Improvements Through the Use of a Rapid Multiplex PCR Enteric Pathogen Detection Kit in Children With Hematochezia
Improvements Through the Use of a Rapid Multiplex PCR Enteric Pathogen Detection Kit in Children With Hematochezia
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.
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]
Inclusion Criteria:

 1. Be aged 6 months - 17.99 years of age

 2. Have ≥3 episodes of diarrhea within the preceding 24 hours and have blood identified
 in the stool (by physician, nurse or parent)

 Exclusion Criteria:

 1. Previously enrolled in the study

 2. Unavailable for Day 14 follow-up

 3. Currently (most recent complete blood count) known to be neutropenic (Neutrophils
 <1000), or at high-risk of being neutropenic (receiving chemotherapy) at present

 4. Blood work performed prior to enrollment

 5. Known to be STEC positive (stool culture, PCT, or toxin)

 6. Pre-existing diagnosis of IBD (Crohn's disease, Ulcerative Colitis)

 7. Language barrier that prevents the ability to obtain informed consent and assent (when
 appropriate)