BackgroundAn outbreak of pneumococcal meningitis among non-infant children and adults occurred in the Brong-Ahafo region of Ghana between December 2015 and April 2016 despite the recent nationwide implementation of a vaccination programme for infants with the 13-valent pneumococcal conjugate vaccine (PCV13).MethodsCerebrospinal fluid (CSF) specimens were collected from patients with suspected meningitis in the Brong-Ahafo region. CSF specimens were subjected to Gram staining, culture and rapid antigen testing. Quantitative PCR was performed to identify pneumococcus, meningococcus and Haemophilus influenzae. Latex agglutination and molecular serotyping were performed on samples. Antibiogram and whole genome sequencing were performed on pneumococcal isolates.ResultsEight hundred eighty six patients were reported with suspected meningitis in the Brong-Ahafo region during the period of the outbreak. In the epicenter district, the prevalence was as high as 363 suspected cases per 100,000 people. Over 95 % of suspected cases occurred in non-infant children and adults, with a median age of 20 years. Bacterial meningitis was confirmed in just under a quarter of CSF specimens tested. Pneumococcus, meningococcus and Group B Streptococcus accounted for 77 %, 22 % and 1 % of confirmed cases respectively. The vast majority of serotyped pneumococci (80 %) belonged to serotype 1. Most of the pneumococcal isolates tested were susceptible to a broad range of antibiotics, with the exception of two pneumococcal serotype 1 strains that were resistant to both penicillin and trimethoprim-sulfamethoxazole. All sequenced pneumococcal serotype 1 strains belong to Sequence Type (ST) 303 in the hypervirulent ST217 clonal complex.ConclusionThe occurrence of a pneumococcal serotype 1 meningitis outbreak three years after the introduction of PCV13 is alarming and calls for strengthening of meningitis surveillance and a re-evaluation of the current vaccination programme in high risk countries.Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-016-1914-3) contains supplementary material, which is available to authorized users.
Serotype 1 Streptococcus pneumoniae is a leading cause of invasive pneumococcal disease (IPD) worldwide, with the highest burden in developing countries. We report the whole-genome sequencing analysis of 448 serotype 1 isolates from 27 countries worldwide (including 11 in Africa). The global serotype 1 population shows a strong phylogeographic structure at the continental level, and within Africa there is further region-specific structure. Our results demonstrate that regionspecific diversification within Africa has been driven by limited cross-region transfer events, genetic recombination and antimicrobial selective pressure. Clonal replacement of the dominant serotype 1 clones circulating within regions is uncommon; however, here we report on the accessory gene content that has contributed to a rare clonal replacement event of ST3081 with ST618 as the dominant cause of IPD in the Gambia.
The coronavirus disease 2019 response in many African countries has been swift, progressive, and adaptable, despite resource limitations. 1 As the novel coronavirus infection spread through Wuhan (China) in January, 2020, African countries rapidly acquired de novo severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing capacity so that by March, most could confirm COVID-19. Airport screening began early and efforts to mitigate the spread of COVID-19 have typically emphasised case identification, contact tracing and isolation, handwashing and hand hygiene, and several social distancing and stay-at-home measures with, in some cases, lockdowns of exceedingly high risk areas (appendix). These strategies are likely to remain integral to disease mitigation until an effective vaccine is deployed or population immunity is sufficient to slow transmission. However, the application of COVID-19 mitigation strategies in sub-Saharan Africa needs careful and continued deliberation because of the unique socioeconomic dynamics in this region. In this Comment, we discuss some of these challenges and suggest potential, non-resource-intensive solutions.Rapid urbanisation has led to an informal sector surge and consequent increase in people living in informal settlements and slums within African cities. 2 These communities are particularly susceptible to economic shock resulting from stay-at-home orders and lockdowns, which need to be tempered with food and basic necessity provisions. 2,3 Water tanks can be set up for handwashing and sanitation in these susceptible communities, as well as public toilets which could potentially serve as sentinel COVID-19 surveillance sites through periodic faecal matter sampling and testing. 4 An added layer of complexity is the multigenerational structure and large size of typical African households. 5 Household transmission is a substantial driver of SARS-CoV-2 spread in the community and multigenerational households might be prone to higher fatality. 6 Interrupting COVID-19 transmission is challenging because a substantial proportion of transmission occurs in the presymptomatic stage. 7 Effective contact tracing, testing in the community, and targeted door-to-door surveillance in high-risk
medRxiv preprint 2The ongoing pandemic of SARS-CoV-2, a novel coronavirus, caused over 3 million reported cases of coronavirus disease 2019 (COVID-19) and 200,000 reported deaths between December 2019 and April 2020 1 . Cases and deaths will increase as the virus continues its global march outward. In the absence of effective pharmaceutical interventions or a vaccine, wide-spread virological screening is required to inform where restrictive isolation measures should be targeted and when they can be lifted 2-6 . However, limitations on testing capacity have restricted the ability of governments and institutions to identify individual clinical cases, appropriately measure community prevalence, and mitigate transmission. Group testing offers a way to increase efficiency, by combining samples and testing a small number of pools 7-9 . Here, we evaluate the effectiveness of group testing designs for individual identification or prevalence estimation of SARS-CoV-2 infection when testing capacity is limited. To do this, we developed mathematical models for epidemic spread, incorporating empirically measured individual-level viral kinetics to simulate changing viral loads in a large population over the course of an epidemic. We used these to construct representative populations and assess pooling strategies for community screening, accounting for variability in viral load samples, dilution effects, changing prevalence and resource constraints. We confirmed our group testing framework through pooled tests on de-identified human nasopharyngeal specimens with viral loads representative of the larger population. We show that group testing designs can both accurately estimate overall prevalence using a small number of measurements and substantially increase the identification rate of infected individuals in resource-limited settings. : medRxiv preprint 3 We aimed to evaluate the effectiveness of group testing for overall prevalence estimation and individual case identification. In the classical version of the identification problem 7 , samples from multiple individuals are combined and tested as a single pool ( Fig. 1a). If the test is negative (which might be likely if the prevalence is low and the pool is not too large), then each of the individuals is assumed to have been negative. If the test is positive, it is assumed that at least one individual in the pool was positive; each of the pooled samples is then tested individually. This strategy leverages the low frequency of cases which would otherwise cause substantial inefficiency, as the majority of pools will test negative when prevalence is low. The simple pooling method can be expanded to combinatorial pooling (each sample represented in multiple pools) for direct sample identification 8,9 ( Fig. 1b) and to pooled testing for prevalence estimation 10,11 ( Fig. 1c).To deploy group testing in the current pandemic, we need designs that can account for the (i) prevalence of infection within the population, (ii) position along the epidemic curve , and (iii) within-host kin...
Virological testing is central to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) containment, but many settings face severe limitations on testing. Group testing offers a way to increase throughput by testing pools of combined samples; however, most proposed designs have not yet addressed key concerns over sensitivity loss and implementation feasibility. Here, we combined a mathematical model of epidemic spread and empirically derived viral kinetics for SARS-CoV-2 infections to identify pooling designs that are robust to changes in prevalence, and to ratify sensitivity losses against the time course of individual infections. We show that prevalence can be accurately estimated across a broad range, from 0.02% to 20%, using only a few dozen pooled tests, and using up to 400 times fewer tests than would be needed for individual identification. We then exhaustively evaluated the ability of different pooling designs to maximize the number of detected infections under various resource constraints, finding that simple pooling designs can identify up to 20 times as many true positives as individual testing with a given budget. We illustrate how pooling affects sensitivity and overall detection capacity during an epidemic and on each day post infection, finding that only 3% of false negative tests occurred when individuals are sampled during the first week of infection following peak viral load, and that sensitivity loss is mainly attributable to individuals sampled at the end of infection when detection for limiting transmission has minimal benefit. Crucially, we confirmed that our theoretical results can be translated into practice using pooled human nasopharyngeal specimens by accurately estimating a 1% prevalence among 2,304 samples using only 48 tests, and through pooled sample identification in a panel of 960 samples. Our results show that accounting for variation in sampled viral loads provides a nuanced picture of how pooling affects sensitivity to detect infections. Using simple, practical group testing designs can vastly increase surveillance capabilities in resource-limited settings.
Genomic evolution, transmission and pathogenesis of Streptococcus pneumoniae, an opportunistic human-adapted pathogen, is driven principally by nasopharyngeal carriage. However, little is known about genomic changes during natural colonisation. Here, we use wholegenome sequencing to investigate within-host microevolution of naturally carried pneumococci in ninety-eight infants intensively sampled sequentially from birth until twelve months in a high-carriage African setting. We show that neutral evolution and nucleotide substitution rates up to forty-fold faster than observed over longer timescales in S. pneumoniae and other bacteria drives high within-host pneumococcal genetic diversity. Highly divergent co-existing strain variants emerge during colonisation episodes through real-time intra-host homologous recombination while the rest are co-transmitted or acquired independently during multiple colonisation episodes. Genic and intergenic parallel evolution occur particularly in antibiotic resistance, immune evasion and epithelial adhesion genes. Our findings suggest that withinhost microevolution is rapid and adaptive during natural colonisation.
BackgroundDrug-resistant tuberculosis (TB) is a global public health problem. Adequate management requires baseline drug-resistance prevalence data. In West Africa, due to a poor laboratory infrastructure and inadequate capacity, such data are scarce. Therefore, the true extent of drug-resistant TB was hitherto undetermined. In 2008, a new research network, the West African Network of Excellence for Tuberculosis, AIDS and Malaria (WANETAM), was founded, comprising nine study sites from eight West African countries (Burkina Faso, The Gambia, Ghana, Guinea-Bissau, Mali, Nigeria, Senegal and Togo). The goal was to establish Good Clinical Laboratory Practice (GCLP) principles and build capacity in standardised smear microscopy and mycobacterial culture across partnering laboratories to generate the first comprehensive West African drug-resistance data.MethodsFollowing GCLP and laboratory training sessions, TB isolates were collected at sentinel referral sites between 2009–2013 and tested for first- and second-line drug resistance.ResultsFrom the analysis of 974 isolates, an unexpectedly high prevalence of multi-drug-resistant (MDR) strains was found in new (6 %) and retreatment patients (35 %) across all sentinel sites, with the highest prevalence amongst retreatment patients in Bamako, Mali (59 %) and the two Nigerian sites in Ibadan and Lagos (39 % and 66 %). In Lagos, MDR is already spreading actively amongst 32 % of new patients. Pre-extensively drug-resistant (pre-XDR) isolates are present in all sites, with Ghana showing the highest proportion (35 % of MDR). In Ghana and Togo, pre-XDR isolates are circulating amongst new patients.ConclusionsWest African drug-resistance prevalence poses a previously underestimated, yet serious public health threat, and our estimates obtained differ significantly from previous World Health Organisation (WHO) estimates. Therefore, our data are reshaping current concepts and are essential in informing WHO and public health strategists to implement urgently needed surveillance and control interventions in West Africa.
Streptococcus pneumoniae serotype 1 is the predominant cause of invasive pneumococcal disease in sub-Saharan Africa, but the mechanism behind its increased invasiveness is not well understood. Here, we use mouse models of lung infection to identify virulence factors associated with severe bacteraemic pneumonia during serotype-1 (ST217) infection. We use BALB/c mice, which are highly resistant to pneumococcal pneumonia when infected with other serotypes. However, we observe 100% mortality and high levels of bacteraemia within 24 hours when BALB/c mice are intranasally infected with ST217. Serotype 1 produces large quantities of pneumolysin, which is rapidly released due to high levels of bacterial autolysis. This leads to substantial levels of cellular cytotoxicity and breakdown of tight junctions between cells, allowing a route for rapid bacterial dissemination from the respiratory tract into the blood. Thus, our results offer an explanation for the increased invasiveness of serotype 1.
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