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.
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
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”
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)
Most infants with reflux have nonacid reflux. PPIs do not help nonacid reflux
PPIs are associated with increased aspiration and infection risks. Acid suppression has been associated with increased risk of allergic diseases
Rumination can look a lot like reflux on pH probe studies
Reflux hypersensitivity, and functional heartburn can result in similar symptoms as reflux (can be distinguished with pH testing)
Pepsin can increase lung inflammation and can be increased by PPI use
Red airway appearance is NOT indicative of reflux (poor specificity, poor sensitivity)
If having symptoms with transpyloric feedings, this indicates that the symptoms are NOT due to reflux; transpyloritc feedings have similar efficacy as a fundoplication
Avoid fundoplication. It does not result in fewer hospitalizations or improve pulmonary outcomes. It can result in a number of complications
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
Bolus feedings result in fewer problems than continuous feedings
Delayed Gastric Emptying (Gastroparesis)
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
In Dr. Rosen’s experience, prucalopride is currently the most useful promotility agent in documented gastroparesis
BRUE:
Infants with BRUE need to be tested for aspiration, not prescribed PPIs.
VSS (aka OPMS) has the highest yield of any test in infants with BRUE (~72% abnormal testing in one study).
Silent aspiration is common -don’t rely on SLP bedside assessment.
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:
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)
In Boston, less than 5% with aspiration on VSS required GT placement
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:
~10% of kids with chronic cough have eosinophilic esophagitis (who have seen GI in Boston)
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.
Liver biopsy risk in children Fox VL, Cohen MB, Whitington PF, Colletti RB. Outpatient liver biopsy in children (n=450). J Pediatr Gastroenterol Nutr 1996;23:213-6. High mortality rate reported, primarily in bone marrow transplant patients
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.
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.”
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.
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.
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.
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.
Methods: Direct stimulated endoscopic pancreatic function test (ePFT) was performed in 74 children with IBD
Key findings:
42 (56.7%) children had either generalized or partial exocrine pancreatic insufficiency (EPI).
Weight z scores were significantly lower in those with abnormal ePFT (Crohn cases: P = 0.008; UC cases: P = 0.046).
In their discussion, the authors assert: “We can confidently recommend ePFT in established or new IBD patients who have stricturing and/or penetrating CD, weight loss, low weight Z-score, or qualify for the diagnosis of malnutrition.”
My take: In my real-world experience (~30 years), I have yet to have one patient presenting with IBD who needed pancreatic enzyme supplementation to reverse growth failure/malnutrition. As a consequence, I have a difficult time accepting the premise that more than 50% have EPI. To me, this suggests that testing children when they are acutely-ill or malnourished is yielding unreliable results.
Methods: A retrospective cohort study was performed using the Military Healthcare System database. N=968,524 children with 1704 cases of celiac disease (CD) in this group (from 2001 to 2013) with prescription for PPIs, H2RAs or antibiotics in first 6 months of life.
Key findings:
PPIs (HR, 2.23; 95% CI, 1.76-2.83), H2RAs (HR, 1.94; 95% CI, 1.67-2.26), and antibiotics (HR, 1.14; 95% CI, 1.02-1.28) were all associated with an increased hazard of CD.
The risk is increased by use of multiple categories of these medications and/or if acid suppression medications are used for longer periods
There have been previous studies indicating an increased risk of CD in patients given acid suppression (Lebwohl et al. Dig Liver Dis 2014; 46: 36-40) and conflicting data regarding the use of antibiotics. With regard to acid suppression, recent studies have indicated that these medications in infancy may increase the risk of food allergies as well. The authors speculate in their discussion that the increased risk for CD could be related to changes in protein degradation, mucosal permeability, microbiome changes, and immune reactivity. The authors note that their dataset did NOT show an increased risk of CD associated with C-section delivery.
One of the limitations of this study is that early presentations of CD could lead to prescriptions of agents to to help reduce symptoms rather than the medications increasing the risk of developing CD. However, this is unlikely as gluten introduction is often later in infancy.
My take: Better stewardship of antibiotics and acid blockers is needed. Use of acid suppression medications is associated with an increased risk of celiac disease as well as food allergies.
gutsandgrowth 