Asian–Pacific perspectives on the management of very early-onset inflammatory bowel disease
Article information
Abstract
Children diagnosed with inflammatory bowel disease (IBD) before the age of 6 years are considered to have “very early-onset IBD (VEO-IBD),” which is challenging to diagnose and treat. Notably, many children with VEO-IBD have monogenic forms of the disease, meaning that early genetic testing is useful. However, because the prevalence of genetic variants causing VEO-IBD differs globally, the diagnosis and treatment of this disease should be tailored to each region. In the present review paper, the IBD Subcommittee of the Scientific Committee of the Asia-Pacific Society of Pediatric Gastroenterology, Hepatology and Nutrition (APSPGHAN) has summarized the epidemiology, presenting features, diagnosis, and treatment of VEO-IBD in the Asia–Pacific region, with an aim to guide clinicians and researchers who work with VEO-IBD in this area. Our 3 main messages are as follows: endoscopy is essential for VEO-IBD diagnosis; all children diagnosed with VEO-IBD should be suspected of having a monogenic form; and children with suspected monogenic IBD should undergo early genetic testing. Our messages aim to improve the early diagnosis and treatment of VEO-IBD in the Asia–Pacific region, including the early detection of monogenic IBD in this area.
INTRODUCTION
The incidence of pediatric inflammatory bowel disease (P-IBD) is rising worldwide [1]. A unique group of children has P-IBD known as “very early-onset IBD (VEO-IBD),” defined as IBD diagnosed before 6 years of age. VEO-IBD is particularly challenging to diagnose because of the inherent difficulties of gastrointestinal endoscopy in very young children. Limited access to appropriately sized endoscopic equipment and technical expertise is one such difficulty within the Asia–Pacific region. In addition, atypical endoscopic and histopathological findings in this age group compared with older children or adults make accurate diagnosis more challenging [2-10]. Optimal control of disease activity is another hurdle in the management of VEO-IBD because of its refractoriness, as well as the limited treatment options secondary to delayed drug approval for children with IBD. Although some off-label use of immunosuppressants and biologics has been administered in this age group, their efficacy and safety have yet to be established. Some children with VEO-IBD eventually require surgery [11,12]. However, a subset of children with VEO-IBD, particularly those with an underlying primary immune deficiency caused by genetic disorders or monogenic IBD, can be cured by hematopoietic cell transplantation (HCT) [13-17]. A well-structured approach for suspected monogenic IBD with early genetic testing is therefore warranted in children with VEO-IBD.
Although position papers and consensus guidelines for VEO-IBD or monogenic IBD have been published from societies in Europe and North America [18-20], regional differences in the underlying etiologies and genetic backgrounds of monogenic IBD should be considered in the management of VEO-IBD. This is the first review paper on VEO-IBD in Asia–Pacific by the Working Group of the IBD Subcommittee of the Scientific Committee of the Asia-Pacific Society of Pediatric Gastroenterology, Hepatology and Nutrition (APSPGHAN)—representing Japan, Thailand, Taiwan, New Zealand, Malaysia, Singapore, the Philippines, Hong Kong, Pakistan, Australia, the Republic of Korea, and India. In this review, we consider the unique genetic traits, racial/ethnic factors, resources, medical insurance systems, and variable challenges within the region.
This paper includes a brief review of the epidemiology and presenting features of VEO-IBD in the Asia–Pacific region. Through this review and discussions among the Working Group members, it was noted that VEO-IBD occurs at a clinically relevant frequency across the Asia–Pacific region, and some of these cases represent monogenic IBD. Although regional differences in healthcare systems and access to endoscopy, genetic testing, and biologics make unified recommendations challenging, the Working Group proposes the following 3 points: (1) endoscopy is essential for diagnosing VEO-IBD; (2) monogenic IBD should be considered in all children with VEO-IBD; and (3) children strongly suspected of having monogenic IBD should undergo appropriate and early genetic testing. In addition, the current paper offers a unique approach to ensure both the early diagnosis of monogenic IBD and the detection of novel forms of monogenic IBD, because there are many children with undiagnosed or undiscovered monogenic IBD within the region.
EPIDEMIOLOGY AND DISEASE CHARACTERISTICS
Trends in the global epidemiology of P-IBD in the 21st century were recently reported by Kuenzig et al. [1] following a systematic review of publications focusing on P-IBD. Although the epidemiological data for VEO-IBD were limited in this review, the incidence of VEO-IBD per 100,000 person-years was reported as 0.2–1.4 in West Asia, 0.2–1.4 in Europe, and 0.5–3.6 in Canada. Furthermore, Choe et al. [21] reported the incidence rates of infantile-onset Crohn’s disease (CD; diagnosed <2 years of age), and VEO-CD were 0.7 and 1.7 per 100,000, respectively, in a retrospective cohort study conducted in Korea from 2006 to 2015. Variable trends in VEO-IBD incidence are observed globally [1]. The review noted that a Canadian study reported a significant increase in the incidence of VEO-IBD, whereas no such changes were observed in studies from France and Saudi Arabia [1]. Moreover, the prevalence of VEO-IBD ranged from 1.9 cases per 100,000 people in Canada to 5.8 cases per 100,000 people in Scotland. Data from Israel of 2.9 cases per 100,000 people were considered representative of VEO-IBD prevalence in the West; however, prevalence rates in most Asia–Pacific countries are lacking.
The proportion of VEO-IBD in children with IBD and the distributions of disease phenotypes of CD, ulcerative colitis (UC), and IBD unclassified (IBD-U) have been reported in 22 studies in the Asia–Pacific region [2-5,12,22-38], 7 studies in Europe and North America [6,39-44], and 6 studies in other regions, including West Asia (Table 1) [45-50]. In the Asia–Pacific region, the frequency of VEO-IBD among cases of P-IBD varies by country; it is more common in Thailand (38%) and Australia (30%) and less common in Japan (11%), Korea (5%), and Malaysia (13%). VEO-IBD appears relatively common in Asia, especially compared with large studies from Canada and France, which report that VEO-IBD makes up merely 3%–6% of P-IBD cases [39,41,42]. However, this high VEO-IBD incidence in the Asia–Pacific region may be an overestimate owing to the common regional practice of older patients (especially teenagers) being cared for by adult gastroenterologists, thus excluding them from participation in P-IBD studies.
Frequencies of VEO-IBD in Cohort Studies and Diagnostic Distributions
Unique features of VEO-IBD have been reported compared with older children with P-IBD diagnosed at 6 years of age and older (Table 2) [2-5,12,23,26-29,33,36,40-42,44,46,48]. The VEO-IBD characteristics reported in both Asian–Pacific and Western countries include a higher proportion of IBD-U [2,4,5,44], a lower proportion of CD [5,38,44], a higher proportion of colonic CD [2,23,29,40-42,46,48], and a higher proportion of severe disease in both UC and CD [3,28,29,33,44,46]. The most common initial symptoms of VEO-IBD are reportedly hematochezia and diarrhea [6,12,27,40,41,44,46], which may reflect the relatively high proportion of colonic involvement [2,23,29,41,42,46,48]. By contrast, the features of VEO-IBD reported specifically from Asia–Pacific countries comprise a higher proportion of pancolitis in UC [3,23], a higher proportion of perianal lesions in CD [4,36], and a higher proportion of positive family history [3,4,26,28]. Interestingly, 2 reports have indicated that disease onset is significantly younger in VEO-CD than in VEO-UC [12,46].
Characteristics of Very Early-Onset Inflammatory Bowel Disease versus Pediatric Inflammatory Bowel Disease (Diagnosed at 6–18 Years)
MONOGENIC IBD AND SPECIFIC GENETIC DISORDERS
Both CD and UC are considered multifactorial disorders with a pathogenesis resulting from a complex interplay of factors, including genetics, environmental factors, the intestinal microbiome, dietary patterns, and host immune responses [51,52]. However, recent advances have revealed specific genetic disorders that can lead to chronic enterocolitis and are especially relevant in VEO-IBD [53]. These genetic disorders, collectively known as “monogenic IBD,” are distinct from typical IBD in that they are caused by a single gene mutation, rather than stemming from a combination of genetic and environmental factors.
A position paper from the Paediatric IBD Porto Group of the European Society of Paediatric Gastroenterology, Hepatology, and Nutrition listed 75 genes that are linked to monogenic IBD [18]. The genes responsible for monogenic IBD encode proteins that play critical roles in intestinal homeostasis, spanning from epithelial barrier function to innate and adaptive immune responses (Fig. 1A) [54].
Overview of innate and adaptive immunity in monogenic inflammatory bowel disease (IBD). The key components involved in monogenic IBD are highlighted with stars. (A) Epithelial barriers consist of intestinal epithelial cells, mucins, antimicrobial peptides, and sIgA, separating luminal microbes from mucosal immunity. In adaptive immunity, naive T cells differentiate into various subsets under the influence of cytokines and antigens. (B) Signaling pathways and molecular interactions affected in some monogenic IBDs, resulting in alterations to epithelial barriers and innate and adaptive immunity. Altered signaling includes PI3K–AKT, NF-κB, NOD2, prostaglandin E2 transport, and immune checkpoint pathways, leading to barrier and immune dysregulation. IL, interleukin; TGF-β, transforming growth factor-beta; STAT, signal transducer and activator of transcription; Bcl6, B-cell lymphoma 6 protein; GATA3, GATA-binding protein 3; T-bet, T-box expressed in T cells (TBX21); RORγT, RAR-related orphan receptor gamma T; Foxp3, forkhead box P3; Tfh, T follicular helper cell; Th, T helper cell; Treg, regulatory T cell; iTreg, inducible regulatory T cell; IFN-γ, interferon-gamma; TLR, Toll-like recepto; TCR, T-cell receptor; TNFR, tumor necrosis factor receptor; TTC7A, tetratricopeptide repeat domain 7A; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; NEMO, nuclear factor κB essential modulator; IKK, I-κB kinase; NOD2, nucleotide-binding oligomerization domain-containing protein 2; SMAC, second mitochondria-derived activator of caspases; PGE2, prostaglandin E2; XIAP, X-linked inhibitor of apoptosis protein; CYBC1, cytochrome B-245 chaperone 1; XIAP, X-linked inhibitor of apoptosis protein; NF-κB, nuclear factor-κB; MHC, major histocompatibility complex; CTLA-4, cytotoxic T-lymphocyte associated protein 4; LRBA, lipopolysaccharide-responsive and beige-like anchor protein. Created in BioRender (2025, https://BioRender.com/x00f410).
The human gut accommodates hundreds of trillions of microorganisms, including potential pathogens, and encounters numerous dietary/xenobiotic antigens. Thus, it possesses a competent and delicate immune system that aims to maintain immunological homeostasis. For the appropriate segregation and sampling of luminal contents by mucosal immune constituents, intestinal epithelial cells function not only as a physical and biochemical (via the secretion of mucins and antimicrobial peptides) barrier but also as an antigen-sensing/sampling port via specialized intestinal epithelial cells, known as microfold (M) cells. To orchestrate immune responses to these environmental triggers, intestinal epithelial cells and dendritic cells/intestine-resident macrophages regulate inflammatory, tolerogenic, or anti-inflammatory responses. These functions are performed through various cytokines, cell surface receptors, signal transducing molecules, transcription factors, and downstream cellular differentiation and functional specification (e.g., via T helper cells [Th]1, Th2, Th17, and regulatory T cells [Tregs]). Overreactive inflammation against pathogens or microbiota is counter-regulated by Tregs secret-ing interleukin (IL)-10, a key protective mediator, to avoid tissue damage. Molecules involved in intracellular signal transduction pathways (such as nuclear factor [NF]-κB, which is a pleiotropic transcription factor controlling immunity, differentiation, cell growth, and apoptosis; inhibitors of NF-κB [I-κB]; and its upstream regulator I-κB kinase [IKK] complex [IKKα, IKKβ, and NF-κB essential modulator (NEMO) or IKKγ]) are important for immune cell destiny after stimulation via surface receptors (Fig. 1B) [18,55-57].
Defects in crucial molecules that affect various steps in intestinal homeostasis—affecting the epithelial barrier, sensing, receptor docking, signal transduction, and immune cell differentiation, survival, and homeostasis—are responsible for many common monogenic IBDs (Fig. 1, yellow stars). Certain monogenic IBDs, such as X-linked inhibitor of apoptosis protein (XIAP) deficiency and colitis associated with IL-10 and IL-10R deficiency, can be effectively cured by HCT [13-16]. Thus, the specific genetic diagnosis of some monogenic IBDs may shift management from standard IBD treatments to disease-specific therapy, which may cure the disease.
Regional Differences in Monogenic IBD Frequencies
Despite the absence of precise epidemiological data on monogenic IBD in Asia, we first compiled and summarized the frequencies of reported monogenic IBD cases in very early onset IBD from published literature (Table 3, Fig. 2) to support a discussion of the distribution and types of monogenic IBD that are most commonly reported in the region [12,17,28,29,31,43,44,50,58-73]. Although single case reports or small series were not included, and some duplication may exist because of overlapping publications, the figures reveal that the distribution of causative genes in monogenic IBD in VEO-IBD appears to differ in frequency between the Asia–Pacific region and Western countries. Notably, colitis associated with IL-10 and IL-10R deficiency, which is frequently reported in mainland China, is encountered more commonly in the Asia–Pacific region than in the West. In a study conducted in Korea to identify monogenic variants in IL10RA, IL10RB, and IL10 in children with P-IBD, IL10RA mutations were detected in 17.5% of 40 patients diagnosed before the age of 10 years and in 50% of 14 patients diagnosed before the age of 1 year [17]. A20 haploinsufficiency (A20HI) is more frequently reported in Asia than in Europe or North America (Fig. 2). Conversely, immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX), tetratricopeptide repeat domain (TTC)7A, and TTC37 deficiencies are less frequent in Asia and more common in Europe and North America. In terms of SLCO2A1, although chronic enteropathy associated with SLCO2A1 (CEAS) is more frequently reported in Asia, the apparent underrepresentation likely occurs because CEAS typically presents in older children. These data highlight some of the regional differences that should be considered when investigating a child with VEO-IBD for potential monogenic disease.
Frequencies of Monogenic Inflammatory Bowel Disease in Very Early-Onset Inflammatory Bowel Disease
Distributions of monogenic inflammatory bowel disease in Asia (A) and Europe/North America (B).
COMMON MONOGENIC FORMS OF IBD
This section provides an overview of the monogenic IBDs that are most frequently reported in the Asia–Pacific region (Fig. 2). In addition, several clinically important monogenic IBDs, such as CEAS, TTC7A deficiency, and X-linked anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID), are also described.
1. Colitis Associated with IL-10 and IL-10R Deficiency (Autosomal Recessive)
IL-10 is a major anti-inflammatory cytokine that is secreted from various immune cells, including Tregs, monocytes, and Th2 cells. It regulates immune responses and maintains immune homeostasis. IL-10 signaling is initiated when the cytokine binds to a heterodimeric receptor complex composed of IL-10R1 and IL-10R2 (coded by IL10A and IL10B, respectively). When IL-10 signaling is impaired by IL10, IL10RA, or IL10RB mutations, severe intestinal inflammation with perianal lesions develops early in life [14]. This condition is usually accompanied by atopic dermatitis-like eczema, and affected patients reportedly have an increased lymphoma risk [14].
The most frequently observed variants in East Asia are IL10RA c.301C>T and c.537G >A, whereas pathogenic IL10RB variants are more frequent in patients from Central and South Asia and Europe, indicating a regional pattern in the genetic landscape of colitis associated with IL-10 and IL-10R deficiency [74]. Research with a geospatial association between infectious diseases and IL10RA variants suggests that Schistosoma japonicum infection may have been a selection pressure for pathogenic IL10RA variants [74].
Colitis associated with IL-10 and IL-10R deficiency is characterized by intractable symptoms and a poor response to conventional IBD treatments. However, Glocker et al. [14] first reported the resolution of severe colitis and destructive perianal disease associated with IL-10R deficiency using HCT in 2009. HCT is now recognized as an effective curative treatment for colitis associated with IL-10 and IL-10R deficiency [15,17]. Moreover, HCT with reduced toxicity conditioning regimens can be safely administered even at a young age [16].
2. CGD (X-Linked Recessive or Autosomal Recessive)
Chronic granulomatous disease (CGD) is caused by mutations in CYBB, CYBA, NCF1, NCF2, NCF4, or CYBC1 (encoding gp91, p22, p47, p67, p40, and CYBC1, respectively), resulting in the defective production of reactive oxygen species in neutrophils. A newly identified form of CGD caused by CYBC1 mutation has been reported in Asian countries [75,76]. The consequent dysfunction can lead to an increased susceptibility to bacterial and fungal infections and repeated abscess formation from early life. In addition, granulomata are formed in multiple organs because of excessive inflammation caused by the dysregulated immune response. Around half of all patients with CGD develop enterocolitis [77]. Although most children with CGD are boys (reflecting its X-linked recessive inheritance), autosomal recessive forms of CGD can be identified in girls or boys. CGD is diagnosed using dihydrorhodamine (DHR) and genetic testing. Although the use of anti-tumor necrosis factor (TNF) agents is contraindicated in CGD because of the high risk of severe infections, some immunosuppressants, such as thalidomide and anakinra, have been reported to be used successfully. Moreover, therapeutic evidence indicates that HCT may be a curative treatment [78].
3. XIAP Deficiency (X-Linked Recessive)
XIAP deficiency is caused by mutations in XIAP, which is a protein that regulates NF-κB activation, inhibits apoptosis, and modulates nucleotide-binding oligomerization domain-containing protein 2 (NOD2) signaling. Although XIAP has been identified as a causative gene for familial hemophagocytic syndrome, 10%–20% of patients develop enterocolitis resembling CD that is often refractory to conventional IBD treatment [79]. Moreover, despite XIAP-associated colitis being more common in early childhood, it is important to note that cases with onset in adulthood have also been reported [56]. A diagnosis of XIAP deficiency requires genetic testing and flow cytometry to assess XIAP expression. Reduced toxicity conditioning regimens of HCT therapy have been established as a safe and effective treatment for XIAP deficiency [13,78].
4. A20HI (Autosomal Dominant)
A20, encoded by TNFAIP3, regulates the intracellular signaling of inflammatory cytokines from Toll-like and TNF-α receptors. Even heterozygous loss-of-function mutations in TNFAIP3 result in the excessive production of inflammatory cytokines, which leads to Behçet’s disease-like symptoms such as gastrointestinal ulcers, arthritis, and recurrent oral aphthae [80]. Patients with A20HI in East Asia are reported to experience recurrent fever more frequently than patients in other regions, whereas typical Behçet’s disease symptoms such as skin rashes and genital ulcers, autoimmune disease complications, and autoantibody detection are reportedly less common [81]. Diagnosis of A20HI relies on genetic testing for TNFAIP3 mutations. Because A20HI is characterized by diverse treatment responses, its treatment is individualized and depends on disease severity. Although mild cases can be managed with colchicine or corticosteroids, severe or refractory cases require biologics, including anti-TNF-α agents, IL-1 or IL-6 inhibitors, and Janus kinase inhibitors. HCT has been reported to be successfully used in a few treatment-resistant cases; however, preexisting organ damage may persist and can potentially cause symptom relapse [81].
5. IPEX Syndrome (X-Linked Recessive)
IPEX syndrome is caused by mutations in FOXP3, which is essential for Treg differentiation. IPEX is characterized by severe immune dysregulation because dysfunctional Tregs lead to autoimmunity that affects multiple organs and is linked to various autoimmune diseases and allergies [82]. Clinically, the disease manifests as a triad of severe diarrhea caused by autoimmune enteropathy, endocrinopathies such as diabetes or thyroiditis, and dermatitis [83]. Diagnosis relies on the genetic confirmation of FOXP3 mutations, and Treg-specific demethylation region analysis may support an early diagnosis [84]. Treatment strategies include immunosuppressive drugs such as glucocorticoids, calcineurin inhibitors, and mammalian target of rapamycin (mTOR) inhibitors; however, HCT remains the only curative approach [78,83].
6. CTLA-4 Haploinsufficiency (Autosomal Dominant) and LRBA Deficiency (Autosomal Recessive)
Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) is a ligand for the auxiliary stimulus that negatively regulates T cells to not react to self-tissue in acquired immunity. Lipopolysaccharide-responsive and beige-like anchor protein (LRBA) is involved in the expression of CTLA-4, and CTLA-4 haploinsufficiency and LRBA deficiency cause a variety of autoimmune diseases as well as enterocolitis [85,86]. CTLA-4 haploinsufficiency and LRBA deficiency present with enteropathy, which causes severe gastrointestinal tract symptoms, as well as autoimmune disorders such as thyroiditis, encephalitis, and cytopenia. A diagnosis of CTLA-4 haploinsufficiency and LRBA deficiency relies on genetic testing and flow cytometry for protein expression. Although the use of mTOR inhibitors, mycophenolate, and HCT in patients with CTLA-4 haploinsufficiency and LRBA deficiency has been reported, the use of abatacept (a CTLA4-Fc fusion protein) to restore CTLA4 function may be considered as a first-line therapy [85,87].
7. CEAS (Autosomal Recessive)
CEAS is exclusively reported in patients of Asian origin and causes multiple, well-demarcated, flat ulcers in the small intestine. Patients with CEAS present with anemia and malnutrition. A diagnosis of CEAS relies on genetic testing for SLCO2A1, which encodes a transporter that is primarily responsible for the intracellular transport of prostaglandin E2 [88]. SLCO2A1 is also the causative gene for pachydermoperiostosis, a condition characterized by a symptom triad of clubbing of the fingers, periostosis of long bones, and skin thickening. CEAS is more common in females, whereas pachydermoperiostosis occurs more frequently in males, suggesting that modifying factors such as sex-related hormones may affect disease onset. Standard IBD therapies are ineffective in CEAS; its management primarily involves the symptomatic treatment of anemia and nutritional deficiencies in addition to the surgical resection of affected areas [89].
8. TTC7A Deficiency (Autosomal Recessive)
TTC7A deficiency is caused by mutations in TTC7A, which is involved in synthesizing phosphoinositide 3-kinase (PI3K) substrates. PI3K-protein kinase B (AKT) signaling affects various physiological activities including intestinal epithelial cell homeostasis. Patients with TTC7A deficiency develop severe intestinal inflammation, multiple intestinal atresia, and immune abnormalities such as lymphocytopenia and hypogammaglobulinemia [90]. Although HCT addresses immune defects, it fails to resolve intestinal inflammation, highlighting the need for novel therapies that target epithelial cell dysfunction [78]. Animal model data suggest the potential therapeutic role of leflunomide in the treatment of TTC7A deficiency [91].
9. X-Linked EDA-ID (X-Linked Recessive)
NEMO, encoded by IKBKG, is critical for epithelial integrity and immune homeostasis in the gastrointestinal tract via the canonical activation of NF-κB. Its dysfunction leads to susceptibility to infection and chronic inflammation [92]. Patients with EDA-ID have a broad spectrum of clinical manifestations, including recurrent infections, severe colitis, and ectodermal dysplasia (such as dental dysplasia and abnormal hair) [93]. Genetic testing is essential for a diagnosis of EDA-ID, and immunosuppressive therapy with anti-TNF agents and HCT may be considered for treatments; however, colitis persists despite HCT [78].
CLINICAL FEATURES LEADING TO A SUSPICION OF MONOGENIC IBD
Features that lead to the suspicion of monogenic IBD include a young age of onset, poor response to conventional treatment, and diverse syndromic or disease-specific findings. Abnormal findings of the skin and ectoderm, joint, and endocrine systems should raise concerns. In addition, associations with autoimmune or autoinflammatory conditions, as well as immunodeficiency (frequent infections, chronic viral infections, and opportunistic infections with malignant tendencies) should not be ignored. Thus, a mnemonic “YOUNG AGE MATTERS MOST” (young onset is the most important) was introduced by Uhlig et al. [94] to alert clinicians to consider a possible diagnosis of monogenic IBD (Table 4).
Phenotypes Suspected of Having Monogenic Inflammatory Bowel Disease
DIFFERENTIAL DIAGNOSIS OF VEO-IBD
Given that colonic inflammation is relatively common in VEO-IBD, IBD should be considered when diarrhea and/or bloody stool are noted in infants or toddlers. A list of conditions that can present in a similar fashion to VEO-IBD, such as infectious enterocolitis and eosinophilic gastrointestinal disorders, is provided in Table 5 [95]. The consideration and exclusion of these conditions is critical for preventing the delayed diagnosis of VEO-IBD.
Differential Diagnosis of Very Early-Onset Inflammatory Bowel Disease
Intestinal infection is the most common cause of diarrhea and bloody stools in children [96]. Moreover, differentiating IBD from infectious enterocolitis can be particularly challenging in Asia because of the high prevalence of enteric infections [97]. Intestinal tuberculosis should be differentiated when CD is suspected in the Asia–Pacific region, where the prevalence of tuberculosis is high. In children with underlying immunodeficiencies, opportunistic infections such as cytomegalovirus enteritis should be considered. These conditions may present in a similar fashion with abdominal pain, fever, diarrhea, or weight loss [98]. Extensive history taking (including outbreaks, travel history, diet, and medication use) and appropriate diagnostic tests (such as stool culture, Gram stain, toxin assay, antigen-antibody assay, and polymerase chain reaction of endoscopic specimens) may lead to the identification of pathogens. To differentiate intestinal tuberculosis from CD, a combination of clinical, endoscopic, and histopathological findings may be required. Furthermore, the prevalent causative microorganisms differ between countries or regions, and diagnostic approaches for VEO-IBD should be tailored to differences in IBD prevalences and healthcare systems across regions. In areas with a high prevalence of IBD, early colonoscopy and IBD-focused evaluation should be prioritized in young children presenting with persistent diarrhea and hematochezia. By contrast, in regions in which enteric infections—including tuberculosis—remain common, infectious etiologies should be systematically excluded before invasive diagnostic procedures are conducted and immunosuppressive therapy is initiated.
For bloody stools, the evaluation of the amount of blood, color, stool consistency, and frequency are possible diagnostic clues. For example, a small amount of blood with mucus may indicate colonic polyps [99]. In infants, food protein-induced allergic proctocolitis of infancy (secondary to dietary antigens, including cow milk protein) is often the cause of bloody stools and diarrhea. To diagnose this condition, the response to the introduction of a hypoallergenic formula and stool eosinophil staining are often helpful. Nonetheless, endoscopy with histopathological evaluation remains the gold standard for differentiating food protein-induced allergic proctocolitis of infancy from IBD.
In newborns and young infants, severe diarrhea with unknown etiology that requires parenteral nutrition is considered to fit within a group of conditions known as congenital diarrheas and enteropathies (CODEs) [100]. Similar to monogenic IBD, recent genetic advances have revealed the causative genes of various CODEs, leading to a better understanding of the underlying pathophysiology. Some CODE-causing variants have been identified in genes that encode transporters and enzymes that are responsible for intestinal epithelial function, involving metabolism and electrolyte transport. Because CODEs do not typically involve gut inflammation, most children with CODEs do not present with bloody stools and do not have elevated C-reactive protein or fecal calprotectin levels.
HISTORY TAKING AND PHYSICAL EXAMINATIONS
History taking and physical examinations are crucial for the early detection of extraintestinal complications (EICs) or unusual immunodeficiency-associated infections, which not only raise suspicion of VEO-IBD but may also allow for the detection of specific monogenic IBDs. When conducting history taking and physical examinations, some key points are important in relation to VEO-IBD and potential monogenic IBD (Table 6).
Key Points Regarding History Taking and Physical Examinations for Very Early-Onset Inflammatory Bowel Disease
Although most monogenic IBDs are autosomal recessive disorders, some, such as A20HI, are autosomal dominant disorders and others, such as CGD, are X-linked recessive disorders. Approximately 20% of patients with monogenic IBD have a family history of IBD within second-degree relatives [56]. However, the genotype–phenotype relationship has not yet been established for some monogenic IBDs [101]. For example, more than half of patients with XIAP deficiency develop only hemophagocytic lymphohistiocytosis, without enterocolitis [102,103]. A family history of other disorders, such as hemophagocytic lymphohistiocytosis and other autoimmune diseases, should therefore be queried. Furthermore, because many monogenic IBDs coexist with immunodeficiency or autoinflammatory diseases, they accompany EICs more frequently than non-monogenic IBD [65]. Seventy percent of patients with monogenic IBD develop EICs, including atypical infections (45%), skin diseases (38%), and autoimmune diseases (38%) [56]. Hemophagocytic lymphohistiocytosis and malignancy are also important EICs in this setting. In patients with infantile-onset monogenic IBD, enterocolitis usually precedes the onset of EICs, suggesting that monogenic IBD may initially present solely with gastrointestinal symptoms.
DIAGNOSTIC TESTS FOR VEO-IBD
1. Blood and Stool Tests
When VEO-IBD is suspected, the standard approach for a diagnosis of IBD should be followed. Blood tests should include complete blood count, serum albumin, C-reactive protein, and erythrocyte sedimentation rate analyses [48,104]. The assessment of fecal calprotectin is also useful as a screening tool for IBD and for evaluating disease activity [105]. However, fecal calprotectin levels may need to be interpreted carefully because normal levels in infants and children under 4 years old are higher than those in older children or adults [106].
2. Endoscopy and Imaging Approaches
Endoscopy is the gold standard for IBD diagnosis; it is reportedly useful and safe even in children younger than 6 years [107,108]. As per the revised Porto criteria, a comprehensive evaluation of the entire gastrointestinal tract—including upper gastrointestinal endoscopy, ileo-colonoscopy, and small bowel evalu-ation—is recommended at diagnosis [109]. Histopathology is also essential; mucosal biopsies should be taken from both inflammatory and non-inflammatory sites because granulomata may also be detected in non-inflammatory sites [109]. In addition, intubation of the terminal ileum should always be performed [110]. The revised Porto criteria also recommend wireless capsule endoscopy or magnetic resonance enterography (MRE) for the evaluation of small intestinal lesions [97]. For capsule endoscopy, the prior use of a patency capsule and the trans-pyloric placement of the capsule using a capsule delivery device may minimize the risk of capsule retention, even in young children or infants who cannot swallow the capsule [111-115]. The smallest patient reported to have successfully undergone capsule endoscopy was a 10-month-old girl weighing 7.9 kg [116]. Device-assisted enteroscopy such as double-balloon enteroscopy and single-balloon enteroscopy are additional diagnostic options for small bowel evaluation in patients who are suspected to have VEO-IBD [108-110]. The smallest reported cases of successful transoral double-balloon enteroscopy and trans-anal double-balloon enteroscopy were a 12-month-old child weighing 7.9 kg and a 1.6-year-old child weighing 10.8 kg, respectively [117,118]. Although MRE is effective for assessing wall thickness and strictures in the small bowel, it may not be feasible in young children (particularly under 4 years old) because of the need for the prior administration of intestinal contrast media and the use of sedation or anesthesia [119]. Computed tomography enterography may serve as an alternative option [120]. For example, a contrast study with small bowel follow-through is useful for evaluating longitudinal ulcers, stenotic lesions, and fistula; however, it does not detect bowel wall thickening [121]. Abdominal ultrasonography is reportedly helpful for evaluating bowel wall thickening or increased blood flow [122,123]. The European Society of Paediatric Radiology Abdominal Imaging Task Force recommends that ultrasound be performed first, and that if the evaluation is inadequate or there is suspicion of small bowel involvement, MRE should follow [124]. This Task Force also recommends computed tomography enterography when MRE is not feasible, despite the associated radiation exposure.
3. Classification and Grading of Phenotypes and Severity
The revised Porto criteria and the Paris classification are widely used for the diagnosis and phenotyping, respectively, of IBD in children [109,125]. Additionally, because P-IBD tends to present in an atypical fashion, a classification of UC or CD may initially be difficult. More objective P-IBD classes have therefore been developed in an attempt to categorize the broad spectrum of P-IBD using more detailed characteristics [126]. However, because VEO-IBD has a wider range of atypical clinical presentations, applying the same diagnostic criteria or classification for VEO-IBD is likely to be challenging. It is crucial to note that a higher proportion of children diagnosed with VEO-IBD have colonic CD and IBD-U compared with older children with IBD, and the classification often changes during follow-up [2-7,24,30,41-43,47,49]. For example, in a North American cohort study, 11.5% of patients changed from UC/IBD-U to CD during follow-up [6]. It is thus essential to consider the reevaluation of disease phenotypes over time in children with VEO-IBD. Regarding histopathological findings, although apoptosis, torsion of the crypts, blunted villi, and eosinophilic infiltrate are reportedly more common in children with VEO-IBD than in older children with IBD, the observation of only nonspecific inflammatory findings is not uncommon [8].
A systematic review of monogenic IBD revealed that 34% of children are described as having CD or CD-like conditions, 6% as having UC or UC-like conditions, and more than half as having IBD or IBD-U [56]. Certain monogenic IBDs have characteristic endoscopic findings and disease extent. For example, colitis associated with IL-10 and IL-10R deficiency is characterized by colonic ulcers and pseudo-polyps, without upper gastrointestinal tract involvement. In children with A20HI, 80% of patients reportedly have colonic ulcers and 40% have ulcers in the ileum and duodenum bulb [72]. Patients with CEAS have multiple, relatively shallow ulcers with rings or oblique ulcers and intestinal stenosis [127]. Furthermore, leopard skin-like colonic mucosa, granulomata, and surrounding lymphocytic infiltrates and pigmented macrophages are features of CGD [128,129].
A report from China indicated that non-monogenic IBD exhibits more chronic architectural changes in crypts, increased apoptosis, and higher eosinophil counts compared with monogenic IBD, which predominantly included colitis associated with IL-10 and IL-10R deficiency [72]. By contrast, XIAP deficiency cannot be differentiated from CD on the basis of endoscopic and pathological findings [102]. Given the possible presence of monogenic disease in children with VEO-IBD, pattern-based approaches for classifying the pathological findings of VEO-IBD have been proposed [9,10]. A noteworthy classification system suggested by Wilkins et al. [9] categorizes VEO-IBD pathological findings into the following 5 distinct patterns: (1) chronic active enteritis, (2) apoptosis/epithelial injury pattern, (3) eosinophil-rich pattern, (4) lymphocytic pattern, and (5) granulomatous pattern.
The absence of typical endoscopic or histopathological findings of IBD upon initial examination does not completely rule out VEO-IBD or monogenic IBD. Rather, a diagnosis of VEO-IBD should rely on a combination of clinical, immunological/serological, stool, diagnostic imaging, endoscopic, histopathological, and enterographic findings. Because these features may evolve over time, re-assessment of the condition should always be considered. Given that current classifications are based on older children and adults, there is a need for a new classification that reflects the characteristics of children with VEO-IBD and monogenic IBD.
DIAGNOSTIC PROCESSES FOR MONOGENIC IBD
In addition to history taking, physical examination, basic blood/stool tests, imaging studies, and endoscopic/histopathological evaluations, a stepwise assessment of immune function is essential for evaluating children with VEO-IBD because most monogenic IBD is caused by inborn errors of immunity. First-line tests encompass basic immunological tests, including total leukocyte count and differentiation, immunoglobulin levels, and vaccine-derived antibodies (Table 7). These tests screen for neutropenia, lymphopenia, or defects of antibody production. For example, a low number and small size of platelets suggests Wiskott-Aldrich syndrome [130].
Tests for Monogenic Inflammatory Bowel Disease
Second-line investigations include advanced immunological tests, such as lymphocyte subset analysis and the DHR test (Table 7). The DHR test is useful for diagnosing CGD with defective reactive oxygen species production [131]. Flow cytometric analysis can also be helpful for some monogenic IBD types involving T-cell or B-cell deficiencies, including IPEX syndrome with defects of regulatory T-cells and severe combined immunodeficiency with absent or defective cluster of differentiation 4 (CD4), CD8, natural killer cells, or B cells [132].
Third-line tests involve genetic testing. Genetic testing varies from targeted sequencing for specific genes to whole genome sequencing, and depends on test availability and the cost or range of insurance coverage by institutions and countries. Sometimes, whole genome sequencing requires participation in research studies or international collaborations. Notably, targeted or panel sequencing can be cost-effective and useful in geographical regions that are enriched in known genetic variants because of founder effects. For example, colitis associated with IL-10 and IL-10R deficiency is more common in mainland China.
Given that disease-specific clinical phenotypes may not be fully developed in early infancy, narrowing down the specific genes for Sanger sequencing can be challenging. Additionally, panel sequencing includes only known pathogenic genes, and therefore cannot identify novel causative genes. Conversely, although they are more expensive and the results take longer to obtain, whole exome and whole genome analyses hold the potential to detect rare and novel genes and variants. Even in countries or institutions where screening or genetic testing for monogenic IBD is not readily available, the preservation of blood or tissue specimens—ideally before starting treatment—may support a future genetic diagnosis and functional analysis.
In the present paper, we propose a model to summarize our recommended approach to differentiating or diagnosing monogenic IBD in children with VEO-IBD (Fig. 3). Compared with a previously recommended straightforward model from clinical data to genetic screening or confirmation [94], our model emphasizes the importance of integrating clinical and genetic data. Our model effectively integrates 3 crucial components: clinical data, functional analysis, and genetic analysis. It provides a framework for evaluating children with VEO-IBD and offers an approach for complex or atypical cases. It also highlights the potential for diagnosing monogenic IBD in a timely manner, regardless of whether the mutations are common or novel variants. The identification of a causative genetic variant may lead to the use of a specific treatment based on its function.
Diagnostic approach for monogenic inflammatory bowel disease (IBD) in very early-onset-IBD. This figure illustrates a diagnostic model that combines clinical data, functional studies, and genetic testing. IBD with onset <2 years, atypical features, or refractoriness raises suspicion for monogenic IBD. Functional analyses provide early diagnostic clues. Genetic testing follows a tiered approach, progressing from panel sequencing to whole-exome and whole-genome sequencing. Results are categorized as pathogenic variants, variants of uncertain significance (VUS) in known genes, or VUS in novel genes. Pathogenic variants support prompt diagnosis and prognosis improvement, whereas VUS requires integration with clinical and functional data to determine pathogenicity or identify novel monogenic IBD. EGID, eosinophilic gastrointestinal disorders; FGID, functional gastrointestinal disorders; IBS, irritable bowel syndrome; DHR, dihydrorhodamine.
However, even with whole exome sequencing, the diagnostic yield was as low as 3% in one study of more than 1,000 children with IBD [65]. We must therefore consider the possibility that many unidentified forms of monogenic IBD remain. A constant review of genetic information is essential for the early detection of updated interpretations of variants of uncertain significance in both known and recently reported monogenic IBD forms. Moreover, the accumulation and review of clinical and genetic data might lead to the identification of potentially pathogenic variants in novel monogenic IBDs.
TREATMENTS OF VEO-IBD
The major goals of VEO-IBD treatment include the control of intestinal inflammation, the achievement of mucosal healing, the maintenance of sufficient nutritional status, and the optimized growth and development of the child. In addition, all treatment recommendations should consider the quality of life and mental health of very young children and their families.
Treatment regimens should be multifaceted, with a combination of pharmacological, nutritional, and sometimes surgical interventions, and should also consider the disease phenotype and activity in each patient. The management of a child with VEO-IBD can be challenging because of the complexity of the condition and the lack of established standardized treatment approaches. Therefore, it is imperative to recognize and address the substantial heterogeneity in disease patterns and severities among patients. Currently, this variability in presentation and progression necessitates an individualized approach to treatment.
Standardized pharmacological therapy for VEO-IBD has yet to be established, and there are limited data that demonstrate efficacy and safety. Because few clinical trials have been conducted in children with VEO-IBD, most common medications have not yet been approved for this vulnerable group. Treatment usually proceeds in the same way as for older children; however, it should be noted that affected children may be immunodeficient. For example, the use of anti-TNF agents in CGD is not recommended because sepsis and death have been reported following infliximab use in children with CGD [133].
1. Corticosteroids and EEN
Cohort studies from Israeli and international children with VEO-IBD have revealed that corticosteroids are most frequently used (53%–77%) as induction therapy, whereas exclusive enteral nutrition (EEN) is used less frequently (3%–10%) in real-world practice [11,49]. However, EEN is a safe and good treatment option for the management of VEO-IBD. In children with suspected immunodeficiency, EEN may be preferred over corticosteroids to avoid the risk of opportunistic infection. EEN can also be a suitable option when the administration of live attenuated vaccines needs to be prioritized [134]. Nutrient deficiencies caused by the long-term predominant use of low-fat amino acid-based formulae have been reported in Japan [135]. Consequently, the adequate evaluation and supplementation of deficient micronutrients should be considered. It should also be noted that the delayed introduction of solid foods in infancy may interfere with chewing and swallowing development or lead to a feeding aversion.
2. 5-Aminosalicylates
5-Aminosalicylate drugs may be useful in children with VEO-IBD because they are relatively safe without systemic immune suppression. In North American, Israeli, and international cohort studies, 5-aminosalicylate agents have been used in 80%, 90%, and 75% of individuals with VEO-IBD, respectively [6,11,49]. In the international study, 22% of all cases were able to maintain disease remission with non-immunosuppressive therapies such as 5-aminosalicylate formulations and nutritional therapy [11]. The results of a single-center cohort study in Japan were similar; 25% of the included children maintained long-term remission with 5-aminosalicylate and partial enteral nutrition [12].
3. Immunomodulators
Immunomodulators (thiopurines and methotrexate) were used in approximately 75% of cases in the international cohort, with 27% remaining in long-term remission [11]. Azathioprine and 6-mercaptoprine are transformed into thioguanine nucleotides, which are the active metabolites. The enzymes thiopurine methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) interfere with the production of active thioguanine nucleotides. Thiopurines are metabolized more quickly in children with VEO-IBD because of higher TPMT activity, resulting from age-related DNA hypomethylation [136,137]. Higher doses of azathioprine may therefore be necessary to generate therapeutic 6-thioguanine nucleotide concentrations [138]. Moreover, when thiopurines are used, doses should be optimized by monitoring 6-thioguanine nucleotide concentrations, lymphocyte counts, or red blood cell mean corpuscular volumes [139-142]. TPMT genotypes and polymorphisms in the NUDT15 gene can affect thiopurine metabolism, thus influencing the incidence of serious side effects such as life-threatening bone marrow suppression. TPMT-deficient variants cause thiopurine toxicity in individuals of European descent, whereas risk alleles in NUDT15 account for myelosuppression in Asian children [142,143]. Consequently, testing for NUDT15 polymorphisms prior to the use of thiopurines is strongly encouraged in Asian children.
4. Biologics
Despite limited data, biologics have shown promising potential in some children with VEO-IBD. This should instill hope in both patients and physicians because it may encourage further research and development of biologics for children with VEO-IBD in the Asia–Pacific region. In a North American cohort, 41% of individuals with VEO-IBD received biologics in the first 5 years after diagnosis [6]. In an international cohort, anti-TNF agents were used most frequently (48%), with vedolizumab (VED; an anti-α4β7 integrin antibody) used in 7% of patients, and ustekinumab (UST; an anti-IL-12/23 p40 antibody) used in 2% of patients [11].
In 2014, Kelsen et al. [144] reported the efficacy of infliximab, with a corticosteroid-free clinical remission rate of 9% at 1 year in 33 patients aged 7 years or younger. Since then, the use of anti-TNF agents has been reported in many countries, with some reports describing successful therapy and others detailing treatment failure (and sometimes moving to a second anti-TNF agent) [4,145-154]. A North American study reported anti-TNF treatment failure in approximately half of the 166 children studied; moreover, adverse events occurred in 23% of those treated with infliximab and 14% of those treated with adalimumab [153]. Additionally, although anti-TNF agents may be effective for improving growth retardation and perianal lesions in some children with VEO-IBD, more treatment failures (particularly with VEO-UC) and more adverse events occur in these patients than in older children [145-147,149,150]. In a single-center cohort study in Japan, 17 children were categorized into 3 groups—UC type (UCT), non-UCT with perianal disease, and non-UCT without perianal disease [145]. Infliximab appeared useful for children with VEO-IBD, with better outcomes and fewer infusion reactions observed in children with non-UCT with perianal disease (steroid sparing rate: 67%; infusion reaction rate: 60%) and non-UCT without perianal disease (steroid sparing rate: 60%; infusion reaction rate: 29%) compared with those with UCT (steroid sparing rate: 0%; infusion reaction rate: 100%) [145]. Furthermore, in a single-center cohort study in China, the rates of clinical remission and mucosal healing were compared between 15 children with VEO-CD and 50 older children [150]. In those with VEOCD, 64% and 40% of patients achieved clinical remission and mucosal healing after induction therapy, respectively. Although VEO-CD was not associated with primary non-response or mucosal non-healing, it was significantly associated with higher rates of adverse events and treatment discontinuation [150].
VED and UST are approved for use in adults [155-158]; however, they are yet to be approved in children with IBD, and there have been particularly few reports of their use in children with VEO-IBD. Because VED does not suppress systemic immunity, it may be a suitable option for children with VEO-IBD with underlying immunodeficiency or for those who require live attenuated vaccine administration.
In a single-center report from Poland, a clinical response after the fourth dose of VED was observed in 56% of 16 children with VEO-IBD [159]. A multicenter cohort study of VED in 48 Japanese children with UC, including 5 with VEO-UC, demonstrated a remission rate of 80% at week 14, similar to that seen in older children [160]. The VEDOKIDS study, a prospective multicenter cohort that included 22 children weighing less than 30 kg (out of 142 children with IBD), did not identify any severe adverse events [161]. In children under 30 kg, the findings suggested that VED should be administered at a higher dose, either based on the child’s body surface area (200 mg/m²) or weight (10 mg/kg), to achieve optimal drug concentrations. By contrast, a dose of 177 mg/m² body surface area (up to a maximum of 300 mg) is recommended by the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition and the European Crohn’s and Colitis Organization guidelines [140,161].
Although Rinawi et al. [162] reported the efficacy of UST in a child with VEO-IBD after anti-TNFα failure in 2016, cohort studies of UST from Europe or North America have not yet been reported. A single-center cohort study in Japan noted that, in 7 of 8 patients who had not responded to anti-TNF agents, UST led to a corticosteroid-free clinical remission rate of 50% at week 52 and 88% at week 88 [163]. Another Japanese single-center study that involved 10 children with VEO-IBD (out of 43 children with CD) with anti-TNF failure also reported good long-term outcomes, with a corticosteroid-free clinical remission rate of 83% at week 106 and without severe side effects requiring UST discontinuation [164]. In this study, although a higher frequency of interval shortening (to every 4–7 weeks) was required for 7 of the patients with VEO-IBD, the long-term outcomes of children with VEO-IBD were similar to those of older children, even after anti-TNF failure [164]. The Uni-Star study, a Phase 1 trial in children with CD, included 18 children weighing less than 40 kg (out of 44 participants); serious adverse events were identified in 16% of patients [165]. Exacerbation of CD was the most frequent adverse event. In this cohort, however, there was no apparent difference in the safety profile between younger or smaller participants and older participants. In children under 40 kg, even in a group that received a higher dose (9 mg/kg), serum UST concentrations were lower than in patients weighing 40 kg or more and the reference Phase 3 adult population [165]. These findings suggest that a different dosing regimen may be required for children under 40 kg to achieve optimal drug concentrations.
5. Surgical Treatment
Children with VEO-IBD with an intractable clinical course or intestinal complications, including stricture or perforation, may require surgical intervention. This may include colectomy or ostomy placement to avoid a life-threatening complication, minimize long-term corticosteroid use, or ensure optimal growth. Bowel-related surgery was performed in 15% of 243 children during follow-up in a multicenter international cohort study, and in 20% of a group of 54 Japanese children [11,12]. The severity and prognosis of VEO-IBD compared with IBD in older children are controversial and vary depending on study setti ngs [6,7,26,39,44,104,147,166-168]. Some reports noted higher rates of surgical intervention in children with VEO-IBD [5,7,104,147,166], whereas other reports indicated similar rates to those seen in older children [6,26,39,44,167,168].
In addition, for severe or complex perianal disease, the placement of a non-cutting seton is recommended as a first-line surgical intervention to allow adequate drainage, reduce inflammation, and enhance the efficacy of biologic therapy [169,170]. When the response to combined medical and surgical treatment is insufficient, fecal diversion by ostomy placement may also be required to preserve anorectal function and improve quality of life [171]. In a Japanese cohort study, over 10 years, 4 of 7 VEO-CD patients with perianal lesions (57.1%) received seton placement, and 3 (42.9%) ultimately required ostomy placement. By contrast, a seton was placed in 13 of 29 older pediatric CD patients with perianal lesions (44.8%), and none underwent ostomy placement [172].
6. Treatments for Monogenic IBD
In some children, monogenic IBD is refractory to conventional IBD treatments. In a systematic review, 27% of 750 children with monogenic IBD required surgical treatment [56]. Bowel resection was required in 63% of the group, whereas 21% underwent ostomy creation. In addition, although various biologic agents were reportedly used, their efficacy was reported to be only 26% [56]. However, the diagnosis of some monogenic IBD types may lead to targeted therapies, resulting in improved disease activity and prognosis (Table 8) [78].
Reportedly Effective Treatments for Monogenic Inflammatory Bowel Disease
The efficacy of HCT has been established in some forms of monogenic IBD. These include colitis associated with IL-10 and IL-10R deficiency and XIAP deficiency. HCT has also been considered in other types of monogenic IBD with associated immunodeficiency (Table 8) [13-16]. However, HCT is not helpful for treating mucosal barrier defects such as TTC7A deficiency and NEMO deficiency; exploratory studies of different therapeutic approaches have therefore been conducted [91,173].
As new IBD therapies become available, more reports of effective treatments for monogenic IBD, including via drug repositioning, are expected to emerge. However, problems remain in the form of a lack of uniformity when expressing efficacy. Uhlig et al. [78] recommend the use of a standardized reporting methodology—including disease activity assessment with a pediatric UC activity index, endoscopic assessment, and fecal calprotectin—to address this issue.
MULTIDISCIPLINARY APPROACH FROM DIAGNOSIS TO MANAGEMENT
The various pathogeneses and unique challenges in the diagnosis and management of children with VEO-IBD necessitate a multidisciplinary approach. Pediatric gastroenterologists must be at the forefront of care and lead the multidisciplinary team. For the diagnosis of VEO-IBD, pathologists, radiologists, immunologists, geneticists, and other specialists who cover specific EICs are required to ensure optimal diagnostic accuracy. To decide on the appropriate pharmacological or surgical treatment, discussions with adult gastroenterologists and pediatric or adult surgeons are important, and hematologists should be involved when HCT is considered. Collaboration with the pharmacy department is also helpful in ensuring the correct administration of medications with limited dosing information and formulations. Nurses not only provide daily physical and emotional support for children and their families, but also enable community-based care that might involve stoma management or home intravenous hyperalimentation. Dietitians are another essential part of the team; their role may include prescribing nutritional products, managing specific nutritional interventions, and ensuring the provision of adequate age-appropriate diets. Psychosocial support for patients and their families must also be provided because VEO-IBD can adversely impact quality of life and mental health [174]. Child life specialists can also facilitate patients’ developmental and mental status-matched education and care.
Upon diagnosis of a specific form of monogenic IBD, genetic counseling by certified personnel should be offered to patients and their families. In addition, collaborations with researchers to identify novel candidate causative genes—and conduct functional analyses specific to these genes—may lead to the establishment of novel forms of monogenic IBD, which might result in the provision of better treatment options based on the underlying pathophysiology.
In settings where a multidisciplinary team is not available, the centralization of diagnostic tests at a local, national, or regional level, or collaboration within research projects, will likely facilitate diagnoses. Furthermore, consultation with specialized personnel or institutions may be helpful for developing the most effective approach with limited resources. Strengthening international and regional collaborations—through telemedicine, training programs, and shared databases—may enhance diagnostic accuracy and management, even in resource-limited settings. Mutual learning between countries with diverse experiences and systems might also support context-appropriate and sustainable care models.
CONCLUSIONS
Children with VEO-IBD face important diagnostic and treatment challenges in the Asia–Pacific region. The present review highlights the need for comprehensive diagnostic protocols—including endoscopy for VEO-IBD and genetic testing for monogenic IBD—to facilitate an early and accurate diagnosis and the provision of appropriate treatments. This paper also promotes a multidisciplinary approach for the holistic care of children with VEO-IBD, which we hope will lead to better clinical outcomes and a higher quality of life for affected children and their families. Given the current lack of data for many aspects of VEO-IBD and monogenic IBD, future research through regional collaborations across the Asia–Pacific region is required.
Notes
Funding Source
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
Takeuchi I received honoraria from AbbVie GK, Takeda Pharmaceutical Co., Ltd., and EA Pharma Co., Ltd. Arai K received honoraria from AbbVie GK, Takeda Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., EA Pharma Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Ltd., Miyarisan Pharmaceutical Co., Ltd., Alfresa Pharma Co., Ltd., and Mochida Pharmaceutical Co., Ltd. He also received grants from AbbVie GK, Takeda Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Janssen Pharmaceutical K.K., Bristol-Myers Squibb Company, and Pfizer Inc. Calixto-Mercado KS received a travel grant from Celltrion. Shim JO received honoraria from Samsung Bioepis, Celltrion, AbbVie, and Janssen. She is also an Editorial Board member of this journal but was not involved in the peer review or decision-making process for this manuscript. The remaining authors have no conflicts of interest to declare.
Data Availability Statement
Data sharing is not applicable as no new data were created or analyzed in this study.
Author Contributions
Conceptualization: Poddar U, Shim JO, Arai K, Takeuchi I. Project administration: Poddar U, Shim JO, Arai K, Takeuchi I. Writing - original draft: Poddar U, Shim JO, Arai K, Takeuchi I. Writing - review & editing: all authors. Approval of final manuscript: all authors.