Very early-onset inflammatory bowel disease: A review

Rubaiyat Alam; Kaniz Fathema; Md. Nazmul Hassan; Mizu Ahmed; Md. Shariful Hasan

doi:10.4103/pnjb.pnjb_10_21

REVIEW ARTICLE

Year : 2021 | Volume : 6 | Issue : 1 | Page : 43-47

Very early-onset inflammatory bowel disease: A review

Rubaiyat Alam¹, Kaniz Fathema¹, Md. Nazmul Hassan¹, Mizu Ahmed², Md. Shariful Hasan¹
¹ Department of Pediatric Gastroenterology and Nutrition, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh
² Department of Dermatology, Shahid Syed Nazrul Islam Medical College Hospital, Kishoregonj, Bangladesh

Date of Submission	12-Sep-2021
Date of Acceptance	23-Sep-2021
Date of Web Publication	29-Dec-2021

Correspondence Address:
Dr. Kaniz Fathema
Department of Paediatric Gastroenterology & Nutrition, Bangabandhu Sheikh Mujib Medical University, Dhaka
Bangladesh

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/pnjb.pnjb_10_21

Abstract

Very early-onset inflammatory bowel disease (VEO-IBD) is a genetically and phenotypically unique entity from adult-onset or older pediatric IBD and a growing subset of IBD. In most cases, a child with VEO-IBD presents with similar manifestations like an older patient with IBD, but some may present with a highly aggressive course and some cases may present with features of immunodeficiency. It differs from adult-onset IBD in many aspects such as disease behavior, location of the disease, and disease type and mostly occurs due to genetic causes. Next-generation genome sequencing could be an important tool for diagnosing genetic defects, especially in children with VEO-IBD disease. Most of the children with VEO-IBD do not comply with conventional therapy, and they ultimately need early immunosuppressive therapy that may grossly affect the child growth and development and also may possess long-term risks of cancer and opportunistic infections.

Keywords: Inflammatory bowel disease, monogenic immunodeficiency, next-generation sequencing, very early-onset inflammatory bowel disease, whole-genome sequencing

How to cite this article:
Alam R, Fathema K, Hassan MN, Ahmed M, Hasan MS. Very early-onset inflammatory bowel disease: A review. Paediatr Nephrol J Bangladesh 2021;6:43-7

How to cite this URL:
Alam R, Fathema K, Hassan MN, Ahmed M, Hasan MS. Very early-onset inflammatory bowel disease: A review. Paediatr Nephrol J Bangladesh [serial online] 2021 [cited 2023 Oct 4];6:43-7. Available from: http://www.pnjb-online.org/text.asp?2021/6/1/43/334112

Introduction

Inflammatory bowel diseases (IBDs), comprising Crohn’s disease and ulcerative colitis traditionally, are chronic inflammatory conditions that are naturally a relapsing and remitting disease of the gastrointestinal tract that affects millions of people worldwide. In most cases, IBDs usually present in early adulthood, and in about 20%–25% of cases, these disorders manifest in childhood.^[1] IBD that becomes symptomatic or is diagnosed before six years of age is termed “very early-onset IBD” (VEO-IBD) and infantile-onset IBD when diagnosed at age below two years. The development of Crohn’s disease and ulcerative colitis is believed to be caused by dysregulated immune responses to environmental changes and microbial dysbiosis in genetically susceptible individuals.^[2] Compared with children whose IBD develops later in life, those with VEO-IBD, and particularly those with onset before two years of age, are more likely to have single gene defects that alter the immune function or disturb epithelial barrier function and often have a more severe disease course.^[3],[4] The development of VEO-IBD is very rare, approximately 6%–15% of pediatric IBD and 1%–2% of total IBD cases.^[1] In this review article, we will shortly overview the pathogenesis, presentation, and management aspects of VEO-IBD.

According to Paris classification, pediatric-onset IBD is divided into^[1]:

A1a (diagnosed before 10 years of age)
- Early-onset IBD: diagnosed before 10 years of age
- Very early-onset IBD (VEO-IBD): those diagnosed before six years of age
- Infantile IBD: diagnosed before two years
- Neonatal IBD: diagnosed before 28 days
A1b (diagnosed between 10 and 17 years of age)

Pathogenesis

There are several genetic variants that have a large effect on gene function typically in infancy and also several spectrums of rare genetic disorders that can produce IBD-like intestinal inflammation.^[5],[6],[7] Over the ages, monogenic IBD disorder has been described in more than 60 ways that affect mucosal homeostasis in diverse ways, including:

Epithelial barrier and response defects
Hyper- and autoinflammatory disorders
Complex defects in T- and B-cell function
Interleukin-10 (IL-10) signaling and regulatory T cells

The disorders that include defects in IL-10 signaling are atypical severe combined immunodeficiency, common variable immunodeficiency, chronic granulomatous disease (CGD), and other neutrophil defects, Wiskott-Aldrich syndrome, agammaglobulinemia, hyper-immunoglobulin M syndrome, familial hemophagocytic lymphohistiocytosis, and immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), or other autoimmune enteropathy.^[5]

Some of these disorders with gene defects affect hematopoietic cells predominantly (e.g., IL-10R, IL-10, X-linked inhibitor of apoptosis protein, and Forkhead box protein P3 [FOXP3]) and respond to stem cell transplantation.

T-Cell Immune Tolerance

^[8]

Different STAT proteins control different regulatory genes. On receiving IFNγ, naïve CD4 T cells get polarized to Th1. However, on receiving IL-6, they get converted to Th17, and on receiving the only IL-2, they get converted to Treg. In Treg cells, STAT5 initiates the transcription of FOXP3, which regulates the transcription of CTLA4 and LRBA. CTLA 4 (CD80/86) helps in regulating T-cell responses. LRBA helps CTLA4 recycling and protecting CTLA4 lysosomal degradation.

Epithelial Barrier Dysfunction

^[8]:

Signaling through GUCY2C activates PTEN that inhibits the AKT and thereby inhibits tight junction expression. It also promotes proliferation and mitochondrial biogenesis and helps in the continuation of the cell cycle.
Toll-like receptors, on receiving the signals, activate NEMO, through reactive oxygen species (ROS)-mediated disulfide bond formation. NEMO along with IKK-alpha IKK-beta activates inhibitory kappa B (IκB) and initiates its ubiquitination to release NFκB.
TTC7A helps in protein trafficking. It takes several proteins (like PI4K) to their destination. Here, it is taking PI4K near the cell membrane so that PI4K can activate PI and helps in the accumulation of PI-4P, which is further involved in maintaining cell polarity and cell survival.
ADAM-17 cleaves the membrane-bound EGFR/TGFR ligands. This helps in receptor–ligand binding and initiation of signaling of the EGFR/TGFR-mediated pathway.
COL7A1 helps hemidesmosomes to keep the cell bound to the basement membrane.
The integrin and integrin–ligand binding protein is increased by Kindler-1.

Neutrophil Dysfunction

^[8]

Subunits of NADPH oxidase are involved in secreting ROS.
G6PT transports glucose from the cytoplasm to the endoplasmic reticulum. G6PTase-α phosphorylates glucose to continue the glycolysis.
Integrin on binding its substrate initiates AKT pathway and helps in cell survival.

Differentiation of VEO-IBD from Adult IBD

The presentation of VEO-IBD is quite variable adult-onset, and the course of VEO-IBD has some notable differences. Ulcerative colitis in children, especially in VEO-IBD, is typically pancolonic extent compared with the more limited proctocolitis and left-sided colitis that is frequently seen in adults. Disease location in CD in these young patients is typically colonic-only, in contrast to adults and teenage-onset CD that involves significant small bowel disease.^[8] This does increase the difficulty in differentiating CD from UC, and frequently, it may take years before a classic CD feature is identified in a patient with VEO-IBD. So, the rate of reclassification of a child with UC to CD is higher in VEO-IBD than in teenage-onset IBD although that rate is only 16%.^[4] In addition, a higher percentage of children with VEO-IBD are classified as having IBD-U compared with their older counterparts.^[5] The presentation of VEO-IBD is similar to that of older-onset pediatric IBD with the exception of an increased rate of rectal bleeding in VEO-IBD patients caused by the colonic predominance seen in VEO-IBD.^[4] Defects in IL-10 signaling (due to the loss of function mutations in IL-10, IL-10RA, or IL-10RB) lead to an aggressive form of ileocolitis that includes severe perianal disease and often also is associated with cellulitis or arthritis.^[3]

When Should We Suspect VEO-IBD

^[1],[3]

Young age of onset
Multiple family members are affected
History of consanguinity
Autoimmunity
Failure to thrive
Recurrent infections or unexplained fever
Severe perianal disease
Macrophage activation syndrome and hemophagocytic lymphohistiocytosis
Obstruction and atresia of the intestine
Failure of conventional treatment.

[Table 1] shows the clinical features that raise suspicion for monogenic IBD.^[1],[9]

Table 1: Suggestive features of monogenic inflammatory bowel disease

Click here to view

Diagnosis of VEO-IBD

^[5]

Serological test:
- Complete blood count—anemia, high erythrocyte sedimentation rate, and thrombocytosis
- C-reactive protein—raised
- Albumin—low
Stool routine and microscopy examination and stool C/S—features of colitis (presence of pus cell, red blood cell, macrophage, and negative culture and sensitivity)
Fecal calprotectin: elevated levels indicate gastrointestinal inflammation
Upper gastrointestinal endoscopy with biopsy
Colonoscopy with biopsy.

Microscopy Feature

Eosinophils in the crypts and apoptotic crypt cells are the characteristic pathological features of VEO-IBD in comparison with older pediatric and adult-onset IBD. These features are usually not seen in adult IBD unless the disease is very active but are common in VEO-IBD. The finding of eosinophils can confuse with allergy or eosinophilic gastroenteritis.^[10] But abundant apoptotic cells may resemble graft versus host disease and can be associated with dyskeratosis congenita pathologically.^[11] Small bowel involvement is less common in VEO-IBD, but villous atrophy may be present. But in Crohn’s disease, the involvement of the small bowel is not uncommon, and the pattern is infiltration of mixed inflammatory cells. Villous blunting or atrophy is seen in as many as 20% of cases of the VEO-IBD cohort but is very uncommon in adult IBD cohorts.^[11]

Small bowel imaging: MR enterography or wireless capsule endoscopy
Molecular diagnosis: Targeted or whole-exome sequencing for genetic mutation analysis.

Differential Diagnosis

There is several similar disease condition of IBD in adults and older children, but they are less common for the VEO-IBD population. The second consideration is food protein–induced enterocolitis syndrome (FPIES). Both conditions can present abruptly with bloody diarrhea. Repetitive vomiting, diarrhea, dehydration, and hypovolemic shock may present in infants with classic acute FPIES, whereas a child with the very acute course of VEO-IBD vomiting is unusual.^[12],[13] Chronic FPIES is a rare entity that may present with chronic diarrhea, anemia, and hypoalbuminemia.^[14] These are characteristics for VEO-IBD, and an additional confusion is the finding of tissue eosinophilia in both on biopsy. Chronic crypt changes are not common in FPIES; however, there are limited data on the pathological features of chronic FPIES.^[15]

Evaluation of VEO-IBD

^[16]

For the diagnostic approach of children with VEO-IBD, no single approach is appropriate. For establishing the diagnosis of IBD, clinicians should:

Rule out infection with stool culture, ova, and parasite examination,
Do fecal calprotectin (this can be low in infants with IBD), and finally
Do-endoscopy and colonoscopy.

In every suspected child of VEO-IBD, primary immunodeficiency should be evaluated. Diagnostic evaluations for primary immunodeficiency are:

Evaluation of family history and suggestive clinical features of a primary immunodeficiency: infections, autoimmunity, complications
Review pathology to identify atypical features
Dihydrorhodamine test for CGD
Flow cytometry to assess T/B-cell subsets and maturation.

Consider:

Natural killer cell function
IL-10 suppression assay (identifies only IL-10 receptor defects)
Sequencing:

Currently, whole-exome sequencing offers the greatest sensitivity when paired with copy number variation
Many IBD sequencing panels are now offered and represent a strategy more likely to get insurance approval.

Management Approaches in VEO-IBD

Medication options for children with VEO-IBD are largely restricted to those available to older IBD patients. Although many patients with VEO-IBD may be controlled with mild medications such as mesalamine, a good number of patients have moderate-to-severe disease requiring immunosuppression. Nutritional therapy such as exclusive enteral nutrition is often used in the youngest of VEO-IBD patients given the potential overlap in the presentation of allergic colitis.^[17] Immunosuppressive medications (such as infliximab) are frequently used but having lower efficacy in VEO-IBD patients compared with standard IBD populations.^[18]

Conventional immunosuppressive therapy of IBD in children responds poorly in the case of VEO-IBD. Understanding the underlying pathogenic mechanism and finding genetic defects are crucial for targeted therapy. Several therapeutic modalities including biological agents have a significant effect in treating this disorder. For example, IL-1b antagonist, anakinra, has been effective in CGD-associated colitis by inhibiting inflammasome and augmenting autophagy.^[19] But in the long run treatment, the response may not sustain, and a satisfactory response is found only in a subgroup of CGD colitis.^[20] Abatacept blocks the T-cell co-stimulatory pathway and has good results in children with colitis in LRBA deficiency and CTLA4 haploinsufficiency.^[21] Similarly, an IL-6 receptor blocking antibody, tocilizumab, is responsive in colitis associated with STAT3 gain-of-function mutation,^[22] and sirolimus improves Treg cell function and has been used in IPEX and its phenocopies.^[23] Unresponsive or poorly responsive case to medical therapy may benefit from colectomy and hematopoietic stem cell transplantation (HSCT). HSCT is effective in treating colitis and gastrointestinal fistulas caused by IPEX and IL-10 signaling defects.^[24],[25] But in primary ectodermal defects (NEMO, TTC7a deficiency) associated with IBD, HSCT fails to improve and may even worsen the disease.^[26] Lastly, gene therapy is a future prospect in the management of monogenic IBD.^[27],[28]

One management approach:^[16]

Enteral nutrition
Aminosalicylate derivatives (Azo-based formulations, such as balsalazide, act only in the colon; mesalamine formulations, such as Pentasa and Asacol, act in the terminal ileum and colon)
Antibiotic treatment
Probiotics
Systemic corticosteroids (acutely)
Topical steroids: budesonide (ileal release and rectal suppositories)
6-mercaptopurine and azathioprine (monitor for idiosyncratic reactions, seldom used in children due to risk of malignancy)
Methotrexate (monitoring required, folate needed at higher doses)
Biological agents:
- Tumor necrosis factor inhibitors (contraindicated in CGD)
- Ustekinumab
- Tofacitinib (limited data)
- Vedolizumab
Surgical diversion, colectomy
Alternative options for refractory disease
- Allogenic or autologous stem cell transplants
- IL-1 blockade
- Rituximab
- Cyclosporine
- Tacrolimus.

Conclusion

Diagnosis of a child with VEO-IBD is very challenging and needs a high index of suspicion. Diagnosis as well as treatment of VEO-IBD is very difficult and needs immunosuppressive medications at a very young age. This disease is associated with various genetic disorders, and diagnosis is confirmed based on clinical and genetic information. Although monogenic IBD is very rare, with increased use of genomic sequencing, more cases of VEO-IBD could be identified, and it will also help for assessing prognosis and proper treatment of VEO-IBD patients. More use of genomic sequencing and advances in genetic knowledge will guide the development of novel therapy for these unique disorders.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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