Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

Paediatric Infections Point-Of-Care (PI-POC)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03900091
Recruitment Status : Not yet recruiting
First Posted : April 2, 2019
Last Update Posted : April 2, 2019
Sponsor:
Collaborators:
Mbarara University of Science and Technology
Science for Life Laboratory
Epicentre Mbarara Research Center
Stockholm South General Hospital
Information provided by (Responsible Party):
Tobias Alfvén, Karolinska Institutet

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.

Condition or disease Intervention/treatment
Meningitis Pediatric Infectious Diseases Diagnostic Test: Multiplex PCR assay for meningitis Diagnostic Test: Multiplex vertical flow microarrray assay for meningitis Diagnostic Test: Profiling of blood proteins by multi-analyte Profiling technology Other: Typing and whole genome sequencing

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.


Layout table for study information
Study Type : Observational
Estimated Enrollment : 600 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Paediatric Infections Point-Of-Care: Point-of-care Approach for Rapid and Easy Meningitis Diagnosis
Estimated Study Start Date : April 1, 2019
Estimated Primary Completion Date : April 2020
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
Cases with clinical meningitis
Patients aged 0-12 years with suspected CNS infection, at the pediatric clinics at Mbarara Regional Referral Hospital or Holy Innocents Children's Hospital, Mbarara, Uganda.
Diagnostic Test: Multiplex PCR assay for meningitis
CSF from cases to be analysed with a FilmArray ME Panel
Other Name: Biomerieux FilmArray ME Panel

Diagnostic Test: Multiplex vertical flow microarrray assay for meningitis
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.

Diagnostic Test: Profiling of blood proteins by multi-analyte Profiling technology
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.
Other Name: Luminex Multi-Analyte Profiling (xMAP)

Other: Typing and whole genome sequencing
Pathogenic strains isolated from nasopharyngeal swabs from cases and controls will undergo whole genome sequencing (WGS) and typing .

Control subjects
Patients aged 0-12 years, visiting the outpatient pediatric clinics at Mbarara Regional Referral Hospital or Holy Innocents Children's Hospital, Mbarara, Uganda, with fever clinically considered non-severe.
Diagnostic Test: Profiling of blood proteins by multi-analyte Profiling technology
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.
Other Name: Luminex Multi-Analyte Profiling (xMAP)

Other: Typing and whole genome sequencing
Pathogenic strains isolated from nasopharyngeal swabs from cases and controls will undergo whole genome sequencing (WGS) and typing .




Primary Outcome Measures :
  1. Diagnostic accuracy of vertical flow microarray printed on paper for pathogen identification in human cerebrospinal fluid samples [ Time Frame: 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. ]
    The newly developed assay will be evaluated with regards to diagnostic accuracy. For this, results will be compared with those from bacterial culture, PCR and FilmArray analyses of the same samples.


Secondary Outcome Measures :
  1. Protein profile variance between children with severe and non-severe infection [ Time Frame: Frozen patient blood samples will be analyzed using Luminex Multiplex Assays in Stockholm, Sweden, within 1 year after sample collection in Mbarara, Uganda. ]
    Protein profile (biomarker) concentration (e.g. μg/L) variance in the blood of children with severe infection as compared to those with uncomplicated infection, as well as longitudinal variance in protein profile during the course of severe infection.

  2. Variance in concentration of MxA in blood of patients with viral vs. non-viral meningitis and non-severe infection. [ Time Frame: MxA concentration measurements will be conducted on the Luminex platform on frozen patient blood samples in Stockholm, Sweden, within a year from sample collection. ]
    Difference in MxA concentration (e.g. μg/L) in peripheral blood of patients with viral/non-viral meningitis and non-severe infection will be studied with the Luminex platform, to identify any feasibility of MxA to be used as a blood biomarker to differentiate between aetiologies of meningitis and to differentiate meningitis to non-severe infection. This in order to assist differential diagnostics in the clinical management of childhood fever.

  3. Diagnostic performance of the FilmArray ME Panel for meningitis diagnostics in children in a low-income setting [ Time Frame: FilmArray analyses on fresh patient CSF samples will be conducted immediately after or within 1 day of sample collection. ]
    Diagnostic accuracy of the FilmArray® (compared to current gold standard methods PCR and culture) for aetiological diagnosis of CNS infections in children. Sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios will be calculated for the results from FilmArray analyses on patient CSF samples.

  4. Clinical impact of the FilmArray ME Panel on management of childhood meningits in a low-income setting. [ Time Frame: FilmArray analyses on fresh patient CSF samples will be conducted immediately after or within 1 day of sample collection. ]
    Parameteres including time to laboratory confirmed diagnosis, time to treatment initiation, duration of hospital stay (all in hours/days) and patient mortality will be measured for suspected cases of meningitis whose CSF has been analyzed using the FilmArray® ME panel.

  5. Usability of the FilmArray ME Panel for meningitis diagnostics in children in a low-income setting. [ Time Frame: Questionnaires will be handed out and collected from participants continuously during the 1 year duration of patient inclusion. ]
    A questionnaire will used to gather experiences from health care personnel in Mbarara involved in clinical management of children with suspected meningitis and laboratory personnel in Mbarara conducting FilmArray analyses, in order to study clinical perspectives on the contribution of FilmArray assays to the management of meningitis, in this low-income setting.

  6. Mapping of Neisseria meningitidis carriage and prevalence in children in Mbarara, Uganda [ Time Frame: 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. ]
    Whole genome sequencing and serotyping of any strains of N. meningitidis isolated from nasopharyngeal swabs from included children in Mbarara (cases and controls) will be done to understand the local prevalence of N. meningitidis in severe/non-severely ill children in the district.

  7. Etiology of childhood meningitis in the Mbarara district, Uganda. [ Time Frame: CSF culture, PCR and FilmArray analyses will be conducted during the 1 year duration of the study, in Mbarara, Uganda. ]
    Current aetiology of childhood meningitis in the Mbarara district, Uganda, will be studied through culture, PCR and FilmArray analyses of CSF samples from children with suspected meningitis.

  8. The impact of pneumococcal conjugate vaccines on aetiology of childhood meningits in the Mbarara district. [ Time Frame: CSF culture, PCR and FilmArray analyses will be conducted during the 1 year duration of the study, in Mbarara, Uganda. ]
    Comparison of current (post-vaccination era) to prior (pre-vaccination era) aetiology of childhood meningitis. The pneumococcal vaccine was recently included in the Ugandan childhood immunization program, and just prior to this, the aetiology of childhood meningitis in the Mbarara district was reported by Page et al, finding S. pneumoniae to be the most frequent agent causing bacterial meningitis in the district. Has this changed?


Biospecimen Retention:   Samples With DNA
Cerebrospinal fluid Nasopharyngeal swabs Whole blood


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   up to 12 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03900091


Contacts
Layout table for location contacts
Contact: Elias Kumbakumba, MD +256 771895971 ekumbakumba@must.ac.ug
Contact: Milly Nassejje, MD nassejjemilly21@gmail.com

Locations
Layout table for location information
Uganda
Holy Innocents Children's Hospital Not yet recruiting
Mbarara, Uganda
Contact: Stephen Businge, MD       stevebusinge@gmail.com   
Principal Investigator: Stephen Businge, MD         
Mbarara Regional Referral Hospital Not yet recruiting
Mbarara, Uganda
Contact: Elias Kumbakumba, MD    +256 771895971    ekumbakumba@must.ac.ug   
Contact: Milly Nassejje, MD       nassejjemilly21@gmail.com   
Principal Investigator: Elias Kumbakumba, MD         
Sponsors and Collaborators
Karolinska Institutet
Mbarara University of Science and Technology
Science for Life Laboratory
Epicentre Mbarara Research Center
Stockholm South General Hospital
Investigators
Layout table for investigator information
Principal Investigator: Elias Kumbakumba, MD Mbarara University of Science and Technology
Principal Investigator: Tobias Alfvén, MD PhD Karolinska Institutet

Layout table for additonal information
Responsible Party: Tobias Alfvén, Associate Professor, Karolinska Institutet
ClinicalTrials.gov Identifier: NCT03900091     History of Changes
Other Study ID Numbers: 2018/1676-31/1
First Posted: April 2, 2019    Key Record Dates
Last Update Posted: April 2, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Tobias Alfvén, Karolinska Institutet:
Point of care
Diagnostics
Low-income countries
Meningitis
Pediatrics
MxA
FilmArray
Low-cost diagnostics

Additional relevant MeSH terms:
Layout table for MeSH terms
Meningitis
Communicable Diseases
Infection
Central Nervous System Diseases
Nervous System Diseases