Category Archives: Uncategorized

Durability of Biologics in Children with Inflammatory Bowel Disease

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JL Kaplan et al. JPGN 2023; 76: 567-575. Open Access! Use, Durability, and Risks for Discontinuation of Initial and Subsequent Biologics in a Large Pediatric-Onset IBD Cohort

Methods: The authors analyzed pediatric inflammatory bowel disease (IBD) data from the ImproveCareNow Network registry (n= 17,649) between May 2006 and September 2016, including time to biologic initiation, choice of first subsequent biologics, biologic durability, and reasons for discontinuation

Key findings:

  • 7585 (43%) were treated with a biologic agent before age 18. 50% of children with Crohn’s disease (CD) received a biologic compared to 25% of children with ulcerative colitis (UC)
  • First biologic agents for all patients were anti-tumor necrosis factor agents (88% infliximab, 12% adalimumab)
  • Probability of remaining on first biologic in patients with CD: 93% at 6 months, 85% at 12 months, 79% at 24 months, and 74% at 36 months
  • Probability of remaining on first biologic in patients with UC: 84% at 6 months, 75% at 12 months, 66% at 24 months, and 55% at 36 months
  • First biologics were discontinued because of loss of response (39%), intolerance (23%), and nonresponse (19%).

My take: This is an important study that shows that anti-TNF therapy durability was 79% in patients with CD and 66% in patients with UC at 2 years. This pediatric-specific information will help with counseling families when starting biologic therapy. There was improvement in durability after 2013 compared to prior -so perhaps perhaps even better durability is occurring in 2023. It is a little ironic that this study is from ImproveCareNow given that the results are quite dated. There have been a lot of changes in the last seven years. These include the widespread use of dose optimization/therapeutic drug levels and the approval of several new classes of targeted medications.

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Tucson Botanical Gardens

Pneumatosis Intestinalis in Children with Intestinal Failure

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Tucson Botanical Gardens

ML Reppucci et al. JPGN 2023; 76: 561-565. Pneumatosis Intestinalis in Children With Intestinal Failure: The Result of Intestinal Stress From Enteral Feeding?

This was a single-center, retrospective review (n=111) of children with intestinal failure (2019-2022). Key findings:

  • 30.6% of patients (34 of 111) developed PI
  • Only one patient had a surgical cause (midgut volvulus) identified

The authors speculate that enteral feedings, in some, cause a stress (?relative ischemia, ?intraluminal pressure) which leads to pneumatosis.

My take: We still don’t understand pneumatosis intestinalis (PI) very well outside of the neonatal population where it is often a life-threatening medical condition.

Related blog post: Image Only: Pneumatosis Intestinalis in Necrotizing Enterocolitis

Does Positioning Help Infants with Reflux?

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IM Paul et al. JPGN Reports 2023; 4(2):p e312. Open Access! Pilot Study of Inclined Position and Infant Gastroesophageal Reflux Indicators

Methods: Healthy infants aged 1–5 months with gastroesophageal reflux disease (GERD) (N = 25) and controls (N = 10) were enrolled into one post-feed observation. Infants were monitored in a prototype reclining device for consecutive 15-minute periods in supine position with head elevations of 0°, 10°, 18°, and 28° in random order. Continuous pulse oximetry assessed hypoxia (O2 saturation <94%) and bradycardia (heart rate <100).

Key findings:

  • Overall, 17 (68%) infants had 80 episodes of hypoxia (median 20 seconds duration), 13 (54%) had 33 episodes of bradycardia (median 22 seconds duration), and 15 (60%) had 28 episodes of regurgitation.
  • For all 3 outcomes, incident rate ratios were not significantly different between positions, and no differences were discovered for observed symptoms or infant comfort.

Limitations: This was a one-feeding study with a small number of infants

My take: This study shows a high frequency of transient hypoxia and bradycardia in healthy infants with regurgitation. In addition, there was not improvement in reflux parameters in the inclined position.

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Tucson Botanical Gardens

Incredible Review of GERD, BRUE, Aspiration, and Gastroparesis

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Recently, Rachel Rosen gave a terrific review of reflux and reflux-related entities as part of our annual William (Billy) Meyers lectureship.  This lecture information would be helpful for every pediatric gastroenterologist as well as every pediatrician, pediatric ENT, pediatric pulmonologist, pediatric SLP and lactation specialist.  It puts to rest many obsolete ideas about reflux and its management. Some of her points have been covered by this blog previously (see links below) and by her bowel sounds podcast (see link below).   Some errors of omission and transcription may have occurred as I took notes during this lecture. 

Main points:

Reflux

  1. Using the label “GERD” increases the likelihood that an infant will be prescribed acid blockers; this phenomenon is noted as well with SLP and lactation specialist team members.  Everyone needs to be careful about ascribing infant symptoms to “reflux disease”
  2. AR formulas need acid to increase their viscosity (don’t use PPIs in infants taking AR formulas). Also, AR formula viscosity is hindered when mixed with breastmilk (don’t mix with breastmilk)
  3. Most infants with reflux have nonacid reflux.  PPIs do not help nonacid reflux
  4. PPIs are associated with increased aspiration and infection risks.  Acid suppression has been associated with increased risk of allergic diseases
  5. Rumination can look a lot like reflux on pH probe studies
  6. Reflux hypersensitivity, and functional heartburn can result in similar symptoms as reflux (can be distinguished with pH testing)
  7. Pepsin can increase lung inflammation and can be increased by PPI use
  8. Red airway appearance is NOT indicative of reflux (poor specificity, poor sensitivity)
  9. If having symptoms with transpyloric feedings, this indicates that the symptoms are NOT due to reflux; transpyloritc feedings have similar efficacy as a fundoplication
  10. Avoid fundoplication.  It does not result in fewer hospitalizations or improve pulmonary outcomes.  It can result in a number of complications
  11. Consider genotyping for CYP2C19 pharmacogenetics in patients receiving chronic PPI.  Those with rapid metabolism could benefit from higher doses.  Those with slow metabolism could benefit from lower doses.  Higher doses of PPIs increase risk for infections
  12. Bolus feedings result in fewer problems than continuous feedings

Delayed Gastric Emptying (Gastroparesis)

  1. Delayed GE is associated with increased lung bile acids.  This is important in lung transplant recipients and increased lung bile acids is seen more commonly in those with frequent admissions for respiratory issues
  2. In Dr. Rosen’s experience, prucalopride is currently the most useful promotility agent in documented gastroparesis

BRUE:

  1.  Infants with BRUE need to be tested for aspiration, not prescribed PPIs.
  2.  VSS (aka OPMS) has the highest yield of any test in infants with BRUE (~72% abnormal testing in one study). 
  3. Silent aspiration is common -don’t rely on SLP bedside assessment.
  4. Even with this diagnosis, many infants are still prescribed PPIs which increase the risk of complications (more hospitalizations, more infections, possible increase in allergies)

Aspiration:

  1. There are a number of potential etiologies, though most infants have aspiration due to neurological reasons (most transitory and improved by 7 months of age)
  2. In Boston, less than 5% with aspiration on VSS required GT placement
  3. Thickeners can be very helpful.  Practitioners need to know the differences (don’t use Simply Thick in 1st year of life due to NEC risk)

Chronic Cough:

  1. ~10% of kids with chronic cough have eosinophilic esophagitis (who have seen GI in Boston)

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Cacti at Tucson Botanical Gardens

Endoscopy Complications in Hematopoietic Stem Cell Transplantation Population

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J Chan et al. JPGN 2023; 76: 494-497. Complications and Utility of Gastrointestinal Endoscopy Post Hematopoietic Stem Cell Transplantation: An 11 Year Experience

In this study, sixty-six of 339 (19%) HSCT needed an “endoscopy episode.” Key findings:

  • Four of 119 (3%) endoscopies had complications: septic shock (1), duodenal hematoma (1), GI bleeding (1), and colonic perforation (1). 
  • Fifty-seven of 62 (92%) endoscopy episodes were “clinically useful,” and 41 of 62 (66%) had a change in immunosuppressive treatment.

My take: Endoscopy provides useful information in children following HSCT. However, the consent needs to reflect the much higher risk in this population.

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Tucson Botanical Gardens

Transplant Medicine: Need to Improve the Miracle

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Amy Silverstein, NY Times 4/18/23: My Transplanted Heart and I Will Die Soon

A few excerpts:

My 35 years living with two different donor hearts (I was 25 at the time of the first transplant) — finishing law school, getting married, becoming a mother and writing two books — has felt like a quest to outlast a limited life expectancy. With compulsive compliance, I adhered to the strictest interpretation of transplant protocols. I honored my gifts of life with self-discipline: not one pat of butter; not one sip of alcohol; running mile after mile hoping to stave off vasculopathy, an insidious artery disease that often besets transplanted hearts within about 10 years...

But now I lower my chin and whisper the words malignant … metastatic … lungs … terminal. It is the end of the road for my heart and me…

Organ transplantation is mired in stagnant science and antiquated, imprecise medicine that fails patients and organ donors. And I understand the irony of an incredibly successful and fortunate two-time heart transplant recipient making this case, but my longevity also provides me with a unique vantage point...

Over the last almost four decades a toxic triad of immunosuppressive medicines — calcineurin inhibitors, antimetabolites, steroids — has remained essentially the same with limited exceptions. These transplant drugs… cause secondary diseases and dangerous conditions, including diabetes, uncontrollable high blood pressure, kidney damage and failure, serious infections and cancers...

Transplantation is no different from lifelong illnesses that need newer, safer, more effective medicines. Improvements in drug regimens are needed for lupus, Parkinson’s and a host of others. The key difference is that only in transplantation are patients expected to see their disease state as a “miracle.” …But this narrative discourages transplant recipients from talking freely about the real problems we face and the compromising and life-threatening side effects of the medicines we must take.

This “gratitude paradox,” as I’ve come to think of it, can manifest itself throughout the transplant professional communities as well. Without vigorous pushback, hospitals and physicians have been allowed to set an embarrassingly low bar for achievement.

My take: Though organ transplantation has extended lives, this touching first-hand account outlines important obstacles/challenges that transplant medicine continues to face. For pediatric providers, the article is even more sobering as good outcomes need to last even longer.

The response letter to this column are worth a read: Letters -Hard Truths About Organ Transplants Some excerpts:

From Roger Mills:The procedure is not a cure, but a trade. Patient and physician agree to manage a short-term life-threatening illness by substituting a long-term life-threatening illness — immunosuppression…I take issue only with her understandably harsh words about “stagnant science and antiquated, imprecise medicine that fails patients and organ donors.” Early on, many thought the immune response would yield to targeted therapies using relatively nontoxic small molecules. But experience has taught us that managing the immune response is like peeling back layers of an onion. There are more layers than we ever dreamed of, and each one brings more tears.

From Judith Hale: Here is another story: I’m a healthy, happy 74-year-old who received a heart transplant at the age of 56. I live a normal life: I walk at least two miles a day, cross-country ski in the winter, and tend my garden the rest of the year. I’m not on any special diet: I eat butter and drink an occasional glass of wine with dinner. I have virtually no side effects from the medications. I couldn’t be more grateful for the advances in medical science that have, so far, given me 18 healthy years of life.

From Ronald Kalen: In fact, the advances of transplant medicine have been remarkable given the complexity of the immune system. It is not a trivial problem for research. Dedicated scientists have spent careers in prolonging the life of the transplanted organ, as well as the life of the person receiving that organ, and are as aware as Ms. Silverstein of the “deeply entrenched problems” that remain. Their research is not “mired in stagnant science and antiquated, imprecise medicine that fails patients and organ donors.”

Related reference: M Tincopa. Liver Transplantation 2023; 29: 548-554. CAQ Corner: Long-term medical complications of liver transplantation

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Sunset on Tumamuc Hill, Tucson AZ

Lipid Changes with IBD Medications

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JAM Sleutjes et al. Inflamm Bowel Dis 2023; 29: 531-538. Open Access! Lipid Changes After Induction Therapy in Patients with Inflammatory Bowel Disease: Effect of Different Drug Classes and Inflammation

In this prospective study (n=198), the authors examined lipid profile changes at week 10 in patients starting IBD medications: corticosteroids, thiopurines, methotrexate, anti-TNF-α agents, vedolizumab, ustekinumab, and tofacitinib.

Key findings:

  • Relative increases in total cholesterol, HDL-c, and LDL-c were significant after prednisone (+26%, +31%, +12%) and tofacitinib therapy (+20%, +25%, +26%), respectively
  • No changes were observed in other drug classes
  • Findings did not correlate with calprotectin or CRP values, likely indicating a direct medication effect

My take: Recent studies have provided some reassurance regarding tofacitinib and the risk of major adverse cardiovascular events (MACEs) (see posts below). Nevertheless, it seems prudent to monitor lipids in patients receiving JAK inhibitors.

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The Oro Valley/Tucson Loop shared use bike path extends over 130 car free miles throughout unincorporated Pima County, Marana, Oro Valley, and Tucson. We managed a 40 mile bike trip.

How Effective and Safe is Fecal Microbiota Transplantation in Immunocompromised Pediatric Patients with Clostridioides difficile?

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KR Conover et al. JPGN 2023; 76: 440-446. Fecal Microbiota Transplantation for Clostridioides difficile Infection in Immunocompromised Pediatric Patients

In this multicenter retrospective cohort (n=42), the authors examined the efficacy and safety of fecal microbiota transplantation (FMT) in immunocompromised (IC) children with Clostridioides difficile infection (CDI).  Etiology of IC included: solid organ transplantation (18, 43%), malignancy (12, 28%), primary immunodeficiency (10, 24%), or other chronic conditions (2, 5%)

Key findings:

  • 23 (55%) of FMT was delivered via colonoscopy, 17 (40%) were delivered via enteric tube, and 2 (5%) via capsule
  • Success rate was 79% after first FMT and 86% after 1 or more FMT.
  • There were serious adverse events (SAEs) in 13 out of 42 (31%) patients; 4 (9.5%) of which were likely treatment-related (all patients recovered). These events included cecal perforation, aspiration pneumonitis, diarrhea and fever. Given retrospective design of study, AEs were likely underreported

My take: Though there are the potential for significant adverse effects, FMT is effective in a high percentage of immunocompromised children with CDI.

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View from Mt Lemmon, Tucson AZ
View from Mt Lemmon

Prognostic Tool for Biliary Atresia after Kasai: Serum Bile Acids

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S Harpavat et al. Hepatology 2023; 77: 862-873. Open Access! Serum bile acids as a prognostic biomarker in biliary atresia following Kasai portoenterostomy

Methods: Participants with biliary atresia from the Childhood Liver Disease Research Network, in a prospective observational cohort, were included if they had normalized bilirubin levels 6 months after KP and stored serum samples from the 6‐month post‐KP clinic visit.

Key Findings:

  • The ≤40 μmol/L group (n=43) had a 10‐year cumulative incidence of liver transplant/death of 8.5% compared with 42.9% for the >40 μmol/L group (n=94) (p = 0.001).
  • At 2 years of age, the ≤40 μmol/L group had significantly lower total bilirubin, aspartate aminotransferase, alanine aminotransferase, gamma‐glutamyltransferase, bile acids, and spleen size, as well as significantly higher albumin and platelet counts.
  • In addition, during 734 person‐years of follow‐up, those in the ≤40 μmol/L group were significantly less likely to develop splenomegaly, ascites, gastrointestinal bleeding, or clinically evident portal hypertension.
  • The 137 patients included in this study were only a small fraction of the 756 children enrolled in these studies. 232 children failed to achieve normalized serum bilirubin levels by 6 months following KP, 279 children did not have a 6‐month post‐KP serum bilirubin value, and 108 children did not have serum available for bile acid testing.

My take: Only a fraction of children with BA normalize their bilirubin by 6 months after Kasai procedure. In those with normalized bilirubin (T bilirubin <1.5 mg/dL or conjugated <0.2 mg/dL), elevated serum bile acid levels indicate a high risk for progressive liver disease.

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