenyan infants. We measured ex vivo activated and bulk memory CD4 and CD8 T-cells and regulatory T-cells by flow cytometry. In addition, we measured the magnitude, quality and memory phenotype of antigen-specific T-cell responses to Bacillus Calmette-Guerin and Tetanus Toxoid vaccine antigens, and the magnitude and quality of the T cell response following polyclonal stimulation with staphylococcal enterotoxin B. Finally, the influence of maternal disease markers on the immunological parameters measured was assessed in HEU infants. Few perturbations were detected in ex vivo T-cell subsets, though amongst HEU infants maternal HIV viral load positively correlated with CD8 T cell immune activation at 12 months. Conversely, we observed age-dependent differences in the magnitude and polyfunctionality of IL-2 and TNF-α responses to vaccine antigens particularly in Th1 cells. These changes mirrored those seen following polyclonal stimulation, where at 3 months, cytokine responses were higher in HEU infants compared to HU infants, and at 12 months, HEU infant cytokine responses were consistently lower than those seen in HU infants. Finally, reduced effector memory Th1 responses to vaccine antigens were observed in HEU infants at 3 and 12 months and higher central memory Th1 responses to M. tuberculosis antigens were observed at 3 months only. Long-term monitoring of vaccine efficacy and T-cell immunity in this vulnerable population is warranted.

Muthumbi E, Morpeth SC, Ooko M, Mwanzu A, Mwarumba S, Mturi N, Etyang AO, Berkley JA, Williams TN, Kariuki S, Scott JAG. 2015. Invasive Salmonellosis in Kilifi, Kenya. Clin Infect Dis, 61 Suppl 4 (suppl 4), pp. S290-S301. | Show Abstract | Read more

BACKGROUND: Invasive salmonelloses are a major cause of morbidity and mortality in Africa, but the incidence and case fatality of each disease vary markedly by region. We aimed to describe the incidence, clinical characteristics, and antimicrobial susceptibility patterns of invasive salmonelloses among children and adults in Kilifi, Kenya. METHODS: We analyzed integrated clinical and laboratory records for patients presenting to the Kilifi County Hospital between 1998 and 2014. We calculated incidence, and summarized clinical features and multidrug resistance. RESULTS: Nontyphoidal Salmonella (NTS) accounted for 10.8% and 5.8% of bacteremia cases in children and adults, respectively, while Salmonella Typhi accounted for 0.5% and 2.1%, respectively. Among 351 NTS isolates serotyped, 160 (45.6%) were Salmonella Enteritidis and 152 (43.3%) were Salmonella Typhimurium. The incidence of NTS in children aged <5 years was 36.6 per 100 000 person-years, being highest in infants aged <7 days (174/100 000 person-years). The overall incidence of NTS in children varied markedly by location and declined significantly during the study period; the pattern of dominance of the NTS serotypes also shifted from Salmonella Enteritidis to Salmonella Typhimurium. Risk factors for invasive NTS disease were human immunodeficiency virus infection, malaria, and malnutrition; the case fatality ratio was 22.1% (71/321) in children aged <5 years and 36.7% (11/30) in adults. Multidrug resistance was present in 23.9% (84/351) of NTS isolates and 46.2% (12/26) of Salmonella Typhi isolates. CONCLUSIONS: In Kilifi, the incidence of invasive NTS was high, especially among newborn infants, but typhoid fever was uncommon. NTS remains an important cause of bacteremia in children <5 years of age.

Nduati EW, Hassan AS, Knight MG, Muema DM, Jahangir MN, Mwaringa SL, Etyang TJ, Rowland-Jones S, Urban BC, Berkley JA. 2015. Outcomes of prevention of mother to child transmission of the human immunodeficiency virus-1 in rural Kenya--a cohort study. BMC Public Health, 15 (1), pp. 1008. | Show Abstract | Read more

BACKGROUND: Success in prevention of mother-to-child transmission (PMTCT) raises the prospect of eliminating pediatric HIV infection. To achieve global elimination, however, strategies are needed to strengthen PMTCT interventions. This study aimed to determine PMTCT outcomes and identify challenges facing its successful implementation in a rural setting in Kenya. METHODS: A retrospective cohort design was used. Routine demographic and clinical data for infants and mothers enrolling for PMTCT care at a rural hospital in Kenya were analysed. Cox and logistic regression were used to determine factors associated with retention and vertical transmission respectively. RESULTS: Between 2006 and 2012, 1338 infants were enrolled and followed up for PMTCT care with earlier age of enrollment and improved retention observed over time. Mother to child transmission of HIV declined from 19.4 % in 2006 to 8.9 % in 2012 (non-parametric test for trend p = 0.024). From 2009 to 2012, enrolling for care after 6 months of age, adjusted Odds Ratio [aOR]: 23.3 [95 % confidence interval (CI): 8.3-65.4], presence of malnutrition ([aOR]: 2.3 [95 % CI: 1.1-5.2]) and lack of maternal use of highly active antiretroviral therapy (HAART) (aOR: 6.5 [95 % CI: 1.4-29.4]) was associated with increased risk of HIV infection. Infant's older age at enrollment, malnutrition and maternal HAART status, were also associated with drop out from care. Infants who were not actively followed up were more likely to drop out from care (adjusted Hazard Ratio: 6.6 [95 % CI: 2.9-14.6]). DISCUSSION: We report a temporal increase in the proportion of infants enrolling for PMTCT care before 3 months of age, improved retention in PMTCT and a significant reduction in the proportion of infants enrolled who became HIV-infected, emphasizing the benefits of PMTCT. CONCLUSION: A simple set of risk factors at enrollment can identify mother-infant pairs most at risk of infection or drop out for targeted intervention.

Muema DM, Macharia GN, Hassan AS, Mwaringa SM, Fegan GW, Berkley JA, Nduati EW, Urban BC. 2015. Control of Viremia Enables Acquisition of Resting Memory B Cells with Age and Normalization of Activated B Cell Phenotypes in HIV-Infected Children. J Immunol, 195 (3), pp. 1082-1091. | Show Abstract | Read more

HIV affects the function of all lymphocyte populations, including B cells. Phenotypic and functional defects of B cells in HIV-infected adults have been well characterized, but defects in children have not been studied to the same extent. We determined the proportion of B cell subsets and frequencies of Ag-specific memory B cells in peripheral blood from HIV-infected children and healthy controls, using flow cytometry and B cell ELISPOT, respectively. In addition, we measured the quantities and avidities of plasma Abs against various Ags by ELISA. We also determined plasma levels of BAFF and expression of BAFF receptors on B cells. Children with high HIV viremia had increased proportions of activated mature B cells, tissue-like memory B cells and plasmablasts, and low proportions of naive B cells when compared with community controls and children with low HIV viremia, similar to adults infected with HIV. HIV-infected groups had lower proportions of resting memory B cells than did community controls. Notably, high HIV viremia prevented the age-dependent accumulation of class-switched resting memory B cells. HIV-infected children, regardless of the level of viremia, showed lower quantities and avidities of IgG and lower frequencies of memory B cells against Expanded Program on Immunization vaccines. The HIV-infected children had an altered BAFF profile that could have affected their B cell compartment. Therefore, B cell defects in HIV-infected children are similar to those seen in HIV-infected adults. However, control of HIV viremia is associated with normalization of activated B cell subsets and allows age-dependent accumulation of resting memory B cells.

Brenna JT, Akomo P, Bahwere P, Berkley JA, Calder PC, Jones KD, Liu L, Manary M, Trehan I, Briend A. 2015. Balancing omega-6 and omega-3 fatty acids in ready-to-use therapeutic foods (RUTF). BMC Med, 13 (1), pp. 117. | Show Abstract | Read more

Ready-to-use therapeutic foods (RUTFs) are a key component of a life-saving treatment for young children who present with uncomplicated severe acute malnutrition in resource limited settings. Increasing recognition of the role of balanced dietary omega-6 and omega-3 polyunsaturated fatty acids (PUFA) in neurocognitive and immune development led two independent groups to evaluate RUTFs. Jones et al. (BMC Med 13:93, 2015), in a study in BMC Medicine, and Hsieh et al. (J Pediatr Gastroenterol Nutr 2015), in a study in the Journal of Pediatric Gastroenterology and Nutrition, reformulated RUTFs with altered PUFA content and looked at the effects on circulating omega-3 docosahexaenoic acid (DHA) status as a measure of overall omega-3 status. Supplemental oral administration of omega-3 DHA or reduction of RUTF omega-6 linoleic acid using high oleic peanuts improved DHA status, whereas increasing omega-3 alpha-linolenic acid in RUTF did not. The results of these two small studies are consistent with well-established effects in animal studies and highlight the need for basic and operational research to improve fat composition in support of omega-3-specific development in young children as RUTF use expands.

Jones KDJ, Ali R, Khasira MA, Odera D, West AL, Koster G, Akomo P, Talbert AWA, Goss VM, Ngari M et al. 2015. 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. BMC Med, 13 (1), pp. 93. | Show Abstract | Read more

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.

Seale AC, Obiero CW, Berkley JA. 2015. Rational development of guidelines for management of neonatal sepsis in developing countries. Curr Opin Infect Dis, 28 (3), pp. 225-230. | Show Abstract | Read more

PURPOSE OF REVIEW: This review discusses the rational development of guidelines for the management of neonatal sepsis in developing countries. RECENT FINDINGS: Diagnosis of neonatal sepsis with high specificity remains challenging in developing countries. Aetiology data, particularly from rural, community-based studies, are very limited, but molecular tests to improve diagnostics are being tested in a community-based study in South Asia. Antibiotic susceptibility data are limited, but suggest reducing susceptibility to first-and second-line antibiotics in both hospital and community-acquired neonatal sepsis. Results of clinical trials in South Asia and sub-Saharan Africa assessing feasibility of simplified antibiotic regimens are awaited. SUMMARY: Effective management of neonatal sepsis in developing countries is essential to reduce neonatal mortality and morbidity. Simplified antibiotic regimens are currently being examined in clinical trials, but reduced antimicrobial susceptibility threatens current empiric treatment strategies. Improved clinical and microbiological surveillance is essential, to inform current practice, treatment guidelines, and monitor implementation of policy changes.

Kinyoki DK, Berkley JA, Moloney GM, Odundo EO, Kandala N-B, Noor AM. 2016. Space-time mapping of wasting among children under the age of five years in Somalia from 2007 to 2010. Spat Spatiotemporal Epidemiol, 16 pp. 77-87. | Show Abstract | Read more

OBJECTIVE: To determine the sub-national seasonal prevalence and trends in wasting from 2007 to 2010 among children aged 6-59 months in Somalia using remote sensing and household survey data from nutritional surveys. METHODS: Bayesian hierarchical space-time model was implemented using a stochastic partial differential equation (SPDE) approach in integrated nested Laplace approximations (INLA) to produce risk maps of wasting at 1 × 1 km(2) spatial resolution and predict to seasons in each year of study from 2007 to 2010. RESULTS: The prevalence of wasting was generally at critical levels throughout the country, with most of the areas remaining in the upper classes of critical and very critical levels. There was minimal variation in wasting from year-to-year, but a well-defined seasonal variation was observed. The mean difference of the prevalence of wasting between the dry and wet season ranges from 0% to 5%. The risks of wasting in the South Central zone were highest in the Gedo (37%) and Bay (32%) regions. In North East zone the risk was highest in Nugaal (25%) and in the North West zone the risk was high in Awdal and Woqooyi Galbeed regions with 23%. CONCLUSION: There was a clear seasonal variation in wasting with minimal year-to-year variability from 2007 to 2010 in Somalia. The prevalence was high during the long dry season, which affects the prevalence in the preceding long rainy season. Understanding the seasonal fluctuations of wasting in different locations and at different times is important to inform timely interventions.

Angood C, McGrath M, Mehta S, Mwangome M, Lung'aho M, Roberfroid D, Perry A, Wilkinson C, Israel A-D, Bizouerne C et al. 2015. Research priorities to improve the management of acute malnutrition in infants aged less than six months (MAMI). PLoS Med, 12 (4), pp. e1001812. | Read more

Obiero CW, Seale AC, Berkley JA. 2015. Empiric treatment of neonatal sepsis in developing countries. Pediatr Infect Dis J, 34 (6), pp. 659-661. | Show Abstract | Read more

Infections are among the leading causes of neonatal mortality, and about 75% of the burden occurs in developing countries. Diagnosis of neonatal sepsis in these countries is dependent on the recognition of a set of nonspecific clinical signs that maximize sensitivity because staff making initial assessments may not have specialist pediatric training. Accurate diagnosis is usually limited by the unavailability of reliable microbiological investigation. The World Health Organization recommends ampicillin (or penicillin; cloxacillin if staphylococcal infection is suspected) plus gentamicin for empiric treatment of neonates with suspected clinical sepsis or meningitis. However, there is a lack of comprehensive data on the causes of infection and antimicrobial susceptibility in developing countries to support these recommendations, especially in rural settings. Bacterial pathogens (predominantly Gram negative) with reduced susceptibility to empiric medication have been reported, with variations both between and within regions. Nosocomial infections with resistant organisms and high case fatality challenge the first-line use of cephalosporins. Improving local surveillance data using standardized antimicrobial susceptibility testing methods and validation of diagnostic algorithms against microbial findings are essential. Standardized reporting of treatment outcomes is required to evaluate practice, provide guidance on second-line regimes and for studies of new approaches, such as simplified community-based regimens, and to determine the appropriate duration of empiric treatment for apparently low-risk neonates with early resolution of clinical signs, or where available, negative blood cultures. Thus, a multifaceted approach, with attention to microbiological quality assurance, is needed to better guide antimicrobial use and reduce mortality and long-term impairments.

Kinyoki DK, Berkley JA, Moloney GM, Kandala N-B, Noor AM. 2015. Predictors of the risk of malnutrition among children under the age of 5 years in Somalia. Public Health Nutr, 18 (17), pp. 3125-3133. | Show Abstract | Read more

OBJECTIVE: To investigate the predictors of wasting, stunting and low mid-upper arm circumference among children aged 6-59 months in Somalia using data from household cross-sectional surveys from 2007 to 2010 in order to help inform better targeting of nutritional interventions. DESIGN: Cross-sectional nutritional assessment surveys using structured interviews were conducted among communities in Somalia each year from 2007 to 2010. A two-stage cluster sampling methodology was used to select children aged 6-59 months from households across three livelihood zones (pastoral, agro-pastoral and riverine). Predictors of three anthropometric measures, weight-for-height (wasting), height-for-age (stunting) and mid-upper arm circumference, were analysed using Bayesian binomial regression, controlling for both spatial and temporal dependence in the data. SETTING: The study was conducted in randomly sampled villages, representative of three livelihood zones in Somalia. SUBJECTS: Children between the ages of 6 and 59 months in Somalia. RESULTS: The estimated national prevalence of wasting, stunting and low mid-upper arm circumference in children aged 6-59 months was 21 %, 31 % and 36 %, respectively. Although fever, diarrhoea, sex and age of the child, household size and access to foods were significant predictors of malnutrition, the strongest association was observed between all three indicators of malnutrition and the enhanced vegetation index. A 1-unit increase in enhanced vegetation index was associated with a 38 %, 49 % and 59 % reduction in wasting, stunting and low mid-upper arm circumference, respectively. CONCLUSIONS: Infection and climatic variations are likely to be key drivers of malnutrition in Somalia. Better health data and close monitoring and forecasting of droughts may provide valuable information for nutritional intervention planning in Somalia.

Badurdeen S, Mulongo M, Berkley JA. 2015. Arginine depletion increases susceptibility to serious infections in preterm newborns PEDIATRIC RESEARCH, 77 (2), pp. 290-297. | Read more

Seale AC, Head MG, Fitchett EJA, Vergnano S, Saha SK, Heath PT, Sharland M, Lawn JE, SPRING. 2015. Neonatal infection: a major burden with minimal funding. Lancet Glob Health, 3 (11), pp. e669-e670. | Read more

Seale AC, Barsosio HC, Koech AC, Berkley JA, KIPMAT group. 2015. Embedding surveillance into clinical care to detect serious adverse events in pregnancy. Vaccine, 33 (47), pp. 6466-6468. | Show Abstract | Read more

Severe maternal complications in pregnancy in sub-Saharan Africa contribute to high maternal mortality and morbidity. Incidence data on severe maternal complications, life-threatening conditions, maternal deaths and birth outcomes are essential for clinical audit and to inform trial design of the types and frequency of expected severe adverse events (SAEs). However, such data are very limited, especially in sub-Saharan Africa. We set up standardized, systematic clinical surveillance embedded into routine clinical care in a rural county hospital in Kenya. Pregnant women and newborns are systematically assessed and investigated. Data are reported using a standardized Maternal Admission Record that forms both the hospital's clinical record and the data collection tool. Integrating clinical surveillance with routine clinical care is feasible and should be expanded in sub-Saharan Africa, both for improving clinical practice and as a basis for intervention studies to reduce maternal and newborn mortality and morbidity where rates are highest.

Ginsburg AS, Izadnegahdar R, Berkley JA, Walson JL, Rollins N, Klugman KP. 2015. Undernutrition and pneumonia mortality. Lancet Glob Health, 3 (12), pp. e735-e736. | Read more

George EC, Walker AS, Kiguli S, Olupot-Olupot P, Opoka RO, Engoru C, Akech SO, Nyeko R, Mtove G, Reyburn H et al. 2015. Predicting mortality in sick African children: the FEAST Paediatric Emergency Triage (PET) Score. BMC Med, 13 (1), pp. 174. | Show Abstract | Read more

BACKGROUND: Mortality in paediatric emergency care units in Africa often occurs within the first 24 h of admission and remains high. Alongside effective triage systems, a practical clinical bedside risk score to identify those at greatest risk could contribute to reducing mortality. METHODS: Data collected during the Fluid As Expansive Supportive Therapy (FEAST) trial, a multi-centre trial involving 3,170 severely ill African children, were analysed to identify clinical and laboratory prognostic factors for mortality. Multivariable Cox regression was used to build a model in this derivation dataset based on clinical parameters that could be quickly and easily assessed at the bedside. A score developed from the model coefficients was externally validated in two admissions datasets from Kilifi District Hospital, Kenya, and compared to published risk scores using Area Under the Receiver Operating Curve (AUROC) and Hosmer-Lemeshow tests. The Net Reclassification Index (NRI) was used to identify additional laboratory prognostic factors. RESULTS: A risk score using 8 clinical variables (temperature, heart rate, capillary refill time, conscious level, severe pallor, respiratory distress, lung crepitations, and weak pulse volume) was developed. The score ranged from 0-10 and had an AUROC of 0.82 (95 % CI, 0.77-0.87) in the FEAST trial derivation set. In the independent validation datasets, the score had an AUROC of 0.77 (95 % CI, 0.72-0.82) amongst admissions to a paediatric high dependency ward and 0.86 (95 % CI, 0.82-0.89) amongst general paediatric admissions. This discriminative ability was similar to, or better than other risk scores in the validation datasets. NRI identified lactate, blood urea nitrogen, and pH to be important prognostic laboratory variables that could add information to the clinical score. CONCLUSIONS: Eight clinical prognostic factors that could be rapidly assessed by healthcare staff for triage were combined to create the FEAST Paediatric Emergency Triage (PET) score and externally validated. The score discriminated those at highest risk of fatal outcome at the point of hospital admission and compared well to other published risk scores. Further laboratory tests were also identified as prognostic factors which could be added if resources were available or as indices of severity for comparison between centres in future research studies.

Kerac M, Mwangome M, McGrath M, Haider R, Berkley JA. 2015. Management of acute malnutrition in infants aged under 6 months (MAMI): current issues and future directions in policy and research. Food Nutr Bull, 36 (1 Suppl), pp. S30-S34. | Show Abstract | Read more

BACKGROUND: Globally, some 4.7 million infants aged under 6 months are moderately wasted and 3.8 million are severely wasted. Traditionally, they have been over-looked by clinicians, nutritionists, and policy makers. OBJECTIVE: To present evidence and arguments for why treating acute malnutrition in infants under 6 months of age is important and outline some of the key debates and research questions needed to advance their care. METHODS: Narrative review. RESULTS AND CONCLUSIONS: Treating malnourished infants under 6 months of age is important to avoid malnutrition-associated mortality in the short-term and adverse health and development outcomes in the long-term. Physiological and pathological differences demand a different approach from that in older children; key among these is a focus on exclusive breastfeeding wherever possible. New World Health Organization guidelines for the management of severe acute malnutrition (SAM) include this age group for the first time and are also applicable to management of moderate acute malnutrition (MAM). Community-based breastfeeding support is the core, but not the sole, treatment. The mother-infant dyad is at the heart of approaches, but wider family and community relationships are also important. An urgent priority is to develop better case definitions; criteria based on mid-upper-arm circumference (MUAC) are promising but need further research. To effectively move forward, clinical trials of assessment and treatment are needed to bolster the currently sparse evidence base. In the meantime, nutrition surveys and screening at health facilities should routinely include infants under 6 months of age in order to better define the burden and outcomes of acute malnutrition in this age group.

Ibinda F, Bauni E, Kariuki SM, Fegan G, Lewa J, Mwikamba M, Boga M, Odhiambo R, Mwagandi K, Seale AC et al. 2015. Incidence and risk factors for neonatal tetanus in admissions to Kilifi County Hospital, Kenya. PLoS One, 10 (4), pp. e0122606. | Show Abstract | Read more

BACKGROUND: Neonatal Tetanus (NT) is a preventable cause of mortality and neurological sequelae that occurs at higher incidence in resource-poor countries, presumably because of low maternal immunisation rates and unhygienic cord care practices. We aimed to determine changes in the incidence of NT, characterize and investigate the associated risk factors and mortality in a prospective cohort study including all admissions over a 15-year period at a County hospital on the Kenyan coast, a region with relatively high historical NT rates within Kenya. METHODS: We assessed all neonatal admissions to Kilifi County Hospital in Kenya (1999-2013) and identified cases of NT (standard clinical case definition) admitted during this time. Poisson regression was used to examine change in incidence of NT using accurate denominator data from an area of active demographic surveillance. Logistic regression was used to investigate the risk factors for NT and factors associated with mortality in NT amongst neonatal admissions. A subset of sera from mothers (n = 61) and neonates (n = 47) were tested for anti-tetanus antibodies. RESULTS: There were 191 NT admissions, of whom 187 (98%) were home deliveries. Incidence of NT declined significantly (Incidence Rate Ratio: 0.85 (95% Confidence interval 0.81-0.89), P<0.001) but the case fatality (62%) did not change over the study period (P = 0.536). Younger infant age at admission (P = 0.001) was the only independent predictor of mortality. Compared to neonatal hospital admittee controls, the proportion of home births was higher among the cases. Sera tested for antitetanus antibodies showed most mothers (50/61, 82%) had undetectable levels of antitetanus antibodies, and most (8/9, 89%) mothers with detectable antibodies had a neonate without protective levels. CONCLUSIONS: Incidence of NT in Kilifi County has significantly reduced, with reductions following immunisation campaigns. Our results suggest immunisation efforts are effective if sustained and efforts should continue to expand coverage.

Hassan AS, Mwaringa SM, Ndirangu KK, Sanders EJ, de Wit TFR, Berkley JA. 2015. Incidence and predictors of attrition from antiretroviral care among adults in a rural HIV clinic in Coastal Kenya: a retrospective cohort study. BMC Public Health, 15 (1), pp. 478. | Show Abstract | Read more

BACKGROUND: Scale up of antiretroviral therapy (ART) has led to substantial declines in HIV related morbidity and mortality. However, attrition from ART care remains a major public health concern and has been identified as one of the key reportable indicators in assessing the success of ART programs. This study describes the incidence and predictors of attrition among adults initiating ART in a rural HIV clinic in Coastal Kenya. METHODS: A retrospective cohort study design was used. Adults (≥ 15 years) initiated ART between January 2008 and December 2010 were followed up for two years. Attrition was defined as individuals who were either reported dead or lost to follow up (LFU, ≥ 180 days late since the last clinic visit). Kaplan Meier survival probabilities and Weibull baseline hazard regression analyses were used to model the incidence and predictors of time to attrition. RESULTS: Of the 928 eligible participants, 308 (33.2% [95% CI, 30.2 - 36.3]) underwent attrition at an incident rate of 23.1 (95% CI, 20.6 - 25.8)/100 pyo. Attrition at 6 and 12 months was 18.4% (95% CI, 16.0 - 21.1) and 23.2% (95% CI, 19.9 - 25.3) respectively. Gender (male vs. female, adjusted hazard ratio [95% CI], p-value: 1.5 [1.1 - 2.0], p = 0.014), age (15 - 24 vs. ≥ 45 years, 2.2 [1.3 - 3.7], p = 0.034) and baseline CD4 T-cell count (100 - 350 cells/uL vs. < 100 cells/uL, 0.5 [0.3 - 0.7], p = 0.002) were independent predictors of time to attrition. CONCLUSIONS: A third of individuals initiating ART were either reported dead or LFU during two years of care, with more than a half of these occurring within six months of treatment initiation. Practical and sustainable biomedical interventions and psychosocial support systems are warranted to improve ART retention in this setting.

Crane RJ, Jones KDJ, Berkley JA. 2015. Environmental enteric dysfunction: an overview. Food Nutr Bull, 36 (1 Suppl), pp. S76-S87. | Show Abstract | Read more

BACKGROUND: Environmental enteric dysfunction (EED) refers to an incompletely defined syndrome of inflammation, reduced absorptive capacity, and reduced barrier function in the small intestine. It is widespread among children and adults in low- and middle-income countries. Understanding of EED and its possible consequences for health is currently limited. OBJECTIVE: A narrative review of the current understanding of EED: epidemiology, pathogenesis, therapies, and relevance to child health. METHODS: Searches for key papers and ongoing trials were conducted using PUBMED 1966-June 2014; ClinicalTrials.gov; the WHO Clinical Trials Registry; the Cochrane Library; hand searches of the references of retrieved literature; discussions with experts; and personal experience from the field. RESULTS: EED is established during infancy and is associated with poor sanitation, certain gut infections, and micronutrient deficiencies. Helicobacter pylori infection, small intestinal bacterial overgrowth (SIBO), abnormal gut microbiota, undernutrition, and toxins may all play a role. EED is usually asymptomatic, but it is important due to its association with stunting. Diagnosis is frequently by the dual sugar absorption test, although other biomarkers are emerging. EED may partly explain the reduced efficacy of oral vaccines in low- and middle-income countries and the increased risk of serious infection seen in children with undernutrition. CONCLUSIONS: Despite its potentially significant impacts, it is currently unclear exactly what causes EED and how it can be treated or prevented. Ongoing trials involve nutritional supplements, water and sanitation interventions, and immunomodulators. Further research is needed to better understand this condition, which is of likely crucial importance for child health and development in low- and middle-income settings.

Oluoch DA, Mwangome N, Kemp B, Seale AC, Koech A, Papageorghiou AT, Berkley JA, Kennedy SH, Jones COH. 2015. "You cannot know if it's a baby or not a baby": uptake, provision and perceptions of antenatal care and routine antenatal ultrasound scanning in rural Kenya. BMC Pregnancy Childbirth, 15 (1), pp. 127. | Show Abstract | Read more

BACKGROUND: Antenatal care early in pregnancy enables service providers to identify and manage risks to mother and fetus. In the global north, ultrasound scans are routinely offered in pregnancy to provide an accurate estimate of gestational age and identify potential problems. In sub-Saharan Africa, such services are rarely available and women often delay initiating antenatal care. This study describes the uptake and provision of antenatal care in a rural Kenyan hospital and explores how pregnant women and healthcare providers perceived the provision of ultrasound scanning, following its introduction in an international foetal growth study. METHODS: A descriptive study, using qualitative and quantitative methods, was conducted in Kilifi District Hospital, Kenya, between June 2011 and April 2012. In-depth interviews were conducted with 10 nurses working in the antenatal clinic (ANC) and 59 pregnant women attending ANC. Structured observations of 357 ANC consultations and 30 ultrasound scans were made. RESULTS: Women sought antenatal care for information about the health of their baby and the protection provided by the ANC services. Uncertainty about pregnancy status contributed to delay in ANC attendance; more than 78 % of women were over 20 weeks' gestation at their first visit. Healthcare workers found it difficult to detect pregnancies below 16 weeks gestation and, accurate assessment of gestational age below 20 weeks' gestation could be problematic. Provision of services depended on the pregnancy being detected and gestational age assessed. The "seeing", made possible through ultrasound scanning was perceived by pregnant women and healthcare workers to be beneficial: confirming the pregnancy, and providing reassurance about the fetus' condition. Few participants raised concerns about ultrasound scanning. CONCLUSIONS: Uncertainty about pregnancy status and gestational age for women and healthcare providers is a key factor influencing timing of ANC attendance, contributing to delays and restricting early provision of ANC services. Ultrasound scanning was perceived to enhance antenatal care through confirmation of pregnancy status and enabling more accurate estimation of gestational age and the health status of the fetus. There is a need to make available more affordable means of pregnancy testing as a strategy towards encouraging early attendance, and delivery of antenatal care.

Jones KDJ, Huenten-Kirsch B, Laving AMR, Munyi CW, Ngari M, Mikusa J, Mulongo MM, Odera D, Nassir HS, Timbwa M et al. 2014. Inflammatory bowel disease in Africa: hiding in plain sight? IMMUNOLOGY, 143 pp. 123-123.

Ahmed T, Auble D, Berkley JA, Black R, Ahern PP, Hossain M, Hsieh A, Ireen S, Arabi M, Gordon JI. 2014. An evolving perspective about the origins of childhood undernutrition and nutritional interventions that includes the gut microbiome. Ann N Y Acad Sci, 1332 (1), pp. 22-38. | Show Abstract | Read more

The Sackler Institute for Nutrition Science and the World Health Organization (WHO) have worked together to formulate a research agenda for nutrition science. Undernutrition of children has profound effects on health, development, and achievement of full human capacity. Undernutrition is not simply caused by a lack of food, but results from a complex interplay of intra- and intergenerational factors. Representative preclinical models and comprehensive well-controlled longitudinal clinical studies are needed to further understand the contributions and the interrelationships among these factors and to develop interventions that are effective and durable. This paper summarizes work on mechanisms underlying the varied manifestations of childhood undernutrition and discusses current gaps in knowledge and challenges to our understanding of undernutrition and infection/immunity throughout the human life cycle, focusing on early childhood growth. It proposes a series of basic and clinical studies to address this global health challenge.

Badurdeen S, Mulongo M, Berkley JA. 2015. Arginine depletion increases susceptibility to serious infections in preterm newborns. Pediatr Res, 77 (2), pp. 290-297. | Show Abstract | Read more

Preterm newborns are highly susceptible to bacterial infections. This susceptibility is regarded as being due to immaturity of multiple pathways of the immune system. However, it is unclear whether a mechanism that unifies these different, suppressed pathways exists. Here, we argue that the immune vulnerability of the preterm neonate is critically related to arginine depletion. Arginine, a "conditionally essential" amino acid, is depleted in acute catabolic states, including sepsis. Its metabolism is highly compartmentalized and regulated, including by arginase-mediated hydrolysis. Recent data suggest that arginase II-mediated arginine depletion is essential for the innate immune suppression that occurs in newborn models of bacterial challenge, impairing pathways critical for the immune response. Evidence that arginine depletion mediates protection from immune activation during first gut colonization suggests a regulatory role in controlling gut-derived pathogens. Clinical studies show that plasma arginine is depleted during sepsis. In keeping with animal studies, small clinical trials of L-arginine supplementation have shown benefit in reducing necrotizing enterocolitis in premature neonates. We propose a novel, broader hypothesis that arginine depletion during bacterial challenge is a key factor limiting the neonate's ability to mount an adequate immune response, contributing to the increased susceptibility to infections, particularly with respect to gut-derived sepsis.

Jones KDJ, Hünten-Kirsch B, Laving AMR, Munyi CW, Ngari M, Mikusa J, Mulongo MM, Odera D, Nassir HS, Timbwa M et al. 2014. Mesalazine in the initial management of severely acutely malnourished children with environmental enteric dysfunction: a pilot randomized controlled trial. BMC Med, 12 (1), pp. 133. | Show Abstract | Read more

BACKGROUND: Environmental enteric dysfunction (EED) is an acquired syndrome of impaired gastrointestinal mucosal barrier function that is thought to play a key role in the pathogenesis of stunting in early life. It has been conceptualized as an adaptive response to excess environmental pathogen exposure. However, it is clinically similar to other inflammatory enteropathies, which result from both host and environmental triggers, and for which immunomodulation is a cornerstone of therapy. METHODS: In this pilot double-blind randomized placebo-controlled trial, 44 children with severe acute malnutrition and evidence of EED were assigned to treatment with mesalazine or placebo for 28 days during nutritional rehabilitation. Primary outcomes were safety and acceptability of the intervention. RESULTS: Treatment with mesalazine was safe: there was no excess of adverse events, evidence of deterioration in intestinal barrier integrity or impact on nutritional recovery. There were modest reductions in several inflammatory markers with mesalazine compared to placebo. Depression of the growth hormone--insulin-like growth factor-1 axis was evident at enrollment and associated with inflammatory activation. Increases in the former and decreases in the latter correlated with linear growth. CONCLUSIONS: Intestinal inflammation in EED is non-essential for mucosal homeostasis and is at least partly maladaptive. Further trials of gut-specific immunomodulatory therapies targeting host inflammatory activation in order to optimize the growth benefits of nutritional rehabilitation and to address stunting are warranted. Funded by The Wellcome Trust. TRIAL REGISTRATION: Registered at Clinicaltrials.gov NCT01841099.

Mwangome MK, Fegan G, Prentice AM, Berkley JA. 2015. Maternal perception of malnutrition among infants using verbal and pictorial methods in Kenya. Public Health Nutr, 18 (5), pp. 869-876. | Show Abstract | Read more

OBJECTIVE: To compare mothers' perceptions of their own infants' nutritional status with anthropometric indicators of undernutrition. DESIGN: A qualitative study and cross-sectional quantitative survey. The qualitative study involved developing tools to assess mother's perception. Two methods of verbal description and a pictorial scale were developed. The quantitative survey involved measuring maternal perception and comparing it with the anthropometric measures of weight-for-age Z-score (WAZ) and mid-upper arm circumference-for-age Z-score (MUACZ). SETTING: A rural community setting in Kenya. SUBJECTS: Seventy-four infants aged between 4 and 6 months, and their mothers, living in rural Kenya were enrolled. RESULTS: Using verbal description, the positive and negative likelihood ratios were 3.57 (95 % CI 1.44, 9.98) and 0.69 (95 % CI 0.50, 0.96) respectively for MUACZ<-2; and 4.60 (95 % CI 1.60, 13.3) and 0.67 (95 % CI 0.49, 0.92) respectively for WAZ<-2. Using the pictorial scale, the positive and negative likelihood ratios were 8.30 (95 % CI 1.91, 36.3) and 0.69 (95 % CI 0.52, 0.93) respectively for MUACZ<-2; and 4.31 (95 % CI 1.22, 15.0) and 0.78 (95 % CI 0.61, 1.00) respectively for WAZ<-2. CONCLUSIONS: In a rural community, mothers better identify undernutrition in their infants using a pictorial scale than verbal description. However, neither can replace formal anthropometric assessment. Objective anthropometric tools should be validated for identification of severe acute malnutrition among infants aged less than 6 months.

Berkley JA. 2014. Randomised trials in developing countries. Arch Dis Child, 99 (7), pp. 607-608. | Read more

Mwangome MK, Fegan G, Prentice AM, Berkley JA. 2015. Maternal perception of malnutrition among infants using verbal and pictorial methods in Kenya Public Health Nutrition, 18 (5), pp. 869-876. | Show Abstract | Read more

Copyright © The Authors 2014. Abstract Objective To compare mothers' perceptions of their own infants' nutritional status with anthropometric indicators of undernutrition. Design A qualitative study and cross-sectional quantitative survey. The qualitative study involved developing tools to assess mother's perception. Two methods of verbal description and a pictorial scale were developed. The quantitative survey involved measuring maternal perception and comparing it with the anthropometric measures of weight-for-age Z-score (WAZ) and mid-upper arm circumference-for-age Z-score (MUACZ). Setting A rural community setting in Kenya. Subjects Seventy-four infants aged between 4 and 6 months, and their mothers, living in rural Kenya were enrolled. Results Using verbal description, the positive and negative likelihood ratios were 3·57 (95 % CI 1·44, 9·98) and 0·69 (95 % CI 0·50, 0·96) respectively for MUACZ < -2; and 4·60 (95 % CI 1·60, 13·3) and 0·67 (95 % CI 0·49, 0·92) respectively for WAZ < -2. Using the pictorial scale, the positive and negative likelihood ratios were 8·30 (95 % CI 1·91, 36·3) and 0·69 (95 % CI 0·52, 0·93) respectively for MUACZ < -2; and 4·31 (95 % CI 1·22, 15·0) and 0·78 (95 % CI 0·61, 1·00) respectively for WAZ < -2. Conclusions In a rural community, mothers better identify undernutrition in their infants using a pictorial scale than verbal description. However, neither can replace formal anthropometric assessment. Objective anthropometric tools should be validated for identification of severe acute malnutrition among infants aged less than 6 months.

Mwangome MK, Berkley JA. 2014. The reliability of weight-for-length/height Z scores in children. Matern Child Nutr, 10 (4), pp. 474-480. | Show Abstract | Read more

The World Health Organisation (WHO) recommends weight-for-length/height (WFL/H), represented as a Z score for diagnosing acute malnutrition among children aged 0 to 60 months. Under controlled conditions, weight, height and length measurements have high degree of reliability. However, the reliability when combined into a WFL/H Z score, in all settings is unclear. We conducted a systematic review of published studies assessing the reliability of WFL/Hz on PubMed and Google scholar. Studies were included if they presented reliability scores for the derived index of WFL/Hz, for children under 5 years. Meta-analysis was conducted for a pooled estimate of reliability overall, and for children above and below 24 months old. Twenty six studies on reliability of anthropometry were identified but only three, all community-based studies, reported reliability scores for WFL/Hz. The overall pooled intra-class correlation coefficient (ICC) estimate for WFL/Hz among children aged 0 to 60 months was 0.81 (95% CI 0.64 to 0.99). Among children aged less than 24 months the pooled ICC estimate from two studies was 0.72 (95% CI 0.67 to 0.77) while the estimate reported for children above 24 months from one study was 0.97 (95% CI 0.97 to 0.99). Although WFL/Hz is recommended for diagnosis of acute under nutrition among children below 5 years, information on its reliability in all settings is sparse. In community settings, reliability of WFL/Hz is considerably lower than for absolute measures of weight and length/height, especially in younger children. The reliability of WFL/Hz needs further evaluation.

Huang H, Ideh RC, Gitau E, Thézénas ML, Jallow M, Ebruke B, Chimah O, Oluwalana C, Karanja H, Mackenzie G et al. 2014. Discovery and validation of biomarkers to guide clinical management of pneumonia in African children. Clin Infect Dis, 58 (12), pp. 1707-1715. | Show Abstract | Read more

BACKGROUND: Pneumonia is the leading cause of death in children globally. Clinical algorithms remain suboptimal for distinguishing severe pneumonia from other causes of respiratory distress such as malaria or distinguishing bacterial pneumonia and pneumonia from others causes, such as viruses. Molecular tools could improve diagnosis and management. METHODS: We conducted a mass spectrometry-based proteomic study to identify and validate markers of severity in 390 Gambian children with pneumonia (n = 204) and age-, sex-, and neighborhood-matched controls (n = 186). Independent validation was conducted in 293 Kenyan children with respiratory distress (238 with pneumonia, 41 with Plasmodium falciparum malaria, and 14 with both). Predictive value was estimated by the area under the receiver operating characteristic curve (AUC). RESULTS: Lipocalin 2 (Lpc-2) was the best protein biomarker of severe pneumonia (AUC, 0.71 [95% confidence interval, .64-.79]) and highly predictive of bacteremia (78% [64%-92%]), pneumococcal bacteremia (84% [71%-98%]), and "probable bacterial etiology" (91% [84%-98%]). These results were validated in Kenyan children with severe malaria and respiratory distress who also met the World Health Organization definition of pneumonia. The combination of Lpc-2 and haptoglobin distinguished bacterial versus malaria origin of respiratory distress with high sensitivity and specificity in Gambian children (AUC, 99% [95% confidence interval, 99%-100%]) and Kenyan children (82% [74%-91%]). CONCLUSIONS: Lpc-2 and haptoglobin can help discriminate the etiology of clinically defined pneumonia and could be used to improve clinical management. These biomarkers should be further evaluated in prospective clinical studies.

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Seale AC, Blencowe H, Manu AA, Nair H, Bahl R, Qazi SA, Zaidi AK, Berkley JA, Cousens SN, Lawn JE et al. 2014. Estimates of possible severe bacterial infection in neonates in sub-Saharan Africa, south Asia, and Latin America for 2012: A systematic review and meta-analysis The Lancet Infectious Diseases, 14 (8), pp. 731-741. | Show Abstract | Read more

Background: Bacterial infections are a leading cause of the 2·9 million annual neonatal deaths. Treatment is usually based on clinical diagnosis of possible severe bacterial infection (pSBI). To guide programme planning, we have undertaken the first estimates of neonatal pSBI, by sex and by region, for sub-Saharan Africa, south Asia, and Latin America. Methods: We included data for pSBI incidence in neonates of 32 weeks' gestation or more (or birthweight ≥1500 g) with livebirth denominator data, undertaking a systematic review and forming an investigator group to obtain unpublished data. We calculated pooled risk estimates for neonatal pSBI and case fatality risk, by sex and by region. We then applied these risk estimates to estimates of livebirths in sub-Saharan Africa, south Asia, and Latin America to estimate cases and associated deaths in 2012. Findings: We included data from 22 studies, for 259 944 neonates and 20 196 pSBI cases, with most of the data (18 of the 22 studies) coming from the investigator group. The pooled estimate of pSBI incidence risk was 7·6% (95% CI 6·1-9·2%) and the case-fatality risk associated with pSBI was 9·8% (7·4-12·2). We estimated that in 2012 there were 6·9 million cases (uncertainty range 5·5 million-8·3 million) of pSBI in neonates needing treatment: 3·5 million (2·8 million-4·2 million) in south Asia, 2·6 million (2·1 million-3·1 million) in sub-Saharan Africa, and 0·8 million (0·7 million-1·0 million) in Latin America. The risk of pSBI was greater in boys (risk ratio 1·12, 95% CI 1·06-1·18) than girls. We estimated that there were 0·68 million (0·46 million-0·92 million) neonatal deaths associated with pSBI in 2012. Interpretation: The need-to-treat population for pSBI in these three regions is high, with ten cases of pSBI diagnosed for each associated neonatal death. Deaths and disability can be reduced through improved prevention, detection, and case management. Funding: The Wellcome Trust and the Bill & Melinda Gates Foundation through grants to Child Health Epidemiology Reference Group (CHERG) and Save the Children's Saving Newborn Lives programme. © 2014 Seale et al.

Jones KD, Thitiri J, Ngari M, Berkley JA. 2014. Childhood malnutrition: toward an understanding of infections, inflammation, and antimicrobials. Food Nutr Bull, 35 (2 Suppl), pp. S64-S70. | Show Abstract | Read more

BACKGROUND: Undernutrition in childhood is estimated to cause 3.1 million child deaths annually through a potentiating effect on common infectious diseases, such as pneumonia and diarrhea. In turn, overt and subclinical infections, and inflammation, especially in the gut, alter nutrient intake, absorption, secretion, diversion, catabolism, and expenditure. OBJECTIVE: A narrative overview of the current understanding of infections, inflammation, and antimicrobials in relation to childhood malnutrition. METHODS: Searches for pivotal papers were conducted using PUBMED 1966-January 2013; hand searches of the references of retrieved literature; discussions with experts; and personal experience from the field. RESULTS: Although the epidemiological evidence for increased susceptibility to life-threatening infections associated with malnutrition is strong, we are only just beginning to understand some of the mechanisms involved. Nutritional status and growth are strongly influenced by environmental enteric dysfunction (EED), which is common among children in developing countries, and by alterations in the gut microbiome. As yet, there are no proven interventions against EED. Antibiotics have long been used as growth promoters in animals. Trials of antibiotics have shown striking efficacy on mortality and on growth in children with uncomplicated severe acute malnutrition (SAM) or HIV infection. Antibiotics act directly by preventing infections and may act indirectly by reducing subclinical infections and inflammation. We describe an ongoing multicenter, randomized, placebo-controlled trial of daily cotrimoxazole prophylaxis to prevent death in children recovering from complicated SAM. Secondary outcomes include growth, frequency and etiology of infections, immune activation and function, the gut microbiome, and antimicrobial resistance. The trial is expected to be reported in mid-2014. CONCLUSIONS: As well as improving nutritional intake, new case management strategies need to address infection, inflammation, and microbiota and assess health outcomes rather than only anthropometry.

Hassan AS, Nabwera HM, Mwaringa SM, Obonyo CA, Sanders EJ, Rinke de Wit TF, Cane PA, Berkley JA. 2014. HIV-1 virologic failure and acquired drug resistance among first-line antiretroviral experienced adults at a rural HIV clinic in coastal Kenya: a cross-sectional study. AIDS Res Ther, 11 (1), pp. 9. | Show Abstract | Read more

BACKGROUND: An increasing number of people on antiretroviral therapy (ART) in sub-Saharan Africa has led to declines in HIV related morbidity and mortality. However, virologic failure (VF) and acquired drug resistance (ADR) may negatively affect these gains. This study describes the prevalence and correlates of HIV-1 VF and ADR among first-line ART experienced adults at a rural HIV clinic in Coastal Kenya. METHODS: HIV-infected adults on first-line ART for ≥6 months were cross-sectionally recruited between November 2008 and March 2011. The primary outcome was VF, defined as a one-off plasma viral load of ≥400 copies/ml. The secondary outcome was ADR, defined as the presence of resistance associated mutations. Logistic regression and Fishers exact test were used to describe correlates of VF and ADR respectively. RESULTS: Of the 232 eligible participants on ART over a median duration of 13.9 months, 57 (24.6% [95% CI: 19.2 - 30.6]) had VF. Fifty-five viraemic samples were successfully amplified and sequenced. Of these, 29 (52.7% [95% CI: 38.8 - 66.3]) had at least one ADR, with 25 samples having dual-class resistance mutations. The most prevalent ADR mutations were the M184V (n = 24), K103N/S (n = 14) and Y181C/Y/I/V (n = 8). Twenty-six of the 55 successfully amplified viraemic samples (47.3%) did not have any detectable resistance mutation. Younger age (15-34 vs. ≥35 years: adjusted odd ratios [95% CI], p-value: 0.3 [0.1-0.6], p = 0.002) and unsatisfactory adherence (<95% vs. ≥95%: 3.0 [1.5-6.5], p = 0.003) were strong correlates of VF. Younger age, unsatisfactory adherence and high viral load were also strong correlates of ADR. CONCLUSIONS: High levels of VF and ADR were observed in younger patients and those with unsatisfactory adherence. Youth-friendly ART initiatives and strengthened adherence support should be prioritized in this Coastal Kenyan setting. To prevent unnecessary/premature switches, targeted HIV drug resistance testing for patients with confirmed VF should be considered.

Seale AC, Blencowe H, Manu AA, Nair H, Bahl R, Qazi SA, Zaidi AK, Berkley JA, Cousens SN, Lawn JE, pSBI Investigator Group. 2014. Estimates of possible severe bacterial infection in neonates in sub-Saharan Africa, south Asia, and Latin America for 2012: a systematic review and meta-analysis. Lancet Infect Dis, 14 (8), pp. 731-741. | Show Abstract | Read more

BACKGROUND: Bacterial infections are a leading cause of the 2·9 million annual neonatal deaths. Treatment is usually based on clinical diagnosis of possible severe bacterial infection (pSBI). To guide programme planning, we have undertaken the first estimates of neonatal pSBI, by sex and by region, for sub-Saharan Africa, south Asia, and Latin America. METHODS: We included data for pSBI incidence in neonates of 32 weeks' gestation or more (or birthweight ≥1500 g) with livebirth denominator data, undertaking a systematic review and forming an investigator group to obtain unpublished data. We calculated pooled risk estimates for neonatal pSBI and case fatality risk, by sex and by region. We then applied these risk estimates to estimates of livebirths in sub-Saharan Africa, south Asia, and Latin America to estimate cases and associated deaths in 2012. FINDINGS: We included data from 22 studies, for 259 944 neonates and 20 196 pSBI cases, with most of the data (18 of the 22 studies) coming from the investigator group. The pooled estimate of pSBI incidence risk was 7·6% (95% CI 6·1-9·2%) and the case-fatality risk associated with pSBI was 9·8% (7·4-12·2). We estimated that in 2012 there were 6·9 million cases (uncertainty range 5·5 million-8·3 million) of pSBI in neonates needing treatment: 3·5 million (2·8 million-4·2 million) in south Asia, 2·6 million (2·1 million-3·1 million) in sub-Saharan Africa, and 0·8 million (0·7 million-1·0 million) in Latin America. The risk of pSBI was greater in boys (risk ratio 1·12, 95% CI 1·06-1·18) than girls. We estimated that there were 0·68 million (0·46 million-0·92 million) neonatal deaths associated with pSBI in 2012. INTERPRETATION: The need-to-treat population for pSBI in these three regions is high, with ten cases of pSBI diagnosed for each associated neonatal death. Deaths and disability can be reduced through improved prevention, detection, and case management. FUNDING: The Wellcome Trust and the Bill & Melinda Gates Foundation through grants to Child Health Epidemiology Reference Group (CHERG) and Save the Children's Saving Newborn Lives programme.

Bezemer D, Faria NR, Hassan A, Hamers RL, Mutua G, Anzala O, Mandaliya K, Cane P, Berkley JA, Rinke de Wit TF et al. 2014. HIV Type 1 transmission networks among men having sex with men and heterosexuals in Kenya. AIDS Res Hum Retroviruses, 30 (2), pp. 118-126. | Show Abstract | Read more

We performed a molecular phylogenetic study on HIV-1 polymerase sequences of men who have sex with men (MSM) and heterosexual patient samples in Kenya to characterize any observed HIV-1 transmission networks. HIV-1 polymerase sequences were obtained from samples in Nairobi and coastal Kenya from 84 MSM, 226 other men, and 364 women from 2005 to 2010. Using Bayesian phylogenetics, we tested whether sequences clustered by sexual orientation and geographic location. In addition, we used trait diffusion analyses to identify significant epidemiological links and to quantify the number of transmissions between risk groups. Finally, we compared 84 MSM sequences with all HIV-1 sequences available online at GenBank. Significant clustering of sequences from MSM at both coastal Kenya and Nairobi was found, with evidence of HIV-1 transmission between both locations. Although a transmission pair between a coastal MSM and woman was confirmed, no significant HIV-1 transmission was evident between MSM and the comparison population for the predominant subtype A (60%). However, a weak but significant link was evident when studying all subtypes together. GenBank comparison did not reveal other important transmission links. Our data suggest infrequent intermingling of MSM and heterosexual HIV-1 epidemics in Kenya.

Ongas M, Standing J, Ogutu B, Waichungo J, Berkley JA, Kipper K. 2017. Liquid chromatography–tandem mass spectrometry for the simultaneous quantitation of ceftriaxone, metronidazole and hydroxymetronidazole in plasma from seriously ill, severely malnourished children Wellcome Open Research, 2 pp. 43-43. | Read more

Mwangome MK, Fegan G, Fulford T, Prentice AM, Berkley JA. 2012. Mid-upper arm circumference at age of routine infant vaccination to identify infants at elevated risk of death: a retrospective cohort study in the Gambia. Bull World Health Organ, 90 (12), pp. 887-894. | Show Abstract | Read more

OBJECTIVE: To determine the predictive value for death before 12 months of age of mid-upper arm circumference (MUAC) and weight-for-length Z score (WFLz). METHODS: A retrospective cohort analysis of infants living in Keneba, in rural Gambia, was conducted. Anthropometric measures were obtained from demographic surveillance system records for infants registered between February 1974 and July 2008 who had had MUAC and WFLz recorded at 6-14 weeks of age and vital status recorded at least once more. Hazard ratios (HRs), population attributable fractions and areas under receiver operating characteristic (ROC) curves were estimated to assess the predictive value for death in infancy of MUAC and WFLz. FINDINGS: Of 2876 infants included in the analysis, 40 died before the age of 12 months. The HR for death in this group versus in well-nourished infants was 5.8 (95% confidence interval, CI: 1.6-21) for a WFLz < -3. HRs for MUACs below the thresholds of 115 mm, 110 mm and 105 mm were 4.5 (95% CI: 1.4-15), 9.5 (95% CI: 2.6-35) and 23 (95% CI: 4.2-122), respectively. The attributable fractions for a MUAC < 130 mm and a WFLz < 0 were 51% and 13%, respectively. The areas under the ROC curve for death in infancy were 0.55 (95% CI: 0.46 to 0.64) for WFLz and 0.64 (95% CI: 0.55 to 0.73) for MUAC. CONCLUSION: Among infants aged 6 to 14 weeks, unadjusted MUAC showed good performance in identifying infants at increased risk of death.

Onyango CO, Njeru R, Kazungu S, Achilla R, Bulimo W, Welch SR, Cane PA, Gunson RN, Hammitt LL, Scott JAG et al. 2012. Influenza surveillance among children with pneumonia admitted to a district hospital in coastal Kenya, 2007-2010. J Infect Dis, 206 Suppl 1 (suppl 1), pp. S61-S67. | Show Abstract | Read more

BACKGROUND: Influenza data gaps in sub-Saharan Africa include incidence, case fatality, seasonal patterns, and associations with prevalent disorders. METHODS: Nasopharyngeal samples from children aged <12 years who were admitted to Kilifi District Hospital during 2007-2010 with severe or very severe pneumonia and resided in the local demographic surveillance system were screened for influenza A, B, and C viruses by molecular methods. Outpatient children provided comparative data. RESULTS: Of 2002 admissions, influenza A virus infection was diagnosed in 3.5% (71), influenza B virus infection, in 0.9% (19); and influenza C virus infection, in 0.8% (11 of 1404 tested). Four patients with influenza died. Among outpatients, 13 of 331 (3.9%) with acute respiratory infection and 1 of 196 without acute respiratory infection were influenza positive. The annual incidence of severe or very severe pneumonia, of influenza (any type), and of influenza A, was 1321, 60, and 43 cases per 100,000 <5 years of age, respectively. Peak occurrence was in quarters 3-4 each year, and approximately 50% of cases involved infants: temporal association with bacteremia was absent. Hypoxia was more frequent among pneumonia cases involving influenza (odds ratio, 1.78; 95% confidence interval, 1.04-1.96). Influenza A virus subtypes were seasonal H3N2 (57%), seasonal H1N1 (12%), and 2009 pandemic H1N1 (7%). CONCLUSIONS: The burden of influenza was small during 2007-2010 in this pediatric hospital in Kenya. Influenza A virus subtype H3N2 predominated, and 2009 pandemic influenza A virus subtype H1N1 had little impact.

Hassan AS, Mwaringa SM, Obonyo CA, Nabwera HM, Sanders EJ, Rinke de Wit TF, Cane PA, Berkley JA. 2013. Low prevalence of transmitted HIV type 1 drug resistance among antiretroviral-naive adults in a rural HIV clinic in Kenya. AIDS Res Hum Retroviruses, 29 (1), pp. 129-135. | Show Abstract | Read more

Low levels of HIV-1 transmitted drug resistance (TDR) have previously been reported from many parts of sub-Saharan Africa (sSA). However, recent data, mostly from urban settings, suggest an increase in the prevalence of HIV-1 TDR. Our objective was to determine the prevalence of TDR mutations among HIV-1-infected, antiretroviral (ARV)-naive adults enrolling for care in a rural HIV clinic in Kenya. Two cross-sectional studies were carried out between July 2008 and June 2010. Plasma samples from ARV-naive adults (>15 years old) at the time of registering for care after HIV diagnosis and before starting ARVs were used. A portion of the pol subgenomic region of the virus containing the protease and part of the reverse transcriptase genes was amplified and sequenced. TDR mutations were identified and interpreted using the Stanford HIV drug resistance database and the WHO list for surveillance of drug resistance strains. Overall, samples from 182 ARV-naive adults [mean age (95% CI): 34.9 (33.3-36.4) years] were successfully amplified and sequenced. Two TDR mutations to nucleoside reverse transcriptase inhibitors [n=1 (T215D)] and protease inhibitors [n=1 (M46L)] were identified, giving an overall TDR prevalence of 1.1% (95% CI: 0.1-3.9). Despite reports of an increase in the prevalence of HIV-1 TDR in some urban settings in sSA, we report a prevalence of HIV-1 TDR of less than 5% at a rural HIV clinic in coastal Kenya. Continued broader surveillance is needed to monitor the extent of TDR in sSA.

Webb C, Ngama M, Ngatia A, Shebbe M, Morpeth S, Mwarumba S, Bett A, Nokes DJ, Seale AC, Kazungu S et al. 2012. Treatment failure among Kenyan children with severe pneumonia--a cohort study. Pediatr Infect Dis J, 31 (9), pp. e152-e157. | Show Abstract | Read more

BACKGROUND: Pneumonia is the leading cause of childhood mortality worldwide. The World Health Organization recommends presumptive treatment based on clinical syndromes. Recent studies raise concerns over the frequency of treatment failure in Africa. METHODS: We applied a definition of treatment failure to data prospectively collected from children who were 2-59 months of age with severe, or very severe, pneumonia admitted to Kilifi District Hospital, Kenya, from May 2007 through May 2008 and treated using World Health Organization guidelines. The primary outcome was treatment failure at 48 hours. RESULTS: Of 568 children, median age 11 months, 165 (29%) had very severe pneumonia, 30 (5.3%) a positive HIV test and 62 (11%) severe malnutrition. One hundred eleven (20%; 95% confidence interval: 17-23%) children failed treatment at 48 hours and 34 (6.0%) died; 22 (65%) deaths occurred before 48 hours. Of 353 children with severe pneumonia, without HIV or severe malnutrition, 42 (12%) failed to respond at 48 hours, 15 (4.3%) failed at 5 days and 1 child (0.3%) died. Among 215 children with either severe pneumonia complicated by HIV or severe malnutrition, or very severe pneumonia, 69 (32%) failed to treatment at 48 hours, 47 (22%) failed at 5 days and 33 (16%) died. Treatment failure at 48 hours was associated with shock, bacteremia, very severe pneumonia, oxygen saturation in hemoglobin <95%, severe malnutrition, HIV and age <1 year in multivariable models. CONCLUSIONS: In this setting, few children with uncomplicated severe pneumonia fail treatment or die under current guidelines. Deaths mainly occurred early and may be reduced by improving prevention, prehospital care and treatment of sepsis.

Mwangome MK, Fegan G, Mbunya R, Prentice AM, Berkley JA. 2012. Reliability and accuracy of anthropometry performed by community health workers among infants under 6 months in rural Kenya. Trop Med Int Health, 17 (5), pp. 622-629. | Show Abstract | Read more

OBJECTIVE: To assess the inter-observer variability and accuracy of Mid Upper Arm Circumference (MUAC) and weight-for-length Z score (WFLz) among infants aged <6 months performed by community health workers (CHWs) in Kilifi District, Kenya. METHODS: A cross-sectional repeatability study estimated inter-observer variation and accuracy of measurements initially undertaken by an expert anthropometrist, nurses and public health technicians. Then, after training, 18 CHWs (three at each of six sites) repeatedly measured MUAC, weight and length of infants aged <6 months. Intra-class correlations (ICCs) and the Pitman's statistic were calculated. RESULTS: Among CHWs, ICCs pooled across the six sites (924 infants) were 0.96 (95% CI 0.95-0.96) for MUAC and 0.71 (95% CI 0.68-0.74) for WFLz. MUAC measures by CHWs differed little from their trainers: the mean difference in MUAC was 0.65 mm (95% CI 0.023-1.07), with no significant difference in variance (P = 0.075). CONCLUSION: Mid Upper Arm Circumference is more reliably measured by CHWs than WFLz among infants aged <6 months. Further work is needed to define cut-off values based on MUAC's ability to predict mortality among younger infants.

Hué S, Hassan AS, Nabwera H, Sanders EJ, Pillay D, Berkley JA, Cane PA. 2012. HIV type 1 in a rural coastal town in Kenya shows multiple introductions with many subtypes and much recombination. AIDS Res Hum Retroviruses, 28 (2), pp. 220-224. | Show Abstract | Read more

The extent of HIV-1 diversity was examined among patients attending a rural district hospital in a coastal area of Kenya. The pol gene was sequenced in samples from 153 patients. Subtypes were designated using the REGA, SCUEAL, and jpHMM programs. The most common subtype was A1, followed by C and D; A2 and G were also detected. However, a large proportion of the samples was found to be recombinants, which clustered within the pure subtype branches. Phylogeographic analysis of Kilifi sequences compared with those from other regions of Africa showed that while many sequences were closely related to sequences from Kenya, others were most closely related to known sequences from other parts of Africa, including West Africa. Overall, these data indicate that there have been multiple introductions of HIV-1 into this small rural town and surroundings with ongoing diversity being generated by recombination.

Walson J, Singa B, Sangaré L, Naulikha J, Piper B, Richardson B, Otieno PA, Mbogo LW, Berkley JA, John-Stewart G. 2012. Empiric deworming to delay HIV disease progression in adults with HIV who are ineligible for initiation of antiretroviral treatment (the HEAT study): a multi-site, randomised trial. Lancet Infect Dis, 12 (12), pp. 925-932. | Show Abstract | Read more

BACKGROUND: Co-infection with HIV and helminths is common in sub-Saharan Africa and findings from previous studies have suggested that anthelmintic treatment might delay immunosuppression in people with HIV. We aimed to assess the efficacy of empiric deworming of adults with HIV in delaying HIV disease progression. METHODS: In this non-blinded randomised trial, we enrolled adults (aged ≥18 years) with HIV who did not meet criteria for the initiation of antiretroviral treatment from three sites in Kenya. Using a computer-generated sequence, we randomly assigned (1:1) eligible participants to either empiric albendazole every 3 months plus praziquantel annually (treatment group) or to standard care (control group). Participants were followed up for 24 months. We measured CD4 cell counts every 6 months and plasma HIV RNA annually. The primary endpoints were a CD4 count of less than 350 cells per μL and a composite endpoint consisting of the first occurrence of a CD4 count of less than 350 cells per μL, first reported use of antiretroviral treatment, and non-traumatic deaths. We compared these measures by use of Cox proportional hazards regression and Kaplan-Meier survival analyses. Primary analysis was done by intention to treat. The trial was registered with ClinicalTrials.gov, number NCT0050722. FINDINGS: Between Feb 6, 2008, and June 21, 2011, we enrolled and followed-up 948 participants; 469 were allocated to the treatment group and 479 to the control group. All participants were provided with co-trimoxazole prophylaxis. Median baseline CD4 cell counts and HIV RNA concentrations did not differ between groups. We recorded no statistically significant difference between the treatment and control groups in the number of people reaching a CD4 count of fewer than 350 cells per μL (41·6 events per 100 person-years vs 46·2 events per 100 person-years; hazard ratio 0·89, 95% CI 0·75-1·06, p=0·2) or the composite endpoint (44·0 events per 100 person-years vs 49·8 events per 100 person-years; 0·88, 0·74-1·04, p=0·1). Serious adverse events, none of which thought to be treatment-related, occurred at a similar frequency in both groups. INTERPRETATION: Our findings do not suggest an effect of empiric deworming in the delaying of HIV disease progression in adults with HIV in an area where helminth infection is common. Alternative approaches are needed to delay HIV disease progression in areas where co-infections are common.

Seale AC, Berkley JA. 2012. Managing severe infection in infancy in resource poor settings Early Human Development, 88 (12), pp. 957-960. | Show Abstract | Read more

Reducing childhood mortality in resource-poor regions depends on effective interventions to decrease neonatal mortality from severe infection, which contributes up to a half of all neonatal deaths. There are key differences in resource-poor, compared to resource-rich, countries in terms of diagnosis, supportive care and treatment. In resource-poor settings, diagnosis is based on identifying clinical syndromes from international guidelines; microbiological investigations are restricted to a few research facilities. Low levels of staffing and equipment limit the provision of basic supportive care, and most facilities cannot provide respiratory support. Empiric antibiotic treatment guidelines are based on few aetiological and antimicrobial susceptibility data. Research on improving health care systems to provide effective supportive care, and implementation of simple pragmatic interventions, such as low-cost respiratory support, are essential, together with improved surveillance to monitor emerging drug resistance and treatment failures. Reductions in mortality will also be achieved through prevention of infection; including emerging vaccination and anti-sepsis strategies. © 2012 Elsevier Ltd.

Talbert A, Thuo N, Karisa J, Chesaro C, Ohuma E, Ignas J, Berkley JA, Toromo C, Atkinson S, Maitland K. 2012. Diarrhoea complicating severe acute malnutrition in Kenyan children: a prospective descriptive study of risk factors and outcome. PLoS One, 7 (6), pp. e38321. | Show Abstract | Read more

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.

Mwangome MK, Fegan G, Mbunya R, Prentice AM, Berkley JA. 2012. Reliability and accuracy of anthropometry performed by community health workers among infants under 6months in rural Kenya Tropical Medicine and International Health, 17 (5), pp. 622-629. | Show Abstract | Read more

Objective To assess the inter-observer variability and accuracy of Mid Upper Arm Circumference (MUAC) and weight-for-length Z score (WFLz) among infants aged < 6months performed by community health workers (CHWs) in Kilifi District, Kenya. Methods A cross-sectional repeatability study estimated inter-observer variation and accuracy of measurements initially undertaken by an expert anthropometrist, nurses and public health technicians. Then, after training, 18 CHWs (three at each of six sites) repeatedly measured MUAC, weight and length of infants aged < 6months. Intra-class correlations (ICCs) and the Pitman's statistic were calculated. Results Among CHWs, ICCs pooled across the six sites (924 infants) were 0.96 (95% CI 0.95-0.96) for MUAC and 0.71 (95% CI 0.68-0.74) for WFLz. MUAC measures by CHWs differed little from their trainers: the mean difference in MUAC was 0.65mm (95% CI 0.023-1.07), with no significant difference in variance (P=0.075). Conclusion Mid Upper Arm Circumference is more reliably measured by CHWs than WFLz among infants aged < 6months. Further work is needed to define cut-off values based on MUAC's ability to predict mortality among younger infants. © 2012 Blackwell Publishing Ltd.

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Hassan AS, Sakwa EM, Nabwera HM, Taegtmeyer MM, Kimutai RM, Sanders EJ, Awuondo KK, Mutinda MN, Molyneux CS, Berkley JA. 2012. Dynamics and constraints of early infant diagnosis of HIV infection in rural Kenya AIDS and Behavior, 16 (1), pp. 5-12. | Show Abstract | Read more

A cohort design was used to determine uptake and drop out of 213 HIV-exposed infants eligible for Early Infant Diagnosis (EID) of HIV. To explore service providers and care givers knowledge, attitudes and perceptions of the EID process, observations and in-depth interviews were conducted. 145 (68%) infants enrolled after 2 months of age. 139 (65%) dropped out before follow up to 18 months old. 60 (43%) drop outs occurred within 2 months of enrolment. Maternal factors associated with infant drop out were maternal loss to follow up (48 [68%] vs. 8 [20%] , P\0.001) and younger maternal age (27.2 vs. 30.1 years, P = 0.033). Service providers and caregivers had inadequate training, knowledge and understanding of EID. Poverty and lack of social support were challenges in accessing EID services. EID should be more closely aligned within PMTCT services, integrated with routine mother and child health (MCH) activities and its implementation more closely monitored. © 2011. The Author (s).

Cited:

26

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Hassan AS, Fielding KL, Thuo NM, Nabwera HM, Sanders EJ, Berkley JA. 2012. Early loss to follow-up of recently diagnosed HIV-infected adults from routine pre-ART care in a rural district hospital in Kenya: a cohort study TROPICAL MEDICINE & INTERNATIONAL HEALTH, 17 (1), pp. 82-93. | Show Abstract | Read more

Objective To determine the rate and predictors of early loss to follow-up (LTFU) for recently diagnosed HIV-infected, antiretroviral therapy (ART)-ineligible adults in rural Kenya. Methods Prospective cohort study. Clients registering for HIV care between July 2008 and August 2009 were followed up for 6months. Baseline data were used to assess predictors of pre-ART LTFU (not returning for care within 2months of a scheduled appointment), LTFU before the second visit and LTFU after the second visit. Logistic regression was used to determine factors associated with LTFU before the second visit, while Cox regression was used to assess predictors of time to LTFU and LTFU after the second visit. Results Of 530 eligible clients, 178 (33.6%) were LTFU from pre-ART care (11.1/100 person-months). Of these, 96 (53.9%) were LTFU before the second visit. Distance ( > 5km vs. < 1km: adjusted hazard ratio 2.6 [1.9-3.7], P < 0.01) and marital status (married vs. single: 0.5 [0.3-0.6], P < 0.01) independently predicted pre-ART LTFU. Distance and marital status were independently associated with LTFU before the second visit, while distance, education status and seasonality showed weak evidence of predicting LTFU after the second visit. HIV disease severity did not predict pre-ART LTFU. Conclusions A third of recently diagnosed HIV-infected, ART-ineligible clients were LTFU within 6months of registration. Predictors of LTFU among ART-ineligible clients are different from those among clients on ART. These findings warrant consideration of an enhanced pre-ART care package aimed at improving retention and timely ART initiation. © 2011 Blackwell Publishing Ltd.

Aiken AM, Mturi N, Njuguna P, Mohammed S, Berkley JA, Mwangi I, Mwarumba S, Kitsao BS, Lowe BS, Morpeth SC et al. 2011. Risk and causes of paediatric hospital-acquired bacteraemia in Kilifi District Hospital, Kenya: a prospective cohort study. Lancet, 378 (9808), pp. 2021-2027. | Show Abstract | Read more

BACKGROUND: In sub-Saharan Africa, community-acquired bacteraemia is an important cause of illness and death in children. Our aim was to establish the magnitude and causes of hospital-acquired (nosocomial) bacteraemia in African children. METHODS: We reviewed prospectively collected surveillance data of 33,188 admissions to Kilifi District Hospital, Kenya, between April 16, 2002, and Sept 30, 2009. We defined bacteraemia as nosocomial if it occurred 48 h or more after admission. We estimated the per-admission risk, daily rate, effect on mortality, and microbial cause of nosocomial bacteraemia and analysed risk factors by multivariable Cox regression. The effect on morbidity was measured as the increase in hospital stay by comparison with time-matched patients without bacteraemia. FINDINGS: The overall risk of nosocomial bacteraemia during this period was 5·9/1000 admissions (95% CI 5·2-6·9) but we recorded an underlying rise in risk of 27% per year. The incidence was 1·0/1000 days in hospital (0·87-1·14), which is about 40 times higher than that of community-acquired bacteraemia in the same region. Mortality in patients with nosocomial bacteraemia was 53%, compared with 24% in community-acquired bacteraemia and 6% in patients without bacteraemia. In survivors, nosocomial bacteraemia lengthened hospital stay by 10·1 days (3·0-17·2). Klebsiella pneumoniae, Escherichia coli, Staphylococcus aureus, Acinetobacter spp, group D streptococci, and Pseudomonas aeruginosa accounted for three-quarters of nosocomial infections. Nosocomial bacteraemia was significantly associated with severe malnutrition (hazard ratio 2·52, 95% CI 1·79-3·57) and blood transfusion in children without severe anaemia (4·99; 3·39-7·37). INTERPRETATION: Our findings show that although nosocomial bacteraemia is rare, it has serious effects on morbidity and mortality, and the microbiological causes are distinct from those of community-acquired bacteraemia. Nosocomial infections are largely unrecognised or undocumented as a health risk in low-income countries, but they are likely to become public health priorities as awareness of their occurrence increases and as other prominent childhood diseases are progressively controlled. FUNDING: Wellcome Trust.

Moïsi JC, Gatakaa H, Berkley JA, Maitland K, Mturi N, Newton CR, Njuguna P, Nokes J, Ojal J, Bauni E et al. 2011. Excess child mortality after discharge from hospital in Kilifi, Kenya: a retrospective cohort analysis. Bull World Health Organ, 89 (10), pp. 725-732A. | Show Abstract | Read more

OBJECTIVE: To explore excess paediatric mortality after discharge from Kilifi District Hospital, Kenya, and its duration and risk factors. METHODS: Hospital and demographic data were used to describe post-discharge mortality and survival probability in children aged < 15 years, by age group and clinical syndrome. Cox regression models were developed to identify risk factors. FINDINGS: In 2004-2008, approximately 111,000 children were followed for 555,000 person-years. We analysed 14,971 discharges and 535 deaths occurring within 365 days of discharge. Mortality was higher in the post-discharge cohort than in the community cohort (age-adjusted rate ratio, RR: 7.7; 95% confidence interval, CI: 6.6-8.9) and declined little over time. An increased post-discharge mortality hazard was found in children aged < 5 years with the following: weight-for-age Z score < -4 (hazard ratio, HR: 6.5); weight-for-age Z score > -4 but < -3 (HR: 3.4); hypoxia (HR: 2.3); bacteraemia (HR: 1.8); hepatomegaly (HR: 2.3); jaundice (HR: 1.8); hospital stay > 13 days (HR: 1.8). Older age was protective (reference < 1 month): 6-23 months, HR: 0.8; 2-4 years, HR: 0.6. Children with at least one risk factor accounted for 545 (33%) of the 1655 annual discharges and for 39 (47%) of the 83 discharge-associated deaths. CONCLUSION: Hospital admission selects vulnerable children with a sustained increased risk of dying. The risk factors identified provide an empiric basis for effective outpatient follow-up.

Kariuki SM, Ikumi M, Ojal J, Sadarangani M, Idro R, Olotu A, Bejon P, Berkley JA, Marsh K, Newton CRJC. 2011. Acute seizures attributable to falciparum malaria in an endemic area on the Kenyan coast. Brain, 134 (Pt 5), pp. 1519-1528. | Show Abstract | Read more

Falciparum malaria is an important cause of acute symptomatic seizures in children admitted to hospitals in sub-Saharan Africa, and these seizures are associated with neurological disabilities and epilepsy. However, it is difficult to determine the proportion of seizures attributable to malaria in endemic areas since a significant proportion of asymptomatic children have malaria parasitaemia. We studied children aged 0-13 years who had been admitted with a history of seizures to a rural Kenyan hospital between 2002 and 2008. We examined the changes in the incidence of seizures with the reduction of malaria. Logistic regression was used to model malaria-attributable fractions for seizures (the proportion of seizures caused by malaria) to determine if the observed decrease in acute symptomatic seizures was a measure of seizures that are attributable to malaria. The overall incidence of acute symptomatic seizures over the period was 651/100,000/year (95% confidence interval 632-670) and it was 400/100,000/year (95% confidence interval 385-415) for acute complex symptomatic seizures (convulsive status epilepticus, repetitive or focal) and 163/100,000/year (95% confidence interval 154-173) for febrile seizures. From 2002 to 2008, the incidence of all acute symptomatic seizures decreased by 809/100,000/year (69.2%) with 93.1% of this decrease in malaria-associated seizures. The decrease in the incidence of acute complex symptomatic seizures during the period was 111/100,000/year (57.2%) for convulsive status epilepticus, 440/100,000/year (73.7%) for repetitive seizures and 153/100,000/year (80.5%) for focal seizures. The adjusted malaria-attributable fractions for seizures with parasitaemia were 92.9% (95% confidence interval 90.4-95.1%) for all acute symptomatic seizures, 92.9% (95% confidence interval 89.4-95.5%) for convulsive status epilepticus, 93.6% (95% confidence interval 90.9-95.9%) for repetitive seizures and 91.8% (95% confidence interval 85.6-95.5%) for focal seizures. The adjusted malaria-attributable fractions for seizures in children above 6 months of age decreased with age. The observed decrease in all acute symptomatic seizures (809/100 000/year) was similar to the predicted decline (794/100,000/year) estimated by malaria-attributable fractions at the beginning of the study. In endemic areas, falciparum malaria is the most common cause of seizures and the risk for seizures in malaria decreases with age. The reduction in malaria has decreased the burden of seizures that are attributable to malaria and this could lead to reduced neurological disabilities and epilepsy in the area.

Berkley JA, Bejon P, Mwangi T, Gwer S, Maitland K, Williams TN. 2011. Erratum Clinical Infectious Diseases, 52 (9), pp. 1202-1202. | Read more

Nair H, Brooks WA, Katz M, Roca A, Berkley JA, Madhi SA, Simmerman JM, Gordon A, Sato M, Howie S et al. 2011. Global burden of respiratory infections due to seasonal influenza in young children: a systematic review and meta-analysis The Lancet,

Mwangome MK, Fegan G, Prentice AM, Berkley JA. 2011. Are diagnostic criteria for acute malnutrition affected by hydration status in hospitalized children? A repeated measures study. Nutr J, 10 (1), pp. 92. | Show Abstract | Read more

INTRODUCTION: Dehydration and malnutrition commonly occur together among ill children in developing countries. Dehydration (change in total body water) is known to alter weight. Although muscle tissue has high water content, it is not known whether mid-upper arm circumference (MUAC) may be altered by changes in tissue hydration. We aimed to determine whether rehydration alters MUAC, MUAC Z score (MUACz), weight-for-length Z-score (WFLz) and classification of nutritional status among hospitalised Kenyan children admitted with signs of dehydration. STUDY PROCEDURE: We enrolled children aged from 3 months to 5 years admitted to a rural Kenyan district hospital with clinical signs compatible with dehydration, and without kwashiorkor. Anthropometric measurements were taken at admission and repeated after 48 hours of treatment, which included rehydration by WHO protocols. Changes in weight observed during this period were considered to be due to changes in hydration status. RESULTS: Among 325 children (median age 11 months) the median weight gain (rehydration) after 48 hours was 0.21 kg, (an increase of 2.9% of admission body weight). Each 1% change in weight was associated with a 0.40 mm (95% CI: 0.30 to 0.44 mm, p < 0.001) change in MUAC, 0.035z (95% CI: 0.027 to 0.043z, P < 0.001) change in MUACz score and 0.115z (95% CI: 0.114 to 0.116 z, p < 0.001) change in WFLz. Among children aged 6 months or more with signs of dehydration at admission who were classified as having severe acute malnutrition (SAM) at admission by WFLz <-3 or MUAC <115 mm, 21% and 19% of children respectively were above these cut offs after 48 hours. CONCLUSION: MUAC is less affected by dehydration than WFLz and is therefore more suitable for nutritional assessment of ill children. However, both WFLz and MUAC misclassify SAM among dehydrated children. Nutritional status should be re-evaluated following rehydration, and management adjusted accordingly.

Hassan AS, Fielding KL, Thuo NM, Nabwera HM, Sanders EJ, Berkley JA. 2012. Early loss to follow-up of recently diagnosed HIV-infected adults from routine pre-ART care in a rural district hospital in Kenya: a cohort study. Trop Med Int Health, 17 (1), pp. 82-93. | Show Abstract | Read more

OBJECTIVE: To determine the rate and predictors of early loss to follow-up (LTFU) for recently diagnosed HIV-infected, antiretroviral therapy (ART)-ineligible adults in rural Kenya. METHODS: Prospective cohort study. Clients registering for HIV care between July 2008 and August 2009 were followed up for 6 months. Baseline data were used to assess predictors of pre-ART LTFU (not returning for care within 2 months of a scheduled appointment), LTFU before the second visit and LTFU after the second visit. Logistic regression was used to determine factors associated with LTFU before the second visit, while Cox regression was used to assess predictors of time to LTFU and LTFU after the second visit. RESULTS: Of 530 eligible clients, 178 (33.6%) were LTFU from pre-ART care (11.1/100 person-months). Of these, 96 (53.9%) were LTFU before the second visit. Distance (>5 km vs. <1 km: adjusted hazard ratio 2.6 [1.9-3.7], P < 0.01) and marital status (married vs. single: 0.5 [0.3-0.6], P < 0.01) independently predicted pre-ART LTFU. Distance and marital status were independently associated with LTFU before the second visit, while distance, education status and seasonality showed weak evidence of predicting LTFU after the second visit. HIV disease severity did not predict pre-ART LTFU. CONCLUSIONS: A third of recently diagnosed HIV-infected, ART-ineligible clients were LTFU within 6 months of registration. Predictors of LTFU among ART-ineligible clients are different from those among clients on ART. These findings warrant consideration of an enhanced pre-ART care package aimed at improving retention and timely ART initiation.

Klein Klouwenberg P, Sasi P, Bashraheil M, Awuondo K, Bonten M, Berkley J, Marsh K, Borrmann S. 2011. Temporal association of acute hepatitis A and Plasmodium falciparum malaria in children. PLoS One, 6 (7), pp. e21013. | Show Abstract | Read more

BACKGROUND: In sub-Saharan Africa, Plasmodium falciparum and hepatitis A (HAV) infections are common, especially in children. Co-infections with these two pathogens may therefore occur, but it is unknown if temporal clustering exists. MATERIALS AND METHODS: We studied the pattern of co-infection of P. falciparum malaria and acute HAV in Kenyan children under the age of 5 years in a cohort of children presenting with uncomplicated P. falciparum malaria. HAV status was determined during a 3-month follow-up period. DISCUSSION: Among 222 cases of uncomplicated malaria, 10 patients were anti-HAV IgM positive. The incidence of HAV infections during P. falciparum malaria was 1.7 (95% CI 0.81-3.1) infections/person-year while the cumulative incidence of HAV over the 3-month follow-up period was 0.27 (95% CI 0.14-0.50) infections/person-year. Children with or without HAV co-infections had similar mean P. falciparum asexual parasite densities at presentation (31,000/µL vs. 34,000/µL, respectively), largely exceeding the pyrogenic threshold of 2,500 parasites/µL in this population and minimizing risk of over-diagnosis of malaria as an explanation. CONCLUSION: The observed temporal association between acute HAV and P. falciparum malaria suggests that co-infections of these two hepatotrophic human pathogens may result from changes in host susceptibility. Testing this hypothesis will require larger prospective studies.

Muema DKM, Ndungu FM, Kinyanjui SM, Berkley JA. 2011. Effect of HIV infection on the acute antibody response to malaria antigens in children: an observational study. Malar J, 10 (1), pp. 55. | Show Abstract | Read more

BACKGROUND: In sub-Saharan Africa, the distributions of malaria and HIV widely overlap. Among pregnant and non-pregnant adults, HIV affects susceptibility to malaria, its clinical course and impairs antibody responses to malaria antigens. However, the relationship between the two diseases in childhood, when most deaths from malaria occur, is less clear. It was previously reported that HIV is associated with admission to hospital in rural Kenya with severe malaria among children, except in infancy. HIV-infected children with severe malaria were older, had higher parasite density and increased mortality, raising a hypothesis that HIV interferes with naturally acquired immunity to malaria, hence with little effect at younger ages (a shorter history of exposure). To test this hypothesis, levels of anti-merozoite and schizont extract antibodies were compared between HIV-infected and uninfected children who participated in the original study. METHODS: IgG responses to malaria antigens that are potential targets for immunity to malaria (AMA1, MSP2, MSP3 and schizont extract) were compared between 115 HIV-infected and 115 age-matched, HIV-uninfected children who presented with severe malaria. The children were classified as high and low responders for each antigen and assigned antibody-response breadth scores according to the number of antigens to which they were responsive. A predictive logistic regression model was used to test if HIV was an effect modifier on the age-related acquisition of antibody responses, with age as a continuous variable. RESULTS: Point estimates of the responses to all antigens were lower amongst HIV-infected children, but this was only statistically significant for AMA1 (P = 0.028). HIV-infected children were less likely to be high responders to AMA1 [OR 0.44 (95%CI, 0.2-0.90) P = 0.024]. HIV was associated with a reduced breadth of responses to individual merozoite antigens (P = 0.02). HIV strongly modified the acquisition of antibodies against schizont extract with increasing age (P < 0.0001), but did not modify the rate of age-related acquisition of responses to individual merozoite antigens. CONCLUSIONS: In children with severe malaria, HIV infection is associated with a lower magnitude and narrower breadth of IgG responses to merozoite antigens and stunting of age-related acquisition of the IgG antibody response to schizont extract.

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Mwangome MK, Fegan G, Prentice AM, Berkley JA. 2011. Are diagnostic criteria for acute malnutrition affected by hydration status in hospitalized children? A repeated measures study Nutrition Journal, 10 (1), | Show Abstract | Read more

Introduction. Dehydration and malnutrition commonly occur together among ill children in developing countries. Dehydration (change in total body water) is known to alter weight. Although muscle tissue has high water content, it is not known whether mid-upper arm circumference (MUAC) may be altered by changes in tissue hydration. We aimed to determine whether rehydration alters MUAC, MUAC Z score (MUACz), weight-for-length Z-score (WFLz) and classification of nutritional status among hospitalised Kenyan children admitted with signs of dehydration. Study procedure. We enrolled children aged from 3 months to 5 years admitted to a rural Kenyan district hospital with clinical signs compatible with dehydration, and without kwashiorkor. Anthropometric measurements were taken at admission and repeated after 48 hours of treatment, which included rehydration by WHO protocols. Changes in weight observed during this period were considered to be due to changes in hydration status. Results: Among 325 children (median age 11 months) the median weight gain (rehydration) after 48 hours was 0.21 kg, (an increase of 2.9% of admission body weight). Each 1% change in weight was associated with a 0.40 mm (95% CI: 0.30 to 0.44 mm, p < 0.001) change in MUAC, 0.035z (95% CI: 0.027 to 0.043z, P < 0.001) change in MUACz score and 0.115z (95% CI: 0.114 to 0.116 z, p < 0.001) change in WFLz. Among children aged 6 months or more with signs of dehydration at admission who were classified as having severe acute malnutrition (SAM) at admission by WFLz < -3 or MUAC < 115 mm, 21% and 19% of children respectively were above these cut offs after 48 hours. Conclusion: MUAC is less affected by dehydration than WFLz and is therefore more suitable for nutritional assessment of ill children. However, both WFLz and MUAC misclassify SAM among dehydrated children. Nutritional status should be re-evaluated following rehydration, and management adjusted accordingly. © 2011 Mwangome et al; licensee BioMed Central Ltd.

Mwaniki MK, Talbert AW, Njuguna P, English M, Were E, Lowe BS, Newton CR, Berkley JA. 2011. Clinical indicators of bacterial meningitis among neonates and young infants in rural Kenya. BMC Infect Dis, 11 (1), pp. 301. | Show Abstract | Read more

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.

Mogeni P, Twahir H, Bandika V, Mwalekwa L, Thitiri J, Ngari M, Toromo C, Maitland K, Berkley JA. 2011. Diagnostic performance of visible severe wasting for identifying severe acute malnutrition in children admitted to hospital in Kenya. Bull World Health Organ, 89 (12), pp. 900-906. | Show Abstract | Read more

OBJECTIVE: To determine the diagnostic value of visible severe wasting in identifying severe acute malnutrition at two public hospitals in Kenya. METHODS: This was a cross-sectional study of children aged 6 to 59.9 months admitted to one rural and one urban hospital. On admission, mid-upper arm circumference (MUAC), weight and height were measured and the presence of visible severe wasting was assessed. The diagnostic performance of visible severe wasting was evaluated against anthropometric criteria. FINDINGS: Of 11,166 children admitted, 563 (5%) had kwashiorkor and 1406 (12.5%) were severely wasted (MUAC < 11.5 cm). The combined sensitivity and specificity of visible severe wasting at the two hospitals, as assessed against a MUAC < 11.5 cm, were 54% (95% confidence interval, CI: 51-56) and 96% (95% CI: 96-97), respectively; at one hospital, its sensitivity and specificity against a weight-for-height z-score below -3 were 44.7% (95% CI: 42-48) and 96.5% (95% CI: 96-97), respectively. Severely wasted children who were correctly identified by visible severe wasting were consistently older, more severely wasted, more often having kwashiorkor, more often positive to the human immunodeficiency virus, ill for a longer period and at greater risk of death. Visible severe wasting had lower sensitivity for determining the risk of death than the anthropometric measures. There was no evidence to support measuring both MUAC and weight-for-height z-score. CONCLUSION: Visible severe wasting failed to detect approximately half of the children admitted to hospital with severe acute malnutrition diagnosed anthropometrically. Routine screening by MUAC is quick, simple and inexpensive and should be part of the standard assessment of all paediatric hospital admissions in the study setting.

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Aiken AM, Mturi N, Njuguna P, Mohammed S, Berkley JA, Mwangi I, Mwarumba S, Kitsao BS, Lowe BS, Morpeth SC et al. 2011. Risk and causes of paediatric hospital-acquired bacteraemia in Kilifi District Hospital, Kenya: A prospective cohort study The Lancet, 378 (9808), pp. 2021-2027. | Show Abstract | Read more

In sub-Saharan Africa, community-acquired bacteraemia is an important cause of illness and death in children. Our aim was to establish the magnitude and causes of hospital-acquired (nosocomial) bacteraemia in African children. We reviewed prospectively collected surveillance data of 33 188 admissions to Kilifi District Hospital, Kenya, between April 16, 2002, and Sept 30, 2009. We defined bacteraemia as nosocomial if it occurred 48 h or more after admission. We estimated the per-admission risk, daily rate, effect on mortality, and microbial cause of nosocomial bacteraemia and analysed risk factors by multivariable Cox regression. The effect on morbidity was measured as the increase in hospital stay by comparison with time-matched patients without bacteraemia. The overall risk of nosocomial bacteraemia during this period was 5·9/1000 admissions (95 CI 5·2-6·9) but we recorded an underlying rise in risk of 27 per year. The incidence was 1·0/1000 days in hospital (0·87-1·14), which is about 40 times higher than that of community-acquired bacteraemia in the same region. Mortality in patients with nosocomial bacteraemia was 53, compared with 24 in community-acquired bacteraemia and 6 in patients without bacteraemia. In survivors, nosocomial bacteraemia lengthened hospital stay by 10·1 days (3·0- 17·2). Klebsiella pneumoniae, Escherichia coli, Staphylococcus aureus, Acinetobacter spp, group D streptococci, and Pseudomonas aeruginosa accounted for three-quarters of nosocomial infections. Nosocomial bacteraemia was significantly associated with severe malnutrition (hazard ratio 2·52, 95 CI 1·79-3·57) and blood transfusion in children without severe anaemia (4·99; 3·39-7·37). Our findings show that although nosocomial bacteraemia is rare, it has serious effects on morbidity and mortality, and the microbiological causes are distinct from those of community-acquired bacteraemia. Nosocomial infections are largely unrecognised or undocumented as a health risk in low-income countries, but they are likely to become public health priorities as awareness of their occurrence increases and as other prominent childhood diseases are progressively controlled. Wellcome Trust. © 2011 Elsevier Ltd.

Nair H, Brooks WA, Katz M, Roca A, Berkley JA, Madhi SA, Simmerman JM, Gordon A, Sato M, Howie S et al. 2011. Global burden of respiratory infections due to seasonal influenza in young children: a systematic review and meta-analysis. Lancet, 378 (9807), pp. 1917-1930. | Show Abstract | Read more

BACKGROUND: The global burden of disease attributable to seasonal influenza virus in children is unknown. We aimed to estimate the global incidence of and mortality from lower respiratory infections associated with influenza in children younger than 5 years. METHODS: We estimated the incidence of influenza episodes, influenza-associated acute lower respiratory infections (ALRI), and influenza-associated severe ALRI in children younger than 5 years, stratified by age, with data from a systematic review of studies published between Jan 1, 1995, and Oct 31, 2010, and 16 unpublished population-based studies. We applied these incidence estimates to global population estimates for 2008 to calculate estimates for that year. We estimated possible bounds for influenza-associated ALRI mortality by combining incidence estimates with case fatality ratios from hospital-based reports and identifying studies with population-based data for influenza seasonality and monthly ALRI mortality. FINDINGS: We identified 43 suitable studies, with data for around 8 million children. We estimated that, in 2008, 90 million (95% CI 49-162 million) new cases of influenza (data from nine studies), 20 million (13-32 million) cases of influenza-associated ALRI (13% of all cases of paediatric ALRI; data from six studies), and 1 million (1-2 million) cases of influenza-associated severe ALRI (7% of cases of all severe paediatric ALRI; data from 39 studies) occurred worldwide in children younger than 5 years. We estimated there were 28,000-111,500 deaths in children younger than 5 years attributable to influenza-associated ALRI in 2008, with 99% of these deaths occurring in developing countries. Incidence and mortality varied substantially from year to year in any one setting. INTERPRETATION: Influenza is a common pathogen identified in children with ALRI and results in a substantial burden on health services worldwide. Sufficient data to precisely estimate the role of influenza in childhood mortality from ALRI are not available. FUNDING: WHO; Bill & Melinda Gates Foundation.

Scott JAG, Berkley JA, Mwangi I, Ochola L, Uyoga S, Macharia A, Ndila C, Lowe BS, Mwarumba S, Bauni E et al. 2011. Relation between falciparum malaria and bacteraemia in Kenyan children: a population-based, case-control study and a longitudinal study. Lancet, 378 (9799), pp. 1316-1323. | Show Abstract | Read more

BACKGROUND: Many investigators have suggested that malaria infection predisposes individuals to bacteraemia. We tested this hypothesis with mendelian randomisation studies of children with the malaria-protective phenotype of sickle-cell trait (HbAS). METHODS: This study was done in a defined area around Kilifi District Hospital, Kilifi, Kenya. We did a matched case-control study to identify risk factors for invasive bacterial disease, in which cases were children aged 3 months to 13 years who were admitted to hospital with bacteraemia between Sept 16, 1999, and July 31, 2002. We aimed to match two controls, by age, sex, location, and time of recruitment, for every case. We then did a longitudinal case-control study to assess the relation between HbAS and invasive bacterial disease as malaria incidence decreased. Cases were children aged 0-13 years who were admitted to hospital with bacteraemia between Jan 1, 1999, and Dec 31, 2007. Controls were born in the study area between Jan 1, 2006, and June 23, 2009. Finally, we modelled the annual incidence of bacteraemia against the community prevalence of malaria during 9 years with Poisson regression. RESULTS: In the matched case-control study, we recruited 292 cases-we recruited two controls for 236, and one for the remaining 56. Sickle-cell disease, HIV, leucocyte haemozoin pigment, and undernutrition were positively associated with bacteraemia and HbAS was strongly negatively associated with bacteraemia (odds ratio 0·36; 95% CI 0·20-0·65). In the longitudinal case-control study, we assessed data from 1454 cases and 10,749 controls. During the study period, the incidence of admission to hospital with malaria per 1000 child-years decreased from 28·5 to 3·45, with a reduction in protection afforded by HbAS against bacteraemia occurring in parallel (p=0·0008). The incidence of hospital admissions for bacteraemia per 1000 child-years also decreased from 2·59 to 1·45. The bacteraemia incidence rate ratio associated with malaria parasitaemia was 6·69 (95% CI 1·31-34·3) and, at a community parasite prevalence of 29% in 1999, 62% (8·2-91) of bacteraemia cases were attributable to malaria. INTERPRETATION: Malaria infection strongly predisposes individuals to bacteraemia and can account for more than half of all cases of bacteraemia in malaria-endemic areas. Interventions to control malaria will have a major additional benefit by reducing the burden of invasive bacterial disease. FUNDING: Wellcome Trust.

Klouwenberg PK, Sasi P, Bashraheil M, Awuondo K, Bonten M, Berkley J, Marsh K, Borrmann S. 2011. Temporal Association of Acute Hepatitis A and Plasmodium falciparum Malaria in Children PLOS ONE, 6 (7), pp. e21013-e21013. | Read more

Hassan AS, Sakwa EM, Nabwera HM, Taegtmeyer MM, Kimutai RM, Sanders EJ, Awuondo KK, Mutinda MN, Molyneux CS, Berkley JA. 2012. Dynamics and constraints of early infant diagnosis of HIV infection in Rural Kenya. AIDS Behav, 16 (1), pp. 5-12. | Show Abstract | Read more

A cohort design was used to determine uptake and drop out of 213 HIV-exposed infants eligible for Early Infant Diagnosis (EID) of HIV. To explore service providers and care givers knowledge, attitudes and perceptions of the EID process, observations and in-depth interviews were conducted. 145 (68%) infants enrolled after 2 months of age. 139 (65%) dropped out before follow up to 18 months old. 60 (43%) drop outs occurred within 2 months of enrolment. Maternal factors associated with infant drop out were maternal loss to follow up (48 [68%] vs. 8 [20%], P < 0.001) and younger maternal age (27.2 vs. 30.1 years, P = 0.033). Service providers and caregivers had inadequate training, knowledge and understanding of EID. Poverty and lack of social support were challenges in accessing EID services. EID should be more closely aligned within PMTCT services, integrated with routine mother and child health (MCH) activities and its implementation more closely monitored.

Chapman SJ, Khor CC, Vannberg FO, Rautanen A, Walley A, Segal S, Moore CE, Davies RJO, Day NP, Peshu N et al. 2010. Common NFKBIL2 polymorphisms and susceptibility to pneumococcal disease: a genetic association study. Crit Care, 14 (6), pp. R227. | Show Abstract | Read more

INTRODUCTION: Streptococcus pneumoniae remains a major global health problem and a leading cause of death in children worldwide. The factors that influence development of pneumococcal sepsis remain poorly understood, although increasing evidence points towards a role for genetic variation in the host's immune response. Recent insights from the study of animal models, rare human primary immunodeficiency states, and population-based genetic epidemiology have focused attention on the role of the proinflammatory transcription factor NF-κB in pneumococcal disease pathogenesis. The possible role of genetic variation in the atypical NF-κB inhibitor IκB-R, encoded by NFKBIL2, in susceptibility to invasive pneumococcal disease has not, to our knowledge, previously been reported upon. METHODS: An association study was performed examining the frequencies of nine common NFKBIL2 polymorphisms in two invasive pneumococcal disease case-control groups: European individuals from hospitals in Oxfordshire, UK (275 patients and 733 controls), and African individuals from Kilifi District Hospital, Kenya (687 patients with bacteraemia, of which 173 patients had pneumococcal disease, together with 550 controls). RESULTS: Five polymorphisms significantly associated with invasive pneumococcal disease susceptibility in the European study, of which two polymorphisms also associated with disease in African individuals. Heterozygosity at these loci was associated with protection from invasive pneumococcal disease (rs760477, Mantel-Haenszel 2 × 2 χ(2) = 11.797, P = 0.0006, odds ratio = 0.67, 95% confidence interval = 0.53 to 0.84; rs4925858, Mantel-Haenszel 2 × 2 χ(2) = 9.104, P = 0.003, odds ratio = 0.70, 95% confidence interval = 0.55 to 0.88). Linkage disequilibrium was more extensive in European individuals than in Kenyans. CONCLUSIONS: Common NFKBIL2 polymorphisms are associated with susceptibility to invasive pneumococcal disease in European and African populations. These findings further highlight the importance of control of NF-κB in host defence against pneumococcal disease.

Färnert A, Gwer S, Berkley JA. 2010. Clinical considerations for antibiotic choices in the treatment of severe malaria. Trends Parasitol, 26 (10), pp. 465-466. | Read more

Berkley JA, Munywoki P, Nokes DJ. 2010. Severe Pneumonia Among Kenyan Infants and Children Reply JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 304 (9), pp. 964-965. | Read more

Khor CC, Vannberg FO, Chapman SJ, Guo H, Wong SH, Walley AJ, Vukcevic D, Rautanen A, Mills TC, Chang K-C et al. 2010. CISH and susceptibility to infectious diseases. N Engl J Med, 362 (22), pp. 2092-2101. | Show Abstract | Read more

BACKGROUND: The interleukin-2-mediated immune response is critical for host defense against infectious pathogens. Cytokine-inducible SRC homology 2 (SH2) domain protein (CISH), a suppressor of cytokine signaling, controls interleukin-2 signaling. METHODS: Using a case-control design, we tested for an association between CISH polymorphisms and susceptibility to major infectious diseases (bacteremia, tuberculosis, and severe malaria) in blood samples from 8402 persons in Gambia, Hong Kong, Kenya, Malawi, and Vietnam. We had previously tested 20 other immune-related genes in one or more of these sample collections. RESULTS: We observed associations between variant alleles of multiple CISH polymorphisms and increased susceptibility to each infectious disease in each of the study populations. When all five single-nucleotide polymorphisms (SNPs) (at positions -639, -292, -163, +1320, and +3415 [all relative to CISH]) within the CISH-associated locus were considered together in a multiple-SNP score, we found an association between CISH genetic variants and susceptibility to bacteremia, malaria, and tuberculosis (P=3.8x10(-11) for all comparisons), with -292 accounting for most of the association signal (P=4.58x10(-7)). Peripheral-blood mononuclear cells obtained from adult subjects carrying the -292 variant, as compared with wild-type cells, showed a muted response to the stimulation of interleukin-2 production--that is, 25 to 40% less CISH expression. CONCLUSIONS: Variants of CISH are associated with susceptibility to diseases caused by diverse infectious pathogens, suggesting that negative regulators of cytokine signaling have a role in immunity against various infectious diseases. The overall risk of one of these infectious diseases was increased by at least 18% among persons carrying the variant CISH alleles.

Thuo N, Ohuma E, Karisa J, Talbert A, Berkley JA, Maitland K. 2010. The prognostic value of dipstick urinalysis in children admitted to hospital with severe malnutrition. Arch Dis Child, 95 (6), pp. 422-426. | Show Abstract | Read more

BACKGROUND: Children with severe malnutrition (SAM) present to hospital with an array of complications, resulting in high mortality despite adherence to WHO guidelines. Diagnostic resources in developing countries are limited and bedside tests could help identify high-risk children. Dipstick urinalysis is a bedside screening test for urinary tract infections (UTIs). UTIs are common in SAM and can lead to secondary invasive bacterial sepsis. Very few studies have examined the usefulness of dipstick screening of urine specimens in SAM and none has explored its prognostic value. PATIENTS AND METHODS: A 2-year prospective study on children admitted in Kilifi District Hospital, Kenya, with SAM. Freshly voided, clean catch urine samples were tested using Multistix reagent test strips. Positive samples were sent for culture. RESULTS: Of the 667 children admitted, 498 children (75%) provided urine samples; of these, 119 (24%) were positive for either leucocyte esterase (LE) or nitrites. Culture-proven UTI was detected in 28 children (6% overall). All isolates were coliforms and were >50% were resistant to cotrimoxazole and gentamicin. There was no difference in severity signs between those with positive dipstick and those without. Case fatality was higher among children with a positive dipstick (29% vs 12%). Presence of a positive dipstick was a strong predictor of mortality (adjusted HR 2.5). CONCLUSIONS: A urine dipstick positive for either LE or nitrites is a useful predictor of death in children admitted with SAM. Prospective studies to determine the role of untreated UTI in these deaths are needed before any treatment recommendations can be made.

Jones KDJ, Berkley JA, Warner JO. 2010. Perinatal nutrition and immunity to infection. Pediatr Allergy Immunol, 21 (4 Pt 1), pp. 564-576. | Show Abstract | Read more

Epidemiological data provide strong evidence for a relationship between undernutrition and life-threatening infection in infants and children. However, the mechanisms that underlie this relationship are poorly understood. Through foetal life, infancy and childhood, the immune system undergoes a process of functional maturation. The adequacy of this process is dependent on environmental factors, and there is accumulating evidence of the impact of pre- and post-natal nutrition in this regard. This review outlines the impact of nutrition during foetal and infant development on the capacity to mount immune responses to infection. It provides an overview of the epidemiologic evidence for such a role and discusses the possible mechanisms involved.

Berkley JA, Munywoki P, Ngama M, Kazungu S, Abwao J, Bett A, Lassauniére R, Kresfelder T, Cane PA, Venter M et al. 2010. Viral etiology of severe pneumonia among Kenyan infants and children. JAMA, 303 (20), pp. 2051-2057. | Show Abstract | Read more

CONTEXT: Pneumonia is the leading cause of childhood death in sub-Saharan Africa. Comparative estimates of the contribution of causative pathogens to the burden of disease are essential for targeted vaccine development. OBJECTIVE: To determine the viral etiology of severe pneumonia among infants and children at a rural Kenyan hospital using comprehensive and sensitive molecular diagnostic techniques. DESIGN, SETTING, AND PARTICIPANTS: Prospective observational and case-control study during 2007 in a rural Kenyan district hospital. Participants were children aged 1 day to 12 years, residing in a systematically enumerated catchment area, and who either were admitted to Kilifi District Hospital meeting World Health Organization clinical criteria for severe pneumonia or very severe pneumonia; (2) presented with mild upper respiratory tract infection but were not admitted; or (3) were well infants and children attending for immunization. MAIN OUTCOME MEASURES: The presence of respiratory viruses and the odds ratio for admission with severe disease. RESULTS: Of 922 eligible admitted patients, 759 were sampled (82% [median age, 9 months]). One or more respiratory viruses were detected in 425 of the 759 sampled (56% [95% confidence interval {CI}, 52%-60%]). Respiratory syncytial virus (RSV) was detected in 260 participants (34% [95% CI, 31%-38%]) and other respiratory viruses were detected in 219 participants (29%; 95% CI, 26%-32%), the most common being Human coronavirus 229E (n = 51 [6.7%]), influenza type A (n = 44 [5.8%]), Parainfluenza type 3 (n = 29 [3.8%]), Human adenovirus (n = 29 [3.8%]), and Human metapneumovirus (n = 23 [3.0%]). Compared with well control participants, detection of RSV was associated with severe disease (5% [corrected] in control participants; adjusted odds ratio, 6.11 [95% CI, 1.65-22.6]) while collectively, other respiratory viruses were not associated with severe disease (23% in control participants; adjusted odds ratio, 1.27 [95% CI, 0.64-2.52]). CONCLUSION: In a sample of Kenyan infants and children admitted with severe pneumonia to a rural hospital, RSV was the predominant viral pathogen.

Talbert AWA, Mwaniki M, Mwarumba S, Newton CRJC, Berkley JA. 2010. Invasive bacterial infections in neonates and young infants born outside hospital admitted to a rural hospital in Kenya. Pediatr Infect Dis J, 29 (10), pp. 945-949. | Show Abstract | Read more

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.

Mwaniki M, Mathenge A, Gwer S, Mturi N, Bauni E, Newton CRJC, Berkley J, Idro R. 2010. Neonatal seizures in a rural Kenyan District Hospital: aetiology, incidence and outcome of hospitalization. BMC Med, 8 (1), pp. 16. | Show Abstract | Read more

BACKGROUND: Acute seizures are common among children admitted to hospitals in resource poor countries. However, there is little data on the burden, causes and outcome of neonatal seizures in sub-Saharan Africa. We determined the minimum incidence, aetiology and immediate outcome of seizures among neonates admitted to a rural district hospital in Kenya. METHODS: From 1st January 2003 to 31st December 2007, we assessed for seizures all neonates (age 0-28 days) admitted to the Kilifi District Hospital, who were resident in a defined, regularly enumerated study area. The population denominator, the number of live births in the community on 1 July 2005 (the study midpoint) was modelled from the census data. RESULTS: Seizures were reported in 142/1572 (9.0%) of neonatal admissions. The incidence was 39.5 [95% confidence interval (CI) 26.4-56.7] per 1000 live-births and incidence increased with birth weight. The main diagnoses in neonates with seizures were sepsis in 85 (60%), neonatal encephalopathy in 30 (21%) and meningitis in 21 (15%), but only neonatal encephalopathy and bacterial meningitis were independently associated with seizures. Neonates with seizures had a longer hospitalization [median period 7 days - interquartile range (IQR) 4 to10] -compared to 5 days [IQR 3 to 8] for those without seizures, P = 0.02). Overall, there was no difference in inpatient case fatality between neonates with and without seizures but, when this outcome was stratified by birth weight, it was significantly higher in neonates >or= 2.5 kg compared to low birth weight neonates [odds ratio 1.59 (95%CI 1.02 to 2.46), P = 0.037]. Up to 13% of the surviving newborn with seizures had neurological abnormalities at discharge. CONCLUSION: There is a high incidence of neonatal seizures in this area of Kenya and the most important causes are neonatal encephalopathy and meningitis. The high incidence of neonatal seizures may be a reflection of the quality of the perinatal and postnatal care available to the neonates.

Berkley JA, Munywoki P, Nokes DJ. 2010. In reply JAMA - Journal of the American Medical Association, 304 (9), pp. 964-965. | Read more

Mwaniki MK, Talbert AW, Mturi FN, Berkley JA, Kager P, Marsh K, Newton CR. 2010. Congenital and neonatal malaria in a rural Kenyan district hospital: an eight-year analysis. Malar J, 9 (1), pp. 313. | Show Abstract | Read more

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.

Mwaniki MK, Gatakaa HW, Mturi FN, Chesaro CR, Chuma JM, Peshu NM, Mason L, Kager P, Marsh K, English M et al. 2010. An increase in the burden of neonatal admissions to a rural district hospital in Kenya over 19 years. BMC Public Health, 10 (1), pp. 591. | Show Abstract | Read more

BACKGROUND: Most of the global neonatal deaths occur in developing nations, mostly in rural homes. Many of the newborns who receive formal medical care are treated in rural district hospitals and other peripheral health centres. However there are no published studies demonstrating trends in neonatal admissions and outcome in rural health care facilities in resource poor regions. Such information is critical in planning public health interventions. In this study we therefore aimed at describing the pattern of neonatal admissions to a Kenyan rural district hospital and their outcome over a 19 year period, examining clinical indicators of inpatient neonatal mortality and also trends in utilization of a rural hospital for deliveries. METHODS: Prospectively collected data on neonates is compared to non-neonatal paediatric (≤ 5 years old) admissions and deliveries' in the maternity unit at Kilifi District Hospital from January 1(st) 1990 up to December 31(st) 2008, to document the pattern of neonatal admissions, deliveries and changes in inpatient deaths. Trends were examined using time series models with likelihood ratios utilised to identify indicators of inpatient neonatal death. RESULTS: The proportion of neonatal admissions of the total paediatric ≤ 5 years admissions significantly increased from 11% in 1990 to 20% by 2008 (trend 0.83 (95% confidence interval 0.45-1.21). Most of the increase in burden was from neonates born in hospital and very young neonates aged < 7 days. Hospital deliveries also increased significantly. Clinical diagnoses of neonatal sepsis, prematurity, neonatal jaundice, neonatal encephalopathy, tetanus and neonatal meningitis accounted for over 75% of the inpatient neonatal admissions. Inpatient case fatality for all ≤ 5 years declined significantly over the 19 years. However, neonatal deaths comprised 33% of all inpatient death among children aged ≤ 5 years in 1990, this increased to 55% by 2008. Tetanus 256/390 (67%), prematurity 554/1,280(43%) and neonatal encephalopathy 253/778(33%) had the highest case fatality. A combination of six indicators: irregular respiration, oxygen saturation of <90%, pallor, neck stiffness, weight < 1.5 kg, and abnormally elevated blood glucose > 7 mmol/l predicted inpatient neonatal death with a sensitivity of 81% and a specificity of 68%. CONCLUSIONS: There is clear evidence of increasing burden in neonatal admissions at a rural district hospital in contrast to reducing numbers of non-neonatal paediatrics' admissions aged ≤ 5 years. Though the inpatient case fatality for all admissions aged ≤ 5 years declined significantly, neonates now comprise close to 60% of all inpatient deaths. Simple indicators may identify neonates at risk of death.

Williams TN, Uyoga S, Macharia A, Ndila C, McAuley CF, Opi DH, Mwarumba S, Makani J, Komba A, Ndiritu MN et al. 2009. Bacteraemia in Kenyan children with sickle-cell anaemia: a retrospective cohort and case-control study. Lancet, 374 (9698), pp. 1364-1370. | Show Abstract | Read more

BACKGROUND: In sub-Saharan Africa, more than 90% of children with sickle-cell anaemia die before the diagnosis can be made. The causes of death are poorly documented, but bacterial sepsis is probably important. We examined the risk of invasive bacterial diseases in children with sickle-cell anaemia. METHODS: This study was undertaken in a rural area on the coast of Kenya, with a case-control approach. We undertook blood cultures on all children younger than 14 years who were admitted from within a defined study area to Kilifi District Hospital between Aug 1, 1998, and March 31, 2008; those with bacteraemia were defined as cases. We used two sets of controls: children recruited by random sampling in the same area into several studies undertaken between Sept 1, 1998, and Nov 30, 2005; and those born consecutively within the area between May 1, 2006, and April 30, 2008. Cases and controls were tested for sickle-cell anaemia retrospectively. FINDINGS: We detected 2157 episodes of bacteraemia in 38 441 admissions (6%). 1749 of these children with bacteraemia (81%) were typed for sickle-cell anaemia, of whom 108 (6%) were positive as were 89 of 13 492 controls (1%). The organisms most commonly isolated from children with sickle-cell anaemia were Streptococcus pneumoniae (44/108 isolates; 41%), non-typhi Salmonella species (19/108; 18%), Haemophilus influenzae type b (13/108; 12%), Acinetobacter species (seven of 108; 7%), and Escherichia coli (seven of 108; 7%). The age-adjusted odds ratio for bacteraemia in children with sickle-cell anaemia was 26.3 (95% CI 14.5-47.6), with the strongest associations for S pneumoniae (33.0, 17.4-62.8), non-typhi Salmonella species (35.5, 16.4-76.8), and H influenzae type b (28.1, 12.0-65.9). INTERPRETATION: The organisms causing bacteraemia in African children with sickle-cell anaemia are the same as those in developed countries. Introduction of conjugate vaccines against S pneumoniae and H influenzae into the childhood immunisation schedules of African countries could substantially affect survival of children with sickle-cell anaemia. FUNDING: Wellcome Trust, UK.

Chapman SJ, Khor CC, Vannberg FO, Rautanen A, Segal S, Moore CE, Davies RJO, Day NP, Peshu N, Crook DW et al. 2010. NFKBIZ polymorphisms and susceptibility to pneumococcal disease in European and African populations. Genes Immun, 11 (4), pp. 319-325. | Show Abstract | Read more

The proinflammatory transcription factor nuclear factor-kappaB (NF-kappaB) has a central role in host defence against pneumococcal disease. Both rare mutations and common polymorphisms in the NFKBIA gene encoding the NF-kappaB inhibitor, IkappaB-alpha, associate with susceptibility to bacterial disease, but the possible role of polymorphisms within the related IkappaB-zeta gene NFKBIZ in the development of invasive pneumococcal disease (IPD) has not been reported previously. To investigate this further, we examined the frequencies of 22 single-nucleotide polymorphisms spanning NFKBIZ in two case-control studies, comprising UK Caucasian (n=1008) and Kenyan (n=723) individuals. Nine polymorphisms within a single UK linkage disequilibrium (LD) block and all four polymorphisms within the equivalent, shorter Kenyan LD block displayed either a significant association with IPD or a trend towards association. For each polymorphism, heterozygosity was associated with protection from IPD when compared with the combined homozygous states (for example, for rs600718, Mantel-Haenszel 2 x 2 chi(2)=7.576, P=0.006, odds ratio (OR)=0.67, 95% confidence interval (95% CI) for OR: 0.51-0.88; for rs616597, Mantel-Haenszel 2 x 2 chi(2)=8.715, P=0.003, OR=0.65, 95% CI: 0.49-0.86). We conclude that multiple NFKBIZ polymorphisms associate with susceptibility to IPD in humans. The study of multiple populations may aid in fine mapping of associations within extensive regions of strong LD ('transethnic mapping').

Berkley JA, Bejon P, Mwangi T, Gwer S, Maitland K, Williams TN, Mohammed S, Osier F, Kinyanjui S, Fegan G et al. 2009. HIV infection, malnutrition, and invasive bacterial infection among children with severe malaria. Clin Infect Dis, 49 (3), pp. 336-343. | Show Abstract | Read more

BACKGROUND: Human immunodeficiency virus (HIV) infection, malnutrition, and invasive bacterial infection (IBI) are reported among children with severe malaria. However, it is unclear whether their cooccurrence with falciparum parasitization and severe disease happens by chance or by association among children in areas where malaria is endemic. METHODS: We examined 3068 consecutive children admitted to a Kenyan district hospital with clinical features of severe malaria and 592 control subjects from the community. We performed multivariable regression analysis, with each case weighted for its probability of being due to falciparum malaria, using estimates of the fraction of severe disease attributable to malaria at different parasite densities derived from cross-sectional parasitological surveys of healthy children from the same community. RESULTS: HIV infection was present in 133 (12%) of 1071 consecutive parasitemic admitted children (95% confidence interval [CI], 11%-15%). Parasite densities were higher in HIV-infected children. The odds ratio for admission associated with HIV infection for admission with true severe falciparum malaria was 9.6 (95% CI, 4.9-19); however, this effect was restricted to children aged 1 year. Malnutrition was present in 507 (25%) of 2048 consecutive parasitemic admitted children (95% CI, 23%-27%). The odd ratio associated with malnutrition for admission with true severe falciparum malaria was 4.0 (95% CI, 2.9-5.5). IBI was detected in 127 (6%) of 2048 consecutive parasitemic admitted children (95% CI, 5.2%-7.3%). All 3 comorbidities were associated with increased case fatality. CONCLUSIONS: HIV, malnutrition and IBI are biologically associated with severe disease due to falciparum malaria rather than being simply alternative diagnoses in co-incidentally parasitized children in an endemic area.

Komba AN, Makani J, Sadarangani M, Ajala-Agbo T, Berkley JA, Newton CRJC, Marsh K, Williams TN. 2009. Malaria as a cause of morbidity and mortality in children with homozygous sickle cell disease on the coast of Kenya. Clin Infect Dis, 49 (2), pp. 216-222. | Show Abstract | Read more

BACKGROUND: To date, it has been widely assumed that malaria is a common cause of morbidity and mortality in children with sickle cell disease (SCD) in malaria-endemic countries, and as a result, malarial prophylaxis is commonly recommended. Nevertheless, few data are available that support this practice. METHODS: We conducted a retrospective analysis of the data collected prospectively from children aged 0-13 years who were admitted to Kilifi District Hospital during the period from July 1998 through June 2005. We studied the prevalence, clinical features, and outcome of malarial infections in these children, stratified by SCD status. RESULTS: Although we estimated the prevalence of SCD in children to be only 0.8% (71 of 8531 children) during the period from August 2006 through September 2008 in the community surrounding the hospital, 555 (1.6%) of 34,529 children admitted to the hospital during the study period (i.e., from July 1998 through June 2005) were children with SCD; in fact, a total of 309 children with SCD were admitted 555 times. The prevalence of Plasmodium falciparum parasitemia was lower among children with SCD than it was among children without SCD (86 [15.6%] of 551 children vs. 13,835 [41.3%] of 33,500 children; P < .001). Similarly, among those infected with P. falciparum parasites, the mean parasite density was significantly lower among children with SCD than it was among children without SCD (2205 vs. 23,878 parasites/microL; P < .001). Fourteen (16.3%) of 86 parasitemic patients with SCD had features consistent with severe malaria, compared with 3424 (24.7%) of 13,835 parasitemic patients without SCD (odds ratio, 0.59; P < .07). We found no association between malarial parasitemia and death. CONCLUSIONS: We found no evidence to support the conclusion that the risk of malaria is higher among children with SCD than it is among children without SCD in a rural area on the coast of Kenya. Further studies should be undertaken to help policy makers develop appropriate guidelines regarding malarial prophylaxis for patients with SCD in malaria-endemic regions.

Seale AC, Mwaniki M, Newton CRJC, Berkley JA. 2009. Maternal and early onset neonatal bacterial sepsis: burden and strategies for prevention in sub-Saharan Africa. Lancet Infect Dis, 9 (7), pp. 428-438. | Show Abstract | Read more

Maternal and child health are high priorities for international development. Through a Review of published work, we show substantial gaps in current knowledge on incidence (cases per live births), aetiology, and risk factors for both maternal and early onset neonatal bacterial sepsis in sub-Saharan Africa. Although existing published data suggest that sepsis causes about 10% of all maternal deaths and 26% of neonatal deaths, these are likely to be considerable underestimates because of methodological limitations. Successful intervention strategies in resource-rich settings and early studies in sub-Saharan Africa suggest that the burden of maternal and early onset neonatal bacterial sepsis could be reduced through simple interventions, including antiseptic and antibiotic treatment. An effective way to expedite evidence to guide interventions and determine the incidence, aetiology, and risk factors for sepsis in sub-Saharan Africa would be through a multiarmed factorial intervention trial aimed at reducing both maternal and early onset neonatal bacterial sepsis in sub-Saharan Africa.

Mwaniki MK, Nokes DJ, Ignas J, Munywoki P, Ngama M, Newton CR, Maitland K, Berkley JA. 2009. Emergency triage assessment for hypoxaemia in neonates and young children in a Kenyan hospital: an observational study. Bull World Health Organ, 87 (4), pp. 263-270. | Show Abstract | Read more

OBJECTIVE: To describe the prevalence of hypoxaemia in children admitted to a hospital in Kenya for the purpose of identifying clinical signs of hypoxaemia for emergency triage assessment, and to test the hypothesis that such signs lead to correct identification of hypoxaemia in children, irrespective of their diagnosis. METHODS: From 2002 to 2005 we prospectively collected clinical data and pulse oximetry measurements for all paediatric admissions to Kilifi District Hospital, Kenya, irrespective of diagnosis, and assessed the prevalence of hypoxaemia in relation to the WHO clinical syndromes of 'pneumonia' on admission and the final diagnoses made at discharge. We used the data collected over the first three years to derive signs predictive of hypoxaemia, and data from the fourth year to validate those signs. FINDINGS: Hypoxemia was found in 977 of 15 289 (6.4%) of all admissions (5% to 19% depending on age group) and was strongly associated with inpatient mortality (age-adjusted risk ratio: 4.5; 95% confidence interval, CI: 3.8-5.3). Although most hypoxaemic children aged > 60 days met the WHO criteria for a syndrome of 'pneumonia' on admission, only 215 of the 693 (31%) such children had a final diagnosis of lower respiratory tract infection (LRTI). The most predictive signs for hypoxaemia included shock, a heart rate < 80 beats per minute, irregular breathing, a respiratory rate > 60 breaths per minute and impaired consciousness. However, 5-15% of the children who had hypoxaemia on admission were missed, and 18% of the children were incorrectly identified as hypoxaemic. CONCLUSION: The syndromes of pneumonia make it possible to identify most hypoxaemic children, including those without LRTI. Shock, bradycardia and irregular breathing are important predictive signs, and severe malaria with respiratory distress is a common cause of hypoxaemia. Overall, however, clinical signs are poor predictors of hypoxaemia, and using pulse oximetry in resource-poor health facilities to target oxygen therapy is likely to save costs.

Okiro EA, Al-Taiar A, Reyburn H, Idro R, Berkley JA, Snow RW. 2009. Age patterns of severe paediatric malaria and their relationship to Plasmodium falciparum transmission intensity. Malar J, 8 (1), pp. 4. | Show Abstract | Read more

BACKGROUND: The understanding of the epidemiology of severe malaria in African children remains incomplete across the spectrum of Plasmodium falciparum transmission intensities through which communities might expect to transition, as intervention coverage expands. METHODS: Paediatric admission data were assembled from 13 hospitals serving 17 communities between 1990 and 2007. Estimates of Plasmodium falciparum transmission intensity in these communities were assembled to be spatially and temporally congruent to the clinical admission data. The analysis focused on the relationships between community derived parasite prevalence and the age and clinical presentation of paediatric malaria in children aged 0-9 years admitted to hospital. RESULTS: As transmission intensity declined a greater proportion of malaria admissions were in older children. There was a strong linear relationship between increasing transmission intensity and the proportion of paediatric malaria admissions that were infants (R2 = 0.73, p < 0.001). Cerebral malaria was reported among 4% and severe malaria anaemia among 17% of all malaria admissions. At higher transmission intensity cerebral malaria was a less common presentation compared to lower transmission sites. There was no obvious relationship between the proportions of children with severe malaria anaemia and transmission intensity. CONCLUSION: As the intensity of malaria transmission declines in Africa through the scaling up of insecticide-treated nets and other vector control measures a focus of disease prevention among very young children becomes less appropriate. The understanding of the relationship between parasite exposure and patterns of disease risk should be used to adapt malaria control strategies in different epidemiological settings.

Lyons EJ, Amos W, Berkley JA, Mwangi I, Shafi M, Williams TN, Newton CR, Peshu N, Marsh K, Scott JAG, Hill AVS. 2009. Homozygosity and risk of childhood death due to invasive bacterial disease. BMC Med Genet, 10 (1), pp. 55. | Show Abstract | Read more

BACKGROUND: Genetic heterozygosity is increasingly being shown to be a key predictor of fitness in natural populations, both through inbreeding depression, inbred individuals having low heterozygosity, and also through chance linkage between a marker and a gene under balancing selection. One important component of fitness that is often highlighted is resistance to parasites and other pathogens. However, the significance of equivalent loci in human populations remains unclear. Consequently, we performed a case-control study of fatal invasive bacterial disease in Kenyan children using a genome-wide screen with microsatellite markers. METHODS: 148 cases, comprising children aged <13 years who died of invasive bacterial disease, (variously, bacteraemia, bacterial meningitis or neonatal sepsis) and 137 age-matched, healthy children were sampled in a prospective study conducted at Kilifi District Hospital, Kenya. Samples were genotyped for 134 microsatellite markers using the ABI LD20 marker set and analysed for an association between homozygosity and mortality. RESULTS: At five markers homozygosity was strongly associated with mortality (odds ratio range 4.7 - 12.2) with evidence of interactions between some markers. Mortality was associated with different non-overlapping marker groups in Gram positive and Gram negative bacterial disease. Homozygosity at susceptibility markers was common (prevalence 19-49%) and, with the large effect sizes, this suggests that bacterial disease mortality may be strongly genetically determined. CONCLUSION: Balanced polymorphisms appear to be more widespread in humans than previously appreciated and play a critical role in modulating susceptibility to infectious disease. The effect sizes we report, coupled with the stochasticity of exposure to pathogens suggests that infection and mortality are far from random due to a strong genetic basis.

Bejon P, Mohammed S, Mwangi I, Atkinson SH, Osier F, Peshu N, Newton CR, Maitland K, Berkley JA. 2008. Fraction of all hospital admissions and deaths attributable to malnutrition among children in rural Kenya. Am J Clin Nutr, 88 (6), pp. 1626-1631. | Show Abstract | Read more

BACKGROUND: Malnutrition is common in the developing world and associated with disease and mortality. Because malnutrition frequently occurs among children in the community as well as those with acute illness, and because anthropometric indicators of nutritional status are continuous variables that preclude a single definition of malnutrition, malnutrition-attributable fractions of admissions and deaths cannot be calculated by simply enumerating individual children. OBJECTIVE: We determined the malnutrition-attributable fractions among children admitted to a rural district hospital in Kenya, among inpatient deaths and among children with the major causes of severe disease. DESIGN: We analyzed data from children between 6 and 60 mo of age, comprising 13,307 admissions, 674 deaths, 3068 admissions with severe disease, and 562 community controls by logistic regression, using anthropometric z scores as the independent variable and admission or death as the outcome, to calculate the probability of admission as a result of "true malnutrition" for individual cases. Probabilities were averaged to calculate attributable fractions. RESULTS: Z scores < -3 were insensitive for malnutrition-attributable deaths and admissions, and no single threshold was both specific and sensitive. The overall malnutrition-attributable fraction for in-hospital deaths was 51% (95% CI: 42%, 61%) with midupper arm circumference. Similar malnutrition-attributable fractions were seen for the major causes of severe disease (severe malaria, gastroenteritis, lower respiratory tract infection, HIV, and invasive bacterial disease). CONCLUSIONS: Despite global improvements, malnutrition still underlies half of the inpatient morbidity and mortality rates among children in rural Kenya. This contribution is underestimated by using conventional clinical definitions of severe malnutrition.

Heikens GT, Bunn J, Amadi B, Manary M, Chhagan M, Berkley JA, Rollins N, Kelly P, Adamczick C, Maitland K et al. 2008. Case management of HIV-infected severely malnourished children: challenges in the area of highest prevalence. Lancet, 371 (9620), pp. 1305-1307. | Read more

Sadarangani M, Seaton C, Scott JAG, Ogutu B, Edwards T, Prins A, Gatakaa H, Idro R, Berkley JA, Peshu N et al. 2008. Incidence and outcome of convulsive status epilepticus in Kenyan children: a cohort study. Lancet Neurol, 7 (2), pp. 145-150. | Show Abstract | Read more

BACKGROUND: Convulsive status epilepticus (CSE) is the most common neurological emergency in childhood and is often associated with fever. In sub-Saharan Africa, the high incidence of febrile illnesses might influence the incidence and outcome of CSE. We aimed to provide data on the incidence, causes, and outcomes of childhood CSE in this region. METHODS: Between March, 2006, and June, 2006, we studied all children who had been admitted with CSE to a Kenyan rural district hospital in 2002 and 2003. Confirmed CSE had been observed directly; probable CSE was inferred from convulsions on arrival, requirement for phenobarbital or phenytoin, or coma with a recent history of seizures. We estimated the incidence with linked demographic surveillance, and risk factors for death and neurological sequelae were analysed by multivariable analysis. FINDINGS: Of 388 episodes of CSE, 155 (40%) were confirmed CSE and 274 (71%) were caused by an infection. The incidence of confirmed CSE was 35 (95% CI 27-46) per 100,000 children per year overall, and was 52 (21-107) and 85 (62-114) per 100,000 per year in children aged 1-11 months and 12-59 months, respectively. The incidence of all CSE was 268 (188-371) and 227 (189-272) per 100,000 per year in these age-groups. 59 (15%) children died in hospital, 81 (21%) died during long-term follow-up, and 46 (12%) developed neurological sequelae. Mortality of children with confirmed CSE while in hospital was associated with bacterial meningitis (adjusted relative risk [RR]=2.6; 95% CI 1.4-4.9) and focal onset seizures (adjusted RR=2.4; 1.1-5.4), whereas neurological sequelae were associated with hypoglycaemia (adjusted RR=3.5; 1.8-7.1) and age less than 12 months (adjusted RR=2.5; 1.2-5.1). INTERPRETATION: Prevention of infections and appropriate early management of seizures might reduce the incidence and improve the outcome of CSE in children in sub-Saharan Africa.

Mturi N, Keir G, Maclennan CA, Ross A, Willis AC, Elford BC, Berkley JA, Newton CRJC. 2008. Cerebrospinal Fluid Studies in Kenyan Children with Severe Falciparum Malaria. Open Trop Med J, 1 (1), pp. 56-62. | Show Abstract | Read more

The pathogenesis of the neurological complications of Plasmodium falciparum malaria is unclear. We measured proteins and amino acids in paired plasma and cerebrospinal fluid (CSF) samples in children with severe falciparum malaria, to assess the integrity of the blood brain barrier (BBB), and look for evidence of intrathecal synthesis of immunoglobulins, excitotoxins and brain damage. METHODS: Proteins of different molecular sizes and immunoglobulins were measured in paired CSF and plasma samples in children with falciparum malaria and either impaired consciousness, prostrate, or seizures. RESULTS: The ratio of CSF to plasma albumin (Q(alb)) exceeded the reference values in 42 (51%) children. The CSF concentrations of the excitotoxic amino acid aspartate and many non-polar amino acids, except alanine, were above the reference value, despite normal plasma concentrations. IgM concentrations were elevated in 21 (46%) and the IgM index was raised in 22 (52%). Identical IgG oligoclonal bands were found in 9 (35%), but only one patient had an increase in the CSF IgG without a concomitant increase in plasma indicating intrathecal synthesis of IgG. CONCLUSIONS: This study indicates that the BBB is mildly impaired in some children with severe falciparum malaria, and this impairment is not confined to cerebral malaria, but also occurs in children with prostrate malaria and to a lesser extent the children with malaria and seizures. There is evidence of intrathecal synthesis of immunoglobulins in children with malaria, but this requires further investigation. This finding, together with raised level of excitotoxic amino acid aspartate could contribute to the pathogenesis of neurological complications in malaria.

Walson JL, Otieno PA, Mbuchi M, Richardson BA, Lohman-Payne B, Macharia SW, Overbaugh J, Berkley J, Sanders EJ, Chung MH, John-Stewart GC. 2008. Albendazole treatment of HIV-1 and helminth co-infection: a randomized, double-blind, placebo-controlled trial. AIDS, 22 (13), pp. 1601-1609. | Show Abstract | Read more

OBJECTIVE: Several co-infections have been shown to impact the progression of HIV-1 infection. We sought to determine if treatment of helminth co-infection in HIV-1-infected adults impacted markers of HIV-1 disease progression. DESIGN: To date, there have been no randomized trials to examine the effects of soil-transmitted helminth eradication on markers of HIV-1 progression. METHODS: A randomized, double-blind, placebo-controlled trial of albendazole (400 mg daily for 3 days) in antiretroviral-naive HIV-1-infected adults (CD4 cell count >200 cells/microl) with soil-transmitted helminth infection was conducted at 10 sites in Kenya (ClinicalTrials.gov NCT00130910). CD4 and plasma HIV-1 RNA levels at 12 weeks following randomization were compared in the trial arms using linear regression, adjusting for baseline values. RESULTS: Of 1551 HIV-1-infected individuals screened for helminth infection, 299 were helminth infected. Two hundred and thirty-four adults were enrolled and underwent randomization and 208 individuals were included in intent-to-treat analyses. Mean CD4 cell count was 557 cells/microl and mean plasma viral load was 4.75 log10 copies/ml at enrollment. Albendazole therapy resulted in significantly higher CD4 cell counts among individuals with Ascaris lumbricoides infection after 12 weeks of follow-up (+109 cells/microl; 95% confidence interval +38.9 to +179.0, P = 0.003) and a trend for 0.54 log10 lower HIV-1 RNA levels (P = 0.09). These effects were not seen with treatment of other species of soil-transmitted helminths. CONCLUSION: Treatment of A. lumbricoides with albendazole in HIV-1-coinfected adults resulted in significantly increased CD4 cell counts during 3-month follow-up. Given the high prevalence of A. lumbricoides infection worldwide, deworming may be an important potential strategy to delay HIV-1 progression.

Gwer S, Newton CRJC, Berkley JA. 2007. Over-diagnosis and co-morbidity of severe malaria in African children: a guide for clinicians. Am J Trop Med Hyg, 77 (6 Suppl), pp. 6-13. | Show Abstract

Severe malaria is clinically similar to other severe febrile illnesses. However, in endemic areas, parasitological confirmation of parasitemia is often unavailable or unreliable. False-positive malaria microscopy is common. The most important consequence of treating only for malaria when no parasitemia exists is failure to address other life-threatening conditions. Invasive bacterial infections are detected in up to one third of children with clinical features of severe malaria but a slide with results negative for malaria. Even among genuinely parasitized children, severe illness is not always due to malaria in endemic areas. We believe that routine use of parenteral antibiotics among children with a slide that indicates malaria and life-threatening disease is warranted because invasive bacterial infections are likely to be under-ascertained and are associated with increased mortality. Published data on co-morbidity with HIV infection and malnutrition are reviewed. A structured approach to assessment and care is essential, and is largely independent of underlying etiology.

Khor CC, Vannberg FO, Chapman SJ, Walley A, Aucan C, Loke H, White NJ, Peto T, Khor LK, Kwiatkowski D et al. 2007. Positive replication and linkage disequilibrium mapping of the chromosome 21q22.1 malaria susceptibility locus. Genes Immun, 8 (7), pp. 570-576. | Show Abstract | Read more

Four cytokine receptor genes are located on Chr21q22.11, encoding the alpha and beta subunits of the interferon-alpha receptor (IFNAR1 and IFNAR2), the beta subunit of the interleukin 10 receptor (IL10RB) and the second subunit of the interferon-gamma receptor (IFNGR2). We previously reported that two variants in IFNAR1 were associated with susceptibility to malaria in Gambians. We now present an extensive fine-scale mapping of the associated region utilizing 45 additional genetic markers obtained from public databases and by sequencing a 44 kb region in and around the IFNAR1 gene in 24 Gambian children (12 cases/12 controls). Within the IFNAR1 gene, a newly studied C --> G single-nucleotide polymorphism (IFNAR1 272354c-g) at position -576 relative to the transcription start was found to be more strongly associated with susceptibility to severe malaria. Association was observed in three populations: in Gambian (P=0.002), Kenyan (P=0.022) and Vietnamese (P=0.005) case-control studies. When all three studies were combined, using the Mantel-Haenszel test, the presence of IFNAR1 -576G was associated with a substantially elevated risk of severe malaria (N=2444, OR=1.38, 95% CI: 1.17-1.64; P=1.7 x 10(-4)). This study builds on previous work to further highlight the importance of the type-I interferon pathway in malaria susceptibility and illustrates the utility of typing SNPs within regions of high linkage disequilibrium in multiple populations to confirm initial positive associations.

Bejon P, Berkley JA, Mwangi T, Ogada E, Mwangi I, Maitland K, Williams T, Scott JAG, English M, Lowe BS et al. 2007. Defining childhood severe falciparum malaria for intervention studies. PLoS Med, 4 (8), pp. e251. | Show Abstract | Read more

BACKGROUND: Clinical trials of interventions designed to prevent severe falciparum malaria in children require a clear endpoint. The internationally accepted definition of severe malaria is sensitive, and appropriate for clinical purposes. However, this definition includes individuals with severe nonmalarial disease and coincident parasitaemia, so may lack specificity in vaccine trials. Although there is no "gold standard" individual test for severe malaria, malaria-attributable fractions (MAFs) can be estimated among groups of children using a logistic model, which we use to test the suitability of various case definitions as trial endpoints. METHODS AND FINDINGS: A total of 4,583 blood samples were taken from well children in cross-sectional surveys and from 1,361 children admitted to a Kenyan District hospital with severe disease. Among children under 2 y old with severe disease and over 2,500 parasites per microliter of blood, the MAFs were above 85% in moderate- and low-transmission areas, but only 61% in a high-transmission area. HIV and malnutrition were not associated with reduced MAFs, but gastroenteritis with severe dehydration (defined by reduced skin turgor), lower respiratory tract infection (clinician's final diagnosis), meningitis (on cerebrospinal fluid [CSF] examination), and bacteraemia were associated with reduced MAFs. The overall MAF was 85% (95% confidence interval [CI] 83.8%-86.1%) without excluding these conditions, 89% (95% CI 88.4%-90.2%) after exclusions, and 95% (95% CI 94.0%-95.5%) when a threshold of 2,500 parasites/mul was also applied. Applying a threshold and exclusion criteria reduced sensitivity to 80% (95% CI 77%-83%). CONCLUSIONS: The specificity of a case definition for severe malaria is improved by applying a parasite density threshold and by excluding children with meningitis, lower respiratory tract infection (clinician's diagnosis), bacteraemia, and gastroenteritis with severe dehydration, but not by excluding children with HIV or malnutrition.

Idro R, Ndiritu M, Ogutu B, Mithwani S, Maitland K, Berkley J, Crawley J, Fegan G, Bauni E, Peshu N et al. 2007. Burden, features, and outcome of neurological involvement in acute falciparum malaria in Kenyan children. JAMA, 297 (20), pp. 2232-2240. | Show Abstract | Read more

CONTEXT: Plasmodium falciparum appears to have a particular propensity to involve the brain but the burden, risk factors, and full extent of neurological involvement have not been systematically described. OBJECTIVES: To determine the incidence and describe the clinical phenotypes and outcomes of neurological involvement in African children with acute falciparum malaria. DESIGN, SETTING, AND PATIENTS: A review of records of all children younger than 14 years admitted to a Kenyan district hospital with malaria from January 1992 through December 2004. Neurological involvement was defined as convulsive seizures, agitation, prostration, or impaired consciousness or coma. MAIN OUTCOME MEASURES: The incidence, pattern, and outcome of neurological involvement. RESULTS: Of 58,239 children admitted, 19,560 (33.6%) had malaria as the primary clinical diagnosis. Neurological involvement was observed in 9313 children (47.6%) and manifested as seizures (6563/17,517 [37.5%]), agitation (316/11,193 [2.8%]), prostration (3223/15,643 [20.6%]), and impaired consciousness or coma (2129/16,080 [13.2%]). In children younger than 5 years, the mean annual incidence of admissions with malaria was 2694 per 100,000 persons and the incidence of malaria with neurological involvement was 1156 per 100,000 persons. However, readmissions may have led to a 10% overestimate in incidence. Children with neurological involvement were older (median, 26 [interquartile range {IQR}, 15-41] vs 21 [IQR, 10-40] months; P<.001), had a shorter duration of illness (median, 2 [IQR, 1-3] vs 3 [IQR, 2-3] days; P<.001), and a higher geometric mean parasite density (42.0 [95% confidence interval {CI}, 40.0-44.1] vs 30.4 [95% CI, 29.0-31.8] x 10(3)/microL; P<.001). Factors independently associated with neurological involvement included past history of seizures (adjusted odds ratio [AOR], 3.50; 95% CI, 2.78-4.42), fever lasting 2 days or less (AOR, 2.02; 95% CI, 1.64-2.49), delayed capillary refill time (AOR, 3.66; 95% CI, 2.40-5.56), metabolic acidosis (AOR, 1.55; 95% CI, 1.29-1.87), and hypoglycemia (AOR, 2.11; 95% CI, 1.31-3.37). Mortality was higher in patients with neurological involvement (4.4% [95% CI, 4.2%-5.1%] vs 1.3% [95% CI, 1.1%-1.5%]; P<.001). At discharge, 159 (2.2%) of 7281 patients had neurological deficits. CONCLUSIONS: Neurological involvement is common in children in Kenya with acute falciparum malaria, and is associated with metabolic derangements, impaired perfusion, parasitemia, and increased mortality and neurological sequelae. This study suggests that falciparum malaria exposes many African children to brain insults.

Khor CC, Chapman SJ, Vannberg FO, Dunne A, Murphy C, Ling EY, Frodsham AJ, Walley AJ, Kyrieleis O, Khan A et al. 2007. A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis. Nat Genet, 39 (4), pp. 523-528. | Show Abstract | Read more

Toll-like receptors (TLRs) and members of their signaling pathway are important in the initiation of the innate immune response to a wide variety of pathogens. The adaptor protein Mal (also known as TIRAP), encoded by TIRAP (MIM 606252), mediates downstream signaling of TLR2 and TLR4 (refs. 4-6). We report a case-control study of 6,106 individuals from the UK, Vietnam and several African countries with invasive pneumococcal disease, bacteremia, malaria and tuberculosis. We genotyped 33 SNPs, including rs8177374, which encodes a leucine substitution at Ser180 of Mal. We found that heterozygous carriage of this variant associated independently with all four infectious diseases in the different study populations. Combining the study groups, we found substantial support for a protective effect of S180L heterozygosity against these infectious diseases (N = 6,106; overall P = 9.6 x 10(-8)). We found that the Mal S180L variant attenuated TLR2 signal transduction.

Maitland K, Berkley JA, Shebbe M, Peshu N, English M, Newton CRJC. 2006. Children with severe malnutrition: can those at highest risk of death be identified with the WHO protocol? PLoS Med, 3 (12), pp. e500. | Show Abstract | Read more

BACKGROUND: With strict adherence to international recommended treatment guidelines, the case fatality for severe malnutrition ought to be less than 5%. In African hospitals, fatality rates of 20% are common and are often attributed to poor training and faulty case management. Improving outcome will depend upon the identification of those at greatest risk and targeting limited health resources. We retrospectively examined the major risk factors associated with early (<48 h) and late in-hospital death in children with severe malnutrition with the aim of identifying admission features that could distinguish a high-risk group in relation to the World Health Organization (WHO) guidelines. METHODS AND FINDINGS: Of 920 children in the study, 176 (19%) died, with 59 (33%) deaths occurring within 48 h of admission. Bacteraemia complicated 27% of all deaths: 52% died before 48 h despite 85% in vitro antibiotic susceptibility of cultured organisms. The sensitivity, specificity, and likelihood ratio of the WHO-recommended "danger signs" (lethargy, hypothermia, or hypoglycaemia) to predict early mortality was 52%, 84%, and 3.4% (95% confidence interval [CI] = 2.2 to 5.1), respectively. In addition, four bedside features were associated with early case fatality: bradycardia, capillary refill time greater than 2 s, weak pulse volume, and impaired consciousness level; the presence of two or more features was associated with an odds ratio of 9.6 (95% CI = 4.8 to 19) for early fatality (p < 0.0001). Conversely, the group of children without any of these seven features, or signs of dehydration, severe acidosis, or electrolyte derangements, had a low fatality (7%). CONCLUSIONS: Formal assessment of these features as emergency signs to improve triage and to rationalize manpower resources toward the high-risk groups is required. In addition, basic clinical research is necessary to identify and test appropriate supportive treatments.

Kariuki S, Revathi G, Kiiru J, Lowe B, Berkley JA, Hart CA. 2006. Decreasing prevalence of antimicrobial resistance in non-typhoidal Salmonella isolated from children with bacteraemia in a rural district hospital, Kenya. Int J Antimicrob Agents, 28 (3), pp. 166-171. | Show Abstract | Read more

We analysed 336 non-typhoidal Salmonella (NTS) isolated from children <13 years of age with bacteraemia admitted to a rural district hospital in Kenya from 1994 to 2005. Pulsed-field gel electrophoresis was used to determine genetic relatedness of strains, and antimicrobial susceptibility testing was also performed. Most NTS were either Salmonella enterica serovar Typhimurium (n=114; 33.9%) or S. enterica serovar Enteritidis (n=128; 38.1%), with minimal genotypic diversity over the study period. The NTS showed a remarkable decrease in levels of resistance especially to two commonly available antimicrobials (amoxicillin and co-trimoxazole), from high of 69.2% and 68.4% during 1994-1997 to 11% and 13%, respectively, in 2002-2005 (P<0.01). All NTS remained fully susceptible to cefotaxime and ciprofloxacin. Our findings show that commonly available drugs may still be useful for treatment of invasive NTS infections in this rural population.

Osier FHA, Berkley JA, Newton CRJC. 2006. Life-threatening hyponatraemia and neurotoxicity during chemotherapy for Burkitt's lymphoma. Trop Doct, 36 (3), pp. 177-178. | Read more

Sasi P, English M, Berkley J, Lowe B, Shebe M, Mwakesi R, Kokwaro G. 2006. Characterisation of metabolic acidosis in Kenyan children admitted to hospital for acute non-surgical conditions. Trans R Soc Trop Med Hyg, 100 (5), pp. 401-409. | Show Abstract | Read more

Metabolic acidosis is associated with most severe malaria deaths in African children, and most deaths occur before maximum antimalarial action is achieved. Thus, specific acidosis treatment may reduce mortality. However, the underlying mechanisms remain poorly understood and no specific interventions have been developed. A detailed characterisation of this acidosis is critical in treatment development. We used the traditional and Stewart's approach to characterise acidosis in consecutive paediatric admissions for malaria and other acute non-surgical conditions to Kilifi District Hospital in Kenya. The overall acidosis prevalence was 21%. Gastroenteritis had the highest prevalence (61%). Both the mean albumin-corrected anion gap and the strong ion gap were high (>13 mmol/l and >0 mmol/l, respectively) in malaria, gastroenteritis, lower respiratory tract infection and malnutrition. Presence of salicylate in plasma was not associated with acidosis but was associated with signs of severe illness (odds ratio 2.11, 95% CI 1.1-4.2). In malaria, mean (95% CI) strong ion gap was 15 (14-7) mmol/l, and lactate, creatinine and inorganic phosphorous explained only approximately 40% of the variability in base excess (adjusted R2 = 0.397). Acidosis may be more common than previously recognised amongst paediatric admissions in Africa and is characterised by the presence of currently unidentified strong anions. In malaria, lactate and ketones, but not salicylate, are associated with acidosis. However, unidentified anions may be more important.

Brent AJ, Oundo JO, Mwangi I, Ochola L, Lowe B, Berkley JA. 2006. Salmonella bacteremia in Kenyan children. Pediatr Infect Dis J, 25 (3), pp. 230-236. | Show Abstract | Read more

BACKGROUND: Nontyphoidal Salmonella spp. are among the leading causes of childhood bacteremia in sub-Saharan Africa, yet there are few published clinical series, and the risk factors for acquiring infection are not fully understood. METHODS: We examined data from 166 cases of nontyphoidal Salmonella bacteremia identified during a large prospective study of bacteremia among all children admitted to a district hospital in Kenya. We also investigated the importance of comorbidities, including current malaria parasitemia, recent malaria (detectable Plasmodium falciparum histidine rich protein 2 in the absence of parasitemia), sickle cell disease, malnutrition and human immunodeficiency virus (HIV) infection. RESULTS: Nontyphoidal Salmonella bacteremia was associated with severe malnutrition (33% cases), HIV infection (18% cases), a history of illness >7 days, recent hospital admission, splenomegaly, anemia and recent (but not current) malaria but was not associated with diarrhea. Seventy-seven (46%) children with nontyphoidal Salmonella bacteremia fulfilled World Health Organization clinical criteria for a diagnosis of pneumonia. Independent risk factors for death were diarrhea, tachypnea, HIV infection, severe malnutrition, meningitis and young age. CONCLUSIONS: Clinical diagnosis of invasive nontyphoidal Salmonella infection in African children is difficult without microbiology facilities because clinical features overlap with other conditions. The common risk factors for nontyphoidal Salmonella infection differ from developed countries, with high a prevalence of malnutrition, HIV, malaria and anemia. Children with nontyphoidal Salmonella infection who fulfill World Health Organization clinical criteria for severe pneumonia may receive ineffective therapy in the form of penicillin.

Brent AJ, Ahmed I, Ndiritu M, Lewa P, Ngetsa C, Lowe B, Bauni E, English M, Berkley JA, Scott JAG. 2006. Incidence of clinically significant bacteraemia in children who present to hospital in Kenya: community-based observational study. Lancet, 367 (9509), pp. 482-488. | Show Abstract | Read more

BACKGROUND: Estimates of the burden of invasive bacterial disease in sub-Saharan Africa have previously relied on selected groups of patients, such as inpatients; they are, therefore, probably underestimated, potentially hampering vaccine implementation. Our aim was to assess the incidence of bacteraemia in all children presenting to a hospital in Kenya, irrespective of clinical presentation or decision to admit. METHODS: We did a community-based observational study for which we cultured blood from 1093 children who visited a Kenyan hospital outpatient department. We estimated bacteraemia incidence with a Demographic Surveillance System, and investigated the clinical significance of bacteraemia and the capacity of clinical signs to identify cases. RESULTS: The yearly incidence of bacteraemia per 100,000 children aged younger than 2 years and younger than 5 years was 2440 (95% CI 1307-3573) and 1192 (692-1693), respectively. Incidence of pneumococcal bacteraemia was 597 (416-778) per 100,000 person-years of observation in children younger than age 5 years. Three-quarters of episodes had a clinical focus or required admission, or both; one in six was fatal. After exclusion of children with occult bacteraemia, the incidence of clinically significant bacteraemia per 100,000 children younger than age 2 years or 5 years fell to 1741 (790-2692) and 909 (475-1343), respectively, and the yearly incidence of clinically significant pneumococcal bacteraemia was 436 (132-739) per 100,000 children younger than 5 years old. Clinical signs identified bacteraemia poorly. INTERPRETATION: Clinically significant bacteraemia in children in Kilifi is twice as common, and pneumococcal bacteraemia four times as common, as previously estimated. Our data support the introduction of pneumococcal vaccine in sub-Saharan Africa.

Hogness CG. 2005. Severe malnutrition assessment in children in rural Kenya. JAMA, 294 (20), pp. 2577. | Read more

Berkley J, Mwangi I, Griffiths K, Ahmed I, Mithwani S, English M, Newton C, Maitland K. 2005. Assessment of severe malnutrition among hospitalized children in rural Kenya: comparison of weight for height and mid upper arm circumference. JAMA, 294 (5), pp. 591-597. | Show Abstract | Read more

CONTEXT: Severe malnutrition has a high mortality rate among hospitalized children in sub-Saharan Africa. However, reports suggest that malnutrition is often poorly assessed. The World Health Organization recommends using weight for height, but this method is problematic and often not undertaken in practice. Mid upper arm circumference (MUAC) and the clinical sign "visible severe wasting" are simple and inexpensive methods but have not been evaluated in this setting. OBJECTIVES: To evaluate MUAC and visible severe wasting as predictors of inpatient mortality at a district hospital in sub-Saharan Africa and to compare these with weight-for-height z score (WHZ). DESIGN, SETTING, AND PARTICIPANTS: Cohort study with data collected at admission and at discharge or death. Predictive values for inpatient death were determined using the area under receiver operating characteristic curves. Participants were children aged 12 to 59 months admitted to a district hospital in rural Kenya between April 1, 1999, and July 31, 2002. MAIN OUTCOME MEASURE: MUAC, WHZ, and visible severe wasting as predictors of inpatient death. RESULTS: Overall, 4.4% (359) of children included in the study died while in the hospital. Sixteen percent (1282/8190) of admitted children had severe wasting (WHZ < or =-3) (n = 756), kwashiorkor (n = 778), or both. The areas under the receiver operating characteristic curves for predicting inpatient death did not significantly differ (MUAC: 0.75 [95% confidence interval, 0.72-0.78]; WHZ: 0.74 [95% confidence interval, 0.71-0.77]) (P = .39). Although sensitivity and specificity for subsequent inpatient death were 46% and 91%, respectively, for MUAC less than or equal to 11.5 cm, 42% and 92% for WHZ less than or equal to -3, and 47% and 93% for visible severe wasting, the 3 indices identified different sets of children and were independently associated with mortality. Clinical features of malnutrition were significantly more common among children with MUAC less than or equal to 11.5 cm than among those with WHZ less than or equal to -3. CONCLUSIONS: MUAC is a practical screening tool that performs at least as well as WHZ in predicting subsequent inpatient mortality among severely malnourished children hospitalized in rural Kenya. Visible severe wasting is also a potentially useful sign at this level, providing appropriate training has been given.

Bejon P, Mwangi I, Ngetsa C, Mwarumba S, Berkley JA, Lowe BS, Maitland K, Marsh K, English M, Scott JAG. 2005. Invasive Gram-negative bacilli are frequently resistant to standard antibiotics for children admitted to hospital in Kilifi, Kenya. J Antimicrob Chemother, 56 (1), pp. 232-235. | Show Abstract | Read more

OBJECTIVES: To determine the pattern of resistance among Gram-negative bacilli causing invasive bacterial disease for the antibiotics that are already in common use in Kilifi, Kenya and for two potential alternatives, ciprofloxacin and cefotaxime. Also, to determine whether prevalence and severity of resistance was increasing over time, to identify patients who are particularly at risk of resistant infections, and to explore which factors are associated with the development of resistance in our setting. METHODS: We used Etest to study antibiotic susceptibility patterns of 90 Gram-negative bacilli cultured in blood or CSF from paediatric inpatients over 8 years. RESULTS: Susceptibility to amoxicillin 28%, cefotaxime 95% and ciprofloxacin 99% did not vary significantly with age. Susceptibilities for isolates from children aged less than 14 days were: chloramphenicol, 81%; trimethoprim/sulfamethoxazole, 71%; and gentamicin, 91%. From older children, susceptibilities were: chloramphenicol, 62%; trimethoprim/sulfamethoxazole, 39%; and gentamicin, 73%. Chloramphenicol susceptibility was significantly more common among non-typhi salmonellae than other species (79% versus 53%, P < 0.0005). The combination of gentamicin and chloramphenicol covered 91% of all isolates. The prevalence of resistance did not increase over time and was not more common in patients with HIV or malnutrition. Age was the only clinical feature that predicted resistance. CONCLUSIONS: Gentamicin or chloramphenicol alone was suboptimal therapy for Gram-negative sepsis, although in this retrospective study, there was no association between resistance and mortality.

Scott JAG, Mwarumba S, Ngetsa C, Njenga S, Lowe BS, Slack MPE, Berkley JA, Mwangi I, Maitland K, English M, Marsh K. 2005. Progressive increase in antimicrobial resistance among invasive isolates of Haemophilus influenzae obtained from children admitted to a hospital in Kilifi, Kenya, from 1994 to 2002. Antimicrob Agents Chemother, 49 (7), pp. 3021-3024. | Show Abstract | Read more

Etest susceptibilities to amoxicillin, chloramphenicol, and trimethoprim-sulfamethoxazole of 240 invasive isolates of Haemophilus influenzae cultured from children in rural Kenya were 66%, 66%, and 38%, respectively. Resistance increased markedly over 9 years and was concentrated among serotype b isolates. In Africa, the increasing cost of treating resistant infections supports economic arguments for prevention through conjugate H. influenzae type b immunization.

Berkley JA, Maitland K, Mwangi I, Ngetsa C, Mwarumba S, Lowe BS, Newton CRJC, Marsh K, Scott JAG, English M. 2005. Use of clinical syndromes to target antibiotic prescribing in seriously ill children in malaria endemic area: observational study. BMJ, 330 (7498), pp. 995. | Show Abstract | Read more

OBJECTIVES: To determine how well antibiotic treatment is targeted by simple clinical syndromes and to what extent drug resistance threatens affordable antibiotics. DESIGN: Observational study involving a priori definition of a hierarchy of syndromic indications for antibiotic therapy derived from World Health Organization integrated management of childhood illness and inpatient guidelines and application of these rules to a prospectively collected dataset. SETTING: Kilifi District Hospital, Kenya. PARTICIPANTS: 11,847 acute paediatric admissions. MAIN OUTCOME MEASURES: Presence of invasive bacterial infection (bacteraemia or meningitis) or Plasmodium falciparum parasitaemia; antimicrobial sensitivities of isolated bacteria. RESULTS: 6254 (53%) admissions met criteria for syndromes requiring antibiotics (sick young infants; meningitis/encephalopathy; severe malnutrition; very severe, severe, or mild pneumonia; skin or soft tissue infection): 672 (11%) had an invasive bacterial infection (80% of all invasive bacterial infections identified), and 753 (12%) died (93% of all inpatient deaths). Among P falciparum infected children with a syndromic indication for parenteral antibiotics, an invasive bacterial infection was detected in 4.0-8.8%. For the syndrome of meningitis/encephalopathy, 96/123 (76%) isolates were fully sensitive in vitro to penicillin or chloramphenicol. CONCLUSIONS: Simple clinical syndromes effectively target children admitted with invasive bacterial infection and those at risk of death. Malaria parasitaemia does not justify withholding empirical parenteral antibiotics. Lumbar puncture is critical to the rational use of antibiotics.

Zimmermann O, de Ciman R, Gross U. 2005. Bacteremia among Kenyan Children. N Engl J Med, 352 (13), pp. 1379-1381. | Read more

Berkley JA, Lowe BS, Scott JAG. 2005. Bacteremia among Kenyan children - Reply NEW ENGLAND JOURNAL OF MEDICINE, 352 (13), pp. 1380-1381.

Berkley JA, Lowe BS, Mwangi I, Williams T, Bauni E, Mwarumba S, Ngetsa C, Slack MPE, Njenga S, Hart CA et al. 2005. Bacteremia among children admitted to a rural hospital in Kenya. N Engl J Med, 352 (1), pp. 39-47. | Show Abstract | Read more

BACKGROUND: There are few epidemiologic data on invasive bacterial infections among children in sub-Saharan Africa. We studied every acute pediatric admission to a rural district hospital in Kenya to examine the prevalence, incidence, types, and outcome of community-acquired bacteremia. METHODS: Between August 1998 and July 2002, we cultured blood on admission from 19,339 inpatients and calculated the incidence of bacteremia on the basis of the population served by the hospital. RESULTS: Of a total of 1783 infants who were under 60 days old, 228 had bacteremia (12.8 percent), as did 866 of 14,787 children who were 60 or more days of age (5.9 percent). Among infants who were under 60 days old, Escherichia coli and group B streptococci predominated among a broad range of isolates (14 percent and 11 percent, respectively). Among infants who were 60 or more days of age, Streptococcus pneumoniae, nontyphoidal salmonella species, Haemophilus influenzae, and E. coli accounted for more than 70 percent of isolates. The minimal annual incidence of community-acquired bacteremia was estimated at 1457 cases per 100,000 children among infants under a year old, 1080 among children under 2 years, and 505 among children under 5 years. Of all in-hospital deaths, 26 percent were in children with community-acquired bacteremia. Of 308 deaths in children with bacteremia, 103 (33.4 percent) occurred on the day of admission and 217 (70.5 percent) within two days. CONCLUSIONS: Community-acquired bacteremia is a major cause of death among children at a rural sub-Saharan district hospital, a finding that highlights the need for prevention and for overcoming the political and financial barriers to widespread use of existing vaccines for bacterial diseases.

Berkley J, Newton C, Mwangi I, Osier F, Shebbe M, Maitland K, Lowe B, Marsh K. 2005. Morbidity and co-morbidity in children with signs of severe malaria [MIM-JB-166260] ACTA TROPICA, 95 pp. S53-S53.

Berkley JA, Versteeg AC, Mwangi I, Lowe BS, Newton CRJC. 2004. Indicators of acute bacterial meningitis in children at a rural Kenyan district hospital. Pediatrics, 114 (6), pp. e713-e719. | Show Abstract | Read more

OBJECTIVE: Acute bacterial meningitis remains an important cause of death and neurologic sequelae in African children. The clinical features of meningitis are often nonspecific and in this setting may overlap with those of malaria. Early diagnosis and appropriate antibiotic treatment are perhaps the most important steps in management, but published data suggest that fewer than half of the cases of childhood meningitis are identified at first assessment in hospitals in this region. The objective of this study was to identify clinical indicators of acute bacterial meningitis by examining components of the World Health Organization Integrated Management of Childhood Illness (IMCI) referral criteria for meningitis (lethargy, unconsciousness, inability to feed, stiff neck, or seizures) and other symptoms and signs. METHODS: Kilifi District Hospital, serving approximately 200,000 people in a rural, malaria-endemic area of the Kenyan coast, was studied. A Kenya Medical Research Institute research center is located at the hospital. All pediatric admissions aged > or =60 days between June 2001 and July 2002 were eligible. RESULTS: A total of 91 (2.0%) of 4582 admissions had meningitis, including 77 (4.0%) of 1929 of those who met the IMCI referral criteria for meningitis at admission (sensitivity: 85%; specificity: 59%). Independent indicators of the presence of meningitis were a bulging fontanel, neck stiffness, cyanosis, impaired consciousness, partial seizures, and seizures outside the febrile convulsions age range. One or more of these indicators was present in 895 (19%) of admissions, 72 (8.0%) of whom had meningitis (sensitivity: 79%; specificity: 80%). Independent indicators of the absence of meningitis were the absence of a history of fever, a history of diarrhea, and a positive malaria slide. The area under the receiver operating characteristic curve for a set of simple screening rules based on the positive indicators identified was 0.88 (95% confidence interval: 0.85-0.92). CONCLUSIONS: The presence of > or =1 of a bulging fontanel, neck stiffness, cyanosis, impaired consciousness, partial seizures, and seizures outside the febrile convulsions age range is a clear indication for lumbar puncture and/or presumptive treatment. However, careful observation and reassessment may be the only practical way to identify one fifth of meningitis cases in this setting.

Berkley JA, Brent A, Mwangi I, English M, Maitland K, Marsh K, Peshu N, Newton CR. 2004. Mortality among Kenyan children admitted to a rural district hospital on weekends as compared with weekdays. Pediatrics, 114 (6), pp. 1737-1738. | Read more

Berkley JA, Mwangi I, Lowe B, Newton CRJC. 2004. Traumatic lumbar punctures. Pediatrics, 113 (1 Pt 1),

Holzman IR, Berkley JA, Mwangi I, Lowe B, Newton CRJC, Mazor S. 2004. Traumatic Lumbar Punctures PEDIATRICS, 113 (1), pp. 172-172. | Read more

Berkley JA, Brent A, Mwangi I, English M, Maitland K, Marsh K, Peshu N, Newton CR, Marcin J, Taylor D. 2004. Mortality among Kenyan children admitted to a rural district hospital on weekends as compared with weekdays [3] (multiple letters) Pediatrics, 114 (6), pp. 1737-1738. | Read more

Berkley JA, Mwangi I, Lowe B, Newton CRJC. 2004. Traumatic lumbar punctures. Pediatrics, 113 (1 Pt 1), pp. 172.

Osier FHA, Berkley JA, Ross A, Sanderson F, Mohammed S, Newton CRJC. 2003. Abnormal blood glucose concentrations on admission to a rural Kenyan district hospital: prevalence and outcome. Arch Dis Child, 88 (7), pp. 621-625. | Show Abstract | Read more

AIMS: To determine the prevalence, clinical characteristics, and outcome of hypoglycaemia on admission in children at a rural Kenyan district hospital. METHODS: Observational study of 3742 children (including 280 neonates) in Kilifi District Hospital, Kenya. MAIN OUTCOME MEASURES: hypoglycaemia (blood glucose <2.2 mmol/l) and hyperglycaemia (blood glucose >10.0 mmol/l). RESULTS: Non-neonates: the prevalence of hypoglycaemia on admission was 7.3%. Severe illness, malnutrition, last meal >12 hours ago, and a positive malaria slide were independently associated with hypoglycaemia. Overall, mortality in hypoglycaemic children was 20.2% compared to 3.8% in normoglycaemic children (p < 0.001). The brunt of mortality in hypoglycaemic children was borne by those who were severely ill or malnourished (31.8%) as opposed to those who were neither severely ill nor malnourished (9.0%). Neonates: 23.0% of neonates were hypoglycaemic on admission. Inability to breast feed and weight <2500 g were independently associated with hypoglycaemia. Mortality was 45.2% compared to 19.6% in normoglycaemic neonates (p < 0.001). Hyperglycaemia was present in 2.7% of children and was associated with a higher mortality than normoglycaemia, 14.0% versus 3.8% respectively (p < 0.001). CONCLUSIONS: Hypoglycaemia is common in children admitted to a rural Kenyan district hospital and is associated with an increased mortality. Apart from features of severe illness and poor feeding, clinical signs have a low sensitivity and specificity for hypoglycaemia. Where diagnostic facilities are lacking, presumptive treatment of severely ill children is recommended. For other children, the continuation of feeding (by nasogastric tube if necessary) should be part of standard management.

Berkley JA, Ross A, Mwangi I, Osier FHA, Mohammed M, Shebbe M, Lowe BS, Marsh K, Newton CRJC. 2003. Prognostic indicators of early and late death in children admitted to district hospital in Kenya: cohort study. BMJ, 326 (7385), pp. 361. | Show Abstract | Read more

OBJECTIVES: To identify clinical indicators of immediate, early, and late mortality in children at admission to a sub-Saharan district hospital and to develop prognostic scores. DESIGN: Prospective cohort study. SETTING: One district hospital in Kenya. PARTICIPANTS: Children aged over 90 days admitted to hospital from 1 July 1998 to 30 June 2001. MAIN OUTCOME MEASURES: Prognostic indicators of mortality. RESULTS: Of 8091 children admitted up to 1 June 2000, 436 (5%) died. Sixty (14%) died within four hours after admission (immediate), 193 (44%) after 4-48 hours (early), and 183 (42%) after 48 hours (late). There were marked differences in the clinical features associated with immediate, early, and late death. Seven indicators (neurological status, respiratory distress (subcostal indrawing or deep breathing), nutritional status (wasting or kwashiorkor), severe anaemia, jaundice, axillary temperature, and length of history) were included in simplified prognostic scores. Data from 4802 children admitted from 1 July 2000 to 30 June 2001 were used to validate the scores. For simplified prognostic scores the areas under the receiver operating characteristic curves were 0.93 (95% confidence interval 0.92 to 0.94), 0.82 (0.80 to 0.83), and 0.82 (0.81 to 0.84) for immediate, early, and late death, respectively. CONCLUSION: In children admitted to a sub-Saharan hospital, the prognostic indicators of early and late deaths differ but a small number of simple clinical signs predict outcome well.

English M, Berkley J, Mwangi I, Mohammed S, Ahmed M, Osier F, Muturi N, Ogutu B, Marsh K, Newton CRJC. 2003. Hypothetical performance of syndrome-based management of acute paediatric admissions of children aged more than 60 days in a Kenyan district hospital. Bull World Health Organ, 81 (3), pp. 166-173. | Show Abstract

OBJECTIVE: To investigate whether the outpatient, syndrome-based approach of the Integrated Management of Childhood Illness (IMCI) protocol could be extended to the inpatient arena to give clear and simple minimum standards of care for poorly resourced facilities. METHODS: A prospective, one-year admission cohort retrospectively compared hypothetical performance of syndrome-based management with paediatrician-defined final diagnosis. Admission syndrome definitions were based on local adaptations to the IMCI protocol that encompassed 20 clinical features, measurement of oxygen saturation, and malaria microscopy. FINDINGS: After 315 children with clinically obvious diagnoses (e.g. sickle cell disease and burns) were excluded, 3705 admission episodes were studied. Of these, 2334 (63%) met criteria for at least one severe syndrome (mortality 8% vs <1% for "non-severe" cases), and half of these had features of two or more severe syndromes. No cases of measles were seen. Syndrome-based treatment would have been appropriate (sensitivity >95%) for severe pneumonia, severe malaria, and diarrhoea with severe dehydration, and probably for severe malnutrition (sensitivity 71%). Syndrome-directed treatment suggested the use of broad-spectrum antibiotics in 75/133 (56% sensitivity) children with bacteraemic and 63/71 (89% sensitivity) children with meningitis. CONCLUSIONS: Twenty clinical features, oxygen saturation measurements, and results of malaria blood slides could be used for inpatient, syndrome-based management of acute paediatric admissions. The addition of microscopy of the cerebrospinal fluid and haemoglobin measurements would improve syndrome-directed treatment considerably. This approach might rationalize admission policy and standardize inpatient paediatric care in resource-poor countries, although the clinical detection of bacteraemia remains a problem.

Mwangi I, Berkley J, Lowe B, Peshu N, Marsh K, Newton CRJC. 2002. Acute bacterial meningitis in children admitted to a rural Kenyan hospital: increasing antibiotic resistance and outcome. Pediatr Infect Dis J, 21 (11), pp. 1042-1048. | Show Abstract | Read more

BACKGROUND: Acute bacterial meningitis (ABM) is an important cause of mortality in Africa, but most studies are based in urban referral hospitals. Poor laboratory facilities make diagnosis difficult, and treatment is limited to inexpensive antibiotics. METHODS: We retrospectively reviewed data from children admitted with ABM to a Kenyan district hospital from 1994 through 2000. We calculated the minimum incidence in children admitted from a defined area. We also examined the antibiotic susceptibility patterns. RESULTS: We identified 390 cases (1.3% of all admissions) of whom 88% were <5 years old. The apparent minimum annual incidence in children younger than 5 years of age increased from 120 to 202 per 100,000 between 1995 and 2000 (P < 0.001). Increasing the lumbar punctures performed by including prostrated or convulsing children significantly increased the number of cases detected (P < 0.005). The most common organisms in infants <3 months were streptococci and Enterobacteriaceae. Streptococcus pneumoniae (43.1%) and Haemophilus influenzae (41.9%) were predominant in the postneonatal period. The overall mortality was 30.1%, and 23.5% of survivors developed neurologic sequelae. Chloramphenicol resistance of H. influenzae rose from 8% in 1994 to 80% in 2000 (P < 0.0001) accompanied by an apparent increase in mortality. A short history, impaired consciousness and hypoglycemia were associated with death. Prolonged coma and low cerebrospinal fluid glucose were associated with neurologic sequelae. CONCLUSION: ABM in rural Kenya is a severe illness with substantial mortality and morbidity. Prognosis could be improved by broadening the criteria for lumbar puncture and use of appropriate antibiotics.

English M, Ahmed M, Ngando C, Berkley J, Ross A. 2002. Blood transfusion for severe anaemia in children in a Kenyan hospital. Lancet, 359 (9305), pp. 494-495. | Show Abstract | Read more

Severe anaemia often secondary to malaria is a major contributor to child mortality in sub-Saharan Africa. We have confirmed that use of simple clinical and laboratory criteria can identify those children likely to benefit most from treatment. We have also shown that the speed of response may be critical. The quality and capacity of blood transfusion services could therefore have a major, direct effect on inpatient child mortality.

Oundo JO, Muli F, Kariuki S, Waiyaki PG, Iijima Y, Berkley J, Kokwaro GO, Ngetsa CJ, Mwarumba S, Torto R, Lowe B. 2002. Non-typhi salmonella in children with severe malaria. East Afr Med J, 79 (12), pp. 633-639. | Show Abstract

OBJECTIVE: To determine the association between Plasmodium falciparum malaria and non-typhi Salmonella in children. DESIGN: Cross-sectional hospital based study. SETTING: Kilifi District Hospital (KDH) between January 1997 and June 2001. SUBJECTS: Children aged between three months to 123 months (mean age 28.28 months) and who had been admitted to the paediatric or High Dependency Research Ward (HDRW) of the KDH. METHODS: A total of 19, 118 blood cultures routinely obtained for all admissions and 1,820 clinically indicated stools samples were obtained from 9,147 children admitted with malaria. The specimens were cultured and antibiotic sensitivity done using standard laboratory procedures with stringent internal and external quality control in place. RESULTS: The total bacterial pathogens isolated from blood and stool were 1,395/19,118 (7.3%) and 342/1,820 (19%) respectively. Non-typhi salmonella consisted of 260/1,395 (18.6%) of the positive blood cultures and 92/324 (28.4%) of the stool cultures out of which a total of 101 NTS occurred in children with severe malaria. Out of the 9,147 malaria cases admitted, 101/9,147 (1.10%) had concomitant NTS infection. NTS with severe malaria as a proportion of all malaria admissions for the period varied between 0.8% and 1.5%. There was a significant association (p-value=0.032) between clinical outcome of death and female sex of the patient. The NTS isolates which occurred with severe malaria showed various levels of antibiotic resistance. They were resistant to ampicillin (35%), chloramphenicol (18%), gentamicin (22%), cefuroxime (29%), sulphamethoxazole-trimethoprim (39%), ciprofloxacin (3%), cefotaxime (14%), amoxycillin-clavulanic acid (26%) and tobramycin (18.0%). Multidrug resistance (MDR) was seen in 34 (33.6%) of the isolates. CONCLUSIONS: NTS and severe malaria occurring together are a problem in this area and that a large number of the isolates are MDR. An elaborate case-controlled study is required to elucidate the chain of events of both NTS and malaria parasite co-existence.

Enwere G, Obaro S. 2001. Diagnosis of bacterial meningitis. Lancet, 358 (9292), pp. 1549-1550. | Read more

Berkley J, Lowe B, Mwangi I, Marsh K, Newton CRJC. 2001. Diagnosis of bacterial meningitis - Reply LANCET, 358 (9292), pp. 1549-1550. | Read more

Berkley JA, Mwangi I, Ngetsa CJ, Mwarumba S, Lowe BS, Marsh K, Newton CR. 2001. Diagnosis of acute bacterial meningitis in children at a district hospital in sub-Saharan Africa. Lancet, 357 (9270), pp. 1753-1757. | Show Abstract | Read more

BACKGROUND: The diagnosis of acute bacterial meningitis in children is difficult in sub-Saharan Africa, because the clinical features overlap with those of other common diseases, and laboratory facilities are inadequate in many areas. We have assessed the value of non-laboratory tests and incomplete laboratory data in diagnosing childhood acute bacterial meningitis in this setting. METHODS: We prospectively studied 905 children undergoing lumbar puncture at a rural district hospital in Kenya over 1 year. We related microbiological findings and cerebrospinal-fluid (CSF) laboratory measurements to tests that would typically be available at such a hospital. FINDINGS: Acute bacterial meningitis was proven in 45 children (5.0% [95% CI 3.7-6.6]) and probable in 26 (2.9% [1.9-4.2]). 21 of the 71 cases of proven or probable acute bacterial meningitis had neither neck stiffness nor turbid CSF. In eight of 45 children with proven disease the CSF leucocyte count was less than 10x10(6)/L or leucocyte counting was not possible because of blood-staining. The presence of either a leucocyte count of 50x10(6)/L or more or a CSF/blood glucose ratio of 0.10 or less detected all but two of the 45 children with proven acute bacterial meningitis; these two samples were grossly blood-stained. INTERPRETATION: The diagnosis of childhood acute bacterial meningitis is likely to be missed in a third of cases at district hospitals in sub-Saharan Africa without adequate and reliable laboratory resources. CSF culture facilities are expensive and difficult to maintain, and greater gains could be achieved with facilities for accurate leucocyte counting and glucose measurement.

Berkley J, Mwarumba S, Bramham K, Lowe B, Marsh K. 1999. Bacteraemia complicating severe malaria in children. Trans R Soc Trop Med Hyg, 93 (3), pp. 283-286. | Show Abstract | Read more

Bacteraemia associated with severe malaria in childhood is a sporadically reported phenomenon but its incidence and clinical importance are unknown. We have reviewed clinical and laboratory data from 783 Kenyan children sequentially admitted with a primary diagnosis of severe malaria. The overall incidence of bacteraemia in children with severe malaria was 7.8% (95% CI 5.5-10.0); however, in children under 30 months of age the incidence was 12.0% (95% CI 8.3-15.7). The presence of bacteraemia was associated with a 3-fold increase in mortality (33.3% vs. 10.4%, P < 0.001). We conclude that invasive bacterial disease may contribute to the pathophysiology of the clinical syndrome of severe malaria in an important subgroup of children. We recommend that young children with severe malaria be treated with broad-spectrum antibiotics in addition to antimalarial drugs.

Berkley JA, Mwangi I, Mellington F, Mwarumba S, Marsh K. 1999. Cerebral malaria versus bacterial meningitis in children with impaired consciousness. QJM, 92 (3), pp. 151-157. | Show Abstract | Read more

Cerebral malaria (CM) and acute bacterial meningitis (ABM) are the two common causes of impaired consciousness in children presenting to hospital in sub-Sahara Africa. Since the clinical features of the two diseases may be very similar, treatment is often guided by the initial laboratory findings. However, no detailed studies have examined the extent to which the laboratory findings in these two diseases may overlap. We reviewed data from 555 children with impaired consciousness admitted to Kilifi District Hospital, Kenya. Strictly defined groups were established based on the malaria slide, cerebrospinal fluid (CSF) leucocyte count and the results of blood and CSF culture and CSF bacterial antigen testing. Our data suggests significant overlap in the initial CSF findings between CM and ABM. The absolute minimum proportions of children with impaired consciousness and malaria parasitaemia who also had definite bacterial meningitis were 4% of all children and 14% of children under 1 year of age. The estimated maximum proportion of all children with impaired consciousness and malaria parasitaemia in whom the diagnosis was dual or unclear was at least 13%. The finding of malaria parasites in the blood of an unconscious child in sub-Saharan Africa is not sufficient to establish a diagnosis of cerebral malaria, and acute bacterial meningitis must be actively excluded in all cases.

Mramba L, Ngari M, Mwangome M, Muchai L, Bauni E, Walker AS, Gibb DM, Fegan G, Berkley JA. 2017. A growth reference for mid upper arm circumference for age among school age children and adolescents, and validation for mortality: growth curve construction and longitudinal cohort study. BMJ, 358 pp. j3423. | Show Abstract | Read more

Objectives To construct growth curves for mid-upper-arm circumference (MUAC)-for-age z score for 5-19 year olds that accord with the World Health Organization growth standards, and to evaluate their discriminatory performance for subsequent mortality.Design Growth curve construction and longitudinal cohort study.Setting United States and international growth data, and cohorts in Kenya, Uganda, and Zimbabwe.Participants The Health Examination Survey (HES)/National Health and Nutrition Examination Survey (NHANES) US population datasets (age 5-25 years), which were used to construct the 2007 WHO growth reference for body mass index in this age group, were merged with an imputed dataset matching the distribution of the WHO 2006 growth standards age 2-6 years. Validation data were from 685 HIV infected children aged 5-17 years participating in the Antiretroviral Research for Watoto (ARROW) trial in Uganda and Zimbabwe; and 1741 children aged 5-13 years discharged from a rural Kenyan hospital (3.8% HIV infected). Both cohorts were followed-up for survival during one year.Main outcome measures Concordance with WHO 2006 growth standards at age 60 months and survival during one year according to MUAC-for-age and body mass index-for-age z scores.Results The new growth curves transitioned smoothly with WHO growth standards at age 5 years. MUAC-for-age z scores of -2 to -3 and less than-3, compared with -2 or more, was associated with hazard ratios for death within one year of 3.63 (95% confidence interval 0.90 to 14.7; P=0.07) and 11.1 (3.40 to 36.0; P<0.001), respectively, among ARROW trial participants; and 2.22 (1.01 to 4.9; P=0.04) and 5.15 (2.49 to 10.7; P<0.001), respectively, among Kenyan children after discharge from hospital. The AUCs for MUAC-for-age and body mass index-for-age z scores for discriminating subsequent mortality were 0.81 (95% confidence interval 0.70 to 0.92) and 0.75 (0.63 to 0.86) in the ARROW trial (absolute difference 0.06, 95% confidence interval -0.032 to 0.16; P=0.2) and 0.73 (0.65 to 0.80) and 0.58 (0.49 to 0.67), respectively, in Kenya (absolute difference in AUC 0.15, 0.07 to 0.23; P=0.0002).Conclusions The MUAC-for-age z score is at least as effective as the body mass index-for-age z score for assessing mortality risks associated with undernutrition among African school aged children and adolescents. MUAC can provide simplified screening and diagnosis within nutrition and HIV programmes, and in research.

Mwangome M, Ngari M, Fegan G, Mturi N, Shebe M, Bauni E, Berkley JA. 2017. Diagnostic criteria for severe acute malnutrition among infants aged under 6 mo. Am J Clin Nutr, 105 (6), pp. 1415-1423. | Show Abstract | Read more

Background: There is an increasing recognition of malnutrition among infants under 6 mo of age (U6M). Current diagnosis criteria use weight-for-length z scores (WLZs), but the 2006 WHO standards exclude infants shorter than 45 cm. In older children, midupper arm circumference (MUAC) predicts mortality better than does WLZ. Outcomes may also be influenced by exposure to HIV and size or gestational age at birth. Diagnostic thresholds for WLZ, MUAC, and other indexes have not been fully evaluated against mortality risk among U6M infants.Objective: The aim was to determine the association of anthropometric indexes with risks of inpatient and postdischarge mortality among U6M infants recruited at the time of hospitalization.Design: We analyzed data from a cohort of U6M infants admitted to Kilifi County Hospital (2007-2013), Kenya. The primary outcomes were inpatient death and death during follow-up over 1 y after discharge. We calculated adjusted RRs for inpatient mortality and HRs for postdischarge mortality for different anthropometric measures and thresholds. Discriminatory value was assessed by using receiver operating characteristic curves.Results: A total of 2882 infants were admitted: 140 (4.9%) died in the hospital and 1405 infants were followed up after discharge. Of these, 75 (5.3%) died within 1 y during 1318 child-years of observation. MUAC and weight-for-age z score (WAZ) predicted inpatient and postdischarge mortality better than did WLZ (P < 0.0001). A single MUAC threshold of <11.0 cm performed similarly to MUAC thresholds that varied with age (all P > 0.05) and performed better than WLZ <-3 for both inpatient and postdischarge mortality (both P < 0.001). Reported small size at birth did not reduce the risk of death associated with anthropometric indexes.Conclusions: U6M infants at the highest risk of death are best targeted by using MUAC or WAZ. Further research into the effectiveness of potential interventions is required.

Berkley JA, Ngari M, Thitiri J, Mwalekwa L, Timbwa M, Hamid F, Ali R, Shangala J, Mturi N, Jones KDJ et al. 2016. Daily co-trimoxazole prophylaxis to prevent mortality in children with complicated severe acute malnutrition: a multicentre, double-blind, randomised placebo-controlled trial. Lancet Glob Health, 4 (7), pp. e464-e473. | Show Abstract | Read more

BACKGROUND: Children with complicated severe acute malnutrition (SAM) have a greatly increased risk of mortality from infections while in hospital and after discharge. In HIV-infected children, mortality and admission to hospital are prevented by daily co-trimoxazole prophylaxis, despite locally reported bacterial resistance to co-trimoxazole. We aimed to assess the efficacy of daily co-trimoxazole prophylaxis on survival in children without HIV being treated for complicated SAM. METHODS: We did a multicentre, double-blind, randomised, placebo-controlled study in four hospitals in Kenya (two rural hospitals in Kilifi and Malindi, and two urban hospitals in Mombasa and Nairobi) with children aged 60 days to 59 months without HIV admitted to hospital and diagnosed with SAM. We randomly assigned eligible participants (1:1) to 6 months of either daily oral co-trimoxazole prophylaxis (given as water-dispersible tablets; 120 mg per day for age <6 months, 240 mg per day for age 6 months to 5 years) or matching placebo. Assignment was done with computer-generated randomisation in permuted blocks of 20, stratified by centre and age younger or older than 6 months. Treatment allocation was concealed in opaque, sealed envelopes and patients, their families, and all trial staff were masked to treatment assignment. Children were given recommended medical care and feeding, and followed up for 12 months. The primary endpoint was mortality, assessed each month for the first 6 months, then every 2 months for the second 6 months. Secondary endpoints were nutritional recovery, readmission to hospital, and illness episodes treated as an outpatient. Analysis was by intention to treat. This trial was registered at ClinicalTrials.gov, number NCT00934492. FINDINGS: Between Nov 20, 2009, and March 14, 2013, we recruited and assigned 1778 eligible children to treatment (887 to co-trimoxazole prophylaxis and 891 to placebo). Median age was 11 months (IQR 7-16 months), 306 (17%) were younger than 6 months, 300 (17%) had oedematous malnutrition (kwashiorkor), and 1221 (69%) were stunted (length-for-age Z score <-2). During 1527 child-years of observation, 122 (14%) of 887 children in the co-trimoxazole group died, compared with 135 (15%) of 891 in the placebo group (unadjusted hazard ratio [HR] 0·90, 95% CI 0·71-1·16, p=0·429; 16·0 vs 17·7 events per 100 child-years observed (CYO); difference -1·7 events per 100 CYO, 95% CI -5·8 to 2·4]). In the first 6 months of the study (while participants received study medication), 63 suspected grade 3 or 4 associated adverse events were recorded among 57 (3%) children; 31 (2%) in the co-trimoxazole group and 32 (2%) in the placebo group (incidence rate ratio 0·98, 95% CI 0·58-1·65). The most common adverse events of these grades were urticarial rash (grade 3, equally common in both groups), neutropenia (grade 4, more common in the co-trimoxazole group), and anaemia (both grades equally common in both groups). One child in the placebo group had fatal toxic epidermal necrolysis with concurrent Pseudomonas aeruginosa bacteraemia. INTERPRETATION: Daily co-trimoxazole prophylaxis did not reduce mortality in children with complicated SAM without HIV. Other strategies need to be tested in clinical trials to reduce deaths in this population. FUNDING: Wellcome Trust, UK.

Seale AC, Koech AC, Sheppard AE, Barsosio HC, Langat J, Anyango E, Mwakio S, Mwarumba S, Morpeth SC, Anampiu K et al. 2016. Maternal colonisation with Streptococcus agalactiae, and associated stillbirth and neonatal disease in coastal Kenya. Nat Microbiol, 1 (7), pp. 16067-16067. | Show Abstract | Read more

Streptococcus agalactiae (Group B Streptococcus, GBS) causes neonatal disease and stillbirth, but its burden in sub-Saharan Africa is uncertain. We assessed maternal recto-vaginal GBS colonisation (7967 women), stillbirth and neonatal disease. Whole genome sequencing was used to determine serotypes, sequence types (ST), and phylogeny. We found low maternal GBS colonisation prevalence (934/7967, 12%), but comparatively high incidence of GBS-associated stillbirth and early onset neonatal disease (EOD) in hospital (0.91(0.25-2.3)/1000 births; 0.76(0.25-1.77)/1000 live-births respectively). However, using a population denominator, EOD incidence was considerably reduced (0.13(0.07-0.21)/1000 live-births). Treated cases of EOD had very high case fatality (17/36, 47%), especially within 24 hours of birth, making under-ascertainment of community-born cases highly likely, both here and in similar facility-based studies. Maternal GBS colonisation was less common in women with low socio-economic status, HIV infection and undernutrition, but when GBS-colonised, they were more likely colonised by the most virulent clone, CC17. CC17 accounted for 267/915(29%) of maternal colonising (265/267(99%) serotype III, 2/267(0.7%) serotype IV), and 51/73(70%) of neonatal disease cases (all serotype III). Trivalent (Ia/II/III) and pentavalent (Ia/Ib/II/III/V) vaccines would cover 71/73(97%) and 72/73(99%) of disease-causing serotypes respectively. Serotype IV should be considered for inclusion, with evidence of capsular switching in CC17 strains.

Seale AC, Davies MR, Anampiu K, Morpeth SC, Nyongesa S, Mwarumba S, Smeesters PR, Efstratiou A, Karugutu R, Mturi N et al. 2016. Invasive Group A Streptococcus Infection among Children, Rural Kenya. Emerg Infect Dis, 22 (2), pp. 224-232. | Show Abstract | Read more

To determine the extent of group A Streptococcus (GAS) infections in sub-Saharan Africa and the serotypes that cause disease, we analyzed surveillance data for 64,741 hospital admissions in Kilifi, Kenya, during 1998-2011. We evaluated incidence, clinical presentations, and emm types that cause invasive GAS infection. We detected 370 cases; of the 369 for which we had data, most were skin and soft tissue infections (70%), severe pneumonia (23%), and primary bacteremia (14%). Overall case-fatality risk was 12%. Incidence of invasive GAS infection was 0.6 cases/1,000 live births among neonates, 101/100,000 person-years among children <1 year of age, and 35/100,000 among children <5 years of age. Genome sequencing identified 88 emm types. GAS causes serious disease in children in rural Kenya, especially neonates, and the causative organisms have considerable genotypic diversity. Benefit from the most advanced GAS type-specific vaccines may be limited, and efforts must be directed to protect against disease in regions of high incidence.

Jones KDJ, Ali R, Khasira MA, Odera D, West AL, Koster G, Akomo P, Talbert AWA, Goss VM, Ngari M et al. 2015. 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. BMC Med, 13 (1), pp. 93. | Show Abstract | Read more

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.

Jones KDJ, Hünten-Kirsch B, Laving AMR, Munyi CW, Ngari M, Mikusa J, Mulongo MM, Odera D, Nassir HS, Timbwa M et al. 2014. Mesalazine in the initial management of severely acutely malnourished children with environmental enteric dysfunction: a pilot randomized controlled trial. BMC Med, 12 (1), pp. 133. | Show Abstract | Read more

BACKGROUND: Environmental enteric dysfunction (EED) is an acquired syndrome of impaired gastrointestinal mucosal barrier function that is thought to play a key role in the pathogenesis of stunting in early life. It has been conceptualized as an adaptive response to excess environmental pathogen exposure. However, it is clinically similar to other inflammatory enteropathies, which result from both host and environmental triggers, and for which immunomodulation is a cornerstone of therapy. METHODS: In this pilot double-blind randomized placebo-controlled trial, 44 children with severe acute malnutrition and evidence of EED were assigned to treatment with mesalazine or placebo for 28 days during nutritional rehabilitation. Primary outcomes were safety and acceptability of the intervention. RESULTS: Treatment with mesalazine was safe: there was no excess of adverse events, evidence of deterioration in intestinal barrier integrity or impact on nutritional recovery. There were modest reductions in several inflammatory markers with mesalazine compared to placebo. Depression of the growth hormone--insulin-like growth factor-1 axis was evident at enrollment and associated with inflammatory activation. Increases in the former and decreases in the latter correlated with linear growth. CONCLUSIONS: Intestinal inflammation in EED is non-essential for mucosal homeostasis and is at least partly maladaptive. Further trials of gut-specific immunomodulatory therapies targeting host inflammatory activation in order to optimize the growth benefits of nutritional rehabilitation and to address stunting are warranted. Funded by The Wellcome Trust. TRIAL REGISTRATION: Registered at Clinicaltrials.gov NCT01841099.

Berkley JA. 2014. Randomised trials in developing countries. Arch Dis Child, 99 (7), pp. 607-608. | Read more

Webb C, Ngama M, Ngatia A, Shebbe M, Morpeth S, Mwarumba S, Bett A, Nokes DJ, Seale AC, Kazungu S et al. 2012. Treatment failure among Kenyan children with severe pneumonia--a cohort study. Pediatr Infect Dis J, 31 (9), pp. e152-e157. | Show Abstract | Read more

BACKGROUND: Pneumonia is the leading cause of childhood mortality worldwide. The World Health Organization recommends presumptive treatment based on clinical syndromes. Recent studies raise concerns over the frequency of treatment failure in Africa. METHODS: We applied a definition of treatment failure to data prospectively collected from children who were 2-59 months of age with severe, or very severe, pneumonia admitted to Kilifi District Hospital, Kenya, from May 2007 through May 2008 and treated using World Health Organization guidelines. The primary outcome was treatment failure at 48 hours. RESULTS: Of 568 children, median age 11 months, 165 (29%) had very severe pneumonia, 30 (5.3%) a positive HIV test and 62 (11%) severe malnutrition. One hundred eleven (20%; 95% confidence interval: 17-23%) children failed treatment at 48 hours and 34 (6.0%) died; 22 (65%) deaths occurred before 48 hours. Of 353 children with severe pneumonia, without HIV or severe malnutrition, 42 (12%) failed to respond at 48 hours, 15 (4.3%) failed at 5 days and 1 child (0.3%) died. Among 215 children with either severe pneumonia complicated by HIV or severe malnutrition, or very severe pneumonia, 69 (32%) failed to treatment at 48 hours, 47 (22%) failed at 5 days and 33 (16%) died. Treatment failure at 48 hours was associated with shock, bacteremia, very severe pneumonia, oxygen saturation in hemoglobin <95%, severe malnutrition, HIV and age <1 year in multivariable models. CONCLUSIONS: In this setting, few children with uncomplicated severe pneumonia fail treatment or die under current guidelines. Deaths mainly occurred early and may be reduced by improving prevention, prehospital care and treatment of sepsis.

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Hassan AS, Fielding KL, Thuo NM, Nabwera HM, Sanders EJ, Berkley JA. 2012. Early loss to follow-up of recently diagnosed HIV-infected adults from routine pre-ART care in a rural district hospital in Kenya: a cohort study TROPICAL MEDICINE & INTERNATIONAL HEALTH, 17 (1), pp. 82-93. | Show Abstract | Read more

Objective To determine the rate and predictors of early loss to follow-up (LTFU) for recently diagnosed HIV-infected, antiretroviral therapy (ART)-ineligible adults in rural Kenya. Methods Prospective cohort study. Clients registering for HIV care between July 2008 and August 2009 were followed up for 6months. Baseline data were used to assess predictors of pre-ART LTFU (not returning for care within 2months of a scheduled appointment), LTFU before the second visit and LTFU after the second visit. Logistic regression was used to determine factors associated with LTFU before the second visit, while Cox regression was used to assess predictors of time to LTFU and LTFU after the second visit. Results Of 530 eligible clients, 178 (33.6%) were LTFU from pre-ART care (11.1/100 person-months). Of these, 96 (53.9%) were LTFU before the second visit. Distance ( > 5km vs. < 1km: adjusted hazard ratio 2.6 [1.9-3.7], P < 0.01) and marital status (married vs. single: 0.5 [0.3-0.6], P < 0.01) independently predicted pre-ART LTFU. Distance and marital status were independently associated with LTFU before the second visit, while distance, education status and seasonality showed weak evidence of predicting LTFU after the second visit. HIV disease severity did not predict pre-ART LTFU. Conclusions A third of recently diagnosed HIV-infected, ART-ineligible clients were LTFU within 6months of registration. Predictors of LTFU among ART-ineligible clients are different from those among clients on ART. These findings warrant consideration of an enhanced pre-ART care package aimed at improving retention and timely ART initiation. © 2011 Blackwell Publishing Ltd.

Mogeni P, Twahir H, Bandika V, Mwalekwa L, Thitiri J, Ngari M, Toromo C, Maitland K, Berkley JA. 2011. Diagnostic performance of visible severe wasting for identifying severe acute malnutrition in children admitted to hospital in Kenya. Bull World Health Organ, 89 (12), pp. 900-906. | Show Abstract | Read more

OBJECTIVE: To determine the diagnostic value of visible severe wasting in identifying severe acute malnutrition at two public hospitals in Kenya. METHODS: This was a cross-sectional study of children aged 6 to 59.9 months admitted to one rural and one urban hospital. On admission, mid-upper arm circumference (MUAC), weight and height were measured and the presence of visible severe wasting was assessed. The diagnostic performance of visible severe wasting was evaluated against anthropometric criteria. FINDINGS: Of 11,166 children admitted, 563 (5%) had kwashiorkor and 1406 (12.5%) were severely wasted (MUAC < 11.5 cm). The combined sensitivity and specificity of visible severe wasting at the two hospitals, as assessed against a MUAC < 11.5 cm, were 54% (95% confidence interval, CI: 51-56) and 96% (95% CI: 96-97), respectively; at one hospital, its sensitivity and specificity against a weight-for-height z-score below -3 were 44.7% (95% CI: 42-48) and 96.5% (95% CI: 96-97), respectively. Severely wasted children who were correctly identified by visible severe wasting were consistently older, more severely wasted, more often having kwashiorkor, more often positive to the human immunodeficiency virus, ill for a longer period and at greater risk of death. Visible severe wasting had lower sensitivity for determining the risk of death than the anthropometric measures. There was no evidence to support measuring both MUAC and weight-for-height z-score. CONCLUSION: Visible severe wasting failed to detect approximately half of the children admitted to hospital with severe acute malnutrition diagnosed anthropometrically. Routine screening by MUAC is quick, simple and inexpensive and should be part of the standard assessment of all paediatric hospital admissions in the study setting.

Scott JAG, Berkley JA, Mwangi I, Ochola L, Uyoga S, Macharia A, Ndila C, Lowe BS, Mwarumba S, Bauni E et al. 2011. Relation between falciparum malaria and bacteraemia in Kenyan children: a population-based, case-control study and a longitudinal study. Lancet, 378 (9799), pp. 1316-1323. | Show Abstract | Read more

BACKGROUND: Many investigators have suggested that malaria infection predisposes individuals to bacteraemia. We tested this hypothesis with mendelian randomisation studies of children with the malaria-protective phenotype of sickle-cell trait (HbAS). METHODS: This study was done in a defined area around Kilifi District Hospital, Kilifi, Kenya. We did a matched case-control study to identify risk factors for invasive bacterial disease, in which cases were children aged 3 months to 13 years who were admitted to hospital with bacteraemia between Sept 16, 1999, and July 31, 2002. We aimed to match two controls, by age, sex, location, and time of recruitment, for every case. We then did a longitudinal case-control study to assess the relation between HbAS and invasive bacterial disease as malaria incidence decreased. Cases were children aged 0-13 years who were admitted to hospital with bacteraemia between Jan 1, 1999, and Dec 31, 2007. Controls were born in the study area between Jan 1, 2006, and June 23, 2009. Finally, we modelled the annual incidence of bacteraemia against the community prevalence of malaria during 9 years with Poisson regression. RESULTS: In the matched case-control study, we recruited 292 cases-we recruited two controls for 236, and one for the remaining 56. Sickle-cell disease, HIV, leucocyte haemozoin pigment, and undernutrition were positively associated with bacteraemia and HbAS was strongly negatively associated with bacteraemia (odds ratio 0·36; 95% CI 0·20-0·65). In the longitudinal case-control study, we assessed data from 1454 cases and 10,749 controls. During the study period, the incidence of admission to hospital with malaria per 1000 child-years decreased from 28·5 to 3·45, with a reduction in protection afforded by HbAS against bacteraemia occurring in parallel (p=0·0008). The incidence of hospital admissions for bacteraemia per 1000 child-years also decreased from 2·59 to 1·45. The bacteraemia incidence rate ratio associated with malaria parasitaemia was 6·69 (95% CI 1·31-34·3) and, at a community parasite prevalence of 29% in 1999, 62% (8·2-91) of bacteraemia cases were attributable to malaria. INTERPRETATION: Malaria infection strongly predisposes individuals to bacteraemia and can account for more than half of all cases of bacteraemia in malaria-endemic areas. Interventions to control malaria will have a major additional benefit by reducing the burden of invasive bacterial disease. FUNDING: Wellcome Trust.

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