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1.  Successive Respiratory Syncytial Virus Epidemics in Local Populations Arise from Multiple Variant Introductions, Providing Insights into Virus Persistence 
Journal of Virology  2015;89(22):11630-11642.
Respiratory syncytial virus (RSV) is a global respiratory pathogen of humans, with infection occurring characteristically as recurrent seasonal epidemics. Unlike influenza viruses, little attention has been paid to the mechanism underlying worldwide spread and persistence of RSV and how this may be discerned through an improved understanding of the introduction and persistence of RSV in local communities. We analyzed 651 attachment (G) glycoprotein nucleotide sequences of RSV B collected over 11 epidemics (2002 to 2012) in Kilifi, Kenya, and contemporaneous data collected elsewhere in Kenya and 18 other countries worldwide (2002 to 2012). Based on phylogeny, genetic distance and clustering patterns, we set out pragmatic criteria to classify local viruses into distinct genotypes and variants, identifying those newly introduced and those locally persisting. Three genotypes were identified in the Kilifi data set: BA (n = 500), SAB1 (n = 148), and SAB4 (n = 3). Recurrent RSV epidemics in the local population were composed of numerous genetic variants, most of which have been newly introduced rather than persisting in the location from season to season. Global comparison revealed that (i) most Kilifi variants do not cluster closely with strains from outside Kenya, (ii) some Kilifi variants were closely related to those observed outside Kenya (mostly Western Europe), and (iii) many variants were circulating elsewhere but were never detected in Kilifi. These results are consistent with the hypothesis that year-to-year presence of RSV at the local level (i.e., Kilifi) is achieved primarily, but not exclusively, through introductions from a pool of variants that are geographically restricted (i.e., to Kenya or to the region) rather than global.
IMPORTANCE The mechanism by which RSV persists and reinvades local populations is poorly understood. We investigated this by studying the temporal patterns of RSV variants in a rural setting in tropical Africa and comparing these variants with contemporaneous variants circulating in other countries. We found that periodic seasonal RSV transmission at the local level appears to require regular new introductions of variants. However, importantly, the evidence suggests that the source of new variants is mostly geographically restricted, and we hypothesize that year-to-year RSV persistence is at the country level rather than the global level. This has implications for control.
PMCID: PMC4645665  PMID: 26355091
2.  Treatment Failure among Kenyan Children with Severe Pneumonia – a Cohort Study 
Pneumonia is the leading cause of childhood mortality worldwide. The WHO recommends presumptive treatment based on clinical syndromes. Recent studies raise concerns over the frequency of treatment failure in Africa.
We applied a definition of treatment failure to data prospectively collected from children who were 2-59 months with severe, or very severe pneumonia admitted to Kilifi District Hospital, Kenya form May 2007 through May 2008 and treated using WHO guidelines. The primary outcome was treatment failure at 48 hours.
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. 111 (20%, 95% CI 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 one 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, Sa02<95%, severe malnutrition, HIV, and age <1 year in multivariable models.
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, pre-hospital care and treatment of sepsis.
PMCID: PMC3691501  PMID: 22692700
Pneumonia; Treatment Failure; Kenya
3.  Estimation of the National Disease Burden of Influenza-Associated Severe Acute Respiratory Illness in Kenya and Guatemala: A Novel Methodology 
PLoS ONE  2013;8(2):e56882.
Knowing the national disease burden of severe influenza in low-income countries can inform policy decisions around influenza treatment and prevention. We present a novel methodology using locally generated data for estimating this burden.
Methods and Findings
This method begins with calculating the hospitalized severe acute respiratory illness (SARI) incidence for children <5 years old and persons ≥5 years old from population-based surveillance in one province. This base rate of SARI is then adjusted for each province based on the prevalence of risk factors and healthcare-seeking behavior. The percentage of SARI with influenza virus detected is determined from provincial-level sentinel surveillance and applied to the adjusted provincial rates of hospitalized SARI. Healthcare-seeking data from healthcare utilization surveys is used to estimate non-hospitalized influenza-associated SARI. Rates of hospitalized and non-hospitalized influenza-associated SARI are applied to census data to calculate the national number of cases. The method was field-tested in Kenya, and validated in Guatemala, using data from August 2009–July 2011. In Kenya (2009 population 38.6 million persons), the annual number of hospitalized influenza-associated SARI cases ranged from 17,129–27,659 for children <5 years old (2.9–4.7 per 1,000 persons) and 6,882–7,836 for persons ≥5 years old (0.21–0.24 per 1,000 persons), depending on year and base rate used. In Guatemala (2011 population 14.7 million persons), the annual number of hospitalized cases of influenza-associated pneumonia ranged from 1,065–2,259 (0.5–1.0 per 1,000 persons) among children <5 years old and 779–2,252 cases (0.1–0.2 per 1,000 persons) for persons ≥5 years old, depending on year and base rate used. In both countries, the number of non-hospitalized influenza-associated cases was several-fold higher than the hospitalized cases.
Influenza virus was associated with a substantial amount of severe disease in Kenya and Guatemala. This method can be performed in most low and lower-middle income countries.
PMCID: PMC3584100  PMID: 23573177
4.  Severe Lower Respiratory Tract Infection in Early Infancy and Pneumonia Hospitalizations among Children, Kenya 
Emerging Infectious Diseases  2013;19(2):223-229.
Close postdischarge follow-up could help prevent future severe respiratory disease.
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.
PMCID: PMC3559052  PMID: 23347702
respiratory syncytial virus; lower respiratory tract infection; pneumonia; infancy; childhood; wheeze; postdischarge; respiratory infections; hospitalization; viruses; Kenya
5.  The Incidence and Clinical Burden of Respiratory Syncytial Virus Disease Identified through Hospital Outpatient Presentations in Kenyan Children 
PLoS ONE  2012;7(12):e52520.
There is little information that describe the burden of respiratory syncytial virus (RSV) associated disease in the tropical African outpatient setting.
We studied a systematic sample of children aged <5 years presenting to a rural district hospital in Kenya with acute respiratory infection (ARI) between May 2002 and April 2004. We collected clinical data and screened nasal wash samples for RSV antigen by immunofluorescence. We used a linked demographic surveillance system to estimate disease incidence.
Among 2143 children tested, 166 (8%) were RSV positive (6% among children with upper respiratory tract infection and 12% among children with lower respiratory tract infection (LRTI). RSV was more likely in LRTI than URTI (p<0.001). 51% of RSV cases were aged 1 year or over. RSV cases represented 3.4% of hospital outpatient presentations. Relative to RSV negative cases, RSV positive cases were more likely to have crackles (RR = 1.63; 95% CI 1.34–1.97), nasal flaring (RR = 2.66; 95% CI 1.40–5.04), in-drawing (RR = 2.24; 95% CI 1.47–3.40), fast breathing for age (RR = 1.34; 95% CI 1.03–1.75) and fever (RR = 1.54; 95% CI 1.33–1.80). The estimated incidence of RSV-ARI and RSV-LRTI, per 100,000 child years, among those aged <5 years was 767 and 283, respectively.
The burden of childhood RSV-associated URTI and LRTI presenting to outpatients in this setting is considerable. The clinical features of cases associated with an RSV infection were more severe than cases without an RSV diagnosis.
PMCID: PMC3530465  PMID: 23300695
7.  A Cost Effectiveness and Capacity Analysis for the Introduction of Universal Rotavirus Vaccination in Kenya: Comparison between Rotarix and RotaTeq Vaccines 
PLoS ONE  2012;7(10):e47511.
Diarrhoea is an important cause of death in the developing world, and rotavirus is the single most important cause of diarrhoea associated mortality. Two vaccines (Rotarix and RotaTeq) are available to prevent rotavirus disease. This analysis was undertaken to aid the decision in Kenya as to which vaccine to choose when introducing rotavirus vaccination.
Cost-effectiveness modelling, using national and sentinel surveillance data, and an impact assessment on the cold chain.
The median estimated incidence of rotavirus disease in Kenya was 3015 outpatient visits, 279 hospitalisations and 65 deaths per 100,000 children under five years of age per year. Cumulated over the first five years of life vaccination was predicted to prevent 34% of the outpatient visits, 31% of the hospitalizations and 42% of the deaths. The estimated prevented costs accumulated over five years totalled US$1,782,761 (direct and indirect costs) with an associated 48,585 DALYs. From a societal perspective Rotarix had a cost-effectiveness ratio of US$142 per DALY (US$5 for the full course of two doses) and RotaTeq US$288 per DALY ($10.5 for the full course of three doses). RotaTeq will have a bigger impact on the cold chain compared to Rotarix.
Vaccination against rotavirus disease is cost-effective for Kenya irrespective of the vaccine. Of the two vaccines Rotarix was the preferred choice due to a better cost-effectiveness ratio, the presence of a vaccine vial monitor, the requirement of fewer doses and less storage space, and proven thermo-stability.
PMCID: PMC3480384  PMID: 23115650
8.  Viral etiology of severe pneumonia among Kenyan young infants and children 
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.
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 & Participants
Prospective observational and case control study during 2007 in a rural Kenyan district hospital. We recruited children age 1 day to 12 years who were resident in a systematically enumerated catchment area: i) those admitted to Kilifi District Hospital meeting WHO clinical criteria for ‘severe pneumonia’ or ‘very severe pneumonia’; ii) those presenting with mild upper respiratory tract infection but not admitted and iii) well infants and children attending for immunization.
Main Outcome Measures
The presence of respiratory viruses and the odds ratio for admission with severe disease.
759/922 (83%) eligible admissions were sampled (median age 9 months). One or more respiratory viruses were detected in 425/759 (56%, 95% CI 52 to 60%). Respiratory syncytial virus (RSV) was detected in 260 (34%, 95% CI 31 to 38%) and other respiratory viruses in 219 (29%, 95% CI 26 to 32%), the commonest being human coronavirus 229E (n=51, 6.7%, 95% CI 5.0 to 8.7%), influenza type A (n=44, 5.8%, 95% CI 4.2 to 7.7%), parainfluenza type 3 (n=29, 3.8%, 95% CI 2.6 to 5.4%), adenovirus (n=29, 3.8%, 95% CI 2.6 to 5.4%) and human metapneumovirus (n=23, 3.0%, 95% CI 1.9 to 4.5%). Compared to well controls, detection of RSV was associated with severe disease (4% in controls, adjusted odds Ratio 6.11 [95% CI 1.65 to 22.6]) whilst collectively, other respiratory viruses were not (23% in controls, adjusted odds Ratio 1.27 [95% CI 0.64 to 2.52]).
In a sample of Kenyan infants and children admitted with severe pneumonia to a rural hospital, RSV was the predominant viral pathogen.
PMCID: PMC2968755  PMID: 20501927
9.  Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis 
Lancet  2010;375(9725):1545-1555.
The global burden of disease attributable to respiratory syncytial virus (RSV) remains unknown. We aimed to estimate the global incidence of and mortality from episodes of acute lower respiratory infection (ALRI) due to RSV in children younger than 5 years in 2005.
We estimated the incidence of RSV-associated ALRI in children younger than 5 years, stratified by age, using data from a systematic review of studies published between January, 1995, and June, 2009, and ten unpublished population-based studies. We estimated possible boundaries for RSV-associated ALRI mortality by combining case fatality ratios with incidence estimates from hospital-based reports from published and unpublished studies and identifying studies with population-based data for RSV seasonality and monthly ALRI mortality.
In 2005, an estimated 33·8 (95% CI 19·3–46·2) million new episodes of RSV-associated ALRI occurred worldwide in children younger than 5 years (22% of ALRI episodes), with at least 3·4 (2·8–4·3) million episodes representing severe RSV-associated ALRI necessitating hospital admission. We estimated that 66 000–199 000 children younger than 5 years died from RSV-associated ALRI in 2005, with 99% of these deaths occurring in developing countries. Incidence and mortality can vary substantially from year to year in any one setting.
Globally, RSV is the most common cause of childhood ALRI and a major cause of admission to hospital as a result of severe ALRI. Mortality data suggest that RSV is an important cause of death in childhood from ALRI, after pneumococcal pneumonia and Haemophilus influenzae type b. The development of novel prevention and treatment strategies should be accelerated as a priority.
WHO; Bill & Melinda Gates Foundation.
PMCID: PMC2864404  PMID: 20399493
10.  Duration of shedding of respiratory syncytial virus in a community study of Kenyan children 
Our understanding of the transmission dynamics of respiratory syncytial virus (RSV) infection will be better informed with improved data on the patterns of shedding in cases not limited only to hospital admissions.
In a household study, children testing RSV positive by direct immunofluorescent antibody test (DFA) were enrolled. Nasal washings were scheduled right away, then every three days until day 14, every 7 days until day 28 and every 2 weeks until a maximum of 16 weeks, or until the first DFA negative RSV specimen. The relationship between host factors, illness severity and viral shedding was investigated using Cox regression methods.
From 151 families a total of 193 children were enrolled with a median age of 21 months (range 1-164 months), 10% infants and 46% male. The rate of recovery from infection was 0.22/person/day (95% CI 0.19-0.25) equivalent to a mean duration of shedding of 4.5 days (95%CI 4.0-5.3), with a median duration of shedding of 4 days (IQR 2-6, range 1-14). Children with a history of RSV infection had a 40% increased rate of recovery i.e. shorter duration of viral shedding (hazard ratio 1.4, 95% CI 1.01-1.86). The rate of cessation of shedding did not differ significantly between males and females, by severity of infection or by age.
We provide evidence of a relationship between the duration of shedding and history of infection, which may have a bearing on the relative role of primary versus re-infections in RSV transmission in the community.
PMCID: PMC2822777  PMID: 20096106
11.  Factors associated with increased risk of progression to respiratory syncytial virus-associated pneumonia in young Kenyan children 
To identify factors associated with developing severe respiratory syncytial virus (RSV) pneumonia and their commonality with all-cause lower respiratory tract infection (LRTI), in order to isolate those risk factors specifically associated with RSV-LRTI and identify targets for control.
A birth cohort of rural Kenyan children was intensively monitored for acute respiratory infection (ARI) over three RSV epidemics. RSV was diagnosed by immunofluorescence of nasal washings collected at each ARI episode. Cox regression was used to determine the relative risk of disease for a range of co-factors.
A total of 469 children provided 937 years of follow-up, and experienced 857 all-cause LRTI, 362 RSV-ARI and 92 RSV-LRTI episodes. Factors associated with RSV-LRTI, but not RSV-ARI, were severe stunting (z-score ≤−2, RR 1.7 95%CI 1.1–2.8), crowding (increased number of children, RR 2.6, 1.0–6.5) and number of siblings under 6 years (RR 2.0, 1.2–3.4). Moderate and severe stunting (z-score ≤−1), crowding and a sibling aged over 5 years sleeping in the same room as the index child were associated with increased risk of all-cause LRTI, whereas higher educational level of the primary caretaker was associated with protection.
We identify factors related to host nutritional status (stunting) and contact intensity (crowding, siblings) which are distinguishable in their association with RSV severe disease in infant and young child. These factors are broadly in common with those associated with all-cause LRTI. The results support targeted strategies for prevention.
PMCID: PMC2635480  PMID: 18482199
respiratory syncytial virus; risk factors; disease; Kenya
12.  Molecular analysis of respiratory syncytial virus reinfections in infants from coastal Kenya 
Individuals are reinfected with respiratory syncytial virus (RSV) repeatedly. The nature of reinfections in relation to RSV genetic and antigenic diversity is ill defined and has implications to persistence and vaccine control.
We examined the molecular relatedness of RSV causing primary and repeat infections by phylogenetic analysis of the attachment (G) gene in 12 infants from a birth cohort in rural Kenya, using nasal washings collected over a 16 month period in 2002-03 spanning two successive epidemics.
Six infants were infected in both epidemics, 4 with RSV-A in the first epidemic followed by RSV-B in the second epidemic and 2 infected with RSV-A strains in both epidemics with no significant G gene sequence variability between samples. Two children showed infection and reinfection with different RSV-A strains within the same epidemic. Possible viral persistence was suspected in the remaining 4 infants, although reinfection with same variant cannot be excluded.
These are the first data specifically addressing strain-specific reinfections in infancy in relation to the primary infecting variant. The data strongly suggest that following primary infection some infants lose strain-specific immunity within 7-9 months (between epidemics) and group-specific immunity within 2-4 months (within an epidemic period).
PMCID: PMC2384051  PMID: 16323133
Respiratory syncytial virus; infants; reinfection
13.  Respiratory Syncytial Virus Infection and Disease in Infants and Young Children Studied from Birth in Kilifi District, Kenya 
Within the developing country setting data are few that characterise the disease burden due to RSV and which clearly define the age group to target vaccine intervention.
Children numbering 635, recruited 2002-03, were intensively monitored until each experienced three RSV epidemics. RSV was diagnosed by use of immunofluorescence on nasal washings collected on occurence of acute respiratory infection. Incidence estimates were adjusted for seasonality in RSV exposure.
From 1187 child years of observation (cyo) a total of 409 RSV episodes were identifed; 365 primary and 82 repeat. Adjusted incidence estimates (per 1000cyo) of lower respiratory tract infection (LRTI), severe LRTI and hospital admission were 90, 43, and 10, respectively, and corresponding estimates in infants were 104, 66 and 13. The proportion of all-cause LRTI, severe-LRTI and hospitalizations in the cohort due to RSV was 13%, 19% and 5%, respectively. 55-65% of RSV LRTI and severe-LRTI occured in children over 6 months old. The risk of RSV disease following primary symptomatic infection remained significant beyond the first year of life and a quarter of all re-infections were associated with LRTI.
RSV accounts for a substantial proportion of the total respiratory disease in this rural population: we estimate 85,000 infant cases of severe LRTI annually in Kenya. The majority of this morbidity occurs in late infancy and early childhood; ages at which the risk of disease following infection remains significant. Disease from re-infection is common. Our results inform the debate on vaccine target age group and effectiveness.
PMCID: PMC2358944  PMID: 18171213
respiratory syncytial virus; incidence; burden of disease; vaccination strategy; Kenya
14.  Molecular Epidemiology of Human Rhinovirus Infections in Kilifi, Coastal Kenya 
Journal of Medical Virology  2012;84:823-831.
This study reports pediatric surveillance over 3 years for human rhinovirus (HRV) at the District Hospital of Kilifi, coastal Kenya. Nasopharyngeal samples were collected from children presenting at outpatient clinic with no signs of acute respiratory infection, or with signs of upper respiratory tract infection, and from children admitted to the hospital with lower respiratory tract infection. Samples were screened by real-time reverse transcriptase polymerase chain reaction (real-time RT-PCR) and classified further to species by nucleotide sequencing of the VP4/VP2 junction. Of 441 HRV positives by real-time RT-PCR, 332 were classified to species, with 47% (155) being HRV-A, 5% (18) HRV-B, and 48% (159) HRV-C. There was no clear seasonal pattern of occurrence for any species. The species were present in similar proportions in the inpatient and outpatient sample sets, and no significant association between species distribution and the severity of lower respiratory tract infection in the inpatients could be determined. HRV sequence analysis revealed multiple but separate clusters in circulation particularly for HRV-A and HRV-C. Most HRV-C clusters were distinct from reference sequences downloaded from GenBank. In contrast, most HRV-A and HRV-B sequences clustered with either known serotypes or strains from elsewhere within Africa and other regions of the world. This first molecular epidemiological study of HRV in the region defines species distribution in accord with reports from elsewhere in the world, shows considerable strain diversity and does not identify an association between any species and disease severity.
PMCID: PMC3500870  PMID: 22431032
acute respiratory illness; rhinovirus; RT-PCR; VP4/VP2 protein; genetic sequencing

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