Very early onset inflammatory bowel disease (IBD) is the fastest-growing incidence of IBD in some patient populations, according to a clinical review published in Inflammatory Bowel Diseases.1 This condition, defined as IBD presenting before 6 years of age, is often represented by the presence of monogenic etiologies.
IBD incidence is rising, particularly in pediatric patients, according to current epidemiologic data. Of the 3 million Americans who have IBD, those, roughly 25% will develop IBD during childhood or adolescence.1 One study found that IBD incidence increased most notably among children 0 to 5 years of age, at 7.2% per year.2
Scott B. Snapper, MD, PhD, chief of the division of gastroenterology, hepatology, and nutrition and the director of the Inflammatory Bowel Disease Center at Boston Children’s Hospital, and colleagues, published an overview of the approach to diagnosis and management of patients with very early onset IBD.1 The goal of this review, the authors noted, was to provide optimized management for these complex cases.
Current Clinical Approaches to Treatment
The current clinical approach to very early onset IBD diagnosis and management is stymied by challenge, particularly when the disease manifests in patients with concurrent underlying primary immune deficiencies (PID) — although, noted Dr Snapper and colleagues, most children with very early onset IBD do not present with an underlying PID.1
As diagnosis is challenging, pediatric gastroenterologists may feel hesitant to diagnose a child with a chronic inflammatory disease; one reason for this is the subsequent medical intervention, which carries a “significant” risk profile.
“Care of a patient with [very early onset] IBD should be a coordinated effort,” the authors wrote, noting that this multidisciplinary team should include, in addition to gastroenterologists, immunologists, geneticists, bone marrow transplant experts, nutritionists, surgeons, and other specialists as required by extraintestinal manifestations.1
Guidelines from the VEO-IDB Consortium suggest that in patients with chronic diarrhea, infections, including Shigella, Salmonella, Yersinia, Escherichia coli, Campylobacter, Cryptosporidium, Giardia, tuberculosis, and HIV, should all be ruled out first.1 For those patients presenting with bloody stools, physicians should rule out intolerance to cow’s milk protein and allergic colitis. Celiac disease should also be considered before diagnosing very early onset IBD, particularly in patients presenting with nonbloody diarrhea, malabsorption, anemia, weight loss, and failure to thrive.1
Dr Snapper and colleagues also suggest that it is “vital” to confirm that common causes of colitis, including infection, have been ruled out. These confirmations can be conducted via stool studies and laboratory tests, including an assessment of serologic markers.
In order to identify any potential underlying immunodeficiencies, PIDs should be considered in patients with very early onset IBD.1 In patients with regular ear infections, severe sinus infections, antibiotic treatment with little effect, pneumonia, and insufficient weight gain, among other symptoms, PIDs should be “strongly considered.”1
After ruling out potential differential diagnoses, a clinical assessment should be undertaken.
The Clinical Exam
“A high index of suspicion is needed to guide the history and physical exam in order to diagnose [very early onset] IBD,” noted the authors, adding that a systemic approach, inclusive of a targeted history, physical examination, blood work, and stool study, should identify which patients “merit further investigation.”1
Physicians should inquire about energy, appetite, tolerance of food, vomiting, and irritability. A review of each patient’s history of frequent or recurrent fevers, opportunistic or refractory infections, rashes, arthritis, arthralgias, and perianal disease is key. Unique physical exam findings associated with very early onset IBD include dysmorphic features, hepatomegaly, splenomegaly, atopic dermatitis, folliculitis, and arthritis, all of which “may increase suspicion for a monogenic etiology.”1 In particular, these symptoms may be suggestive of interleukin (IL)-10 signaling defects.
In infants younger than 12 months, expedited upper endoscopy should be conducted if initial laboratory results and exam findings are concerning.1 Endoscopies in this patient population should be performed by an experienced pediatric gastroenterologist. Multiple biopsies will aid in diagnosis, and it is important that very early onset IBD not be definitively ruled out based only on a lack of chronic features, particularly in the face of high clinical suspicion.
According to the authors, a feature suggestive of underlying monogenic etiology is epithelial cell apoptosis, which has been identified across several monogenic etiologies of epithelial barrier function and IPEX syndrome.1
Small intestine imaging is helpful in determining the extent of intestinal disease, despite the predominance of colonic inflammation associated with this condition. However, the authors noted, this can be complicated in very small children. Procedurally, the use of a wireless capsule endoscopy requires sedation, and magnetic resonance enterography requires a “significant” amount of contrast as well as an experienced radiologist.1 Safety concerns also exist regarding the practice of sedation for these lengthy procedures. Other feasible options for small intestine imaging include a small intestine abdominal ultrasound, a small intestinal contrast ultrasound, a minimized radiation computed tomography scan, or a small bowel follow-through.
All patients with very early onset IBD should undergo consultation with an expert immunologist for the purpose of considering potential underlying immunodeficiency and molecular mechanisms. A basic immune workup should be undertaken, in addition to investigations of IL-2 receptors, IL-18, Forkhead box P3, and X-linked inhibitor of apoptosis.1 These studies, note Dr Snapper and colleagues, can direct “further specialized workup.”1
Genetic Sequencing and Functional Testing
If clinical suspicion for an underlying monogenetic etiology is unclear, or if specialized testing is “unrevealing,”1 evaluation via targeted very early onset IBD gene panels or next-generation sequencing can be undertaken. Successful identification of known causal variants typically ranges between 5% to 20%” — although researchers of 1 study3 reported an identification rate of up to 31%.
Currently, Clinical Laboratory Improvement Amendments–certified genetic panels for very early onset IBD do exist. These panels allow researchers to investigate a large number of genes known to be causative for infantile and very early onset IBD. However, these panels often contain “only a subset” of the known genetic etiologies and can miss critical candidate genes.1
If genetic panels are unrevealing, next-generation sequencing should be conducted immediately — but, the authors caution, any findings must be Clinical Laboratory Improvement Amendments–confirmed, and appropriate patient and parent expectations should be set prior to any genetic testing.1
In the future, though, the study researchers are optimistic about an improve detection rate for causative variants of the disease,1 especially as research continues and more understanding of monogenic etiologies of very early onset IBD is gained.
Functional testing is also an option when physicians have a strong suspicion toward a specific underlying genetic etiology. Results are often returned faster than with genetic sequencing, but targeted functional tests should be further confirmed via targeted genetic sequencing evaluations.
Currently, no randomized controlled studies focused on young patients with very early onset IBD exist. As such, medication choices often reflect data from studies of older children and adults with IBD.
Some investigators4-8 suggest that patients with very early onset IBD may be “more refractory” to standard therapeutic courses, including 5-ASA, immunomodulators, and antitumor necrosis factor antibodies — particularly in infants younger than 1 year.1 No comprehensive studies of vedolizumab, ustekinumab, tofacitinib, tacrolimus, or thalidomide exist in this age group.
Some promising results of antibiotic treatment have been demonstrated,9,10 particularly with metronidazole, amoxicillin, and doxycycline therapy; researchers have also assessed oral gentamycin and/or vancomycin for very early onset IBD.11
With monogenic cause, the identification of the underlying genetic etiology can result in more targeted, and ultimately successfully, therapeutic intervention.
Reports focused on surgical intervention in this patient population are inconclusive. One study reported that there is “less need” for surgical intervention in patients with very early onset IBD compared with patients with older-onset IBD12; another study reported “no significant difference” in surgical interventions in a very early onset IBD cohort.13
A seperate contrasting study identified an increased need for surgical intervention in infants with Crohn-like disease diagnosed prior to 2 years,3 while researchers of a single-center study of patients with monogenic etiologies of IBD indicated that surgical interventions should be performed sooner due to the risk for perforation.14
Another nonsurgical option is hematopoietic stem cell transplantation, which the authors noted may be “curative” for several monogenic causes of very early onset IBD.1 Before undertaking this course of treatment, physicians with experience in transplantation for PID should be consulted, as risks include life-threatening infection, engraftment failure, graft vs host disease, and both acute and long-term toxicity.1 Patients, for example, with IL-10 signaling defects often experience life-threatening very early onset IBD; in these cases, hematopoietic stem cell transplantation can be life-saving. However, a more nuanced approach should be taken in patients with very early onset IBD with chronic granulomatous disease.1
No quality studies assessing nutritional approaches to very early onset IBD treatment currently exist; physicians exploring these avenues must rely on data from studies of patients with older-onset pediatric IBD.1 Currently, several diets, including the Specific Carbohydrate Diet, the Mediterranean diet, and other newer anti-inflammatory diets are being “actively investigated.”1
In this patient population, many patients and families may be fearful of the risks associated with available medications. Although physicians can encourage families to discuss the potential role that alternative therapies can play, they must, the authors caution, “ascertain whether alternative or complimentary agents [will] interact with prescribed therapy or cause harm.”1
Finally, the efficacy of fecal microbiota transplant is unclear, although its application is being actively studied.15 There is no current evidence of “consistent benefit” in very early onset IBD,16 and long-term effects are unknown.
Prior to initiating any therapeutic approach, physicians should be aware of the unique health supervision considerations necessary to this patient population. Before beginning immunomodulators or biologic therapies, a complete vaccination schedule should be completed if time permits.1 Moreover, annual influenza and hepatitis B vaccination are
“imperative.”1 Patients should be counseled on appropriate vitamin D and calcium intake to ensure bone health; dual-energy x-ray absorptiometry scans can be performed starting at 3 years to monitor bone density. Finally, skin protection in the form of SPF 50 sunblock should be utilized, and children should be assessed yearly by an ophthalmologist for “possible ocular manifestations” of very early onset IBD.1
Ongoing Research and Future Considerations
“Very early onset IBD presents unique challenges in comparison with later onset IBD, such as increased risk [for] a monogenic disorder, anticipation of a long disease time course, and lack of clinical and scientific research in this young age group,” the study authors wrote. “Very early onset IBD is increasing in frequency, paralleled by an increasing awareness of the need to better understand these diseases and their management.”1
Presently, there are little data to guide the optimal management of very early onset IBD.1 However, several promising knowledge developments are currently underway. Clinical understanding of the genetics and immunologic status of these patients, as well as a deeper understanding of next-generation sequencing, is increasing, leading to further clarification of potential alternate and targeted therapies.1
“With a better understanding of the underlying genetics and pathophysiology of disease in patients with [very early onset] IBD, one strives to target the underlying defect directly in a personalized fashion,” Dr Snapper and colleagues concluded.1
Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.
1. Ouahed J, Spencer E, Kotlarz D, et al. Very early onset inflammatory bowel disease: A clinical approach with a focus on the role of genetics and underlying immune deficiencies [published online December 3, 2019]. Inflamm Bowel Dis. doi: 10.1093/ibd/izz259
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