Category Archives: Pediatric Gastroenterology Intestinal Disorder

Paternal Exposure to IBD Medications and Neonatal Outcomes

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COVID-19 Vaccine Effectiveness (8/10/21):

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J Meserve et al. Gastroenterol 2021; 161: 107-115. Full text: Paternal Exposure to Immunosuppressive and/or Biologic Agents and Birth Outcomes in Patients With Immune-Mediated Inflammatory Diseases

Methods: The investigators used a deidentified administrative claims database (OptumLabs Data Warehouse) with a total of 7453 expectant fathers with immune-mediated diseases.

Key findings:

  • As compared to unexposed fathers (3.4% prevalence of major congenital malformations), exposure to immunosuppressives/biologics were not associated with increased risk of major congenital malformations: thiopurines (relative risk [RR], 1.12; 95% confidence interval [CI], 0.66–1.76), methotrexate (RR, 0.67; 95% CI, 0.21–1.55), TNF-α antagonists (RR, 1.14; 95% CI, 0.81-1.57), and non–TNF-targeting biologic agents (RR, 1.75; 95% CI, 0.80–3.24).
  • No association was observed between paternal medication exposure and risk of preterm birth or low birth weight.

Editorial, pg 24-27: S Friedman et al. Full text: Does Fatherhood Matter? Preconception Use of Biologics and Immunomodulators by Fathers With Immune-Mediated Diseases and Birth Outcomes of Their Offspring

“Regarding major congenital malformations, we believe that the results should be interpreted with caution. The numbers of these outcomes are relatively low and the statistical precision of the risk estimates should be taken into consideration.”

My take: Overall, this study is reassuring. Though it is difficult to prove these medications do not have impacts on newborns, if these effects were frequent, it would likely be evident in this type of study.

Hepatitis B: Natural History and Difficulty Treating Immunotolerant Children

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S Mo et al. JPGN 2021; 73: 150-155. Natural History of Chronic Hepatitis B Infection Among Chinese Children and Young Adults: A Single-Center Experience

Key findings:

  • Of the 353 patients, there were immune-tolerant 112 (34%), HBeAg-positive immune-active 47 (14%), and inactive carrier 82 (25%). The remaining 88 patients (27%) did not fit into a particular category with 26 of 88 patients meeting the criteria for inactive carrier except for mildly elevated alanine aminotransferase
  • Among 179 patients followed for ≥5 years, the spontaneous seroconversion rate was 38% (from HBeAg-positive to HBeAg-negative along with anti-HBeAb positivity)

In their discussion, the authors make two key points:

  1. “No substantial benefit from anti-viral therapy” has been evident in children in the immuno-tolerant phase (MM Jonas et al. Hepatology 2016; 63: 307-318.)
  2. The updated AASLD guidelines “strongly recommend anti-viral therapy for HBeAg-positive pregnant women with a serum HBV DNA >200,000 IU/mL”

G Mieli-Vergani et al. JPGN 2021; 73: 156-160. Peginterferon Alfa-2a (40KD) Plus Lamivudine or Entecavir in Children With Immune-Tolerant Chronic Hepatitis B

As noted above, antiviral therapy has not been shown to be effective in children who are in the immuno-tolerant phase; however, the authors of this study explored whether combination therapy could be effective in a randomized, controlled, multicenter study (n=59).

  • Key finding: At 24 weeks post-treatment, 1 of 26 patients in the antiviral treatment group experienced HBsAg loss (vs none of 33 patients in the control group)

My take: These studies reinforce the notion that children in the immuno-tolerant phase of HBV infection do not benefit from antiviral therapy. Prevention of infection is the most promising strategy.

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Confirmation Bias diagram. From Steve Stewart-Williams

Jim Heubi

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So sad to hear that Jim Heubi has passed away. Jim Heubi was the person I interviewed with when I was considering where to do my pediatric residency and he helped convince me to come to Cincinnati. During my fellowship, I came to admire how he was so good at everything though it was always unassuming. He was such a kind person in addition to being a mentor and role model.

Here is a link from Cincinnati Children’s: In Memoriam: James E. Heubi, MD 1948-2021

Differentiating NERD from Functional Heartburn

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D Patel et al. Clin Gastroenterol Hepatol 2021; 19: 1314-26. Full text: Untangling Nonerosive Reflux Disease From Functional Heartburn. This is an excellent review.

Key points:

  • PPI response: 56% for erosive reflux disease, 37% for NERD, and 25% for functional heartburn (FH) per Figure 3 (*”FH might be a placebo effect owing to short follow-up evaluation”
  • Determination of abnormal acid exposure time (AET >6% in adults) is key in distinguishing NERD from FH which in turn helps with selection of treatment. NERD is notable for AET >6% in adults. Many patients with NERD may also have esophageal hypersensitivity
  • Table 2 reviews efficacy of neuromodulators for functional esophageal disorders; these include TCAs, SNRIs, SSRIs, and other agents (eg. gabapentin)
Heartburn etiologies in adults, per Yamasak T et al. J Neurogastroenterol Motil 2017; 23: 495-503.

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SAD diet vs Low Fat Diet for Ulcerative Colitis

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J Fritsch et al. Clin Gastroenterol Hepatol 2021; 19: 1189-1199. Full text: Low-Fat, High-Fiber Diet Reduces Markers of Inflammation and Dysbiosis and Improves Quality of Life in Patients With Ulcerative Colitis

Background: “A high-fat diet has been associated with an increased risk of ulcerative colitis (UC). We studied the effects of a low-fat, high-fiber diet (LFD) vs an improved standard American diet (iSAD, included higher quantities of fruits, vegetables, and fiber than a typical SAD)”

Key findings:

  • Compared with baseline, the iSAD and LFD each increased quality of life, based on the short IBD questionnaire and Short-Form 36 health survey scores (baseline short IBD questionnaire score, 4.98; iSAD, 5.55; LFD, 5.77; baseline vs iSAD, P = .02; baseline vs LFD, P = .001)
  • Fecal levels of acetate (an anti-inflammatory metabolite) increased from a relative abundance of 40.37 at baseline to 42.52 on the iSAD and 53.98 on the LFD (baseline vs LFD, P = .05; iSAD vs LFD, P = .09)
  • Overall, in this small cross-over study (cross-over study) of 17 patients with UC in remission, a catered LFD or a iSAD were each well tolerated and increased quality of life. However, the LFD decreased markers of inflammation and reduced intestinal dysbiosis in fecal samples

My take: While dietary intervention is recognized as a more effective intervention in Crohn’s disease, this study shows that a low-fat high fiber diet for patients with ulcerative colitis may be beneficial.

How Important is Heparin for Preventing Occlusion of Catheters in Pediatrics?

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According to a recent Cochrane review, heparin use is NOT more effective than saline flushes. Thanks to Ben Gold for providing this reference.

Bradford NK, Edwards RM, Chan RJ. Link: Normal saline (0.9% sodium chloride) versus heparin intermittent flushing for the prevention of occlusion in long-term central venous catheters in infants and children. Cochrane Database Syst Rev. 2020;4(4):CD010996. doi: 10.1002/14651858.CD010996.pub3.

Key findings:

  • The four trials (n=255) directly compared the use of normal saline and heparin; the studies all used different protocols for the intervention and control arms, however, and all used different concentrations of heparin.
  • The estimated RR for CVC occlusion per 1000 catheter days between the normal saline and heparin groups was 0.75 (95% CI 0.10 to 5.51; 2 studies, 229 participants; very low certainty evidence).
  • The estimated RR for CVC‐associated blood stream infection was 1.48 (95% CI 0.24 to 9.37; 2 studies, 231 participants; low‐certainty evidence).
  • The duration of catheter placement was reported to be similar for the two study arms in one study (203 participants; moderate‐certainty evidence), and not reported in the remaining studies.
  • This is in agreement with another updated Cochrane review assessing the effectiveness and safety of intermittent locking of CVCs with heparin vs. normal saline to prevent occlusion in adults (11 studies; N=2,392). The pooled analysis did show fewer occlusions with heparin than with normal saline (RR 0.70, 95% CI 0.51 to 0.95; P = 0.02; 1672 participants; 1025 catheters from 10 studies; I² = 14%), but it is based on a very low-quality of evidence given the differences in methodology, unclear allocation concealment, imprecision, and suspicion of publication bias. (López-Briz E, Ruiz Garcia V, Cabello JB, et al. Heparin versus 0.9% sodium chloride locking for prevention of occlusion in central venous catheters in adults. Cochrane Database Syst Rev. 2018;7(7):CD008462. doi: 10.1002/14651858.CD008462.pub3)

My take: This review found there was not enough evidence to determine which solution, saline or heparin, is more effective for reducing complications.

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Better Levels –>Better Outcomes with Adalimumab

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More data is accumulating that show that higher levels of adalimumab are associated with better outcomes: F Rinawi et al. Inflamm Bowel Dis 2021; 27 1079-1087. Association of Early Postinduction Adalimumab Exposure With Subsequent Clinical and Biomarker Remission in Children with Crohn’s Disease. This pediatric study included 65 patients with Crohn’s disease; the author’s note that children weighing less than 40 kg frequently received higher dosing than on-label ADA dosing.

Key findings:

  • Adalimumab trough levels (TLs) at both weeks 4 and 8 were significantly higher in remitters vs nonremitters at week 24 (P < 0.001 and P = 0.002, respectively)
  • The best ADA TL cutoffs at weeks 4 and 8 for predicting clinical/biomarker remission at week 24 were 22.5 µg/mL (80% sensitivity, 90% specificity) and 12.5 µg/mL (94% sensitivity, 60% specificity) respectively

My take (borrowed from authors): Greater early ADA exposure is associated with superior clinical/biomarker outcomes at week 24. ADA pediatric dosing is looking a lot like infliximab dosing in which nearly 75% would be underdosed if using on-label dosing.

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From Illuminarium Show Wild

Impact of NG Feeding Program for NICU Graduates

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A recent prospective cohort study (JM Lagatta et al. J Pediatr 2021; 234: 38-45. Full text: Actual and Potential Impact of a Home Nasogastric Tube Feeding Program for Infants Whose Neonatal Intensive Care Unit Discharge Is Affected by Delayed Oral Feedings) shows that an NG home feeding program can get infants home sooner without tube-related readmissions.

The abstract, in my view, makes a mistake by emphasizing that NG fed infants (n=35) had less hospital readmissions and ED encounters than G-tube fed infants (n=65). This is problematic because infants who received G-tubes were much sicker than NG fed infants (see Table 1). Compared to NG patients, G-tube patients were more premature (32% 22-28 weeks vs 20% for NG), lower birthweight (2510 g vs 1664 g), more chromosomal anomalies (suspected & confirmed 38% vs. 23%), more likely to have abnormal brain imaging (32% vs 20%), and more likely to have a tracheostomy (34% vs. 0%). In addition, as noted below, the institution reports a very high rate of G-tube dislodgement.

Key points (in my view):

  • “Our institution uses a a bridle to secure NG tubes just before NICU discharge”
  • The authors delineate specific criteria for NG discharge: “at least 36 weeks of postmenstrual age (PMA) and weight of 2 kg; 5 days free of apnea or bradycardia requiring nursing intervention after discontinuation of caffeine; 2 days of temperature stability in an open crib; receiving home respiratory support (either room air, or at or below 0.5 liters per minute nasal cannula); at least 25% of feedings by mouth; age-appropriate weight gain; and without anatomic anomalies precluding NG tube placement”
  • “By 3 months after NICU discharge, 27 of 35 (77%) infants discharged with NG tubes had progressed to full oral feeds; of the remaining 8 infants, 3 received G tubes during the study period, and an additional 3 were scheduled to receive a G tube”
  • Median duration of NG use was 29 days. The discussion notes that discharge to home may facilitate quicker weaning from NG tubes (SL Williams et al. Tube feeding outcomes of infants in a Level IV NICU.J Perinatol. 2019; 39: 1406-1410)
  • The authors report a very high rate of G-tube dislodgement, 19 of 65, in a 3-month period. This point is not analyzed by the authors but suggests that the institution utilizes a G-tube prone to dislodgement (eg. secured by a balloon).

My take: This article makes two key points: 1. An NG feeding program can help get infants home sooner and safely (especially with bridle placement) 2. In their institution, G-tubes are dislodged a lot and this leads to frequent returns for medical care; this high rate of dislodgement may indicate a potential benefit to using a different type of G-tube.

Related blog posts: N2U -Part 2: Poor Growth and Short Bowel Syndrome, Nutrition Symposium Georgia AAP (Part 3) | gutsandgrowth

From Illuminarium Atlanta – WILD: A Safari Experience

“Our Gene-Edited Future”

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NPR: He Inherited A Devastating Disease. A CRISPR Gene-Editing Breakthrough Stopped It

Previously the CRISPR gene-editing has been used to counter genetic defects in conditions like sickle cell and thalasemia. This has involved taking cells out of the body, editing them in the lab, and infusing them back in or injecting CRISPR directly into cells that need fixing.

Now, scientists are directly injecting nanoparticles with the CRISPR gene-editing tools. Here’s an excerpt:

Doctors infused billions of microscopic structures known as nanoparticles carrying genetic instructions for the CRISPR gene-editor into four patients in London and two in New Zealand. The nanoparticles were absorbed by their livers, where they unleashed armies of CRISPR gene-editors. The CRISPR editor honed in on the target gene in the liver and sliced it, disabling production of the destructive protein.

Within weeks, the levels of protein causing the disease plummeted, especially in the volunteers who received a higher dose. Researchers reported at the Peripheral Nerve Society Annual Meeting and in a paper published in The New England Journal of Medicine.

“This is really opening a new era as we think about gene-editing where we can begin to think about accessing all kinds of different tissue in the body via systemic administration“

Related study: JD Gilmore et al. NEJM. 2021. DOI: 10.1056/NEJMoa2107454. CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis.

My take: This type of discovery could dramatically improve the treatment of many diseases including heart disease, muscular dystrophy and brain diseases such as Alzheimer’s.

Related blog post: Genetically Modified Humans: Genome Editing 101