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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.

Negligible Effect of Eosinophilic Esophagitis Treatment on Longitudinal Growth

Briefly noted: ET Jensen et al. JPGN 2019; 68: 50-5. This retrospective study with 409 patients with eosinophilic esophagitis (EoE) examined longitudinal growth over 12 months.  “In general, treatment approach was not associated with any significant increase or decrease in expected growth.” In a subset of patients with combined elemental diet and topical steroids (n=13), there was a subtle decrease in linear growth with a change in height z-score of -0.04, CI -0.08 to  -0.01. Interestingly, in these patients with EoE, the baseline height z-scores were lower than expected indicating that a subset may have impaired growth prior to treatment.

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pictures from Zabriskie Point at sunrise, Death Valley

 

Briefly Noted: Breastfeeding and Microbiome Diversity

A recent study (JH Savage et al J Pediatr 2018; 203: 47-54) examined the impact of breastfeeding compared with formula on microbiome diversity in 323 infants; this included 95 exclusively breastfed, 169 exclusively formula fed at time of stool collection.

Breastfed infants were more likely to have been born vaginally (74% vs 62%) and less likely to be African-American (11% vs. 36% for hispanic infants, and 52% for caucasian).

Key finding:

  • Breastfeeding was independently associated with infant intestinal microbiome diversity at age 3-6 months
  • Maternal diet during pregnancy and solid food introduction were less associated with infant gut microbiome changes than breastfeeding status

My take: We still don’t understand the long-term implications of these differences in microbiome alterations between breastfeeding and formula.  That being said, the development/evolution of breastmilk has taken place over thousands of years and it is likely that formula, while an important substitute, will never replicate all of the useful components.

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Chattanooga Riverwalk Sculpture

Probiotics for Colic -Another Negative Study

A recent study (MD Cabana et al. JPGN 2019; 68: 17-9) enrolled 184 infants and found that administration of Lactobacillus GG probiotic, starting at the 4th day of life, was not effective in prevention of colic. Colic was ascertained in a secondary analysis of the ‘Trial of Infant Probiotic Supplementation’ (TIPS) study in which parents were asked monthly if their infant had either symptoms of colic or had been diagnosed with colic.

Key findings:

  • Overall the rate of colic was low at 9.8%, with at rate of 6.5% for control and 13.0% of probiotic

The authors note that there “is only 1 randomized controlled trial for the use of LGG for colic…which showed no difference.”

My take: As with all probiotic studies, the interpretation needs to be limited to this specific strain.

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Golden Gulch Trail, Death Valley

 

Subclinical Liver Transplant Rejection

A recent study (S Feng, JC Bucuvalas, et al. Gastroenterol 2018; 155: 1838-51) found a high prevalence of chronic histologic injury even among highly selected long term liver transplant recipients with consistently normal liver biochemical tests. The authors were able to enroll 157 patients. In addition to histology, the authors examined gene expression/microarray transcriptional analysis, and immunohistochemical staining.

Key findings:

  • Three clusters of patients were identified: interface activity (group 1, n=34), periportal/perivenular fibrosis without interface activity (group 2, n=45), and a group with neither (group 3, n=78).
  • In this cohort, 96 (61%) had Ishak Fibrosis of Stage 0-1, 27  (17%) had Stage 2, 33 (21%) had Stage 3, and 1 (1%) had Stage 4-5.
  • The authors identified a module of genes that regulate T-cell-mediated rejection that were associated with interface activity. Thus, interface activity in these patients connotes subclinical rejection, even in patients with consistently normal liver biochemistries.

What to do with this information:

“For patients whose biopsy samples harbor neither inflammation nor fibrosis, immunosuppression dose reduction may be reasonable…For patients, whose biopsy samples show fibrosis in the absence of inflammation, our data do not support any recommendations…for patients whose biopsy samples show interface hepatitis, our data indicate that dose reduction may be unwise.  Although the intuitive response may be to escalate immunosuppression, data evidencing the benefit of this approach are lacking.”

My take: This study shows why a liver biopsy has been important prior to reducing immunosuppression (in liver transplantation and autoimmune hepatitis). My question is whether the authors could identify a gene signature/biomarker (like their gene module) that could be used as an alternative to a liver biopsy.

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View from Golden Gulch Trail, Death Valley

AntiTNF Therapy Associated with Reduced Surgical Resections

Full text: Increased prevalence of anti‐TNF therapy in paediatric inflammatory bowel disease is associated with a decline in surgical resections during childhood JJ Ashton et al. Alim Pham Ther 2019; https://doi.org/10.1111/apt.15094

From absract:

Design: All patients diagnosed with PIBD within Wessex from 1997 to 2017 were assessed. The prevalence of anti‐TNF‐therapy and yearly surgery rates (resection and perianal) during childhood (<18 years) were analysed

Results: Eight‐hundred‐and‐twenty‐five children were included (498 Crohn’s disease, 272 ulcerative colitis, 55 IBD‐unclassified), mean age at diagnosis 13.6 years (1.6‐17.6), 39.6% female. The prevalence of anti‐TNF‐treated patients increased from 5.1% to 27.1% (2007‐2017), P = 0.0001. Surgical resection‐rate fell (7.1%‐1.5%, P = 0.001), driven by a decrease in Crohn’s disease resections (8.9%‐2.3%, P = 0.001)…

Patients started on anti‐TNF‐therapy less than 3 years post‐diagnosis (11.6%) vs later (28.6%) had a reduction in resections, P = 0.047. Anti‐TNF‐therapy prevalence was the only significant predictor of resection‐rate using multivariate regression (P = 0.011).

Conclusion: The prevalence of anti‐TNF‐therapy increased significantly, alongside a decrease in surgical resection‐rate. Patients diagnosed at younger ages still underwent surgery during childhood. Anti‐TNF‐therapy may reduce the need for surgical intervention in childhood, thereby influencing the natural history of PIBD.

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Big Pharma Neglecting ‘Required’ Pediatric Studies

A recent retrospective study (TJ Hwang et al. JAMA Pediatr 2019; 173: 68-74) examined the completion rate of FDA-required pediatric studies. Thanks to Ben Gold for this reference.

Background: In 2003, the Pediatric Research Equity Act (PREA) was signed into law and authorized the FDA to require clinical stuides to assess the safety and efficacy of new drugs and drugs with new indications in pediatric subpopulations.  However, the FDA cannot withdraw approval for a drug if a manufacturer fails to comply with PREA.  In addition, the authors note that “to our knowledge, to date, no financial penalties or enforcement proceedings have been brought against manufacturers fo noncompliance…and only 31 noncompliance letters have been issued.”

Key findings:

  • Between 2007-2014, there were 438 new drugs and/or new indications.  114 were subject to PREA. 84 were new drugs and 30 were new indications.
  • 222 studies required pediatric postmarketing clinical studies (in these 114 drugs). Only 75 (33.8%) were completed; rates were lower for efficacy studies (38 of 132 –28.8%) compared to pharmacokinetic studies (19 of 34 –55.9%).
  • As a result of the PREA-mandated studies, there was an increase in some pediatric information of drug labels in 41.2% after a median follow-up of 6.8 years, compared with 15.8% at time of approval of these 114 drugs.

The authors note that PREA is responsible for “nearly 80% of pediatric drug studies completed for FDA.” Congress also passed the Best Pharmaceuticals for Children Act which provides a financial incentive to companies if they perform certain pediatric studies.

My take: Pharmaceutical companies, for a multitude of reasons, are not completing requied pediatric studies.

The Health Consequences of Climate Change

A recent review article, “The Imperative for Climate Action to Protect Health,” (A Haines, K Ebi. NEJM 2019; 380: 263-73, and commentary 209-11) explains why many brilliant minds are so concerned about our climate.

What is happening to our climate:

  • “Climate change is already adversely affecting human health…if no additional actions are taken, then over the coming decades, substantial increases in morbidity and mortality are expected.”
  • “August 2018 was the 406th straight month during which global mean temperatures were above the long-term mean.”
  • “Carbon dioxide (the primary greenhouse gas) have risen from approximately 280 ppm in preindustrial times to approximately 410 ppm today. Carbon dioxide remains in the atmosphere for centuries, with about 20% persisting for more than 1000 years.”
  • “The global mean temperature is currently increasing at a rate of 0.2 degrees C per decade owing to past and continuing emissions.”

Health Consequenes:

  • Major climate events including heat waves, floods, rising sea levels, droughts and storms with their immediate and long-term effects of health: heat-related illnesses, fatalities, injuries, and mental health effects
  • Worsened air quality: asthma and COPD exaccerbations, worsened cardiovascular outcomes
  • Water-borne illnesses due to effects on water quality: cholera, campylobacter infection, algae blooms, cryptosporidium, leptospirosis are some examples
  • Disruption of food supply and safety –heat can interfere with soil moisture and crop yield: malnutrition
  • Proliferation of vector-related illnesses: zika virus, dengue, lyme disease, malaria to name a few
  • Social: flooding and heat are likely to lead to social upheaval, mass migration, and violent conflicts

Even if all of the goals of the Paris Agreement were honored by all of the signatories, “it would not be sufficient to limit warming to 2 degree C above preindustrial levels…[it] would be expected to result in a temperature increase of approximately 3.2 degree C by the year 2100, relative to the preindustrial period.”

The authors cite estimates that mitigating adverse climate effects could prevent more than 175,000 premature deaths and 22,000 fewer deaths annually by 2030.

The associated commentary link the recent destructive California wildfires to climate change.  They note that “tackling this challenge may feel overwhelming.” Working on this can include both individual lifestyle actions and institutional efforts.

Individual actions:

  • Walking/cycling more
  • Eating less meat
  • Reducing food waste
  • Conserving energy

Institutional actions:

  • Health care system accounts for 1/10th of greenhouse gas emissions and health systems need to work on cutting their emissions
  • Health care institutions can invest/divest in industries who are helping and harming efforts to limit fossil fuel consumption

Resources:

From review article by Haines and Ebi:  “Health professionals have leading roles to play in addressing climate change. They can support health systems in developing effective adaptation to reduce the health risks of climate change, promote healthy behaviors and policies with low environmental impact.”

My take: Interestingly, the issue of delay in addressing problems is discussed in an unrelated commentary (NEJM 2019; 380: 118-9) related to denial.  For the author, she was attempting to deny the possibility that her father had ALS.  At the end, she quotes Elisabeth Kubler-Ross: “Denial helps us to pace our feelings of grief. There is a grace in denial.  It is nature’s way of letting in only as much as we can handle.”  Clearly, much of the world remains in denial of the necessitiy to address climate change.

Related blog post:

Badwater Basin, Death Valley -salt-covered dried up basin

FDA Approves Adalimumab Biosimilar -But Will Enter U.S. Market in 2023!

October 31, 2018: FDA Approves Sandoz’s Biosimilar Adalimumab, Hyrimoz

An excerpt:

The FDA has approved Sandoz’s biosimilar adalimumab, Hyrimoz (adalimumab-adaz). 

The drug has been approved to treat rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn disease, ulcerative colitis, and plaque psoriasis…

Despite today’s approval, US patients will have to continue to wait for access to Hyrimoz, as the biosimilar will not enter the US market until 2023. Earlier this month, Sandoz announced a global settlement of patent disputes with AbbVie over the drug. While the settlement allowed Sandoz to launch Hyrimoz in the European Union on October 16, 2018, it forestalled US market entry until September 30, 2023. 

My take: Why will this biosimilar be allowed in Europe but not U.$?

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Zabriskie Point at Sunrise, Death Valley

Probiotics and Recurrent Abdominal Pain

Numerous articles have questioned the effectiveness of probiotics for many of the conditions for which they have been promoted.  A recent systematic review (T Newlover-Delgado, et al. JAMA PediatrPublished online December 28, 2018. doi:10.1001/jamapediatrics.2018.4575) concludes that probiotics “may be effective in the shorter term in improving pain in children with” recurrent abdominal pain (RAP). Thanks to Ben Gold for this reference.

This study extended findings from a 2009 Cochrane review (Huertas-Ceballos AA, et al Cochrane Database Syst Rev 2009; (1):CD003019).  In total, the authors identified 19 eligible studies; of these 15 were not included in the previous review. The most common probiotic studied was Lactobacillus rhamnosus GG in 5 trials.

Key findings:

  • At 0 to 3 months postintervention, ‘based on moderate-quality evidence (odds ratio [OR], 1.63, 95% CI 1.07-2.47; 7 studies, 772 children). The number needed to treat for an additional beneficial outcome was 8.” 
  • There were only 2 studies with results extending 3 to 6 months.  These studies also found reduction in pain in the probiotic-treated children, OR 1.94 (CI 1.10-3.43). 
  • Interestingly, the authors note that fiber-based treatments were not considered more effective than placebo, despite a similar OR of 1.83.  Due to the small number of children in these studies with fiber (n=136), the CI were wide: 0.92-3.65.

The authors discuss some of the limitations such as variations in definitions, choice of probiotic and dosage, and short-term duration.  There is not a discussion of selection bias.  It is quite possible that some negative studies were completed which were not published which could further lower or eliminate the potential benefit.

My take: Probiotics may be helpful for children with recurrent abdominal pain; it is certainly not a panacea.

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Moon over Zabriskie Point, Death Valley -just before sunrise

Almost sunrise at Zabriskie Point, Death Valley

 

What to Do with Adolescents with Common Bile Duct Stones

Many times throughout the year we will receive a request to accept a 15-17 year old weighing more than 200 pounds with gallstones who needs to be transferred so that he/she can be cared for in a pediatric facility. The really crazy part is that some of these ‘kids’ need to transferred back to an adult facility to have an ERCP to remove the gallstones if they are lodged in the common bile duct (CBD). Very few pediatric gastroenterologists are adequately trained in ERCP.

A recent retrospective study (PC Bonasso et al JPGN 2019; 68: 64-7) shows some of the consequences of this problem –longer hospitalizations and delays in treatment. The authors compared 79 (48%) pediatric patients who required transfer compared to 85 (52%) who were managed at the tertiary care pediatric hospital.  The median age was 15 years with 42% obese and 23% overweight.

Key findings:

  • Transfer group patients had longer length of stay, median 7 days vs 5 days for non-transfer group (P< 0.0001) and more days between ERCP and surgery.
  • Transfer patients were more likely to have an MRCP (34% vs 8% for non-transfer).
  • Transfer patients were more likely to have a stent placement, 9% vs 5% (which would require a subsequent anesthetic to remove).
  • Transfer patients were more likely to have a non-therapeutic ERCP;  stone/sludge removal was 70% in transfer group vs 86% in non-transfer group. This could be related to the delay (eg. more time for stone to pass) or due to the evaluation by team not responsible for ERCP.

The authors note that there are fewer than 20 pediatric gastroenterologists trained in ERCP; this is not likely to change much in the near term due to the large number of ERCPs needed to become proficient and few options for pediatric training. Their study notes that 46% had adult gastroenterologist management for non-transfer group.

My take: This is clearly an area in need of collaboration.  More pediatric hospitals need to have adult gastroenterologists available and adult hospitals need to consider keeping some of these young adults to improve both the care and costs for these individuals.

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This article was referenced previously on this blog