Key findings: HEV Ag was specifically taken up by renal cells and was disposed into urine, during which the level of Ag was concentrated >10‐fold, resulting in the higher diagnosing sensitivity of urine Ag than serum Ag. Moreover, Ag in urine appeared 6 days earlier, lasted longer than viremia and antigenemia, and showed good concordance with fecal RNA in a rabbit model.
Background: Autoimmune enteropathy (AIE) is a severe form of enteropathy characterized by chronic diarrhea refractory to any exclusion diet and associated with autoimmunity…In a recent cohort of 40 AIE patients, anti-enterocyte antibodies were reported in only 14% (4/28) of the cases, likely caused by the high frequency of patients with primary hypogammaglobulinemia…30%–50% of adult AIE can display anti-transglutaminase antibodies. The common histopathologic presentation of AIE includes intestinal villous atrophy with variable lymphocytic infiltration and various features of follicular lymphoid hyperplasia, cryptitis, graft-versus-host disease-like lesions, and loss of Paneth and goblet cells.
Key findings: Pathogenic variants were identified in 20/48 adult patients (41.6%); most common variants: CTLA4, LRBA, STAT3, and STAT1; 12/20; 60% of those with variants. Thus, specific therapeutics were available for more than half of the patients who received a molecular diagnosis
Representative endoscopic aspects in patients with CTLA4 variants and AIE.
Key finding: In this prospective pediatric cohort (n=59) with EoE, distensibility index (DI) <4.5 mm2/mmHg predicted grade 2 rings on endoscopy. Lower DI was associated with increased risk of food impaction but did not correlate with eosinophilic count. DI was “superior to diameter in assessing fibrostenotic severity.”
This small retrospective study with 10 adults examined the efficacy of using a calcineurin inhibitor (cyclosporin (n=9) or tacrolimus (n=1)) as a bridge therapy for long-term ustekinumab treatment. Most patients had failed infliximab (90%) and vedolizumab (80%). Patients received an induction of ustekinumab (6 mg/kg) followed by every 8 week treatment. Calcineurin inhibitor use was used for a median of 45 days.
Key finding:
None of the patients underwent a colectomy at 6 months
One patient remained on steroids at 6 monhts and one patient failed to obtain a clinical response or remission
My take (borrowed from authors): This small retrospective study shows that bridging therapy with a calcineurin inhibitor followed by maintenance therapy with ustekinumab is feasible. Bridging therapy has also been used for vedolizumab (Pellet et al. Clin Gastroenterol Hepatol 2019; 17: 494-501; Ollech et al. Aliment Pharmacol Ther 2020; 51; 637-643)
In Tucson, we stayed adjacent to a bunch of animals that we fed each morning.
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.
This article reviews the results of a venous thromboembolism (VTE) protocol that was implemented in 2018 in children with inflammatory bowel disease (IBD). A total of 313 hospitalizations across 187 different patients were identified that met criteria including IBD and central venous access. This retrospective review focused on children with IBD and and central venous catheter (CVC) Key findings:
VTE prophylaxis increased from 5.24% (n = 12) prior to the intervention to 63.10% (n = 53) after the intervention
Rate of Doppler US increased from 9.17% (n = 21) prior to the intervention to 17.86% (n = 15) after the intervention
Diagnosis of VTE increased from 0.87% (n = 2) prior to the intervention to 7.14% (n = 6) after the intervention (attributed to better detection)
This article provides an algorithm for implementing VTE prophylaxis, recommending prophylaxis if 2 or more risk factors –both IBD and CVCs are risk factors. Mechanical prophylaxis (along with frequent ambulation, if feasible) is generally recommended if there are at least 2 risk factors, whereas anticoagulation prophylaxis is generally recommended if there are at least 4 risk factors. Other risk factors include being post-pubertal, obese, prolonged surgery (>90 minutes) within 2 weeks, altered mobility, and mechanical ventilation (see full protocol in article).
My take: In children at increased risk, the approach to reducing VTE in this article is quite sensible. Nevertheless, more research, especially with regard to institution of anticoagulation, is needed.
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.
This was a multicenter prospective cohort of hospitalized children initiating IFX for ASUC or IBD-unclassified (n=38).
Key findings:
Compared to previous publications of pediatric ASUC, there was a low colectomy rate in this cohort of 2.7% at week 26 and 10.8% at 2 years
Median initial IFX dose was 9.9 mg/kg
Early rapid clearance was strongly associated with colectomy
Faster clearance was associated with higher WBC, presence of antibodies to infliximab and lower albumin. Higher platelets were associated with increased volumes of distribution. Concomitant immunomodulator use (26% with methotrexate, 13% thiopurine) “was not a significant covariate for PK parameters”
Discussion points:
Higher IFX dosing (10 mg/kg) may sufficiently optimize early outcomes in pediatric ASUC. Prior retrospective studies of adult and pediatric ASUC patients have supported lower colectomy rates with intensified induction regimens compared to standard induction regimens
The availability of vedolizumab may also have contributed to a lower colectomy rate
WBCs, “specifically neutrophils, may participate in the elimination of IFX”
Limitations: observational study, lack of dose standardization, lack of endoscopic outcomes
My take: Especially in pediatric patients, there is ample data to support using 10 mg/kg dosing for infliximab in patients with more severe inflammatory bowel disease, both ulcerative colitis and Crohn’s disease.
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.
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.
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.”
