Molecular epidemiology of pneumococci obtained from Gambian children aged 2–29 months with invasive pneumococcal disease during a trial of a 9-valent pneumococcal conjugate vaccine

BACKGROUND: The study describes the molecular epidemiology of Streptococcus pneumoniae causing invasive disease in Gambian children METHODS: One hundred and thirty-two S. pneumoniae isolates were recovered from children aged 2-29 months during the course of a pneumococcal conjugate vaccine trial conducted in The Gambia of which 131 were characterized by serotyping, antibiotic susceptibility, BOX-PCR and MLST. RESULTS: Twenty-nine different serotypes were identified; serotypes 14, 19A, 12F, 5, 23F, and 1 were common and accounted for 58.3% of all serotypes overall. MLST analysis showed 72 sequence types (STs) of which 46 are novel. eBURST analysis using the stringent 6/7 identical loci definition, grouped the isolates into 17 clonal complexes and 32 singletons. The population structure of the 8 serotype 1 isolates obtained from 4 vaccinated and 2 unvaccinated children were the same (ST 618) except that one (ST3336) of the isolates from an unvaccinated child had a novel ST which is a single locus variant of ST 618. CONCLUSION: We provide the first background data on the genetic structure of S. pneumoniae causing IPD prior to PC7V use in The Gambia. This data will be important for assessing the impact of PC7V in post-vaccine surveillance from The Gambia

Bacteraemia in patients admitted to an urban hospital in West Africa

BACKGROUND: Few studies on bacteraemia in Africa have been published. We aimed to prospectively identify the causative organisms of bacteraemia in The Gambia and their relation to clinical diagnoses, outcome and antimicrobial susceptibility. METHODS: Between November 2003 and February 2005 we studied those admitted to the Medical Research Council hospital who were suspected of having bacteraemia. We documented clinical features, outcome, pathogens identified and their susceptibility patterns, and searched for factors associated with bacteraemia. RESULTS: 871 patients were admitted and had a blood culture taken. The median age was 2 years (range 2 months to 80 years) and 36 of 119 tested were HIV positive; 54.5% were male. 297 (34%) had a positive result and 93 (10.7% overall) were considered a genuine pathogen. Those with bacteraemia were more likely to die in hospital (OR 2.79; 1.17–6.65, p = 0.017) and to have a high white cell count (WCC; OR 1.81;95% CI 1.09–3.02; p = 0.022). Three organisms accounted for 73% of bacteraemias: Streptococcus pneumoniae (45.2%), Staphylococcus aureus (18.3%) and Escherichia coli (9.7%) while non-typhoidal salmonellae (NTS) accounted for 8.6%. Antimicrobial susceptibility of S. pneumoniae was very high to penicillin (97.5%); high resistance was found to co-trimoxazole. S. aureus was generally highly susceptible to cloxacillin, gentamicin and chloramphenicol. E. coli and NTS were all susceptible to ciprofloxacin and mostly susceptible to gentamicin. Thirteen (33%) S. pneumoniae isolates were of serotypes contained in a 7-valent pneumococcal conjugate vaccine and 20 (51.3%) were of the same serogroup. CONCLUSION: In The Gambia, those with bacteraemia are more likely than those without to die in hospital and to have a raised peripheral blood WCC. S. pneumoniae is the most common organism isolated. Introduction of a pneumococcal conjugate vaccine can be expected to lead to a reduction in disease incidence

Seasonality and outbreak of a predominant Streptococcus pneumoniae serotype 1 clone from The Gambia: Expansion of ST217 hypervirulent clonal complex in West Africa

BACKGROUND: Streptococcus pneumoniae serotype 1 causes > 20% of invasive disease, among all age groups combined, in The Gambia. In contrast, it is rarely detected in carriage studies. This study compares the molecular epidemiology of S. pneumoniae serotype 1 causing invasive disease in The Gambia between 1996 and 2005 to those carried in the nasopharynx between 2004 and 2006. RESULTS: A total of 127 invasive and 36 nasopharyngeal carriage serotype 1 isolates were recovered from individuals of all age groups and were analyzed by serotyping, antibiotic susceptibility testing and MLST. MLST analysis revealed 23 different sequence types (STs), 18 of which were novel. The most prevalent clone among the 163 isolates was ST618 (70.5%), followed by ST3575 (7.4%), ST2084 (2.5%) and ST612 (2.5%). A single ST (ST618), previously shown to belong to the ST217 hypervirulent clonal complex, was frequent among carriage (61.1%) and invasive (72.7%) serotype 1 isolates. ST618 causing both paediatric and adult disease peaked annually in the hot dry season and caused outbreak in 1997 and 2002. CONCLUSION: For over a decade, isolates of ST618 have been the dominant lineage among serotype 1 carriage and disease isolates circulating in the Gambia. This lineage shows similar epidemiological features to those of the meningococcus in the African meningitis belt being able to cause outbreaks of disease

A Novel Campylobacter jejuni Sequence Type from a Culture-Negative Patient in The Gambia

The introduction of molecular diagnostic methods is crucial for improved understanding of the aetiology and epidemiology of bacterial infections in communities in resource poor settings. A blood sample from a 7 month old patient diagnosed with malaria in 2001 in a Gambian outpatient clinic was reported as culture negative after it was subjected to traditional bacterial culture protocols. We re-addressed the analysis of the blood sample from this case more recently (after 6.5 years in archival storage) in pilot work establishing 16S rRNA PCR in our molecular laboratory. Initial 16S rRNA PCR results confirmed the presence of bacterial DNA in the sample. 16S rRNA sequence analysis identified the organism as Campylobacter spp. In light of the molecular evidence we successfully grew the organism using appropriate culture conditions and subsequently biochemically confirmed that the isolate was Campylobacter jejuni. PCR and DNA sequencing of a set of seven C. jejuni housekeeping genes and in silico Multilocus Sequence Typing (MLST) analysis revealed that the isolate exhibits a novel sequence type (ST) of C. jejuni (ST 2928) and belongs to ST-443 clonal complex. This study demonstrates the potential for molecular tools to enhance the diagnosis of bacterial infections, which remain a major killer globally, not least in children in the developing world. Improvements in diagnostics are needed, and will be important not only for sick individuals but also for populations, where better measures of disease burden will contribute significantly to the improvement of public health policy

Economic evaluation of pneumococcal conjugate vaccination in The Gambia

<p>Abstract</p> <p>Background</p> <p>Gambia is the second GAVI support-eligible country to introduce the 7-valent pneumococcal conjugate vaccine (PCV7), but a country-specific cost-effectiveness analysis of the vaccine is not available. Our objective was to assess the potential impact of PCVs of different valences in The Gambia.</p> <p>Methods</p> <p>We synthesized the best available epidemiological and cost data using a state-transition model to simulate the natural histories of various pneumococcal diseases. For the base-case, we estimated incremental cost (in 2005 US dollars) per disability-adjusted life year (DALY) averted under routine vaccination using PCV9 compared to no vaccination. We extended the base-case results for PCV9 to estimate the cost-effectiveness of PCV7, PCV10, and PCV13, each compared to no vaccination. To explore parameter uncertainty, we performed both deterministic and probabilistic sensitivity analyses. We also explored the impact of vaccine efficacy waning, herd immunity, and serotype replacement, as a part of the uncertainty analyses, by assuming alternative scenarios and extrapolating empirical results from different settings.</p> <p>Results</p> <p>Assuming 90% coverage, a program using a 9-valent PCV (PCV9) would prevent approximately 630 hospitalizations, 40 deaths, and 1000 DALYs, over the first 5 years of life of a birth cohort. Under base-case assumptions ($3.5 per vaccine), compared to no intervention, a PCV9 vaccination program would cost$670 per DALY averted in The Gambia. The corresponding values for PCV7, PCV10, and PCV13 were $910,$670, and $570 per DALY averted, respectively. Sensitivity analyses that explored the implications of the uncertain key parameters showed that model outcomes were most sensitive to vaccine price per dose, discount rate, case-fatality rate of primary endpoint pneumonia, and vaccine efficacy against primary endpoint pneumonia.</p> <p>Conclusions</p> <p>Based on the information available now, infant PCV vaccination would be expected to reduce pneumococcal diseases caused by <it>S. pneumoniae </it>in The Gambia. Assuming a cost-effectiveness threshold of three times GDP per capita, all PCVs examined would be cost-effective at the tentative Advance Market Commitment (AMC) price of$3.5 per dose. Because the cost-effectiveness of a PCV program could be affected by potential serotype replacement or herd immunity effects that may not be known until after a large scale introduction, type-specific surveillance and iterative evaluation will be critical.</p

Accelerating Policy Decisions to Adopt Haemophilus influenzae Type b Vaccine: A Global, Multivariable Analysis

Jessica Shearer and colleagues analyze data from 147 countries to identify factors that influence the time taken to introduce routine vaccination against Haemophilus influenzae type b (Hib)

Clonal Differences between Non-Typhoidal Salmonella (NTS) Recovered from Children and Animals Living in Close Contact in The Gambia

Salmonellosis is a neglected tropical disease causing serious dysentery and septicaemia particularly in young infants, elderly and immunocompromised individuals such as HIV patients and associated with substantial mortality in developing countries. Salmonellosis also constitutes a major public health problem as it is considered the most widespread bacterial zoonosis of food origin throughout the world. Many epidemiological data exist from developed countries concerning transmission of Non-Typhoidal Salmonella (NTS) but few are available from developing countries. In addition few studies in sub-Saharan Africa have considered the interface between humans and their environment in relation to animals present in the household and food hygiene. This study describes the prevalence of NTS among fourteen Gambian children and 210 domestic animals living in close proximity (household) to the children in a rural setting in The Gambia. We found that the domestic animals living in the same household as patients carried different NTS serovar and genotypes; indicating that zoonotic transmission does not occur in our setting. This study provides baseline data for future studies of transmission of NTS in rural Africa

Sequelae due to bacterial meningitis among African children: a systematic literature review

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>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 <it>Haemophilus influenzae </it>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.</p> <p>Conclusion</p> <p>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.</p

Ten Years of Surveillance for Invasive Streptococcus pneumoniae during the Era of Antiretroviral Scale-Up and Cotrimoxazole Prophylaxis in Malawi

OBJECTIVE: To document trends in invasive pneumococcal disease (IPD) in a central hospital in Malawi during the period of national scale-up of antiretroviral therapy (ART) and cotrimoxazole prophylaxis. METHODS: Between 1 January 2000 and 31 December 2009 almost 100,000 blood cultures and 40,000 cerebrospinal fluid (CSF) cultures were obtained from adults and children admitted to the Queen Elizabeth Central Hospital, Blantyre, Malawi with suspected severe bacterial infection. RESULTS: 4,445 pneumococcal isolates were obtained over the 10 year period. 1,837 were from children: 885 (19.9%) from blood and 952 (21.4%) from CSF. 2,608 were from adults: 1,813 (40.8%) from blood and 795 (17.9%) from CSF. At the start of the surveillance period cotrimoxazole resistance was 73.8% and at the end was 92.6%. Multidrug resistance (MDR) was present in almost one third of isolates and was constant over time. Free ART was introduced in Malawi in 2004. From 2005 onwards there was a decline in invasive pneumococcal infections with a negative correlation between ART scale-up and the decline in IPD (Pearson's correlation r = -0.91; p<0.001). CONCLUSION: During 2004-2009, national ART scale-up in Malawi was associated with a downward trend in IPD at QECH. The introduction of cotrimoxazole prophylaxis in HIV-infected groups has not coincided with a further increase in pneumococcal cotrimoxazole or multidrug resistance. These data highlight the importance of surveillance for high disease burden infections such as IPD in the region, which will be vital for monitoring pneumococcal conjugate vaccine introduction into national immunisation programmes

Interleukin 12B (IL12B) Genetic Variation and Pulmonary Tuberculosis: A Study of Cohorts from The Gambia, Guinea-Bissau, United States and Argentina

We examined whether polymorphisms in interleukin-12B (IL12B) associate with susceptibility to pulmonary tuberculosis (PTB) in two West African populations (from The Gambia and Guinea-Bissau) and in two independent populations from North and South America. Nine polymorphisms (seven SNPs, one insertion/deletion, one microsatellite) were analyzed in 321 PTB cases and 346 controls from Guinea-Bissau and 280 PTB cases and 286 controls from The Gambia. For replication we studied 281 case and 179 control African-American samples and 221 cases and 144 controls of European ancestry from the US and Argentina. First-stage single locus analyses revealed signals of association at IL12B 3′ UTR SNP rs3212227 (unadjusted allelic p = 0.04; additive genotypic p = 0.05, OR = 0.78, 95% CI [0.61–0.99]) in Guinea-Bissau and rs11574790 (unadjusted allelic p = 0.05; additive genotypic p = 0.05, OR = 0.76, 95% CI [0.58–1.00]) in The Gambia. Association of rs3212227 was then replicated in African-Americans (rs3212227 allelic p = 0.002; additive genotypic p = 0.05, OR = 0.78, 95% CI [0.61–1.00]); most importantly, in the African-American cohort, multiple significant signals of association (seven of the nine polymorphisms tested) were detected throughout the gene. These data suggest that genetic variation in IL12B, a highly relevant candidate gene, is a risk factor for PTB in populations of African ancestry, although further studies will be required to confirm this association and identify the precise mechanism underlying it