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1.  What Is the Future for Global Case Management Guidelines for Common Childhood Diseases? 
PLoS Medicine  2008;5(12):e241.
Mike English and J. Anthony G. Scott propose a framework for national surveillance, monitoring, and research that could help inform guideline development in low-income settings.
PMCID: PMC2596856  PMID: 19071957
2.  Clinical and Epidemiological Implications of 24‐Hour Ambulatory Blood Pressure Monitoring for the Diagnosis of Hypertension in Kenyan Adults: A Population‐Based Study 
The clinical and epidemiological implications of using ambulatory blood pressure monitoring (ABPM) for the diagnosis of hypertension have not been studied at a population level in sub‐Saharan Africa. We examined the impact of ABPM use among Kenyan adults.
Methods and Results
We performed a nested case–control study of diagnostic accuracy. We selected an age‐stratified random sample of 1248 adults from the list of residents of the Kilifi Health and Demographic Surveillance System in Kenya. All participants underwent a screening blood pressure (BP) measurement. All those with screening BP ≥140/90 mm Hg and a random subset of those with screening BP <140/90 mm Hg were invited to undergo ABPM. Based on the 2 tests, participants were categorized as sustained hypertensive, masked hypertensive, “white coat” hypertensive, or normotensive. Analyses were weighted by the probability of undergoing ABPM. Screening BP ≥140/90 mm Hg was present in 359 of 986 participants, translating to a crude population prevalence of 23.1% (95% CI 16.5–31.5%). Age standardized prevalence of screening BP ≥140/90 mm Hg was 26.5% (95% CI 19.3–35.6%). On ABPM, 186 of 415 participants were confirmed to be hypertensive, with crude prevalence of 15.6% (95% CI 9.4–23.1%) and age‐standardized prevalence of 17.1% (95% CI 11.0–24.4%). Age‐standardized prevalence of masked and white coat hypertension were 7.6% (95% CI 2.8–13.7%) and 3.8% (95% CI 1.7–6.1%), respectively. The sensitivity and specificity of screening BP measurements were 80% (95% CI 73–86%) and 84% (95% CI 79–88%), respectively. BP indices and validity measures showed strong age‐related trends.
Screening BP measurement significantly overestimated hypertension prevalence while failing to identify ≈50% of true hypertension diagnosed by ABPM. Our findings suggest significant clinical and epidemiological benefits of ABPM use for diagnosing hypertension in Kenyan adults.
PMCID: PMC5210452  PMID: 27979807
ambulatory blood pressure monitoring; diagnostic accuracy; hypertension; masked hypertension; sub‐Saharan Africa; white coat hypertension; High Blood Pressure; Hypertension; Diagnostic Testing
3.  Pertussis-Associated Pneumonia in Infants and Children From Low- and Middle-Income Countries Participating in the PERCH Study 
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 with World 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 stratum 1–5 months, 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 pertussis-negative 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/µL (aOR, 4.6), and to have lymphocyte counts >10 000 cells/µL (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.
PMCID: PMC5106621  PMID: 27838672
pertussis; infant; pneumonia; whooping cough; vaccination
4.  The Malaria-High Blood Pressure Hypothesis 
Circulation Research  2016;119(1):36-40.
Several studies have demonstrated links between infectious diseases and cardiovascular conditions. Malaria and hypertension are widespread in many low- and middle-income countries, but the possible link between them has not been considered.
In this article, we outline the basis for a possible link between malaria and hypertension and discuss how the hypothesis could be confirmed or refuted.
Methods and Results:
We reviewed published literature on factors associated with hypertension and checked whether any of these were also associated with malaria. We then considered various study designs that could be used to test the hypothesis. Malaria causes low birth weight, malnutrition, and inflammation, all of which are associated with hypertension in high-income countries. The hypothetical link between malaria and hypertension can be tested through the use of ecological, cohort, or Mendelian randomization studies, each of which poses specific challenges.
Confirmation of the existence of a causative link with malaria would be a paradigm shift in efforts to prevent and control hypertension and would stimulate wider research on the links between infectious and noncommunicable disease.
PMCID: PMC4920207  PMID: 27151400
arterial stiffness; blood pressure; epidemiology; inflammation; malaria
5.  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  2015;10(6):e0128064.
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).
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.
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.
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 NCT01028326
PMCID: PMC4471099  PMID: 26083474
6.  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 
The Lancet. Global Health  2016;4(3):e185-e194.
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.
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.
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.
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.
Gavi, the Vaccine Alliance, Wellcome Trust, European Society for Paediatric Infectious Diseases, and National Institute for Health Research.
PMCID: PMC4763163  PMID: 26853149
7.  Invasive Group A Streptococcus Infection among Children, Rural Kenya 
Emerging Infectious Diseases  2016;22(2):224-232.
These infections cause serious illness, especially in neonates.
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.
PMCID: PMC4734542  PMID: 26811918
child; children; neonatal; infection; Streptococcus pyogenes; group A Streptococcus; GAS; children; Kenya; bacteria
8.  Use of vaccines as probes to define disease burden 
Lancet (London, England)  2014;383(9930):1762-1770.
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.
PMCID: PMC4682543  PMID: 24553294
9.  Risk of Injection-Site Abscess among Infants Receiving a Preservative-Free, Two-Dose Vial Formulation of Pneumococcal Conjugate Vaccine in Kenya 
PLoS ONE  2015;10(10):e0141896.
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.
PMCID: PMC4625023  PMID: 26509274
10.  Invasive Salmonellosis in Kilifi, Kenya 
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.
PMCID: PMC4596936  PMID: 26449944
Salmonella; nontyphoidal; Typhi; incidence; Kenya
11.  What Are the Implications for Childhood Pneumonia of Successfully Introducing Hib and Pneumococcal Vaccines in Developing Countries? 
PLoS Medicine  2008;5(4):e86.
The authors look to the future and imagine the implications of a successful vaccination campaign againstH. influenzae type b and pneumococcus.
PMCID: PMC2292749  PMID: 19226734
12.  Mapping pneumonia research: A systematic analysis of UK investments and published outputs 1997–2013 
EBioMedicine  2015;2(9):1193-1199.
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.
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.
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.
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.
•Pneumonia has historically received little research funding in the UK.•Pneumonia-related funding is increasing, particularly in translational research.•Compared to global burden, pneumonia remains poorly-funded compared to influenza and tuberculosis.
PMCID: PMC4588381  PMID: 26501117
Pneumonia; Pneumococcal; Investments; Financing; Policy; Bibliometrics; Publications
13.  The Potential for Reducing the Number of Pneumococcal Conjugate Vaccine Doses While Sustaining Herd Immunity in High-Income Countries 
PLoS Medicine  2015;12(6):e1001839.
Stefan Flasche and colleagues consider whether the number of PCV doses in the infant schedule could be reduced without compromising its public health benefit in high-income settings.
PMCID: PMC4461163  PMID: 26057994
14.  Quantifying maternally derived respiratory syncytial virus specific neutralising antibodies in a birth cohort from coastal Kenya 
Vaccine  2015;33(15):1797-1801.
•We report on the characteristics of RSV neutralising antibodies in a birth cohort.•The levels of cord RSV antibodies increase during seasonal virus transmission.•The rate of decay of RSV antibodies following birth is independent of cord titre.•There is a high degree of variation between individuals in rate of decay.•Important baseline data to maternal RSV vaccine development are provided.
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.
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.
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.
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.
PMCID: PMC4376380  PMID: 25725445
Vaccine design; Respiratory syncytial virus; Maternal antibody; Birth cohort; Neutralisation; Rate of decay
15.  The Definition of Pneumonia, the Assessment of Severity, and Clinical Standardization in the Pneumonia Etiology Research for Child Health Study 
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.
PMCID: PMC3297550  PMID: 22403224
16.  Estimating the proportion of pneumonia attributable to pneumococcus in Kenyan adults: Latent class analysis 
Epidemiology (Cambridge, Mass.)  2010;21(5):719-725.
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.
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 five validation studies of pneumococcal diagnostic tests performed on 281 Kenyan adults with pneumonia.
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 anti-microbial 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.
The large contribution of pneumococcus to adult pneumonia provides a strong case for the investigation of pneumococcal vaccines in African adults.
PMCID: PMC2923075  PMID: 20562627
17.  Making standards for quantitative real-time pneumococcal PCR 
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.
PMCID: PMC5121202  PMID: 27896138
Quantitative; Real-time PCR; Streptococcus pneumoniae; Standards
18.  Diagnosis of Childhood Tuberculosis and Host RNA Expression in Africa 
The New England journal of medicine  2014;370(18):1712-1723.
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).
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.
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%.
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).
PMCID: PMC4069985  PMID: 24785206
19.  Carriage of Staphylococcus aureus in Thika Level 5 Hospital, Kenya: a cross-sectional study 
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.
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.
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.
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.
PMCID: PMC4107749  PMID: 25057351
Staphylococcus aureus; MRSA; Kenya; Hospitals; Carriage prevalence
20.  Pneumonia research to reduce childhood mortality in the developing world 
The Journal of Clinical Investigation  2008;118(4):1291-1300.
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.
PMCID: PMC2276784  PMID: 18382741
21.  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 
The Lancet Global Health  2014;2(4):e216-e224.
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.
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.
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).
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.
The Wellcome Trust, GAVI Alliance.
PMCID: PMC3986034  PMID: 24782954
22.  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  2014;9(1):e85459.
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.
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.
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.
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 NCT01028326
PMCID: PMC3897448  PMID: 24465570
24.  Population Genetic Structure of Streptococcus pneumoniae in Kilifi, Kenya, Prior to the Introduction of Pneumococcal Conjugate Vaccine 
PLoS ONE  2013;8(11):e81539.
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.
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.
PMCID: PMC3839905  PMID: 24282605
25.  Changing Use of Surgical Antibiotic Prophylaxis in Thika Hospital, Kenya: A Quality Improvement Intervention with an Interrupted Time Series Design 
PLoS ONE  2013;8(11):e78942.
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.
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.
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.
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.
PMCID: PMC3823974  PMID: 24244390

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