Biomarkers of Acute Serious Illness in Children
Condition: Critical Illness; Infection, Mixed; Children, Only
MeSH terms: Coinfection; Critical Illness
Study type: Observational

Summary: 
      This study is a large multi-centre collaboration between a busy regional paediatric intensive
      care transport service (Children's Acute Transport Service, CATS), four large paediatric
      intensive care units (PICUs at Great Ormond Street Hospital, St Mary's Hospital and Royal
      London Hospital in London, and Addenbrookes Hospital in Cambridge) and the Department of
      Paediatrics at Imperial College, London. CATS transports over 800 sick children on life
      support to the three PICUs each year.

      We aim to improve our understanding of the genetic basis and biological pathways by which
      children with acute infection or injury become critically ill and develop failure of vital
      organs, and how these factors influence outcome. We will establish well-characterised cohorts
      of sick children with diverse pathologies, in whom blood, urine and other samples will be
      collected at an early stage of critical illness. Samples will be analysed using genomic,
      transcriptomic, proteomic and metabolomic approaches. Advanced bioinformatics techniques will
      be used to identify biomarkers for early diagnosis and robust risk stratification. We will
      focus on biomarkers to help distinguish between serious bacterial infections, viral
      infections and other causes of critical illness; diagnose incipient organ failure; and
      accurately identify, early on, children at high risk of developing a poor outcome.

      We will recruit critically ill children at first contact with the CATS team, during emergency
      transport to PICU. Due to the emergency nature of the research, and minimal risk associated
      with the study procedure, we will seek deferred, written informed consent from
      parents/guardians once their child has been stabilised, within 24-48 hours following PICU
      admission.

      By studying these important questions, we aim to better understand how we can diagnose and
      provide early life-saving treatments to critically ill children. The research team have an
      established track record of successful completion of several large clinical studies in
      critical care as well as validation of biomarkers in other diseases.
    

Detailed description: 
      This is a prospective cohort study involving the collection of clinical data and biological
      samples. No interventions will be performed on patients.

      Sample collection Blood and urine samples will be collected at two time points. Stool and
      throat swabs will also be collected if possible.

      Timepoint 1: During stabilisation by the CATS team (first contact with an intensive care
      team) The CATS team will collect samples during routine sampling, prioritised in the
      following order: DNA (2 ml); RNA (2 ml); Serum (2 ml); Plasma (2 ml) and Urine (10 ml).

      Timepoint 2: Within 24-48 hours of PICU admission The research team in the participating PICU
      will collect samples during routine sampling, prioritised in the following order: DNA (2 ml);
      RNA (2 ml); Serum (2 ml); Plasma (2 ml) and Urine (10 ml). In addition, stool and throat swab
      samples will be collected on the PICU.

      In infants less than 10 kg in weight, we will restrict total blood volume collected at each
      time point to 0.8 ml/kg body weight, in line with MCRN Clinical Trials Guidelines, 25 July
      2008.

      In addition, faecal samples will be collected on admission to PICU (day 1) and 24-48 hours
      after PICU admission. If faeces are not available, an anal swab will be taken for
      microbiological analysis. SCFA will be measured on the first available faecal sample.

      Sample transport, processing and storage Samples will be transported by the CATS team to the
      admitting PICUs in cool boxes (4°C). Sample processing and storage will occur at the hospital
      where the patient is admitted. Processing will include anonymisation of the sample by
      generating a unique study number, which will be used for all references to the samples
      thereafter.

      Clinical data collection A standardised case report form and data collection manual with
      definitions and rules will be produced. Data will be collected by research staff at each
      unit. Clinical data will cover the key stages of the patient's pathway - intensive care
      referral and transport, PICU course and outcome. We will perform detailed clinical
      phenotyping of the patient, including reason for PICU referral/admission (infection, trauma,
      neurological, cardiac, respiratory and other), severity of illness (PIM-2 score), severity of
      organ failure (PELOD) and outcome at discharge from PICU (death, severe disability).
      Recognising that short-term outcome at PICU discharge may not be the most meaningful outcome
      for parents/carers, or provide an accurate picture of long-term outcome in children, we will
      also seek parents/carers' consent to be contacted 1 year after PICU admission to complete
      short questionnaires to assess the child's functional status and quality of life.
      Questionnaires will be either administered by telephone, email or web-based means, depending
      on parental preference.

      Where possible, in order to avoid duplication of effort, clinical data from CATS retrieval
      and PICU admission will be obtained by electronic linkage from the paediatric intensive care
      national clinical audit (PICANet, University of Leeds and Leicester). Data linkage will be
      performed using the CATS retrieval number, at the end of the study period. Collection of
      these data will follow a standard procedure - any transfer of data (requests for data and the
      return of the full dataset) will be performed securely (with full encryption).

      Data analysis Initially, each type of information, i.e. genetic, transcriptomic, proteomic,
      epigenetic, clinical will be analyzed separately to identify associations and correlations at
      a first stage. Differential behaviour and association patterns will be derived by various
      statistical and bioinformatic analyses, both univariate and multivariate, as described above.
      At a second stage, information will be combined across datatypes into predictive models. A
      systems biology approach will be employed in which networks of co-regulated genetic,
      transcriptomic, proteomic and epigenetic modules will be constructed in both case and control
      cohorts. Network connections which will be different between cases and controls will be
      identified as "predictors" of the outcome.

      Graphical modelling will be used to visualize those complex networks. Heavy statistical
      analysis will be required to identify the most influential connections that once removed they
      would have the greatest impact on the network topology. Models will be refined, re-evaluated,
      validated and replicated across the different disease cohorts until the best possible out of
      sample classification is achieved. The expertise of the mathematical and statistical group
      will provide the ability to link the multiple layers of biological information from DNA to
      phenotype into a network systems biology approach.

      Sample size No formal sample size calculations are possible but we will recruit a minimum
      number of patients in each group of interest. We aim to recruit adequate numbers of patients
      with different reasons for intensive care admission into the study (50-80 patients per group
      of interest).

      Study duration Patient recruitment will take place over a 24 month period, with a 6 month
      lead in time for staff training and 6 months lead out time for patient follow up and
      completion of databases.

      Patient recruitment Eligible patients will be recruited to the study during transport by
      medical and nursing staff from the CATS intensive care transport team.

      Consenting procedure We will seek deferred written informed consent from parents/guardians
      once their child's condition stabilises, usually within 24-48 hours following PICU admission.
      The consent process will be supported by Patient Information Leaflets. There are several
      precedents for this approach in emergency research, including in paediatric intensive care.
      Support for deferred consent in urgent life-threatening situations is also provided through
      the latest EU Regulation on Clinical Trials (2013).

      The main reasons for seeking deferred consent in this study are:

        1. Clinical: Emergency intensive care transport of children represents an urgent situation
           where life-saving treatment cannot be delayed and transport to a PICU needs to be
           undertaken rapidly. In addition, parents/guardians may not be present at the time of
           stabilisation to discuss consent.

        2. Practical: Taking an additional staff member for the transport purely for research
           consent is not feasible due to the limited space in the ambulance. The 24/7 nature of
           the CATS service and the fact that multiple transports occur concurrently also makes
           having dedicated research staff impractical.

        3. Methodological: Difficulties in obtaining full informed consent may result in selection
           bias being introduced. In addition, if study samples are not taken at an early stage of
           critical illness, before treatments (such as fluids or inotropes) are initiated,
           deriving robust biomarkers of critical illness may be flawed. While methodological
           issues cannot provide an argument for including data when research subjects expressly
           deny consent, it does make an ethically valid case for including samples or data
           collected before consent has been taken, and where such explicit denial of consent does
           not exist.

        4. Ethical: Due to the difficulties of obtaining informed consent in emergency situation,
           the sickest patients are often subjected to anecdotal medical practice. It may be
           unethical to deny sick children the benefits of new research and therapeutic strategies
           based on the most robust scientific understanding of critical illness, which is what our
           study aims to advance.

      If parents/guardians do not wish to consent or are unable to consent, or staff are unable to
      make contact with parents/guardians, the samples will be discarded and no clinical data will
      be collected.
    

Intervention name(s): None, observational study
Intervention type(s): Other
Intervention description(s): Observational study, no interventions
Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Critically ill children transported to an intensive care unit in an emergency
      
Biospecimen description: 
      Blood in EDTA tube (DNA), PAX gene tube (RNA), Plasma, Serum (5 ml in total, or 0.8 ml/kg
      whichever is lower)

      Urine in universal container (5-10 ml)
    
Keywords: Critical illness; PICU; biomarkers