register interest

Professor Anthony Scott

Research Area: Global Health
Scientific Themes: Tropical Medicine & Global Health and Clinical Trials & Epidemiology
Keywords: Pneumococcus, Vaccine policy, Epidemiology, Clinical Trials and Pneumonia
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Anthony Scott is based in Kilifi, Kenya, where he leads a group focused on invasive bacterial diseases of children. His interests lie in the evaluation of vaccines, particularly against Hib and the pneumococcus; the epidemiology of invasive bacterial infections and their interaction with malaria: the transmission of Streptococcus pneumoniae among children in Kenya; host susceptibility to pneumococcal disease; the aetiology of pneumonia in children; and the social and epidemiological determinants of mortality in children. He is the co-director, with Tom Williams, of the Kilifi Health and Demographic Surveillance System (KHDSS), a population-based surveillance of vital events and migration among 250,000 people linked to morbidity surveillance Kilifi District Hospital.  His current research themes are:

  • The impact of pneumococcal conjugate vaccine on the incidence of invasive pneumococcal disease in children. This project, nested in the KHDSS, aims to describe the population impact of vaccine introduction and estimate the magnitude of the vaccine indirect effect.
  • PERCH (Pneumonia Etiology Research for Child Health) is a comprehensive case-control study to determine the aetiology of pneumonia among children aged 1-59 months. Kilifi is one of seven study sites across Africa and Asia.

Anthony works closely with the Ministry of Public Health and Sanitation in Kenya providing disease burden, vaccine effectiveness, and cost effectiveness data to inform vaccine policy decisions.

He is currently supervising Ph.D. students in the areas of epidemiology and modelling of invasive pneumococcal disease, the dynamics and spread of pneumococcal infection throughout the body in different disease states using real-time PCR, and the interaction between childhood malaria and development of hypertension in later life.

Name Department Institution Country
Professor Thomas N Williams MRCP Tropical Medicine Oxford University, Kilifi Kenya
Professor Mike English Tropical Medicine Oxford University, Nairobi Kenya
Dr Orin S Levine International Health Johns Hopkins School of Public Health United States
Professor Kate L O'Brien International Health Johns Hopkins School of Public Health United States
Professor David Goldblatt Institute of Child Health, London United Kingdom
Dr Hervé Tettelin Institute for Genomic Sciences University of Maryland United States
Professor Adrian VS Hill Jenner Institute Oxford University, Old Road Campus Research Building United Kingdom
Dr Kayla Laserson KEMRI Centre for Global Health Research CDC Kenya Kenya
Professor Kari Auranen National Institute for Health and Welfare Finland
Dr Jukka Jokinen Dept of Vaccines National Institute of Health and Welfare Finland
Professor Marc Lipsitch Dept of Epidemiology Harvard School of Public Health United States
Professor Andy Hall London School of Hygiene & Tropical Medicine United Kingdom
Kamau A, Nyaga V, Bauni E, Tsofa B, Noor AM, Bejon P, Scott JAG, Hammitt LL. 2017. Trends in bednet ownership and usage, and the effect of bednets on malaria hospitalization in the Kilifi Health and Demographic Surveillance System (KHDSS): 2008-2015 BMC INFECTIOUS DISEASES, 17 (1), | Show Abstract | Read more

© 2017 The Author(s). Background: Use of bednets reduces malaria morbidity and mortality. In Kilifi, Kenya, there was a mass distribution of free nets to children < 5 years in 2006. In 2009, a new policy was implemented to offer bednets to pregnant women and children < 5 years free of charge. Nets were again distributed to children and adults through national mass campaigns in 2012 and 2015. We aimed to evaluate trends in bednet ownership and usage, and the effect of bednets on the incidence of malaria hospitalization in children < 5 years within the Kilifi Health and Demographic Surveillance System (KHDSS). Methods: Bednet ownership and usage were assessed during eight routine enumeration rounds of the KHDSS between 2008 and 2015. Malaria admissions (i.e. admissions to hospital with P. falciparum > 2500 parasitemia per μl) among children < 5 years were captured using a system of continuous vital registration that links admissions at Kilifi County Hospital to the KHDSS population register. Survival analysis was used to assess relative risk of hospitalization with malaria among children that reported using a bednet compared to those who did not. Results: We observed 63% and 62% mean bednet ownership and usage, respectively, over the eight-survey period. Among children < 5 years, reported bednet ownership in October-December 2008 was 69% and in March-August 2009 was 73% (p < 0.001). An increase was also observed following the mass distribution campaigns in 2012 (62% in May-July 2012 vs 90% in May-October 2013, p < 0.001) and 2015 (68% in June-September 2015 vs 93% in October-November 2015, p < 0.001). Among children < 5 years who reported using a net the night prior to the survey, the incidence of malaria hospitalization per 1000 child-years was 2.91 compared to 4.37 among those who did not (HR = 0.67, 95% CI: 0.52, 0.85 [p = 0.001]). Conclusion: On longitudinal surveillance, increasing bednet ownership and usage corresponded to mass distribution campaigns; however, this method of delivering bednets did not result in sustained improvements in coverage. Among children < 5 years old bednet use was associated with a 33% decreased incidence of malaria hospitalization.

Brent AJ, Mugo D, Musyimi R, Mutiso A, Morpeth S, Levin M, Scott JAG. 2017. Bacteriological diagnosis of childhood TB: a prospective observational study. Sci Rep, 7 (1), pp. 11808. | Show Abstract | Read more

Childhood TB diagnosis is challenging. Studies in adults suggest Microscopic Observation Drug Susceptibility (MODS) culture or the Xpert MTB/RIF assay might be used to expand bacteriological diagnosis. However data from children are more limited. We prospectively compared MODS and Xpert MTB/RIF with standard microscopy and culture using the BD MGIT 960 system among 1442 Kenyan children with suspected TB. 97 specimens from 54 children were TB culture-positive: 91 (94%) by MGIT and 74 (76%) by MODS (p = 0.002). 72 (74%) culture-positive and 7 culture-negative specimens were Xpert MTB/RIF positive. Xpert MTB/RIF specificity was 100% (99.7-100%) among 1164 specimens from 892 children in whom TB was excluded, strongly suggesting all Xpert MTB/RIF positives are true positives. The sensitivity of MGIT, MODS and Xpert MTB/RIF was 88%, 71% and 76%, respectively, among all 104 true positive (culture and/or Xpert MTB/RIF positive) specimens. MGIT, MODS and Xpert MTB/RIF on the initial specimen identified 40/51 (78%), 33/51 (65%) and 33/51 (65%) culture-confirmed pulmonary TB cases, respectively; Xpert MTB/RIF detected 5 additional culture-negative cases. The high sensitivity and very high specificity of the Xpert MTB/RIF assay supports its inclusion in the reference standard for bacteriological diagnosis of childhood TB in research and clinical practice.

Ojal J, Hammitt LL, Gaitho J, Scott JAG, Goldblatt D. 2017. Pneumococcal conjugate vaccine induced IgG and nasopharyngeal carriage of pneumococci: Hyporesponsiveness and immune correlates of protection for carriage Vaccine, 35 (35), pp. 4652-4657. | Show Abstract | Read more

© 2017 The Author(s) Background Prior studies have demonstrated hyporesponsiveness to pneumococcal conjugate vaccines (PCVs) when administered in the presence of homologous carriage. This may be substantially more important in Africa where carriage prevalence is high. Deriving a correlate of protection (CoP) for carriage is important in guiding the future use of extended PCVs as population control of pneumococcal disease by vaccination is now focused principally on its indirect effect. We therefore explored the complex relationship between existing carriage and vaccine responsiveness, and between serum IgG levels and risk of acquisition. Methods We undertook secondary analyses of data from two previously published clinical trials of the safety and immunogenicity of PCV in Kenya. We compared responses to vaccination between serotype-specific carriers and non-carriers at vaccination. We assessed the risk of carriage acquisition in relation to PCV-induced serum IgG levels using either a step- or continuous-risk function. Results For newborns, the immune response among carriers was 51–82% lower than that among non-carriers, depending on serotype. Among toddlers, for serotypes 6B, 14 and 19F the post-vaccination response among carriers was lower by between 29 and 70%. The estimated CoP against acquisition ranged from 0.26 to 1.93 μg/mL across serotypes, however, these thresholds could not be distinguished statistically from a model with constant probability of carriage independent of assay value. Conclusion We have confirmed hyporesponsiveness in an equatorial African setting in both infants and toddlers. Population responses to vaccination are likely to improve with time as carriage prevalence of vaccine serotypes is reduced. We have not found clear correlates of protection against carriage acquisition among toddlers in this population. Assessing the potential of new vaccines through the use of CoP against carriage is still difficult as there are no clear-cut serotype specific correlates.

Ojal J, Flasche S, Hammitt LL, Akech D, Kiti MC, Kamau T, Adetifa I, Nurhonen M, Scott JAG, Auranen K. 2017. Sustained reduction in vaccine-type invasive pneumococcal disease despite waning effects of a catch-up campaign in Kilifi, Kenya: A mathematical model based on pre-vaccination data Vaccine, 35 (35), pp. 4561-4568. | Show Abstract | Read more

© 2017 The Author(s) Background In 2011, Kenya introduced the 10-valent pneumococcal conjugate vaccine together with a catch-up campaign for children aged < 5 years in Kilifi County. In a post-vaccination surveillance study based in Kilifi, there was a substantial decline in invasive pneumococcal disease (IPD). However, given the continued circulation of the vaccine serotypes it is possible that vaccine-serotype disease may re-emerge once the effects of the catch-up campaign wear off. Methods We developed a compartmental, age-structured dynamic model of pneumococcal carriage and invasive disease for three serotype groups: the 10-valent vaccine serotypes and two groups of non-vaccine serotypes based on their susceptibility to mutual competition. The model was calibrated to age- and serotype-specific data on carriage and IPD in the pre-vaccination era and used to predict carriage prevalence and IPD up to ten years post-vaccination in Kilifi. The model was validated against the observed carriage prevalence after vaccine introduction. Results The model predicts a sustained reduction in vaccine-type pneumococcal carriage prevalence from 33% to 8% in infants and from 30% to 8% in 1–5 year olds over the 10-year period following vaccine introduction. The incidence of IPD is predicted to decline across all age groups resulting in an overall reduction of 56% in the population, corresponding to 10.4 cases per 100,000 per year. The vaccine-type IPD incidence is estimated to decline by 83% while non-vaccine-type IPD incidence is predicted to increase by 52%. The model's predictions of carriage prevalence agrees well with the observed data in the first five years post-vaccination. Conclusion We predict a sustained and substantial decline in IPD through PCV vaccination and that the current regimen is insufficient to fully eliminate vaccine-serotype circulation in the model. We show that the observed impact is likely to be sustained despite waning effects of the catch-up campaign.

Nackers F, Cohuet S, le Polain de Waroux O, Langendorf C, Nyehangane D, Ndazima D, Nanjebe D, Karani A, Tumwesigye E, Mwanga-Amumpaire J et al. 2017. Carriage prevalence and serotype distribution of Streptococcus pneumoniae prior to 10-valent pneumococcal vaccine introduction: A population-based cross-sectional study in South Western Uganda, 2014 Vaccine, 35 (39), pp. 5271-5277. | Show Abstract | Read more

© 2017 The Authors Background Information on Streptococcus pneumoniae nasopharyngeal (NP) carriage before the pneumococcal conjugate vaccine (PCV) introduction is essential to monitor impact. The 10-valent PCV (PCV10) was officially introduced throughout Ugandan national childhood immunization programs in 2013 and rolled-out countrywide during 2014. We aimed to measure the age-specific Streptococcus pneumoniae carriage and serotype distribution across all population age groups in the pre-PCV10 era in South Western Uganda. Methods We conducted a two-stage cluster, age-stratified, cross-sectional community-based study in Sheema North sub-district between January and March 2014. One NP swab was collected and analyzed for each participant in accordance with World Health Organization guidelines. Results NP carriage of any pneumococcal serotype was higher among children < 2 years old (77%; n = 387) than among participants aged ≥15 years (8.5%; n = 325) (chi 2 p < 0.001). Of the 623 positive cultures, we identified 49 serotypes among 610 (97.9%) isolates; thirteen (2.1%) isolates were non-typeable. Among < 2 years old, serotypes 6A, 6B, 14, 15B, 19F and 23F accounted for half of all carriers. Carriage prevalence with PCV10 serotypes was 29.4% among individuals aged < 2 years (n = 387), 23.4% in children aged 2–4 years (n = 217), 11.4% in 5–14 years (n = 417), and 0.4% among individuals ≥15 years of age (n = 325). The proportion of carried pneumococci serotypes contained in PCV10 was 38.1% (n = 291), 32.8% (n = 154), 29.4% (n = 156), and 4.4% (n = 22) among carriers aged < 2 years, 2–4 years, 5–14 years and ≥15 years, respectively. Discussion In Sheema district, the proportion of PCV10 serotypes was low ( < 40%), across all age groups, especially among individuals aged 15 years or older ( < 5%). PCV10 introduction is likely to impact transmission among children and to older individuals, but less likely to substantially modify pneumococcal NP ecology among individuals aged 15 years or older.

Henson SP, Boinett CJ, Ellington MJ, Kagia N, Mwarumba S, Nyongesa S, Mturi N, Kariuki S, Scott JAG, Thomson NR, Morpeth SC. 2017. Molecular epidemiology of Klebsiella pneumoniae invasive infections over a decade at Kilifi County Hospital in Kenya. Int J Med Microbiol, 307 (7), pp. 422-429. | Show Abstract | Read more

Multidrug resistant (MDR) Klebsiella pneumoniae is a common cause of nosocomial infections worldwide. Recent years have seen an explosion of resistance to extended-spectrum β-lactamases (ESBLs) and emergence of carbapenem resistance. Here, we examine 198 invasive K. pneumoniae isolates collected from over a decade in Kilifi County Hospital (KCH) in Kenya. We observe a significant increase in MDR K. pneumoniae isolates, particularly to third generation cephalosporins conferred by ESBLs. Using whole-genome sequences, we describe the population structure and the distribution of antimicrobial resistance genes within it. More than half of the isolates examined in this study were ESBL-positive, encoding CTX-M-15, SHV-2, SHV-12 and SHV-27, and 79% were MDR conferring resistance to at least three antimicrobial classes. Although no isolates in our dataset were found to be resistant to carbapenems we did find a plasmid with the genetic architecture of a known New Delhi metallo-β-lactamase-1 (NDM)-carrying plasmid in 25 isolates. In the absence of carbapenem use in KCH and because of the instability of the NDM-1 gene in the plasmid, the NDM-1 gene has been lost in these isolates. Our data suggests that isolates that encode NDM-1 could be present in the population; should carbapenems be introduced as treatment in public hospitals in Kenya, resistance is likely to ensue rapidly.

Shi T, McAllister DA, O'Brien KL, Simoes EAF, Madhi SA, Gessner BD, Polack FP, Balsells E, Acacio S, Aguayo C et al. 2017. Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study. Lancet, 390 (10098), pp. 946-958. | Show Abstract | Read more

BACKGROUND: We have previously estimated that respiratory syncytial virus (RSV) was associated with 22% of all episodes of (severe) acute lower respiratory infection (ALRI) resulting in 55 000 to 199 000 deaths in children younger than 5 years in 2005. In the past 5 years, major research activity on RSV has yielded substantial new data from developing countries. With a considerably expanded dataset from a large international collaboration, we aimed to estimate the global incidence, hospital admission rate, and mortality from RSV-ALRI episodes in young children in 2015. METHODS: We estimated the incidence and hospital admission rate of RSV-associated ALRI (RSV-ALRI) in children younger than 5 years stratified by age and World Bank income regions from a systematic review of studies published between Jan 1, 1995, and Dec 31, 2016, and unpublished data from 76 high quality population-based studies. We estimated the RSV-ALRI incidence for 132 developing countries using a risk factor-based model and 2015 population estimates. We estimated the in-hospital RSV-ALRI mortality by combining in-hospital case fatality ratios with hospital admission estimates from hospital-based (published and unpublished) studies. We also estimated overall RSV-ALRI mortality by identifying studies reporting monthly data for ALRI mortality in the community and RSV activity. FINDINGS: We estimated that globally in 2015, 33·1 million (uncertainty range [UR] 21·6-50·3) episodes of RSV-ALRI, resulted in about 3·2 million (2·7-3·8) hospital admissions, and 59 600 (48 000-74 500) in-hospital deaths in children younger than 5 years. In children younger than 6 months, 1·4 million (UR 1·2-1·7) hospital admissions, and 27 300 (UR 20 700-36 200) in-hospital deaths were due to RSV-ALRI. We also estimated that the overall RSV-ALRI mortality could be as high as 118 200 (UR 94 600-149 400). Incidence and mortality varied substantially from year to year in any given population. INTERPRETATION: Globally, RSV is a common cause of childhood ALRI and a major cause of hospital admissions in young children, resulting in a substantial burden on health-care services. About 45% of hospital admissions and in-hospital deaths due to RSV-ALRI occur in children younger than 6 months. An effective maternal RSV vaccine or monoclonal antibody could have a substantial effect on disease burden in this age group. FUNDING: The Bill & Melinda Gates Foundation.

Crawley J, Prosperi C, Baggett HC, Brooks WA, Deloria Knoll M, Hammitt LL, Howie SRC, Kotloff KL, Levine OS, Madhi SA et al. 2017. Standardization of Clinical Assessment and Sample Collection Across All PERCH Study Sites. Clin Infect Dis, 64 (suppl_3), pp. S228-S237. | Show Abstract | Read more

Background.: Variable adherence to standardized case definitions, clinical procedures, specimen collection techniques, and laboratory methods has complicated the interpretation of previous multicenter pneumonia etiology studies. To circumvent these problems, a program of clinical standardization was embedded in the Pneumonia Etiology Research for Child Health (PERCH) study. Methods.: Between March 2011 and August 2013, standardized training on the PERCH case definition, clinical procedures, and collection of laboratory specimens was delivered to 331 clinical staff at 9 study sites in 7 countries (The Gambia, Kenya, Mali, South Africa, Zambia, Thailand, and Bangladesh), through 32 on-site courses and a training website. Staff competency was assessed throughout 24 months of enrollment with multiple-choice question (MCQ) examinations, a video quiz, and checklist evaluations of practical skills. Results.: MCQ evaluation was confined to 158 clinical staff members who enrolled PERCH cases and controls, with scores obtained for >86% of eligible staff at each time-point. Median scores after baseline training were ≥80%, and improved by 10 percentage points with refresher training, with no significant intersite differences. Percentage agreement with the clinical trainer on the presence or absence of clinical signs on video clips was high (≥89%), with interobserver concordance being substantial to high (AC1 statistic, 0.62-0.82) for 5 of 6 signs assessed. Staff attained median scores of >90% in checklist evaluations of practical skills. Conclusions.: Satisfactory clinical standardization was achieved within and across all PERCH sites, providing reassurance that any etiological or clinical differences observed across the study sites are true differences, and not attributable to differences in application of the clinical case definition, interpretation of clinical signs, or in techniques used for clinical measurements or specimen collection.

Flasche S, Ojal J, Le Polain de Waroux O, Otiende M, O'Brien KL, Kiti M, Nokes DJ, Edmunds WJ, Scott JAG. 2017. Assessing the efficiency of catch-up campaigns for the introduction of pneumococcal conjugate vaccine: a modelling study based on data from PCV10 introduction in Kilifi, Kenya. BMC Med, 15 (1), pp. 113. | Show Abstract | Read more

BACKGROUND: The World Health Organisation recommends the use of catch-up campaigns as part of the introduction of pneumococcal conjugate vaccines (PCVs) to accelerate herd protection and hence PCV impact. The value of a catch-up campaign is a trade-off between the costs of vaccinating additional age groups and the benefit of additional direct and indirect protection. There is a paucity of observational data, particularly from low- and middle-income countries, to quantify the optimal breadth of such catch-up campaigns. METHODS: In Kilifi, Kenya, PCV10 was introduced in 2011 using the three-dose Expanded Programme on Immunisation infant schedule and a catch-up campaign in children <5 years old. We fitted a transmission dynamic model to detailed local data, including nasopharyngeal carriage and invasive pneumococcal disease (IPD), to infer the marginal impact of the PCV catch-up campaign over hypothetical routine cohort vaccination in that setting and to estimate the likely impact of alternative campaigns and their dose efficiency. RESULTS: We estimated that, within 10 years of introduction, the catch-up campaign among children <5 years old prevents an additional 65 (48-84) IPD cases across age groups, compared to PCV cohort introduction alone. Vaccination without any catch-up campaign prevented 155 (121-193) IPD cases and used 1321 (1058-1698) PCV doses per IPD case prevented. In the years after implementation, the PCV programme gradually accrues herd protection, and hence its dose efficiency increases: 10 years after the start of cohort vaccination alone the programme used 910 (732-1184) doses per IPD case averted. We estimated that a two-dose catch-up among children <1 year old uses an additional 910 (732-1184) doses per additional IPD case averted. Furthermore, by extending a single-dose catch-up campaign to children aged 1 to <2 years and subsequently to those aged 2 to <5 years, the campaign uses an additional 412 (296-606) and 543 (403-763) doses per additional IPD case averted. These results were not sensitive to vaccine coverage, serotype competition, the duration of vaccine protection or the relative protection of infants. CONCLUSIONS: We find that catch-up campaigns are a highly dose-efficient way to accelerate population protection against pneumococcal disease.

Adetifa IMO, Bwanaali T, Wafula J, Mutuku A, Karia B, Makumi A, Mwatsuma P, Bauni E, Hammitt LL, Nokes DJ et al. 2017. Cohort Profile: The Kilifi Vaccine Monitoring Study International Journal of Epidemiology, 46 (3), pp. dyw202-dyw202. | Read more

Verani JR, Baqui AH, Broome CV, Cherian T, Cohen C, Farrar JL, Feikin DR, Groome MJ, Hajjeh RA, Johnson HL et al. 2017. Case-control vaccine effectiveness studies: Data collection, analysis and reporting results. Vaccine, 35 (25), pp. 3303-3308. | Show Abstract | Read more

The case-control methodology is frequently used to evaluate vaccine effectiveness post-licensure. The results of such studies provide important insight into the level of protection afforded by vaccines in a 'real world' context, and are commonly used to guide vaccine policy decisions. However, the potential for bias and confounding are important limitations to this method, and the results of a poorly conducted or incorrectly interpreted case-control study can mislead policies. In 2012, a group of experts met to review recent experience with case-control studies evaluating vaccine effectiveness; we summarize the recommendations of that group regarding best practices for data collection, analysis, and presentation of the results of case-control vaccine effectiveness studies. Vaccination status is the primary exposure of interest, but can be challenging to assess accurately and with minimal bias. Investigators should understand factors associated with vaccination as well as the availability of documented vaccination status in the study context; case-control studies may not be a valid method for evaluating vaccine effectiveness in settings where many children lack a documented immunization history. To avoid bias, it is essential to use the same methods and effort gathering vaccination data from cases and controls. Variables that may confound the association between illness and vaccination are also important to capture as completely as possible, and where relevant, adjust for in the analysis according to the analytic plan. In presenting results from case-control vaccine effectiveness studies, investigators should describe enrollment among eligible cases and controls as well as the proportion with no documented vaccine history. Emphasis should be placed on confidence intervals, rather than point estimates, of vaccine effectiveness. Case-control studies are a useful approach for evaluating vaccine effectiveness; however careful attention must be paid to the collection, analysis and presentation of the data in order to best inform evidence-based vaccine policies.

Verani JR, Baqui AH, Broome CV, Cherian T, Cohen C, Farrar JL, Feikin DR, Groome MJ, Hajjeh RA, Johnson HL et al. 2017. Case-control vaccine effectiveness studies: Preparation, design, and enrollment of cases and controls. Vaccine, 35 (25), pp. 3295-3302. | Show Abstract | Read more

Case-control studies are commonly used to evaluate effectiveness of licensed vaccines after deployment in public health programs. Such studies can provide policy-relevant data on vaccine performance under 'real world' conditions, contributing to the evidence base to support and sustain introduction of new vaccines. However, case-control studies do not measure the impact of vaccine introduction on disease at a population level, and are subject to bias and confounding, which may lead to inaccurate results that can misinform policy decisions. In 2012, a group of experts met to review recent experience with case-control studies evaluating the effectiveness of several vaccines; here we summarize the recommendations of that group regarding best practices for planning, design and enrollment of cases and controls. Rigorous planning and preparation should focus on understanding the study context including healthcare-seeking and vaccination practices. Case-control vaccine effectiveness studies are best carried out soon after vaccine introduction because high coverage creates strong potential for confounding. Endpoints specific to the vaccine target are preferable to non-specific clinical syndromes since the proportion of non-specific outcomes preventable through vaccination may vary over time and place, leading to potentially confusing results. Controls should be representative of the source population from which cases arise, and are generally recruited from the community or health facilities where cases are enrolled. Matching of controls to cases for potential confounding factors is commonly used, although should be reserved for a limited number of key variables believed to be linked to both vaccination and disease. Case-control vaccine effectiveness studies can provide information useful to guide policy decisions and vaccine development, however rigorous preparation and design is essential.

Wang L, Ko ER, Gilchrist JJ, Pittman KJ, Rautanen A, Pirinen M, Thompson JW, Dubois LG, Langley RJ, Jaslow SL et al. 2017. Human genetic and metabolite variation reveals that methylthioadenosine is a prognostic biomarker and an inflammatory regulator in sepsis. Sci Adv, 3 (3), pp. e1602096. | Show Abstract | Read more

Sepsis is a deleterious inflammatory response to infection with high mortality. Reliable sepsis biomarkers could improve diagnosis, prognosis, and treatment. Integration of human genetics, patient metabolite and cytokine measurements, and testing in a mouse model demonstrate that the methionine salvage pathway is a regulator of sepsis that can accurately predict prognosis in patients. Pathway-based genome-wide association analysis of nontyphoidal Salmonella bacteremia showed a strong enrichment for single-nucleotide polymorphisms near the components of the methionine salvage pathway. Measurement of the pathway's substrate, methylthioadenosine (MTA), in two cohorts of sepsis patients demonstrated increased plasma MTA in nonsurvivors. Plasma MTA was correlated with levels of inflammatory cytokines, indicating that elevated MTA marks a subset of patients with excessive inflammation. A machine-learning model combining MTA and other variables yielded approximately 80% accuracy (area under the curve) in predicting death. Furthermore, mice infected with Salmonella had prolonged survival when MTA was administered before infection, suggesting that manipulating MTA levels could regulate the severity of the inflammatory response. Our results demonstrate how combining genetic data, biomolecule measurements, and animal models can shape our understanding of disease and lead to new biomarkers for patient stratification and potential therapeutic targeting.

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.

Barger-Kamate B, Deloria Knoll M, Kagucia EW, Prosperi C, Baggett HC, Brooks WA, Feikin DR, Hammitt LL, Howie SRC, Levine OS et al. 2016. Pertussis-Associated Pneumonia in Infants and Children From Low- and Middle-Income Countries Participating in the PERCH Study Clinical Infectious Diseases, 63 (suppl 4), pp. S187-S196. | Show Abstract | Read more

© The Author 2016. Background. Few data exist describing pertussis epidemiology among infants and children in low-and middle-income countries to guide preventive strategies. Methods. Children 1-59 months of age hospitalized withWorld Health Organization-defined severe or very severe pneumonia in 7 African and Asian countries and similarly aged community controls were enrolled in the Pneumonia Etiology Research for Child Health study. They underwent a standardized clinical evaluation and provided nasopharyngeal and oropharyngeal swabs and induced sputum (cases only) for Bordetella pertussis polymerase chain reaction. Risk factors and pertussis-associated clinical findings were identified. Results. Bordetella pertussis was detected in 53 of 4200 (1.3%) cases and 11 of 5196 (0.2%) controls. In the age stratum1-5months, 40 (2.3% of 1721) cases were positive, all from African sites, as were 8 (0.5% of 1617) controls. Pertussis-positive African cases 1-5 months old, compared to controls, were more often human immunodeficiency virus (HIV) uninfected-exposed (adjusted odds ratio [aOR], 2.2), unvaccinated (aOR, 3.7), underweight (aOR, 6.3), and too young to be immunized (aOR, 16.1) (all P ? .05). Compared with pertussisnegative African cases in this age group, pertussis-positive cases were younger, more likely to vomit (aOR, 2.6), to cough ?14 days (aOR, 6.3), to have leukocyte counts > 20 000 cells/?L (aOR, 4.6), and to have lymphocyte counts > 10 000 cells/?L (aOR, 7.2) (all P ? .05). The case fatality ratio of pertussis-infected pneumonia cases 1-5 months of age was 12.5% (95% confidence interval, 4.2%-26.8%; 5/40); pertussis was identified in 3.7% of 137 in-hospital deaths among African cases in this age group. Conclusions. In the postneonatal period, pertussis causes a small fraction of hospitalized pneumonia cases and deaths; however, case fatality is substantial. The propensity to infect unvaccinated infants and those at risk for insufficient immunity (too young to be vaccinated, premature, HIV-infected/exposed) suggests that the role for maternal vaccination should be considered along with efforts to reduce exposure to risk factors and to optimize childhood pertussis vaccination coverage.

Nyiro JU, Sande CJ, Mutunga M, Kiyuka PK, Munywoki PK, Scott JAG, Nokes DJ. 2016. Absence of Association between Cord Specific Antibody Levels and Severe Respiratory Syncytial Virus (RSV) Disease in Early Infants: A Case Control Study from Coastal Kenya. PLoS One, 11 (11), pp. e0166706. | Show Abstract | Read more

BACKGROUND: The target group for severe respiratory syncytial virus (RSV) disease prevention is infants under 6 months of age. Vaccine boosting of antibody titres in pregnant mothers could protect these young infants from severe respiratory syncytial virus (RSV) associated disease. Quantifying protective levels of RSV-specific maternal antibody at birth would inform vaccine development. METHODS: A case control study nested in a birth cohort (2002-07) was conducted in Kilifi, Kenya; where 30 hospitalised cases of RSV-associated severe disease were matched to 60 controls. Participants had a cord blood and 2 subsequent 3-monthly blood samples assayed for RSV-specific neutralising antibody by the plaque reduction neutralisation test (PRNT). Two sample paired t test and conditional logistic regression were used in analyses of log2PRNT titres. RESULTS: The mean RSV log2PRNT titre at birth for cases and controls were not significantly different (P = 0.4) and remained so on age-stratification. Cord blood PRNT titres showed considerable overlap between cases and controls. The odds of RSV disease decreased with increase in log2PRNT cord blood titre. There was a 30% reduction in RSV disease per unit increase in log2PRNT titre (<3months age group) but not significant (P = 0.3). CONCLUSIONS: From this study, there is no strong evidence of protection by maternal RSV specific antibodies from severe RSV disease. Cord antibody levels show wide variation with considerable overlap between cases and controls. It is likely that, there are additional factors to specific PRNT antibody levels which determine susceptibility to severe RSV disease. In addition, higher levels of neutralizing antibody beyond the normal range may be required for protection; which it is hoped can be achieved by a maternal RSV vaccine.

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.

Hammitt LL, Crane RJ, Karani A, Mutuku A, Morpeth SC, Burbidge P, Goldblatt D, Kamau T, Sharif S, Mturi N, Scott JAG. 2016. Effect of Haemophilus influenzae type b vaccination without a booster dose on invasive H influenzae type b disease, nasopharyngeal carriage, and population immunity in Kilifi, Kenya: a 15-year regional surveillance study. Lancet Glob Health, 4 (3), pp. e185-e194. | Show Abstract | Read more

BACKGROUND: Haemophilus influenzae type b (Hib) conjugate vaccine, delivered as a three-dose series without a booster, was introduced into the childhood vaccination programme in Kenya in 2001. The duration of protection and need for a booster dose are unknown. We aimed to assess vaccine effectiveness, the impact of the vaccine on nasopharyngeal carriage, and population immunity after introduction of conjugate Hib vaccine in infancy without a booster dose in Kenya. METHODS: This study took place in the Kilifi Health and Demographic Surveillance System (KHDSS), an area of Kenya that has been monitored for vital events and migration every 4 months since 2000. We analysed sterile site cultures for H influenzae type b from children (aged ≤12 years) admitted to the Kilifi County Hospital (KCH) from Jan 1, 2000, through to Dec 31, 2014. We determined the prevalence of nasopharyngeal carriage by undertaking cross-sectional surveys in random samples of KHDSS residents (of all ages) once every year from 2009 to 2012, and measured Hib antibody concentrations in five cross-sectional samples of children (aged ≤12 years) within the KHDSS (in 1998, 2000, 2004-05, 2007, and 2009). We calculated incidence rate ratios between the prevaccine era (2000-01) and the routine-use era (2004-14) and defined vaccine effectiveness as 1 minus the incidence rate ratio, expressed as a percentage. FINDINGS: 40,482 children younger than 13 years resident in KHDSS were admitted to KCH between 2000 and 2014, 38,206 (94%) of whom had their blood cultured. The incidence of invasive H influenzae type b disease in children younger than 5 years declined from 62·6 (95% CI 46·0-83·3) per 100,000 in 2000-01 to 4·5 (2·5-7·5) per 100,000 in 2004-14, giving a vaccine effectiveness of 93% (95% CI 87-96). In the final 5 years of observation (2010-14), only one case of invasive H influenzae type b disease was detected in a child younger than 5 years. Nasopharyngeal H influenzae type b carriage was detected in one (0·2%) of 623 children younger than 5 years between 2009 and 2012. In the 2009 serosurvey, 92 (79%; 95% CI 70-86) of 117 children aged 4-35 months had long-term protective antibody concentrations. INTERPRETATION: In this region of Kenya, use of a three-dose primary series of Hib vaccine without a booster dose has resulted in a significant and sustained reduction in invasive H influenzae type b disease. The prevalence of nasopharyngeal carriage is low and the profile of Hib antibodies suggests that protection wanes only after the age at greatest risk of disease. Although continued surveillance is important to determine whether effective control persists, these findings suggest that a booster dose is not currently required in Kenya. FUNDING: Gavi, the Vaccine Alliance, Wellcome Trust, European Society for Paediatric Infectious Diseases, and National Institute for Health Research.

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.

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.

Burton DC, Bigogo GM, Audi AO, Williamson J, Munge K, Wafula J, Ouma D, Khagayi S, Mugoya I, Mburu J et al. 2015. Risk of Injection-Site Abscess among Infants Receiving a Preservative-Free, Two-Dose Vial Formulation of Pneumococcal Conjugate Vaccine in Kenya. PLoS One, 10 (10), pp. e0141896. | Show Abstract | Read more

There is a theoretical risk of adverse events following immunization with a preservative-free, 2-dose vial formulation of 10-valent-pneumococcal conjugate vaccine (PCV10). We set out to measure this risk. Four population-based surveillance sites in Kenya (total annual birth cohort of 11,500 infants) were used to conduct a 2-year post-introduction vaccine safety study of PCV10. Injection-site abscesses occurring within 7 days following vaccine administration were clinically diagnosed in all study sites (passive facility-based surveillance) and, also, detected by caregiver-reported symptoms of swelling plus discharge in two sites (active household-based surveillance). Abscess risk was expressed as the number of abscesses per 100,000 injections and was compared for the second vs first vial dose of PCV10 and for PCV10 vs pentavalent vaccine (comparator). A total of 58,288 PCV10 injections were recorded, including 24,054 and 19,702 identified as first and second vial doses, respectively (14,532 unknown vial dose). The risk ratio for abscess following injection with the second (41 per 100,000) vs first (33 per 100,000) vial dose of PCV10 was 1.22 (95% confidence interval [CI] 0.37-4.06). The comparator vaccine was changed from a 2-dose to 10-dose presentation midway through the study. The matched odds ratios for abscess following PCV10 were 1.00 (95% CI 0.12-8.56) and 0.27 (95% CI 0.14-0.54) when compared to the 2-dose and 10-dose pentavalent vaccine presentations, respectively. In Kenya immunization with PCV10 was not associated with an increased risk of injection site abscess, providing confidence that the vaccine may be safely used in Africa. The relatively higher risk of abscess following the 10-dose presentation of pentavalent vaccine merits further study.

Feazel LM, Santorico SA, Robertson CE, Bashraheil M, Scott JAG, Frank DN, Hammitt LL. 2015. Effects of Vaccination with 10-Valent Pneumococcal Non-Typeable Haemophilus influenza Protein D Conjugate Vaccine (PHiD-CV) on the Nasopharyngeal Microbiome of Kenyan Toddlers. PLoS One, 10 (6), pp. e0128064. | Show Abstract | Read more

OBJECTIVE: Pneumococcal conjugate vaccines reduce the prevalence of vaccine serotypes carried in the nasopharynx. Because this could alter carriage of other potential pathogens, we assessed the nasopharyngeal microbiome of children who had been vaccinated with 10-valent pneumococcal non-typeable Haemophilus influenzae protein-D conjugate vaccine (PHiD-CV). METHODS: Profiles of the nasopharyngeal microbiota of 60 children aged 12-59 months, who had been randomized to receive 2 doses of PHiD-CV (n=30) or Hepatitis A vaccine (n=30) 60 days apart, were constructed by 16S rRNA gene pyrosequencing of swab specimens collected before vaccination and 180 days after dose 1. RESULTS: Prior to vaccination, Moraxella catarrhalis (median of 12.3% of sequences/subject), Streptococcus pneumoniae (4.4%) and Corynebacterium spp. (5.6%) were the most abundant nasopharyngeal bacterial species. Vaccination with PHiD-CV did not significantly alter the species composition, abundance, or prevalence of known pathogens. Distinct microbiomes were identified based on the abundances of Streptococcus, Moraxella, and Haemophilus species. These microbiomes shifted in composition over the study period and were independent of age, sex, school attendance, antibiotic exposure, and vaccination. CONCLUSIONS: Vaccination of children with two doses of PHiD-CV did not significantly alter the nasopharyngeal microbiome. This suggests limited replacement carriage with pathogens other than non-vaccine strains of S. pneumoniae. TRIAL REGISTRATION: clinicaltrials.gov NCT01028326.

Head MG, Fitchett JR, Newell M-L, Scott JAG, Harris JN, Clarke SC, Atun R. 2015. Mapping pneumonia research: A systematic analysis of UK investments and published outputs 1997-2013. EBioMedicine, 2 (9), pp. 1193-1199. | Show Abstract | Read more

BACKGROUND: The burden of pneumonia continues to be substantial, particularly among the poorest in global society. We describe here the trends for UK pneumonia R&D investment and published outputs, and correlate with 2013 global mortality. METHODS: Data related to awards to UK institutions for pneumonia research from 1997 to 2013 were systematically sourced and categorised by disease area and type of science. Investment was compared to mortality figures in 2010 and 2013 for pneumonia, tuberculosis and influenza. Investment was also compared to publication data. RESULTS: Of all infectious disease research between 2011 and 2013 (£917.0 million), £28.8 million (3.1%) was for pneumonia. This was an absolute and proportionate increase from previous time periods. Translational pneumonia research (33.3%) received increased funding compared with 1997-2010 where funding was almost entirely preclinical (87.5%, here 30.9%), but high-burden areas such as paediatrics, elderly care and antimicrobial resistance received little investment. Annual investment remains volatile; publication temporal trends show a consistent increase. When comparing investment to global burden with a novel 'investment by mortality observed' metric, tuberculosis (£48.36) and influenza (£484.21) receive relatively more funding than pneumonia (£43.08), despite investment for pneumonia greatly increasing in 2013 compared to 2010 (£7.39). Limitations include a lack of private sector data and the need for careful interpretation of the comparisons with burden, plus categorisation is subjective. CONCLUSIONS: There has been a welcome increase for pneumonia funding awarded to UK institutions in 2011-2013 compared with 1997-2010, along with increases for more translational research. Published outputs relating to pneumonia rose steadily from 1997 to 2013. Investment relative to mortality for pneumonia has increased, but it remains low compared to other respiratory infections and clear inequities remain. Analyses that measure investments in pneumonia can provide an insight into funding trends and research gaps. RESEARCH IN CONTEXT: Pneumonia continues to be a high-burden illness around the globe. This paper shows that although research funding is increasing in the UK (between 1997 and 2013), it remains poorly funded compared to other important respiratory infectious diseases such as tuberculosis and influenza. Publications about pneumonia have been steadily increasing over time, indicating continuing academic and clinical interest in the topic. Though global mortality of pneumonia is declining, it should still be an area of high priority for funders, policymakers and researchers.

Gilchrist JJ, Mills TC, Naranbhai V, Chapman SJ, Fairfax BP, Knight JC, Williams TN, Scott JAG, MacLennan CA, Rautanen A et al. 2015. Genetic variants associated with non-typhoidal Salmonella bacteraemia in African children. Lancet, 385 Suppl 1 pp. S13. | Show Abstract | Read more

BACKGROUND: Non-typhoidal Salmonella (NTS) causes invasive and frequently fatal disease in African children. Existing strategies to prevent, diagnose, and treat NTS disease are inadequate. An improved understanding of the biology of invasive Salmonella infection will facilitate the development of novel NTS control measures. Despite evidence in mice and man showing a clear role for host genetics in NTS susceptibility, there are no published studies investigating host genetic susceptibility to NTS in African populations. METHODS: We conducted a genome-wide association study (SNP Array 6.0, Affymetrix, CA, USA) of NTS bacteraemia in Kenyan children, with replication in Malawian children. We assessed the function of NTS-associated variants in an expression quantitative trait locus (eQTL) dataset of interferon γ (IFNγ) and lipopolysaccharide-stimulated monocytes from 432 healthy European adults. Serum IFNγ (Bio-Plex immunoassay, Bio-Rad Laboratories, CA, USA) in Malawian NTS cases (n=106) during acute disease was correlated with genotype by linear regression. FINDINGS: After whole-genome imputation and quality control, 180 Kenyan cases and 2677 controls were included in an association analysis at 7 951 614 (additive model) and 4 669 537 (genotypic model) loci. After quality control, 143 Malawian cases and 336 controls were included in the replication analysis. An intronic variant in STAT4 was associated (recessive model) with NTS in both Kenyan and Malawian children (Kenya p=5·6 × 10(-9), Malawi p=0·02, combined p=1·4 × 10(-9); odds ratio 7·2, 95% CI 3·8-13·5). The NTS-associated variant was an eQTL for STAT4 expression in IFNγ-stimulated monocytes (p=9·59 × 10(-6)), the NTS risk allele being associated with lower STAT4 expression. In Malawian children with NTS bacteraemia, the same NTS risk allele was associated with lower serum concentrations of IFNγ (p=0·02) at presentation. INTERPRETATION: STAT4 is highly plausible as a susceptibility locus for invasive NTS disease. STAT4 mediates IFNγ release in T cells and natural killer cells in response to interleukin 12 (IL12). Individuals with rare mutations elsewhere in the IL12-IFNγ axis are at risk of disseminated NTS infection. We provide the first evidence, to our knowledge, of a host genetic determinant of NTS disease in African children, and of a STAT4 variant conferring susceptibility to an infectious disease in man. FUNDING: Wellcome Trust.

Muema DM, Nduati EW, Uyoga M, Bashraheil M, Scott JAG, Hammitt LL, Urban BC. 2015. 10-valent pneumococcal non-typeable Haemophilus influenzae protein-D conjugate vaccine (PHiD-CV) induces memory B cell responses in healthy Kenyan toddlers. Clin Exp Immunol, 181 (2), pp. 297-305. | Show Abstract | Read more

Memory B cells are long-lived and could contribute to persistence of humoral immunity by maintaining the plasma-cell pool or making recall responses upon re-exposure to an antigen. We determined the ability of a pneumococcal conjugate vaccine to induce anti-pneumococcal memory B cells. Frequencies of memory B cells against pneumococcal capsular polysaccharides from serotypes 1, 6B, 14, 19F and 23F were determined by cultured B cell enzyme-linked immunospot (ELISPOT) in 35 children aged 12-23 months who received pneumococcal non-typeable Haemophilus influenzae protein-D conjugate vaccine (PHiD-CV). The relationships between plasma antibodies and memory B cell frequencies were also assessed. After two doses of PHiD-CV, the proportion of subjects with detectable memory B cells against pneumococcal capsular polysaccharides increased significantly for serotypes 1 (3-45%; P < 0·01), 19F (21-66%; P < 0·01) and 23F (13-36%; P = 0·02), but not serotypes 6B (24-42%; P = 0·24) and 14 (21-40%; P = 0·06). Correlations between antibodies and memory B cells were weak. Carriage of serotype 19F at enrolment was associated with poor memory B cell responses against this serotype at subsequent time-points (day 30: non-carriers, 82% versus carriers, 0%, P < 0·01; day 210: non-carriers, 72% versus carriers, 33%, P = 0·07). PHiD-CV is capable of inducing memory B cells against some of the component pneumococcal capsular polysaccharides.

Nyiro JU, Sande C, Mutunga M, Kiyuka PK, Munywoki PK, Scott JAG, Nokes DJ. 2015. Quantifying maternally derived respiratory syncytial virus specific neutralising antibodies in a birth cohort from coastal Kenya. Vaccine, 33 (15), pp. 1797-1801. | Show Abstract | Read more

BACKGROUND: Severe respiratory syncytial virus (RSV) disease occurs predominantly in children under 6 months of age. There is no licensed RSV vaccine. Protection of young infants could be achieved by a maternal vaccine to boost titres of passively transferred protective antibodies. Data on the level and kinetics of functional RSV-specific antibody at birth and over the early infant period would inform vaccine product design. METHODS: From a birth cohort study (2002-2007) in Kilifi, Kenya, 100 participants were randomly selected for whom cord blood and 2 subsequent 3-monthly blood samples within the first year of life, were available. RSV antibodies against the A2 strain of RSV were assayed and recorded as the logarithm (base 2) plaque reduction neutralisation test (PRNT) titre. Analysis by linear regression accounted for within-person clustering. RESULTS: The geometric mean neutralisation antibody titre was 10.6 (SD: 1.13) at birth with a log-linear decay over the first 6 months of life. The estimated rate of decay was -0.58 (SD: 0.20) log2PRNT titre per month and a half-life of 36 days. There was no significant interaction between cord titre and rate of decay with age. Mean cord titres rose and fell in a pattern temporally tracking community virus transmission. CONCLUSIONS: In this study population, RSV neutralising antibody titres decay approximately two-fold every one month. The rate of decay varies widely by individual but is not related to titre at birth. RSV specific cord titres vary seasonally, presumably due to maternal boosting.

Nyiro JU, Sande C, Mutunga M, Kiyuka PK, Munywoki PK, Scott JAG, Nokes DJ. 2015. Quantifying maternally derived respiratory syncytial virus specific neutralising antibodies in a birth cohort from coastal Kenya Vaccine, 33 (15), pp. 1797-1801. | Show Abstract | Read more

Background: Severe respiratory syncytial virus (RSV) disease occurs predominantly in children under 6 months of age. There is no licensed RSV vaccine. Protection of young infants could be achieved by a maternal vaccine to boost titres of passively transferred protective antibodies. Data on the level and kinetics of functional RSV-specific antibody at birth and over the early infant period would inform vaccine product design. Methods: From a birth cohort study (2002-2007) in Kilifi, Kenya, 100 participants were randomly selected for whom cord blood and 2 subsequent 3-monthly blood samples within the first year of life, were available. RSV antibodies against the A2 strain of RSV were assayed and recorded as the logarithm (base 2) plaque reduction neutralisation test (PRNT) titre. Analysis by linear regression accounted for within-person clustering. Results: The geometric mean neutralisation antibody titre was 10.6 (SD: 1.13) at birth with a log-linear decay over the first 6 months of life. The estimated rate of decay was -0.58 (SD: 0.20) log2PRNT titre per month and a half-life of 36 days. There was no significant interaction between cord titre and rate of decay with age. Mean cord titres rose and fell in a pattern temporally tracking community virus transmission. Conclusions: In this study population, RSV neutralising antibody titres decay approximately two-fold every one month. The rate of decay varies widely by individual but is not related to titre at birth. RSV specific cord titres vary seasonally, presumably due to maternal boosting.

Anderson ST, Kaforou M, Brent AJ, Wright VJ, Banwell CM, Chagaluka G, Crampin AC, Dockrell HM, French N, Hamilton MS et al. 2014. Diagnosis of childhood tuberculosis and host RNA expression in Africa. N Engl J Med, 370 (18), pp. 1712-1723. | Show Abstract | Read more

BACKGROUND: Improved diagnostic tests for tuberculosis in children are needed. We hypothesized that transcriptional signatures of host blood could be used to distinguish tuberculosis from other diseases in African children who either were or were not infected with the human immunodeficiency virus (HIV). METHODS: The study population comprised prospective cohorts of children who were undergoing evaluation for suspected tuberculosis in South Africa (655 children), Malawi (701 children), and Kenya (1599 children). Patients were assigned to groups according to whether the diagnosis was culture-confirmed tuberculosis, culture-negative tuberculosis, diseases other than tuberculosis, or latent tuberculosis infection. Diagnostic signatures distinguishing tuberculosis from other diseases and from latent tuberculosis infection were identified from genomewide analysis of RNA expression in host blood. RESULTS: We identified a 51-transcript signature distinguishing tuberculosis from other diseases in the South African and Malawian children (the discovery cohort). In the Kenyan children (the validation cohort), a risk score based on the signature for tuberculosis and for diseases other than tuberculosis showed a sensitivity of 82.9% (95% confidence interval [CI], 68.6 to 94.3) and a specificity of 83.6% (95% CI, 74.6 to 92.7) for the diagnosis of culture-confirmed tuberculosis. Among patients with cultures negative for Mycobacterium tuberculosis who were treated for tuberculosis (those with highly probable, probable, or possible cases of tuberculosis), the estimated sensitivity was 62.5 to 82.3%, 42.1 to 80.8%, and 35.3 to 79.6%, respectively, for different estimates of actual tuberculosis in the groups. In comparison, the sensitivity of the Xpert MTB/RIF assay for molecular detection of M. tuberculosis DNA in cases of culture-confirmed tuberculosis was 54.3% (95% CI, 37.1 to 68.6), and the sensitivity in highly probable, probable, or possible cases was an estimated 25.0 to 35.7%, 5.3 to 13.3%, and 0%, respectively; the specificity of the assay was 100%. CONCLUSIONS: RNA expression signatures provided data that helped distinguish tuberculosis from other diseases in African children with and those without HIV infection. (Funded by the European Union Action for Diseases of Poverty Program and others).

Etyang AO, Munge K, Bunyasi EW, Matata L, Ndila C, Kapesa S, Owiti M, Khandwalla I, Brent AJ, Tsofa B et al. 2014. Burden of disease in adults admitted to hospital in a rural region of coastal Kenya: an analysis of data from linked clinical and demographic surveillance systems. Lancet Glob Health, 2 (4), pp. e216-e224. | Show Abstract | Read more

BACKGROUND: Estimates of the burden of disease in adults in sub-Saharan Africa largely rely on models of sparse data. We aimed to measure the burden of disease in adults living in a rural area of coastal Kenya with use of linked clinical and demographic surveillance data. METHODS: We used data from 18,712 adults admitted to Kilifi District Hospital (Kilifi, Kenya) between Jan 1, 2007, and Dec 31, 2012, linked to 790,635 person-years of observation within the Kilifi Health and Demographic Surveillance System, to establish the rates and major causes of admission to hospital. These data were also used to model disease-specific disability-adjusted life-years lost in the population. We used geographical mapping software to calculate admission rates stratified by distance from the hospital. FINDINGS: The main causes of admission to hospital in women living within 5 km of the hospital were infectious and parasitic diseases (303 per 100,000 person-years of observation), pregnancy-related disorders (239 per 100,000 person-years of observation), and circulatory illnesses (105 per 100,000 person-years of observation). Leading causes of hospital admission in men living within 5 km of the hospital were infectious and parasitic diseases (169 per 100,000 person-years of observation), injuries (135 per 100,000 person-years of observation), and digestive system disorders (112 per 100,000 person-years of observation). HIV-related diseases were the leading cause of disability-adjusted life-years lost (2050 per 100,000 person-years of observation), followed by non-communicable diseases (741 per 100,000 person-years of observation). For every 5 km increase in distance from the hospital, all-cause admission rates decreased by 11% (95% CI 7–14) in men and 20% (17–23) in women. The magnitude of this decline was highest for endocrine disorders in women (35%; 95% CI 22–46) and neoplasms in men (30%; 9–45). INTERPRETATION: Adults in rural Kenya face a combined burden of infectious diseases, pregnancy-related disorders, cardiovascular illnesses, and injuries. Disease burden estimates based on hospital data are affected by distance from the hospital, and the amount of underestimation of disease burden differs by both disease and sex. FUNDING: The Wellcome Trust, GAVI Alliance.

Hammitt LL, Ojal J, Bashraheil M, Morpeth SC, Karani A, Habib A, Borys D, Goldblatt D, Scott JAG. 2014. Immunogenicity, impact on carriage and reactogenicity of 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine in Kenyan children aged 1-4 years: a randomized controlled trial. PLoS One, 9 (1), pp. e85459. | Show Abstract | Read more

BACKGROUND: The impact on carriage and optimal schedule for primary vaccination of older children with 10-valent pneumococcal non-typeable Haemophilus influenzae protein-D conjugate vaccine (PHiD-CV) are unknown. METHODS: 600 Kenyan children aged 12-59 months were vaccinated at days 0, 60 and 180 in a double-blind randomized controlled trial according to the following vaccine sequence: Group A: PHiD-CV, PHiD-CV, diphtheria/tetanus/acellular pertussis vaccine (DTaP); Group B: PHiD-CV, DTaP, PHiD-CV; Group C: hepatitis A vaccine (HAV), DTaP, HAV. Nasopharyngeal carriage of Streptococcus pneumoniae was measured at five timepoints. In 375 subjects, serotype-specific responses were measured by 22F-inhibition ELISA and opsonophagocytic killing assays (OPA) one month after vaccination. RESULTS: Following one dose of PHiD-CV, >90% of recipients developed IgG≥0.35 µg/mL to serotypes 1, 4, 5, 7F, 9V and 18C and OPA≥8 to serotypes 4, 7F, 9V, 18C, 23F. After a second dose >90% of recipients had IgG≥0.35 µg/mL to all vaccine serotypes and OPA≥8 to all vaccine serotypes except 1 and 6B. At day 180, carriage of vaccine-type pneumococci was 21% in recipients of two doses of PHiD-CV (Group A) compared to 31% in controls (p = 0.04). Fever after dose 1 was reported by 41% of PHiD-CV recipients compared to 26% of HAV recipients (p<0.001). Other local and systemic adverse experiences were similar between groups. CONCLUSIONS: Vaccination of children aged 12-59 months with two doses of PHiD-CV two to six months apart was immunogenic, reduced vaccine-type pneumococcal carriage and was well-tolerated. Administration of PHiD-CV would be expected to provide effective protection against vaccine-type disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT01028326.

Morpeth SC, Huggett JF, Murdoch DR, Scott JAG. 2014. Making standards for quantitative real-time pneumococcal PCR Biomolecular Detection and Quantification, 2 (C), pp. 1-3. | Show Abstract | Read more

© 2014 The Authors. Quantitative lytA PCR is often performed using in-house standards. We hypothesised equivalence when measuring a standard suspension of Streptococcus pneumoniae by colony-forming-units (CFU) or genome-copies. Median (IQR) ratio of CFU/genome-copies was 0.19 (0.1-1.2). Genome-copies were less variable than CFU, but the discrepancy between the methods highlights challenges with absolute quantification.

Aiken AM, Mutuku IM, Sabat AJ, Akkerboom V, Mwangi J, Scott JAG, Morpeth SC, Friedrich AW, Grundmann H. 2014. Carriage of Staphylococcus aureus in Thika Level 5 Hospital, Kenya: a cross-sectional study. Antimicrob Resist Infect Control, 3 (1), pp. 22. | Show Abstract | Read more

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is an important nosocomial pathogen but little is known about its circulation in hospitals in developing countries. We aimed to describe carriage of S.aureus amongst inpatients in a mid-sized Kenyan government hospital. METHODS: We determined the frequency of S.aureus and MRSA carriage amongst inpatients in Thika Hospital, Kenya by means of repeated cross-sectional ward surveys. For all S.aureus isolates, we performed antibiotic susceptibility tests, genomic profiling using a DNA microarray and spa typing and MLST. RESULTS: In this typical mid-sized Kenyan Government hospital, we performed 950 screens for current carriage of S.aureus amongst inpatients over a four month period. We detected S.aureus carriage (either MSSA or MRSA) in 8.9% (85/950; 95%CI 7.1-10.8) of inpatient screens, but patients with multiple screens were more likely have detection of carriage. MRSA carriage was rare amongst S.aureus strains carried by hospital inpatients - only 7.0% (6/86; 95%CI 1.5-12.5%) of all isolates were MRSA. Most MRSA (5/6) were obtained from burns patients with prolonged admissions, who only represented a small proportion of the inpatient population. All MRSA strains were of the same clone (MLST ST239; spa type t037) with concurrent resistance to multiple antibiotic classes. MSSA isolates were diverse and rarely expressed antibiotic resistance except against benzyl-penicillin and co-trimoxazole. CONCLUSIONS: Although carriage rates for S.aureus and the MRSA prevalence in this Kenyan hospital were both low, burns patient were identified as a high risk group for carriage. The high frequency of genetically indistinguishable isolates suggests that there was local transmission of both MRSA and MSSA.

Feikin DR, Scott JAG, Gessner BD. 2014. Use of vaccines as probes to define disease burden. Lancet, 383 (9930), pp. 1762-1770. | Show Abstract | Read more

Vaccine probe studies have emerged in the past 15 years as a useful way to characterise disease. By contrast, traditional studies of vaccines focus on defining the vaccine effectiveness or efficacy. The underlying basis for the vaccine probe approach is that the difference in disease burden between vaccinated and unvaccinated individuals can be ascribed to the vaccine-specific pathogen. Vaccine probe studies can increase understanding of a vaccine's public health value. For instance, even when a vaccine has a seemingly low efficacy, a high baseline disease incidence can lead to a large vaccine-preventable disease burden and thus that population-based vaccine introduction would be justified. So far, vaccines have been used as probes to characterise disease syndromes caused by Haemophilus influenzae type b, pneumococcus, rotavirus, and early infant influenza. However, vaccine probe studies have enormous potential and could be used more widely in epidemiology, for example, to define the vaccine-preventable burden of malaria, typhoid, paediatric influenza, and dengue, and to identify causal interactions between different pathogens.

Hammitt LL, Akech DO, Morpeth SC, Karani A, Kihuha N, Nyongesa S, Bwanaali T, Mumbo E, Kamau T, Sharif SK, Scott JAG. 2014. Population effect of 10-valent pneumococcal conjugate vaccine on nasopharyngeal carriage of Streptococcus pneumoniae and non-typeable Haemophilus influenzae in Kilifi, Kenya: findings from cross-sectional carriage studies. Lancet Glob Health, 2 (7), pp. e397-e405. | Show Abstract | Read more

BACKGROUND: The effect of 7-valent pneumococcal conjugate vaccine (PCV) in developed countries was enhanced by indirect protection of unvaccinated individuals, mediated by reduced nasopharyngeal carriage of vaccine-serotype pneumococci. The potential indirect protection of 10-valent PCV (PCV10) in a developing country setting is unknown. We sought to estimate the effectiveness of introduction of PCV10 in Kenya against carriage of vaccine serotypes and its effect on other bacteria. METHODS: PCV10 was introduced into the infant vaccination programme in Kenya in January, 2011, accompanied by a catch-up campaign in Kilifi County for children aged younger than 5 years. We did annual cross-sectional carriage studies among an age-stratified, random population sample in the 2 years before and 2 years after PCV10 introduction. A nasopharyngeal rayon swab specimen was collected from each participant and was processed in accordance with WHO recommendations. Prevalence ratios of carriage before and after introduction of PCV10 were calculated by log-binomial regression. FINDINGS: About 500 individuals were enrolled each year (total n=2031). Among children younger than 5 years, the baseline (2009-10) carriage prevalence was 34% for vaccine-serotype Streptococcus pneumoniae, 41% for non-vaccine-serotype Streptococcus pneumoniae, and 54% for non-typeable Haemophilus influenzae. After PCV10 introduction (2011-12), these percentages were 13%, 57%, and 40%, respectively. Adjusted prevalence ratios were 0·36 (95% CI 0·26-0·51), 1·37 (1·13-1·65), and 0·62 (0·52-0·75), respectively. Among individuals aged 5 years or older, the adjusted prevalence ratios for vaccine-serotype and non-vaccine-serotype S pneumoniae carriage were 0·34 (95% CI 0·18-0·62) and 1·13 (0·92-1·38), respectively. There was no change in prevalence ratio for Staphylococcus aureus (adjusted prevalence ratio for those <5 years old 1·02, 95% CI 0·52-1·99, and for those ≥5 years old 0·90, 0·60-1·35). INTERPRETATION: After programmatic use of PCV10 in Kilifi, carriage of vaccine serotypes was reduced by two-thirds both in children younger than 5 years and in older individuals. These findings suggest that PCV10 introduction in Africa will have substantial indirect effects on invasive pneumococcal disease. FUNDING: GAVI Alliance and Wellcome Trust.

Cited:

57

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Hammitt LL, Akech DO, Morpeth SC, Karani A, Kihuha N, Nyongesa S, Bwanaali T, Mumbo E, Kamau T, Sharif SK, Scott JAG. 2014. Population effect of 10-valent pneumococcal conjugate vaccine on nasopharyngeal carriage of Streptococcus pneumoniae and non-typeable Haemophilus influenzae in Kilifi, Kenya: Findings from cross-sectional carriage studies The Lancet Global Health, 2 (7), pp. e397-e405. | Show Abstract | Read more

© 2014 Hammitt et al. Open Access article distributed under the terms of CC BY. Background: The effect of 7-valent pneumococcal conjugate vaccine (PCV) in developed countries was enhanced by indirect protection of unvaccinated individuals, mediated by reduced nasopharyngeal carriage of vaccine-serotype pneumococci. The potential indirect protection of 10-valent PCV (PCV10) in a developing country setting is unknown. We sought to estimate the effectiveness of introduction of PCV10 in Kenya against carriage of vaccine serotypes and its effect on other bacteria. Methods: PCV10 was introduced into the infant vaccination programme in Kenya in January, 2011, accompanied by a catch-up campaign in Kilifi County for children aged younger than 5 years. We did annual cross-sectional carriage studies among an age-stratified, random population sample in the 2 years before and 2 years after PCV10 introduction. A nasopharyngeal rayon swab specimen was collected from each participant and was processed in accordance with WHO recommendations. Prevalence ratios of carriage before and after introduction of PCV10 were calculated by log-binomial regression. Findings: About 500 individuals were enrolled each year (total n=2031). Among children younger than 5 years, the baseline (2009-10) carriage prevalence was 34% for vaccine-serotype Streptococcus pneumoniae, 41% for non-vaccine-serotype Streptococcus pneumoniae, and 54% for non-typeable Haemophilus influenzae. After PCV10 introduction (2011-12), these percentages were 13%, 57%, and 40%, respectively. Adjusted prevalence ratios were 0·36 (95% CI 0·26-0·51), 1·37 (1·13-1·65), and 0·62 (0·52-0·75), respectively. Among individuals aged 5 years or older, the adjusted prevalence ratios for vaccine-serotype and non-vaccine-serotype S pneumoniae carriage were 0·34 (95% CI 0·18-0·62) and 1·13 (0·92-1·38), respectively. There was no change in prevalence ratio for Staphylococcus aureus (adjusted prevalence ratio for those < 5 years old 1·02, 95% CI 0·52-1·99, and for those ≥5 years old 0·90, 0·60-1·35). Interpretation: After programmatic use of PCV10 in Kilifi, carriage of vaccine serotypes was reduced by two-thirds both in children younger than 5 years and in older individuals. These findings suggest that PCV10 introduction in Africa will have substantial indirect effects on invasive pneumococcal disease. Funding: GAVI Alliance and Wellcome Trust.

Aiken AM, Allegranzi B, Scott JA, Mehtar S, Pittet D, Grundmann H. 2014. Antibiotic resistance needs global solutions. Lancet Infect Dis, 14 (7), pp. 550-551. | Read more

Satzke C, Turner P, Virolainen-Julkunen A, Adrian PV, Antonio M, Hare KM, Henao-Restrepo AM, Leach AJ, Klugman KP, Porter BD et al. 2013. Standard method for detecting upper respiratory carriage of Streptococcus pneumoniae: updated recommendations from the World Health Organization Pneumococcal Carriage Working Group. Vaccine, 32 (1), pp. 165-179. | Show Abstract | Read more

In 2003 the World Health Organization (WHO) convened a working group and published a set of standard methods for studies measuring nasopharyngeal carriage of Streptococcus pneumoniae (the pneumococcus). The working group recently reconvened under the auspices of the WHO and updated the consensus standard methods. These methods describe the collection, transport and storage of nasopharyngeal samples, as well as provide recommendations for the identification and serotyping of pneumococci using culture and non-culture based approaches. We outline the consensus position of the working group, the evidence supporting this position, areas worthy of future research, and the epidemiological role of carriage studies. Adherence to these methods will reduce variability in the conduct of pneumococcal carriage studies undertaken in the context of pneumococcal vaccine trials, implementation studies, and epidemiology studies more generally so variability in methodology does not confound the interpretation of study findings.

Brueggemann AB, Muroki BM, Kulohoma BW, Karani A, Wanjiru E, Morpeth S, Kamau T, Sharif S, Scott JAG. 2013. Population genetic structure of Streptococcus pneumoniae in Kilifi, Kenya, prior to the introduction of pneumococcal conjugate vaccine PLoS ONE, 8 (11), | Show Abstract | Read more

Background: The 10-valent pneumococcal conjugate vaccine (PCV10) was introduced in Kenya in 2011. Introduction of any PCV will perturb the existing pneumococcal population structure, thus the aim was to genotype pneumococci collected in Kilifi before PCV10. Methods and Findings: Using multilocus sequence typing (MLST), we genotyped > 1100 invasive and carriage pneumococci from children, the largest collection genotyped from a single resource-poor country and reported to date. Serotype 1 was the most common serotype causing invasive disease and was rarely detected in carriage; all serotype 1 isolates were members of clonal complex (CC) 217. There were temporal fluctuations in the major circulating sequence types (STs); and although 1-3 major serotype 1, 14 or 23F STs co-circulated annually, the two major serotype 5 STs mainly circulated independently. Major STs/CCs also included isolates of serotypes 3, 12F, 18C and 19A and each shared ≤2 MLST alleles with STs that circulate widely elsewhere. Major CCs associated with non-PCV10 serotypes were predominantly represented by carriage isolates, although serotype 19A and 12F CCs were largely invasive and a serotype 10A CC was equally represented by invasive and carriage isolates. Conclusions: Understanding the pre-PCV10 population genetic structure in Kilifi will allow for the detection of changes in prevalence of the circulating genotypes and evidence for capsular switching post-vaccine implementation. © 2013 Brueggemann et al.

Aiken AM, Wanyoro AK, Mwangi J, Juma F, Mugoya IK, Scott JAG. 2013. Changing use of surgical antibiotic prophylaxis in Thika Hospital, Kenya: a quality improvement intervention with an interrupted time series design. PLoS One, 8 (11), pp. e78942. | Show Abstract | Read more

INTRODUCTION: In low-income countries, Surgical Site Infection (SSI) is a common form of hospital-acquired infection. Antibiotic prophylaxis is an effective method of preventing these infections, if given immediately before the start of surgery. Although several studies in Africa have compared pre-operative versus post-operative prophylaxis, there are no studies describing the implementation of policies to improve prescribing of surgical antibiotic prophylaxis in African hospitals. METHODS: We conducted SSI surveillance at a typical Government hospital in Kenya over a 16 month period between August 2010 and December 2011, using standard definitions of SSI and the extent of contamination of surgical wounds. As an intervention, we developed a hospital policy that advised pre-operative antibiotic prophylaxis and discouraged extended post-operative antibiotics use. We measured process, outcome and balancing effects of this intervention in using an interrupted time series design. RESULTS: From a starting point of near-exclusive post-operative antibiotic use, after policy introduction in February 2011 there was rapid adoption of the use of pre-operative antibiotic prophylaxis (60% of operations at 1 week; 98% at 6 weeks) and a substantial decrease in the use of post-operative antibiotics (40% of operations at 1 week; 10% at 6 weeks) in Clean and Clean-Contaminated surgery. There was no immediate step-change in risk of SSI, but overall, there appeared to be a moderate reduction in the risk of superficial SSI across all levels of wound contamination. There were marked reductions in the costs associated with antibiotic use, the number of intravenous injections performed and nursing time spent administering these. CONCLUSION: Implementation of a locally developed policy regarding surgical antibiotic prophylaxis is an achievable quality improvement target for hospitals in low-income countries, and can lead to substantial benefits for individual patients and the institution.

Ngugi AK, Bottomley C, Scott JAG, Mung'Ala-Odera V, Bauni E, Sander JW, Kleinschmidt I, Newton CR. 2013. Incidence of convulsive epilepsy in a rural area in Kenya Epilepsia, 54 (8), pp. 1352-1359. | Show Abstract | Read more

Purpose There are only a few studies of incidence of epilepsy in low and middle income countries (LMICs). These are often small and conducted in specific age groups or areas where the prevalence of risk factors is high; therefore, these studies are not representative of the wider populations. We determined the incidence of convulsive epilepsy (CE) in a large rural population in Kenya. Methods We conducted two cross-sectional surveys 5 years apart within a health and demographic surveillance system. Initially we identified residents without epilepsy who were then reexamined in the follow-up survey to determine incidence. We estimated the overall incidence of CE and incidence by age-group, sex, and by administrative location. Estimates were adjusted for attrition during case identification and for the sensitivity of the screening method. Key Findings In a cohort of 151,408 people, 194 developed CE over the 5 years. The minimum crude incidence rate was 37.6/100,000 persons per year (95% confidence interval (CI) 32.7-43.3) and adjusted for loss to follow-up, and the sensitivity of the survey methodology was 77.0/100,000 persons per year (95% CI 67.7-87.4). Incidence was highest in children 6-12 years (96.1/100,000 persons per year; 95% CI 78.4-117.9), and was lowest in the 29-49 year age group (37.4/100,000 persons per year; 95% CI 25.7-54.7). Significance We estimated a high incidence of convulsive epilepsy in this population. Incidence was highest early and late in life, suggesting that preventive interventions should target exposures that occur in these age groups. Incidence of focal epilepsy was more than twice that of generalized epilepsy, suggesting that etiologies that are amenable to intervention were most important in this population. It is likely that incidence is underestimated because of the early mortality of incident cases. © 2013 The Authors. Epilepsia published by Wiley Periodicals, Inc.

Ayieko P, Griffiths UK, Ndiritu M, Moisi J, Mugoya IK, Kamau T, English M, Scott JAG. 2013. Assessment of health benefits and cost-effectiveness of 10-valent and 13-valent pneumococcal conjugate vaccination in Kenyan children. PLoS One, 8 (6), pp. e67324. | Show Abstract | Read more

BACKGROUND: The GAVI Alliance supported 10-valent pneumococcal conjugate vaccine (PCV10) introduction in Kenya. We estimated the cost-effectiveness of introducing either PCV10 or the 13-valent vaccine (PCV13) from a societal perspective and explored the incremental impact of including indirect vaccine effects. METHODS: The costs and effects of pneumococcal vaccination among infants born in Kenya in 2010 were assessed using a decision analytic model comparing PCV10 or PCV13, in turn, with no vaccination. Direct vaccine effects were estimated as a reduction in the incidence of pneumococcal meningitis, sepsis, bacteraemic pneumonia and non-bacteraemic pneumonia. Pneumococcal disease incidence was extrapolated from a population-based hospital surveillance system in Kilifi and adjustments were made for variable access to care across Kenya. We used vaccine efficacy estimates from a trial in The Gambia and accounted for serotype distribution in Kilifi. We estimated indirect vaccine protection and serotype replacement by extrapolating from the USA. Multivariable sensitivity analysis was conducted using Monte Carlo simulation. We assumed a vaccine price of US$ 3.50 per dose. FINDINGS: The annual cost of delivering PCV10 was approximately US$14 million. We projected a 42.7% reduction in pneumococcal disease episodes leading to a US$1.97 million reduction in treatment costs and a 6.1% reduction in childhood mortality annually. In the base case analysis, costs per discounted DALY and per death averted by PCV10, amounted to US$ 59 (95% CI 26-103) and US$ 1,958 (95% CI 866-3,425), respectively. PCV13 introduction improved the cost-effectiveness ratios by approximately 20% and inclusion of indirect effects improved cost-effectiveness ratios by 43-56%. The break-even prices for introduction of PCV10 and PCV13 are US$ 0.41 and 0.51, respectively. CONCLUSIONS: Introducing either PCV10 or PCV13 in Kenya is highly cost-effective from a societal perspective. Indirect effects, if they occur, would significantly improve the cost-effectiveness.

Kimaro Mlacha SZ, Romero-Steiner S, Hotopp JCD, Kumar N, Ishmael N, Riley DR, Farooq U, Creasy TH, Tallon LJ, Liu X et al. 2013. Phenotypic, genomic, and transcriptional characterization of Streptococcus pneumoniae interacting with human pharyngeal cells. BMC Genomics, 14 (1), pp. 383. | Show Abstract | Read more

BACKGROUND: Streptococcus pneumoniae is a leading cause of childhood morbidity and mortality worldwide, despite the availability of effective pneumococcal vaccines. Understanding the molecular interactions between the bacterium and the host will contribute to the control and prevention of pneumococcal disease. RESULTS: We used a combination of adherence assays, mutagenesis and functional genomics to identify novel factors involved in adherence. By contrasting these processes in two pneumococcal strains, TIGR4 and G54, we showed that adherence and invasion capacities vary markedly by strain. Electron microscopy showed more adherent bacteria in association with membranous pseudopodia in the TIGR4 strain. Operons for cell wall phosphorylcholine incorporation (lic), manganese transport (psa) and phosphate utilization (phn) were up-regulated in both strains on exposure to epithelial cells. Pneumolysin, pili, stress protection genes (adhC-czcD) and genes of the type II fatty acid synthesis pathway were highly expressed in the naturally more invasive strain, TIGR4. Deletion mutagenesis of five gene regions identified as regulated in this study revealed attenuation in adherence. Most strikingly, ∆SP_1922 which was predicted to contain a B-cell epitope and revealed significant attenuation in adherence, appeared to be expressed as a part of an operon that includes the gene encoding the cytoplasmic pore-forming toxin and vaccine candidate, pneumolysin. CONCLUSION: This work identifies a list of novel potential pneumococcal adherence determinants.

Kimaro Mlacha SZ, Peret TCT, Kumar N, Romero-Steiner S, Dunning Hotopp JC, Ishmael N, Grinblat-Huse V, Riley DR, Erdman DD, Carlone GM et al. 2013. Transcriptional adaptation of pneumococci and human pharyngeal cells in the presence of a virus infection. BMC Genomics, 14 (1), pp. 378. | Show Abstract | Read more

BACKGROUND: Viral upper respiratory tract infections are associated with increased colonization by Streptococcus pneumoniae but the mechanisms underlying this relationship are unclear. The objective of this study is to describe a comprehensive picture of the cellular interaction between the adhering bacteria and host cells in the presence or absence of a viral co-infection. RESULTS: Gene expression profiles of Detroit-562 pharyngeal cells, which were either mock-infected or infected with human respiratory syncytial virus (RSV) or human parainfluenza virus 3 (HPIV3), were analyzed using human microarrays. Transcription response of S. pneumoniae strain TIGR4 (serotype 4) in the presence of either mock- or viral-infected cells was analyzed by pneumococcal microarray. Significantly regulated genes were identified by both significance analysis of microarray (SAM) and a ≥ 2-fold change ratio cut-off. The adherence of S. pneumoniae to human pharyngeal cells was significantly augmented in the presence of RSV or HPIV3 infection. Global gene expression profiling of the host cells during infection with RSV or HPIV3 revealed increased transcription of carcinoembryonic antigen-related cell adhesion molecules (CEACAM1), CD47, fibronectin, interferon-stimulated genes and many other host cell adhesion molecules. Pneumococci increased transcription of several genes involved in adhesive functions (psaA, pilus islet), choline uptake and incorporation (lic operon), as well as transport and binding. CONCLUSIONS: We have identified a core transcriptome that represents the basic machinery required for adherence of pneumococci to D562 cells infected or not infected with a virus. These bacterial genes and cell adhesion molecules can potentially be used to control pneumococcal adherence occurring secondary to a viral infection.

Cited:

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Nair H, Simões EAF, Rudan I, Gessner BD, Azziz-Baumgartner E, Zhang JSF, Feikin DR, MacKenzie GA, Moïsi JC, Roca A et al. 2013. Global and regional burden of hospital admissions for severe acute lower respiratory infections in young children in 2010: A systematic analysis The Lancet, 381 (9875), pp. 1380-1390. | Show Abstract | Read more

Background The annual number of hospital admissions and in-hospital deaths due to severe acute lower respiratory infections (ALRI) in young children worldwide is unknown. We aimed to estimate the incidence of admissions and deaths for such infections in children younger than 5 years in 2010. Methods We estimated the incidence of admissions for severe and very severe ALRI in children younger than 5 years, stratifi ed by age and region, with data from a systematic review of studies published between Jan 1, 1990, and March 31, 2012, and from 28 unpublished population-based studies. We applied these incidence estimates to population estimates for 2010, to calculate the global and regional burden in children admitted with severe ALRI in that year. We estimated in-hospital mortality due to severe and very severe ALRI by combining incidence estimates with case fatality ratios from hospital-based studies. Findings We identifi ed 89 eligible studies and estimated that in 2010, 11•9 million (95% CI 10•3-13•9 million) episodes of severe and 3•0 million (2•1-4•2 million) episodes of very severe ALRI resulted in hospital admissions in young children worldwide. Incidence was higher in boys than in girls, the sex disparity being greatest in South Asian studies. On the basis of data from 37 hospital studies reporting case fatality ratios for severe ALRI, we estimated that roughly 265 000 (95% CI 160 000-450 000) in-hospital deaths took place in young children, with 99% of these deaths in developing countries. Therefore, the data suggest that although 62% of children with severe ALRI are treated in hospitals, 81% of deaths happen outside hospitals. Interpretation Severe ALRI is a substantial burden on health services worldwide and a major cause of hospital referral and admission in young children. Improved hospital access and reduced inequities, such as those related to sex and rural status, could substantially decrease mortality related to such infection. Community-based management of severe disease could be an important complementary strategy to reduce pneumonia mortality and health inequities.

Munywoki PK, Ohuma EO, Ngama M, Bauni E, Scott JAG, Nokes DJ. 2013. Severe lower respiratory tract infection in early infancy and pneumonia hospitalizations among children, Kenya. Emerg Infect Dis, 19 (2), pp. 223-229. | Show Abstract | Read more

Severe lower respiratory tract infection (LRTI) in infants caused by respiratory syncytial virus (RSV) has been associated with later pneumonia hospitalization among children. To determine risk for pneumonia after RSV hospitalization in infancy, we conducted a retrospective cohort analysis of 2,813 infants admitted to a hospital in Kenya and identified readmissions for pneumonia among this group during early childhood (<60 months of age). Incidence of readmission for pneumonia was higher for children whose first admission as infants was for LRTI and who were <3 months of age than for children who were first admitted as infants for non-LRTI, irrespective of RSV status. Incidence of readmission for pneumonia with wheeze was higher for children whose first admission involved RSV compared with those who had non-RSV LRTI. Excess pneumonia risk persisted for 2 years after the initial hospitalization. Close postdischarge follow-up of infants with LRTI, with or without RSV, could help prevent severe pneumonia later in childhood.

Nair H, Simões EAF, Rudan I, Gessner BD, Azziz-Baumgartner E, Zhang JSF, Feikin DR, Mackenzie GA, Moïsi JC, Roca A et al. 2013. Global and regional burden of hospital admissions for severe acute lower respiratory infections in young children in 2010: a systematic analysis. Lancet, 381 (9875), pp. 1380-1390. | Show Abstract | Read more

BACKGROUND: The annual number of hospital admissions and in-hospital deaths due to severe acute lower respiratory infections (ALRI) in young children worldwide is unknown. We aimed to estimate the incidence of admissions and deaths for such infections in children younger than 5 years in 2010. METHODS: We estimated the incidence of admissions for severe and very severe ALRI in children younger than 5 years, stratified by age and region, with data from a systematic review of studies published between Jan 1, 1990, and March 31, 2012, and from 28 unpublished population-based studies. We applied these incidence estimates to population estimates for 2010, to calculate the global and regional burden in children admitted with severe ALRI in that year. We estimated in-hospital mortality due to severe and very severe ALRI by combining incidence estimates with case fatality ratios from hospital-based studies. FINDINGS: We identified 89 eligible studies and estimated that in 2010, 11·9 million (95% CI 10·3-13·9 million) episodes of severe and 3·0 million (2·1-4·2 million) episodes of very severe ALRI resulted in hospital admissions in young children worldwide. Incidence was higher in boys than in girls, the sex disparity being greatest in South Asian studies. On the basis of data from 37 hospital studies reporting case fatality ratios for severe ALRI, we estimated that roughly 265,000 (95% CI 160,000-450,000) in-hospital deaths took place in young children, with 99% of these deaths in developing countries. Therefore, the data suggest that although 62% of children with severe ALRI are treated in hospitals, 81% of deaths happen outside hospitals. INTERPRETATION: Severe ALRI is a substantial burden on health services worldwide and a major cause of hospital referral and admission in young children. Improved hospital access and reduced inequities, such as those related to sex and rural status, could substantially decrease mortality related to such infection. Community-based management of severe disease could be an important complementary strategy to reduce pneumonia mortality and health inequities. FUNDING: WHO.

Brueggemann AB, Muroki BM, Kulohoma BW, Karani A, Wanjiru E, Morpeth S, Kamau T, Sharif S, Scott JAG. 2013. Population genetic structure of Streptococcus pneumoniae in Kilifi, Kenya, prior to the introduction of pneumococcal conjugate vaccine. PLoS One, 8 (11), pp. e81539. | Show Abstract | Read more

BACKGROUND: The 10-valent pneumococcal conjugate vaccine (PCV10) was introduced in Kenya in 2011. Introduction of any PCV will perturb the existing pneumococcal population structure, thus the aim was to genotype pneumococci collected in Kilifi before PCV10. METHODS AND FINDINGS: Using multilocus sequence typing (MLST), we genotyped >1100 invasive and carriage pneumococci from children, the largest collection genotyped from a single resource-poor country and reported to date. Serotype 1 was the most common serotype causing invasive disease and was rarely detected in carriage; all serotype 1 isolates were members of clonal complex (CC) 217. There were temporal fluctuations in the major circulating sequence types (STs); and although 1-3 major serotype 1, 14 or 23F STs co-circulated annually, the two major serotype 5 STs mainly circulated independently. Major STs/CCs also included isolates of serotypes 3, 12F, 18C and 19A and each shared ≤ 2 MLST alleles with STs that circulate widely elsewhere. Major CCs associated with non-PCV10 serotypes were predominantly represented by carriage isolates, although serotype 19A and 12F CCs were largely invasive and a serotype 10A CC was equally represented by invasive and carriage isolates. CONCLUSIONS: Understanding the pre-PCV10 population genetic structure in Kilifi will allow for the detection of changes in prevalence of the circulating genotypes and evidence for capsular switching post-vaccine implementation.

Lundblom K, Murungi L, Nyaga V, Olsson D, Rono J, Osier F, Ogada E, Montgomery S, Scott JAG, Marsh K, Färnert A. 2013. Plasmodium falciparum infection patterns since birth and risk of severe malaria: a nested case-control study in children on the coast of Kenya. PLoS One, 8 (2), pp. e56032. | Show Abstract | Read more

Children in malaria endemic areas acquire immunity to severe malaria faster than to mild malaria. Only a minority of children suffers from severe malaria and it is not known what determines this. The aim of this study was to establish how P. falciparum infections during the first years of life affect the risk of severe malaria. A matched case-control study was nested within a large birth cohort set up to study the immunoepidemiology of pneumococci on the Kenyan coast. Infection patterns in three-monthly blood samples in cohort children admitted to hospital with severe malaria were compared to controls matched on age, residential location and time of sampling. P. falciparum detected at least once from birth conferred an increased risk of severe malaria and particularly if multiclonal infections, as characterized by genotyping of a polymorphic antigen gene, were ever detected. The results show for the first time that children with severe malaria have more infections early in life compared to community controls. These findings provide important insights on the immunity to severe disease, knowledge essential for the development of a vaccine against severe malaria.

Ngugi AK, Bottomley C, Scott JAG, Mung'ala-Odera V, Bauni E, Sander JW, Kleinschmidt I, Newton CR. 2013. Incidence of convulsive epilepsy in a rural area in Kenya. Epilepsia, 54 (8), pp. 1352-1359. | Show Abstract | Read more

PURPOSE: There are only a few studies of incidence of epilepsy in low and middle income countries (LMICs). These are often small and conducted in specific age groups or areas where the prevalence of risk factors is high; therefore, these studies are not representative of the wider populations. We determined the incidence of convulsive epilepsy (CE) in a large rural population in Kenya. METHODS: We conducted two cross-sectional surveys 5 years apart within a health and demographic surveillance system. Initially we identified residents without epilepsy who were then reexamined in the follow-up survey to determine incidence. We estimated the overall incidence of CE and incidence by age-group, sex, and by administrative location. Estimates were adjusted for attrition during case identification and for the sensitivity of the screening method. KEY FINDINGS: In a cohort of 151,408 people, 194 developed CE over the 5 years. The minimum crude incidence rate was 37.6/100,000 persons per year (95% confidence interval (CI) 32.7-43.3) and adjusted for loss to follow-up, and the sensitivity of the survey methodology was 77.0/100,000 persons per year (95% CI 67.7-87.4). Incidence was highest in children 6-12 years (96.1/100,000 persons per year; 95% CI 78.4-117.9), and was lowest in the 29-49 year age group (37.4/100,000 persons per year; 95% CI 25.7-54.7). SIGNIFICANCE: We estimated a high incidence of convulsive epilepsy in this population. Incidence was highest early and late in life, suggesting that preventive interventions should target exposures that occur in these age groups. Incidence of focal epilepsy was more than twice that of generalized epilepsy, suggesting that etiologies that are amenable to intervention were most important in this population. It is likely that incidence is underestimated because of the early mortality of incident cases.

Aiken AM, Wanyoro AK, Mwangi J, Mulingwa P, Wanjohi J, Njoroge J, Juma F, Mugoya IK, Scott JAG, Hall AJ. 2013. Evaluation of surveillance for surgical site infections in Thika Hospital, Kenya Journal of Hospital Infection, 83 (2), pp. 140-145. | Show Abstract | Read more

Background: In low-income countries, surgical site infections (SSIs) are a very frequent form of hospital-acquired infection. Surveillance is an important method for controlling SSI but it is unclear how this can best be performed in low-income settings. Aim: To examine the epidemiological characteristics of various components of an SSI surveillance programme in a single Kenyan hospital. Methods: The study assessed the inter-observer consistency of the surgical wound class (SWC) and American Society of Anesthesiologists (ASA) scores using the kappa statistic. Post-discharge telephone calls were evaluated against an outpatient clinician review 'gold standard'. The predictive value of components of the Centers for Disease Control and Prevention - National Healthcare Safety Network (CDC-NHNS) risk index was examined in patients having major obstetric or gynaecological surgery (O & G) between August 2010 and February 2011. Findings: After appropriate training, surgeons and anaesthetists were found to be consistent in their use of the SWC and ASA scores respectively. Telephone calls were found to have a sensitivity of 70% [95% confidence interval (CI): 47-87] and a specificity of 100% (95% CI: 95-100) for detection of post-discharge SSI in this setting. In 954 patients undergoing major O & G operations, the SWC score was the only parameter in the CDC-NHNS risk index model associated with the risk of SSI (odds ratio: 4.00; 95% CI: 1.21-13.2; P = 0.02). Conclusions: Surveillance for SSI can be conducted in a low-income hospital setting, although dedicated staff, intensive training and local modifications to surveillance methods are necessary. Surveillance for post-discharge SSI using telephone calls is imperfect but provides a practical alternative to clinic-based diagnosis. The SWC score was the only predictor of SSI risk in O & G surgery in this context. © 2012 The Healthcare Infection Society.

Etyang AO, Scott JAG. 2013. Medical causes of admissions to hospital among adults in Africa: a systematic review. Glob Health Action, 6 (1), pp. 1-14. | Show Abstract | Read more

BACKGROUND: Despite the publication of several studies on the subject, there is significant uncertainty regarding the burden of disease among adults in sub-Saharan Africa (sSA). OBJECTIVES: To describe the breadth of available data regarding causes of admission to hospital, to systematically analyze the methodological quality of these studies, and to provide recommendations for future research. DESIGN: We performed a systematic online and hand-based search for articles describing patterns of medical illnesses in patients admitted to hospitals in sSA between 1950 and 2010. Diseases were grouped into bodily systems using International Classification of Disease (ICD) guidelines. We compared the proportions of admissions and deaths by diagnostic category using χ2. RESULTS: Thirty articles, describing 86,307 admissions and 9,695 deaths, met the inclusion criteria. The leading causes of admission were infectious and parasitic diseases (19.8%, 95% confidence interval [CI] 19.6-20.1), respiratory (16.2%, 95% CI 16.0-16.5) and circulatory (11.3%, 95% CI 11.1-11.5) illnesses. The leading causes of death were infectious and parasitic (17.1%, 95% CI 16.4-17.9), circulatory (16%, 95% CI 15.3-16.8) and digestive (16.2%, 95% CI 15.4-16.9). Circulatory diseases increased from 3.9% of all admissions in 1950-59 to 19.9% in 2000-2010 (RR 5.1, 95% CI 4.5-5.8, test for trend p<0.00005). The most prevalent methodological deficiencies, present in two-thirds of studies, were failures to use standardized case definitions and ICD guidelines for classifying illnesses. CONCLUSIONS: Cardiovascular and infectious diseases are currently the leading causes of admissions and in-hospital deaths in sSA. Methodological deficiencies have limited the usefulness of previous studies in defining national patterns of disease in adults. As African countries pass through demographic and health transition, they need to significantly invest in clinical research capacity to provide an accurate description of the disease burden among adults for public health policy.

Aiken AM, Wanyoro AK, Mwangi J, Mulingwa P, Wanjohi J, Njoroge J, Juma F, Mugoya IK, Scott JAG, Hall AJ. 2013. Evaluation of surveillance for surgical site infections in Thika Hospital, Kenya. J Hosp Infect, 83 (2), pp. 140-145. | Show Abstract | Read more

BACKGROUND: In low-income countries, surgical site infections (SSIs) are a very frequent form of hospital-acquired infection. Surveillance is an important method for controlling SSI but it is unclear how this can best be performed in low-income settings. AIM: To examine the epidemiological characteristics of various components of an SSI surveillance programme in a single Kenyan hospital. METHODS: The study assessed the inter-observer consistency of the surgical wound class (SWC) and American Society of Anesthesiologists (ASA) scores using the kappa statistic. Post-discharge telephone calls were evaluated against an outpatient clinician review 'gold standard'. The predictive value of components of the Centers for Disease Control and Prevention - National Healthcare Safety Network (CDC-NHNS) risk index was examined in patients having major obstetric or gynaecological surgery (O&G) between August 2010 and February 2011. FINDINGS: After appropriate training, surgeons and anaesthetists were found to be consistent in their use of the SWC and ASA scores respectively. Telephone calls were found to have a sensitivity of 70% [95% confidence interval (CI): 47-87] and a specificity of 100% (95% CI: 95-100) for detection of post-discharge SSI in this setting. In 954 patients undergoing major O&G operations, the SWC score was the only parameter in the CDC-NHNS risk index model associated with the risk of SSI (odds ratio: 4.00; 95% CI: 1.21-13.2; P = 0.02). CONCLUSIONS: Surveillance for SSI can be conducted in a low-income hospital setting, although dedicated staff, intensive training and local modifications to surveillance methods are necessary. Surveillance for post-discharge SSI using telephone calls is imperfect but provides a practical alternative to clinic-based diagnosis. The SWC score was the only predictor of SSI risk in O&G surgery in this context.

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.

Tigoi CC, Gatakaa H, Karani A, Mugo D, Kungu S, Wanjiru E, Jomo J, Musyimi R, Ojal J, Glass NE et al. 2012. Rates of acquisition of pneumococcal colonization and transmission probabilities, by serotype, among newborn infants in Kilifi District, Kenya. Clin Infect Dis, 55 (2), pp. 180-188. | Show Abstract | Read more

BACKGROUND: Herd protection and serotype replacement disease following introduction of pneumococcal conjugate vaccine (PCV) are attributable to the vaccine's impact on colonization. Prior to vaccine introduction in Kenya, we did an epidemiological study to estimate the rate of pneumococcal acquisition, by serotype, in an uncolonized population. METHODS: Nasopharyngeal swab specimens were taken from newborns aged ≤ 7 days and weekly thereafter for 13 weeks. Parents, and siblings aged <10 years, were swabbed at monthly intervals. Swabs were transported in skim milk-tryptone-glucose-glycerin and cultured on gentamicin blood agar. Pneumococci were serotyped by the Quellung reaction. We used survival analysis and Cox regression analysis to examine serotype-specific acquisition rates and risk factors and calculated transmission probabilities from the pattern of acquisitions within the family. RESULTS: Of 1404 infants recruited, 887 were colonized by 3 months of age, with the earliest acquisition detected on the first day of life. The median time to acquisition was 38.5 days. The pneumococcal acquisition rate was 0.0189 acquisitions/day (95% confidence interval, .0177-.0202 acquisitions/day). Serotype-specific acquisition rates varied from 0.00002-0.0025 acquisitions/day among 49 different serotypes. Season, coryza, and exposure to cigarettes, cooking fumes, and other children in the home were each significant risk factors for acquisition. The transmission probability per 30-day duration of contact with a carrier was 0.23 (95% CI, .20-.26). CONCLUSIONS: Newborn infants in Kilifi have high rates of nasopharyngeal acquisition of pneumococci. Half of these acquisitions involve serotypes not included in any current vaccine. Several risk factors are modifiable through intervention. Newborns represent a consistent population of pneumococcus-naive individuals in which to estimate the impact of PCV on transmission.

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.

Scott JAG, Bauni E, Moisi JC, Ojal J, Gatakaa H, Nyundo C, Molyneux CS, Kombe F, Tsofa B, Marsh K et al. 2012. Profile: The Kilifi Health and Demographic Surveillance System (KHDSS). Int J Epidemiol, 41 (3), pp. 650-657. | Show Abstract | Read more

The Kilifi Health and Demographic Surveillance System (KHDSS), located on the Indian Ocean coast of Kenya, was established in 2000 as a record of births, pregnancies, migration events and deaths and is maintained by 4-monthly household visits. The study area was selected to capture the majority of patients admitted to Kilifi District Hospital. The KHDSS has 260 000 residents and the hospital admits 4400 paediatric patients and 3400 adult patients per year. At the hospital, morbidity events are linked in real time by a computer search of the population register. Linked surveillance was extended to KHDSS vaccine clinics in 2008. KHDSS data have been used to define the incidence of hospital presentation with childhood infectious diseases (e.g. rotavirus diarrhoea, pneumococcal disease), to test the association between genetic risk factors (e.g. thalassaemia and sickle cell disease) and infectious diseases, to define the community prevalence of chronic diseases (e.g. epilepsy), to evaluate access to health care and to calculate the operational effectiveness of major public health interventions (e.g. conjugate Haemophilus influenzae type b vaccine). Rapport with residents is maintained through an active programme of community engagement. A system of collaborative engagement exists for sharing data on survival, morbidity, socio-economic status and vaccine coverage.

Aiken AM, Mturi N, Morpeth SC, Seale AC, Scott JAG. 2012. Paediatric hospital-acquired bacteraemia in developing countries reply LANCET, 379 (9825), pp. 1484-1485. | Read more

Turner GDH, Bunthi C, Wonodi CB, Morpeth SC, Molyneux CS, Zaki SR, Levine OS, Murdoch DR, Scott JAG. 2012. The role of postmortem studies in pneumonia etiology research. Clin Infect Dis, 54 Suppl 2 (suppl_2), pp. S165-S171. | Show Abstract | Read more

The diagnosis of etiology in severe pneumonia remains a challenging area. Postmortem lung tissue potentially increases the sensitivity of investigations for identification of causative pathogens in fatal cases of pneumonia and can confirm antemortem microbiological diagnoses. Tissue sampling allows assessment of histological patterns of disease and ancillary immunohistochemical or molecular diagnostic techniques. It may also enhance the recognition of noninfectious conditions that clinically simulate acute pneumonia. Biobanking of lung tissue or postmortem culture isolates offers opportunities for new pathogen discovery and research into host-pathogen interactions. The Pneumonia Etiology Research for Child Health study proposes a percutaneous needle biopsy approach to obtain postmortem samples, rather than a full open autopsy. This has the advantage of greater acceptability to relatives, but risks greater sampling error. Both approaches may be susceptible to microbiological contamination or pathogen degradation. However, previous autopsy studies have confirmed the value of histological examination in revealing unsuspected pathogens and influencing clinical guidelines for the diagnosis and treatment of future pneumonia cases.

Abdullahi O, Karani A, Tigoi CC, Mugo D, Kungu S, Wanjiru E, Jomo J, Musyimi R, Lipsitch M, Scott JAG. 2012. Rates of acquisition and clearance of pneumococcal serotypes in the nasopharynges of children in Kilifi District, Kenya. J Infect Dis, 206 (7), pp. 1020-1029. | Show Abstract | Read more

BACKGROUND: To understand and model the impact of pneumococcal conjugate vaccines at the population level, we need to know the transmission dynamics of individual pneumococcal serotypes. We estimated serotype-specific clearance and acquisition rates of nasopharyngeal colonization among Kenyan children. METHODS: Children aged 3-59 months who were identified as carriers in a cross-sectional survey were followed-up approximately 1, 2, 4, 8, 16, and 32 days later and monthly thereafter until culture of 2 consecutive swabs yielded an alternative serotype or no pneumococcus. Serotype-specific clearance rates were estimated by exponential regression of interval-censored carriage durations. Duration was estimated as the reciprocal of the clearance rate, and acquisition rates were estimated on the basis of prevalence and duration, assuming an equilibrium state. RESULTS: Of 2840 children sampled between October 2006 and December 2008, 1868 were carriers. The clearance rate was 0.032 episodes/day (95% confidence interval [CI], .030-.034), for a carriage duration of 31.3 days, and the rate varied by serotype (P< .0005). Carriage durations for the 28 serotypes with ≥ 10 carriers ranged from 6.7 to 50 days. Clearance rates increased with year of age, adjusted for serotype (hazard ratio, 1.21; 95% CI, 1.15-1.27). The acquisition rate was 0.061 episodes/day (95% CI, .055-.067), which did not vary with age. Serotype-specific acquisition rates varied from 0.0002 to 0.0022 episodes/day. Serotype-specific acquisition rates correlated with prevalence (r=0.91; P< .00005) and with acquisition rates measured in a separate study involving 1404 newborns in Kilifi (r=0.87; P< .00005). CONCLUSIONS: The large sample size and short swabbing intervals provide a precise description of the prevalence, duration, and acquisition of carriage of 28 pneumococcal serotypes. In Kilifi, young children experience approximately 8 episodes of carriage per year. The declining prevalence with age is attributable to increasing clearance rates.

Lipsitch M, Abdullahi O, DʼAmour A, Xie W, Weinberger DM, Tchetgen Tchetgen E, Scott JAG. 2012. Estimating rates of carriage acquisition and clearance and competitive ability for pneumococcal serotypes in Kenya with a Markov transition model. Epidemiology, 23 (4), pp. 510-519. | Show Abstract | Read more

BACKGROUND: There are more than 90 serotypes of Streptococcus pneumoniae, with varying biologic and epidemiologic properties. Animal studies suggest that carriage induces an acquired immune response that reduces duration of colonization in a nonserotype-specific fashion. METHODS: We studied pneumococcal nasopharyngeal carriage longitudinally in Kenyan children 3-59 months of age, following up positive swabs at days 2, 4, 8, 16, and 32 and then monthly thereafter until 2 swabs were negative for the original serotype. As previously reported, 1868/2840 (66%) of children swabbed at baseline were positive. We estimated acquisition, clearance, and competition parameters for 27 serotypes using a Markov transition model. RESULTS: Point estimates of type-specific acquisition rates ranged from 0.00025/d (type 1) to 0.0031/d (type 19F). Point estimates of time to clearance (inverse of type-specific immune clearance rate) ranged from 28 days (type 20) to 124 days (type 6A). For the serotype most resistant to competition (type 19F), acquisition of other serotypes was 52% less likely (95% confidence interval = 37%-63%) than in an uncolonized host. Fitness components (carriage duration, acquisition rate, lack of susceptibility to competition) were positively correlated with each other and with baseline prevalence, and were associated with biologic properties previously shown to associate with serotype. Duration of carriage declined with age for most serotypes. CONCLUSIONS: Common S. pneumoniae serotypes appear superior in many dimensions of fitness. Differences in rate of immune clearance are attenuated as children age and become capable of more rapid clearance of the longest-lived serotypes. These findings provide information for comparison after introduction of pneumococcal conjugate vaccine.

Aiken AM, Mturi N, Morpeth SC, Seale AC, G Scott JA. 2012. Authors' reply The Lancet, 379 (9825), pp. 1484-1485.

Scott JAG, Wonodi C, Moïsi JC, Deloria-Knoll M, DeLuca AN, Karron RA, Bhat N, Murdoch DR, Crawley J, Levine OS et al. 2012. The definition of pneumonia, the assessment of severity, and clinical standardization in the Pneumonia Etiology Research for Child Health study. Clin Infect Dis, 54 Suppl 2 (suppl_2), pp. S109-S116. | Show Abstract | Read more

To develop a case definition for the Pneumonia Etiology Research for Child Health (PERCH) project, we sought a widely acceptable classification that was linked to existing pneumonia research and focused on very severe cases. We began with the World Health Organization's classification of severe/very severe pneumonia and refined it through literature reviews and a 2-stage process of expert consultation. PERCH will study hospitalized children, aged 1-59 months, with pneumonia who present with cough or difficulty breathing and have either severe pneumonia (lower chest wall indrawing) or very severe pneumonia (central cyanosis, difficulty breastfeeding/drinking, vomiting everything, convulsions, lethargy, unconsciousness, or head nodding). It will exclude patients with recent hospitalization and children with wheeze whose indrawing resolves after bronchodilator therapy. The PERCH investigators agreed upon standard interpretations of the symptoms and signs. These will be maintained by a clinical standardization monitor who conducts repeated instruction at each site and by recurrent local training and testing.

Levine OS, O'Brien KL, Deloria-Knoll M, Murdoch DR, Feikin DR, DeLuca AN, Driscoll AJ, Baggett HC, Brooks WA, Howie SRC et al. 2012. The Pneumonia Etiology Research for Child Health Project: a 21st century childhood pneumonia etiology study. Clin Infect Dis, 54 Suppl 2 (suppl 2), pp. S93-101. | Show Abstract | Read more

The Pneumonia Etiology Research for Child Health (PERCH) project is a 7-country, standardized, comprehensive evaluation of the etiologic agents causing severe pneumonia in children from developing countries. During previous etiology studies, between one-quarter and one-third of patients failed to yield an obvious etiology; PERCH will employ and evaluate previously unavailable innovative, more sensitive diagnostic techniques. Innovative and rigorous epidemiologic and analytic methods will be used to establish the causal association between presence of potential pathogens and pneumonia. By strategic selection of study sites that are broadly representative of regions with the greatest burden of childhood pneumonia, PERCH aims to provide data that reflect the epidemiologic situation in developing countries in 2015, using pneumococcal and Haemophilus influenzae type b vaccines. PERCH will also address differences in host, environmental, and/or geographic factors that might determine pneumonia etiology and, by preserving specimens, will generate a resource for future research and pathogen discovery.

Hammitt LL, Kazungu S, Morpeth SC, Gibson DG, Mvera B, Brent AJ, Mwarumba S, Onyango CO, Bett A, Akech DO et al. 2012. A preliminary study of pneumonia etiology among hospitalized children in Kenya. Clin Infect Dis, 54 Suppl 2 (suppl_2), pp. S190-S199. | Show Abstract | Read more

BACKGROUND: Pneumonia is the leading cause of childhood death in the developing world. Higher-quality etiological data are required to reduce this mortality burden. METHODS: We conducted a case-control study of pneumonia etiology among children aged 1-59 months in rural Kenya. Case patients were hospitalized with World Health Organization-defined severe pneumonia (SP) or very severe pneumonia (VSP); controls were outpatient children without pneumonia. We collected blood for culture, induced sputum for culture and multiplex polymerase chain reaction (PCR), and obtained oropharyngeal swab specimens for multiplex PCR from case patients, and serum for serology and nasopharyngeal swab specimens for multiplex PCR from case patients and controls. RESULTS: Of 984 eligible case patients, 810 (84%) were enrolled in the study; 232 (29%) had VSP. Blood cultures were positive in 52 of 749 case patients (7%). A predominant potential pathogen was identified in sputum culture in 70 of 417 case patients (17%). A respiratory virus was detected by PCR from nasopharyngeal swab specimens in 486 of 805 case patients (60%) and 172 of 369 controls (47%). Only respiratory syncytial virus (RSV) showed a statistically significant association between virus detection in the nasopharynx and pneumonia hospitalization (odds ratio, 12.5; 95% confidence interval, 3.1-51.5). Among 257 case patients in whom all specimens (excluding serum specimens) were collected, bacteria were identified in 24 (9%), viruses in 137 (53%), mixed viral and bacterial infection in 39 (15%), and no pathogen in 57 (22%); bacterial causes outnumbered viral causes when the results of the case-control analysis were considered. CONCLUSIONS: A potential etiology was detected in >75% of children admitted with SP or VSP. Except for RSV, the case-control analysis did not detect an association between viral detection in the nasopharynx and hospitalization for pneumonia.

Gilani Z, Kwong YD, Levine OS, Deloria-Knoll M, Scott JAG, O'Brien KL, Feikin DR. 2012. A literature review and survey of childhood pneumonia etiology studies: 2000-2010. Clin Infect Dis, 54 Suppl 2 (suppl_2), pp. S102-S108. | Show Abstract | Read more

The Pneumonia Etiology Research for Child Health (PERCH) project is the largest multicountry etiology study of childhood pneumonia since the Board on Science and Technology in International Development studies of the 1980s. However, it is not the only recent or ongoing pneumonia etiology study, and even with seven sites, it cannot capture all epidemiologic settings in the developing world. Funding providers, researchers and policymakers rely on the best available evidence to strategically plan programs, new research directions and interventions. We aimed to describe the current landscape of recent pneumonia etiology studies in children under 5 years of age in the developed and developing world, as ascertained by a literature review of relevant studies with data since the year 2000 and a survey of researchers in the field of childhood pneumonia. We collected information on the study population, study design, case definitions, laboratory samples and methods and identified pathogens. A literature review identified 88 studies with child pneumonia etiology results. As of June 2010, our survey of researchers identified an additional 65 ongoing and recently completed child pneumonia etiology studies. This demonstrates the broad existing context into which the PERCH study must be placed. However, the landscape analysis also reveals a multiplicity of case definitions, levels of clinician involvement, facility types, specimen collection, and laboratory techniques. It reinforces the need for the standardization of methods and analyses for present and future pneumonia etiology studies in order to optimize their cumulative potential to accurately describe the microbial causes of childhood pneumonia.

Deloria-Knoll M, Feikin DR, Scott JAG, O'Brien KL, DeLuca AN, Driscoll AJ, Levine OS, Pneumonia Methods Working Group. 2012. Identification and selection of cases and controls in the Pneumonia Etiology Research for Child Health project. Clin Infect Dis, 54 Suppl 2 (suppl_2), pp. S117-S123. | Show Abstract | Read more

Methods for the identification and selection of patients (cases) with severe or very severe pneumonia and controls for the Pneumonia Etiology Research for Child Health (PERCH) project were needed. Issues considered include eligibility criteria and sampling strategies, whether to enroll hospital or community controls, whether to exclude controls with upper respiratory tract infection (URTI) or nonsevere pneumonia, and matching criteria, among others. PERCH ultimately decided to enroll community controls and an additional human immunodeficiency virus (HIV)-infected control group at high HIV-prevalence sites matched on age and enrollment date of cases; controls with symptoms of URTI or nonsevere pneumonia will not be excluded. Systematic sampling of cases (when necessary) and random sampling of controls will be implemented. For each issue, we present the options that were considered, the advantages and disadvantages of each, the rationale for the methods selected for PERCH, and remaining implications and limitations.

Grant LR, Hammitt LL, Murdoch DR, O'Brien KL, Scott JA. 2012. Procedures for collection of induced sputum specimens from children. Clin Infect Dis, 54 Suppl 2 (suppl_2), pp. S140-S145. | Show Abstract | Read more

In most settings, sputum is not routinely collected for microbiological diagnosis from children with lower respiratory disease. To evaluate whether it is feasible and diagnostically useful to collect sputum in the Pneumonia Etiology Research for Child Health (PERCH) study, we reviewed the literature on induced sputum procedures. Protocols for induced sputum in children were collated from published reports and experts on respiratory disease and reviewed by an external advisory group for recommendation in the PERCH study. The advisory group compared 6 protocols: 4 followed a nebulization technique using hypertonic saline, and 2 followed a chest or abdomen massage technique. Grading systems for specimen quality were evaluated. Collecting sputum from children with lower respiratory tract illness is feasible and is performed around the world. An external advisory group recommended that sputum be collected from children hospitalized with severe and very severe pneumonia who participate in the PERCH study provided no contraindications exist. PERCH selected the nebulization technique using hypertonic saline.

Hammitt LL, Murdoch DR, Scott JAG, Driscoll A, Karron RA, Levine OS, O'Brien KL, Pneumonia Methods Working Group. 2012. Specimen collection for the diagnosis of pediatric pneumonia. Clin Infect Dis, 54 Suppl 2 (suppl_2), pp. S132-S139. | Show Abstract | Read more

Diagnosing the etiologic agent of pneumonia has an essential role in ensuring the most appropriate and effective therapy for individual patients and is critical to guiding the development of treatment and prevention strategies. However, establishing the etiology of pneumonia remains challenging because of the relative inaccessibility of the infected tissue and the difficulty in obtaining samples without contamination by upper respiratory tract secretions. Here, we review the published and unpublished literature on various specimens available for the diagnosis of pediatric pneumonia. We discuss the advantages and limitations of each specimen, and discuss the rationale for the specimens to be collected for the Pneumonia Etiology Research for Child Health study.

Wonodi CB, Deloria-Knoll M, Feikin DR, DeLuca AN, Driscoll AJ, Moïsi JC, Johnson HL, Murdoch DR, O'Brien KL, Levine OS et al. 2012. Evaluation of risk factors for severe pneumonia in children: the Pneumonia Etiology Research for Child Health study. Clin Infect Dis, 54 Suppl 2 (suppl 2), pp. S124-S131. | Show Abstract | Read more

As a case-control study of etiology, the Pneumonia Etiology Research for Child Health (PERCH) project also provides an opportunity to assess the risk factors for severe pneumonia in hospitalized children at 7 sites. We identified relevant risk factors by literature review and iterative expert consultation. Decisions for inclusion in PERCH were based on comparability to published data, analytic plans, data collection costs and logistic feasibility, including interviewer time and subject fatigue. We aimed to standardize questions at all sites, but significant variation in the economic, cultural, and geographic characteristics of sites made it difficult to obtain this objective. Despite these challenges, the depth of the evaluation of multiple risk factors across the breadth of the PERCH sites should furnish new and valuable information about the major risk factors for childhood severe and very severe pneumonia, including risk factors for pneumonia caused by specific etiologies, in developing countries.

Abdullahi O, Karani A, Tigoi CC, Mugo D, Kungu S, Wanjiru E, Jomo J, Musyimi R, Lipsitch M, Scott JAG. 2012. The prevalence and risk factors for pneumococcal colonization of the nasopharynx among children in Kilifi District, Kenya. PLoS One, 7 (2), pp. e30787. | Show Abstract | Read more

BACKGROUND: Pneumococcal conjugate vaccines (PCV) reduce nasopharyngeal carriage of vaccine-serotype pneumococci but increase in the carriage of non-vaccine serotypes. We studied the epidemiology of carriage among children 3-59 months old before vaccine introduction in Kilifi, Kenya. METHODS: In a rolling cross-sectional study from October 2006 to December 2008 we approached 3570 healthy children selected at random from the population register of the Kilifi Health and Demographic Surveillance System and 134 HIV-infected children registered at a specialist clinic. A single nasopharyngeal swab was transported in STGG and cultured on gentamicin blood agar. A single colony of pneumococcus was serotyped by Quellung reaction. RESULTS: Families of 2840 children in the population-based sample and 99 in the HIV-infected sample consented to participate; carriage prevalence was 65.8% (95% CI, 64.0-67.5%) and 76% (95% CI, 66-84%) in the two samples, respectively. Carriage prevalence declined progressively with age from 79% at 6-11 months to 51% at 54-59 months (p<0.0005). Carriage was positively associated with coryza (Odds ratio 2.63, 95%CI 2.12-3.25) and cough (1.55, 95%CI 1.26-1.91) and negatively associated with recent antibiotic use (0.53 95%CI 0.34-0.81). 53 different serotypes were identified and 42% of isolates were of serotypes contained in the 10-valent PCV. Common serotypes declined in prevalence with age while less common serotypes did not. CONCLUSION: Carriage prevalence in children was high, serotypes were diverse, and the majority of strains were of serotypes not represented in the 10-valent PCV. Vaccine introduction in Kenya will provide a natural test of virulence for the many circulating non-vaccine serotypes.

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.

Scott JAG, Ojal J, Ashton L, Muhoro A, Burbidge P, Goldblatt D. 2011. Pneumococcal conjugate vaccine given shortly after birth stimulates effective antibody concentrations and primes immunological memory for sustained infant protection. Clin Infect Dis, 53 (7), pp. 663-670. | Show Abstract | Read more

BACKGROUND: In developing countries, newborn immunization with pneumococcal conjugate vaccines (PCVs) could protect young infants who are at high risk of invasive pneumococcal disease (IPD) but might lead to immune tolerance. METHODS: In a randomized trial, young infants received 7-valent PCV at 6, 10, and 14 weeks (Expanded Programme on Immunization [EPI] group) or 0, 10, and 14 weeks (newborn group). Safety was monitored actively at 2-7 days and then passively. Serum samples obtained at birth and 6, 10, 14, 18, 36, and 37 weeks were assayed by enzyme-linked immunosorbent assay for anticapsular immunoglobulin G concentration and avidity. Infants were boosted with either 7-valent PCV or one-fifth dose of pneumococcal polysaccharide vaccine at 36 weeks. Nasopharyngeal swab samples were obtained at 18 and 36 weeks. RESULTS: Three-hundred neonates and young infants were enrolled. Newborn vaccination was well tolerated. Adverse events occurred equally in each group; none was related to immunization. One infant, immunized at birth, died of unrelated neonatal sepsis. At 18 weeks, protective concentrations (≥0.35 μg/mL) were achieved against each serotype by ≥87% of infants with no significant differences between groups. Geometric mean concentrations were higher in the EPI group for serotypes 4, 9V, 18C, and 19F at 18 weeks and for serotype 4 at 36 weeks. Avidity was greater in the newborn group for serotypes 4, 6B, and 19F at 18 weeks and for serotype 19F at 36 weeks. Booster responses and vaccine-type/nonvaccine-type carriage prevalence did not differ between groups. CONCLUSIONS: PCV was safe, immunogenic, and primed for memory when given at birth. There was no evidence of immune tolerance. Vaccination beginning at birth offers an alternative to control IPD in vulnerable young infants.

Hammitt LL, Kazungu S, Welch S, Bett A, Onyango CO, Gunson RN, Scott JAG, Nokes DJ. 2011. Added value of an oropharyngeal swab in detection of viruses in children hospitalized with lower respiratory tract infection. J Clin Microbiol, 49 (6), pp. 2318-2320. | Show Abstract | Read more

Paired nasopharyngeal and oropharyngeal swabs collected from 533 children hospitalized with lower respiratory tract infection were assessed by multiplex reverse transcription-PCR. Oropharyngeal swabs increased the number of viral infections detected by 15%, compared to collection of a nasopharyngeal swab alone. This advantage was most pronounced for detection of influenza, parainfluenza, and adenovirus.

Moïsi JC, Nokes DJ, Gatakaa H, Williams TN, Bauni E, Levine OS, Scott JAG. 2011. Sensitivity of hospital-based surveillance for severe disease: a geographic information system analysis of access to care in Kilifi district, Kenya. Bull World Health Organ, 89 (2), pp. 102-111. | Show Abstract | Read more

OBJECTIVE: To explore the relationship between homestead distance to hospital and access to care and to estimate the sensitivity of hospital-based surveillance in Kilifi district, Kenya. METHODS: In 2002-2006, clinical information was obtained from all children admitted to Kilifi District Hospital and linked to demographic surveillance data. Travel times to the hospital were calculated using geographic information systems and regression models were constructed to examine the relationships between travel time, cause-specific hospitalization rates and probability of death in hospital. Access to care ratios relating hospitalization rates to community mortality rates were computed and used to estimate surveillance sensitivity. FINDINGS: The analysis included 7200 admissions (64 per 1000 child-years). Median pedestrian and vehicular travel times to hospital were 237 and 61 minutes, respectively. Hospitalization rates decreased by 21% per hour of travel by foot and 28% per half hour of travel by vehicle. Distance decay was steeper for meningitis than for pneumonia, for females than for males, and for areas where mothers had less education on average. Distance was positively associated with the probability of dying in hospital. Overall access to care ratios, which represent the probability that a child in need of hospitalization will have access to care at the hospital, were 51-58% for pneumonia and 66-70% for meningitis. CONCLUSION: In this setting, hospital utilization rates decreased and the severity of cases admitted to hospital increased as distance between homestead and hospital increased. Access to hospital care for children living in remote areas was low, particularly for those with less severe conditions. Distance decay was attenuated by increased levels of maternal education. Hospital-based surveillance underestimated pneumonia and meningitis incidence by more than 45% and 30%, respectively.

Weinberger DM, Harboe ZB, Flasche S, Scott JA, Lipsitch M. 2011. Prediction of serotypes causing invasive pneumococcal disease in unvaccinated and vaccinated populations. Epidemiology, 22 (2), pp. 199-207. | Show Abstract | Read more

INTRODUCTION: Before the introduction of the heptavalent pneumococcal conjugate vaccine (Prevnar-7), the relative prevalence of serotypes of Streptococcus pneumoniae was fairly stable worldwide. We sought to develop a statistical tool to predict the relative frequency of different serotypes among disease isolates in the pre- and post-Prevnar-7 eras using the limited amount of data that is widely available. METHODS: We initially used pre-Prevnar-7 carriage prevalence and estimates of invasiveness derived from case-fatality data as predictors for the relative abundance of serotypes causing invasive pneumococcal disease during the pre- and post-Prevnar-7 eras, using negative binomial regression. We fit the model to pre-Prevnar-7 invasive pneumococcal disease data from England and Wales and used these data to (1) evaluate the performance of the model using several datasets and (2) evaluate the utility of the country-specific carriage data. We then fit an alternative model that used polysaccharide structure, a correlate of prevalence that does not require country-specific information and could be useful in determining the postvaccine population structure, as a predictor. RESULTS: Predictions from the initial model fit data from several pediatric populations in the pre-Prevnar-7 era. After the introduction of Prevnar-7, the model still had a good negative predictive value, though substantial unexplained variation remained. The alternative model had a good negative predictive value but poor positive predictive value. Both models demonstrate that the pneumococcal population follows a somewhat predictable pattern even after vaccination. CONCLUSIONS: This approach provides a preliminary framework to evaluate the potential patterns and impact of serotypes causing invasive pneumococcal disease.

Cited:

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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.

Brent AJ, Mugo D, Musyimi R, Mutiso A, Morpeth S, Levin M, Scott JAG. 2011. Performance of the MGIT TBc identification test and meta-analysis of MPT64 assays for identification of the Mycobacterium tuberculosis complex in liquid culture. J Clin Microbiol, 49 (12), pp. 4343-4346. | Show Abstract | Read more

Rapid MPT64-based immunochromatographic tests (MPT64 ICTs) have been developed to detect Mycobacterium tuberculosis complex (MTBC) in culture. We demonstrated the noninferiority of one commercial MTP64 ICT, the MGIT TBc identification (TBcID) test, to GenoType line probe assays for MTBC identification in positive MGIT cultures. Meta-analysis of MPT64 ICT performance for identification of MTBC in liquid culture confirmed similar very high sensitivities and specificities for all three commercial MPT64 assays for which sufficient data were available.

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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Scott JAG, Ojal J, Ashton L, Muhoro A, Burbidge P, Goldblatt D. 2011. Pneumococcal conjugate vaccine given shortly after birth stimulates effective antibody concentrations and primes immunological memory for sustained infant protection Clinical Infectious Diseases, 53 (7), pp. 663-670. | Show Abstract | Read more

Background.In developing countries, newborn immunization with pneumococcal conjugate vaccines (PCVs) could protect young infants who are at high risk of invasive pneumococcal disease (IPD) but might lead to immune tolerance.Methods.In a randomized trial, young infants received 7-valent PCV at 6, 10, and 14 weeks (Expanded Programme on Immunization [EPI] group) or 0, 10, and 14 weeks (newborn group). Safety was monitored actively at 2-7 days and then passively. Serum samples obtained at birth and 6, 10, 14, 18, 36, and 37 weeks were assayed by enzyme-linked immunosorbent assay for anticapsular immunoglobulin G concentration and avidity. Infants were boosted with either 7-valent PCV or one-fifth dose of pneumococcal polysaccharide vaccine at 36 weeks. Nasopharyngeal swab samples were obtained at 18 and 36 weeks.Results.Three-hundred neonates and young infants were enrolled. Newborn vaccination was well tolerated. Adverse events occurred equally in each group; none was related to immunization. One infant, immunized at birth, died of unrelated neonatal sepsis. At 18 weeks, protective concentrations (≥0.35 μg/mL) were achieved against each serotype by ≥87% of infants with no significant differences between groups. Geometric mean concentrations were higher in the EPI group for serotypes 4, 9V, 18C, and 19F at 18 weeks and for serotype 4 at 36 weeks. Avidity was greater in the newborn group for serotypes 4, 6B, and 19F at 18 weeks and for serotype 19F at 36 weeks. Booster responses and vaccine-type/nonvaccine-type carriage prevalence did not differ between groups.Conclusions.PCV was safe, immunogenic, and primed for memory when given at birth. There was no evidence of immune tolerance. Vaccination beginning at birth offers an alternative to control IPD in vulnerable young infants. The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please email:journals.permissions@oup.com.2011This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2011 The Author.

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.

Weinberger DM, Harboe ZB, Sanders EAM, Ndiritu M, Klugman KP, Rückinger S, Dagan R, Adegbola R, Cutts F, Johnson HL et al. 2010. Association of serotype with risk of death due to pneumococcal pneumonia: a meta-analysis. Clin Infect Dis, 51 (6), pp. 692-699. | Show Abstract | Read more

BACKGROUND: The 92 capsular serotypes of Streptococcus pneumoniae differ greatly in nasopharyngeal carriage prevalence, invasiveness, and disease incidence. There has been some debate, though, regarding whether serotype independently affects the outcome of invasive pneumococcal disease (IPD). Published studies have shown variable results with regard to case-fatality ratios for specific serotypes and the role of host factors in affecting these relationships. We evaluated whether risk of death due to IPD is a stable serotype-associated property across studies and then compared the pooled effect estimates with epidemiologic and biological correlates. METHODS: We performed a systematic review and meta-analysis of serotype-specific disease outcomes for patients with pneumonia and meningitis. Study-specific estimates of risk of death (risk ratio [RR]) were pooled from 9 studies that provided serotype-specific data on pneumonia and meningitis using a random-effects method with serotype 14 as the reference. Pooled RRs were compared with RRs from adults with low comorbidity scores to evaluate potential confounding by host factors. RESULTS: Significant differences were found in the RR estimates among serotypes in patients with bacteremic pneumonia. Overall, serotypes 1, 7F, and 8 were associated with decreased RRs, and serotypes 3, 6A, 6B, 9N, and 19F were associated with increased RRs. Outcomes among meningitis patients did not differ significantly among serotypes. Serotypes with increased RRs had a high carriage prevalence, had low invasiveness, and were more heavily encapsulated in vitro. CONCLUSIONS: These results suggest that IPD outcome, like other epidemiologic measures, is a stable serotype-associated property.

Moïsi JC, Kabuka J, Mitingi D, Levine OS, Scott JAG. 2010. Spatial and socio-demographic predictors of time-to-immunization in a rural area in Kenya: Is equity attainable? Vaccine, 28 (35), pp. 5725-5730. | Show Abstract | Read more

We conducted a vaccine coverage survey in Kilifi District, Kenya in order to identify predictors of childhood immunization. We calculated travel time to vaccine clinics and examined its relationship to immunization coverage and timeliness among the 2169 enrolled children (median age: 12.5 months). 86% had vaccine cards available, >95% had received three doses of DTP-HepB-Hib and polio vaccines and 88% of measles. Travel time did not affect vaccination coverage or timeliness. The Kenyan EPI reaches nearly all children in Kilifi and delays in vaccination are few, suggesting that vaccines will have maximal impact on child morbidity and mortality.

Jokinen J, Scott JAG. 2010. Estimating the proportion of pneumonia attributable to pneumococcus in Kenyan adults: latent class analysis. Epidemiology, 21 (5), pp. 719-725. | Show Abstract | Read more

BACKGROUND: Community-acquired pneumonia is a common cause of hospitalization among African adults, and Streptococcus pneumoniae is assumed to be a frequent cause. Pneumococcal conjugate vaccine is currently being introduced into childhood immunization programs in Africa. The case for adult vaccination is dependent on the contribution of the pneumococcus to the hospital pneumonia burden. METHODS: Pneumococcal diagnosis is complex because there is no gold standard, and culture methods are invalidated by antibiotic use. We used latent class analysis to estimate the proportion of pneumonia episodes caused by pneumococcus. Furthermore, we extended this methodology to evaluate the effect of antimicrobial treatment on test accuracies and the prevalence of the disease. The study combined data from 5 validation studies of pneumococcal diagnostic tests performed on 281 Kenyan adults with pneumonia. RESULTS: The proportion of pneumonia episodes attributable to pneumococcus was 0.46 (95% confidence interval = 0.36-0.57). Failure to account for the effect of antimicrobial exposure underestimates this proportion as 0.32. A history of antibiotic exposure was a poor predictor of antimicrobial activity in patients' urine. Blood culture sensitivity for pneumococcus was estimated at 0.24 among patients with antibiotic exposure, and 0.75 among those without. CONCLUSIONS: The large contribution of pneumococcus to adult pneumonia provides a strong case for the investigation of pneumococcal vaccines in African adults.

McAuley CF, Webb C, Makani J, Macharia A, Uyoga S, Opi DH, Ndila C, Ngatia A, Scott JAG, Marsh K, Williams TN. 2010. High mortality from Plasmodium falciparum malaria in children living with sickle cell anemia on the coast of Kenya. Blood, 116 (10), pp. 1663-1668. | Show Abstract | Read more

Although malaria is widely considered a major cause of death in young children born with sickle cell anemia (SCA) in sub-Saharan Africa, this is poorly quantified. We attempted to investigate this question through 4 large case-control analyses involving 7164 children living on the coast of Kenya. SCA was associated with an increased risk of admission to hospital both with nonmalaria diseases in general (odds ratio [OR] = 4.17; 95% confidence interval [CI], 1.95-8.92; P < .001) and with invasive bacterial diseases in particular (OR = 8.73; 95% CI, 4.51-16.89; P < .001). We found no evidence for a strongly increased risk of either uncomplicated malaria (OR = 0.43; 95% CI, 0.09-2.10; P = .30) or malaria complicated by a range of well-described clinical features of severity (OR = 0.80; 95% CI, 0.25-2.51; P = .70) overall; nevertheless, mortality was considerably higher among SCA than non-SCA children hospitalized with malaria. Our findings highlight both the central role that malaria plays in the high early mortality seen in African children with SCA and the urgent need for better quantitative data. Meanwhile, our study confirms the importance of providing all children living with SCA in malaria-endemic areas with effective prophylaxis.

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.

Niederer HA, Willcocks LC, Rayner TF, Yang W, Lau YL, Williams TN, Scott JAG, Urban BC, Peshu N, Dunstan SJ et al. 2010. Copy number, linkage disequilibrium and disease association in the FCGR locus. Hum Mol Genet, 19 (16), pp. 3282-3294. | Show Abstract | Read more

The response of a leukocyte to immune complexes (ICs) is modulated by receptors for the Fc region of IgG (FcgammaRs), and alterations in their affinity or function have been associated with risk of autoimmune diseases, including systemic lupus erythematosus (SLE). The low-affinity FcgammaR genomic locus is complex, containing regions of copy number variation (CNV) which can alter receptor expression and leukocyte responses to IgG. Combined paralogue ratio tests (PRTs) were used to distinguish three intervals within the FCGR locus which undergo CNV, and to determine FCGR gene copy number (CN). There were significant differences in FCGR3B and FCGR3A CNV profiles between Caucasian, East Asian and Kenyan populations. A previously noted association of low FCGR3B CN with SLE in Caucasians was supported [OR = 1.57 (1.08-2.27), P = 0.018], and replicated in Chinese [OR = 1.65 (1.25-2.18), P = 4 x 10(-4)]. There was no association of FCGR3B CNV with vasculitis, nor with malarial or bacterial infection. Linkage disequilibrium (LD) between multi-allelic FCGR3B CNV and SLE-associated SNPs in the FCGR locus was defined for the first time. Despite LD between FCGR3B CNV and a variant in FcgammaRIIB (I232T) which abolishes inhibitory function, both reduced CN of FCGR3B and homozygosity of the FcgammaRIIB-232T allele were individually strongly associated with SLE risk. Thus CN of FCGR3B, which controls IC responses and uptake by neutrophils, and variations in FCGR2B, which controls factors such as antibody production and macrophage activation, are important in SLE pathogenesis. Further interpretations of contributions to pathogenesis by FcgammaRs must be made in the context of LD involving CNV regions.

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.

Shann F, Nohynek H, Scott JA, Hesseling A, Flanagan KL, Working Group on Nonspecific Effects of Vaccines. 2010. Randomized trials to study the nonspecific effects of vaccines in children in low-income countries. Pediatr Infect Dis J, 29 (5), pp. 457-461. | Show Abstract | Read more

The Expanded Program on Immunization (EPI) has led to large reductions in morbidity and mortality among children in low-income countries. However, the basic EPI schedule may no longer be optimal because of changes in vaccines, programs, and epidemiologic circumstances. In addition, evidence has accumulated that some EPI vaccines may have nonspecific effects that increase or decrease mortality from subsequent infections with other unrelated organisms. There is therefore a need for randomized trials to evaluate the effects of alternative EPI schedules on all-cause mortality, as well as vaccine efficacy against the target diseases. We have reviewed the available literature on the nonspecific effects of vaccines on mortality, and compiled a list of potential trials that might address this issue. We have then ranked the trials based on the potential importance of the results and the ethical and practical considerations. Trials of early BCG vaccination in low-birth-weight babies, early measles vaccination, and altered timing of DTP vaccination all have a high priority.

Willcocks LC, Carr EJ, Niederer HA, Rayner TF, Williams TN, Yang W, Scott JAG, Urban BC, Peshu N, Vyse TJ et al. 2010. A defunctioning polymorphism in FCGR2B is associated with protection against malaria but susceptibility to systemic lupus erythematosus. Proc Natl Acad Sci U S A, 107 (17), pp. 7881-7885. | Show Abstract | Read more

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease more prevalent in people of African and Asian origin than Caucasian origin. FcgammaRIIb is an inhibitory Fc receptor with a critical role in immune regulation. Mouse data suggest that FcgammaRIIb deficiency increases susceptibility to autoimmune disease but protects against infection. We show that a SNP in human FCGR2B that abrogates receptor function is strongly associated with susceptibility to SLE in both Caucasians and Southeast Asians. The minor allele of this SNP is more common in Southeast Asians and Africans, populations from areas where malaria is endemic, than in Caucasians. We show that homozygosity for the minor allele is associated with substantial protection against severe malaria in an East African population (odds ratio = 0.56; P = 7.1 x 10(-5)). This protective effect against malaria may contribute to the higher frequency of this SNP and hence, SLE in Africans and Southeast Asians.

Moïsi JC, Gatakaa H, Noor AM, Williams TN, Bauni E, Tsofa B, Levine OS, Scott JAG. 2010. Geographic access to care is not a determinant of child mortality in a rural Kenyan setting with high health facility density. BMC Public Health, 10 (1), pp. 142. | Show Abstract | Read more

BACKGROUND: Policy-makers evaluating country progress towards the Millennium Development Goals also examine trends in health inequities. Distance to health facilities is a known determinant of health care utilization and may drive inequalities in health outcomes; we aimed to investigate its effects on childhood mortality. METHODS: The Epidemiological and Demographic Surveillance System in Kilifi District, Kenya, collects data on vital events and migrations in a population of 220,000 people. We used Geographic Information Systems to estimate pedestrian and vehicular travel times to hospitals and vaccine clinics and developed proportional-hazards models to evaluate the effects of travel time on mortality hazard in children less than 5 years of age, accounting for sex, ethnic group, maternal education, migrant status, rainfall and calendar time. RESULTS: In 2004-6, under-5 and under-1 mortality ratios were 65 and 46 per 1,000 live-births, respectively. Median pedestrian and vehicular travel times to hospital were 193 min (inter-quartile range: 125-267) and 49 min (32-72); analogous values for vaccine clinics were 47 (25-73) and 26 min (13-40). Infant and under-5 mortality varied two-fold across geographic locations, ranging from 34.5 to 61.9 per 1000 child-years and 8.8 to 18.1 per 1000, respectively. However, distance to health facilities was not associated with mortality. Hazard Ratios (HR) were 0.99 (95% CI 0.95-1.04) per hour and 1.01 (95% CI 0.95-1.08) per half-hour of pedestrian and vehicular travel to hospital, respectively, and 1.00 (95% CI 0.99-1.04) and 0.97 (95% CI 0.92-1.05) per quarter-hour of pedestrian and vehicular travel to vaccine clinics in children <5 years of age. CONCLUSIONS: Significant spatial variations in mortality were observed across the area, but were not correlated with distance to health facilities. We conclude that given the present density of health facilities in Kenya, geographic access to curative services does not influence population-level mortality.

Williams TN, Uyoga S, Macharia A, Sharif SK, Scott JA. 2010. Preventable deaths in sickle-cell anaemia in African children Reply LANCET, 375 (9713), pp. 461-461. | Read more

Nokes DJ, Ngama M, Bett A, Abwao J, Munywoki P, English M, Scott JAG, Cane PA, Medley GF. 2009. Incidence and severity of respiratory syncytial virus pneumonia in rural Kenyan children identified through hospital surveillance. Clin Infect Dis, 49 (9), pp. 1341-1349. | Show Abstract | Read more

BACKGROUND: Although necessary for developing a rationale for vaccination, the burden of severe respiratory syncytial virus (RSV) disease in children in resource-poor settings remains poorly defined. METHODS: We conducted prospective surveillance of severe and very severe pneumonia in children aged <5 years admitted from 2002 through 2007 to Kilifi district hospital in coastal Kenya. Nasal specimens were screened for RSV antigen by immunofluorescence. Incidence rates were estimated for the well-defined population. RESULTS: Of 25,149 hospital admissions, 7359 patients (29%) had severe or very severe pneumonia, of whom 6026 (82%) were enrolled. RSV prevalence was 15% (20% among infants) and 27% during epidemics (32% among infants). The proportion of case patients aged 3 months was 65%, and the proportion aged 6 months was 43%. Average annual hospitalization rates were 293 hospitalizations per 100,000 children aged <5 years (95% confidence interval, 271-371 hospitalizations per 100,000 children aged <5 years) and 1107 hospitalizations per 100,000 infants (95% confidence interval, 1012-1211 hospitalizations per 100,000 infants). Hospital admission rates were double in the region close to the hospital. Few patients with RSV infection had life-threatening clinical features or concurrent serious illnesses, and the associated mortality was 2.2%. CONCLUSIONS: In this low-income setting, rates of hospital admission with RSV-associated pneumonia are substantial; they are comparable to estimates from the United States but considerably underestimate the burden in the full community. An effective vaccine for children aged >2 months (outside the age group of poor responders) could prevent a large portion of RSV disease. Severity data suggest that the justification for RSV vaccination will be based on the prevention of morbidity, not mortality.

Murdoch DR, O'Brien KL, Scott JAG, Karron RA, Bhat N, Driscoll AJ, Knoll MD, Levine OS. 2009. Breathing new life into pneumonia diagnostics. J Clin Microbiol, 47 (11), pp. 3405-3408. | Read more

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').

Moïsi JC, Saha SK, Falade AG, Njanpop-Lafourcade B-M, Oundo J, Zaidi AKM, Afroj S, Bakare RA, Buss JK, Lasi R et al. 2009. Enhanced diagnosis of pneumococcal meningitis with use of the Binax NOW immunochromatographic test of Streptococcus pneumoniae antigen: a multisite study. Clin Infect Dis, 48 Suppl 2 (s2), pp. S49-S56. | Show Abstract | Read more

BACKGROUND: Accurate etiological diagnosis of meningitis in developing countries is needed, to improve clinical care and to optimize disease-prevention strategies. Cerebrospinal fluid (CSF) culture and latex agglutination testing are currently the standard diagnostic methods but lack sensitivity. METHODS: We prospectively assessed the utility of an immunochromatographic test (ICT) of pneumococcal antigen (NOW Streptococcus pneumoniae Antigen Test; Binax), compared with culture, in 5 countries that are conducting bacterial meningitis surveillance in Africa and Asia. Most CSF samples were collected from patients aged 1-59 months. RESULTS: A total of 1173 CSF samples from suspected meningitis cases were included. The ICT results were positive for 68 (99%) of the 69 culture-confirmed pneumococcal meningitis cases and negative for 124 (99%) of 125 culture-confirmed bacterial meningitis cases caused by other pathogens. By use of culture and latex agglutination testing alone, pneumococci were detected in samples from 7.4% of patients in Asia and 15.6% in Africa. The ICT increased pneumococcal detection, resulting in similar identification rates across sites, ranging from 16.2% in Nigeria to 20% in Bangladesh. ICT detection in specimens from culture-negative cases varied according to region (8.5% in Africa vs. 18.8% in Asia; P< .001), prior antibiotic use (24.2% with prior antibiotic use vs. 12.2% without; P< .001), and WBC count (9.0% for WBC count of 10-99 cells/mL, 22.1% for 100-999 cells/mL, and 25.4% for >or=1000 cells/mL; P< .001 by test for trend). CONCLUSIONS: The ICT provided substantial benefit over the latex agglutination test and culture at Asian sites but not at African sites. With the addition of the ICT, the proportion of meningitis cases attributable to pneumococci was determined to be similar in Asia and Africa. These results suggest that previous studies have underestimated the proportion of pediatric bacterial meningitis cases caused by pneumococci.

Knoll MD, Moïsi JC, Muhib FB, Wonodi CB, Lee EH, Grant L, Gilani Z, Anude CJ, O'Brien KL, Cherian T et al. 2009. Standardizing surveillance of pneumococcal disease. Clin Infect Dis, 48 Suppl 2 (s2), pp. S37-S48. | Show Abstract | Read more

BACKGROUND: Surveillance for invasive pneumococcal disease has been conducted using a variety of case ascertainment methods and diagnostic tools. Interstudy differences in observed rates of invasive pneumococcal disease could reflect variations in surveillance methods or true epidemiological differences in disease incidence. To facilitate comparisons of surveillance data among countries, investigators of Pneumococcal Vaccines Accelerated Development and Introduction Plan-sponsored projects have developed standard case definitions and data reporting methods. METHODS: Investigators developed case definitions for meningitis, pneumonia, and very severe disease using existing World Health Organization guidelines and clinical definitions from Africa and Asia. Standardized case definitions were used to standardize reporting of aggregated results. Univariate analyses were conducted to compare results among countries and to identify factors contributing to detection of Streptococcus pneumoniae. RESULTS: Surveillance sites varied with regard to the age groups targeted, disease syndromes monitored, specimens collected, and laboratory methods employed. The proportion of specimens positive for pneumococcus was greater for cerebrospinal fluid specimens (1.2%-19.4%) than for blood specimens (0.1%-1.4%) in all countries (range, 1.3-38-fold greater). The distribution of disease syndromes and pneumonia severity captured by surveillance differed among countries. The proportion of disease cases with pneumococcus detected varied by syndrome (meningitis, 1.4%-10.8%; pneumonia, 0.2%-1.3%; other, 0.2%-1.2%) and illness severity (nonsevere pneumonia, 0%-2.7%; severe pneumonia, 0.2%-1.2%), although these variations were not consistent for all sites. Antigen testing and polymerase chain reaction increased the proportion of cerebrospinal fluid specimens with pneumococcus identified by 1.3-5.5-fold, compared with culture alone. CONCLUSIONS: Standardized case definitions and data reporting enhanced our understanding of pneumococcal epidemiology and enabled us to assess the contributions of specimen type, disease syndrome, pneumonia severity, and diagnostic tools to rate of pneumococcal detection. Broader standardization and more-detailed data reporting would further improve interpretation of surveillance results.

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.

English M, Scott JAG. 2008. What is the future for global case management guidelines for common childhood diseases? PLoS Med, 5 (12), pp. e241. | Read more

Nokes DJ, Abwao J, Pamba A, Peenze I, Dewar J, Maghenda JK, Gatakaa H, Bauni E, Scott JAG, Maitland K, Williams TN. 2008. Incidence and clinical characteristics of group A rotavirus infections among children admitted to hospital in Kilifi, Kenya. PLoS Med, 5 (7), pp. e153. | Show Abstract | Read more

BACKGROUND: Rotavirus, predominantly of group A, is a major cause of severe diarrhoea worldwide, with the greatest burden falling on young children living in less-developed countries. Vaccines directed against this virus have shown promise in recent trials, and are undergoing effectiveness evaluation in sub-Saharan Africa. In this region limited childhood data are available on the incidence and clinical characteristics of severe group A rotavirus disease. Advocacy for vaccine intervention and interpretation of effectiveness following implementation will benefit from accurate base-line estimates of the incidence and severity of rotavirus paediatric admissions in relevant populations. The study objective was to accurately define the incidence and severity of group A rotavirus disease in a resource-poor setting necessary to make informed decisions on the need for vaccine prevention. METHODS AND FINDINGS: Between 2002 and 2004 we conducted prospective surveillance for group A rotavirus infection at Kilifi District Hospital in coastal Kenya. Children < 13 y of age were eligible as "cases" if admitted with diarrhoea, and "controls" if admitted without diarrhoea. We calculated the incidence of hospital admission with group A rotavirus using data from a demographic surveillance study of 220,000 people in Kilifi District. Of 15,347 childhood admissions 3,296 (22%) had diarrhoea, 2,039 were tested for group A rotavirus antigen and, of these, 588 (29%) were positive. 372 (63%) rotavirus-positive cases were infants. Of 620 controls 19 (3.1%, 95% confidence interval [CI] 1.9-4.7) were rotavirus positive. The annual incidence (per 100,000 children) of rotavirus-positive admissions was 1,431 (95% CI 1,275-1,600) in infants and 478 (437-521) in under-5-y-olds, and highest proximal to the hospital. Compared to children with rotavirus-negative diarrhoea, rotavirus-positive cases were less likely to have coexisting illnesses and more likely to have acidosis (46% versus 17%) and severe electrolyte imbalance except hyponatraemia. In-hospital case fatality was 2% among rotavirus-positive and 9% among rotavirus-negative children. CONCLUSIONS: In Kilifi > 2% of children are admitted to hospital with group A rotavirus diarrhoea in the first 5 y of life. This translates into over 28,000 vaccine-preventable hospitalisations per year across Kenya, and is likely to be a considerable underestimate. Group A rotavirus diarrhoea is associated with acute life-threatening metabolic derangement in otherwise healthy children. Although mortality is low in this clinical research setting this may not be generally true in African hospitals lacking rapid and appropriate management.

Scott JAG. 2008. The global epidemiology of childhood pneumonia 20 years on. Bull World Health Organ, 86 (6), pp. 494-496. | Read more

Scott JAG, Brooks WA, Peiris JSM, Holtzman D, Mulholland EK. 2008. Pneumonia research to reduce childhood mortality in the developing world. J Clin Invest, 118 (4), pp. 1291-1300. | Show Abstract | Read more

Pneumonia is an illness, usually caused by infection, in which the lungs become inflamed and congested, reducing oxygen exchange and leading to cough and breathlessness. It affects individuals of all ages but occurs most frequently in children and the elderly. Among children, pneumonia is the most common cause of death worldwide. Historically, in developed countries, deaths from pneumonia have been reduced by improvements in living conditions, air quality, and nutrition. In the developing world today, many deaths from pneumonia are also preventable by immunization or access to simple, effective treatments. However, as we highlight here, there are critical gaps in our understanding of the epidemiology, etiology, and pathophysiology of pneumonia that, if filled, could accelerate the control of pneumonia and reduce early childhood mortality.

Scott JAG, English M. 2008. What are the implications for childhood pneumonia of successfully introducing Hib and pneumococcal vaccines in developing countries? PLoS Med, 5 (4), pp. e86. | 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.

Edwards T, Scott AG, Munyoki G, Odera VM, Chengo E, Bauni E, Kwasa T, Sander LW, Neville BG, Newton CR. 2008. Active convulsive epilepsy in a rural district of Kenya: a study of prevalence and possible risk factors. Lancet Neurol, 7 (1), pp. 50-56. | Show Abstract | Read more

BACKGROUND: Few large-scale studies of epilepsy have been done in sub-Saharan Africa. We aimed to estimate the prevalence of, treatment gap in, and possible risk factors for active convulsive epilepsy in Kenyan people aged 6 years or older living in a rural area. METHODS: We undertook a three-phase screening survey of 151,408 individuals followed by a nested community case-control study. Treatment gap was defined as the proportion of cases of active convulsive epilepsy without detectable amounts of antiepileptic drugs in blood. FINDINGS: Overall prevalence of active convulsive epilepsy was 2.9 per 1000 (95% CI 2.6-3.2); after adjustment for non-response and sensitivity, prevalence was 4.5 per 1000 (4.1-4.9). Substantial heterogeneity was noted in prevalence, with evidence of clustering. Treatment gap was 70.3% (65.9-74.5), with weak evidence of a difference by sex and area. Adjusted odds of active convulsive epilepsy for all individuals were increased with a family history of non-febrile convulsions (odds ratio 3.3, 95% CI 2.4-4.7; p<0.0001), family history of febrile convulsions (14.6, 6.3-34.1; p<0.0001), history of both seizure types (7.3, 3.3-16.4; p<0.0001), and previous head injury (4.1, 2.1-8.1; p<0.0001). Findings of multivariable analyses in children showed that adverse perinatal events (5.7, 2.6-12.7; p<0.0001) and the child's mother being a widow (5.1, 2.4-11.0; p<0.0001) raised the odds of active convulsive epilepsy. INTERPRETATION: Substantial heterogeneity exists in prevalence of active convulsive epilepsy in this rural area in Kenya. Assessment of prevalence, treatment use, and demographic variation in screening response helped to identify groups for targeted interventions. Adverse perinatal events, febrile illness, and head injury are potentially preventable associated factors for epilepsy in this region.

Abdullahi O, Nyiro J, Lewa P, Slack M, Scott JAG. 2008. The descriptive epidemiology of Streptococcus pneumoniae and Haemophilus influenzae nasopharyngeal carriage in children and adults in Kilifi district, Kenya. Pediatr Infect Dis J, 27 (1), pp. 59-64. | Show Abstract | Read more

BACKGROUND: Transmission and nasopharyngeal colonization are necessary steps en route to invasive pneumococcal or Haemophilus influenzae disease but their patterns vary geographically. In East Africa we do not know how these pathogens are transmitted between population subgroups nor which serotypes circulate commonly. METHODS: We did 2 cross-sectional nasopharyngeal swab surveys selecting subjects randomly from a population register to estimate prevalence and risk-factors for carriage in 2004. H. influenzae type b vaccine was introduced in 2001. RESULTS: Of 450 individuals sampled in the dry season, 414 were resampled during the rainy season. Among subjects 0-4, 5-9, and 10-85 years old pneumococcal carriage prevalence was 57%, 41%, and 6.4%, respectively. H. influenzae prevalence was 26%, 24%, and 3.0%, respectively. Prevalence of H. influenzae type b in children <5 years was 1.7%. Significant risk factors for pneumococcal carriage were rainy season (odds ratio [OR]: 1.65), coryza (OR: 2.29), and coculture of noncapsulate H. influenzae (OR: 7.46). Coryza was also a risk factor for H. influenzae carriage (OR: 1.90). Of 128 H. influenzae isolates, 113 were noncapsulate. Among 279 isolates of Streptococcus pneumoniae, 40 serotypes were represented and the distribution of serotypes varied significantly with age; 7-valent vaccine-types, vaccine-related types, and nonvaccine types comprised 47%, 19%, and 34% of strains from children aged <5 years. Among older persons they comprised 25%, 28%, and 47%, respectively (P = 0.005). CONCLUSIONS: The study shows that pneumococcal carriage is common up to 9 years of age and that the majority of serotypes carried at all ages are not covered specifically by the 7-valent pneumococcal conjugate vaccine.

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.

Abdullahi O, Wanjiru E, Musyimi R, Glass N, Scott JAG. 2007. Validation of nasopharyngeal sampling and culture techniques for detection of Streptococcus pneumoniae in children in Kenya. J Clin Microbiol, 45 (10), pp. 3408-3410. | Show Abstract | Read more

We compared nasopharyngeal swabs against nasal wash cultures for detecting colonizing pneumococci and examined the effect of frozen storage in skim milk-tryptone-glucose-glycerin on culture. Among the 55 children with positive nasal wash cultures, swab cultures were positive for 47 (85%). Of the 96 swabs positive on direct plating, 94 (98%) were positive when recultured after freezing.

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.

Akumu AO, English M, Scott JAG, Griffiths UK. 2007. Economic evaluation of delivering Haemophilus influenzae type b vaccine in routine immunization services in Kenya. Bull World Health Organ, 85 (7), pp. 511-518. | Show Abstract | Read more

OBJECTIVE: Haemophilus influenzae type b (Hib) vaccine was introduced into routine immunization services in Kenya in 2001. We aimed to estimate the cost-effectiveness of Hib vaccine delivery. METHODS: A model was developed to follow the Kenyan 2004 birth cohort until death, with and without Hib vaccine. Incidence of invasive Hib disease was estimated at Kilifi District Hospital and in the surrounding demographic surveillance system in coastal Kenya. National Hib disease incidence was estimated by adjusting incidence observed by passive hospital surveillance using assumptions about access to care. Case fatality rates were also assumed dependent on access to care. A price of US$ 3.65 per dose of pentavalent diphtheria-tetanus-pertussis-hep B-Hib vaccine was used. Multivariate Monte Carlo simulations were performed in order to assess the impact on the cost-effectiveness ratios of uncertainty in parameter values. FINDINGS: The introduction of Hib vaccine reduced the estimated incidence of Hib meningitis per 100,000 children aged < 5 years from 71 to 8; of Hib non-meningitic invasive disease from 61 to 7; and of non-bacteraemic Hib pneumonia from 296 to 34. The costs per discounted disability adjusted life year (DALY) and per discounted death averted were US$ 38 (95% confidence interval, CI: 26-63) and US$ 1197 (95% CI: 814-2021) respectively. Most of the uncertainty in the results was due to uncertain access to care parameters. The break-even pentavalent vaccine price--where incremental Hib vaccination costs equal treatment costs averted from Hib disease--was US$ 1.82 per dose. CONCLUSION: Hib vaccine is a highly cost-effective intervention in Kenya. It would be cost-saving if the vaccine price was below half of its present level.

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.

Cowgill KD, Ndiritu M, Nyiro J, Slack MPE, Chiphatsi S, Ismail A, Kamau T, Mwangi I, English M, Newton CRJC et al. 2006. Effectiveness of Haemophilus influenzae type b Conjugate vaccine introduction into routine childhood immunization in Kenya. JAMA, 296 (6), pp. 671-678. | Show Abstract | Read more

CONTEXT: Haemophilus influenzae type b (Hib) conjugate vaccine is not perceived as a public health priority in Africa because data on Hib disease burden and vaccine effectiveness are scarce. Hib immunization was introduced in Kenyan infants in 2001. OBJECTIVE: To define invasive Hib disease incidence and Hib vaccine program effectiveness in Kenya. DESIGN, SETTING, AND PATIENTS: Culture-based surveillance for invasive Hib disease at Kilifi District Hospital from 2000 through 2005 was linked to demographic surveillance of 38,000 children younger than 5 years in Kilifi District, Kenya. Human immunodeficiency virus (HIV) infection and Hib vaccination status were determined for children with Hib disease admitted 2002-2005. INTERVENTIONS: Introduction of conjugate Hib vaccine within the routine childhood immunization program at ages 6, 10, and 14 weeks beginning November 2001. MAIN OUTCOME MEASURES: Incidence of culture-proven Hib invasive disease before and after vaccine introduction and vaccine program effectiveness. RESULTS: Prior to vaccine introduction, the median age of children with Hib was 8 months; case fatality was 23%. Among children younger than 5 years, the annual incidence of invasive Hib disease 1 year before and 1 and 3 years after vaccine introduction was 66, 47, and 7.6 per 100,000, respectively. For children younger than 2 years, incidence was 119, 82, and 16 per 100,000, respectively. In 2004-2005, vaccine effectiveness was 88% (95% confidence interval, 73%-96%) among children younger than 5 years and 87% (95% confidence interval, 66%-96%) among children younger than 2 years. Of 53 children with Hib admitted during 2002-2005, 29 (55%) were age-ineligible to have received vaccine, 12 (23%) had not been vaccinated despite being eligible, and 12 (23%) had received 2 or more doses of vaccine (2 were HIV positive). CONCLUSIONS: In Kenya, introduction of Hib vaccine into the routine childhood immunization program reduced Hib disease incidence among children younger than 5 years to 12% of its baseline level. This impact was not observed until the third year after vaccine introduction.

Levine OS, O'Brien KL, Knoll M, Adegbola RA, Black S, Cherian T, Dagan R, Goldblatt D, Grange A, Greenwood B et al. 2006. Pneumococcal vaccination in developing countries. Lancet, 367 (9526), pp. 1880-1882. | Read more

Ndiritu M, Cowgill KD, Ismail A, Chiphatsi S, Kamau T, Fegan G, Feikin DR, Newton CRJC, Scott JAG. 2006. Immunization coverage and risk factors for failure to immunize within the Expanded Programme on Immunization in Kenya after introduction of new Haemophilus influenzae type b and hepatitis b virus antigens. BMC Public Health, 6 (1), pp. 132. | Show Abstract | Read more

BACKGROUND: Kenya introduced a pentavalent vaccine including the DTP, Haemophilus influenzae type b and hepatitis b virus antigens in Nov 2001 and strengthened immunization services. We estimated immunization coverage before and after introduction, timeliness of vaccination and risk factors for failure to immunize in Kilifi district, Kenya. METHODS: In Nov 2002 we performed WHO cluster-sample surveys of >200 children scheduled for vaccination before or after introduction of pentavalent vaccine. In Mar 2004 we conducted a simple random sample (SRS) survey of 204 children aged 9-23 months. Coverage was estimated by inverse Kaplan-Meier survival analysis of vaccine-card and mothers' recall data and corroborated by reviewing administrative records from national and provincial vaccine stores. The contribution to timely immunization of distance from clinic, seasonal rainfall, mother's age, and family size was estimated by a proportional hazards model. RESULTS: Immunization coverage for three DTP and pentavalent doses was 100% before and 91% after pentavalent vaccine introduction, respectively. By SRS survey, coverage was 88% for three pentavalent doses. The median age at first, second and third vaccine dose was 8, 13 and 18 weeks. Vials dispatched to Kilifi District during 2001-2003 would provide three immunizations for 92% of the birth cohort. Immunization rate ratios were reduced with every kilometre of distance from home to vaccine clinic (HR 0.95, CI 0.91-1.00), rainy seasons (HR 0.73, 95% CI 0.61-0.89) and family size, increasing progressively up to 4 children (HR 0.55, 95% CI 0.41-0.73). CONCLUSION: Vaccine coverage was high before and after introduction of pentavalent vaccine, but most doses were given late. Coverage is limited by seasonal factors and family size.

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.

Scott JAG, Mlacha Z, Nyiro J, Njenga S, Lewa P, Obiero J, Otieno H, Sampson JS, Carlone GM. 2005. Diagnosis of invasive pneumococcal disease among children in Kenya with enzyme-linked immunosorbent assay for immunoglobulin G antibodies to pneumococcal surface adhesin A. Clin Diagn Lab Immunol, 12 (10), pp. 1195-1201. | Show Abstract | Read more

Diagnostic techniques for invasive pneumococcal disease (IPD) in children are insensitive and underestimate both the burden of disease and the cost-effectiveness of pneumococcal conjugate vaccination (PCV). Consequently, there is little demand for the highly effective PCV outside the United States and Europe. In Kenya, diagnosis of pneumococcal pneumonia in adults was achieved with a sensitivity of 0.70 and a specificity of 0.98 using enzyme-linked immunosorbent assays (ELISAs) of paired plasma samples for immunoglobulin G (IgG) to pneumococcal surface adhesin A (PsaA). We aimed to validate the same technique in children. We assayed paired blood samples from 98 children with IPD, 95 age-matched children with malaria/anemia, and 97 age-matched healthy controls by using an ELISA for anti-PsaA IgG. Sensitivity and specificity were determined in IPD patients and healthy controls. Specificity (0.97; 95% confidence interval [CI], 0.91 to 0.99) and sensitivity (0.42; 95% CI, 0.32 to 0.52) were optimized at a 2.7-fold rise in anti-PsaA antibody concentration. Sensitivity was improved to a maximum of 0.50 by restricting testing to children of <2 years old, by excluding IPD patients who were not sampled on the first day of presentation, and by incorporating high existing antibody concentrations in the analysis. Assay performance was independent of nasopharyngeal carriage of pneumococci at recruitment. This assay improves on existing diagnostic tools for IPD in children but would still leave over half of all cases undetected in epidemiological studies. Effective diagnosis of pneumococcal disease in children is urgently required but poorly served by existing technology.

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.

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.

Laine C, Mwangi T, Thompson CM, Obiero J, Lipsitch M, Scott JAG. 2004. Age-specific immunoglobulin g (IgG) and IgA to pneumococcal protein antigens in a population in coastal kenya. Infect Immun, 72 (6), pp. 3331-3335. | Show Abstract | Read more

Streptococcus pneumoniae is the primary etiological agent of community-acquired pneumonia and a major cause of meningitis and bacteremia. Three conserved pneumococcal proteins-pneumolysin, pneumococcal surface adhesin A (PsaA), and pneumococcal surface protein A (PspA)-are currently being investigated as vaccine candidates. Such protein-based vaccines, if proven effective, could provide a cheaper alternative to conjugate vaccine formulae. Few data from sub-Saharan Africa exist concerning the development of natural antibody to these antigens, however. To investigate the age-specific development of antiprotein immunoglobulin G (IgG) and IgA antibody responses, the sera of 220 persons 2 weeks to 84 years of age from coastal Kenya were assayed using enzyme-linked immunosorbent assays. IgG and IgA antibody responses to each antigen were observed in all age groups. Serum concentrations of IgG and IgA antibody responses to PspA and PdB (a recombinant toxoid derivative of pneumolysin), but not to PsaA, increased significantly with age (P < 0.001). No decline was observed in the sera of the elderly. Anti-protein IgG concentrations were only weakly correlated (0.30 < r < 0.56; P < 0.0001), as were IgA concentrations (0.24 < r < 0.54; P < 0.0001).

Scott JAG, Marston EL, Hall AJ, Marsh K. 2003. Diagnosis of pneumococcal pneumonia by psaA PCR analysis of lung aspirates from adult patients in Kenya. J Clin Microbiol, 41 (6), pp. 2554-2559. | Show Abstract | Read more

psaA is the gene encoding pneumococcal surface adhesin A (PsaA), a 37-kDa protein expressed on the surface of Streptococcus pneumoniae. PCR primers for psaA have been shown to amplify the target DNA sequence in all 90 serotypes of S. pneumoniae and in none of 67 heterologous pathogens and colonizing bacteria of the upper respiratory tract. Pathogenic bacteria identified in lung aspirate specimens cannot normally be dismissed as contaminants or colonizers, which limit the assay specificity of other respiratory tract specimens. psaA PCR analysis was evaluated in 171 lung aspirates from Kenyan adults with acute pneumonia. The limit of detection was one genome equivalent. Sensitivity, estimated in 35 culture-positive lung aspirates, was 0.83 (95% confidence interval, 0.70 to 0.95). psaA PCR analysis extended the number of identifications of S. pneumoniae in lung aspirates from 35 on culture to 61 by both methods. Of 26 new pneumococcal diagnoses, 19 were corroborated by results of blood culture or urine antigen detection. Sequences of the PCR products from 12 positive samples were identical to the psaA target gene fragment. Using an internal control for the PCR, inhibition of psaA PCR was demonstrated in 17% (8 of 47) of false-negative specimens. The results of a control PCR for the human gene beta-actin suggested that false-negative psaA PCR results are attributable to problems of specimen collection, processing, or DNA extraction in 30% of cases (14 of 47). psaA PCR analysis is a sensitive tool for diagnosis of pneumococcal pneumonia in adults.

Nurkka A, Obiero J, Käyhty H, Scott JAG. 2003. Effects of sample collection and storage methods on antipneumococcal immunoglobulin A in saliva. Clin Diagn Lab Immunol, 10 (3), pp. 357-361. | Show Abstract | Read more

Saliva contains components of both the mucosal and systemic immune systems. Variable flow rates, immunoglobulin proteases, and variation in collection and storage methods all introduce differences in the estimated concentrations of antibodies. We evaluated the effect of four collection methods and three storage protocols on the concentrations of immunoglobulin A (IgA) antibodies to pneumococcal capsular antigens 1, 5, 6B, and 14 and to pneumococcal surface adhesin A (PsaA) in saliva. Specimens were collected from 30 healthy Kenyan adults by collecting drool, by pipette suction, and with two commercial kits, OraSure and Oracol. Aliquots from each specimen were snap-frozen with glycerol in liquid nitrogen or stored for 4 to 8 h at +4 degrees C either with or without the addition of protease enzyme inhibitors prior to storage at -70 degrees C. Anticapsular IgA concentrations were not significantly different with different collection methods, but snap-freezing the specimens in liquid nitrogen led to concentrations 41 to 47% higher than those of specimens stored by the other methods (P < 0.0005).

Scott JA, Hall AJ, Muyodi C, Lowe B, Ross M, Chohan B, Mandaliya K, Getambu E, Gleeson F, Drobniewski F, Marsh K. 2000. Aetiology, outcome, and risk factors for mortality among adults with acute pneumonia in Kenya. Lancet, 355 (9211), pp. 1225-1230. | Show Abstract | Read more

BACKGROUND: Despite a substantial disease burden, there is little descriptive epidemiology of acute pneumonia in sub-Saharan Africa. We did this study to define the aetiology of acute pneumonia, to estimate mortality at convalescence, and to analyse mortality risk-factors. METHODS: We studied 281 Kenyan adults who presented to two public hospitals (one urban and one rural) with acute radiologically confirmed pneumonia during 1994-96. We did blood and lung-aspirate cultures, mycobacterial cultures, serotype-specific pneumococcal antigen detection, and serology for viral and atypical agents. FINDINGS: Aetiology was defined in 182 (65%) patients. Streptococcus pneumoniae was the most common causative agent, being found in 129 (46%) cases; Mycobacterium tuberculosis was found in 26 (9%). Of 255 patients followed up for at least 3 weeks, 25 (10%) died at a median age of 33 years. In multivariate analyses, risk or protective factors for mortality were age (odds ratio 1.51 per decade [95% CI 1.04-2.19]), unemployment (4.42 [1.21-16.1]), visiting a traditional healer (5.26 [1.67-16.5]), visiting a pharmacy (0.30 [0.10-0.91]), heart rate (1.64 per 10 beats [1.24-2.16]), and herpes labialis (15.4 [2.22-107]). HIV-1 seropositivity, found in 52%, was not associated with mortality. Death or failure to recover after 3 weeks was more common in patients with pneumococci of intermediate resistance to benzylpenicillin, which comprised 28% of pneumococcal isolates, than in those infected with susceptible pneumococci (5.60 [1.33-23.6]). INTERPRETATION: We suggest that tuberculosis is a sufficiently common cause of acute pneumonia in Kenyan adults to justify routine sputum culture, and that treatment with benzylpenicillin remains appropriate for clinical failure due to M. tuberculosis, intermediate-resistant pneumococci, and other bacterial pathogens. However, interventions restricted to hospital management will fail to decrease mortality associated with socioeconomic, educational, and behavioural factors.

Scott JA, Hall AJ, Leinonen M. 2000. Validation of immune-complex enzyme immunoassays for diagnosis of pneumococcal pneumonia among adults in Kenya. Clin Diagn Lab Immunol, 7 (1), pp. 64-67. | Show Abstract

The efficacy of pneumococcal vaccines in protecting against pneumococcal pneumonia can feasibly be measured only with a diagnostic technique that has a high specificity (0.98 to 1.00) and a sensitivity greatly exceeding that of blood cultures (>0.2 to 0.3). In this context immune-complex enzyme immunoassays (EIAs) offer a novel, convenient diagnostic method, and we have investigated three such assays with appropriate study populations in Kenya. Sera from 129 Kenyan adults with pneumococcal pneumonia and 97 ill controls from the same clinics, but without pneumococcal disease syndromes, were assayed with immune-complex EIAs for pneumolysin, C-polysaccharide, and mixed capsular polysaccharides (Pneumovax II). At an optical density (OD) threshold yielding a specificity of 0.95, the sensitivities (95% confidence intervals) of the assays were 0.22 (0.15 to 0.30), 0.26 (0.19 to 0.34), and 0.22 (0.15 to 0.29), respectively. For pneumolysin immune complexes, human immunodeficiency virus (HIV)-positive patients had a higher mean OD than HIV-negative patients (639 versus 321; P < 0.0001), but stratification by HIV infection status did not alter the performance of this test. Combining the results of all three EIAs did not enhance the diagnostic performances of the individual assays. In Kenyan adults the sensitivities of the immune-complex EIAs could exceed that of blood cultures only at levels of specificity that were insufficient for the performance of vaccine efficacy studies.

Scott JA, Hall AJ. 1999. The value and complications of percutaneous transthoracic lung aspiration for the etiologic diagnosis of community-acquired pneumonia. Chest, 116 (6), pp. 1716-1732. | Read more

Fedson DS, Scott JA. 1999. The burden of pneumococcal disease among adults in developed and developing countries: what is and is not known. Vaccine, 17 Suppl 1 pp. S11-S18. | Show Abstract | Read more

The burden of pneumococcal disease among adults in developed countries is neither widely known nor appreciated. The incidence of pneumococcal pneumonia is uncertain because a precise diagnosis cannot be obtained for most patients. Population-based data on invasive pneumococcal disease (e.g., bacteraemia and meningitis) suggest an annual incidence in all developed countries of > or =15-20 cases per 100,000 persons of all ages and > or =50 cases per 100,000 elderly adults (> or =65 years). In developing countries there are no population-based data on the burden of pneumococcal disease among adults. Studies of high risk groups, hospital-based studies, vaccine efficacy trials, extrapolations from surveillance of "native populations" in developed countries, and demographic studies in developing regions all suggest a high burden of disease. The broad variation in these estimates, however, indicates that better studies are needed. Increased use of pneumococcal vaccines among adults in all countries will depend on better scientific and public understanding of the burden of pneumococcal disease. In developing countries, intensive community-based studies of the impact of pneumococcal disease, or, alternatively, a "vaccine probe" approach, in which a population is vaccinated and the reduction in pneumonia is compared with that in a control population, could give more accurate estimates of the burden of disease and of the potential effectiveness of pneumococcal vaccination among adults.

Scott JA, Hall AJ, Hannington A, Edwards R, Mwarumba S, Lowe B, Griffiths D, Crook D, Marsh K. 1998. Serotype distribution and prevalence of resistance to benzylpenicillin in three representative populations of Streptococcus pneumoniae isolates from the coast of Kenya. Clin Infect Dis, 27 (6), pp. 1442-1450. | Show Abstract | Read more

As surveillance data from sub-Saharan Africa are few, three representative populations of Streptococcus pneumoniae isolates were examined in Kenya for serotype distribution and Etest minimum inhibitory concentrations (MICs) of benzylpenicillin: (1) 75 lung aspirate or blood culture isolates from 301 consecutive adult patients with pneumonia, (2) 112 invasive isolates from continuous pediatric inpatient surveillance over 4 years, and (3) 97 nasopharyngeal isolates from systematically selected sick children. The proportions with benzylpenicillin MICs of > or = 0.1 microgram/mL were 0.27, 0.29, and 0.47, respectively. Vaccine-related serotypes accounted for 96% of invasive isolates from children and 90% of those from human immunodeficiency virus (HIV)-seropositive adults. Serotype 1 accounted for 44% of pneumococci from HIV-seronegative patients but only 5% of those from HIV-seropositive patients (P = .0002). Of serotype 1 isolates, 98% were susceptible to benzylpenicillin, but serogroups 13, 14, 19, and 23 were strongly associated with an MIC of > or = 0.1 microgram/mL.

Scott JA, Hall AJ, Dagan R, Dixon JM, Eykyn SJ, Fenoll A, Hortal M, Jetté LP, Jorgensen JH, Lamothe F et al. 1996. Serogroup-specific epidemiology of Streptococcus pneumoniae: associations with age, sex, and geography in 7,000 episodes of invasive disease. Clin Infect Dis, 22 (6), pp. 973-981. | Show Abstract | Read more

A study sample of 7,010 episodes of invasive Streptococcus pneumoniae disease was obtained by combining 13 existing datasets. Disease episodes due to each of 12 pneumococcal serogroups (1, 3-9, 14, 18, 19, and 23) were then compared with episodes in a constant internal control group to describe serogroup-specific variations in disease frequency by age, sex, and geographic origin. The results are presented as odds ratios (with 95% confidence intervals) derived by logistic regression, with adjustment for the major confounders, including dataset of origin. Variation in the male:female ratios between serogroups is small, suggesting that capsular characteristics are an unlikely explanation for the male preference of S. pneumoniae. Serogroups associated with higher nasopharyngeal prevalence (e.g., 19 and 24) are relatively more common in Europe and North American, while the invasive serotypes 1 and 5 are much more common in South America. The custom of reporting serogroup frequencies in two age groups, children and adults, conceals much of the variation in the age distributions across the whole span of life. The reduction of risk associated with serogroups 6, 14, 18, 19, and 23 beyond childhood follows different gradients, being most abrupt in serogroups 14 and most gradual in serogroup 18. The relative risk of disease with serotype 1 declines steadily throughout life, while with serotypes 3 and 8 it increases over middle age. Serogroups 7 and 23 are found unusually frequently in the third decade of life. Because of the wide differences in the epidemiology of individual serogroups of S. pneumoniae, it is questionable whether pneumococcal infection should continue to be classified as a single disease entity.

Michie C, Scott A, Cheesbrough J, Beverley P, Pasvol G. 1994. Streptococcal toxic shock-like syndrome: evidence of superantigen activity and its effects on T lymphocyte subsets in vivo. Clin Exp Immunol, 98 (1), pp. 140-144. | Show Abstract | Read more

Toxic shock-like syndrome is a serious complication of invasive streptococcal disease. The syndrome is believed to be the consequence of exposure to exotoxins produced by the infecting organisms which behave as superantigens. We describe two patients who fulfilled clinical criteria for this syndrome, one of whom died. Streptococci isolated from both patients were found to produce a mitogen specific for the V beta 2+ T lymphocyte subset in vitro, which had the characteristics of a superantigen. The phenotype and function of lymphocytes collected from both patients during the acute phase of their illness demonstrated a marked reduction in circulating CD4+ ('helper') and CD45RA+ ('naive') T lymphocytes expressing the V beta 2 chain, and an increase of those expressing CD8, CD45RO and the V beta 2 chain. This effect resolved within 4 weeks in the patient who survived. Proliferation assays demonstrated no T cell anergy in either patient. Stimulation of lymphocytes by superantigen in these clinical situations does not appear to cause permanent deletion of T cell subsets, as has been observed in animal models.

Godfrey-Faussett P, Stoker NG, Scott JA, Pasvol G, Kelly P, Clancy L. 1993. DNA fingerprints of Mycobacterium tuberculosis do not change during the development of rifampicin resistance. Tuber Lung Dis, 74 (4), pp. 240-243. | Show Abstract | Read more

Drug-resistant tuberculosis has become a major public health problem. Resistance to rifampicin probably arises through mutations in the mycobacterial RNA polymerase. Patients may acquire rifampicin resistant tuberculosis by three mechanisms: (1) infection with a resistant organism, (2) selection of a sub-population of resistant organisms that remain contained whilst the more virulent wild type is present, (3) mutations within the population of bacilli causing the original infection. Sequential isolates of Mycobacterium tuberculosis were collected from 2 patients who developed rifampicin resistance whilst on treatment. One patient was immunosuppressed with HIV-infection; in the other patient the original isolate was also resistant to isoniazid. DNA fingerprinting techniques were used to type the isolates. No differences were found between the fingerprints of isolates from before and after the development of resistance. These data suggest that the third of the mechanisms listed above was responsible for the acquisition of rifampicin resistance in these 2 patients.

Davidson RN, Scott JA, Behrens RH, Warhurst D. 1993. Under-reporting of malaria, a notifiable disease, in Britain. J Infect, 26 (3), pp. 348-349. | Read more

Scott JA, Davidson RN, Moody AH, Grant HR, Felmingham D, Scott GM, Olliaro P, Bryceson AD. 1992. Aminosidine (paromomycin) in the treatment of leishmaniasis imported into the United Kingdom. Trans R Soc Trop Med Hyg, 86 (6), pp. 617-619. | Show Abstract | Read more

We report 11 patients with leishmaniasis from different endemic areas, treated in the UK with intravenous aminosidine alone or in combination with other drugs. Clinical and parasitological cures were achieved in all 7 patients from the Mediterranean zone who had visceral disease, with one relapse. Two of 4 patients with cutaneous or mucosal disease were cured; the other 2, from Iraq and Iran, did not respond. Toxic effects were high-tone deafness in 2 patients, one of whom had pre-existing renal impairment, and transient, mild elevation of serum creatinine in 3. Aminosidine is an effective, tolerable and relatively non-toxic alternative to existing antileishmanial drugs for the treatment of visceral leishmaniasis. Further studies will be needed to assess its place in cutaneous and mucosal disease.

Davidson RN, Croft SL, Scott A, Maini M, Moody AH, Bryceson AD. 1991. Liposomal amphotericin B in drug-resistant visceral leishmaniasis. Lancet, 337 (8749), pp. 1061-1062. | Show Abstract | Read more

The treatment of visceral leishmaniasis (VL) may be complicated by drug toxicity or intolerance, and by drug resistance. Amphotericin B (AmB) is effective, but its use is limited by toxicity: renal impairment, anaemia, fever, malaise, and hypokalaemia are common. Liposomes have been proposed as an effective way to target drugs at macrophages, which are the cells infected in visceral leishmaniasis. In animals AmB incorporated into liposomes is highly effective against experimental leishmaniasis, with low toxicity. This report is of the successful treatment of a patient with multiply drug-resistant visceral leishmaniasis with a commercially prepared formulation of liposomal amphotericin B (L-AmB) ('AmBisome', Vestar, San Dimas, California, USA). We also report, for comparison, a patient treated with conventional AmB, and preliminary studies in mice comparing the two agents.

Scott JA, Davidson RN, Moody AH, Bryceson AD. 1991. Diagnosing multiple parasitic infections: trypanosomiasis, loiasis and schistosomiasis in a single case. Scand J Infect Dis, 23 (6), pp. 777-780. | Show Abstract | Read more

A case is reported of a 32-year-old traveller with loiasis, schistosomiasis and African trypanosomiasis. The patient had been working in oil exploration in Nigeria and Gabon and presented with Calabar swellings and carpal tunnel syndrome. Serology for all 3 diseases was positive but microfilariae of Loa loa and ova of schistosomiasis were not found. Treatment with diethylcarbamazine and praziquantel was given for loiasis and schistosomiasis respectively. Trypanosomes were isolated from a lymph node aspirate only after repetition of the procedure 2 months later and the patient was treated with suramin. He developed a drug induced nephritis and was then treated successfully with alpha-difluoromethylornithine. There is a discussion of the difficulties encountered making these diagnoses in Europeans particularly where there are atypical clinical features. The risks of rural work in West Africa are noted and the importance of considering all parasitic diseases relevant to the travel/occupational history is emphasised.

Etyang AO, Munge K, Bunyasi EW, Matata L, Ndila C, Kapesa S, Owiti M, Khandwalla I, Brent AJ, Tsofa B et al. 2014. Burden of disease in adults admitted to hospital in a rural region of coastal Kenya: an analysis of data from linked clinical and demographic surveillance systems. Lancet Glob Health, 2 (4), pp. e216-e224. | Show Abstract | Read more

BACKGROUND: Estimates of the burden of disease in adults in sub-Saharan Africa largely rely on models of sparse data. We aimed to measure the burden of disease in adults living in a rural area of coastal Kenya with use of linked clinical and demographic surveillance data. METHODS: We used data from 18,712 adults admitted to Kilifi District Hospital (Kilifi, Kenya) between Jan 1, 2007, and Dec 31, 2012, linked to 790,635 person-years of observation within the Kilifi Health and Demographic Surveillance System, to establish the rates and major causes of admission to hospital. These data were also used to model disease-specific disability-adjusted life-years lost in the population. We used geographical mapping software to calculate admission rates stratified by distance from the hospital. FINDINGS: The main causes of admission to hospital in women living within 5 km of the hospital were infectious and parasitic diseases (303 per 100,000 person-years of observation), pregnancy-related disorders (239 per 100,000 person-years of observation), and circulatory illnesses (105 per 100,000 person-years of observation). Leading causes of hospital admission in men living within 5 km of the hospital were infectious and parasitic diseases (169 per 100,000 person-years of observation), injuries (135 per 100,000 person-years of observation), and digestive system disorders (112 per 100,000 person-years of observation). HIV-related diseases were the leading cause of disability-adjusted life-years lost (2050 per 100,000 person-years of observation), followed by non-communicable diseases (741 per 100,000 person-years of observation). For every 5 km increase in distance from the hospital, all-cause admission rates decreased by 11% (95% CI 7–14) in men and 20% (17–23) in women. The magnitude of this decline was highest for endocrine disorders in women (35%; 95% CI 22–46) and neoplasms in men (30%; 9–45). INTERPRETATION: Adults in rural Kenya face a combined burden of infectious diseases, pregnancy-related disorders, cardiovascular illnesses, and injuries. Disease burden estimates based on hospital data are affected by distance from the hospital, and the amount of underestimation of disease burden differs by both disease and sex. FUNDING: The Wellcome Trust, GAVI Alliance.

Hammitt LL, Akech DO, Morpeth SC, Karani A, Kihuha N, Nyongesa S, Bwanaali T, Mumbo E, Kamau T, Sharif SK, Scott JAG. 2014. Population effect of 10-valent pneumococcal conjugate vaccine on nasopharyngeal carriage of Streptococcus pneumoniae and non-typeable Haemophilus influenzae in Kilifi, Kenya: findings from cross-sectional carriage studies. Lancet Glob Health, 2 (7), pp. e397-e405. | Show Abstract | Read more

BACKGROUND: The effect of 7-valent pneumococcal conjugate vaccine (PCV) in developed countries was enhanced by indirect protection of unvaccinated individuals, mediated by reduced nasopharyngeal carriage of vaccine-serotype pneumococci. The potential indirect protection of 10-valent PCV (PCV10) in a developing country setting is unknown. We sought to estimate the effectiveness of introduction of PCV10 in Kenya against carriage of vaccine serotypes and its effect on other bacteria. METHODS: PCV10 was introduced into the infant vaccination programme in Kenya in January, 2011, accompanied by a catch-up campaign in Kilifi County for children aged younger than 5 years. We did annual cross-sectional carriage studies among an age-stratified, random population sample in the 2 years before and 2 years after PCV10 introduction. A nasopharyngeal rayon swab specimen was collected from each participant and was processed in accordance with WHO recommendations. Prevalence ratios of carriage before and after introduction of PCV10 were calculated by log-binomial regression. FINDINGS: About 500 individuals were enrolled each year (total n=2031). Among children younger than 5 years, the baseline (2009-10) carriage prevalence was 34% for vaccine-serotype Streptococcus pneumoniae, 41% for non-vaccine-serotype Streptococcus pneumoniae, and 54% for non-typeable Haemophilus influenzae. After PCV10 introduction (2011-12), these percentages were 13%, 57%, and 40%, respectively. Adjusted prevalence ratios were 0·36 (95% CI 0·26-0·51), 1·37 (1·13-1·65), and 0·62 (0·52-0·75), respectively. Among individuals aged 5 years or older, the adjusted prevalence ratios for vaccine-serotype and non-vaccine-serotype S pneumoniae carriage were 0·34 (95% CI 0·18-0·62) and 1·13 (0·92-1·38), respectively. There was no change in prevalence ratio for Staphylococcus aureus (adjusted prevalence ratio for those <5 years old 1·02, 95% CI 0·52-1·99, and for those ≥5 years old 0·90, 0·60-1·35). INTERPRETATION: After programmatic use of PCV10 in Kilifi, carriage of vaccine serotypes was reduced by two-thirds both in children younger than 5 years and in older individuals. These findings suggest that PCV10 introduction in Africa will have substantial indirect effects on invasive pneumococcal disease. FUNDING: GAVI Alliance and Wellcome Trust.

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.

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.

Jokinen J, Scott JAG. 2010. Estimating the proportion of pneumonia attributable to pneumococcus in Kenyan adults: latent class analysis. Epidemiology, 21 (5), pp. 719-725. | Show Abstract | Read more

BACKGROUND: Community-acquired pneumonia is a common cause of hospitalization among African adults, and Streptococcus pneumoniae is assumed to be a frequent cause. Pneumococcal conjugate vaccine is currently being introduced into childhood immunization programs in Africa. The case for adult vaccination is dependent on the contribution of the pneumococcus to the hospital pneumonia burden. METHODS: Pneumococcal diagnosis is complex because there is no gold standard, and culture methods are invalidated by antibiotic use. We used latent class analysis to estimate the proportion of pneumonia episodes caused by pneumococcus. Furthermore, we extended this methodology to evaluate the effect of antimicrobial treatment on test accuracies and the prevalence of the disease. The study combined data from 5 validation studies of pneumococcal diagnostic tests performed on 281 Kenyan adults with pneumonia. RESULTS: The proportion of pneumonia episodes attributable to pneumococcus was 0.46 (95% confidence interval = 0.36-0.57). Failure to account for the effect of antimicrobial exposure underestimates this proportion as 0.32. A history of antibiotic exposure was a poor predictor of antimicrobial activity in patients' urine. Blood culture sensitivity for pneumococcus was estimated at 0.24 among patients with antibiotic exposure, and 0.75 among those without. CONCLUSIONS: The large contribution of pneumococcus to adult pneumonia provides a strong case for the investigation of pneumococcal vaccines in African adults.

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.

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.

Scott JAG, Brooks WA, Peiris JSM, Holtzman D, Mulholland EK. 2008. Pneumonia research to reduce childhood mortality in the developing world. J Clin Invest, 118 (4), pp. 1291-1300. | Show Abstract | Read more

Pneumonia is an illness, usually caused by infection, in which the lungs become inflamed and congested, reducing oxygen exchange and leading to cough and breathlessness. It affects individuals of all ages but occurs most frequently in children and the elderly. Among children, pneumonia is the most common cause of death worldwide. Historically, in developed countries, deaths from pneumonia have been reduced by improvements in living conditions, air quality, and nutrition. In the developing world today, many deaths from pneumonia are also preventable by immunization or access to simple, effective treatments. However, as we highlight here, there are critical gaps in our understanding of the epidemiology, etiology, and pathophysiology of pneumonia that, if filled, could accelerate the control of pneumonia and reduce early childhood mortality.

Cowgill KD, Ndiritu M, Nyiro J, Slack MPE, Chiphatsi S, Ismail A, Kamau T, Mwangi I, English M, Newton CRJC et al. 2006. Effectiveness of Haemophilus influenzae type b Conjugate vaccine introduction into routine childhood immunization in Kenya. JAMA, 296 (6), pp. 671-678. | Show Abstract | Read more

CONTEXT: Haemophilus influenzae type b (Hib) conjugate vaccine is not perceived as a public health priority in Africa because data on Hib disease burden and vaccine effectiveness are scarce. Hib immunization was introduced in Kenyan infants in 2001. OBJECTIVE: To define invasive Hib disease incidence and Hib vaccine program effectiveness in Kenya. DESIGN, SETTING, AND PATIENTS: Culture-based surveillance for invasive Hib disease at Kilifi District Hospital from 2000 through 2005 was linked to demographic surveillance of 38,000 children younger than 5 years in Kilifi District, Kenya. Human immunodeficiency virus (HIV) infection and Hib vaccination status were determined for children with Hib disease admitted 2002-2005. INTERVENTIONS: Introduction of conjugate Hib vaccine within the routine childhood immunization program at ages 6, 10, and 14 weeks beginning November 2001. MAIN OUTCOME MEASURES: Incidence of culture-proven Hib invasive disease before and after vaccine introduction and vaccine program effectiveness. RESULTS: Prior to vaccine introduction, the median age of children with Hib was 8 months; case fatality was 23%. Among children younger than 5 years, the annual incidence of invasive Hib disease 1 year before and 1 and 3 years after vaccine introduction was 66, 47, and 7.6 per 100,000, respectively. For children younger than 2 years, incidence was 119, 82, and 16 per 100,000, respectively. In 2004-2005, vaccine effectiveness was 88% (95% confidence interval, 73%-96%) among children younger than 5 years and 87% (95% confidence interval, 66%-96%) among children younger than 2 years. Of 53 children with Hib admitted during 2002-2005, 29 (55%) were age-ineligible to have received vaccine, 12 (23%) had not been vaccinated despite being eligible, and 12 (23%) had received 2 or more doses of vaccine (2 were HIV positive). CONCLUSIONS: In Kenya, introduction of Hib vaccine into the routine childhood immunization program reduced Hib disease incidence among children younger than 5 years to 12% of its baseline level. This impact was not observed until the third year after vaccine introduction.

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.

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.

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.

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