IL-17-producing lymphocytes are involved in both tissue repair and the propagation of inflammation, with their effects highly context-dependent. Mucosal-Associated-Invariant-T-cells (MAIT), a subset of innate-like T cells with features of both Th1 and Th17 lineages, are increasingly recognized for their roles in mucosal immunity. Here, we identified the Collaborative-Cross CC011/Unc strain, which spontaneously develops chronic colitis, as being enriched for MAIT cells. This expansion coincides with an age-related loss of intestinal barrier permeability and colonic inflammation. Microbiota from CC011 mice activated MAIT cells in an MR1-dependent manner and selectively promoted the accumulation of MAIT17 cells in peripheral tissues. Single-cell transcriptomic analyses revealed colon MAIT cells from colitic CC011 mice expressed a pathogenic Th17-like signature, characterized by IL-1 and IL-23 signaling, IL-17A and IFNγ co-expression, and upregulation of IL-23R, features that correlated with inflammatory Ly6Chi monocyte abundance. Genetic deletion of Traj33, essential for MAIT development, significantly reduced colonic inflammation in this model. These findings demonstrate that MAIT cells integrate microbial and cytokine cues to adopt a pathogenic effector phenotype that exacerbates chronic intestinal inflammation.

COVID-19 is known to induce cytokine storms and inappropriate cytotoxic immune responses. Hemophagocytic lymphohistiocytosis (HLH) is an underrecognized condition due to a hyperinflammatory syndrome characterized by fulminant hypercytokinemia with a high mortality burden. Cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induced secondary HLH during and post-infection have been sparsely reported in children. Inflammatory bowel disease (IBD) is a chronic, relapsing disorder of the gastrointestinal tract with a multifactorial etiology involving genetic, environmental, and immunological factors. To date, secondary HLH associated with COVID-19 in very early-onset inflammatory bowel disease (VEO-IBD) has not been reported. This case report aims to enhance understanding of the clinical manifestations of VEO-IBD and HLH, thereby facilitating the timely diagnosis and management of this rare condition.

We present the case of a 5-month-old Chinese female infant diagnosed with HLH following COVID-19 infection. The patient presented with hemophagocytic syndrome, which included recurrent fever, hepatosplenomegaly, cytopenia, hyperferritinemia, hypertriglyceridemia, and hypofibrinogenemia, after exposure to her mother, who had been diagnosed with COVID-19. Whole-exome sequencing(WES) identified heterozygous mutations in the IL-10RA gene: c.537 G > A (inherited from her mother) and c.301 C > T (inherited from her father), who was ultimately identified as having VEO-IBD. Despite receiving nutritional support, intravenous immunoglobulin (IVIG), and dexamethasone therapy, the patient continued to experience anemia, diarrhea, and refractory gastrointestinal bleeding. Following a brief improvement after interventional treatment, the parents declined further medical interventions, signed for discharge, and the infant sadly passed away three months later.

Rare genetic variants play a pivotal role in the pathogenesis of VEO-IBD, particularly in infants diagnosed before the age of one. These cases often demonstrate resistance to various immunosuppressive therapies and have a poor prognosis with conventional treatments. Our findings highlight the potential increased risk of severe HLH in patients with VEO-IBD and concurrent COVID-19, underscoring the need for comprehensive and vigilant differential diagnosis when patients exhibit symptoms suggestive of multi-organ damage.

Paediatric congenital enteropathies (PCEs) are a group of rare inherited diseases with a typical early onset in life. Prompt identification and treatment are crucial to avoid potentially fatal consequences. This review aims to provide a paradigmatic framework for clinical and histological identification of PCEs, with an emphasis on congenital conditions involving epithelial shape, trafficking and polarity, enteroendocrine function, immunomodulatory diseases, and extremely early onset inflammatory bowel illness. A proper classification is founded on histopathological characteristics and clinical parameters (such as consanguinity, anomalies in amniotic fluid, prenatal expression or early neonatal onset, stool appearance, persistence of symptoms despite fasting, and extra-intestinal manifestations, etc.). The increasing accessibility and convenience of genetic tests has also accelerated the identification of genes related to specific phenotypes of PCEs, improving the diagnostic and care pathway. As a "niche" pathology, PCEs are susceptible to misdiagnosis due to a limited awareness of these entities, and their identification requires extensive training and specialized facilities. The aim of our review is to emphasize the importance of an integrated approach, combining clinical, histological, and molecular analysis, to achieve a definitive diagnosis and guide the treatment.

Inflammatory bowel disease (IBD) in the pediatric population presents distinct characteristics compared to adult cases. Pathology plays a critical role in its diagnosis, and this review underscores key considerations in the pathologic evaluation of pediatric IBD. Recognizing inflammatory patterns in the upper gastrointestinal tract can improve disease classification and aid in diagnosing IBD in certain scenarios, such as isolated upper gastrointestinal or small bowel involvement. Additionally, familiarity with distinctive subtypes, including IBD associated with primary sclerosing cholangitis and monogenic forms of IBD, supports early comorbidity detection, enhances patient management, and improves prognostication.

The genetic contribution to inflammatory bowel disease (IBD), encompassing both Crohn's disease (CD) and ulcerative colitis (UC), accounts for around 20% of disease variance, highlighting the need to characterize environmental and epigenetic influences. Recently, considerable progress has been made in characterizing the adult methylome in epigenome-wide association studies.

We report detailed analysis of the circulating methylome in 86 patients with childhood-onset CD and UC and 30 controls using the Illumina Infinium Human MethylationEPIC platform.

We derived and validated a 4-probe methylation biomarker (RPS6KA2, VMP1, CFI, and ARHGEF3), with specificity and high diagnostic accuracy for pediatric IBD in UK and North American cohorts (area under the curve: 0.90-0.94). Significant epigenetic age acceleration is present at diagnosis, with the greatest observed in CD patients. Cis-methylation quantitative trait loci (meQTL) analysis identifies genetic determinants underlying epigenetic alterations notably within the HLA 6p22.1-p21.33 region. Passive smoking exposure is associated with the development of UC rather than CD, contrary to previous findings.

These data provide new insights into epigenetic alterations in IBD and illustrate the reproducibility and translational potential of epigenome-wide association studies in complex diseases.

Very early-onset inflammatory bowel disease (VEO-IBD) is a clinical umbrella term referring to IBD-like symptoms arising in children before 6 years of age, encompassing 'pure' IBD (Crohn's Colitis/Ulcerative Colitis)/non IBD colitis, and monogenic diseases (MDs), the latter often related to primary immunodeficiency disorders. A multidisciplinary approach is imperative for correct therapeutic management, as endoscopy and histology are not always completely informative. In this setting, the study aims to describe the extent/features of histologic lesions in both endoscopically damaged mucosa and otherwise endoscopically healthy (normal/near normal) mucosa.

Endoscopic data were retrospectively recorded, and histologic slides were collegially re-evaluated in a 93 VEO-IBD multicenter cohort, 76 (76/93 - 81,7 %) of which with complete endoscopic/histologic data.

At endoscopy, lesions were reported by the clinician in 66/76 (86,8 %) cases. When endoscopic lesions were reported, histologic damage was also seen. Interestingly, histologic mucosal damage was also documented in 43,3 % (13/30) of cases with endoscopically healthy/nearly healthy mucosa. This misalignment between endoscopy and pathology was seen in about a third of (29,1 % - 7/24) 'true' IBD and all MDs (100 % - 6/6) (p = 0.0029).

In VEO-IBD, histologic lesions can be present in endoscopically 'healthy' intestinal mucosa. This finding is more frequent in MDs, suggesting the need to accurately sample all the mucosal tract in VEO-IBD patients, even when no endoscopic lesions are seen at endoscopy.

Background: Interleukin-10 (IL-10) is a crucial anti-inflammatory cytokine essential for maintaining immune homeostasis, particularly in the gastrointestinal system. Defects in the IL-10 signaling pathway, including mutations in interlaukin-10 receptor (IL-10R) beta, have been implicated in early-onset inflammatory bowel disease (IBD), often resistant to conventional treatments. Case Presentation: We report a 1.5-month-old male patient with IL-10R beta deficiency presenting with fever, vomiting, malnutrition, and sepsis. Despite normal initial evaluations, persistent fever and elevated inflammatory markers prompted the initiation of anakinra, an interleukin-1 receptor antagonist. Genetic testing confirmed a homozygous deletion in the IL10RB gene. Anakinra led to significant clinical improvement, including weight gain and symptom resolution. The patient was enrolled in an allogeneic hematopoietic stem cell transplantation (HSCT) program and successfully received HSCT from an HLA-matched related donor. Discussion: IL-10R beta deficiency presents with severe and early-onset symptoms, often unresponsive to standard IBD therapies. Anakinra has shown promise in bridging to HSCT by reducing inflammation and improving clinical outcomes in patients with IL-10 pathway defects. This case highlights the effectiveness of anakinra as a treatment strategy in severe, refractory IBD associated with IL-10R beta deficiency and underscores the importance of genetic testing for accurate diagnosis and treatment planning. Conclusion: Anakinra may provide significant clinical benefits in patients with IL-10R beta deficiency, serving as a bridge to definitive treatment with HSCT. Early genetic diagnosis and targeted therapy are crucial for managing this challenging condition.

Interleukin-10 (IL-10) is an immunomodulatory cytokine critical for intestinal immune homeostasis. IL-10 is produced by various immune cells but IL-10 receptor signaling in intestinal CX3CR1+ mononuclear phagocytes is necessary to prevent spontaneous colitis in mice. Here, we utilized fluorescent protein reporters and cell-specific targeting and found that Rorc-expressing innate lymphoid cells (ILCs) produce IL-10 in response to anti-CD40-mediated intestinal inflammation. Deletion of Il10 specifically in Rorc-expressing ILCs led to phenotypic changes in intestinal macrophages and exacerbated both innate and adaptive immune-mediated models of experimental colitis. The population of IL-10+ producing ILCs shared markers with both ILC2 and ILC3 with nearly all ILC3s being of the NCR+ subtype. Interestingly, Ccl26 was enriched in IL-10+ ILCs and was markedly reduced in IL-10-deficient ILC3s. Since CCL26 is a ligand for CX3CR1, we employed RNA in situ hybridization and observed increased numbers of ILCs in close proximity to Cx3cr1-expressing cells under inflammatory conditions. Finally, we generated transgenic RorctdTomato reporter mice that faithfully marked RORγt+ cells that could rescue disease pathology and aberrant macrophage phenotype following adoptive transfer into mice with selective Il10 deficiency in ILC3s. These results demonstrate that IL-10 production by a population of ILCs functions to promote immune homeostasis in the intestine possibly via direct effects on intestinal macrophages.

Inflammatory bowel diseases (IBDs), encompassing Crohn's disease and ulcerative colitis, are complex chronic disorders characterized by an intricate interplay between genetic predisposition, immune dysregulation, gut microbiota alterations, and environmental exposures. This review aims to synthesize recent advances in IBD pathogenesis, exploring key mechanisms and potential avenues for prevention and personalized therapy. A comprehensive literature search was conducted across major bibliographic databases, selecting the most recent and impactful studies on IBD pathogenesis. The review integrates findings from multi-omics analyses, single-cell transcriptomics, and longitudinal cohort studies, focusing on immune regulation, gut microbiota dynamics, and environmental factors influencing disease onset and progression. Immune dysregulation, including macrophage polarization (M1 vs. M2) and Th17 activation, emerges as a cornerstone of IBD pathogenesis. Dysbiosis, as a result of reduced alpha and beta diversity and overgrowth of harmful taxa, is one of the main contributing factors in causing inflammation in IBD. Environmental factors, including air and water pollutants, maternal smoking, and antibiotic exposure during pregnancy and infancy, significantly modulate IBD risk through epigenetic and microbiota-mediated mechanisms. While recent advances have supported the development of new therapeutic strategies, deeply understanding the complex dynamics of IBD pathogenesis remains challenging. Future efforts should aim to reduce the burden of disease with precise, personalized treatments and lower the incidence of IBD through early-life prevention and targeted interventions addressing modifiable risk factors.

Enterostomy is utilized to mitigate severe clinical symptoms in children with very early-onset inflammatory bowel disease (VEO-IBD) and to provide a window for stem cell transplantation. Nevertheless, the incidence of postoperative complications is significant, and there is currently a lack of research exploring the risk factors associated with complications related to the stoma and incision following the procedure. The objective of this study is to investigate the risk factors for stoma and incision complications after enterostomy in patients with VEO-IBD. From January 2015 to December 2023, 49 children with VEO-IBD who underwent enterostomy were enrolled in the study. Demographic characteristics, blood biochemical indices, weighted Pediatric Crohn's Disease Activity Index (wPCDAI), and enterostomy-related information were prospectively collected. Multivariate logistic regression was employed to identify the risk factors for ostomy and incision-related complications. All 49 included VEO-IBD children had interleukin-10 (IL-10) signaling defects, with 27 (55.1%) having stomal-related complications and 10 (20.4%) had incision complications after enterostomy. Univariate analysis revealed that wPCDAI (OR, 1.03; 95% CI, 1.00-1.07; P = 0.05) showed a tendency towards statistical significance in the occurrence of ostomy complications. Weight-for-age Z-score (WAZ) (OR, 0.57; 95% CI, 0.39-0.84; P = 0.004), height-for-age Z-score (HAZ) (OR, 0.57; 95% CI, 0.37-0.88; P = 0.01), type of surgery (OR, 0.12; 95% CI, 0.03-0.56, P = 0.007), C-reactive protein (CRP) (OR, 1.02; 95% CI, 1.01-1.04; P = 0.007), and wPCDAI (OR, 1.08; 95% CI, 1.01-1.14; P = 0.009) demonstrated statistical significance in the occurrence of incision complications. However, multivariate binary logistic regression did not reveal any statistically significant factors.

Although emergency surgery is unavoidable, our study suggests that improving nutritional status, reducing CRP levels, and increasing preoperative wPCDAI scores may help reduce post-enterostomy stoma and incision complications in VEO-IBD children with interleukin-10 (IL-10) signaling defects. Further large-scale studies are needed to confirm these findings.

• Enterostomy is commonly used to manage severe symptoms in children with VEO-IBD and to provide a window for stem cell transplantation. • The incidence of postoperative complications, including stoma and incision-related issues, is significant in these patients.

• This study identifies potential risk factors for stoma and incision complications following enterostomy in children with VEO-IBD, particularly those with IL-10 signaling defects. • Factors such as nutritional status (WAZ and HAZ), CRP levels, type of surgery, and the wPCDAI were found to be associated with stoma and incision complications in univariate analysis, although multivariate analysis did not show statistical significance for these factors.

Patients with very early-onset inflammatory bowel disease (VEO-IBD), with an age of onset < 6 years, can present with severe manifestations and may require biologic therapy. Infliximab and adalimumab are approved for induction and maintenance in pediatric IBD patients but are licensed only above the age of 6 years. Effectiveness and safety data on adalimumab in this patient population are lacking. We assessed the therapeutic response to help close this gap.

This retrospective study involved 30 sites worldwide. Demographic, clinical, and laboratory data were collected from patients with VEO-IBD who commenced adalimumab therapy before the age of 6 years.

Seventy-eight patients (37 Crohn's disease, 26 ulcerative colitis, and 15 with IBD-unclassified) were included. Median age of IBD onset was 2.6 (1.3-4.1) years, with 30 (38.5%) patients diagnosed at age <2 years. Median age at adalimumab initiation was 4.2 (2.8-5.1) years. Adalimumab was used as second-line biologic therapy in 45 (57.7%) patients after infliximab. The median time to last follow-up was 63 (22-124) weeks. Significant improvement in clinical scores, CRP, fecal calprotectin, and weight Z-score were observed by Week 52. Adalimumab durability rates were 61.9%, 48.1%, and 35.6% after 1, 2, and 3 years, respectively. Drug discontinuation rates were not dependent on IBD type, age, prior anti-TNF exposure, or concomitant immunomodulatory treatment. Four (5.1%) patients developed serious infections, including 1 patient with TTC7A deficiency who died following adenovirus sepsis.

Adalimumab therapy is a viable therapeutic option in patients with VEO-IBD with an acceptable safety profile.

Genetic discovery in very early-onset inflammatory bowel disease (VEO-IBD) can elucidate not only the origins of VEO-IBD, but also later-onset inflammatory bowel disease. We aimed to investigate the polygenic origins of VEO-IBD in a cohort with a high proportion of Hispanic patients.

Patients with VEO-IBD who underwent whole exome sequencing at our center were included. Genes were categorized as genes of interest (GOIs) (129 genes previously described to be associated with VEO-IBD) or non-GOIs. VEO-IBD "susceptibility" single nucleotide variants (SNVs) were identified through enrichment compared with gnomAD (Genome Aggregation Database) and ALFA (Allele Frequency Aggregator) and were scored by Combined Annotation Dependent Depletion for deleteriousness. Gene networks carrying susceptibility SNVs were created. Myosin 5b immunofluorescence was also studied.

Fifty-six patients met inclusion criteria, and 32.1% identified as Hispanic. Monogenic disease was infrequent (8.9%). Significant enrichment of GOI susceptibility SNVs was observed, notably in MYO5B, especially in Hispanics. MEFV, TNFAIP3, SH3TC2, and NCF2 were also central participants in the GOI networks. Myosin 5b immunofluorescence in colonic mucosa was significantly reduced in those with MYO5B susceptibility SNVs compared with control subjects. Seven genes (ESRRA, HLA-DQ1, RETSAT, PABPC1, PARP4, CCDC102A, and SUSD2) were central participants in the non-GOI networks.

Our results support the polygenic nature of VEO-IBD, in which key participants, like MYO5B, were identified through network analytics. Rare variant load within susceptibility genes may be relevant not only for the genetic origins of inflammatory bowel disease, but also for the age of disease onset. Our findings could guide future work in precision medicine.

The development of diseases with a possible autoimmune pathogenesis is common in adults with inflammatory bowel disease (IBD). In early onset IBD, it may differ but the evidence is sparse. We aimed to investigate the risk and time span from IBD diagnosis to outcomes with different associated disorders with possible autoimmune pathogenesis.

A register-based study included all Danish patients with early onset of IBD (≤18 years) between 1980 and 2021 and 50 matched references without IBD for each case. We examined the risk of type 1 and type 2 diabetes, celiac disease, thyroid disease, rheumatoid arthritis, psoriatic arthritis, and spondyloarthritis in Cox regression models.

In total, 6822 patients with IBD were identified, and 337 728 matched references. The median age at the time of IBD diagnosis or index date for the matched references was 16 years (25-75 percentile: 13-18 years), and the median age at the time of an outcome or at the end of follow-up was 28.1 years (25-75 percentile: 21.5-37.0 years). According to the cumulative incidence plots psoriatic arthritis, and spondyloarthritis was diagnosed approximately 10 years after the IBD onset, and the remaining outcomes later. The adjusted hazard ratio after full follow-up was 4.72 (95% CI, 3.85-5.80) for psoriatic arthritis, 5.21 (95% CI, 4.17-6.50) for spondyloarthritis, 2.77 (95% CI, 1.92-4.00) for celiac disease, 2.15 (95% CI, 1.54-3.01) for rheumatoid arthritis, 1.69 (95% CI, 1.23-2.32) and 1.64 (95% CI, 1.21-2.21) for type 1 and type 2 diabetes, respectively. For thyroid disease, it was 1.16 (95% CI, 0.97-1.40).

The risk estimates were significantly increased for all outcomes at the end of follow-up, except for thyroid disease, but according to the cumulative incidence plots, only psoriatic arthritis and spondyloarthritis occurred earlier in the IBD cohort than in the matched references.

Pediatric-onset inflammatory bowel disease (PIBD) is increasingly recognized in Germany. Patients with PIBD often present with more extensive and active disease. Clinical suspicion of IBD requires early initiation of the diagnostic work-up (e.g., non-invasive fecal marker for inflammation) and referral to a pediatric gastroenterology center. In the presence of very early-onset IBD, as well as further criteria such as family history, relevant comorbidities, and extraintestinal manifestations, genetic testing for monogenic forms of IBD should be considered. The aim of treatment is to normalize quality of life and prevent bowel damage and complications, thereby enabling normal physical, social, and emotional development of the child. The selection of treatment is based on individual risk stratification, which considers disease severity and activity. PIBD patients often receive more intensified therapies, including biologics and small molecules. However, anti-tumor necrosis factor (TNF) antibodies are the only approved biologics for PIBD (above the age of 6 years). Therefore, licensed anti-TNF is a mainstay of PIBD therapy. Regular PIBD and drug monitoring should be performed according to the treat-to-target approach. Patients with PIBD and their families have special health care needs and require an interdisciplinary team of specialized medical doctors, psychologists, social workers, dieticians, and nurses. Close cooperation between the local pediatrician/family doctor and the pediatric gastroenterologist is important to achieve the long-term goals. Psychosocial consequences are important but are often underestimated.

Biological similarities between inflammatory bowel disease (IBD) and familial Mediterranean fever (FMF) have been described in humans and animal models suggesting a possible common genetic basis. FMF is caused by variants in the MEFV gene which encodes pyrin, an immune regulator. This study aimed to investigate the carrier rate of disease-causing MEFV variants in children of different ethnicities diagnosed with very-early-onset IBD (VEO-IBD).

The study included 23 children diagnosed with VEO-IBD who had undergone whole exome sequencing. The exomes were evaluated for MEFV monoallelic and biallelic disease-causing variants and compared to exome sequencing data of 250 probands with suspected monogenic diseases other than IBD.

Of the 23 children diagnosed with VEO-IBD, 12 (52%) were carriers of at least one MEFV disease-causing variant, which was threefold higher than in individuals without IBD. The most frequent variants identified were p.M694V and p.E148Q (42% each). The allelic frequency of MEFV variants was found to be higher across the VEO-IBD group in 13 of 14 ethnicities compared to the control group.

The study suggests that disease-causing variants in the MEFV gene should be sought in cases of VEO-IBD. However, the clinical importance of this finding is yet to be defined.

There are biological similarities between inflammatory bowel disease and familial Mediterranean fever, suggesting a possible genetic relationship. Children less than 6 years old clinically diagnosed with inflammatory bowel disease have a threefold higher rate of disease-causing variants in the MEFV gene than controls. Monogenic testing in children with very-early-onset inflammatory bowel disease should include a search for MEFV variants.

Very early-onset inflammatory bowel disease (VEO-IBD) is a distinct subtype of inflammatory bowel disease (IBD) characterized by onset before the age of 6 years, and patients often exhibit more severe clinical features. Interleukin 10 receptor alpha (IL10RA) is a hotspot mutation in the Chinese population and is associated with a poor prognosis closely linked to the onset of IBD. However, limited knowledge exists regarding how the IL10RA mutation influences the host microbiota and its role in disease development. We employed 16S rRNA sequencing to conduct a comprehensive assessment of microbial changes in different types of IBD, employed database to thoroughly examine the influence of Bifidobacterium in IBD and to demonstrate a potential positive effect exerted by Bifidobacterium breve M16V (M16V) through a mouse model. The study demonstrated a significant reduction in the abundance and diversity of the gut microbiota among children with IL10RA mutations compared to those with late-onset pediatric IBD and nonmutated VEO-IBD. Furthermore, the analysis identified genera capable of distinguishing between various types of IBD, with the genus Bifidobacterium emerging as a potential standalone diagnostic indicator and Bifidobacterium may also be involved in related pathways that influence the progression of IBD, such as the biosynthesis of amino acids and inflammation-related pathways. This study corroborated the efficacy of Bifidobacterium in alleviating intestinal inflammation. The impact of IL10RA mutations on VEO-IBD may be mediated by alterations in microbes. M16V demonstrates efficacy in alleviating colitis and holds promise as a novel microbial therapy.

Inflammatory bowel diseases are complex chronic disorders with a relapsing-remitting course that affect the gut due to dysregulated immune response. The incidence of these disorders is increasing globally along with an increase in the incidence in pediatric population. Very early onset inflammatory bowel diseases are seen in children with age less than 6 years, where monogenic causes predominate. With the advent of next-generation sequencing methods, these disorders are being diagnosed more. Interleukin-10 receptor mutation-associated inflammatory bowel diseases is one such monogenic disorder where immunosuppression shows poor response.

We report the case of an 8-month-old child of Indian origin who presented with severe enterocolitis and rectovaginal fistulas. She was evaluated on lines of a very early onset inflammatory bowel disease. She was found to have a mutation in the interleukin-10 receptor causing severe enterocolitis. She underwent a diversion colostomy. She was admitted at 25 months of age for the hematopoietic-stem-cell-transplant (HSCT). The conditioning regimen used consisted of busulfan, fludarabine, and anti-thymocyte-globulin (ATG). The child received a 10/10 human leukocyte antigen (HLA) matched from a matched-unrelated adult female donor with bone marrow stem cell product at a dose of 5.6 million CD34+ cells per kg.

She was treated successfully by a matched unrelated donor HSCT. At present, she is 2 years and 4 months posttransplant and is cured.

Early recognition and prompt genetic testing can help in diagnosing and establishing the cause of a very early onset inflammatory bowel disease. Very early onset inflammatory bowel disease caused due to interleukin-10 receptor mutations can be cured by HSCT.

Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS) in children with inflammatory bowel disease (IBD) has been reported only anecdotally. This study aimed at describing the clinical features and outcomes of children diagnosed with both IBD and HLH/MAS. Data on IBD and HLH/MAS characteristics, biochemical, microbiological and genetic assessments, treatments, and outcomes were collected from the Italian Pediatric IBD Registry and presented using descriptive statistics. Out of 4643 patients with IBD, 18 (0.4%) were diagnosed with HLH/MAS, including 12 with ulcerative colitis and 6 with Crohn disease. Among the 18 patients, 7 (39%) had early-onset IBD, but the median age at HLH/MAS diagnosis was 14.0 years (IQR 11.9-16.0). Half of the patients had active IBD at HLH/MAS diagnosis, 11 (61%) patients were on thiopurines, and 6 (33%) were on anti-TNF biologics. An infectious trigger was identified in 15 (83%) patients. One (5%) patients was diagnosed with XIAP deficiency. All patients discontinued thiopurines and 5 (83.3%) discontinued anti-TNF biologics; 16 (80%) patients received steroids for HLH/MAS. Three (17%) patients had a relapse of HLH/MAS. No patient developed lymphoma or died during a median follow-up of 2.7 years (IQR 0.8-4.4). Conclusions: HLH/MAS mainly affects children with early-onset IBD but primarily develops during adolescence, following an infection while on immunosuppressant treatment. Although the prognosis is generally favorable, it is crucial to investigate an underlying immune deficiency.

The rapid emergence of inflammatory bowel disease (IBD) in Asia in the last two decades is anticipated to pose significant challenges to the healthcare systems of developing countries including India. Several epidemiological factors in the Asia Pacific region have been explored as risk factors for the development of IBD. In this narrative review, we discuss the evolution of adult-onset and paediatric IBD in South Asia and India, in relation to the current global epidemiology, over the last decade. The focus lies on the changing epidemiological landscape of IBD in Asia which signals a paradigm shift in the disease trajectory of a chronic, relapsing, complex disease. We enumerate the disease burden of IBD in India and Asia, analyse the risk factors for its recent rise in incidence and briefly discuss the unique entity of very early-onset IBD. We also list the locoregional challenges in diagnosis and management along with suggestions to overcome them. We highlight the lacunae in data which warrants further research. The anticipated infrastructural challenges and disease evolution are likely to be similar in most newly industrialized countries across South Asia. A combined effort led by IBD experts in the region to understand the true disease burden is important. A strong collaborative network on research and formulation of preventive strategies relevant to the region will help reduce the burden in the future.

A wide variety of diseases mimic inflammatory bowel disease (IBD). This study aimed to reduce the misdiagnosis among children with colonic ulcers.

Eighty-six pediatric patients with colonic ulcers detected by colonoscopy were enrolled in the retrospective study. Children were divided into different groups according to the final diagnosis. The clinical characteristics, laboratory examinations, endoscopic findings, and histopathological results were compared.

IBD (n = 37) was just responsible for 43% of patients with colonic ulceration. Other diagnosis included autoimmune diseases (n = 9), infectious enteritis (n = 13), gastrointestinal allergy (n = 8), and other diseases (n = 19). Comparing IBD and non-IBD groups, children with IBD had a higher frequency of symptoms like weight loss/failure to thrive (P < 0.001), perianal lesions (P = 0.001), and oral ulcers (P = 0.022), and higher expression levels of platelet (P = 0.006), neutrophil-to-lymphocyte ratio (NLR) (P = 0.001), erythrocyte sedimentation rate (P < 0.001), C-reactive protein (P < 0.001), Immunoglobulin G (P = 0.012), Interleukin-1β (P = 0.003), Interleukin-6 (P = 0.024) and TNF-α (P = 0.026), and a wider ulcer distribution in the lower gastrointestinal tract (LGIT) (P < 0.001). Expression levels of hemoglobin (P < 0.001) and albumin (P = 0.001) were lower in IBD patients. Multivariate analysis showed hemoglobin, NLR, Score of ulceration in LGIT, and pseudopolyps contributing to the diagnosis of pediatric IBD with colonic ulcers.

We displayed potential indicators to help diagnose pediatric IBD differentiating from other disorders with colonic ulcers more prudently.

The incidence of inflammatory bowel disease [IBD] is rising most rapidly among children and adolescents. Paediatric-onset IBD is associated with a more extensive and severe disease course compared to adult-onset IBD. At a young age, screening for underlying genetic and immunological disorders is important and may impact treatment management. Early and effective treatment is crucial to reach disease remission and prevent complications of ongoing active disease. In children with Crohn's disease, exclusive enteral nutrition is an effective induction therapy. Other promising dietary therapies, such as the Crohn's disease exclusion diet, are emerging. Within paediatric IBD, anti-tumour necrosis factor therapy is the only approved biological thus far and additional treatment options are crucially needed. Other biological therapies, such as vedolizumab and ustekinumab, are currently prescribed off-label in this population. A specific challenge in paediatric IBD is the unacceptable and major delay in approval of drugs for children with IBD. A guided transfer period of paediatric patients to adult care is associated with improved disease outcomes and is required. Major knowledge gaps and challenges within paediatric IBD include the aetiology, diagnostics, and monitoring of disease, tailoring of treatment, and both understanding and coping with the physical and psychological consequences of living with IBD. Challenges and research gaps in paediatrics should be addressed without any delay in comparison with the adult field, in order to ensure a high quality of care for all patients with IBD, irrespective of the age of onset.

Neonatal diagnosis of inflammatory bowel disease (IBD) proves challenging due to its non-specific symptoms. A term-born neonate showing states of inflammation and aphthae was treated for sepsis and candidiasis before being diagnosed with interleukin-10 receptor deficiency and consecutive IBD. The patient was finally successfully treated by stem cell transplantation. The case illustrates the difficulties of the diagnostic course in IBD as it may mimic other diseases and emphasizes the importance of considering rare differential diagnoses early in the diagnostic process.

This study investigated the effects of solid-state fermentation with Clostridium butyricum on the microstructure of wheat bran, the release of dietary fiber and phenolic compounds, and antioxidant capacity. Compared with unfermented wheat bran, insoluble dietary fiber and phytic acid content decreased, whereas soluble dietary fiber and water-extractable arabinoxylan content increased in C. butyricum culture. Because of the increased release of phenolic compounds, such as ferulic acid and apigenin, and organic acids, such as isobutyric acid, the antioxidant capacity of the culture was considerably improved. Furthermore, the culture of C. butyricum treated with dextran sulfate sodium-induced ulcerative colitis in mice enhanced the expression of intestinal mucus and tight-junction proteins, modulating the gut microbiota structure, increasing the levels of short-chain fatty acids in the intestine, and restoring the essential functions of the gut microbiota. These anti-inflammatory effects stemmed from the combined action of various effective components.

Whether primary sclerosing cholangitis related to inflammatory bowel disease (PSC-IBD) diagnosed before 6 years (ie, VEO-IBD) has a distinct phenotype and disease course is uninvestigated. We aimed to analyze the characteristics and natural history of VEO-PSC-IBD, compared with early and adolescent-onset PSC-IBD.

This is a multicenter, retrospective, case-control study from 15 centers affiliated with the Porto and Interest IBD group of ESPGHAN. Demographic, clinical, laboratory, endoscopic, and imaging data were collected at baseline and every 6 months. Inflammatory bowel disease-related (clinical remission, need for systemic steroids and biologics, and surgery) and PSC-related (biliary and portal hypertensive complications, need for treatment escalation and liver transplantation, cholangiocarcinoma, or death) outcomes were compared between the 2 groups.

Sixty-nine children were included, with a median follow-up of 3.63 years (interquartile range, 1-11): 28 with VEO-PSC-IBD (23 UC [82%], 2 IBD-U [7%] and 3 [11%] CD), and 41 with PSC-IBD (37 UC [90%], 3 IBDU [7.5%] and 1 [2.5%] CD). Most patients with UC presented with pancolitis (92% in VEO-PSC-UC vs 85% in PSC-UC, P = .2). A higher number of patients with VEO-PSC-IBD were diagnosed with PSC/autoimmune hepatitis overlap syndrome than older children (24 [92%] vs 27 [67.5%] PSC-IBD, P = .03), whereas no other differences were found for PSC-related variables. Time to biliary strictures and infective cholangitis was lower in the VEO-PSC-IBD group (P = .01 and P = .04, respectively), while no difference was found for other outcomes. No cases of cholangiocarcinoma were reported.

Primary sclerosing cholangitis related to inflammatory bowel disease has similar baseline characteristics whether diagnosed as VEO-IBD or thereafter. A milder disease course in terms of biliary complications characterizes VEO-PSC-IBD.

The patient is a 12-year-old male who has experienced recurrent perianal abscesses for over 10 years, along with recurrent oral ulcers and deformities in the joints of hands and feet. Gastrointestinal endoscopy and capsule endoscopy revealed multiple ulcers in the digestive tract. Combined with his histopathological examinations, the patient was diagnosed with Crohn's disease. Whole exome sequencing and peripheral blood karyotype analysis indicated a karyotype of 47,XY,+8. The patient was treated with a "step-up" strategy. His clinical symptoms were under control, with significant improvement observed during endoscopic examination. This case suggests that early-onset inflammatory bowel disease may have genetic susceptibility, and when accompanied by other multi-system involvement, the possibility of chromosomal abnormalities, such as trisomy 8, should be considered and given due attention.

Very early onset inflammatory bowel disease (VEOIBD) is defined as disease onset in patients younger than 6 years. Challenges in treatment of VEOIBD include lack of approved therapies and increased incidence of monogenic immunodeficiencies. We report on patterns of anti-TNF use, efficacy, and safety in a large cohort of patients with VEOIBD.

Very early onset inflammatory bowel disease patients receiving care at a single center were prospectively enrolled in a data registry and biorepository starting in 2012. Whole exome sequencing was available to all patients. Clinical data including IBD medication use and response were extracted from the medical record. We examined antitumor necrosis factor (anti-TNF) cumulative exposure and time to failure and evaluated the effect of covariates on anti-TNF failure using Cox proportional hazard regression.

In this cohort of 216 VEOIBD patients with median 5.8-year follow-up, 116 (53.7%) were TNF-exposed. Sixty-two TNF-exposed patients (53.4%) received their first dose at younger than 6 years. Cumulative exposure to anti-TNF was 23.6% at 1 year, 38.4% at 3 years, and 43.4% at 5 years after diagnosis. Cumulative exposure was greater in patients with Crohn's disease (P = .0004) and in those diagnosed in 2012 or later (P < .0001). Tumor necrosis factor failure occurred in 50.9% of those exposed. Features predictive of anti-TNF failure included ulcerative colitis/IBD-unclassified (hazard ratio, 1.94; P = .03), stricturing (hazard ratio, 2.20; P = .04), and younger age at diagnosis (hazard ratio, 1.25; P = .01). Adverse events occurred in 22.6% of infliximab-exposed and 14.3% of adalimumab-exposed.

Efficacy and safety of anti-TNFs in VEOIBD is comparable to what has previously been reported in older patients.

Congenital diarrhoeas and enteropathies (CODE) are a heterogeneous group of disorders. Many affected infants present with catastrophic dehydration in the first few days of life, although the clinical phenotype is variable. Advances in the understanding of underlying pathomechanisms and genetic testing, as well as improved management, in particular intravenous nutrition support, have allowed affected patients to survive well beyond childhood. Awareness and understanding of these rare diseases are hence needed, both amongst paediatricians and adult physicians. In this review, we discuss the different groups of disorders based on a review of the current literature and provide a diagnostic and therapeutic approach. Many of the subtypes of CODE result in the need for prolonged or indefinite parenteral nutrition. Further research is needed to identify new CODE to improve the recognition and management of these children, which can assist in developing new targeted therapies and potentially a long-term cure.

Very early onset inflammatory bowel disease (VEO-IBD) is a clinical term referring to IBD-like symptomatology arising in children younger than 6 years. VEO-IBD may be due to polygenic etiology in "pure" IBD (Crohn disease-CD and ulcerative colitis-UC), or it may be caused by primary immunodeficiency underlined by monogenic disease. Primary immunodeficiency monogenic diseases have a Mendelian inheritance and affect the immune system with multiorgan morbidity and possible effects on the gastrointestinal system. Primary Immunodeficiency monogenic diseases differ from "pure" IBD as the latter primarily affect the gastrointestinal tract with mitigated extraintestinal symptomatology. Since their first description, primary immunodeficiency monogenic diseases, although rare, have been the subject of increasing interest due to their dramatic phenotype, difficulty in reaching a timely diagnosis, and specific therapeutic approach. In this paper, we present a brief review of primary immunodeficiency monogenic diseases, focusing on to their clinicopathologic features as well as delving, in greater detail, into monogenic diseases caused by IFIH1 mutations. The clinicopathologic features of 4 patients with IFIH1, a gene involved in interferon pathway deficiency, will be described using a histologic pattern of damage approach confirming the need to avoid the histologic diagnosis of VEO-IBD in children younger than 6 years.

This study described disease characteristics and long-term outcomes in patients diagnosed with very early onset inflammatory bowel disease (VEOIBD) (diagnosed before 6 years of age) and infantile-IBD (before 2 years).

Cases from 21 centers worldwide diagnosed with VEOIBD (2008-2018), with minimum 2 years of follow-up, were retrospectively reviewed.

The cohort included 243 patients (52% males, median follow-up of 5.8 [range 2-18] years, including 69 [28%]) with infantile-IBD. IBD subtypes included Crohn's disease (CD), ulcerative colitis (UC), or IBD-unclassified (IBDU) in 30%, 59%, and 11%, respectively. Among patients with CD, 94% had colonic involvement, and among patients with UC/IBDU, 75% had pancolitis. Patients with infantile-IBD presented with higher rates of IBDU, lower hemoglobin and albumin levels, and higher C-reactive protein, and had lower response rates to first-induction therapy and corticosteroids therapy (P < .05 for all). Colectomy and diversion surgeries were performed in 11% and 4%, respectively, with no significant differences between age groups. Corticosteroid-free remission rates were 74% and 78% after 3 and 5 years, respectively, and 86% at end of follow-up. Genetic testing was performed in 96 (40%) patients. Among tested population, 15 (16%) were identified with monogenic disease. This group demonstrated lower response rates to induction therapies, higher rates of surgical intervention, and higher rates of major infections (P < .05 for all).

Patients with VEOIBD, including infantile-IBD, exhibit low rate of complications and surgical interventions at the long term. Patients with monogenic IBD are at risk for more severe disease course.