Improvements Through the Use of a Rapid Multiplex PCR Enteric Pathogen Detection Kit in Children With Hematochezia
Condition: Diarrhea Bloody
MeSH terms: Gastrointestinal Hemorrhage; Diarrhea
Study type: Interventional

Summary: 
      Children presenting for emergency department (ED) care with bloody diarrhea (i.e.
      hematochezia) represent a diagnostic challenge. Infectious enteric pathogens - Salmonella,
      Shigella and Shiga toxin-producing Escherichia coli (STEC) - are at the top of the
      differential diagnosis list. STEC is of greatest concern because ~15% of infected children
      develop the Hemolytic Uremic Syndrome (HUS). Our team has demonstrated that antibiotic
      administration to STEC-infected children increases the risk of developing HUS while
      dehydration is associated with mortality. Rapidly identifying children with STEC infection
      can reduce unnecessary resource use in uninfected children while providing them to those with
      confirmed STEC infection. The study team will conduct a prospective ED-based study that will
      randomly allocate 60 children to either standard care as dictated by the treating physician
      or to the use of a 22-pathogen, nucleic acid based, 1-hour run time diagnostic test. The
      study team will evaluate the impact of testing on clinical resource use, clinical outcomes,
      costs and patient satisfaction.
    

Detailed description: 
      Background:

      The rapid identification of STEC-infected children will enable the provision of appropriate
      and timely care to such children. The rapid identification of other enteric pathogens
      (bacteria, virus, parasite) will enable the provision of targeted therapies as appropriate
      and the withholding of avoidable interventions. It will also provide information for
      clinicians to consider alternate, non-infectious etiologies as appropriate. The study team
      hypothesize that the BioFire FilmArray can be used selectively in children with hematochezia
      to identify children with STEC infection and therefore will expeditiously identify children
      in need of therapeutic interventions and those for whom blood testing, intravenous fluids,
      and follow-up visits are unnecessary. Knowledge of the etiology early in the course of
      disease will enhance the provision of a patient-level precision medicine approach to what is
      otherwise an ill-defined symptom.

      Study Design:

      The study team will prospectively identify children who present with hematochezia.
      Potentially eligible subjects will be identified by our Pediatric Emergency Medicine Research
      Associate Program (PEMRAP) and the Pediatric Emergency Research Team (PERT) nurses (ED
      coverage 14 hours per day). Eligible children will have ≥3 episodes of diarrhea within the
      preceding 24 hours and will have had blood identified in the stool (by physician, nurse or
      parent ). Eligible subjects will be approached by a PERT team member to obtain consent (and
      assent when appropriate). Once consent has been obtained, study participants will be
      randomized by a REDCap randomization tool to ensure allocation concealment (i.e. research
      team, ED physicians will be unaware until after enrolled into the study and randomized).

      Children randomized to the standard of care arm will have demographic and clinical
      information collected and the treating physician will be informed to proceed as per their
      usual practice and treatment patterns. If stool is unavailable a rectal swab will be
      collected and sent to Calgary Laboratory Services (CLS) for routine culture. A routine stool
      specimen for back-up culture will still be requested as per standard of care. Home stool
      collection will be performed for those unable to provide a sample at enrolment and will be
      achieved by providing families with collection kits. Sample specimens may be stored at CLS as
      per routine procedures for standard clinical care. Following the completion of the visit,
      data regarding all testing, procedures, and medications administered will be collected. The
      family will be contacted 14 days later to collect outcome information (clinical and health
      resource use) and satisfaction. The medical records and select administrative databases may
      be reviewed to ascertain and confirm outcome data on Day 28.

      Children randomized to the BioFire FilmArray arm will have the same data collected, but
      stool, if available, will be sent STAT to Calgary Laboratory Services (CLS) for the
      performance of the BioFire FilmArray test and routine culture. If stool is unavailable, a
      rectal swab will be performed and sent to CLS for the performance of the BioFire FilmArray
      test and routine culture. A routine stool specimen for back-up culture will still be
      requested as per standard of care once it is available. Sample specimens may be stored at CLS
      as per routine procedures for standard clinical care. The result of the BioFire test will be
      printed and brought to the ED where it will be provided to the ED physician for immediate
      review and management as appropriate. The result will be included in the ED chart for
      documentation purposes. Education regarding the interpretation of BioFire FilmArray results
      will have been performed in advance to all faculty members and a research team member will be
      available to answer any questions should they arise. We have worked with leaders at CLS
      including Drs. Gregson, Berenger and Vanderkooi who believe we should be able to receive a
      result within 2-3 hours of receipt of the specimen at CLS. Treatment decisions will be at the
      sole discretion of the ED treating physician who receives the result. Following the
      completion of the visit, data regarding all testing, procedures, and medications administered
      will be collected. The family will be contacted 14 days later to collect outcome information
      (clinical and health resource use) and satisfaction. The medical records and select
      administrative databases may be reviewed to ascertain and confirm outcome data on Day 28.

      For those who decline consent, the study team will request consent to access select
      administrative data, Netcare and/or access to the child's medical records related to the
      illness to document interventions and outcomes in order to be able to assess bias by
      comparing participating and non-participating children in this study.

      Objectives:

      Primary Objective

      1. To determine if use of the BioFire FilmArray in children with hematochezia results in a
      reduction in resource utilization. Primary outcome - any blood tests (dichotomous with
      sub-analysis by specific blood tests); secondary - intravenous fluid administration, ED
      encounters.

      Secondary Objectives

        1. To quantify clinical outcomes - development of HUS, acute kidney injury, need for renal
           replacement therapy, turnaround time from BioFire result relative to stool culture
           result.

        2. To determine if use of the BioFire FilmArray is associated with greater family
           satisfaction with care.

        3. To determine testing criteria to optimize the clinical improvement emerging from use of
           the BioFire FilmArray (i.e. predictors of bacterial etiology).

      Significance:

      The study team intend to determine new knowledge:

        1. If use of the BioFire FilmArray, a rapid, multi-analyte enteric pathogen detection
           device, reduces resource utilization in a pediatric ED when employed on children with
           bloody diarrhea. The study team hypothesize that use of the test combined with
           behavioural changes by physicians will reduce the use of baseline blood tests, the
           administration of intravenous fluids and future health-care resource use (children are
           often brought back for repeat blood tests and fluids while awaiting culture results).

        2. If satisfaction is higher in individuals randomized to testing with the BioFire
           FilmArray arm compared with children in the standard care arm.

      Potential child health improvements:

        1. Children with STEC infection will be rapidly identified: The study team has shown that
           in the 2014 STEC outbreak in Alberta, the median time from initial health care
           presentation to stool sample collection was 7 hours (IQR 2, 28) and to sample receipt at
           the laboratory was 33 hours (IQR 18, 42). Even more concerning is that the time from
           initial health care encounter to positive culture was 120 (IQR 86, 205) hours. By
           collecting rectal swabs at the point of care, the study team will initiate specimen
           processing an average of 30 hours earlier. By employing the BioFire FilmArray the study
           team will reduce stool processing time by over 80 hours.

        2. Children with STEC infection will have dehydration reversed rapidly and they will be
           closely monitored: Following the rapid identification of children with STEC infection,
           all such children will be managed in accordance with a protocol developed by the
           APPETITE team for Alberta Health Services
           (http://www.albertahealthservices.ca/assets/info/hp/diseases/if-hp-dis-ecoli-stec.pdf),
           which includes the performance and monitoring of serum biochemistry and hematologic
           profiles and the prevention of dehydration. It is believed that the early administration
           of intravascular volume expansion has the potential to reduce the morbidity of HUS in
           affected children. [Ake et al., 2005 & Hickey et al., 2011]

        3. Children who do not have STEC infection will avoid unnecessary blood tests, intravenous
           fluids and repeat visits: As ~10% of eligible children will have STEC infection, [Klein
           et al., 2006 & Klein et al., 2002] the routine performance of blood tests,
           administration of intravascular hydration, and frequent monitoring is unnecessary in the
           vast majority of children with hematochezia. As such, knowledge that a result will be
           rapidly available will enable clinicians to confidently discharge children without
           performing unnecessary procedures. Those who test positive can be recalled to the ED for
           the appropriate management.

        4. Children will have alternative etiologies identified rapidly: The BioFire FilmArray will
           also enable the rapid identification of other pathogens, some of which will require
           immediate therapy such as Shigella sp., Clostridium difficile, and others that have
           public health implications such as Salmonella sp., and norovirus.

        5. Children who do not have infectious gastroenteritis will be rapidly identified: Children
           with a negative BioFire FilmArray will also be identified. This would raise the
           suspicion for alternative etiologies.

        6. Transmission will be reduced: The rapid identification of infected children has the
           potential to reduce spread, which is common and occurs early in the course of disease.
           Transmission might be reduced by separating infected index cases from their at risk
           siblings. [Werber et al., 2008]
    

Intervention name(s): BioFire Gastrointestinal Panel FilmArray®; Standard of Care
Intervention type(s): Device; Other
Intervention description(s): The BioFire Gastrointestinal Panel FilmArray® is a multiplexed nucleic acid (NA) based device that simultaneously identifies 22 enteric pathogens. It specifically tests for the presence of Shiga toxin and for O157. It requires 2 minutes of hands-on-time, returns results in ~2-3 hour, and is Health Canada and Food and Drug Administration approved. The device, which has been validated, hopefully will enable the early identification of infected children and initiation (or withholding) of interventions directed by previously unavailable clinical data. It will enable us to bring a precision medicine approach into ED care.; Standard practices for children with hematochezia upon the discretion of the treating physician. If investigations are ordered, results have a turn-around time up to 72 hours.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Investigator, Outcomes Assessor)
Primary purpose: Health Services Research
Keywords: Bloody Diarrhea; STEC; Hematochezia; BioFire FilmArray; Child