Paediatric Infections Point-Of-Care
Condition: Meningitis; Pediatric Infectious Diseases
MeSH terms: Infections; Communicable Diseases; Meningitis
Study type: Observational

Summary: 
      This study aims to identify the aetiology of childhood meningitis in Southwestern Uganda and
      develop and evaluate new methods for point-of-care diagnosis of childhood meningitis in a
      low-income setting. A prospective observational study including 600 children aged 0-12 years
      will be conducted during 1 year in Mbarara, Uganda. We estimate to recruit about 300 children
      with suspected meningitis (cases), and 300 with non-severe infection age-matched as controls.
    

Detailed description: 
      The current gold standard for laboratory diagnostics of suspected childhood meningitis are
      microbiology culture of CSF and polymerase chain reaction (PCR). However, these methods are
      expensive, time-consuming, require dedicated facilities and trained professionals, that are
      often lacking in low-income health systems. Our team has developed a new vertical flow paper
      printed microarray method for rapid, inexpensive and multiplexed microbiology analysis of
      cerebrospinal fluid (CSF), with potential for point-of-care use in low-income settings. This
      study will evaluate the diagnostic accuracy of this newly developed paper printed microarray
      method.

      The bioMérieux FilmArray® ME Panel is an existing multiplexed PCR based system for rapid
      microbiology analyses of CSF. Even though previous studies have reported good diagnostic
      accuracy of the FilmArray® system, the studies have mostly been focused on evaluating the
      system in high-income settings.

      This study will do a field evaluation of the diagnostic performance and clinical usability of
      the FilmArray® ME Panel in a low-income setting in Mbarara, Uganda.

      A study by Page et al, conducted 2009-2012 in Mbarara, Uganda, identified the most frequent
      pathogen causing childhood bacterial meningitis to be Streptococcus pneumoniae. This is also
      the case on a global level, with the addition of the bacteria Neisseria meningitidis and
      Haemophilus influenzae type B. However, the Page study did not find a single case of
      Neisseria meningitidis, which is in contrast to most other reports from low-, middle- and
      high-income countries. Furthermore, after the finalisation of the Page study, pneumococcal
      conjugate vaccines were introduced to the Ugandan childhood immunisation program. This study
      will identify the current aetiology of childhood meningitis and the impact of the
      pneumococcal conjugate vaccine, in Mbarara, Uganda, and also study the carriage and
      characteristics of Neisseria meningitis in children in the area.

      Myxovirus resistance protein A (MxA) blood levels have been reported to be elevated in
      children with respiratory tract infections of viral aetiology, as compared to bacterial
      aetiology. Previous studies have also shown a higher abundance of MxA in viral encephalitis,
      however this only through histological analyses of post-mortem brain tissue samples.

      This study aims to investigate the correlation of blood MxA levels in children with viral,
      bacterial and malarial meningitis in Mbarara, Uganda by analysing the protein profile and
      temporal dynamic in blood of children with severe and non-severe infection.
    

Intervention name(s): Multiplex PCR assay for meningitis; Multiplex vertical flow microarrray assay for meningitis; Profiling of blood proteins by multi-analyte Profiling technology; Typing and whole genome sequencing
Intervention type(s): Diagnostic Test; Diagnostic Test; Diagnostic Test; Other
Intervention description(s): CSF from cases to be analysed with a FilmArray ME Panel; CSF from cases will also undergo analysis with a newly developed prototype for point-of-care diagnostic tool for CNS infections identification. The tool is a DNA-based vertical flow microarray technology printed on paper.; Blood from cases and controls to be analysed using Luminex technology to identify protein profiles associated with severe and non-severe infection. Myxovirus protein A (MxA) will also be analysed by the Luminex assay, to associate MxA levels with severe/non-severe infection.; Pathogenic strains isolated from nasopharyngeal swabs from cases and controls will undergo whole genome sequencing (WGS) and typing .
Other intervention name(s): Biomerieux FilmArray ME Panel; Luminex Multi-Analyte Profiling (xMAP)
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        CASE DEFINITION:

        Patients aged 0-12 years, with suspected CNS infection understood as, having fever in the
        past 48 hours (children <9 months may present with any temp)) AND recent onset of any of
        the following:

          -  Non-traumatic reduced consciousness; in pre-verbals <9 months Blantyre coma score <4;
             Blantyre coma score <5 for older pre-verbals. In verbal children Glasgow Coma Scale
             <15

          -  prostration, hypotonia/hypertonia, unexplained irritability

          -  severe headache

          -  photophobia

          -  neck stiffness or bulging fontanel

          -  seizure(s)

          -  focal neurological signs

          -  age >18 months: positive Kernig or Brudzinski signs

          -  Skin petechiae

          -  Cheyne Stokes CNS infection can be suspected for other reasons

        CONTROL DEFINITION:

        Patients aged 0-12 years, visiting the outpatient pediatric clinics with fever and not
        meeting the case inclusion criteria.

        For every case, one age-matched control will be sought until included.
      
Biospecimen description: 
      Cerebrospinal fluid Nasopharyngeal swabs Whole blood
    
Keywords: Point of care; Diagnostics; Low-income countries; Meningitis; Pediatrics; MxA; FilmArray; Low-cost diagnostics