Promoting early testing and appropriate referral to reduce diagnostic delay for children with suspected inflammatory bowel disease, a narrative review

Introduction

Chronic gastrointestinal (GI) symptoms among children are a frequent cause of presentation to primary care, and for subsequent referral for tertiary assessment (1). Chronic GI symptoms are characterised as developing over time, as opposed to rapid onset, and lasting more than four consecutive weeks. Chronic GI symptoms in children may be due to organic disease, specific bacterial infection, or functional GI disorders (FGID). There is a high degree of cross-over symptoms between them, such as the triad of abdominal pain, diarrhoea, and weight loss.

The challenge facing primary care physicians and general paediatricians is to differentiate between FGID and organic disease while avoiding invasive diagnostic testing, and ensuring appropriate referral for specialist paediatric gastroenterology review (2). It is often relatively simple to exclude specific conditions that frequently present with common GI symptoms using minimal testing, such as coeliac disease (3), Helicobacter pylori infection (4), and infectious diarrhoea (5). However, no one specific test is available for FGIDs such as irritable bowel syndrome (IBS), and functional abdominal pain (FAP), nor yet for the immune-mediated condition inflammatory bowel disease (IBD). The clinical presentation of these specific FGID’s and IBD can be remarkably similar, although it is estimated that while FAP and diarrhoea accounts for up to 5% of all paediatric primary care visits, 90% will not have an organic cause for their symptoms (2,6-9). The global prevalence of FGID and IBD in the paediatric population are reported in difference ways so are not directly comparable. For children up to the age of four years aggregated data show that approximately 22% of children will experience at least one FGID (10), and 21.8–23% of those aged four to eighteen years (10,11). The worldwide prevalence of IBD varies by region and clinical sub-type, but for IBD overall has been reported to range from 21.7 to 75 per 100,000 person years (12,13). The annual global incidence of IBD, representing new diagnoses, has been reported at approximately 23 per 100,000 per year (13,14). The incidence and prevalence of paediatric IBD is increasing across all global regions (12-14).

In primary care, or general paediatric secondary care, the incidence of IBD is low so the likelihood of missing a child with IBD will be smaller than the likelihood of referring a child with FGID for unnecessary specialist assessments (15). For those children who may have IBD, prompt testing, referral, and diagnosis will avoid the sequelae of delayed diagnosis and maximise the benefit to their longitudinal disease outcomes. With the incidence and prevalence of paediatric IBD rising worldwide, the burden of the disease to individuals, as well as health-care systems, is of great significance and finding ways to improve early diagnosis and treatment is of paramount importance.

This review aims to highlight how symptoms of paediatric IBD may differentiate from FGIDs, and what is known of the prodromal IBD period and the implications of delayed diagnosis. The research questions addressed include: what clinical testing strategies may be utilised to refine clinical suspicion of IBD and facilitate prompt referral to specialist care for diagnostic testing; which risk factors are known to be associated with paediatric IBD and delayed diagnosis; which clinical information should be included in a referral to a paediatric gastroenterologist that will enable a timely assessment and diagnosis. This review will highlight the importance of identifying, and providing detailed referral information, to reduce delays to an IBD diagnosis. We present this article in accordance with the Narrative Review reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-23-35/rc).

Methods

Literature databases (Medline, Embase) were searched between 1^st November 2022 and 31^st December 2022. The search terms used consistently included the population studied, with topic specific additional terms added for each section (Table 1). Searches were limited to between 2010 and 2022, unless additional data were required for the review that were not considered time sensitive in which case the search was expanded to the years 2000 to 2022. The year parameters were implemented in order to retrieve the most up-to-date data and practices available as the diagnosis and management of chronic conditions can be dynamic and information becomes less relevant over time. Both authors (Vernon-Roberts and Day) reviewed the included literature. Of the citations included in the review 99/111 (89%) were published between the years 2010 and 2022, and 53 (48%) in the most recent 5 years [2018–2022].

Diagnostic delay in paediatric IBD

The time period prior to getting a confirmed diagnosis of IBD in children is associated with a phased longitudinal progression relating to the time between first IBD symptoms and presenting to a primary care physician, the primary care physician making a referral to a tertiary care centre, and a tertiary care specialist obtaining a definitive diagnosis via endoscopy with histology (16). Variation between these periods is considerable and determined by the individual, age group, disease course, IBD clinical sub-type, and country of residence. When these periods are prolonged, it is termed ‘Diagnostic delay’ (DD). DD has been reported to average four and a half months for IBD overall, with a median of five months for children with Crohn’s disease (CD), and three months for children with ulcerative colitis (UC) (16). DD for children with IBD has been associated with an increased likelihood of complications and comorbidities (17), disease extension for those with UC (18), and a higher rate of strictures or internal fistulae, and linear growth delay for children with CD (19-21). A few studies show that there is no increased risk of surgery for those with prolonged DD, as related to colectomy risk for children with UC (22,23), nor surgical resection or internal/perianal fistula surgery for children with CD (20). There is a considerable prodromal period for many children with IBD. Symptoms may be mild and heterogenous, and many may hide their symptoms due to anxiety or embarrassment, thus prolonging presentation to their primary care clinician or general paediatrician (24). When heterogeneous clinical characteristics are accompanied by normal laboratory parameters a differential diagnosis of FGID may be made before more overt symptoms appear, thereby prolonging the time to diagnosis. Such findings emphasize the importance of identifying factors that may increase a child’s risk of a prolonged DD period and highlighting effective testing strategies that may be implemented.

Association between presenting symptoms and DD

Symptoms

The most common symptoms across all clinical sub-types of IBD are considered to be the triad of diarrhoea, abdominal pain, and weight loss (25,26), also a common finding among children with FGID. However, studies have shown that only 25–64% of children with CD may present with this specific combination (25,27,28) and other symptoms play an important role in diagnosis (Table 2). Rectal bleeding is more common than diarrhoea among children with UC (17,21,25,26,30), and fatigue a more frequent finding then rectal bleeding among children with CD (25,26,29,30). In addition to this inconsistency of dominant symptoms, many children may have ambiguous presentations involving symptoms external to the GI tract, known as extra-intestinal manifestations (EIMs). EIM may dominate the clinical presentation initially, further contributing to DD (33). The relevance of these symptom classifications has been explored in their relation to DD.

Abdominal pain

Abdominal pain as an isolated symptom is an infrequent finding among children prior to diagnosis of IBD (26). Pain may predict a prolonged DD when in isolation from other GI findings (21) as well as when presenting among other symptoms (17). It could be postulated that abdominal pain, unless severe, may be considered a vague, subjective symptom that can be difficult for parents and physicians to recognize as associated with organic disease and more easily assigned to FGID. The prevalence of functional abdominal pain disorders (FAPDs) specifically is high, with pooled estimates showing approximately 13.5% of children experience FAPD (34). While there are varying estimates for the prevalence of the four FAPD sub-categories of functional dyspepsia, IBS, abdominal migraine, and FAP, IBS is generally experienced most frequently and by up to 8.8% of children (10,34,35).

Bloody diarrhoea

Having a child present with rectal bleeding (also termed bloody diarrhoea) is generally shown to be protective against DD (17,19,25,28). This may be the reason that children diagnosed with UC typically have a shorter DD period than children with CD. While the terms rectal bleeding and bloody diarrhoea are used interchangeably there may be distinct differences depending on the origin of the bleed, with melaena (black tarry stools) indicating blood loss proximal to the ileocecal valve, and haematochezia (bright red blood per rectum) indicative of a colonic bleed (36,37). Both melaena and haematochezia may be present in a diagnosis of IBD as well as a number of other organic and benign disorders (36,37). However, fresh blood is an alarming symptom and may prompt more rapid investigation and a subsequent reduced DD, with rectal bleeding being the main presenting symptom for children with UC (38).

Perianal symptoms

While perianal symptoms, such as abscesses, fistula, or fissures, may be a presenting symptom in 8–45% of children who go on to develop CD, and 1% of those with UC (26,28,31,39), causes may also be benign (40). Approximately 3% of children presenting with perianal symptoms may go on to develop CD specifically, but over 40% may not experience accompanying classic CD symptoms (40). Perianal disease as the sole presenting symptom for children with CD has been shown to be associated with DD (40), as has perianal involvement among other symptoms (25). However, this finding is not universal (19-21,29).

Growth

It is generally considered that a history of weight loss (or slow weight gain), as well as poor linear growth, is a frequent finding among children and adolescents prior to diagnosis with IBD (41). However, studies have shown that being underweight at diagnosis is significantly more common for children with CD (20–39%) than UC (6–25%) (42-45). In addition, children with IBD may present as being overweight or obese at diagnosis, with this finding being more likely in those with UC (5–30%) than children with CD (0–10%) (42,44-46). The reported risk of overweight/obesity is 3.5 times higher for UC than CD (46).

Linear growth failure is more frequent among those with CD (16%) than UC (5%) (26). These findings highlight that children with IBD may align with population trends towards being overweight or obese at the time of diagnosis, or present with a normalising body mass index (BMI) due to ongoing weight loss from previously being overweight (42,45,46). Children presenting with high BMI should not be overlooked for their risk of IBD due to this factor.

Poor weight gain or linear growth failure have been reported as protective against DD for children with CD and UC (19,21,24,26,47). However, this finding is not universal with studies also reporting no association between weight loss or growth failure for those with CD or UC (25,26,29,48,49).

EIMs at diagnosis

The presence of EIM in children at the time of IBD diagnosis is a common finding and may be the only clinical presentation of IBD and in fact precede GI symptoms in up to 18% of cases (50-52). The spectrum of what may be considered an EIM is broad. Further, there is overlap between what are considered EIM and those considered as comorbidities of IBD.

Much is published on EIM in paediatric IBD as related to the following systems: musculoskeletal, dermatological, respiratory, hepatobiliary, haematological, cardiovascular, ocular, oral GI, and pulmonary (53-57). The most frequently experienced EIM correspond to musculoskeletal, oral, skin, and eye manifestations, and no distinct presenting patterns seen for each clinical sub-type (Table 3). Evidence as to whether the presence of EIM at diagnosis significantly affects DD, either to shorten or prolong it, is mixed. A number of studies have shown that the presence of EIM has no association with the time taken to obtain a diagnosis (19,21,29). Other work has published evidence that EIM at presentation causes significantly shorter DD (26,49). EIM at diagnosis have been shown to be associated with an increased risk for corticosteroids and immunosuppressive therapy in children (59), possibly indicating a more severe underlying disease. Nonetheless, improving awareness of the frequency of EIM may expedite diagnosis and treatment (51).

Testing

A definitive diagnosis of IBD can currently only be obtained once children are under specialist GI care as diagnosis requires an endoscopic assessment along with microscopic analysis of mucosal biopsies. However, serum and stool tests may be utilised to differentiate between organic disease and non-organic conditions such as FGID and increase suspicion of underlying IBD. No one individual serum or stool test has been shown to be sufficiently predictive of IBD in terms of accuracy at identifying either true positive or true negative cases. However, patterns of abnormal test results may assist in making rapid and appropriate referrals for specialist assessment and thus reduce DD.

Serum biomarkers

While single blood tests are of limited utility in the diagnostic work-up of IBD (63), specific tests are sensitive markers of inflammation and likely disease activity (50). When compared with control subjects, children with IBD (UC and CD) were shown to have significantly lower levels of: haemoglobin, haematocrit, mean corpuscular volume, iron, albumin, and zinc, and higher erythrocyte sedimentation rate (ESR) and platelets (63-66). While all of these tests are linked to systemic inflammation or anaemia, children may also present with normal blood tests, with this more commonly seen in children with UC than CD (63,64). Children with IBD presenting with specific laboratory abnormalities, in particular: albumin, C-reactive protein (CRP), ESR, and ferritin, have been shown to have lower DD (19,21,49). It should be noted that up to 9% of children diagnosed with IBD present with normal serum markers (63). Up to 22% may have normal CRP and ESR specifically, and children with UC are more likely to have normal test results than those with CD (63), a finding also seen in adults diagnosed with IBD (67).

Normal inflammatory markers were more common in UC compared with CD (UC, 34%; CD, 15.8%; P=0.0035). UC (14.4% normal) presented with all normal results more frequently than CD (CD, 5.3%; P=0.02). CRP, ESR, and platelets were significantly higher in CD compared with UC. Albumin and hemoglobin were significantly lower.

Faecal calprotectin (FC)

A marker of inflammation frequently measured in those presenting with GI symptoms is FC, a calcium- and zinc-binding protein derived from neutrophilic granulocytes (68). Elevated FC levels are associated with gut inflammation, indicating that neutrophils have migrated to the affected area. While FC levels have been shown to also be abnormal (high) in children with infectious diarrhoea and necrotising enterocolitis (NEC) (69), additional stool tests can be used to exclude infectious diarrhoea (5), and NEC is generally seen in early infancy so unlikely to be a differential diagnosis to IBD. Importantly, FC levels are usually normal for children with FGID (70).

The level of FC considered to be ‘abnormal’ in the situation of possible IBD is much debated, and the age of the child must also be taken into consideration (24,71-73). For children over the age of four years a level greater than 50 µg/g is the laboratory defined ‘abnormal’ but using this cut-off in suspected IBD may not be sufficiently accurate to eliminate individuals with other diagnoses and may lead to unnecessary invasive diagnostic procedures (66,74-77). Accuracy may be determined using the metrics of ‘sensitivity and specificity’ referring to the percentage of true positives and true negatives, respectively, with values closer to 100% being most accurate.

A number of studies have assessed the diagnostic accuracy of FC at different levels but with great variation in their findings (Table 4). One meta-analysis provides more specific guidance in reporting that the optimal cut-off value is 212 mg/g, providing a sensitivity of 90% and specificity of 85% (73).While the effect of FC level on DD is infrequently studied, at levels greater than 500 µg/g DD has been shown to be reduced (49), and at levels greater than 100 µg/g were more likely to be referred to GI services, although there was no reduction in DD at this level (66). It has been suggested that the utility of FC testing within the primary care setting may be more for the negative predictive value of excluding IBD at normal levels, as opposed to the positive predictive value of indicating a likely diagnosis of IBD (2).

Alarm symptoms

Specific symptoms have been identified as ‘red flag’ or ‘alarm symptoms’ to indicate an increased likelihood of IBD when children first present to primary or secondary care. Given the diversity of symptoms at presentation, and the number of differential diagnoses, these have been suggested as a way to discriminate between children with and without an underlying organic condition such as IBD (9). The use of alarm symptoms may improve risk stratification for those with IBD, with the potential to reduce DD, and prevent unnecessary referrals for those with FGID that may delay implementation of appropriate interventions and decrease well-being (8,82).

Recommended alarm symptom criteria vary greatly across the literature (Table 5), although the most common metrics include rectal bleeding, weight loss, family history of IBD, and peri-anal disease. Two papers include a raised FC above 50 µg/g, although the diagnostic utility at this level is debated, as above. When FC testing is added to an alarm symptom algorithm it has been shown to increase the diagnostic accuracy of IBD, whereas inclusion of raised CRP does not (82). The association between the presence of defined alarm symptoms and DD has not been studied, although a recent systematic review (16) reported that there was no difference in DD for those presenting with EIM, but was reduced in a number of papers reporting on children presenting with rectal bleeding (19,25,28), linear growth failure (19,21,26), and family history of IBD (26).

Benefit of combining test results

While serum markers, alarm symptoms, and FC are useful indicators of illness when they are studied individually, in combination their efficacy at identifying children at high or low risk of a diagnosis of IBD improves. While this factor has not been tested for association with DD, it is logical that obtaining a combination of results that indicate a higher suspicion of IBD may enable a more rapid and appropriate referral and diagnosis. Previous work has shown that the combination of raised FC and albumin levels improves identification of true positive and true negative IBD cases (78). The combination of FC, alarm symptoms, and raised ESR also improved this identification, as well as enabling effective classification of groups at low and high risk of IBD (82). When primary care physicians and paediatricians are able to utilise ultrasound imaging the combination of raised FC and serum inflammatory markers alongside sonographic evidence of bowel wall thickening also had very high predictability of true positives and negatives (1).

Risk factors for IBD and prolonged DD

A number of risk factors have been identified that increases a person’s likelihood of being diagnosed with IBD (83). While some relate specifically to adults, some are more relevant to the paediatric population. The following risk factors may be considered for a child presenting with suspected IBD and are relevant information to include in referral letters for specialist gastroenterology review.

Family history

Having a family history of IBD (generally as a first degree relative) is consistently shown to be a risk factor for developing IBD (83), as well as sub-types of CD (83-86) and UC (83-85). The number of children diagnosed with IBD who report a family history range from 8.5% to 23.5% (19,49,87), although this may be dependent on how the term is defined between studies. However, an association between family history of IBD and a shortened DD period is rarely reported (19,21,25,29,49,87-89), except in one large cohort study (26).

Demographic factors

While the majority of children are diagnosed with IBD during the ages of eleven and sixteen years, more children are being diagnosed below the age of ten years (90,91). Generally those diagnosed earlier experience a more aggressive disease course (92). Younger children have been reported to be at greater risk of DD (25,26,29,87), although this is not a universal finding (19,88,93). Few studies report gender as being associated with longer DD (93), with most research reporting no association (19,25,26,49,87,88).

Environment

Additional, specific risk factors relating to the environment and a child’s early years are associated with developing IBD during childhood. While these have not been shown to increase the DD period, their relevance should be considered at the time of presentation of a child to their primary care or general paediatric clinician and this information included in subsequent specialist gastroenterology referrals.

Diet

The diet a child consumes may increase their risk of developing IBD. Consumption of fewer weekly portions of fruits and vegetables have been shown to have a significant association for developing IBD (94), or UC (83). Additionally, for children with CD, white bread consumption, and high weekly intake of sugary drinks have also been identified (83).

Breast feeding

The effect of breastfeeding is generally associated with a decreased risk of IBD and UC if for more than three to six months (83,95). Ever being breastfed was protective against IBD, CD and UC with longer exposures decreasing risk further (96). However, some studies show an increased risk for IBD and CD (84,85), or no association (86).

Gastroenteritis and antibiotic exposure

Childhood GI infections are consistently shown to be associated with an increased risk of IBD, CD and UC (83,95). The use of antibiotics during early childhood years is also associated with IBD, UC and CD (95,97-99). Both factors contribute to intestinal dysbiosis, and there is a clear consensus on the involvement of the gut microbiome in the development of IBD (100).

Referrals

Primary care physicians and secondary care paediatricians must balance the need for ensuring appropriate referrals are made to specialist paediatric gastroenterologists, with the need to protect against DD for those children with a high suspicion of IBD requiring rapid assessment, diagnosis, and treatment. Identification of the IBD phenotype, and achieving mucosal healing, are the critical first stages of IBD treatment (101). There is also considered to be a window of opportunity for those with IBD during which early treatment in the time following first symptoms, using drugs such as anti-tumor necrosis factor α agents, increases treatment efficacy and alters disease progression (102). However, until effective early identification and testing strategies for IBD are developed to enable early intervention, this approach is not feasible and would lead to unnecessary and inappropriate treatment for many children.

Some reports show that children referred for suspected IBD by paediatricians had shorter DD than those referred by primary care physicians (15,29,49). Children referred by paediatricians are more likely to have unambiguous symptoms such as weight loss, growth failure, rectal bleeding and extra-intestinal symptoms, as well as higher calculated disease activity, leading to earlier diagnosis of IBD (15,29,49).

For primary care physicians and paediatricians who may see children with non-specific symptoms, such as linear growth delay, a pragmatic approach to monitoring may be implemented. This should involve a combination of detailed symptom recording, laboratory testing (serum inflammatory markers, FC), and physical examination (including perianal region) when first presenting with symptoms (103-105). Regarding FC levels, for example, those with levels between 50 and 250 µg/g may benefit from having assessment of additional parameters tested (e.g., CRP, albumin) with repeat measurement in 2–3 months, along with clinical reassessment, as has been suggested for adults in primary care with IBS (8). Close monitoring and re-testing may identify worsening of relevant parameters, especially in combination, that may then be utilised to enable a detailed referral with a higher suspicion of IBD. For those children with worsening parameters and symptoms, as well as those presenting with alarm symptoms, in order to enable a rapid assessment, the clinician must provide all the necessary information in their referral.

In order to facilitate prioritization of a child with a high suspicion of IBD, thereby enabling a rapid assessment and eligibility for timely endoscopic assessment, it is imperative that the primary care physician or paediatrician provide a thorough referral to paediatric gastroenterologists containing all necessary clinical information (74). This should include test results utilised to exclude other conditions (coeliac disease or infectious diarrhoea). It should also include longitudinal symptom and growth records with documented changes in parameters such as pain, stool metrics, and weight loss. Laboratory testing results and changes of monitored variables such as inflammatory markers, iron levels, and FC should be included. In addition, the results of physical examination, and the presence of known risk factors such as family history should be shared in a referral for assessment by a paediatric gastroenterologist (74). Providing comprehensive referrals such as this have been shown to reduce DD for adults with IBD being referred by primary care physicians (106), and to reduce DD in children referred by secondary care paediatricians (107). A number of countries have established referral pathways between primary and secondary care to facilitate prompt and specific referrals for children suspected of having IBD. Pathways such as these may reduce the chance of DD relating to system factors, as opposed to patient factors. However, these are dependent on the health care infrastructure of each country and may not be generalisable to all centres. A reliable source of evidence-based guidelines and up-to-date publications on IBD diagnosis are national and international scientific societies relating to paediatric gastroenterology, hepatology and nutrition (PGHAN), such as those in North America (NASPGHAN), Europe (ESPGHAN), Australasia (AuSPGHAN) and Asia Pacific (APPSPGHAN), among others (101,108,109).

Conclusions

This review aimed to provide a comprehensive overview of factors related to the presentation, testing, and referral of children with suspected IBD that have been shown to relate to minimizing DD in this population. The fact that prolonged DD is still evident for children with IBD may suggest a need for improved awareness and education among primary care physicians and secondary care paediatricians on early, unusual or atypical presentations, as well as the need for appropriate and comprehensive testing, monitoring, and referrals (16). As IBD remains an uncommon condition in children (even though rates are increasing), primary care physicians or paediatricians may not consider IBD in their differential diagnosis when a child presents with non-specific symptoms (49). While the prediction and prevention of IBD remains conceptual, and definitive preclinical signs and symptoms remain elusive, finding ways of ameliorating the possible damage done to the intestinal mucosa during the early evolution of the condition remains a priority and should be the focus of large-scale studies (102,110,111). By improving awareness, it is hoped that fast and comprehensive referral channels for children are developed that may reduce the number of unnecessary referrals and invasive investigations for those at low risk of IBD, as well as protecting against DD for those in need of rapid and effective treatment. The continuation of research to refine a matrix of symptoms, laboratory tests, and risk factors that increase the accuracy of case identification is imperative. The body of work presented in this narrative review may be utilised to refine clinical practice guidelines for primary care physicians and general paediatricians in order to ensure appropriate and timely referrals are made to paediatric gastroenterologists for those children with a high likelihood of having IBD.

Acknowledgments

Funding: Professor Andrew S. Day is supported in his research by funding from Cure Kids New Zealand.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-23-35/rc

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-23-35/coif). ASD has received consulting fees from AMCA, and honoraria from Abbvie. ASD is Secretary of the Executive Committee of the New Zealand Society of Gastroenterology. ASD’s research activities are supported by Cure Kids New Zealand (Cure Kids Chair of Paediatric Research). AVR has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Dilillo D, Zuccotti GV, Galli E, et al. Noninvasive testing in the management of children with suspected inflammatory bowel disease. Scand J Gastroenterol 2019;54:586-91. [Crossref] [PubMed]
2. Ansems S, Berger M, Rheenen PV, et al. Effect of faecal calprotectin testing on referrals for children with chronic gastrointestinal symptoms in primary care: study protocol for a cluster randomised controlled trial. BMJ Open 2021;11:e045444. [Crossref] [PubMed]
3. Husby S, Koletzko S, Korponay-Szabó I, et al. European Society Paediatric Gastroenterology, Hepatology and Nutrition Guidelines for Diagnosing Coeliac Disease 2020. J Pediatr Gastroenterol Nutr 2020;70:141-56. [Crossref] [PubMed]
4. van Doorn OJ, Bosman DK, van't Hoff BW, et al. Helicobacter pylori Stool Antigen test: a reliable non-invasive test for the diagnosis of Helicobacter pylori infection in children. Eur J Gastroenterol Hepatol 2001;13:1061-5. [Crossref] [PubMed]
5. Truong J, Cointe A, Le Roux E, et al. Clinical impact of a gastrointestinal PCR panel in children with infectious diarrhoea. Arch Dis Child 2022;107:601-5. [Crossref] [PubMed]
6. Martins GP, Sandy NS, Alvarenga LR, et al. Functional abdominal pain is the main etiology among children referred to tertiary care level for chronic abdominal pain. Arq Gastroenterol 2022;59:97-101. [Crossref] [PubMed]
7. Spee LA, Lisman-Van Leeuwen Y, Benninga MA, et al. Prevalence, characteristics, and management of childhood functional abdominal pain in general practice. Scand J Prim Health Care 2013;31:197-202. [Crossref] [PubMed]
8. Holtman GA, Lisman-van Leeuwen Y, Kollen BJ, et al. Diagnostic Accuracy of Fecal Calprotectin for Pediatric Inflammatory Bowel Disease in Primary Care: A Prospective Cohort Study. Ann Fam Med 2016;14:437-45. [Crossref] [PubMed]
9. Andrews ET, Beattie RM, Tighe MP. Functional abdominal pain: what clinicians need to know. Arch Dis Child 2020;105:938-44. [Crossref] [PubMed]
10. Vernon-Roberts A, Alexander I, Day AS. Systematic Review of Pediatric Functional Gastrointestinal Disorders (Rome IV Criteria). J Clin Med 2021;10:5087. [Crossref] [PubMed]
11. Velasco-Benítez CA, Collazos-Saa LI, García-Perdomo HA. A systematic review and meta-analysis in schoolchildren and adolescents with functional gastrointestinal disorders according to Rome IV criteria. Arq Gastroenterol 2022;59:304-13. [Crossref] [PubMed]
12. Roberts SE, Thorne K, Thapar N, et al. A Systematic Review and Meta-analysis of Paediatric Inflammatory Bowel Disease Incidence and Prevalence Across Europe. J Crohns Colitis 2020;14:1119-48. [Crossref] [PubMed]
13. Kuenzig ME, Fung SG, Marderfeld L, et al. Twenty-first Century Trends in the Global Epidemiology of Pediatric-Onset Inflammatory Bowel Disease: Systematic Review. Gastroenterology 2022;162:1147-1159.e4. [Crossref] [PubMed]
14. Sýkora J, Pomahačová R, Kreslová M, et al. Current global trends in the incidence of pediatric-onset inflammatory bowel disease. World J Gastroenterol 2018;24:2741-63. [Crossref] [PubMed]
15. Holtman GA, Lisman-van Leeuwen Y, van Rheenen PF, et al. Evaluation of point-of-care test calprotectin and lactoferrin for inflammatory bowel disease among children with chronic gastrointestinal symptoms. Fam Pract 2017;34:400-6. [PubMed]
16. Vernon-Roberts A, Aluzaite K, Khalilipour B, et al. Systematic Review of Diagnostic Delay for Children With Inflammatory Bowel Disease. J Pediatr Gastroenterol Nutr 2023;76:304-12. [Crossref] [PubMed]
17. Sulkanen E, Repo M, Huhtala H, et al. Impact of diagnostic delay to the clinical presentation and associated factors in pediatric inflammatory bowel disease: a retrospective study. BMC Gastroenterol 2021;21:364. [Crossref] [PubMed]
18. Gower-Rousseau C, Dauchet L, Vernier-Massouille G, et al. The natural history of pediatric ulcerative colitis: a population-based cohort study. Am J Gastroenterol 2009;104:2080-8. [Crossref] [PubMed]
19. Ricciuto A, Fish JR, Tomalty DE, et al. Diagnostic delay in Canadian children with inflammatory bowel disease is more common in Crohn's disease and associated with decreased height. Arch Dis Child 2018;103:319-26. [Crossref] [PubMed]
20. Schoepfer A, Santos J, Fournier N, et al. Systematic Analysis of the Impact of Diagnostic Delay on Bowel Damage in Paediatric Versus Adult Onset Crohn's Disease. J Crohns Colitis 2019;13:1334-42. [Crossref] [PubMed]
21. Ricciuto A, Mack DR, Huynh HQ, et al. Diagnostic Delay Is Associated With Complicated Disease and Growth Impairment in Paediatric Crohn's Disease. J Crohns Colitis 2021;15:419-31. [Crossref] [PubMed]
22. Rinawi F, Assa A, Eliakim R, et al. Risk of Colectomy in Patients With Pediatric-onset Ulcerative Colitis. J Pediatr Gastroenterol Nutr 2017;65:410-5. [Crossref] [PubMed]
23. Krishna M, Britto S, Qian J, et al. Diagnostic delay and colectomy risk in pediatric ulcerative colitis. J Pediatr Surg 2020;55:403-5. [Crossref] [PubMed]
24. Ashton JJ, Harden A, Beattie RM. Paediatric inflammatory bowel disease: improving early diagnosis. Arch Dis Child 2018;103:307-8. [Crossref] [PubMed]
25. Sawczenko A, Sandhu BK. Presenting features of inflammatory bowel disease in Great Britain and Ireland. Arch Dis Child 2003;88:995-1000. [Crossref] [PubMed]
26. Timmer A, Behrens R, Buderus S, et al. Childhood onset inflammatory bowel disease: predictors of delayed diagnosis from the CEDATA German-language pediatric inflammatory bowel disease registry. J Pediatr 2011;158:467-473.e2. [Crossref] [PubMed]
27. Ashton JJ, Coelho T, Ennis S, et al. Presenting phenotype of paediatric inflammatory bowel disease in Wessex, Southern England 2010-2013. Acta Paediatr 2015;104:831-7. [Crossref] [PubMed]
28. Spray C, Debelle GD, Murphy MS. Current diagnosis, management and morbidity in paediatric inflammatory bowel disease. Acta Paediatr 2001;90:400-5. [Crossref] [PubMed]
29. Arcos-Machancoses JV, Donat-Aliaga E, Polo-Miquel B, et al. Description and study of risk factors for the diagnostic delay of pediatric inflammatory bowel disease. An Pediatr (Barc) 2015;82:247-54. [Crossref] [PubMed]
30. Castro M, Papadatou B, Baldassare M, et al. Inflammatory bowel disease in children and adolescents in Italy: data from the pediatric national IBD register (1996-2003). Inflamm Bowel Dis 2008;14:1246-52. [Crossref] [PubMed]
31. Saadah OI, El Mouzan M, Al Mofarreh M, et al. Characteristics of Pediatric Crohn's Disease in Saudi Children: A Multicenter National Study. Gastroenterol Res Pract 2016;2016:7403129. [Crossref] [PubMed]
32. Saadah OI. Ulcerative colitis in children and adolescents from the Western Region of Saudi Arabia. Saudi Med J 2011;32:943-7. [PubMed]
33. Working IBD. Group of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition. Inflammatory bowel disease in children and adolescents: recommendations for diagnosis--the Porto criteria. J Pediatr Gastroenterol Nutr 2005;41:1-7. [Crossref]
34. Korterink JJ, Diederen K, Benninga MA, et al. Epidemiology of pediatric functional abdominal pain disorders: a meta-analysis. PLoS One 2015;10:e0126982. [Crossref] [PubMed]
35. Rajindrajith S, Zeevenhooven J, Devanarayana NM, et al. Functional abdominal pain disorders in children. Expert Rev Gastroenterol Hepatol 2018;12:369-90. [Crossref] [PubMed]
36. Mushtaq F, Tudor G, El-Hadi S. Rectal bleeding in children – causes and investigations. Paediatr Child Health 2014;24:491-500. [Crossref]
37. Metezai H, Wahid A, Jones C, et al. Fifteen-minute consultation: Rectal bleeding in children. Arch Dis Child Educ Pract Ed 2022;edpract-2022-324626.
38. Day AS, Ledder O, Leach ST, et al. Crohn's and colitis in children and adolescents. World J Gastroenterol 2012;18:5862-9. [Crossref] [PubMed]
39. Savoye G, Salleron J, Gower-Rousseau C, et al. Clinical predictors at diagnosis of disabling pediatric Crohn's disease. Inflamm Bowel Dis 2012;18:2072-8. [Crossref] [PubMed]
40. Goddard GR, Lim IIP, Cheng YC, et al. A child presents with perianal symptoms - how often is this Crohn's disease? J Pediatr Surg 2021;56:1618-22. [Crossref] [PubMed]
41. Moeeni V, Day AS. Impact of Inflammatory Bowel Disease upon Growth in Children and Adolescents. ISRN Pediatr 2011;2011:365712. [Crossref] [PubMed]
42. Kugathasan S, Nebel J, Skelton JA, et al. Body mass index in children with newly diagnosed inflammatory bowel disease: observations from two multicenter North American inception cohorts. J Pediatr 2007;151:523-7. [Crossref] [PubMed]
43. El Mouzan MI, Al Edreesi MH, Al-Hussaini AA, et al. Nutritional status of children with inflammatory bowel disease in Saudi Arabia. World J Gastroenterol 2016;22:1854-8. [Crossref] [PubMed]
44. Chandrakumar A, Wang A, Grover K, et al. Obesity Is More Common in Children Newly Diagnosed With Ulcerative Colitis as Compared to Those With Crohn Disease. J Pediatr Gastroenterol Nutr 2020;70:593-7. [Crossref] [PubMed]
45. Medina Carbonell FR, Choyudhry Chandan O. Body Mass Index at Presentation of Inflammatory Bowel Disease in Children. Pediatr Gastroenterol Hepatol Nutr 2020;23:439-46. [Crossref] [PubMed]
46. Pituch-Zdanowska A, Banaszkiewicz A, Dziekiewicz M, et al. Overweight and obesity in children with newly diagnosed inflammatory bowel disease. Adv Med Sci 2016;61:28-31. [Crossref] [PubMed]
47. Sawczenko A, Ballinger AB, Savage MO, et al. Clinical features affecting final adult height in patients with pediatric-onset Crohn's disease. Pediatrics 2006;118:124-9. [Crossref] [PubMed]
48. Yap J, Wesley A, Mouat S, et al. Paediatric inflammatory bowel disease in New Zealand. N Z Med J 2008;121:19-34. [PubMed]
49. Jiménez Treviño S, Pujol Muncunill G, Martín-Masot R, et al. Spanish Pediatric Inflammatory Bowel Disease Diagnostic Delay Registry: SPIDER Study From Sociedad Española de Gastroenterología, Hepatología y Nutrición Pediátrica. Front Pediatr 2020;8:584278. [Crossref] [PubMed]
50. Dubinsky MC, Ofman JJ, Urman M, et al. Clinical utility of serodiagnostic testing in suspected pediatric inflammatory bowel disease. Am J Gastroenterol 2001;96:758-65. [Crossref] [PubMed]
51. Levy R, Amarilyo G, Tal R, et al. Musculoskeletal Manifestations as Presenting Symptoms of Inflammatory Bowel Disease in Children and Adolescents. J Pediatr 2019;209:233-5. [Crossref] [PubMed]
52. Shentova-Eneva R, Baycheva M, Hadjiiski P, et al. Extraintestinal manifestations in paediatric patients with inflammatory bowel disease. J Crohns Colitis 2019;13:S236-S237. [Crossref]
53. Ottaviano G, Salvatore S, Salvatoni A, et al. Ocular Manifestations of Paediatric Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. J Crohns Colitis 2018;12:870-9. [Crossref] [PubMed]
54. Jang HJ, Kang B, Choe BH. The difference in extraintestinal manifestations of inflammatory bowel disease for children and adults. Transl Pediatr 2019;8:4-15. [Crossref] [PubMed]
55. Barfield E, Deshmukh F, Slighton E, et al. Pulmonary Manifestations in Adolescents With Inflammatory Bowel Disease. Clin Pediatr (Phila) 2020;59:573-9. [Crossref] [PubMed]
56. Ali A, Schmidt M, Piskin D, et al. Epidemiology of Musculoskeletal Manifestations in Pediatric Inflammatory Bowel Disease: A Systematic Review. ACR Open Rheumatol 2022;4:547-54. [Crossref] [PubMed]
57. Shazib MA, Byrd KM, Gulati AS. Diagnosis and Management of Oral Extraintestinal Manifestations of Pediatric Inflammatory Bowel Disease. J Pediatr Gastroenterol Nutr 2022;74:7-12. [Crossref] [PubMed]
58. Jang HJ, Suh HR, Choi S, et al. Severe Disease Activity Based on the Paris Classification Is Associated with the Development of Extraintestinal Manifestations in Korean Children and Adolescents with Ulcerative Colitis. J Korean Med Sci 2021;36:e278. [Crossref] [PubMed]
59. Duricova D, Sarter H, Savoye G, et al. Impact of Extra-Intestinal Manifestations at Diagnosis on Disease Outcome in Pediatric- and Elderly-Onset Crohn's Disease: A French Population-Based Study. Inflamm Bowel Dis 2019;25:394-402. [Crossref] [PubMed]
60. Jose FA, Garnett EA, Vittinghoff E, et al. Development of extraintestinal manifestations in pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis 2009;15:63-8. [Crossref] [PubMed]
61. Greuter T, Bertoldo F, Rechner R, et al. Extraintestinal Manifestations of Pediatric Inflammatory Bowel Disease: Prevalence, Presentation, and Anti-TNF Treatment. J Pediatr Gastroenterol Nutr 2017;65:200-6. [Crossref] [PubMed]
62. Rahmani P, Rasti G, Gorgi M, et al. Extraintestinal manifestation of inflammatory bowel disease and associated factors in pediatric patients. Ann Med Surg (Lond) 2022;75:103363. [Crossref] [PubMed]
63. Ashton JJ, Borca F, Mossotto E, et al. Analysis and Hierarchical Clustering of Blood Results Before Diagnosis in Pediatric Inflammatory Bowel Disease. Inflamm Bowel Dis 2020;26:469-75. [PubMed]
64. Day SA, Hamilton D, Leach TS, et al. Inflammatory Markers in Children with Newly Diagnosed Inflammatory Bowel Disease. J Gastroenterol Hepatol Res 2017;6:2329-32. [Crossref]
65. Sikora SK, Spady D, Prosser C, et al. Trace elements and vitamins at diagnosis in pediatric-onset inflammatory bowel disease. Clin Pediatr (Phila) 2011;50:488-92. [Crossref] [PubMed]
66. Walker GJ, Chanchlani N, Thomas A, et al. Primary care faecal calprotectin testing in children with suspected inflammatory bowel disease: a diagnostic accuracy study. Arch Dis Child 2020;105:957-63. [Crossref] [PubMed]
67. Irwin JR, Ferguson E, Simms LA, et al. Detectable Laboratory Abnormality Is Present up to 12 Months Prior to Diagnosis in Patients with Crohn's Disease. Dig Dis Sci 2019;64:503-17. [Crossref] [PubMed]
68. Tavabie OD, Hughes SA, Loganayagam A. The role of faecal calprotectin in the differentiation of organic from functional bowel disorders. Br J Gen Pract 2014;64:595-6. [Crossref] [PubMed]
69. Jeong SJ. The role of fecal calprotectin in pediatric disease. Korean J Pediatr 2019;62:287-91. [Crossref] [PubMed]
70. Flagstad G, Helgeland H, Markestad T. Faecal calprotectin concentrations in children with functional gastrointestinal disorders diagnosed according to the Pediatric Rome III criteria. Acta Paediatr 2010;99:734-7. [Crossref] [PubMed]
71. Bourdillon G, Biskou O, MacKinder M, et al. The routine use of fecal calprotectin in clinical pediatric practice: almost there or still issues to address? Am J Gastroenterol 2013;108:1811-3. [Crossref] [PubMed]
72. Orfei M, Gasparetto M, Hensel KO, et al. Guidance on the interpretation of faecal calprotectin levels in children. PLoS One 2021;16:e0246091. [Crossref] [PubMed]
73. Degraeuwe PL, Beld MP, Ashorn M, et al. Faecal calprotectin in suspected paediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2015;60:339-46. [Crossref] [PubMed]
74. Auth MK. The diagnostic accuracy of faecal calprotectin in investigations for suspected inflammatory bowel disease in children. Br J Gen Pract 2015;65:628-9. [Crossref] [PubMed]
75. Van de Vijver E, Schreuder AB, Cnossen WR, et al. Safely ruling out inflammatory bowel disease in children and teenagers without referral for endoscopy. Arch Dis Child 2012;97:1014-8. [Crossref] [PubMed]
76. Waugh N, Cummins E, Royle P, et al. Faecal calprotectin testing for differentiating amongst inflammatory and non-inflammatory bowel diseases: systematic review and economic evaluation. Health Technol Assess 2013;17:xv-xix, 1-211. [Crossref] [PubMed]
77. Henderson P, Anderson NH, Wilson DC. The diagnostic accuracy of fecal calprotectin during the investigation of suspected pediatric inflammatory bowel disease: a systematic review and meta-analysis. Am J Gastroenterol 2014;109:637-45. [Crossref] [PubMed]
78. Henderson P, Casey A, Lawrence SJ, et al. The diagnostic accuracy of fecal calprotectin during the investigation of suspected pediatric inflammatory bowel disease. Am J Gastroenterol 2012;107:941-9. [Crossref] [PubMed]
79. Güven B, İssi F, Sağ E, et al. Impact of Fecal Calprotectin Measurement for Inflammatory Bowel Disease in Children with Alarm Symptoms. Journal of Pediatric Research 2022;9:126-31. [Crossref]
80. Heida A, Van de Vijver E, van Ravenzwaaij D, et al. Predicting inflammatory bowel disease in children with abdominal pain and diarrhoea: calgranulin-C versus calprotectin stool tests. Arch Dis Child 2018;103:565-71. [Crossref] [PubMed]
81. Soubieres A, Shandro B, Mathur J, et al. The clinical utility and diagnostic accuracy of faecal calprotectin for IBD in paediatric patients. Gut 2019;68:A97.
82. Holtman GA, Lisman-van Leeuwen Y, Kollen BJ, et al. Diagnostic test strategies in children at increased risk of inflammatory bowel disease in primary care. PLoS One 2017;12:e0189111. [Crossref] [PubMed]
83. Jakobsen C, Paerregaard A, Munkholm P, et al. Environmental factors and risk of developing paediatric inflammatory bowel disease -- a population based study 2007-2009. J Crohns Colitis 2013;7:79-88. [Crossref] [PubMed]
84. Baron S, Turck D, Leplat C, et al. Environmental risk factors in paediatric inflammatory bowel diseases: a population based case control study. Gut 2005;54:357-63. [Crossref] [PubMed]
85. Strisciuglio C. Environmental risk factors in pediatric IBD according to the hygiene hypothesis: A case-control study. J Crohns Colitis 2015;9:S59-S60. [Crossref]
86. Kobashi G, Hata A, Uchida K, et al. A Case-Control Study to Detect Genetic and Acquired Risk Factors for Pediatric Inflammatory Bowel Disease. Int J Epidemiol 2015;44:i232. [Crossref]
87. El Mouzan MI, AlSaleem BI, Hasosah MY, et al. Diagnostic delay of pediatric inflammatory bowel disease in Saudi Arabia. Saudi J Gastroenterol 2019;25:257-61. [Crossref] [PubMed]
88. Schoepfer AM, Vavricka S, Safroneeva E, et al. Systematic Evaluation of Diagnostic Delay in Pediatric Inflammatory Bowel Disease. J Pediatr Gastroenterol Nutr 2017;64:245-7. [Crossref] [PubMed]
89. De Greef E, Mahachie John JM, Hoffman I, et al. Profile of pediatric Crohn's disease in Belgium. J Crohns Colitis 2013;7:e588-98. [Crossref] [PubMed]
90. Benchimol EI, Bernstein CN, Bitton A, et al. Trends in Epidemiology of Pediatric Inflammatory Bowel Disease in Canada: Distributed Network Analysis of Multiple Population-Based Provincial Health Administrative Databases. Am J Gastroenterol 2017;112:1120-34. [Crossref] [PubMed]
91. Kelsen JR, Russo P, Sullivan KE. Early-Onset Inflammatory Bowel Disease. Immunol Allergy Clin North Am 2019;39:63-79. [Crossref] [PubMed]
92. Gasparetto M, Guariso G, Pozza LV, et al. Clinical course and outcomes of diagnosing Inflammatory Bowel Disease in children 10 years and under: retrospective cohort study from two tertiary centres in the United Kingdom and in Italy. BMC Gastroenterol 2016;16:35. [Crossref] [PubMed]
93. Herzog D, Buehr P, Koller R, et al. Gender differences in paediatric patients of the swiss inflammatory bowel disease cohort study. Pediatr Gastroenterol Hepatol Nutr 2014;17:147-54. [Crossref] [PubMed]
94. El Mouzan MI, Al Mofarreh MA, Al Sarkhy AA, et al. Pre-illness diet as risk factor in pediatric inflammatory bowel disease in Saudi Arabia. Saudi J Gastroenterol 2017;23:287-90. [Crossref] [PubMed]
95. Lee WS, Song ZL, Wong SY, et al. Environmental risk factors for inflammatory bowel disease: A case control study in Southeast Asian children. J Paediatr Child Health 2022;58:782-90. [Crossref] [PubMed]
96. Piovani D, Danese S, Peyrin-Biroulet L, et al. Environmental Risk Factors for Inflammatory Bowel Diseases: An Umbrella Review of Meta-analyses. Gastroenterology 2019;157:647-659.e4. [Crossref] [PubMed]
97. Kamphorst K, Van Daele E, Vlieger AM, et al. Early life antibiotics and childhood gastrointestinal disorders: a systematic review. BMJ Paediatr Open 2021;5:e001028. [Crossref] [PubMed]
98. Shaw SY, Blanchard JF, Bernstein CN. Association between the use of antibiotics in the first year of life and pediatric inflammatory bowel disease. Am J Gastroenterol 2010;105:2687-92. [Crossref] [PubMed]
99. Canova C, Ludvigsson JF, Di Domenicantonio R, et al. Perinatal and Antibiotic Exposures and the Risk of Developing Childhood-Onset Inflammatory Bowel Disease: A Nested Case-Control Study Based on a Population-Based Birth Cohort. Int J Environ Res Public Health 2020;17:2409. [Crossref] [PubMed]
100. Khan I, Ullah N, Zha L, et al. Alteration of Gut Microbiota in Inflammatory Bowel Disease (IBD): Cause or Consequence? IBD Treatment Targeting the Gut Microbiome. Pathogens 2019;8:126. [Crossref] [PubMed]
101. Levine A, Koletzko S, Turner D, et al. ESPGHAN revised porto criteria for the diagnosis of inflammatory bowel disease in children and adolescents. J Pediatr Gastroenterol Nutr 2014;58:795-806. [Crossref] [PubMed]
102. Colombel JF. Targeting the Preclinical Phase of Inflammatory Bowel Disease. Gastroenterol Hepatol (N Y) 2015;11:711-3. [PubMed]
103. Dipasquale V, Corica D, Gramaglia SMC, et al. Gastrointestinal symptoms in children: Primary care and specialist interface. Int J Clin Pract 2018;72:e13093. [Crossref] [PubMed]
104. Moran CJ, Kaplan JL, Winter HS, et al. Occult Blood and Perianal Examination: Value Added in Pediatric Inflammatory Bowel Disease Screening. J Pediatr Gastroenterol Nutr 2015;61:52-5. [Crossref] [PubMed]
105. McCracken M. Importance of Physical Examination: Occult Blood and Perianal Examination in Screening for Pediatric Inflammatory Bowel Disease. J Pediatr Gastroenterol Nutr 2015;61:3. [Crossref] [PubMed]
106. Htet H, Mudege T, Hoque S. Telephone straight-to-test (tSTT) improves early diagnosis of inflammatory bowel disease (IBD). J Crohns Colitis 2019;13:S162-S163. [Crossref]
107. Thorpe M, Rodulson V, Harbinson C, et al. Improving Time to Diagnosis in Children Referred Locally with Suspected Inflammatory Bowel Disease Within a Managed Clinical Network - A Single Centre, Secondary Care Experience. Arch Dis Child 2014;99:A294. [Crossref]
108. Rufo PA, Denson LA, Sylvester FA, et al. Health supervision in the management of children and adolescents with IBD: NASPGHAN recommendations. J Pediatr Gastroenterol Nutr 2012;55:93-108. [Crossref] [PubMed]
109. Child and Youth Clinical Network for Gastroenterology. Inflammatory bowel disease (IBD) in children and adolescents: New Zealand Child and Youth Clinical Networks; 2021 [Accessed 02/05/2023]. Available online: https://starship.org.nz/guidelines/inflammatory-bowel-disease-ibd-in-children-and-adolescents/
110. Sorrentino D. Preclinical and Undiagnosed Crohn's Disease: The Submerged Iceberg. Inflamm Bowel Dis 2016;22:476-86. [Crossref] [PubMed]
111. Torres J, Ungaro RC, Colombel JF. Is Prevention the Best Way to Modify Inflammatory Bowel Disease? How Close Are We? Gastroenterology 2022;162:1452-5. [Crossref] [PubMed]