Safety of Live-Virus Vaccines in Infants After In Utero Biologic Medicine Exposures

O Zerbo et al. Pediatrics 2022; 150: e2021056021. Open access: Safety of Live-Attenuated Vaccines in Children Exposed to Biologic Response Modifiers in Utero

This large retrospective cohort study (2006-2017) identified 960 infants with in utero biologic medicine exposures (most commonly etanercept, anakinra, adalimumab, and infliximab) among 582,759 infants. Key findings:

  • Receipt of live-attenuated rotavirus vaccine in their first year or measles vaccine during their first 24 months were not at increased risk of prespecified adverse events compared to unexposed children
  • There was not a significant difference in diarrhea, bloody stools, intussusception, vomiting, encephalitis, myelitis, hepatitis, ataxia, or fevers
  • Receipt of the recommended number of doses of rotavirus vaccines in the first year of life was lower among biologic-exposed than among unexposed children (81.00% vs 85.20%, adjusted OR = 0.74)

Examples of guideline recommendations with regard to live-virus vaccination:

The Toronto Consensus Statements for the Management of Inflammatory Bowel Disease in Pregnancy,” (Gastroenterology. 2016; 150(3):734–757) states the following: “live vaccinations are not recommended within the first 6 months of life in the offspring of women who were on anti-TNF therapy during pregnancy.”

Inflammatory Bowel Disease in Pregnancy Clinical Care Pathway: A Report From the American Gastroenterological Association IBD Parenthood Project Working Group (Gastroenterology. 2019; 156(5):1508–1524.open access)” states the following: “if the mother is exposed to any biologic therapy, other than certolizumab, during the third trimester of pregnancy (ie, after 27 weeks gestation) avoidance of live vaccines is recommended for the first 6 months of life.”

In their discussion, the authors note that this “provide some reassurance to parents and pediatricians regarding live-attenuated vaccines for children exposed to BRM [biologics] in utero. Professional societies may want to consider reevaluating their live-attenuated vaccines recommendations for these children as new safety data accumulates.”

My take: There are clearly theoretical concerns about biologic-exposures of infants in utero since some are actively transported across the placenta barrier and can remain in infants for up to 12 months after birth. However, this study could not identify significant adverse effects in exposed infants.

This is an impression from a starfish (no starfish in this picture)

Long-Term Treatment of Eosinophilic Esophagitis with Budesonide

ES Dellon et al. Clin Gastroenterol Hepatol 2022; 1488-1498. Open access: Long-Term Treatment of Eosinophilic Esophagitis With Budesonide Oral Suspension

Methods: 48 patients who had fully responded to a 12-week induction course of budesonide 2 mg BID oral suspension were randomized to continuation of therapy or to placebo, for 36 weeks.

Key findings:

  • Patients randomized to placebo experienced relapse at a numerically higher rate than those who continued budesonide (43.5% vs 24.0%; p=.13). This reached statistical significance in a per-protocol analysis
  • In a separate arm, 13% of the 106 patients with previous partial or no response did subsequently fully respond to budesonide
  • Budesonide therapy was well-tolerated; candidiasis-related events occurred in 17 patients overall and were mild to moderate, and abnormal adrenocorticotropic hormone stimulation tests were reported in 5%

My take: Most patients who respond to induction with budesonide will continue to respond to ongoing treatment. A high rate of relapse is seen in those randomized to placebo.

Related blog posts:

Artificial Intelligence in the Endoscopy Suite

I never saw the show, “Office Space.” However, I did see the opening trailer (1 min) recently and it is very funny. YouTube Link: Office Space – Peter’s Original Traffic Scene

Hydrangeas in Sandy Springs

MB Wallace et al. Gastroenterol 2022; 162: 295-304. Open access: Impact of Artificial Intelligence on Miss Rate of Colorectal Neoplasia

Design: In a multicenter and multicountry randomized crossover trial, patients (n=230) undergoing CRC screening or surveillance were enrolled in 8 centers (Italy, UK, US), and randomized (1:1) to undergo 2 same-day, back-to-back colonoscopies with or without AI (deep learning computer aided diagnosis endoscopy) in 2 different arms, namely AI followed by colonoscopy without AI or vice-versa.

Key finding: There was an approximately 50% reduction of the miss rate of colorectal neoplasia, mainly due to a decreased miss rate of flat and small lesions.

The editorial (pg 35-38, DK Rex et al. Artificial Intelligence Improves Detection at Colonoscopy: Why Aren’t We All Already Using It?) provides some perspective regarding the study limitations and why AI will not be widely adopted in the near term.

Limitations:

  • “Tandem studies are more often positive than parallel design studies.  In a parallel design study, endoscopist bias toward any study arm is mitigated by the clinical and medical-legal demands to protect patients from colorectal cancer in a single withdrawal.”
  • “Detection gains for AI are largely for diminutive lesions.3 This is generally true for detection gains from ancillary devices, because powering trials for improved advanced lesion detection is not practical”

Slow Uptake of AI:

  • First, other adjunctive detection devices have received approval from the US Food and Drug Administration and then failed to reach widespread use…the limited adoption of this entire category suggests that physicians attach a relatively low price point to the value of detection gains produced by add-on devices…Incorporating detection devices with add-on cost is particularly problematic in US ambulatory surgery centers.”
  • The authors indicate that an endoscopy company could add AI to standard equipment as one way to advance use of this technology

My take: AI will likely improve interpretation and usefulness of colonoscopy, whether for cancer surveillance and other reasons. Cost and familiarity are current barriers to early adoption.

Related blog post: #NASPGHAN19 Impact of New Technologies on Patient Health

Biologics in Children with Very Early Onset Inflammatory Bowel Disease

B Kerur et al. JPGN 2022; 75: 64-69. Utilization of Antitumor Necrosis Factor Biologics in Very Early Onset Inflammatory Bowel Disease: A Multicenter Retrospective Cohort Study From North America

In this retrospective study, 120 of 294 children with VEO-IBD (diagnosed 2008 and 2013, PRO-KIDS network) received anti-TNF therapy (96% infliximab). 101 of these 120 had adequate data recorded. It is noted that additional data on this cohort has been previously published (IBD Updates: Outcomes of VEO-IBD, PIANO Study Update, and Insurance-Disparity Relationship). Key findings:

  • Anti-TNF durability was 90% at 1 year, 75% at 3 years, and 55% at 5 years
  • Patients with Crohn’s disease had better durability than those with UC/IBD-U (Hazard ratio 0.17)
  • The most common reason for discontinuation of anti-TNF were loss of response in 24 (57%) children
  • 67 (66%) received combined therapy with an immunomodulator and this was associated with improved anti-TNF durability (Hazard ratio 0.30). However, authors note this was in era preceding widespread therapeutic drug monitoring.
  • The majority of children in the current study did not undergo testing for monogenic mutations

My take: Data for use of anti-TNF agents in this age group (< 6 yrs) has been limited. This study suggests similar effectiveness of anti-TNF agents in VEO-IBD compared to older groups. Given this groups increased risk for monogenic mutations, it is still a good idea, if feasible, to test for these disorders.

Related blog posts:

Outcomes with Enteral Nutrition

Notice: At this time, gutsandgrowth intends to post blogs 2-3 times per week rather than daily.

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N Davidson et al. JPGN 2022; 75: 70-75. 6- and 12-Month Outcomes after 90:10 Enteral Nutrition Induction Therapy in Pediatric Crohn’s Disease

In this retrospective study (2013-2018), the authors examined outcomes in 105 children treated with a 90:10 enteral feeds (90% formula).

Key findings:

  • 44/105 (42%) patients completed 8–12 weeks
  • After induction, 18 continued EN maintenance with a 80:20 then 70:30 protocol; however, only 10 remained on EN at 6 months and 4 remained on EN at 12 months

The associated editorial (pg: 1-2) make several points:

  1. While EEN is effective and safe, this study and others have shown poor adherence
  2. It is unclear how exclusive enteral nutrition needs to be in order to be effective. And, many patients instructed to receive 90% of their calories as formula are likely consuming higher amounts of table foods
  3. We still are working out which foods need to be excluded

My take: This study shows that EEN is NOT a practical option for most patients beyond induction. Only 4 patients remained on EEN at 12 months.

Related blog posts:

Gastrostomy Tube Recommendations in Pediatrics

L Berman et al. Pediatrics 2022; 149 (6): e2021055213. Gastrostomy Tube Use in Pediatrics: A Systematic Review

This lengthy review (27 pages) authored by a multispecialty team makes 17 graded recommendations regarding gastrostomy tubes/gastrostomy tube (GT) placement. The authors state that this review was based on nearly 900 publications with 58 influencing final recommendations.

Here are several of them:

  1. Trial of home nasogastric feeding is safe and should be strongly considered before GT placement, especially for patients who are likely to learn to eat by mouth
  2. Routine contrast studies are not indicated before gastrostomy placement
  3. Laparoscopic placement is associated with the best safety profile
  4. For most patients, a low-profile balloon GT is preferred

Elaborating on these recommendations::

  • Home NG: The authors note that Lagatta et al found that infants sent home with NG from nursery had shorter length of stay and fewer readmissions/emergency encounters than patient sent home with GT. However, this statement ignores the significant differences in the patient characteristics in the two groups noted in this article (see related blog post: Impact of NG Feeding Program for NICU Graduates). Interestingly, many of the return visits are due to dislodgements of button GTs.
  • Preoperative workup: While the authors discourage use of preoperative UGI and except in patients not achieving adequate enteral nutrition due to emesis, they also recommend “GT should only be pursued after appropriate workup has been performed to investigate the underlying medical diagnosis.” I find this vague recommendation to be problematic. Shortly before making this recommendation, the authors state “proper identification and management of the underlying diagnosis (eg. diet modification for eosinophilic esophagitis) may obviate the need for GT placement.” So, do the authors want every child who may need a GT to undergo an EGD? Or perhaps even more, such as an MRI or full exome sequencing? Also, which diet trial do they recommend for potential eosinophilic esophagitis -does this mean an amino acid based formula or is a hydrolysate sufficient?
  • GT technique: The review of the techniques of GT placement cite data comparing the techniques and complication rates (though noting critical risk of bias in these studies):

My take: This article’s recommendations need to be carefully considered by pediatric gastroenterologists along with pediatric surgeons and interventional radiologists.

Related blog posts:

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.

Lavender field (off season) at Poblanos Ranch, Albuquerque

Reliable Scoring System for Constipation Management

CMA de Bruijn et al. J Pediatr 2022; 244: 107-114. Open Access: Development of a Bowel Management Scoring Tool in Pediatric Patients with Constipation

This report describes the “newly developed and validated PBMST (Pediatric Bowel Management Scoring Tool) is a reliable tool for evaluating bowel management strategies in children with constipation.”

Key finding:

“This study shows that use of the PBMST (see below) can better guide management of childhood constipation, with its fair reproducibility indicating that it is stable over a specified time period. Indeed, consistent use of the PBMST can objectify the patient’s clinical condition over a longer period. Consequently, the score provides feedback regarding the effect of the applied bowel management strategy for each individual patient.”

From PDF version of article

My take: 6 key questions for constipation visits: stool form, anorectal pain, abdominal pain, soiling, support from parents, and social limitations.

Related blog posts:

Modified Bristol Stool Form (see link: CAM Wegh et al. JPGN 2021; 73: 210-216. The Modified Bristol Stool Form Scale: A Reliable and Valid Tool to Score Stool Consistency in Dutch (Non)Toilet-trained Toddlers)

What About the Risk of Not Intervening to Prevent Necrotizing Enterocolitis?

J Tobias et al. J Pediatr 2022; 244; 64-71. Open Access: Bifidobacterium longum subsp. infantis EVC001 Administration Is Associated with a Significant Reduction in the Incidence of Necrotizing Enterocolitis in Very Low Birth Weight Infants

Editorial: MA Underwood J Pediatr 2022; 64: 14-16. Open Access: Bifidobacterium infantis, Necrotizing Enterocolitis, Death, and the Role of Parents in the Neonatal Intensive Care Unit

Methods: Nonconcurrent retrospective analysis of 2 cohorts of 483 very low birth weight (VLBW) infants not exposed and exposed to B infantis EVC001 probiotic at Oregon Health & Science University from 2014 to 2020

Key findings:

  • The cumulative incidence of NEC diagnoses decreased from 11.0% (n = 301) in the no EVC001 (unexposed) cohort to 2.7% (n = 182) in the EVC001 (exposed) cohort (P < .01); this was a 73% risk reduction of NEC
  • NEC-associated mortality decreased from 2.7% in the no EVC001 cohort to 0% in the EVC001 cohort (P = .03)
  • There was a lack of adverse events (including probiotic sepsis)

Key points from editorial:

  • “The first cohort study showing a significant decrease in necrotizing enterocolitis (NEC) with the routine administration of probiotic dietary supplements [was] more than 20 years ago”
  • “The most recent Cochrane Database systematic review 2 included 56 randomized or quasi-randomized trials in which 10 812 infants participated. Meta-analysis found evidence for decreased risk of NEC (Risk ratio [RR] 0.54)”
  • Both the AGA and ESPGHAN have recommended routine probiotics administration to preterm infants. However, the AAP recommends “against routine probiotic administration citing ‘the lack of FDA-regulated pharmaceutical-grade products in the United States, conflicting data on safety and efficacy, and potential for harm in a highly vulnerable population.’”
  • “Recognizing that many neonatologists have opted to adopt routine probiotic administration to infants born preterm, the recent American Academy of Pediatrics statement6 recommends that an informed consent process for utilizing probiotics. Dr. Underwood counters: “there is no mention of a need to discuss these risks and benefits by those well-informed clinicians who may not believe that the data support administering probiotics. Inclusion of parents in decision-making in the NICU improves parent satisfaction and infant outcomes.”
  • Parent and clinician resource: necsociety.org. 9 Things You Need to Know About Necrotizing Enterocolitis and NEC Facts

My take: It is hard to understand that, despite 20 years of research showing probiotics can reduce mortality and morbidity in premature infants, we have not been able to manufacture a consistent, reliable high-quality probiotic capable of meeting FDA standards.

An Alternative to Ethanol Locks (Not Available in U.S.)

J Strauss et al. JPGN 2022; 74: 776-781. Mechanical Complications in Central Lines Using Taurolidine Versus Ethanol Lock Therapy in Children With Intestinal Failure

This retrospective study with 13 patients (10,187 catheter days [CDs]) compared ethanol locks (EL) with taurolidine locks (TL). Taurolidine is a “non-toxic, broad-spectrum antimicrobial” with growing use outside the U.S. Manufacturing issues still need to be addressed to gain FDA approval. Link: CORMEDIX RECEIVES COMPLETE RESPONSE LETTER FROM FDA FOR DEFENCATH™ CATHETER LOCK SOLUTION

Key findings from this study:

  • TL (vs EL) had lower rates of CVC breaks (1.11 vs 5.19/1000 CDs, P < 0.001), occlusions (0.83 vs 4.06/1000 CDs, P= 0.01) and repairs (1.94 vs 5.64/1000 CDs, P= 0.01)
  • There was no significant difference in CRBSI rates: 0.83/1000 CDs for TL vs 2.03/1000 CDs for EL (P= 0.25)

My take: Taurolidine, when available in U.S., may be a suitable alternative to ethanol, when available in U.S., in preventing CRBSI. In addition, taurolidine locks appear to have fewer mechanical risks.

Related blog posts:

Yesterday’s T-shirt

EEN: It Only Works If You Do It

S Mckirdy et al. JPGN 2022; 74: 801-804. The Impact of Compliance During Exclusive Enteral Nutrition on Faecal Calprotectin in Children With Crohn Disease

The expression ‘90% of Success is Showing Up’ has been attributed to Woody Allen. With dietary and medical treatments, adherence is the equivalent of showing up.

In this study, the authors measured fecal gluten immunogenic peptides (GIP), a biomarker of gluten intake, in 45 children (3– 17 years) with Crohn’s disease to assess adherence to enteral nutrition. This, in turn, was correlated with fecal calprotectin (FC) levels.

Key findings:

  • FC decreased in patients with undetectable GIP at both 33 and 54 days of EEN (mean decrease, 33 days: −743 mg/kg, 54 days: –1043 mg/kg, P< 0.001) but not in patients who had detectable GIP levels
  • At EEN completion, patients with undetectable GIP had a lower FC by 717 mg/kg compared with patients with a positive GIP result (P = 0.042) and demonstrated a greater decline from baseline FC (–69% vs +5%, P = 0.011)
  • 13% and 23% had detectable GIP levels at 33 days and 54 days respectively. It is noted that GIP levels are only indicative of short-term consumption (eg. prior 1-2 days) of gluten-containing foods

My take: Dietary therapies are really difficult for most people. This study shows that those with poor compliance are unlikely to benefit.

Related blog posts:

Related blog post: Why I No Longer Need to Be A Billionaire