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

Juliet Mwanga-Amumpaire,Giulia Gaudenzi,Dan Nyehangane,Milly Nassejje,Jens Karlsson,Tobias Alfvén,Pedro Réu,Helene Andersson-Svahn,Deborah Nanjebe,Edmund Loh,John Mzee,Stephen Businge,Reza Rasti,Andreas Mårtensson,Elias Kumbakumba,Peter Nilsson,Yap Boum II,Jesper Gantelius

doi:10.2196/21430

Abstract

BackgroundA 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.ObjectiveThe 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.MethodsThe 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.ResultsA 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.ConclusionsThe 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 RegistrationClinicalTrials.gov NCT03900091; https://clinicaltrials.gov/ct2/show/NCT03900091International Registered Report Identifier (IRRID)DERR1-10.2196/21430

Highlights

Pediatric Central Nervous System Infections and Their EtiologyInfections of the central nervous system (CNS) are life-threatening conditions affecting thousands of children worldwide, resulting in significant morbidity and mortality, and contributing to the current burden of disease in low-income countries [1,2]
The Pediatric Infection-Point-of-Care (PI-POC) trial is a prospective observational study of children aged 0 months to 12 years presenting with symptoms of CNS infection
A pilot study was performed from January 2019 to April 2019, to evaluate the study protocol, the sample transfer logistics from the hospitals to the Epicentre Research Laboratory, and the turnover of patients with suspected CNS infections at both facilities

Summary

Introduction

Pediatric Central Nervous System Infections and Their Etiology. Infections of the central nervous system (CNS) are life-threatening conditions affecting thousands of children worldwide, resulting in significant morbidity and mortality, and contributing to the current burden of disease in low-income countries [1,2]. The common symptoms of CNS infection make it difficult to distinguish between different causes of infection clinically, posing challenges to clinical fever case management. In order to minimize preventable deaths and severe outcomes in children, it is crucial to direct research toward better and robust diagnosis of CNS infections. 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

Methods

Results

Conclusion