Author Archives: gutsandgrowth

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About gutsandgrowth

I am a pediatric gastroenterologist at GI Care for Kids (previously called CCDHC) in Atlanta, Georgia. The goal of my blog is to share some of my reading in my field more broadly. In addition, I wanted to provide my voice to a wide range of topics that often have inaccurate or incomplete information. Before starting this blog in 2011, I would tear out articles from journals and/or keep notes in a palm pilot. This blog helps provide an updated source of information that is easy to access and search, along with links to useful multimedia sources. I was born and raised in Chattanooga. After graduating from the University of Virginia, I attended Baylor College of Medicine. I completed residency and fellowship training at the University of Cincinnati at the Children’s Hospital Medical Center. I received funding from the National Institutes of Health for molecular biology research of the gastrointestinal tract. During my fellowship, I had the opportunity to work with some of the most amazing pediatric gastroenterologists and mentors. Some of these individuals included Mitchell Cohen, William Balistreri, James Heubi, Jorge Bezerra, Colin Rudolph, John Bucuvalas, and Michael Farrell. I am grateful for their teaching and their friendship. During my training with their help, I received a nationwide award for the best research by a GI fellow. I have authored numerous publications/presentations including original research, case reports, review articles, and textbook chapters on various pediatric gastrointestinal problems. In addition, I have been recognized by Atlanta Magazine as a "Top Doctor" in my field multiple times. Currently, I am the vice chair of the section of nutrition for the Georgia Chapter of the American Academy of Pediatrics. In addition, I am an adjunct Associate Clinical Professor of Pediatrics at Emory University School of Medicine. Other society memberships have included the North American Society for Pediatric Gastroenterology Hepatology and Nutrition (NASPGHAN), American Academy of Pediatrics, the Food Allergy Network, the American Gastroenterology Association, the American Association for the Study of Liver Diseases, and the Crohn’s and Colitis Foundation. As part of a national pediatric GI organization called NASPGHAN (and its affiliated website GIKids), I have helped develop educational materials on a wide-range of gastrointestinal and liver diseases which are used across the country. Also, I have been an invited speaker for national campaigns to improve the evaluation and treatment of gastroesophageal reflux disease, celiac disease, eosinophilic esophagitis, hepatitis C, and inflammatory bowel disease (IBD). Some information on these topics has been posted at my work website, www.gicareforkids.com, which has links to multiple other useful resources. I am fortunate to work at GI Care For Kids. Our group has 17 terrific physicians with a wide range of subspecialization, including liver diseases, feeding disorders, eosinophilic diseases, inflammatory bowel disease, cystic fibrosis, DiGeorge/22q, celiac disease, and motility disorders. Many of our physicians are recognized nationally for their achievements. Our group of physicians have worked closely together for many years. None of the physicians in our group have ever left to join other groups. I have also worked with the same nurse (Bernadette) since I moved to Atlanta in 1997. For many families, more practical matters about our office include the following: – 14 office/satellite locations – physicians who speak Spanish – cutting edge research – on-site nutritionists – on-site psychology support for abdominal pain and feeding disorders – participation in ImproveCareNow to better the outcomes for children with inflammatory bowel disease – office endoscopy suite (lower costs and easier scheduling) – office infusion center (lower costs and easier for families) – easy access to nursing advice (each physician has at least one nurse) I am married and have two sons (both adults). I like to read, walk/hike, bike, swim, and play tennis with my free time. I do not have any financial relationships with pharmaceutical companies or other financial relationships to disclose. I have helped enroll patients in industry-sponsored research studies.

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

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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)

Head-to-Head (Sort of): Infliximab vs Ustekinumab for Crohn’s Disease

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N Narula et al. Clin Gastroenterol Hepatol 2022; 20: 1579-1587. Comparative Efficacy and Rapidity of Action for Infliximab vs Ustekinumab in Biologic Naïve Crohn’s Disease

Using a post hoc analysis of 2 large Crohn’s disease (CD) trial with 420 biologic-naive adult patients, the authors found the following Key Findings:

  • At week 6, a comparable number of patients achieved clinical remission with infliximab compared with patients treated with ustekinumab (44.9% vs 37.9%; adjusted odds ratio [aOR], 1.22)
  • At week 6 the clinical response rates were not significantly different (58.4% infliximab vs 54.9% ustekinumab; aOR, 1.25)
  • At week 6, 42.3% infliximab vs 34.7% ustekinumab had fecal calprotectin level less than 250 mcg/L in those with increased values at baseline

My take: A true head-to-head trial, rather than a post-hoc analysis, would more definitively determine relative efficacy and relative time to response. This study indicates that both agents have similar efficacy by week 6.

Related blog posts:

Fountain at Forsyth Park in Savannah

More Data: COVID-19 Vaccine Effective in Patients with IBD & Maternal COVID-19 Vaccination Protects Infants

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A Jena et al. Clin Gastroenterol Hepatol 2022; 20: 1456-1479. Open access: Effectiveness and Durability of COVID-19 Vaccination in 9447 Patients With IBD: A Systematic Review and Meta-Analysis

This was a systematic review and meta-analysis that included 46 studies.

  • Key findings:
    In 9,447 subjects who were completely vaccinated, the pooled seroconversion relative risk was 0.96 (95%CI, 0.94-0.97), and was higher for mRNA vaccines (0.97, 95%CI 0.96-0.98) than for adeno-associated vaccines (0.87, 95%CI: 0.78-0.93)
  • The pooled seroconversion rates were similar regardless of IBD therapy, and ranged from 0.93 to 0.99.
  • The pooled relative risk of breakthrough COVID-19 infections in vaccinated patients with IBD was not significantly different from that of vaccinated controls. However, a decay in antibody titers after 4 weeks from vaccination appeared to be accelerated in those on anti-TNF agents, immunomodulators or their combination.

My take: IBD patients benefit from complete COVID-19 vaccination similar to healthy controls.

Related blog post: COVID Booster Advice for IBD from Dr. David Rubin (@IBDMD)

NB Halasa et al. NEJM 2022; 387: 109-119. Open access: Maternal Vaccination and Risk of Hospitalization for Covid-19 among Infants

Using a case-control design, the authors found that complete (2 dose) vaccination during pregnancy —Key findings:

  • The effectiveness of maternal vaccination against hospitalization for Covid-19 among infants < 6 months was 52% overall, 80% during the delta period, and 38% during the omicron period.

My take: Vaccination protects mother and infant. “Maternal vaccination with two doses of mRNA vaccine was associated with a reduced risk of hospitalization for Covid-19, including for critical illness, among infants younger than 6 months of age.”

Long-Term Treatment of Eosinophilic Esophagitis with Budesonide

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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.

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Artificial Intelligence in the Endoscopy Suite

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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

AGA Guidelines for Pharmacologic Therapy of IBS-D and IBS-C

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A Lembo, S Sultan et al. Gastroenterol 2022; 162: 137-151. Open access PDF: AGA Clinical Practice Guideline on the Pharmacological Management of Irritable Bowel Syndrome With Diarrhea

LChang, S Sultan et al. Gastroenterol 2022; 162: 118-136. Open access: AGA Clinical Practice Guideline on the Pharmacological Management of Irritable Bowel Syndrome With Constipation

The associated 1-page summary (“Spotlight: IBS Treatment“) on pg 153 reviews society guidelines on testing in IBS. This includes for IBS-D celiac serology, calprotectin/lactoferrin, CRP, possilby Giardia antigen (if in endemic area) and possibly bile acid diarrhea testing. Not recommended include food allergy/sensitivity testing, colonoscopy if <45 years and lactulose or glucose hydrogen breath testing. This 1-page summary details therapeutic dosing and costs. Monthly costs of selected medications according to this report:

  • Lubiprostone (Amitiza): $374
  • Linaclotide (Linzess): $523
  • Pleacnatide (Trulance): $528
  • Tegaserod (Zelnorm): $480
  • Tenapanor (IBSRELA): $1680
  • Rifaximin (Xifaxan) $1544 (for 14 day course)
  • Eluxadoline (Viberzi): $1550
  • Alosetron (Lotronex): $1457-1929 (starting dose), $2915-3859 (max dose)

My take: These guideline publications provide comprehensive information regarding potential pharmacological therapies.

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Covid Updates

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Vaccines have been estimated to have saved more than 20 million deaths. The Lancet Infectious Diseases new release: COVID-19 vaccines are estimated to have prevented 20 million deaths worldwide in the first year of the vaccine program, modelling study find

Omicron has been associated with lower rates of MIS-C in children compared to other surges –95% less than alpha. WSJ: Covid-19 Complication Among Children Fades in Latest Wave of Virus.

Getting boosted is important for those >50 years. There was a 29-fold reduction when comparing 2 boosters vs unvaccinated and a 4-fold reduction when comparing 2nd booster vs 1 booster. CDC: Rates of COVID-19 Cases and Deaths by Vaccination Status

Good Review of Cholestatic Liver Diseases

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SH Ibrahim et al. Hepatology 2022; 75: 1627-1646. Cholestatic liver diseases of genetic etiology: Advances and controversies

Table 1 lists more than 40 monogenic disorders of cholestasis. Examples:

  • Disorders of membrane transporter or polarity: PFIC1, PFIC2, PFIC3, Dubin-Johnson
  • Basolateral disorders: NTCP deficiency, Rotor syndrome, Organic solute transporter deficiency
  • Disorders of nuclear receptors: PFIC5
  • Disorders of intracellular trafficking: Arthrogryposis-renal dysfunction-cholestasis, PFIC6 microvillous inclusion (MYO5B gene), Osteo-oto-hepato-enteric, Fanconi renotubullar syndrome
  • Disorders of cytoskeletal and tight junction protein: PFIC4, Neonatal ichthyosis sclerosing cholangitis
  • Cholangiopathies-Ciliopathy: Neonatal sclerosing cholangitis, Nephronophthisis, Meckel-Joubert syndrome, renal cysts and diabetes syndrome, BASM
  • Cholangiopathies-Bile duct paucity: Alagille
  • Cholangiopathies-cholangiocyte channelopathy: Cystic Fibrosis
  • Hepatocellular disease: A1AT deficiency, mitochondrial depletion, mitochondrial translation defect, transaldolase deficiency
  • Inborn errors of metabolism -bile acids: BASD, bile acid conjugation defects, peroxisomal defects
  • Inborn errors of metabolism -carbohydrates: galactosemia, hereditary fructose intolerance
  • Inborn errors of metabolism -amino acids: tyrosinemia type 1

Key Points:

  • Low GGT genetic disorders (>25 genetic mutations) include canalicular transporter defects, basolateral transporter defects, intracellular trafficking defects, defects of cytoskeletal and tight junction protein, transaldolase deficiency, bile duct paucity, and inborn errors of metabolism.
  • The authors note that the timing and utility of a liver biopsy is changing due to the advent of rapid molecular testing.
  • Potential treatments are reviewed include ursodeoxycholic acid, IBAT inhibitors, cholic acid, biliary diversion, and liver transplantation.
  • Multidisciplinary evaluation is often needed in patients with Alagille. 87% have cardiac anomalies, up to 36% have/develop cerebral vasculopathy, 21% develop post-transplant renal dysfunction, and 22% develop spontaneous or procedure-associate systemic bleeding (need for hematology consultation). In addition, pathologic fractures are common; one report found the rate of femur fractures was 50 times that in the general population which is likely related to intrinsic bone defects (as well as cholestasis).

My take: With the widespread availability of genetic testing which is needed due to the numerous etiologies, the diagnosis of ‘idiopathic’ chronic cholestasis has decreased and targeted therapies have emerged.

Related article: L Matarazzo et al. JPGN 2022; 74; p e115-e121. MYO5B Gene Mutations: A Not Negligible Cause of Intrahepatic Cholestasis of Infancy With Normal Gamma-Glutamyl Transferase Phenotype

Key finding:

In this multicenter retrospective and prospective study was conducted in 32 children with cryptogenic intrahepatic cholestasis, whole exome sequencing identified 6 with MYO5B mutations.  The most common signs were pruritus, poor growth, hepatomegaly, jaundice, and hypocholic stools. 

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Biologics in Children with Very Early Onset Inflammatory Bowel Disease

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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.

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Misinformation in Medicine

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RJ Baron, YD Ejnes. NEJM 2022; 387:1-3. Physicians Spreading Misinformation on Social Media — Do Right and Wrong Answers Still Exist in Medicine?

The authors, representing the American Board of Internal Medicine (ABIM), assert that “there aren’t always right answers, but some answers are clearly wrong.” In their commentary, they note that there is “growing allegiance to crowd-endorsed ‘facts.'” Yet, they expect physicians to adhere to higher standards; however, they note the inherent conflict between speech that can be prohibited by licensing boards and speech protected by the First Amendment.

My take: While the authors state that physicians risk disciplinary action for spreading misinformation, I remain skeptical that licensing boards have the appetite to do this, particularly when it comes to disciplining high-profile offenders like Mehmet Oz or Joseph Ladapo (Florida Surgeon General) (Business Insider: Dr. Oz is running for US Senate in Pennsylvania. Here are 8 times he’s made false or baseless medical claims; Insider: Florida’s surgeon general breaks with CDC advice, says the state will be the first to ‘officially recommend against the COVID-19 vaccine for healthy children‘).

PA Cohen et al. NEJM 2022; 387: 3-5. Institutionalizing Misinformation — The Dietary Supplement Listing Act of 2022

Dietary supplements are another part of medicine with rampant misinformation. In fact, there is nearly ubiquitous misinformation through advertisements across all media segments. Americans spent ~$55 billion on dietary supplements in 2020. This commentary discusses a Senate bill, the Dietary Supplement Listing Act of 2022, which ostensibly would improve this situation.

However, this is NOT the case. This bill requires manufacturers to provide the FDA with a product’s name, ingredients and health claims. It mandates the FDA create a searchable database. What the legislation doesn’t do:

  • Provide the the FDA with a mechanism to confirm a product’s ingredients
  • Enable regulation of misleading health claims
  • Stop the promotion and sale of supplements with dangerous ingredients
  • Allow the FDA to remove products from its registry determined to have unlawful ingredients and remove products deemed hazardous

My take: This legislation needs to be strengthened to limit deception. In its current form, this registry would appear to confer FDA oversight to dietary supplements (which is minimal) and paradoxically legitimize dietary supplements .

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Hilton Head at Sunrise