James A Berkley

KEMRI-Wellcome Trust Research Programme, Kilifi, Kilifi, Kenya

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Publications (103)1030.68 Total impact

  • Anna C Seale, Christina W Obiero, James A Berkley
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    ABSTRACT: This review discusses the rational development of guidelines for the management of neonatal sepsis in developing countries. 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. 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.
    Current Opinion in Infectious Diseases 04/2015; DOI:10.1097/QCO.0000000000000163 · 5.03 Impact Factor
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    ABSTRACT: 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.
    PLoS ONE 04/2015; · 3.53 Impact Factor
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    ABSTRACT: By engaging expert opinion, Marko Kerac and colleagues set research priorities for the management of acute malnutrition in infants.
    PLoS Medicine 04/2015; 12(4):e1001812. DOI:10.1371/journal.pmed.1001812 · 14.00 Impact Factor
  • Christina W Obiero, Anna C Seale, James A Berkley
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    ABSTRACT: 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 non-specific clinical signs that maximise sensitivity since staff making initial assessments may not have specialist paediatric training. Accurate diagnosis is usually limited by the unavailability of reliable microbiological investigation. The World Health Organization recommends ampicillin (or penicillin; cloxacilllin 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 challenges the first-line use of cephalosporins. Improving local surveillance data using standardised antimicrobial susceptibility testing methods and validation of diagnostic algorithms against microbial findings are essential. Standardised 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.
    The Pediatric Infectious Disease Journal 03/2015; DOI:10.1097/INF.0000000000000692 · 3.14 Impact Factor
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    ABSTRACT: 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 overlooked 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.
    Food and nutrition bulletin 01/2015; 36(1):S30. · 1.50 Impact Factor
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    Kelsey D J Jones, James A Berkley
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    ABSTRACT: Severe acute malnutrition (SAM) is associated with increased severity of common infectious diseases, and death amongst children with SAM is almost always as a result of infection. The diagnosis and management of infection are often different in malnourished versus well-nourished children. The objectives of this brief are to outline the evidence underpinning important practical questions relating to the management of infectious diseases in children with SAM and to highlight research gaps. Overall, the evidence base for many aspects covered in this brief is very poor. The brief addresses antimicrobials; antipyretics; tuberculosis; HIV; malaria; pneumonia; diarrhoea; sepsis; measles; urinary tract infection; nosocomial Infections; soil transmitted helminths; skin infections and pharmacology in the context of SAM. The brief is structured into sets of clinical questions, which we hope will maximise the relevance to contemporary practice.
    Annals of Tropical Paediatrics International Child Health 12/2014; 34 Suppl 1:S1-S29. DOI:10.1179/2046904714Z.000000000218 · 1.17 Impact Factor
  • Shiraz Badurdeen, Musa Mulongo, James A Berkley
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    ABSTRACT: 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 compartmentalised 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 colonisation 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 necrotising 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.Pediatric Research (2014); doi:10.1038/pr.2014.177.
    Pediatric Research 10/2014; 77(2). DOI:10.1038/pr.2014.177 · 2.84 Impact Factor
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    ABSTRACT: 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.
    BMC Medicine 08/2014; 12(1):133. DOI:10.1186/s12916-014-0133-2 · 7.28 Impact Factor
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    ABSTRACT: 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 induded 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 induded 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.
    The Lancet Infectious Diseases 08/2014; DOI:10.1016/S1473-3099(14)70804-7 · 19.45 Impact Factor
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    ABSTRACT: 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.
    Annals of the New York Academy of Sciences 08/2014; DOI:10.1111/nyas.12487 · 4.31 Impact Factor
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    ABSTRACT: 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.
    Food and nutrition bulletin 06/2014; 35(2 Suppl):S64-70. · 1.50 Impact Factor
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    ABSTRACT: To compare mothers' perceptions of their own infants' nutritional status with anthropometric indicators of undernutrition.
    Public Health Nutrition 05/2014; DOI:10.1017/S1368980014001074 · 2.48 Impact Factor
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    James A Berkley
    Archives of Disease in Childhood 05/2014; 99(7). DOI:10.1136/archdischild-2014-306163 · 2.91 Impact Factor
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    Martha K. Mwangome, James A. Berkley
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    ABSTRACT: 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.
    Maternal and Child Nutrition 05/2014; 10(4). DOI:10.1111/mcn.12124 · 2.97 Impact Factor
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    ABSTRACT: 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.
    Clinical Infectious Diseases 04/2014; 58(12). DOI:10.1093/cid/ciu202 · 9.42 Impact Factor
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    ABSTRACT: 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. 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. 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. 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.
    AIDS Research and Therapy 01/2014; 11(1):9. DOI:10.1186/1742-6405-11-9 · 1.84 Impact Factor
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    Ultrasound in Obstetrics and Gynecology 10/2013; 42(s1). DOI:10.1002/uog.12712 · 3.14 Impact Factor
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    Ultrasound in Obstetrics and Gynecology 10/2013; 42(s1). DOI:10.1002/uog.12714 · 3.14 Impact Factor

Publication Stats

3k Citations
1,030.68 Total Impact Points

Institutions

  • 2002–2014
    • KEMRI-Wellcome Trust Research Programme
      Kilifi, Kilifi, Kenya
  • 1999–2014
    • University of Oxford
      • • Centre for Clinical Vaccinology and Tropical Medicine (CCVTM)
      • • Nuffield Department of Clinical Medicine
      • • Department of Paediatrics
      Oxford, England, United Kingdom
  • 2013
    • University of Amsterdam
      Amsterdamo, North Holland, Netherlands
  • 2002–2012
    • Kenya Medical Research Institute
      • Centre for Clinical Research
      Nairoba, Nairobi Area, Kenya
  • 2006–2011
    • Oxford University Hospitals NHS Trust
      • Nuffield Department of Medicine
      Oxford, England, United Kingdom