Point-of-Care Approaches for Meningitis Diagnosis in a Low-Resource Setting (Southwestern Uganda): Observational Cohort Study Protocol of the "PI-POC" Trial.

BACKGROUND: A timely differential diagnostic is essential to identify the etiology of central nervous system (CNS) infections in children, in order to facilitate targeted treatment, manage patients, and improve clinical outcome. OBJECTIVE: The Pediatric Infection-Point-of-Care (PI-POC) trial is investigating novel methods to improve and strengthen the differential diagnostics of suspected childhood CNS infections in low-income health systems such as those in Southwestern Uganda. This will be achieved by evaluating (1) a novel DNA-based diagnostic assay for CNS infections, (2) a commercially available multiplex PCR-based meningitis/encephalitis (ME) panel for clinical use in a facility-limited laboratory setting, (3) proteomics profiling of blood from children with severe CNS infection as compared to outpatient controls with fever yet not severely ill, and (4) Myxovirus resistance protein A (MxA) as a biomarker in blood for viral CNS infection. Further changes in the etiology of childhood CNS infections after the introduction of the pneumococcal conjugate vaccine against Streptococcus pneumoniae will be investigated. In addition, the carriage and invasive rate of Neisseria meningitidis will be recorded and serotyped, and the expression of its major virulence factor (polysaccharide capsule) will be investigated. METHODS: The PI-POC trial is a prospective observational study of children including newborns up to 12 years of age with clinical features of CNS infection, and age-/sex-matched outpatient controls with fever yet not severely ill. Participants are recruited at 2 Pediatric clinics in Mbarara, Uganda. Cerebrospinal fluid (for cases only), blood, and nasopharyngeal (NP) swabs (for both cases and controls) sampled at both clinics are analyzed at the Epicentre Research Laboratory through gold-standard methods for CNS infection diagnosis (microscopy, biochemistry, and culture) and a commercially available ME panel for multiplex PCR analyses of the cerebrospinal fluid. An additional blood sample from cases is collected on day 3 after admission. After initial clinical analyses in Mbarara, samples will be transported to Stockholm, Sweden for (1) validation analyses of a novel nucleic acid-based POC test, (2) biomarker research, and (3) serotyping and molecular characterization of S. pneumoniae and N. meningitidis. RESULTS: A pilot study was performed from January to April 2019. The PI-POC trial enrollment of patients begun in April 2019 and will continue until September 2020, to include up to 300 cases and controls. Preliminary results from the PI-POC study are expected by the end of 2020. CONCLUSIONS: The findings from the PI-POC study can potentially facilitate rapid etiological diagnosis of CNS infections in low-resource settings and allow for novel methods for determination of the severity of CNS infection in such environment. TRIAL REGISTRATION: ClinicalTrials.gov NCT03900091; https://clinicaltrials.gov/ct2/show/NCT03900091. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/21430.

Aetiology and Outcomes of Suspected Infections of the Central Nervous System in Children in Mbarara, Uganda.

Infections of the central nervous system (CNS) are severe conditions, leading to neurological sequelae or death. Knowledge of the causative agents is essential to develop guidelines for case management in resource-limited settings. Between August 2009 and October 2012, we conducted a prospective descriptive study of the aetiology of suspected CNS infections in children two months to 12 years old, with fever and at least one sign of CNS involvement in Mbarara Hospital, Uganda. Children were clinically evaluated on admission and discharge, and followed-up for 6 months for neurological sequelae. Pathogens were identified from cerebrospinal fluid (CSF) and blood using microbiological and molecular methods. We enrolled 459 children. Plasmodium falciparum (36.2%) and bacteria in CSF (13.3%) or blood (3.3%) were the most detected pathogens. Viruses were found in 27 (5.9%) children. No pathogen was isolated in 207 (45.1%) children. Patterns varied by age and HIV status. Eighty-three (18.1%) children died during hospitalisation, and 23 (5.0%) during follow-up. Forty-one (13.5%) children had neurological sequelae at the last visit. While malaria remains the main aetiology in children with suspected CNS infections, no pathogen was isolated in many children. The high mortality and high rate of neurological sequelae highlight the need for efficient diagnosis.

Timing of malaria in pregnancy and impact on infant growth and morbidity: a cohort study in Uganda.

BACKGROUND: Malaria in pregnancy (MiP) is a major cause of fetal growth restriction and low birth weight in endemic areas of sub-Saharan Africa. Understanding of the impact of MiP on infant growth and infant risk of malaria or morbidity is poorly characterized. The objective of this study was to describe the impact of MIP on subsequent infant growth, malaria and morbidity. METHODS: Between 2006 and 2009, 82 % (832/1018) of pregnant women with live-born singletons and ultrasound determined gestational age were enrolled in a prospective cohort with active weekly screening and treatment for malaria. Infants were followed monthly for growth and morbidity and received active monthly screening and treatment for malaria during their first year of life. Multivariate analyses were performed to analyse the association between malaria exposure during pregnancy and infants' growth, malaria infections, diarrhoea episodes and acute respiratory infections. RESULTS: Median time of infant follow-up was 12 months and infants born to a mother who had MiP were at increased risk of impaired height and weight gain (-2.71 cm, 95 % CI -4.17 to -1.25 and -0.42 kg, 95 % CI -0.76 to -0.08 at 12 months for >1 MiP compared to no MiP) and of malaria infection (relative risk 10.42, 95 % CI 2.64-41.10 for infants born to mothers with placental malaria). The risks of infant growth restriction and infant malaria infection were maximal when maternal malaria occurred in the 12 weeks prior to delivery. Recurrent MiP was also associated with acute respiratory infection (RR 1.96, 95 % CI 1.25-3.06) and diarrhoea during infancy (RR 1.93, 95 % CI 1.02-3.66). CONCLUSION: This study shows that despite frequent active screening and prompt treatment of MiP, impaired growth and an increased risk of malaria and non-malaria infections can be observed in the infants. Effective preventive measures in pregnancy remain a research priority. This study was registered with ClinicalTrials.gov, number NCT00495508.