Clinical trial NCT03900091: Paediatric Infections Point-Of-Care
Official title: Paediatric Infections Point-Of-Care: Point-of-care Approach for Rapid and Easy Meningitis Diagnosis
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Meningitis
Pediatric Infectious Diseases
Keywords: Point of care
Diagnostics
Low-income countries
Meningitis
Pediatrics
MxA
FilmArray
Low-cost diagnostics
Lead sponsor: Karolinska Institutet
Sponsor class: OTHER
Collaborators: name: Mbarara University of Science and Technology
name: Science for Life Laboratory
name: Epicentre Mbarara Research Center
name: Stockholm South General Hospital
First posted: 2019-04-02
Enrollment: 351
Sex: ALL
Minimum age (years): 1
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
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.

Brief 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.

Eligibility criteria: Inclusion Criteria:

* Children aged 0 months to 12 years of age, who
* meet the case or control definition criteria, and where
* informed consent is obtained from the parent or guardian

Exclusion Criteria:

* all 3 inclusion criteria not met
* No, insufficient or inappropriate CSF sample collection

Primary outcomes:
measure: Diagnostic accuracy of vertical flow microarray printed on paper for pathogen identification in human cerebrospinal fluid samples
timeFrame: Patient CSF will be analysed with culture, PCR and FilmArray during ongoing patient management in Mbarara, Uganda. Analyses on frozen patient CSF samples with vertical flow paper printed microarray will be done in Stockholm, Sweden within 1 year.
Secondary outcomes:
measure: Protein profile variance between children with severe and non-severe infection
timeFrame: Frozen patient blood samples will be analyzed using Luminex Multiplex Assays in Stockholm, Sweden, within 1 year after sample collection in Mbarara, Uganda.
measure: Variance in concentration of MxA in blood of patients with viral vs. non-viral meningitis and non-severe infection.
timeFrame: MxA concentration measurements will be conducted on the Luminex platform on frozen patient blood samples in Stockholm, Sweden, within a year from sample collection.
measure: Diagnostic performance of the FilmArray ME Panel for meningitis diagnostics in children in a low-income setting
timeFrame: FilmArray analyses on fresh patient CSF samples will be conducted immediately after or within 1 day of sample collection.
measure: Clinical impact of the FilmArray ME Panel on management of childhood meningits in a low-income setting.
timeFrame: FilmArray analyses on fresh patient CSF samples will be conducted immediately after or within 1 day of sample collection.
measure: Usability of the FilmArray ME Panel for meningitis diagnostics in children in a low-income setting.
timeFrame: Questionnaires will be handed out and collected from participants continuously during the 1 year duration of patient inclusion.
measure: Mapping of Neisseria meningitidis carriage and prevalence in children in Mbarara, Uganda
timeFrame: Nasopharyngeal swabs will be collected upon inclusion to the study. Sequencing and serotyping will be done in Stockholm, Sweden, within 1 year after sample collection.
measure: Etiology of childhood meningitis in the Mbarara district, Uganda.
timeFrame: CSF culture, PCR and FilmArray analyses will be conducted during the 1 year duration of the study, in Mbarara, Uganda.
measure: The impact of pneumococcal conjugate vaccines on aetiology of childhood meningits in the Mbarara district.
timeFrame: CSF culture, PCR and FilmArray analyses will be conducted during the 1 year duration of the study, in Mbarara, Uganda.
Other outcomes:
Locations:
city: Mbarara
country: Uganda
facility: Holy Innocents Children's Hospital
city: Mbarara
country: Uganda
facility: Mbarara Regional Referral Hospital
Study officials:
affiliation: Mbarara University of Science and Technology
name: Elias Kumbakumba, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Karolinska Institutet
name: Tobias Alfvén, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gaudenzi G, Kumbakumba E, Rasti R, Nanjebe D, Reu P, Nyehangane D, Martensson A, Nassejje M, Karlsson J, Mzee J, Nilsson P, Businge S, Loh E, Boum Ii Y, Andersson-Svahn H, Gantelius J, Mwanga-Amumpaire J, Alfven T. Point-of-Care Approaches for Meningitis Diagnosis in a Low-Resource Setting (Southwestern Uganda): Observational Cohort Study Protocol of the "PI-POC" Trial. JMIR Res Protoc. 2020 Nov 4;9(11):e21430. doi: 10.2196/21430.