Very-Early-Onset Inflammatory Bowel Disease

Very-early-onset inflammatory bowel disease is chronic intestinal inflammation with onset before 6 years of age. It includes infantile onset disease (before 2 years) and neonatal onset disease, which are more likely to have a monogenic cause.

It makes up about 5 to 6% of paediatric inflammatory bowel disease, and the incidence is rising. Colitis is the commonest phenotype, followed by Crohn type disease and unclassified disease. Perianal disease, severe growth failure, and poor response to conventional treatment are frequent.

Monogenic causes include defects in interleukin-10 signalling (IL10, IL10RA, IL10RB), XIAP deficiency, chronic granulomatous disease, FOXP3 deficiency, and others involving epithelial barrier function and immune regulation. More than 80 genes have been implicated.

Pathophysiology.

Genetic defects cause a loss of mucosal immune tolerance or epithelial barrier integrity, producing uncontrolled inflammation to gut flora. Some defects are haematopoietic, others epithelial.

Polygenic risk, microbiome changes and environmental factors contribute in later onset disease.

• Bloody diarrhoea, abdominal pain, failure to thrive, severe perianal disease (fistulae, abscess, skin tags) and oral ulcers.
• Extraintestinal features: arthritis, rash, folliculitis, recurrent infections, hepatitis and haemophagocytic features.
• Family history of consanguinity, early death or immune disease in relatives.

Red flags.

• Onset in infancy or severe perianal disease.
• Recurrent or unusual infections, haemophagocytic lymphohistiocytosis, autoimmunity or lymphoma.
• Toxic dilatation, perforation or haemorrhage.

• Ileocolonoscopy with biopsies, and upper endoscopy. Findings include patchy or continuous inflammation, granulomas, crypt abscesses and apoptosis.
• Stool culture, Clostridioides difficile toxin, cytomegalovirus testing and other infective causes.
• Blood tests: full blood count, CRP, ESR, albumin, ferritin, vitamin D, liver tests, faecal calprotectin.
• Immunological assessment: immunoglobulins, lymphocyte subsets, neutrophil oxidative burst, HIV and specific protein expression.
• Genetic testing by exome or panel sequencing in all with onset under 6 years.
• MR enterography in suspected small bowel disease.

Differential diagnosis. Infectious colitis, food protein induced enterocolitis syndrome and proctocolitis, eosinophilic gastroenteritis, necrotising enterocolitis, Hirschsprung enterocolitis, immunodeficiency enteropathy and intestinal lymphangiectasia.

Induction of remission.

• Exclusive enteral nutrition for 6 to 8 weeks in Crohn type disease.
• Corticosteroids: prednisolone 1 mg/kg/day orally (maximum 40 mg), or methylprednisolone 1 mg/kg IV in severe colitis, with a tapered course over 8 to 12 weeks.

Maintenance.

• Azathioprine 2 to 2.5 mg/kg/day after checking thiopurine methyltransferase activity, with monitoring of blood count and liver function.
• Infliximab 5 mg/kg IV at weeks 0, 2 and 6, then every 8 weeks, or adalimumab, with drug level monitoring and dose escalation. Methotrexate is used in Crohn type disease.
• Vedolizumab or ustekinumab for non-response, in selected children.
• Treat perianal disease with antibiotics (metronidazole 7.5 mg/kg every 8 hours), drainage of abscesses and early surgical review.

Definitive therapy. Haematopoietic stem cell transplantation is curative for interleukin-10 signalling defects, XIAP deficiency and some immune defects. Surgery (colectomy, diversion) is used for refractory disease.

Monitoring. Growth, nutrition, calprotectin, drug levels, vaccination and bone health. Repeat endoscopy to confirm healing.

Referral and escalation. Early referral to a paediatric gastroenterology and immunology centre for all infants and young children, and urgent referral for severe colitis.