Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract (GIT) characterised by the repetitive inflammation of the GIT caused by an abnormal immune response1. Despite IBD is often described as a bimodal disease, it has recently gained attention since there has been an increase in the number of cases of paediatric IBD (pIBD) in children below the age of 152. Due to the diagnostic delay and limited treatment options available for these patients, the risk of growth failure and long-term complications remain a serious parental concern3. This underscores the urgent and pressing need for improved treatment options to address the challenges of pIBD.
IBD is a chronic inflammatory disease of the GIT, divided into Crohn’s disease (CD), ulcerative colitis (UC) and IBD unclassified1. The disease is characterised by the repetitive inflammation of the GIT caused by an abnormal immune response, and the disease distribution varies in each subtype. For instance, UC often affects the rectum (proctitis) but may extend into the sigmoid colon (proctosigmoiditis) or beyond (distal UC) or affect the entire colon up to the caecum (pancolitis). Contrarily, CD results in transmural ulceration, which means the inflammation extends through the entire thickness of the intestinal wall of any portion of the GIT, affecting the terminal ileum and the colon4. Despite IBD is often described as a bimodal disease with an incidence peak seen in those aged 15-25 and a second, smaller peak seen during the fifth to seventh decade in life5, the disease has recently gained research interest since there has been an increase in the number of cases related to pIBD in children below the age of 152.
The factors driving this increase in pIBD cases remain uncertain. Some experts speculate that a combination of genetic predisposition, a diet that is typical of Westernised societies (referred to as ‘Westernised diet’), poor generation of immune tolerance, and gut microbiota dysbiosis may possibly be the culprits1. The rising incidence of pIBD is likely to put more strain on the already burdened healthcare system, as these patients often present with a more severe phenotype, requiring more surgeries and escalated treatment regimens1. The diagnosis of IBD continues to be challenging, as it manifests with a variety of intestinal and extraintestinal symptoms that can present insidiously or in a fulminant manner. The diagnostic delay in pIBD is particularly concerning, as it can lead to an increased risk of complications, loss of opportunity to recover optimal growth, and a negative impact on overall psychosocial and physical development6.
"pIBD maybe driven by combination of genetic and environmental exposure"
In up to 10% of paediatric cases, the distinction between CD and UC can be difficult. As the disease progresses, patients with IBD-unclassified may develop into either CD or UC. Furthermore, in a small proportion of children with IBD, UC may co-exist with primary sclerosing cholangitis (PSC-IBD) and these children may have a critical risk of developing colorectal cancer or cholangiocarcinoma7. Patients with IBD may present with non-classical signs of IBD, such as mild abdominal discomfort, lethargy, delayed puberty, and growth failure3, which may delay the child’s opportunity to recover optimal growth due to diagnostic delay6. The extent of the diagnostic delay for pIBD was evaluated in a systematic review by Ajbar et al. (2022) that included 24 paediatric studies that reported the overall median diagnostic delay ranged from 2.0-10.4 months for IBD, 2.0-18.0 months from UC and 4.0-24.0 months from CD. However, for approximately two-thirds of UC (68.8%) and CD (66.7%) studies, delay ranged from 2.0-3.0 and 4.0-6.3 months, respectively. This highlights the crucial need for early diagnosis to prevent further complications.
The study found that children continued to wait for several months for a final diagnosis of IBD, and those with CD experienced longer delays than those with UC3. These findings demonstrate that diagnostic delays are the major contributing factor to the poor prognosis of the disease in children due to a lack of awareness among parents8. Apart from the diagnostic delay, patients who develop IBD during childhood are at higher risk for a more severe disease course and intestinal complications compared to adult-onset cases. As a result, this may be attributed to a longer lifetime risk, thus increasing the all-cause mortality risk secondary to GI cancers for children with IBD by up to threefold compared to children without IBD. Importantly, pIBD is also plagued by limitations in the therapeutic arsenal and psychosocial impact during the transition of children with IBD to adulthood7. Additionally, paediatric studies have suggested children exposed to antibiotics during their infancy may have a higher risk of developing IBD due to gut microbiome dysbiosis9.
"Diagnostic delay in pIBD is among the major contributing factor for a poor prognosis in children due to longer lifetime exposure"
Antibiotic treatment is sometimes required to treat infections, fistulas, abscesses in pIBD, and antibiotic therapy can influence the course of IBD by decreasing luminal bacteria concentrations and possibly altering the composition, favouring beneficial bacteria10. The effects of antibiotics use in the paediatric population, particularly during the first 5 years of life, and the risk of developing pIBD was evaluated in a nationwide cohort by Jawad et al. (2023). The study identified 1,927 paediatric IBD patients and 18,318 reference individuals from a National Patient Registry in Denmark between 1995 and 2018. Antibiotic exposure was defined as being prescribed antibiotics during the first 5 years of life11. Strikingly, the study found that oral antibiotic exposure during the first 5 years of life was associated with a higher risk of developing pIBD (hazard ratio [HR]= 1.33; 95% confidence interval [CI]: 1.2-1.5, p<0.0001). This finding underscores the need for caution use of antibiotic in this population. Interestingly, the risk escalated further in patients treated with ≥4 antibiotics prescriptions compared to those without antibiotic exposure (p<0.0001). Furthermore, broad-spectrum antibiotics increased the risk of pIBD more than narrow-spectrum antibiotics (p<0.0001), particularly in patients with CD (p=0.002), but not UC. These findings suggested that early antibiotic exposure was associated with an increased risk of pIBD, and repeated exposure increased the risk estimate further11.
Not surprisingly, a pooled analysis by Mårild et al. (2024) evaluated childhood antibiotics use in early-life infection and the subsequent risk of developing IBD. The study included data from 103,046 patients (11,872 from Sweden, and 91,174 from Norway) with 395 patients diagnosed with IBD. Remarkably, the study revealed that the use of non-penicillin antibiotics at 1 to <3 years of age was associated with an increased risk of UC but not CD12. Similarly, Andersen et al. (2024) evaluated antibiotic exposure prenatally and the risk of developing pIBD before the age of 2 in 536,819 children with 797 identified cases of pBID in Norway from 2004-
2012 until the study’s end on 31st December 2020. The study found that children exposed to antibiotics before the age of 2 were 1.3-fold more likely to develop pIBD than unexposed controls, and this association was only applicable to patients who developed CD but not UC13. Considering that all three Scandinavian studies have clearly highlighted the association between antibiotic exposure and subsequent development of pIBD, it is undeniable that broad-spectrum antibiotic use seems to be a common denominator and causative factor in pIBD development.
"Children of the age 2 exposed to antibiotics were 1.3-fold more likely to develop pIBD than unexposed children"
Despite recent treatment advances over the last few decades for adult IBD, the limited availability of new biologics remains in pIBD, necessitating the urgent need to optimise paediatric care in this area14. The unmet treatment need is confounded by a significant time lag of around 7 years seen between marketing authorisation being granted for IBD treatment. Furthermore, the time for the primary completion of pIBD clinical trials is often long due to the slow recruitment process, and this inadvertently leads to limitations on choices of treatment that can be used for pIBD in clinical settings2. Due to this inadequacy, it is estimated that the risk of needing surgery 10 years post-diagnosis among the pIBD population is approximately 1 in 3 for CD and 1 in 5 for UC15. The current guidelines from both the European Crohn’s and Colitis Organisation (ECCO) and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) emphasise early intervention with biologics for children at risk of severe disease or those who are unable to achieve remission with exclusive enteral nutrition or corticosteroids8. ECCO-ESPGHAN guidelines also recommend considering anti-TNF therapy for maintenance and induction of remission in patients with delayed growth or severe disease presentations. Similar recommendations are echoed by the North American Society for Paediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN), in addition to the use of combination therapy to enhance treatment durability and reduce the risk of antibody formation against biologics8.
Not surprisingly, only infliximab and adalimumab are approved by the Food and Drug Administration (FDA) as treatment options for pIBD. Despite this, other agents such as vedolizumab (VDZ), a humanised monoclonal antibody that selectively binds to the alpha-4-beta-7 integrin, is currently being trialled. However, the long-term efficacy and safety of VDZ as maintenance therapy in the paediatric population have not been evaluated. Thus, VEDOKIDS, which was a multicentre, prospective cohort study in children <18 years with CD, UC or IBD unclassified with cohorts from 17 centres in 6 countries (Israel, the United States of America [USA], Italy, Ireland, Denmark, and Slovenia). A total of 137 patients (47% with UC, 47% with CD and 7% with IBD-unclassified) were prospectively followed up to 54 weeks and the primary outcome was complete remission (CR) at week 54, defined as CR (weighted Paediatric Crohn’s Disease Activity Index [wPCDAI] of <12.5 points in CD and Paediatric Ulcerative Colitis Activity Index [PUCAI] of <10 in UC) without the need for surgery, exclusive enteral nutrition for children with CD, or steroid (steroid-free and exclusive enteral nutrition-free clinical remission) plus C-reactive protein (CRP) concentration lower than 1.5 times the upper limit of normal (ULN) of 0.5 mg/dL. Conspicuously, the PUCAI score in children with UC decreased from 25 at baseline to 5 after week 54, and the median wPCDAI score also decreased from a baseline of 35 to 13 at week 54. Improvements in the disease activity were significant by week 6, and 25% of children with CD and 47% with UC or IBD unclassified remained in CR. The study supported the use of VDZ in pIBD for maintaining remission, more so in UC than in CD16.
The availability of new biologics holds promise, but further paediatric-focused research and updated clinical guidelines are required to reduce the disease burden of pIBD in the paediatric population.
References
1. Green Z, et al. Inflamm Bowel Dis 2024; 30(12): 2271-9. 2. Croft NM, et al. J Crohns Colitis 2023; 17(2): 249-58. 3. Ajbar A, et al. Digestive Diseases and Sciences 2022; 67(12): 5444-54. 4. McDowell C, et al. StatPearls Publishing LLC.; 2025. 5. Johnston RD, et al. Inflamm Bowel Dis 2008; 14 Suppl 2: S4-5. 6. Manuel AR, et al. Arq Gastroenterol 2023; 60(1): 91-7. 7. Bouhuys M, et al. Pediatrics 2022; 151(1). 8. Bhalla A, et al. Cureus 2025; 17(2). 9. Vangay P, et al. Cell Host Microbe 2015; 17(5): 553-64. 10. Verburgt CM, et al. Expert Review of Gastroenterology & Hepatology 2021; 15(8): 891-908. 11. Jawad AB, et al. J Pediatr Gastroenterol Nutr 2023; 77(3): 366-72. 12. Mårild K, et al. Aliment Pharmacol Ther 2025; 61(2): 323-34. 13. Andersen S, et al. J Pediatr Clin Pract 2024; 12: 200096. 14. O’Donnell JEM, et al. Expert Review of Gastroenterology & Hepatology 2024; 18(12): 815-27. 15. Hudson AS, et al. Paediatrics & Child Health 2024; 29(3): 144-9. 16. Atia O, et al. The Lancet Gastroenterology & Hepatology 2025; 10(3): 234-47.
