[Show abstract][Hide abstract] ABSTRACT: Background:
Many surface proteins thought to promote Streptocococcus pneumoniae virulence have recently been discovered and are currently being considered as future vaccine targets. We assessed the prevalence of 16 virulence genes among 435 S. pneumoniae invasive isolates from France and the "African meningitis belt" region, with particular focus on serotype 1 (Sp1), to compare their geographical distribution, assess their association with site of infection and evaluate their potential interest as new vaccine candidates.
Detection by PCR of pspA (+families), pspC (+pspC.4), pavA, lytA, phtA,B,D,E, nanA,B,C, rrgA (Pilus-1), sipA (Pilus-2), pcpA and psrp was performed on all isolates, as well as antibiotic resistance testing and MLVA typing (+MLST on 54 representative strains). Determination of ply alleles was performed by sequencing (Sp1 isolates).
MLVA and virulence genes profiles segregated Sp1 isolates into 2 groups that followed continent distribution. The ply allele 5 and most of the genes that were variable (nanC, Pilus-2, psrp, pcpA, phtD) were present in the French Sp1 isolates (PMEN clone Sweden1-28, ST306) but absent from the African ones. Whereas all African Sp1 isolates clustered into a single MLST CC (CC217), MLVA distinguished two CCs that followed temporal evolution. Pilus-2 and psrp were more prevalent in bacteraemic pneumonia yielded isolates and phtB in meningitis-related isolates. Considering vaccine candidates, phtD was less prevalent than anticipated (50%) and pcpA varied importantly between France and Africa (98% versus 34%). Pilus-1 was carried by 7-11% of isolates and associated with β-lactams resistance.
Most virulence genes were carried by the European ST306 clone but were lacking on Sp1 isolates circulating in the African meningitis belt, where a more serious pattern of infection is observed. While virulence proteins are now considered as vaccine targets, the geographical differences in their prevalence could affect the efficacy expected from future vaccines.
PLoS ONE 07/2015; 10(7):e0133885. DOI:10.1371/journal.pone.0133885 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The GAVI Alliance supported10-valent pneumococcal conjugate vaccine (PCV10) introduction in Kenya. We estimated the cost-effectiveness of introducing either PCV10 or the13-valent vaccine (PCV13) from a societal perspective and explored the incremental impact of including indirect vaccine effects.
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.
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.
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.
PLoS ONE 06/2013; 8(6):e67324. DOI:10.1371/journal.pone.0067324 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dakar discussion group on priorities for research on epidemic meningococcal disease in Africa,. For over 100 years, large epidemics of meningococcal meningitis have occurred every few years in areas of the African Sahel and sub-Sahel known as the African meningitis belt. Until recently, the main approach to the control of these epidemics has been reactive vaccination with a polysaccharide vaccine after an outbreak has reached a defined threshold and provision of easy access to effective treatment but this approach has not prevented the occurrence of new epidemics. Meningococcal conjugate vaccines, which can prevent meningococcal carriage and thus interrupt transmission, may be more effective than polysaccharide vaccines at preventing epidemics. Because the majority of African epidemics have been caused by serogroup A meningococci, a serogroup A polysaccharide/tetanus toxoid protein conjugate vaccine (PsA-TT) has recently been developed. Results from an initial evaluation of the impact of this vaccine on meningococcal disease and meningococcal carriage in Burkina Faso have been encouraging. To review how the research agenda for meningococcal disease in Africa has been changed by the advent of PsA-TT and to define a new set of research priorities for study of meningococcal infection in Africa, a meeting of 41 scientists was held in Dakar, Senegal on April 24th and 25th 2012. The research recommendations developed during the course of this meeting are presented in this paper. The need for enhanced surveillance for meningitis in defined populations with good diagnostic facilities in African countries at risk of epidemics was identified as the highest priority. This is needed to determine the duration of protection against serogroup A meningococcal disease provided by PsA-TT and to determine the risk of disease and carriage caused by meningococci of other serogroups. Other research areas given high priority included identification and validation of serological correlates of protection against meningococcal disease and carriage, development of improved methods for detecting carriage and epidemiological studies aimed at determining the reasons underlying the peculiar epidemiology of meningococcal disease in the African meningitis belt. Minutes and working papers from the meeting are provided in supplementary tables and some of the presentations made at the meeting are available on the MenAfriCar consortium website (www.menafricar.org) and on the web site of the Centers for Disease Control (www.cdc.gov).
[Show abstract][Hide abstract] ABSTRACT: We evaluated pneumococcal serotype/group distribution using polymerase chain reaction (PCR) testing on cerebrospinal fluid collected from patients from Burkina Faso and Togo who presented for care during 2007–2009. We identified 282 pneumococcal meningitis cases based on PCR, latex agglutination, or culture, of which 206 underwent serotyping. Serotype 1 was identified for 18% of serotyped cases from patients aged <5 years and 66% of those aged ≥5 years. The 13-valent and 10-valent pneumococcal conjugate vaccines (PCV-13 and PCV-10) contain 53% of serotypes identified among children age <5 years and 76–77% among persons aged ≥5 years. Pneumococcal meningitis was highly seasonal regardless of serotype. Data from this study emphasize the potential usefulness of PCVs among older children and adults.
[Show abstract][Hide abstract] ABSTRACT: Summary 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.
International Journal of Epidemiology 04/2012; 41(3):650-7. DOI:10.1093/ije/dys062 · 9.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: We conducted a prospective pilot study over a 1-year period in New Caledonia in preparation for the Pneumonia Research for Child Health (PERCH) project. The pathogens associated with hospitalized lower respiratory infections in children were identified through the use of culture of induced sputum and blood, urinary antigen detection, polymerase chain reaction (PCR) on respiratory specimens, and serology on paired sera. Respiratory viruses were detected on respiratory specimens by immunofluorescence and PCR, and by serology on paired sera. Pathogens were detected in 87.9% of the 108 hospitalized cases. Viruses represented 81.6% of the 152 pathogens detected. Respiratory syncytial virus and rhinovirus were the most frequent, accounting for 32.2% and 24.3% of the pathogens identified, respectively. Only 26.3% of 99 induced sputum specimens collected were determined to be of good quality, which may be a consequence of the collection method used.
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: To explore excess paediatric mortality after discharge from Kilifi District Hospital, Kenya, and its duration and risk factors.
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.
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.
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.
Bulletin of the World Health Organisation 10/2011; 89(10):725-32, 732A. DOI:10.2471/BLT.11.089235 · 5.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
Bulletin of the World Health Organisation 02/2011; 89(2):102-11. DOI:10.2471/BLT.10.080796 · 5.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: Few population-based studies have investigated the epidemiology of adult community-acquired pneumonia (CAP). We aimed to determine the incidence of CAP in a population at high-risk for pneumococcal disease and to evaluate a standardized method for interpreting chest radiographs adapted from the World Health Organization paediatric chest radiograph interpretation guidelines. We reviewed radiology records at the two healthcare facilities serving the White Mountain Apache tribe to identify possible pneumonia cases > or =40 years of age. We categorized patients with clinical criteria and a physician diagnosis of pneumonia as clinical CAP and those with clinical criteria and an acute infiltrate as radiographic CAP. We identified 100 (27/1000 person-years) and 60 (16/1000 person-years) episodes of clinical and radiographic CAP, respectively. The incidence of CAP increased with age. Both radiographic and clinical CAP were serious illnesses with more than half of patients hospitalized. Our case definitions and methods may be useful for comparing data across studies and conducting vaccine trials.
Epidemiology and Infection 08/2010; 138(8):1146-54. DOI:10.1017/S0950268809991464 · 2.54 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Children with sickle-cell disease are at great risk of serious infections and early mortality. Our Review investigates the association between sickle-cell disease and invasive bacterial disease among populations in Africa. We systematically searched published work extracted data on pneumonia, meningitis, and bacteraemia by sickle-cell disease status. Most studies identified lacked a control group and did not use best laboratory methods for culturing fastidious bacteria. Only seven case-control or case-cohort studies provided data on the association between invasive bacterial disease and sickle-cell disease status. For all-cause laboratory-confirmed invasive bacterial disease, the pooled odds of sickle-cell disease was 19-times greater among cases than controls. For disease caused by Streptococcus pneumoniae, the pooled odds of sickle-cell disease was 36-times greater; and for Haemophilus influenzae type b disease it was 13-times greater.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
BMC Public Health 03/2010; 10(1):142. DOI:10.1186/1471-2458-10-142 · 2.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Streptococcus pneumoniae is a common cause of community-acquired pneumonia (CAP) but existing diagnostic tools have limited sensitivity and specificity. We enrolled adults undergoing chest radiography at three Indian Health Service clinics in the Southwestern United States and collected acute and convalescent serum for measurement of PsaA and PspA titres and urine for pneumococcal antigen detection. Blood and sputum cultures were obtained at the discretion of treating physicians. We compared findings in clinical and radiographic CAP patients to those in controls without CAP. Urine antigen testing showed the largest differential between CAP patients and controls (clinical CAP 13%, radiographic CAP 17%, control groups 2%). Serological results were mixed, with significant differences between CAP patients and controls for some, but not all changes in titre. Based on urine antigen and blood culture results, we estimated that 11% of clinical and 15% of radiographic CAP cases were due to pneumococcus in this population.
Epidemiology and Infection 03/2010; 138(12):1796-803. DOI:10.1017/S0950268810000555 · 2.54 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: African children have some of the highest rates of bacterial meningitis in the world. Bacterial meningitis in Africa is associated with high case fatality and frequent neuropsychological sequelae. The objective of this study is to present a comprehensive review of data on bacterial meningitis sequelae in children from the African continent.
We conducted a systematic literature search to identify studies from Africa focusing on children aged between 1 month to 15 years with laboratory-confirmed bacterial meningitis. We extracted data on neuropsychological sequelae (hearing loss, vision loss, cognitive delay, speech/language disorder, behavioural problems, motor delay/impairment, and seizures) and mortality, by pathogen.
A total of 37 articles were included in the final analysis representing 21 African countries and 6,029 children with confirmed meningitis. In these studies, nearly one fifth of bacterial meningitis survivors experienced in-hospital sequelae (median = 18%, interquartile range (IQR) = 13% to 27%). About a quarter of children surviving pneumococcal meningitis and Haemophilus influenzae type b (Hib) meningitis had neuropsychological sequelae by the time of hospital discharge, a risk higher than in meningococcal meningitis cases (median = 7%). The highest in-hospital case fatality ratios observed were for pneumococcal meningitis (median = 35%) and Hib meningitis (median = 25%) compared to meningococcal meningitis (median = 4%). The 10 post-discharge studies of children surviving bacterial meningitis were of varying quality. In these studies, 10% of children followed-up post discharge died (range = 0% to 18%) and a quarter of survivors had neuropsychological sequelae (range = 3% to 47%) during an average follow-up period of 3 to 60 months.
Bacterial meningitis in Africa is associated with high mortality and risk of neuropsychological sequelae. Pneumococcal and Hib meningitis kill approximately one third of affected children and cause clinically evident sequelae in a quarter of survivors prior to hospital discharge. The three leading causes of bacterial meningitis are vaccine preventable, and routine use of conjugate vaccines could provide substantial health and economic benefits through the prevention of childhood meningitis cases, deaths and disability.
BMC Medicine 09/2009; 7(1):47. DOI:10.1186/1741-7015-7-47 · 7.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.