Pneumonia, Meningitis, and Septicemia in Adults and Older Children in Rural Gambia: 8 Years of Population-Based Surveillance.

BACKGROUND: Representative data describing serious infections in children aged ≥5 years and adults in Africa are limited. METHODS: We conducted population-based surveillance for pneumonia, meningitis, and septicemia in a demographic surveillance area in The Gambia between 12 May 2008 and 31 December 2015. We used standardized criteria to identify, diagnose, and investigate patients aged ≥5 years using conventional microbiology and radiology. RESULTS: We enrolled 1638 of 1657 eligible patients and investigated 1618. Suspected pneumonia, septicemia, or meningitis was diagnosed in 1392, 135, and 111 patients, respectively. Bacterial pathogens from sterile sites were isolated from 105 (7.5%) patients with suspected pneumonia, 11 (8.1%) with suspected septicemia, and 28 (25.2%) with suspected meningitis. Streptococcus pneumoniae (n = 84), Neisseria meningitidis (n = 16), and Staphylococcus aureus (n = 15) were the most common pathogens. Twenty-eight (1.7%) patients died in hospital and 40 (4.1%) died during the 4 months after discharge. Thirty postdischarge deaths occurred in patients aged ≥10 years with suspected pneumonia. The minimum annual incidence was 133 cases per 100 000 person-years for suspected pneumonia, 13 for meningitis, 11 for septicemia, 14 for culture-positive disease, and 46 for radiological pneumonia. At least 2.7% of all deaths in the surveillance area were due to suspected pneumonia, meningitis, or septicemia. CONCLUSIONS: Pneumonia, meningitis, and septicemia in children aged ≥5 years and adults in The Gambia are responsible for significant morbidity and mortality. Many deaths occur after hospital discharge and most cases are culture negative. Improvements in prevention, diagnosis, inpatient, and follow-up management are urgently needed.

Insights Into Pneumococcal Pneumonia Using Lung Aspirates and Nasopharyngeal Swabs Collected From Pneumonia Patients in The Gambia.

BACKGROUND: We investigated the pathogenesis of pneumococcal pneumonia using clinical specimens collected for pneumonia surveillance in The Gambia. METHODS: Lung aspirates and nasopharyngeal swabs from 31 patients were examined by culture, quantitative polymerase chain reaction (qPCR), whole genome sequencing, serotyping, and reverse-transcription qPCR. RESULTS: Five lung aspirates cultured pneumococci, with a matching strain identified in the nasopharynx. Three virulence genes including ply (pneumolysin) were upregulated >20-fold in the lung compared with the nasopharynx. Nasopharyngeal pneumococcal density was higher in pediatric pneumonia patients compared with controls (P < .0001). CONCLUSIONS: Findings suggest that changes in pneumococcal gene expression occurring in the lung environment may be important in pathogenesis.

Staphylococcus aureus Bacteremia in Children of Rural Areas of The Gambia, 2008-2015.

Staphylococcus aureus bacteremia is a substantial cause of childhood disease and death, but few studies have described its epidemiology in developing countries. Using a population-based surveillance system for pneumonia, sepsis, and meningitis, we estimated S. aureus bacteremia incidence and the case-fatality ratio in children <5 years of age in 2 regions in the eastern part of The Gambia during 2008-2015. Among 33,060 children with suspected pneumonia, sepsis, or meningitis, we performed blood culture for 27,851; of 1,130 patients with bacteremia, 198 (17.5%) were positive for S. aureus. S. aureus bacteremia incidence was 78 (95% CI 67-91) cases/100,000 person-years in children <5 years of age and 2,080 (95% CI 1,621-2,627) cases/100,000 person-years in neonates. Incidence did not change after introduction of the pneumococcal conjugate vaccine. The case-fatality ratio was 14.1% (95% CI 9.6%-19.8%). Interventions are needed to reduce the S. aureus bacteremia burden in The Gambia, particularly among neonates.

Microscopic Analysis and Quality Assessment of Induced Sputum From Children With Pneumonia in the PERCH Study.

BACKGROUND.: It is standard practice for laboratories to assess the cellular quality of expectorated sputum specimens to check that they originated from the lower respiratory tract. The presence of low numbers of squamous epithelial cells (SECs) and high numbers of polymorphonuclear (PMN) cells are regarded as indicative of a lower respiratory tract specimen. However, these quality ratings have never been evaluated for induced sputum specimens from children with suspected pneumonia. METHODS.: We evaluated induced sputum Gram stain smears and cultures from hospitalized children aged 1-59 months enrolled in a large study of community-acquired pneumonia. We hypothesized that a specimen representative of the lower respiratory tract will contain smaller quantities of oropharyngeal flora and be more likely to have a predominance of potential pathogens compared to a specimen containing mainly saliva. The prevalence of potential pathogens cultured from induced sputum specimens and quantity of oropharyngeal flora were compared for different quantities of SECs and PMNs. RESULTS.: Of 3772 induced sputum specimens, 2608 (69%) had <10 SECs per low-power field (LPF) and 2350 (62%) had >25 PMNs per LPF, measures traditionally associated with specimens from the lower respiratory tract in adults. Using isolation of low quantities of oropharyngeal flora and higher prevalence of potential pathogens as markers of higher quality, <10 SECs per LPF (but not >25 PMNs per LPF) was the microscopic variable most associated with high quality of induced sputum. CONCLUSIONS.: Quantity of SECs may be a useful quality measure of induced sputum from young children with pneumonia.

Association of C-Reactive Protein With Bacterial and Respiratory Syncytial Virus-Associated Pneumonia Among Children Aged <5 Years in the PERCH Study.

BACKGROUND.: Lack of a gold standard for identifying bacterial and viral etiologies of pneumonia has limited evaluation of C-reactive protein (CRP) for identifying bacterial pneumonia. We evaluated the sensitivity and specificity of CRP for identifying bacterial vs respiratory syncytial virus (RSV) pneumonia in the Pneumonia Etiology Research for Child Health (PERCH) multicenter case-control study. METHODS.: We measured serum CRP levels in cases with World Health Organization-defined severe or very severe pneumonia and a subset of community controls. We evaluated the sensitivity and specificity of elevated CRP for "confirmed" bacterial pneumonia (positive blood culture or positive lung aspirate or pleural fluid culture or polymerase chain reaction [PCR]) compared to "RSV pneumonia" (nasopharyngeal/oropharyngeal or induced sputum PCR-positive without confirmed/suspected bacterial pneumonia). Receiver operating characteristic (ROC) curves were constructed to assess the performance of elevated CRP in distinguishing these cases. RESULTS.: Among 601 human immunodeficiency virus (HIV)-negative tested controls, 3% had CRP ≥40 mg/L. Among 119 HIV-negative cases with confirmed bacterial pneumonia, 77% had CRP ≥40 mg/L compared with 17% of 556 RSV pneumonia cases. The ROC analysis produced an area under the curve of 0.87, indicating very good discrimination; a cut-point of 37.1 mg/L best discriminated confirmed bacterial pneumonia (sensitivity 77%) from RSV pneumonia (specificity 82%). CRP ≥100 mg/L substantially improved specificity over CRP ≥40 mg/L, though at a loss to sensitivity. CONCLUSIONS.: Elevated CRP was positively associated with confirmed bacterial pneumonia and negatively associated with RSV pneumonia in PERCH. CRP may be useful for distinguishing bacterial from RSV-associated pneumonia, although its role in discriminating against other respiratory viral-associated pneumonia needs further study.

Pneumococcal conjugate vaccination schedules in infants-acquisition, immunogenicity, and pneumococcal conjugate and yellow fever vaccine co-administration study: statistical analysis plan.

RATIONALE: The effectiveness of immunisation with pneumococcal conjugate vaccine (PCV) has been demonstrated in many countries. However, the global impact of PCV is limited by its cost, which has prevented its introduction in some countries. Reducing the cost of PCV programmes will facilitate further vaccine introductions and improve the sustainability of PCV in low-income countries when they transition from subsidised vaccine supply. We are conducting a large, population-level, cluster-randomised field trial (PVS) of an alternative reduced-dose schedule of PCV compared to the standard schedule. We are also conducting a nested sub-study at the individual level to investigate the immunogenicity of the two schedules and their effects on pneumococcal carriage acquisition (PVS-AcqImm). METHODS AND DESIGN: PVS-AcqImm is a prospective, cluster-randomised trial of an alternative schedule of one dose of PCV scheduled at age 6 weeks with a booster dose at age 9 months compared to the standard of three primary doses scheduled at 6, 10, and 14 weeks of age. Sub-groups within the alternative schedule group receive yellow fever vaccine separately or co-administered with PCV at 9 months of age. The primary endpoints are (a) concentrations of vaccine-type anti-pneumococcal IgG at 18 months of age, (b) proportions with yellow fever neutralising antibody titre ≥ 1:8 4 weeks after separate or co-administration of PCV and yellow fever vaccines, and (c) rate of nasopharyngeal vaccine-type pneumococcal acquisition from 10-14 months of age. Participants and field staff are not masked to group allocation while measurement of the laboratory endpoints is masked. Approximately equal numbers of participants are resident in each of 28 randomly allocated geographic clusters (14 clusters in each group); 784 enrolled for acquisition measurements and 336 for immunogenicity measurements. PURPOSE: This statistical analysis plan (SAP) describes the PVS-AcqImm cohort and follow-up criteria to be used in different analyses. The SAP defines the endpoints and describes how adherence to the interventions will be presented. We describe the approach to analyses and how we will account for the effect of clustering. Defining the SAP prior to the conduct of analysis will avoid bias in analyses that may arise from prior knowledge of trial findings. TRIAL REGISTRATION: ISRCTN, ISRCTN7282161328. Registered on 28 November 2019. https://www.isrctn.com/ISRCTN72821613 . PROTOCOL: MRCG SCC number 1670, LSHTM Ref 17683. Current protocol version: 6.0, 24 May 2021. Version: 1.0 (5 April 2023); SAP revisions-none.

Stenotrophomonas maltophilia neonatal sepsis: a case report.

BACKGROUND: Stenotrophomonas maltophilia is a gram-negative bacteria known for causing opportunistic and nosocomial infections in humans. S. maltophilia is an emerging pathogen of concern due to it's increasing prevalence, diverse disease spectrum, intrinsic multi-drug resistance and high mortality rates in immunocompromised individuals. S. maltophilia is a rare cause of neonatal sepsis associated with significant morbidity and mortality. The bacterium's multi-drug resistance poses a considerable challenge for treatment, with various mechanisms contributing to its resistance. CASE PRESENTATION: We report a case involving a 40-h-old male African neonate who exhibited symptoms of neonatal sepsis. The blood culture revealed Stenotrophomonas maltophilia, which was sensitive to ciprofloxacin and gentamicin but resistant to other antibiotics. Lumbar puncture for CSF could not be done because the father declined. We treated the newborn with the empirical first-line antibiotics as per the national guideline intravenous ampicillin and gentamicin for six days, and the child recovered fully with a repeated negative blood culture. CONCLUSIONS: This report describes a neonatal sepsis case caused by S. maltophilia, a multi-drug resistant bacteria and a rare cause of neonatal sepsis. We report that early detection of the bacterial and antimicrobial management based on local antibiogram data may be essential for successful patient's management.

Impact of pneumococcal conjugate vaccination on pneumococcal nasopharyngeal carriage in the Gambia: Population-based cross-sectional surveys.

BACKGROUND: The introduction of pneumococcal conjugate vaccines (PCV) has reduced carriage of vaccine-type (VT) pneumococci in many settings. We determined the impact of The Gambia's national PCV programme on carriage of VT pneumococci in the population. METHODS: Seven-valent PCV (PCV7) was introduced in August 2009 without catch-up and with doses scheduled at 2, 3, 4 months of age; it was replaced by PCV13 in May 2011. We did cross-sectional carriage surveys in 2009, 2015, and 2017 in age-stratified, population-based samples. Nasopharyngeal specimens were collected and processed according to WHO guidelines. We calculated observed and adjusted prevalence ratios (PR) of VT carriage before and after PCV introduction. FINDINGS: We enrolled 2988, 3162, and 2709 participants in 2009, 2015, and 2017 respectively. The baseline (2009) prevalence of VT pneumococcal carriage among children aged 0-4 years was 42.6 %, which declined to 14.9 % and 17.5 % in 2015 and 2017 respectively (adjPR 0.32 [95 % CI 0.27, 0.38] and 0.38 [0.31, 0.46] respectively). VT prevalence among children aged 5-14 years was 16.6 %, 15.1 %, and 15.8 % in the three surveys (2017 vs 2009, adjPR 0.70 [0.58, 0.83]). VT prevalence among 15-44 year-olds was 6.4 %, 5.7 %, and 7.1 % in the three surveys (2017 vs 2009, adjPR 0.59 [0.46, 0.75]), while in those aged ≥ 45 years it was 4.5 %, 6.5 %, and 4.5 % respectively. Non-VT carriage increased in all age-groups. Prevalent residual serotypes were 34 and 15B (age 0-4 years), 3 and 34 (age 5-14 years), and 3 and 16F (age ≥ 15 years). CONCLUSIONS: Introduction of PCV was associated with reduced VT pneumococcal carriage in young, and older children, although with substantial residual prevalence. Persisting VT, and non-VT, carriage indicate significant, persistent transmission of pneumococci in the population.

Ochrobactrum anthropi sepsis in a 15-month-old child: A case report.

Key Clinical Message: Ochrobactrum anthropi (O. anthropi), a rare opportunistic pathogen, caused sepsis in a malnourished 15-month-old African child. Early detection and appropriate antibiotics led to full recovery, highlighting the importance of robust surveillance for emerging pathogens in vulnerable populations. Abstract: While rarely causing infections, O. anthropi, a non-fermenting, obligately aerobic, flagellated gram-negative bacillus, demonstrates oxidase positivity and indole negativity. Traditionally, Ochrobactrum spp is considered a low threat due to its environmental abundance and mild virulence. It is, however, a multidrug-resistant bacteria known for causing opportunistic infections in humans. O. anthropi is typically associated with catheter-related bloodstream infections. The first documented case was in 1998; most cases have been reported in developed countries. We present a case of O. anthropi sepsis in a malnourished child in sub-Saharan Africa. We report a case involving a 15-month-old African female who presented with symptoms and signs of protein-energy malnutrition and sepsis. The blood culture revealed O.anthropi. We treated the child with the empirical first-line antibiotics per the national guidelines, intravenous ampicillin and gentamicin for a week, and the child fully recovered. This report describes a rare case of O. anthropi sepsis with malnutrition in an African female child. O. anthropi is an emerging pathogen causing opportunistic infections in both immunocompetent and immunocompromised patients. We report that early bacterial detection, appropriate antibiotic susceptibility and antimicrobial management based on local antibiogram data may be essential for excellent patient outcomes. Additionally, we recommend more robust surveillance to detect such rare emerging pathogens.

Community-acquired multidrug-resistant Enterobacter cloacae sepsis in a 25-month-old child in rural Gambia: A case report.

Enterobacter cloacae is the leading cause of morbidity and mortality in the genus Enterobacter. It mostly causes nosocomial infections, especially in children, the elderly and those with underlying diseases. However, cases of community-acquired bacteraemia caused by E. cloacae have been reported. The increasing inclination of E. cloacae to cause multidrug-resistant infections has made it particularly challenging to treat. A 25-month-old male child presented to a rural hospital in The Gambia with a one-week history of persistent high-grade fever, dyspnoea, and anorexia. Two days before presentation, he began to have generalized tonic-clonic seizures. On examination, he was found to be febrile, dyspnoeic, pale, and tachycardic. He had a modified Glasgow Coma Scale score of 9/15. Investigations revealed an elevated C-reactive protein, low haemoglobin, and elevated white blood cell count. Cerebrospinal fluid culture did not yield any growth. E. cloacae was isolated from a blood culture taken on the day of admission. The pathogen was resistant to all available antibiotics. He was transfused with whole blood and initially treated empirically with amoxicillin-clavulanic acid and gentamicin. The former was changed to cefuroxime because the child had not improved. The child died nine days after admission. Although E. cloacae is primarily known for causing nosocomial infections, fatal community-acquired infections also occur. This case report demonstrates the difficulty in treating multidrug-resistant E. cloacae in a low-resource setting and its propensity to cause fatal infections.

Epidemiology of human metapneumovirus among children with severe or very severe pneumonia in high pneumonia burden settings: the PERCH study experience.

OBJECTIVES: After respiratory syncytial virus (RSV), human metapneumovirus (hMPV) was the second-ranked pathogen attributed to severe pneumonia in the PERCH study. We sought to characterize hMPV-positive cases in high burden settings, which have limited data, by comparing to RSV-positive and other cases. METHODS: Children aged 1-59 months hospitalized with suspected severe pneumonia and age/season-matched community controls in seven African and Asian countries had nasopharyngeal/oropharyngeal swabs tested by multiplex PCR for 32 respiratory pathogens, among other clinical and lab assessments at admission. Odds ratios adjusted for age and site (aOR) were calculated using logistic regression. Etiologic probability was estimated using Bayesian nested partial latent class analysis. Latent class analysis identified syndromic constellations of clinical characteristics. RESULTS: HMPV was detected more frequently among cases (267/3887, 6.9%) than controls (115/4976, 2.3%), among cases with pneumonia chest X-ray findings (8.5%) than without (5.5%), and among controls with respiratory tract illness (3.8%) than without (1.8%; all p≤0.001). HMPV-positive cases were negatively associated with the detection of other viruses (aOR=0.18), especially RSV (aOR=0.11; all p<0.0001), and positively associated with the detection of bacteria (aORs 1.77, p=0.03). No single clinical syndrome distinguished hMPV-positive from other cases. Among hMPV-positive cases, 65.2% were aged <1 year and 27.5% had pneumonia danger signs; positive predictive value was 74.5%; mortality was 3.9%, similar to RSV-positive (2.4%) and lower than other cases (9.6%). CONCLUSIONS: HMPV-associated severe pediatric pneumonia in high burden settings was predominantly in young infants and clinically indistinguishable from RSV. HMPV-positives had low case fatality, similar to that in RSV-positives.

Invasive bacterial disease in young infants in rural Gambia: Population-based surveillance.

Background: Invasive bacterial diseases (IBD) cause significant mortality in young infants. There are limited population-based data on IBD in young infants in Sub-Saharan Africa. Methods: We conducted population-based surveillance for IBD among infants aged 0-90 days in a demographic surveillance area in rural Gambia between 1 March 2011 and 31 December 2017. Infants admitted to health facilities within the study area had standardised clinical evaluation plus conventional microbiological investigation. We defined IBD as isolation of pathogenic bacteria from blood, cerebrospinal fluid, lung, or pleural aspirate. We determined incidence, aetiology and case-fatality of IBD. Results: A total of 3794 infants were admitted and 3605 (95%) had at least one sample collected for culture. We detected 254 (8.0%) episodes of IBD (bacteraemia 241; meningitis 14; pneumonia seven). The incidence of IBD in infants aged 0-90 days was 25 episodes/1000 person-years (95% confidence interval (CI) = 22-28), the incidence in neonates was 50 episodes/1000 person-years (95% CI = 43-58) and the incidence in infants aged 29-90 days was 12 episodes/1000 person-years (95% CI = 9-15). The most common pathogens causing IBD were Staphylococcus aureus (n = 102, 40%), Escherichia coli (n = 37, 15%), Streptococcus pneumoniae (n = 24, 9%) and Klebsiella pneumoniae (n = 12, 5%). Case-fatality was 29% (95% CI = 23-37) in neonates and 19% (95% CI = 11-29) in infants aged 29-90 days. A minimum of 7.3% of all young infant deaths in the population were caused by IBD. Conclusions: IBD are common in young infants in rural Gambia and have a high case-fatality. Strategies are needed to prevent IBD in young infants. Overcoming barriers to widespread implementation of existing vaccines and developing new vaccines against the most common pathogens causing IBD should be among top priorities for reducing the high mortality rate in young infants.

Impact of the COVID-19 pandemic on a clinical trial of pneumococcal vaccine scheduling (PVS) in rural Gambia.

The COVID-19 pandemic represents an unprecedented challenge for clinical research. The Pneumococcal Vaccine Schedules (PVS) study is a non-inferiority, interventional trial in which infants resident in 68 geographic clusters are randomised to two different schedules for pneumococcal vaccination. From September 2019 onwards, all infants resident in the study area became eligible for trial enrolment at all Expanded Programme on Immunisation (EPI) clinics in the study area. Surveillance for clinical endpoints is conducted at all 11 health facilities in the study area. PVS is conducted as a collaboration between the Medical Research Council Unit The Gambia (MRCG) at LSHTM and the Gambian Ministry of Health (MoH). The COVID-19 pandemic caused many disruptions to PVS. MRCG instructed interventional studies that participant enrolment be suspended on 26 March 2020, and a public health emergency was declared in The Gambia on 28 March 2020. Enrolment in PVS restarted on 1 July 2020 and was suspended again on 5 August 2020 after The Gambia experienced a sharp increase in COVID-19 cases in late July 2020 and restarted again on 1 September 2020. During periods of suspended enrolment of infants at EPI clinics, PVS continued safety surveillance at health facilities, albeit with disruptions. During the periods of suspended enrolment, infants who had been enrolled before 26 March 2020 continued to receive the PCV schedule to which they had been randomly allocated based on their village of residence, whereas all other infants received the standard PCV schedule. Throughout 2020 and 2021, the trial faced numerous technical and operational challenges: disruption to MoH delivery of EPI services and clinical care at health facilities; episodes of staff illness and isolation; disruption of MRCG transport, procurement, communications and human resource management; and also a range of ethical, regulatory, sponsorship, trial monitoring and financial challenges. In April 2021, a formal review concluded that the pandemic had not compromised the scientific validity of PVS and that the trial should continue as per protocol. The continuing challenges that COVID-19 poses to PVS, and other clinical trials will persist for some time.

Pneumococcal conjugate vaccination schedules in infants-acquisition, immunogenicity, and pneumococcal conjugate and yellow fever vaccine co-administration study.

BACKGROUND: Pneumococcal conjugate vaccines (PCVs) effectively prevent pneumococcal disease, but the global impact of pneumococcal vaccination is hampered by its cost. The evaluation of reduced dose schedules of PCV includes measurement of effects on immunogenicity and carriage acquisition compared to standard schedules. The relevance and feasibility of trials of reduced dose schedules is greatest in middle- and low-income countries, such as The Gambia, where the introduction of PCV resulted in good disease control but where transmission of vaccine-type pneumococci persists. We designed a large cluster-randomised field trial of an alternative reduced dose schedule of PCV compared to the standard schedule, the PVS trial. We will also conduct a sub-study to evaluate the individual-level effect of the two schedules on carriage acquisition, immunogenicity, and co-administration of PCV with yellow fever vaccine, the PVS-AcqImm trial. METHODS: PVS-AcqImm is a prospective, cluster-randomised trial of one dose of PCV scheduled at age 6 weeks with a booster dose at age 9 months (i.e. alternative '1+1' schedule) compared to three primary doses scheduled at 6, 10, and 14 weeks of age (i.e. standard '3+0' schedule). Sub-groups within the alternative schedule group will receive yellow fever vaccine separately or co-administered with PCV at 9 months of age. The primary endpoints are (a) rate of nasopharyngeal vaccine-type pneumococcal acquisition from 9 to 14 months of age, (b) geometric mean concentration of vaccine-type pneumococcal IgG at 18 months of age, and (c) proportions with yellow fever neutralising antibody titre ≥8 four weeks after administration of yellow fever vaccine. Participants and field staff will not be masked to group allocation while the measurement of laboratory endpoints will be masked. Approximately equal numbers of participants will be resident in each of 28 geographic clusters (14 clusters in alternative and standard schedule groups); 784 enrolled for acquisition measurements and 336 for immunogenicity measurements. DISCUSSION: Analysis will account for potential non-independence of measurements by cluster and so interpretation of effects will be at the individual level (i.e. a population of individuals). PVS-AcqImm will evaluate whether acquisition of vaccine-type pneumococci is reduced by the alternative compared to the standard schedule, which is required if the alternative schedule is to be effective. Likewise, evidence of superior immune response at 18 months of age and safety of PCV co-administration with yellow fever vaccine will support decision-making regarding the use of the alternative 1+1 schedule. Acquisition and immunogenicity outcomes will be essential for the interpretation of the results of the large field trial comparing the two schedules. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number 72821613 .

Childhood meningitis in rural Gambia: 10 years of population-based surveillance.

BACKGROUND: The introduction in many countries of conjugate vaccines against Haemophilus influenzae type b, Streptococcus pneumoniae, and Neisseria meningitidis has led to significant reductions in acute bacterial meningitis (ABM) in children. However, recent population-based data on ABM in sub-Saharan Africa are limited. METHODS: Population-based surveillance for meningitis was carried out in a rural area of The Gambia under demographic surveillance from 2008 to 2017, using standardised criteria for referral, diagnosis and investigation. We calculated incidence using population denominators. RESULTS: We diagnosed 1,666 patients with suspected meningitis and collected cerebrospinal fluid (n = 1,121) and/or blood (n = 1,070) from 1,427 (88%) of cases. We identified 169 cases of ABM, 209 cases of suspected non-bacterial meningitis (SNBM) and 1,049 cases of clinically suspected meningitis (CSM). The estimated average annual incidence of ABM was high at 145 per 100,000 population in the <2-month age group, 56 per 100,000 in the 2-23-month age group, but lower at 5 per 100,000 in the 5-14-year age group. The most common causes of ABM were Streptococcus pneumoniae (n = 44), Neisseria meningitidis (n = 42), and Gram-negative coliform bacteria (n = 26). Eighteen of 22 cases caused by pneumococcal serotypes included in PCV13 occurred prior to vaccine introduction and four afterwards. The overall case fatality ratio for ABM was 29% (49/169) and was highest in the <2-month age group 37% (10/27). The case fatality ratio was 8.6% (18/209) for suspected non-bacterial meningitis and 12.8% (134/1049) for clinically suspected meningitis cases. CONCLUSIONS: Gambian children continue to experience substantial morbidity and mortality associated with suspected meningitis, especially acute bacterial meningitis. Such severely ill children in sub-Saharan Africa require improved diagnostics and clinical care.

A cluster-randomised, non-inferiority trial of the impact of a two-dose compared to three-dose schedule of pneumococcal conjugate vaccination in rural Gambia: the PVS trial.

BACKGROUND: Pneumococcal conjugate vaccines (PCV) effectively prevent pneumococcal disease but the global impact of pneumococcal vaccination is hampered by the cost of PCV. The relevance and feasibility of trials of reduced dose schedules is greatest in middle- and low-income countries, such as The Gambia, where PCV has been introduced with good disease control but where transmission of vaccine-type pneumococci persists. We are conducting a large cluster-randomised, non-inferiority, field trial of an alternative reduced dose schedule of PCV compared to the standard schedule, the PVS trial. METHODS: PVS is a prospective, cluster-randomised, non-inferiority, real-world field trial of an alternative schedule of one dose of PCV scheduled at age 6 weeks with a booster dose at age 9 months (i.e. the alternative '1 + 1' schedule) compared to the standard schedule of three primary doses scheduled at 6, 10, and 14 weeks of age (i.e. the standard '3 + 0' schedule). The intervention will be delivered for 4 years. The primary endpoint is the population-level prevalence of nasopharyngeal vaccine-type pneumococcal carriage in children aged 2 weeks to 59 months with clinical pneumonia in year 4 of the trial. Participants and field staff are not masked to group allocation while measurement of the laboratory endpoint will be masked. Sixty-eight geographic population clusters have been randomly allocated, in a 1:1 ratio, to each schedule and all resident infants are eligible for enrolment. All resident children less than 5 years of age are under continuous surveillance for clinical safety endpoints measured at 11 health facilities; invasive pneumococcal disease, radiological pneumonia, clinical pneumonia, and hospitalisations. Secondary endpoints include the population-level prevalence of nasopharyngeal vaccine-type pneumococcal carriage in years 2 and 4 and vaccine-type carriage prevalence in unimmunised infants aged 6-12 weeks in year 4. The trial includes components of mathematical modelling, health economics, and health systems research. DISCUSSION: Analysis will account for potential non-independence of measurements by cluster, comparing the population-level impact of the two schedules with interpretation at the individual level. The non-inferiority margin is informed by the 'acceptable loss of effect' of the alternative compared to the standard schedule. The secondary endpoints will provide substantial evidence to support the interpretation of the primary endpoint. PVS will evaluate the effect of transition from a standard 3+ 0 schedule to an alternative 1 + 1 schedule in a setting of high pneumococcal transmission. The results of PVS will inform global decision-making concerning the use of reduced-dose PCV schedules. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number 15056916 . Registered on 15 November 2018.

Invasive atypical non-typhoidal Salmonella serovars in The Gambia.

Invasive non-typhoidal Salmonella (iNTS) disease continues to be a significant public health problem in sub-Saharan Africa. Common clinical misdiagnosis, antimicrobial resistance, high case fatality and lack of a vaccine make iNTS a priority for global health research. Using whole genome sequence analysis of 164 invasive Salmonella isolates obtained through population-based surveillance between 2008 and 2016, we conducted genomic analysis of the serovars causing invasive Salmonella diseases in rural Gambia. The incidence of iNTS varied over time. The proportion of atypical serovars causing disease increased over time from 40 to 65 % compared to the typical serovars Enteritidis and Typhimurium that decreased from 30 to 12 %. Overall iNTS case fatality was 10%, but case fatality associated with atypical iNTS alone was 10 %. Genetic virulence factors were identified in 14/70 (20 %) typical serovars and 45/68 (66 %) of the atypical serovars and were associated with: invasion, proliferation and/or translocation (Clade A); and host colonization and immune modulation (Clade G). Among Enteritidis isolates, 33/40 were resistant to four or more of the antimicrobials tested, except ciprofloxacin, to which all isolates were susceptible. Resistance was low in Typhimurium isolates, but all 16 isolates were resistant to gentamicin. The increase in incidence and proportion of iNTS disease caused by atypical serovars is concerning. The increased proportion of atypical serovars and the high associated case fatality may be related to acquisition of specific genetic virulence factors. These factors may provide a selective advantage to the atypical serovars. Investigations should be conducted elsewhere in Africa to identify potential changes in the distribution of iNTS serovars and the extent of these virulence elements.

Molecular Epidemiology of Group A Streptococcus Infections in The Gambia.

Molecular epidemiological data on Group A Streptococcus (GAS) infection in Africa is scarce. We characterized the emm-types and emm-clusters of 433 stored clinical GAS isolates from The Gambia collected between 2004 and 2018. To reduce the potential for strain mistyping, we used a newly published primer for emm-typing. There was considerable strain diversity, highlighting the need for vaccine development offering broad strain protection.

Seeking diagnostic and prognostic biomarkers for childhood bacterial pneumonia in sub-Saharan Africa: study protocol for an observational study.

INTRODUCTION: Clinically diagnosed pneumonia in children is a leading cause of paediatric hospitalisation and mortality. The aetiology is usually bacterial or viral, but malaria can cause a syndrome indistinguishable from clinical pneumonia. There is no method with high sensitivity to detect a bacterial infection in these patients and, as result, antibiotics are frequently overprescribed. Conversely, unrecognised concomitant bacterial infection in patients with malarial infections occur with omission of antibiotic therapy from patients with bacterial infections. Previously, we identified two combinations of blood proteins with 96% sensitivity and 86% specificity for detecting bacterial disease. The current project aimed to validate and improve these combinations by evaluating additional biomarkers in paediatric patients with clinical pneumonia. Our goal was to describe combinations of a limited number of proteins with high sensitivity and specificity for bacterial infection to be incorporated in future point-of-care tests. Furthermore, we seek to explore signatures to prognosticate clinical pneumonia. METHODS AND ANALYSIS: Patients (n=900) aged 2-59 months presenting with clinical pneumonia at two Gambian hospitals will be enrolled and classified according to criteria for definitive bacterial aetiology (based on microbiological tests and chest radiographs). We will measure proteins at admission using Luminex-based immunoassays in 90 children with definitive and 160 with probable bacterial aetiology, and 160 children classified according to the prognosis of their disease. Previously identified diagnostic signatures will be assessed through accuracy measures. Moreover, we will seek new diagnostic and prognostic signatures through machine learning methods, including support vector machine, penalised regression and classification trees. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the Gambia Government/Medical Research Council Unit The Gambia Joint Ethics Committee (protocol 1616) and the institutional review board of Boston University Medical Centre (STUDY00000958). Study results will be disseminated to the staff of the study hospitals, in scientific seminars and meetings, and in publications. TRIAL REGISTRATION NUMBER: H-38462.

The Etiology of Childhood Pneumonia in The Gambia: Findings From the Pneumonia Etiology Research for Child Health (PERCH) Study.

BACKGROUND: Pneumonia remains the leading cause of death in young children globally. The changing epidemiology of pneumonia requires up-to-date data to guide both case management and prevention programs. The Gambia study site contributed a high child mortality, high pneumonia incidence, low HIV prevalence, Haemophilus influenzae type b and pneumococcal conjugate vaccines-vaccinated rural West African setting to the Pneumonia Etiology Research for Child Health (PERCH) Study. METHODS: The PERCH study was a 7-country case-control study of the etiology of hospitalized severe pneumonia in children 1-59 months of age in low and middle-income countries. Culture and nucleic acid detection methods were used to test nasopharyngeal/oropharyngeal swabs, blood, induced sputum and, in selected cases, lung or pleural fluid aspirates. Etiology was determined by integrating case and control data from multiple specimens using the PERCH integrated analysis based on Bayesian probabilistic methods. RESULTS: At The Gambia study site, 638 cases of World Health Organization-defined severe and very severe pneumonia (286 of which were chest radiograph [CXR]-positive and HIV-negative) and 654 age-frequency matched controls were enrolled. Viral causes predominated overall (viral 58% vs. bacterial 28%), and of CXR-positive cases respiratory syncytial virus (RSV) accounted for 37%, Streptococcus pneumoniae 13% and parainfluenza was responsible for 9%. Nevertheless, among very severe cases bacterial causes dominated (77% bacterial vs. 11% viral), led by S. pneumoniae (41%); Mycobacterium tuberculosis, not included in "bacterial", accounted for 9%. 93% and 80% of controls ≥1 year of age were, respectively, fully vaccinated for age against Haemophilus influenzae and S. pneumoniae. CONCLUSIONS: Viral causes, notably RSV, predominated in The Gambia overall, but bacterial causes dominated the severest cases. Efforts must continue to prevent disease by optimizing access to existing vaccines, and to develop new vaccines, notably against RSV. A continued emphasis on appropriate case management of severe pneumonia remains important.