Evaluation of Faecal Volatile Organic Compounds in the Diagnosis of Paediatric Inflammatory Bowel Disease
Condition: Inflammatory Bowel Diseases
MeSH terms: Intestinal Diseases; Inflammatory Bowel Diseases
Study type: Observational

Summary: 
      Please see description below
    

Detailed description: 
      Inflammatory bowel disease (IBD) is a growing and significant problem in childhood. The
      diagnosis and monitoring of IBD in children is highly invasive and is accompanied by risk,
      stress/anxiety for children and families and significant use of healthcare resources.
      Children, young people and families have told investigators that a non-invasive diagnostic
      test is a priority for the NHS.

      IBD is an incurable chronic, relapsing condition of unknown aetiology. Its frequency has
      increased markedly across the world in recent years with the highest prevalence reported in
      Europe (322/100,000 population for CD; 505/100,000 for UC). A marked increased incidence has
      been seen in children especially in the Northern Hemisphere and largely due to an increase in
      Crohn's disease. Up to 25% of IBD starts in childhood or adolescence.

      Early-onset IBD, possibly due to inheritance of a greater number of susceptibility genes
      and/or earlier exposure to environmental triggers, differs from that occurring in adults. In
      children, inflammation occurs most commonly in the colon complicating differentiation between
      CD and UC. Early-onset CD is more common in boys (whereas adult-onset disease occurs more
      commonly in females) and tends to be more extensive with greater involvement of the upper
      intestine. Colonic inflammation in children with UC also tends to be more extensive than in
      adults.

      At initial presentation in all suspected children, upper and lower intestinal endoscopy
      (requiring two days of bowel cleansing and usually a general anaesthetic) and small bowel
      imaging by magnetic resonance enterography or wireless capsule endoscopy are required.
      Although serious adverse events are uncommon, these invasive investigations are highly
      stressful for children and their families and consume considerable hospital resources.
      Undertaking these investigations delays diagnosis and the start of treatment.

      Accurate, non-invasive, rapid and cost-effective diagnostic tools that can be used in the
      clinic or ward setting and better means of differentiating CD from UC are needed. Faecal
      calprotectin (FC), a non-specific marker of intestinal inflammation, is recommended by NICE
      to distinguish IBD from non-inflammatory gut disorders such as irritable bowel syndrome
      (https://www.nice.org.uk/guidance/dg11) and a near-patient test has been developed
      (http://www.buhlmannlabs.ch/core/quantum-blue/calprotectin/). A recent meta-analysis (394
      IBD/321 non-IBD controls) reported a pooled sensitivity and specificity of FC in the
      diagnosis of IBD in children of 0.98 (95% confidence interval: 0.95-1.0) and 0.68 (0.50-
      0.86) respectively. The low specificity indicates that an alternative or additional test with
      higher specificity is needed to reduce the time to diagnosis and avoid many children
      undergoing unnecessary investigations.

      There is great interest in the measurement of volatile organic compounds (VOCs) in breath and
      vapours from various human tissues (urine, stool, blood) in the diagnosis and monitoring of a
      wide range of diseases. VOCs emitted from stool are responsible for stool odour and consist
      of a large number of carbon based molecules of low molecular mass (<1.5Kd) including organic
      acids, alcohols, esters, heterocyclic compounds, aldehydes, ketones and alkanes. They result
      from the metabolism of the intestinal mucosa and the gut microbiota and their abundance
      changes according to the specific effects of intestinal diseases on these processes.

      Investigators have demonstrated that faecal VOCs are relatively stable over time within and
      between individuals despite day-to-day variation in diet and are not affected by freezing and
      storage of stool samples. We have optimized procedures for stool handling for metabolite
      extraction for gas chromatography-mass spectrometry (GC-MS) analysis (sample volume, solid
      phase micro-extraction fibre coating, extraction conditions [temperature and time] and vial
      volume and also developed the advanced statistical methods required for determining and
      comparing VOC profiles.

      Investigators have shown that the analysis of VOCs separates adult patients with
      diarrhoea-predominant irritable bowel syndrome (n=30) from those with active CD (62) and UC
      (n=48; sensitivity of 94% and 96% and specificity of 82% and 80% respectively; p<0.05). Our
      data in adults strongly suggests that VOCs differentiate CD from UC, and also Crohn's colitis
      from UC (Ahmed 2013). More recently, research has shown that VOCs also distinguish between
      active and inactive CD and UC in adult patients (Ahmed 2016).

      Despite these encouraging findings, given the differences in IBD between adults and children
      and that gut microbiota changes with age, it cannot be assumed that diagnostic tests that are
      effective in adults will necessarily work in children. Therefore, this technology needs to be
      tested in children. In a proof of principle study, faecal VOCs differentiated children with
      IBD from healthy children both during active disease and remission. However, investigators
      are not aware of any previous studies in children that have evaluated the utility of faecal
      VOCs in differentiating IBD from other common gastrointestinal disorders in an out-patient
      setting or in monitoring response to treatment.

      Measurement of VOCs in fresh stool samples using bench-top equipment in the clinic or ward
      will be possible in the near future. The University of Liverpool owns the intellectual
      property for the development of a point-of-care instrument. The development of this
      technology is supported by the University of Liverpool and Cancer Research UK (the latter for
      measurement of VOCs in urine to detect bladder and prostate cancer). Industrial partners are
      engaged in refining the prototype ready for moulding and production this year. The aim is to
      have a fully tested, CE marked, point-of-care instrument on sale in the EU for bladder and
      prostate cancer in 2020/1 and for IBD/irritable bowel syndrome in 2022.
    

Intervention name(s): Intervention group
Intervention type(s): Diagnostic Test
Intervention description(s): This group will provide a stool sample that will be analysed for VOCs and followed up after 3 months
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Recruitment of children will be undertaken in 3 paediatric gastroenterology referral
        centres in the UK: Alder Hey Children's Hospital, Liverpool; Bristol Royal Hospital for
        Children, Bristol; and Birmingham Children's Hospital, Birmingham.
      
Keywords: children; paediatrics; faecal volitile organic compounds; diagnosis; pathogenesis