Category Archives: Pediatric Gastroenterology Intestinal Disorder

Infliximab: Reach Higher and Be Stronger

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M Gibson et al. JPGN 2023; 77: 207-213. Safety and Durability of Accelerated Infliximab Dosing Strategies in Pediatric IBD: A Single Center, Retrospective Study

This pediatric retrospective study (n=291, 2010-2020) showed a high response to infliximab in patients with inflammatory bowel disease (n=234 Crohn’s disease (CD), n=53 ulcerative colitis (UC)) over a 10-period. Mean duration of treatment among study participants was 2.9 years. Key findings:

  • 53% (n=135) started with doses of 10 mg/kg and 64% (n=87) of those who started on 5 mg/kg were dose-escalated; thus, approximately 76% of patients in their cohort needed doses of 10 mg/kg.
  • Only 12% of patients discontinued treatment over the observed timeframe.
  • Patients with UC (P ≤ 0.01) and patients with extensive disease (P = 0.01) had lower durability, despite a higher starting dose of IFX (P = 0.03).  Figure 2 indicated that durability in CD was ~93% compared to ~60% for UC with HR of 5.12. The HR for extensive disease (n=77) was 3.74 compared to those with limited disease (n=108). Still, ~75% of those with extensive disease continued on treatment
  • Common adverse events included 18 with skin findings (14 with psoriasis, 3 nonspecific rash, 1 with lupus), 23 with infusion reactions, 7 with AST/ALT >3 times ULN (or >120 IU/L), and 3 with serious infections.

Like the theme song from the 1996 Olympics (Reach, Gloria Estefan) reaching higher (dosing) resulted in being stronger (i.e.. better outcomes).

My take: This study showed really good outcomes associated with “accelerated” infliximab dosing.

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The view before starting a climb at NRocks (Circleville, WV)
Highest point of our climb

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Giving Tacrolimus Another Look for Severe Colitis

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The retrospective study by Zimmerman et al involved 170 pediatric patients (IFX (n = 84) and TAC (n = 86)) with acute severe colitis (ASC) form 2005 to 2017; TAC was generally used prior to 2014 and patients were more likely to be receiving 6MP as a long-term maintenance agent; the mean TAC level was 10.7 ng/mL. The mean dose of infliximab (IFX) initially was 7 mg/kg. Key findings:

  • The rate of colectomy 6 months from rescue therapy was similar whether patients received IFX or TAC (22.6% vs 26.7%, respectively, P = 0.53).
  • The mean decline in Pediatric Ulcerative Colitis Activity Index scores from admission to discharge in those treated with IFX (31.9) or TAC (29.8) was similar (P = 0.63).
  • Similar rates of adverse effects were seen. 4 patients in the TAC group experienced neurologic symptoms.
  • About half of the steroid-refractory ASC patients failing either agent as initial rescue therapy required colectomy, even if they switched to the alternative agent.
  • 17.9% of patients receiving high-dose IFX required colectomy by 6 months compared to 25% in the “typical” IFX dosing group; this was not statistically significant, likely due to limitations of sample size.

In the systematic review/meta-analysis study by Bolia et al., the authors identified 7 studies with 166 children (111 steroid-refractory, 52 steroid-dependent, 3 no steroids). The majority of cases (150/166 [90%]) were naïve to biologics. None of the participants in these studies have been treated recently (only 10 patients since 2014 and none after 2016). The two most recently published studies in 2018 and 2019 had enrollment in 2014-2016 and 2000-2012, respectively. Key findings:

  • An initial response to tacrolimus therapy was seen in 84% 
  • No difference was observed between children with high (>10 ng/mL) or low tacrolimus levels (127/150 [85%] vs 12/16 [75%], P = 0.3).
  • The pooled frequency of 1-year colectomy-free survival in children treated with initial oral tacrolimus was 64% (95% CI: 53%–75%). Twelve (7.2%) patients required cessation of therapy because of side effects.

My take: Both of these studies indicate that tacrolimus could be a useful agent for ASC and may find a role as a bridge therapy for biologic agents with slower onset of action.

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NRocks Climb in Circleville, WV

AAP GI Review Articles: GI Bleeding in the Neonate, Cystic Fibrosis in Neonates, and Intestinal Transplantation in Children

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A couple good review articles (though behind paywall):

PT Reeves, L James-Davis, M Khan. Neoreviews 2023;24(7):e403-e413. Gastrointestinal Bleeding in the Neonate: Updates on Diagnostics, Therapeutics, and Management This reviews covers the most important etiologies of GI bleeding in the neonate. A few interesting points were the potential use of calprotectin as a potential screen for necrotizing enterocolitis; “the median fecal calprotectin levels in infants with NEC were between 210 and 400 mg/g of stool.” The authors also point out that there is “limited evidence for performing endoscopy in infants with GIB…][In one study] Only 3 of 56 infants underwent therepeutic intervention during endoscopy. Five percent (n=3) of these neonates exhibited gastrointestinal perforation in the acute postoperative period after endoscopy.”

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JT Duong, ZM Sellers. Neoreviews (2023) 24 (7): e414–e430. Cystic Fibrosis-Associated Gastrointestinal Disease in Neonates

Associated slides (13 slides) and presentation (~7 minutes ): Cystic Fibrosis-Associated Gastrointestinal Disease in Neonates

The article notes that meconium is typically passed in 24 to 48 hours after gastrograffin enema and recommends abdominal imaging every 8 to 12 hours after enema administration to exclude perforation along with adequate intravenous hydration (“at least 150 mL/kg per day”).

The actual article has many other useful points. For example:

  • CFTR is not expressed in hepatocytes; “however, liver injury may occur patients with CF due to proximity to cholangiocytes (which may be inflamed) and/or through increased intestinal permeability.”
  • Elastase levels are not affected by exogenous pancreatic enzyme supplementation and is expected to display levels within the normal adult range by 2 weeks of age.
  • Sodium deficiency is common and needs to be prevented with sodium supplementation in first 12 months of life (one-eighth teaspoon (= 12.5 mEq) of salt in first 6 months, and one-fourth teaspoon (=25.2 mEq) from 6-12 months)
  • The newest CFTR modulator, elexacaftor/tezacaftor/ivacaftor is approved for children 2 years of age and older
  • There are case reports of in utero exposure to CFTR modulators associated with resolution/prevention of disease (eg. pregnant women starting CFTR-targeted treatment at 32 weeks gestation which resolved meconium ileus).

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K McNelis, ME Rogers, S Kocoshis. Neoreviews. 2023 Jul 1;24(7):e431-e439. Pediatric Intestinal Transplantation Management and Outcomes This is another useful review for pediatricians. Pediatric intestinal transplantation is most commonly (65%) related to short bowel syndrome, 20% due to motility disorders, 9% due to mucosal diseases, 5% due to retransplantation and 1% are due to a variety of causes. The evaluation and management of patients needing intestinal transplantation is succinctly summarized. “Overall, survival of pediatric patients after intestinal transplantation is 72.7% at 1 year and 57.2% at 5 years. The most common causes of death are sepsis/multiorgan system failure and cardiovascular/stroke (Fig 2).” Also, “current statistics about organ transplantation can be publicly accessed by health care team members, patients, and families at srtr.transplant.
hrsa.gov.” This site also includes data on transplantation for kidney, pancreas, heart, lung and liver.

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Briefly Noted: Male Reproductive Safety with IBD Medications

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J Gubatan et al. Clin Gastroenterol Hepatol 2023; 21: 2222-2238. Paternal Medications in Inflammatory Bowel Disease and Male Fertility and Reproductive Outcomes: A Systematic Review and Meta-analysis

After a literature review, the authors included 10 studies reporting semen parameters (268 patients with IBD) and 16 studies reporting adverse pregnancy outcomes (over 25,000 patients with IBD). Key findings:

  • Biologic, thiopurine, or methotrexate use were not associated with decreased sperm count, motility, or abnormal morphology compared with nonexposed patients.
  • Biologic, thiopurine, or methotrexate use among male patients with IBD are not associated with increased odds of adverse pregnancy outcomes
Cap D’Ail Trail near Monaco

Nonspecific Duodenal Histologic Findings Common in Children with Trisomy 21

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E Alexander et al. JPGN 2023; 77: 184-190. The Spectrum of Duodenal Histologic Findings in Patients With Trisomy 21: A Multicenter Study

This retrospective study of patients with trisomy 21 (T21) who underwent EGD between 2000-2020. Key findings:

  • Among 836 patients with T21, 419 (50.1%) of whom had duodenal histologic abnormalities.
  • 290 of 419 had villous atrophy (VA) and of those, 172 of 290 met celiac disease (CD) diagnostic criteria, while 118 of 290 did not meet CD criteria (nonspecific VA).
  • Only one of the 118 with nonspecific VA had markedly abnormal celiac serology (TTG IGA >10 times ULN) but had no IELs on biopsy and did not respond to GFD. Four patients with nonspecific VA were later diagnosed with celiac disease over a median of 2.5 years with conversion to abnormal celiac serology.
  • Among the 129 with duodenitis without villous atrophy, 38 (29%) had increased intraepithelial lymphocytes and two patients were diagnosed with CD many years later (development of VA and positive celiac serology.

The authors offer an algorithm (Figure 2) to assist clinical approach based on biopsy results in this population.

  • In those with no villous atrophy, if Marsh score of 0/1, biopsies not consistent with celiac disease. In those with Marsh score of 2 (which is rare), consider as consistent with celiac disease (see next bullet point).
  • In those with villous atrophy consistent with celiac disease, assess response to gluten free diet (GFD). In those without a response, consider RD consult to evaluate exposures and HLA-typing as next steps.
  • In those with villous atrophy NOT consistent with celiac disease, obtain serology (TTG IgA, EMA, IgA, DGP IgG). If serology is negative, consider peptic duodenitis or SIBO treatments and assess/discontinue medications for potential for mucosal damage. If serology is positive, consider HLA-typing, review pathology slides, assess for competing disorders, and could need f/u endoscopy.

My take: Overall, ~20% of patients with T21 undergoing endoscopy, will have pathology consistent with celiac disease; this represents ~40% of those with abnormal histology. In the other 60% with abnormal histology, many have alternative explanations for the histologic findings (like peptic duodenitis). Some will evolve to meeting the diagnostic criteria for CD with time indicating need for ongoing monitoring. This study highlights the diagnostic uncertainty in those with potential for seronegative celiac disease.

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How Many Cases of Celiac Disease Are We Missing?

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A Bhattacharjee et al. JPGN 2023; 77: 240-243. Clinical Features of Children With Serology Negative, Biopsy Positive Celiac Disease

At the start of my training in pediatric gastroenterology, the serological testing was not reliable and as a result, very few cases of children who did not have a ‘classical’ phenotype (eg. abdominal distention, poor growth, anemia) were diagnosed. The main exception was the diagnosis in children already recognized as high risk (eg. children with type 1 diabetes).

This recent retrospective study indicates that even with improvement in celiac serology, there are cases of seronegative celiac disease (SN-CD) that are difficult to diagnose. In this study, SN-CD diagnosis required clinical correlation and either confirmatory genetics or follow up endoscopy on a gluten-free diet. Key findings:

  • Of the 424 patients who met celiac disease (CD) criteria, 4.7% (n = 20) fulfilled the criteria for SN-CD
  • Nearly 65% of SN-CD were IgA sufficient compared with 98.4% in the seropositive group
  • All SN-CD patients were symptomatic whereas 82% of seropositive group was symptomatic

The discussion notes that it has been understood that the sensitivity of TTG IgA is about 95% and specificity about 96%. However, the authors caution that this may be “largely overestimated due to failure to account for verification bias. Only 3.6% of IgA-ATTG negative individuals were referred for biopsy” in Hujoel et al meta-analysis (J Clin Gastroenterol 2021; 55: 327-334); thus, the sensitivity could be as low as 57% based on this meta-analysis. In addition, gluten restriction prior to serological testing can further reduce the sensitivity of serological tests.

An important limitation of the study is proving that SN-CD was in fact SN-CD and not one of the mimics for CD (eg. inflammatory bowel disease, autoimmune disorders, medication effect). However, they noted that their cohort had followup over 6-9 years and with symptom resolution with a gluten free diet.

My take: Identifying SN-CD is difficult since so many children have similar digestive symptoms unrelated to celiac disease. Most children with vague digestive complaints do not need to undergo endoscopy; as such, SN-CD can be easily overlooked.

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Pilot Study of Elafibranor in Children with NASH (MASH)

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NP Goyal et al. JPGN 2023; 77: 160-165. An Open Label, Randomized, Multicenter Study of Elafibranor in Children With Nonalcoholic Steatohepatitis

Ten males [mean 15.1 years, standard deviation (SD) 2.2] with NASH were randomized to once daily treatment with Elafibranor: 80 mg (n = 5) or 120 mg (n = 5). Elafibranor, a dual peroxisome proliferator-activated receptor α/δ agonist, has been proposed as a treatment for nonalcoholic steatohepatitis (NASH, aka Metabolic dysfunction-associated steatohepatitis (MASH)). Key findings:

  • End of treatment mean ALT was 52 U/L (SD 20) for the 120 mg group, with a relative mean ALT change from baseline of −37.4% (SD 23.8%) at 12 weeks.
  • Elafibranor was rapidly absorbed and well tolerated.

My take: I think we are on the verge of identifying medications which will be able to improve outcomes for those with steatotic liver disease.

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Rock Jumping -from Cap D;Ail Trail (near Eze, France)

Is Infantile Colic a Biorhythm Disorder?

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TU Egeli et al. JPGN 2023; 77: 171-177. A New Perspective on the Pathogenesis of Infantile Colic: Is Infantile Colic a Biorhythm Disorder?

In this prospective cohort with a colic group (n=46) and a control group (n=49), the key findings:

  • “In the melatonin analysis, the difference between day and night levels was significant in the control group, indicating an established circadian rhythm (P = 0.014). In the colic group, there was no day-night difference (P = 0.216) in melatonin, but serotonin levels were higher at night.”
  • “Day-night variability of H3f3b mRNA levels between the groups was significant, indicating circadian rhythm disturbance in the colic group compared to the control group (P = 0.003).”

The authors note that migraine “has recently been discovered as one of the disease related to biorhythm regulation.” For colic, the authors propose that increases in serotonin, which can cause intestinal distress, contribute to colic, particularly when this is unopposed by increases in melatonin. “Serotonin-melatonin counterbalancing system in the gastrointestinal system generally develops around 3 monhts, and serotonin causes painful intestinal cramps and crying in the evening.”

H3f3b is “expressed in peripheral buccal tissue and is thought to reflect the activity of the central clock.”

My take: If this study is confirmed by others, it could lead to diagnostic testing for colic. Perhaps, then reflux would not be blamed for causing screaming babies. Though, I doubt any effective treatments would be available for biorhythm disturbances in this age group due to safety concerns.

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“Moral distress” or “Moral Injury” in Medicine

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8/2/23 NPR Lisa Doggett: Doctors have their own diagnosis: ‘Moral distress’ from an inhumane health system

This article describes the terms “moral injury” and “moral distress” which contribute to job dissatisfaction for physicians.

Here are excerpts:

The terms “moral distress” and “moral injury” were first used in a military context to characterize the torment felt by soldiers as they tried to process and justify their actions amid the cruelty of war. In more recent years, these terms have been used to describe the feelings of guilt, sadness and defeat felt by health care professionals when we know what our patients need but can’t provide it...

At Austin’s CD Doyle clinic for people who are homeless, where I volunteer, nearly every patient has unmet needs impacting their health…Even in well-resourced private clinics, doctors often feel frustrated that they can’t spend time with patients who need it and have little control over their schedules…

Doctors struggle to meet productivity demands, rushing in and out of exam rooms, working late into the evening to finish documenting in cumbersome electronic medical record systems. Despite some efforts to move away from a “fee-for-service” payment model, in most cases, our system still rewards volume of patients seen over value of care provided…

In Texas and other states, recent legislation, such as abortion bans and prohibitions against gender-affirming care for trans-youth, have introduced new moral dilemmas for doctors. We want to do right by our patients but face added barriers – even the potential for jail time – if we overreach or misinterpret the laws…

A commitment from health care leaders, health insurance plans, and all levels of government to address the nonmedical conditions in which we live, work, learn and play — the social determinants of health that drive 80% to 90% of health outcomes on a population level – would improve the health of individuals and communities. It would also decrease the pressure on doctors to treat medical conditions stemming from unhealthy environments that we can’t change.

A survey published last fall in Mayo Clinic Proceedings showed an alarming increase in physician burnout, with 62.8% of respondents reporting at least one symptom in 2021 compared to just 38.2% in 2020.

Physicians, too, face rates of depression and suicide that are higher than the among the general population. While moral distress doesn’t fully account for the difference, it is a contributing factor for some.

My take: My role as a physician is often constrained by troubling factors out of my control including lack of resources and poor social situations.

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Garlic from market in Nice, France

But How Well Does It Work in Theory and Eosinophilic Esophagitis Treatments

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C Mayerhofer et al. Clin Gastroenterol Hepatol 2023; 21: 2197-2210. Open Access! Efficacy of Elimination Diets in Eosinophilic Esophagitis: A Systematic Review and Meta-analysis

“That’s all well and good in practice… but how does it work in theory?” I saw this quote many years ago when I was visiting the University of Chicago.

This quote came to mind as I was reading this article which showed relatively little change in the efficacy between more and less stringent elimination diets for eosinophilic esophagitis. This meta-analysis included 915 children and 847 adults and assessed the efficacy rates of 4 major dietary treatment regimens in eosinophilic esophagitis: 6-food (SFED), 4-food (FFED), 1-food (OFED), and a targeted elimination diet (TED).

Key findings:

  • The overall rate of histologic remission was 53.8% and in the individual dietary groups was 61.3% for SFED, 49.4% for FFED, 51.4% for OFED, and 45.7% for TED.
  • The overall rate of clinical response was 80.8%, with response rates of 92.8% for SFED, 74.1% for FFED, 87.1% for OFED, and 69.0% for TED.
Percentage of food antigen triggers identified via endoscopic
and clinical evaluation after food re-introduction.

My take: It is clear to me that more restrictive diets can yield better response rates; however, in clinical practice they are difficult to maintain and this study shows that the improvement with more food restrictions may be quite limited.

Another reference on eosinophilic esophagitis: CJ Ketchem et al. Clin Gastroenterol Hepatol. 2023 Aug;21(9):2252-2259. Open Access! Higher Body Mass Index Is Associated With Decreased Treatment Response to Topical Steroids in Eosinophilic Esophagitis. Key finding: Histologic response (n=296) to topic steroids was higher for those who were nonobese compared with obese at fewer than 15 eosinophils per high-power field (61% vs 47%; P = .049); in addition, nonobese patients had significantly greater endoscopic and symptomatic responses.

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