This study utilized the Swedish nationwide health registry (2002-2017; n = 5767 with IBD) and controls from the general population (n= 58,418). One reason for this study is the increased frequency and changing patterns of immunosuppressive medications that are being used in pediatric IBD. Key findings:
672 serious infections (38.6/1000 person-years) occurred among the children with IBD compared with 778 serious infections in the control group (4.0/1000 person years; adjusted HR 9.46 ). HRs were increased for children with ulcerative colitis 8.48, Crohn’s disease 9.30, and IBD unclassified 12.1
Particularly high HRs were also seen in the first year of diagnosis with HR of 12.1 and n children with IBD undergoing surgery, HR 17.1. This 17-fold risk translates to an average of 6 per 100 children having a serious infection among those with operations.
340 of the 672 serious infections were gastrointestinal, including 34 due to Clostridium difficile
20 opportunistic infections were identified during 19,000 person-years
Potential risk factors for infection, besides medications, include malnutrition, chronic inflammation, impaired response to vaccination, and dysregulation of immune responses. A limitation of this study is ascertainment bias as families/patients with underlying disease may be more likely to seek medical attention for otherwise self-limited infections.
My take: This report confirms and quantitates daily clinical practice: children with IBD are more frequently hospitalized due to infections.
Best Practice Advice 1: Precancerous colorectal lesions in inflammatory bowel disease should be described as either polypoid (≥2.5 mm tall), nonpolypoid (<2.5 mm), or invisible (detected on nontargeted biopsy), using a modified Paris Classification. The older terms dysplasia-associated lesion or mass, adenoma-like mass, and flat dysplasia (when referring to dysplasia detected in nontargeted biopsies) should be abandoned.
Best Practice Advice 3: Initial colonoscopy screening for dysplasia should be performed at 8–10 years after disease diagnosis in all people with colonic inflammatory bowel disease, and immediately on diagnosis of primary sclerosing cholangitis. Staging biopsies should be taken from multiple colonic segments to assess histologic disease activity and extent and to help guide future surveillance intervals.
Best Practice Advice 8: Extensive nontargeted biopsies (roughly 4 adequately spaced biopsies every 10 cm) should be taken from flat colorectal mucosa in areas previously affected by colitis when white light endoscopy is used without dye spray chromoendoscopy or virtual chromoendoscopy. Additional biopsies should be taken from areas of prior dysplasia or poor mucosal visibility. Nontargeted biopsies are not routinely required if dye spray chromoendoscopy or virtual chromoendoscopy is performed using a high-defintion endoscope, but should be considered if there is a history of dysplasia or primary sclerosing cholangitis.
Methods: Fecal samples were obtained from 99 twins (belonging to 51 twin pairs), 495 healthy age-, sex-, and body mass index–matched controls, and 99 unrelated patients with IBD. Whole-genome metagenomic shotgun sequencing was performed.
No significant differences were observed in the relative abundance of species and pathways between healthy cotwins and their IBD-twins.
Compared with healthy controls, 13, 19, and 18 species, and 78, 105, and 153 pathways were found to be differentially abundant in healthy cotwins, IBD-twins, and unrelated patients with IBD, respectively.
Discussion: “The gut microbiome composition of individuals at increased risk of developing IBD (i.e. healthy cotwins from IBD-discordant twin pairs) displays IBD-like signatures on a species and pathway level…The overlap in gut microbial features between healthy cotwins at increased risk of developing IBD and related and unrelated IBD patients suggests that these IBD-like microbiome signatures might precede the onset of IBD. This potentially opens new avenues for diagnosis and therapy in individuals with pre-symptomatic IBD.”
My take This study indicates that the microbiome changes in persons with IBD are also found in their healthy twins. In many ways, this is similar to the frequent finding of abnormal serology in Crohn’s disease; ASCA antibodies were considered much less helpful as a diagnostic test after the realization that ~20% of healthy first degree relatives also have detectable levels.
Figure 4 (pg 1979) shows the relative abundance of a selection of IBD-associated species and highlights similarities between the healthy cotwins and IBD twins.
Two recent articles delve into the topic of Pediatric to Adult Care Transition.
M Katz et al. J Pediatr (Epub head of publication) 2021. African American Pediatric Liver Transplant Recipients Have an Increased Risk of Death After Transferring to Adult Healthcare (Thanks to a friend who shared this reference & congratulations to my Emory colleagues and senior author Nitika Gupta on this publication)
This retrospective study examined 101 patients between 1990 and 2015. 64 had long-term followup data available.
African Americans had higher rates of death after transfer than patients of other races (44% mor- tality vs 16%, representing 67% of all cases of death; P = .032)
18 of the 64 (28%) died. Of those 18 deaths, 4 (22%) occurred within the first 2 years after transfer, and 10 (55%) within 5 years of transfer.
There was a high rate of medication nonadherence in patients who died. ” Death in our cohort was typically caused by chronic rejection and graft failure, with a high frequency of severe infections or bleeding events ultimately causing a patient to die.”
The average age of transplant in deceased patients was 15. Transplantation in teenage years could be a risk factor as well.
The authors note that “the years directly after transfer of care from pediatrics to adult medicine are high risk for death and poor patient outcomes. Racial disparities seen in pediatric medicine also hold true after transfer to adulthood.”
This retrospective study with 104 subjects defined suboptimal transition as “either a return to pediatric care or requiring care escalation within 1 year of transfer.
37 (36%) were determined to have a suboptimal transition.
Risk factors: mental health diagnosis (OR 4.15), medication non-adherence (OR 5.15), public insurance (OR 6.60), and higher Physician Global Assessment score at time of transition (OR 6.64).
Comments: This is a small study and included only 26 patients receiving public insurance, which the authors considered as a proxy measure of socioeconomic status.
My take: These studies show the difficulties and potential deadly outcomes that face these young adults during transition from pediatrics to adult care. In many cases, medication non-adherence is a key factor and can be affected by access to care, insurance coverage, and mental health. Most young adults with serious medical problems probably would benefit from keeping their parents actively involved in their care.
Using the Inform Diagnostics database, which is a national electronic repository of histopathologic records from patients distributed throughout the entire United States, the authors performed a case-control study among 302,061 patients undergoing bidirectional endoscopy on the same day.
The database contained 3860 ulcerative colitis (UC) patients, 3330 Crohn’s disease (CD) patients, 1476 patients with indeterminate colitis with respect to UC or CD, and 5296 MC (microscopic colitis) patients.
EoE was less common in the overall IBD, CD, and MC case populations than the control population. Adjusted odds ratios (compared to control) :
EoE and IBD aOR 0.64
EoE and Crohn’s aOR 0.41
EoE and UC aOR 0.97
EoE and Indeterminate Colitis aOR 0.29
EoE and MC aOR 0.68
My take: (partly from authors) “Unexpectedly, the present analysis revealed statistically significant inverse relationships between EoE and CD or MC, but not UC.” Because endoscopy is often undertaken in those with a suspicion of IBD, EoE can be identified in the IBD population surreptiously; however, its frequency is likely less than in the general population.
In this retrospective observational longitudinal cohort study with 3007 patients with IBD from the ImproveCareNow Network, the authors found a high rate of continued linear growth after expected growth plate closure (15 years in females, 17 years in males).
80% manifested continued growth beyond the time of expected growth plate closure, more commonly in CD (81%) than UC (75%; P = 0.0002)
Median height gain was greater in males with CD (1.6 cm) than in males with UC (1.3 cm; P = 0.0004), and in females with CD (1.8 cm) than in females with UC (1.5 cm; P = 0.025)
My take: This study provides additional information about delayed skeletal maturation in the pediatric population with inflammatory bowel disease. Interestingly, the rate of continued growth with ulcerative colitis was nearly as high as with Crohn’s disease.
A recent review (JT Chang. NEJM 2020; 383: 2652-2664. Pathophysiology of Inflammatory Bowel Diseases) provides an in-depth description of the pathophysiology of inflammatory bowel disease (IBD). Digesting the article is akin to putting together a 1000 piece puzzle due to the complex interactions.
Some of the Key Points:
Based on genomewide association studies, there are “more than 240 risk variants that affect intracellular pathways recognizing microbial products (eg. NOD2); the autophagy pathway, which facilitates recycling intracellular organelles and removal of intracellular microorganisms (eg. ATG16L1); genes regulating epithelial barrier function (eg. ECM1); and pathways regulating innate and adaptive immunity (eg. IL23R and IL10).”
In this article, Figure 1 and 2 describe the intestinal mucosal immune system in health and disease. At baseline, this system promotes an antiinflammatory state “by virtue of active down-regulation of immune responses. For example, unlike macrophages in other parts of the body, intestinal macrophages do not produce inflammatory cytokines” after exposure to bacteria.
Dysbiosis is present with IBD; however, studies have been “unable to infer causal relationships.”
Germ-free mice, when given fecal material from patients with IBD have increased susceptibility to colitis as compared to those who received fecal material from a healthy person.
Thus, this leads to potential for mitigating intestinal inflammation by modulation of the microbiome.
However, the authors note that humans are colonized by trillions of viral, fungal, bacterial, and eukaryotic microbes.
Other components of IBD pathophysiology: reduced mucus layer, increased microbial adherence, dysregulation of tight junctions/increased permeability, dysfunctional Paneth cells, TNF, IL23, IL12, IL6, IL 17A, IL17F, IL22, Interferon-gamma, integrins, JAK inhibitors, T-cells
My take: This article is a useful reference detailing the complexity of IBD pathophysiology and tries to summarize a whole textbook of information into 12 pages.
Methods: The authors linked prospectively collected data from national health care registries maintained for all adults in England on hospital attendances, imaging and endoscopic evaluations, surgical procedures, cancer, and deaths.
Over 10 years, we identified 284,560 incident cases of IBD nationwide; of these, 2588 patients developed PSC. This study excluded patients <18 years of age.
Development of PSC was associated with increased risk of death and CRC (hazard ratios [HRs], 3.20 and 2.43, respectively; P < .001) and a lower median age at CRC diagnosis (59 y vs 69 y without PSC; P < .001)
Compared to patients with IBD alone, patients with PSC-IBD had a 4-fold higher risk of CRC if they received a diagnosis of IBD at an age younger than 40 years
Development of PSC also increased risks of cholangiocarcinoma (HR, 28.46), hepatocellular carcinoma (HR, 21.00), pancreatic cancer (HR, 5.26), and gallbladder cancer (HR, 9.19) ( P < .001 for all)
The greatest difference in mortality between the PSC-IBD alone group vs the IBD alone group was for patients younger than 40 years
Patients with PSC-UC had >40% risk of colonic resection compared to patients with IBD alone (aHR 1.65)
My take: This study shows the impact the added diagnosis of PSC has for patients with IBD. One of the limitations in assessing outcomes is determining whether someone with IBD has PSC as there are a lot of patients with IBD who have asymptomatic changes in their biliary tree.