Category Archives: Pediatric Gastroenterology Intestinal Disorder

Intestinal Failure -Concise Review

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A recent review (CP Duggan, T Jaksic. NEJM 2017; 377: 666-75) concisely reviews recent advances in pediatric intestinal failure.  Most of the review has been covered elsewhere in this blog.  A couple of key points:

Outcomes of intestinal failure:

  • The authors note that a 2012 study identified a 25% mortality rate of infants enrolled between 2000-2004.  “More recent advances have resulted in substantially improved survival rates (>90%).”

Epidemiology of intestinal failure:

  • Using a definition of needing parenteral nutrition for more than 42 days after bowel resection or a residual small-bowel length of less than 25% of normal (for gestational age), intestinal failure was identified in 24.5 cases per 100,000 live births
  • Among infants with birth weight <1500 g, the incidence is 7 per 1000 live births.
  • Frequent causes: necrotizing enterocolitis, gastroschisis

Adaptation of Intestine:

  • Improved chances of attaining enteral autonomy if longer residual small bowel, younger age at time of intestinal resection, preservation of ileocecal valve, absence of severe liver disease, diagnosis of necrotizing enterocolitis, and normal motility.

Parenteral nutrition:

  • Lower rates of liver disease noted with routine restriction of soy-based fat emulsions to 1 g per kilogram
  • Fish oil preparations (with n-3 fatty acids): switching to fish oil preparation “reduces biochemical measures of cholestasis.”
  • Newer preparations of fat emulsions: Smoflipid, Clinolipid are FDA-approved for adults.  Smoflipid, in small studies, is associated with lower conjugated bilirubin compared with soy-based lipids.

Enteral nutrition:

  • “Prompt initiation of enteral feeding after bowel resection has been reported to improve the rate of enteral autonomy….little justification for prolonged ‘gut rest'”
  • The authors note that human milk is often chosen for enteral nutrition and when unavailable, amino acid based formulas are typically chosen due to “more favorable outcomes than protein hydrolysates.”
  • Chronic diarrhea is improved with drip feedings, though bolus feeds may have trophic effects.  “In our experience, a combined approach (e.g. continuous feeding at night and bolus feeding during the day) is feasible.”
  • Oral motor stimulation is important.  Thus, try to give oral human milk feeds when feasible.

Medical Therapies:

  • Acid blockers: used for hyperacidity after massive resection
  • Loperamide
  • Bile acid sequestrants (eg. cholestyramine)
  • NOT evaluated in intestinal failure: octreotide, racecadotril, crofelemer
  • Motility agents
  • Antibiotics for bacterial overgrowth.  “Cyclical use (1 week per month) of broad-spectrum antibiotics…is the mainstay of therapy…at many centers.”
  • Probiotics: “No evidence of benefit in small studies; risk of sepsis”
  • Pancreatic enzymes: rarely used. Indicated if pancreatic atrophy or exocrine insufficiency
  • Growth factors: Teduglutide -licensed for adults, studies in children are ongoing

Surgical Therapies:

  • Central lines
  • Gastrostomy Tubes
  • STEP procedure or possibly lengthening procedure (Bianchi).  STEP procedure is less technically difficult.

Previous related blog entries:

The Non-Biopsy Diagnosis of Pediatric Celiac Disease

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In some corners, experts have suggested the need for a followup intestinal biopsy to assure that celiac disease is responding to a gluten-free diet (Related blog post: Are followup biopsies necessary in celiac disease? Look beyond the headlines).  Meanwhile, many are looking at performing zero biopsies –at diagnosis or later. A recent study (J Wolf et al. Gastroenterol 2017; 153: 410-9) involved a prospective enrollment of 898 children undergoing duodenal biopsy to confirm or rule out celiac disease (CD).  Patients had tissue transglutaminase IgA (TTG IgA), total IgA and deamidated gliadin IgG (DGL-IgG) measured.

Key findings:

  • 592 had CD and 345 did not have CD.  24 did not have a final diagnosis.
  • In examining non-IgA deficient patients that had either TTG IgA >10 times ULN or normal (<1 times ULN), the positive predictive value for CD was 0.988 and the negative predictive value was 0.934.
  • In examining patients with both TTG IgA elevation (>10 times ULN) and DGP-IgG (>10 times ULN) or normal labs, the positive predictive value (PPV) for CD was also 0.988 and the negative predictive value (NPV) was 0.958.  The authors estimated that the PPV and NPV would remain >0.95 even at disease prevalence rates as low as 4%.
  • In this high prevalence population, the authors note that only 23% would have required an endoscopy to confirm or exclude CD; however, they note that in another study using consecutive serologic data, a much higher proportion (57%) needed biopsies due to serology that was <10 times ULN.
  • The authors note that HLA status genotyping, which has been recommended as needed in non-biopsy diagnosis, is not helpful.  Compatible HLA status was noted in all 277 cases of TTG-IgA >10 times ULN and was deemed “unnecessary” by the study authors in those with high titers.

The ESPGHAN guidelines for non-biopsy diagnosis indicate that a repeat serologic study should be performed to exclude a sample mix-up and to only forego biopsies in symptomatic patients.

My take: This study show\ed that individuals with high celiac serology titers have celiac disease >98% of the time.  This information should be discussed with families in determining whether endoscopic biopsy is needed.  Among those who pursue a non-biopsy approach, some individuals could have competing etiologies for their symptoms; thus, a low threshold for evaluation is needed in those who do not respond to a gluten free diet

Related blog posts:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  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.

Rotunda View at UVa

 

Followup Biopsies in Pediatric Celiac Disease?

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Last December, this blog site discussed a widely-reported, provocative study suggesting that “1 in 5 pediatric celiac disease patients on gluten-free diet sustain persistent intestinal damage” (Are followup biopsies necessary for Celiac disease? Look beyond the headlines).

Apparently a great number of celiac disease (CD) experts took exception to the authors’ conclusion that “neither the presence of symptoms nor positive serology were predictive of a patient’s histology at the time of repeat biopsy. These findings suggest a revisitation of monitoring and management criteria of celiac disease in childhood.” 

A recent commentary (S Koletzko et al. JPGN 2017; 65: 267-9) from the CD working group of ESPGHAN critiques the limitations of the study. Limitations included the following:

  • Selection bias -70% of patients in this retrospective study had repeat endoscopy were symptomatic
  • Retrospective study
  • Including children with admitted non-adherence to gluten-free diet (GFD)
  • Including ~25% of children who were rebiopsied within 17 months of starting GFD
  • Lack of standardized tTG testing
  • Lack of blinding of pathologist

Their conclusions:

  • “We do not think that the data..give sufficient support…that routine biopsies should be performed in all children at diagnosis and after the initiation of GFD.”
  • “The CD working group of ESPGHAN strongly advises against regular rebiopsy in children on a GFD…Re-endoscopy should be reserved for symptomatic patients–in particular when seronegative.”

The authors of the initial study (MM Leonard, A Fasano. JPGN 2017; 65: 270-1) were given an opportunity to defend their conclusions. Their commentary was much less provocative in my view, and titled: “Zero, One, or Two Endoscopies to Diagnosis and Monitor Pediatric Celiac Disease? The Jury is Still Out”

They note that there is a lack of data to know whether there are “no real clinical consequences” of persistent enteropathy, as stated by S Koletzko et al.  They state that until further research is completed a “personalized approach to follow-up care is needed.”  It is encouraging that they have started a prospective study to address the limitations of their retrospective study.

My commentary:

  • For patients with CD who are strictly-adherent, asymptomatic and with normal serology, repeat endoscopy is of questionable benefit.  If there are abnormalities in the histology, what is the appropriate intervention?
  • There has been a study (Gastroenterology 2010; 139: 763) which showed that mortality was NOT worsened in undiagnosed CD (identified by review of serology) in Olmstead County. In this population, the main long-term detrimental effect was reduced bone density. My inference is that for CD patients who are asymptomatic, particularly those with normalized serology, they are unlikely to have easily-identifiable adverse effects noted, even if their histology is abnormal.

My take (unchanged from last year): I think it is premature to recommend routine followup biopsies in asymptomatic patients with normal serology.

Prague Castle -clever door knocker

AGA Guidelines on Therapeutic Monitoring

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From Healio Gastro: AGA releases guidelines on therapeutic drug monitoring in IBD

Key points from Healio Gastro for Adult Patients with IBD:

  • Reactive monitoring: for patients with a flare or active symptoms: “For patients on maintenance therapy with infliximab, adalimumab or certolizumab pegol who flare after initially responding, if trough levels are below 5 µg/mL, 7.5 µg/mL or 20 µg/mL, respectively without anti-drug antibodies or with low-titer antibodies, then it may be reasonable to try optimizing the index therapy (escalating anti-TNF agent by increasing dose, shortening interval and/or adding immunomodulator)”
  • Proactive monitoring: the guideline states that “no recommendation can be made regarding routine proactive TDM in patients with quiescent IBD being treated with anti-TNFs, as this is a critical knowledge gap in need of further study…careful and selective use of proactive TDM could be beneficial, but current evidence for its routine use is limited and its overall benefits remain uncertain”
  • Thiopurines: the guideline suggests TPMT testing of enzymatic activity or genotype before adults with IBD start treatment with thiopurines.
  • New biologics:  the guideline does not address therapeutic drug monitoring in patients treated with Entyvio (vedolizumab, Takeda) or Stelara (ustekinumab, Janssen) due to a lack of available data.

Reference: JD Feuerstein et al. Gastroenterol 2017; 153: 827-34. Technical review: NV Casteele et al. Gastroenterol 2017; 153: 835-57.

My take: Therapeutic monitoring has become widespread and is quite helpful.  My impression is that most pediatric gastroenterologists have adopted both proactive and reactive monitoring.

Related blog posts:

Looking towards the  top of John Rock Hike, near Brevard, NC

CCFA: Updates in Inflammatory Bowel Disease 2017 (Part 4)

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Our local CCFA chapter provided a useful physician CME meeting.  The following are my notes. My notes may include some errors in transcription and errors of omission.

Ashish Patel  -Updates in Pediatric Inflammatory Bowel Disease Treatments

Key points:

  • Top-down or step-up models are outdated –use appropriate agent for each patient
  • Discussed therapeutic drug monitoring.  In pediatrics, checking infliximab (IFX) level after 14 weeks is recommended by ICN per Dr. Patel.
  • Veolizumab -no pediatric FDA indication yet..  Alpha4Beta7 integrin blocker –blocks recruitment of WBC
  • Stelara -off label in pediatrics.  Seems to be helpful for patients who have psoriasis on TNF agents.
  • Exclusive enteral nutrition (EEN) like medical therapies are therapies and not cures.  It has to be maintained to be effective.

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) and changes in diet should be confirmed by prescribing physician.  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.

Disappointing Results from Small Study of Specific Carbohydrate Diet

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A recent retrospective study (GT Wahbeh et al. JPGN 2017; 65: 289-92) examined seven patients who were receiving a modified specific carbohydrate diet (SCD).  While this is a small stud,y there are several lessons in this report and the thoughtful editorial (pg 266-67): “Alas, Who and What Can We Trust? Patients, Parents, Surrogate Markers of the Specific Carbohydrate Diet” by Stan Cohen (one of my partners).

The participants in the study had a median age of 11 yrs and received their mSCD for a median duration of 26 months.  Key finding: despite lack of symptoms, all subjects had ongoing active disease on endoscopy; the majority had normal biomarkers: CRP, albumin, and hematocrit and only mildly elevated calprotectin (median 201, range 65-312).

Dr. Cohen notes the following lessons from this study:

  • “First, the SCD is very restrictive and young patients often find it difficult to perpetuate”
  • “Families are often presumptive about how well they are doing. Significant signs of malnutrition and lack of weight gain may be ignored.”
  • Patients often “underreport their symptoms and overrerport their adherence.”
  • “Wahbeh et al have taught us…about the lack of effectiveness of a modified SCD [and]…we should use caution in gauging and interpreting patient-reported outcomes and surrogates as well.”

My take: The modified SCD appears to be only partly effective and how this impacts the long-term outcomes for patients is not clear.

Related article: A McCombie. JPGN 2017; 65: 311-13. Summer camp for IBD.  This study of 36 participants: “most reported that camp improved their confidence (86%), acceptance (83%), and overall quality of life (75%). 72% endorsed meeting their fellow campers as the most beneficial experience.  My take: Camp helps ease social isolation associated with a diagnosis of pediatric IBD.

Related blog posts:

Biosimilars: “The Horse is Out of the Barn”

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A recent study (J Sieczkowska-Golub et al. JPGN 2017; 65: 285-88) reports on 36 pediatric patients who received CT-P13, an infliximab biosimilar.  Key findings:

  • 34 of 36 (94.4%) completed induction therapy
  • Clinical response based on pCDAI was noted in 31 of 36 (86%)
  • Clinical remission based on pCDAI was noted in 24 of 36 (67%)

The authors concluded that the induction was effective and similar to the reference infliximab.

In the accompanying editorial, Dr. de Ridder and Dr. Winter make some crucial observations:

  • “Although the study…is important, the number of subjects in this study are low and follow-up is short (14 weeks).”
  • “It is still a large step from adults to children.” Children may have important differences in IBD pathogenesis and pharmocokinetics may not be the same as in adults.
  • The studies supporting CT-P13 (Planetas, Planetra, and NOR-SWITCH) were studies of adult patients.
  • “The data in children are scarce.” However, “the horse has already left the barn. In many European countries both naive pediatric patients with IBD and patients who have switched from the originator are treated with CT-P13.”
  • While “caution is still needed,” the lower costs of CT-P13 will “lead to wider availability.”

My take: We still have a lot to learn.  Until more studies are available, switching stable patients could increase risk of losing response.

Related blog posts:

Eiffel Tower

NEJM: Analysis of the Graham-Cassidy Plan

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NEJM: The Graham-Cassidy Plan -The Most Harmful ACA-Repeal Bill Yet

An excerpt:

The Graham–Cassidy bill would begin by repealing the individual and employer mandates retroactive to 2016. The Congressional Budget Office (CBO) previously estimated that repeal of the individual and employer mandates would immediately increase the number of uninsured Americans by 15 million or more and increase individual market insurance premiums by 20%…

The Graham–Cassidy formula would shift money from states that expanded Medicaid coverage under the ACA or increased take-up among previously eligible groups to those that did not. It would also shift money from high-cost to low-cost areas…

the bill would permit states to waive the ACA requirements that insurance sold in the individual market cover essential health benefits and that insurers not vary premiums on the basis of health status, thereby restoring the ability of insurers to engage in “medical underwriting” and effectively deny coverage or limit services on the basis of preexisting health condition..

All told, we estimate that under Graham–Cassidy, an additional 21 million people would be without insurance coverage in 2020 and later years, and this figure may be conservative..

It replaces effective coverage programs with a block grant that is inadequate in the aggregate and blind to variations in local costs, shifting considerable risk onto states. It would slash the program that provides health insurance coverage for the poor. 

 

CCFA: Updates in Inflammatory Bowel Disease 2017 (part 3)

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More from our recent CCFA Conference.  My notes may include some errors in transcription and errors of omission.

Subra Kugasthasan -RISK Updates

Dr. Kugasthasan’s lecture was excellent.  He reviewed the typical clinical course of Crohn’s disease; in most patients, it has a remitting and relapsing course.  The goal of the CCFA-sponsored RISK study was to determine how early approaches to treatment affect long-term outcomes.  There is likely a window of opportunity to more favorably affect natural history of the disease. In addition, the goal is to determine whether there are predictive markers of severe disease course.  This prospective study analyzed 913 patients.  In this cohort, 835 remained with B1 (inflammatory) phenotype and 90 developed either B2 (stricturing) phenotype or B3 (penetrating) phenotype.

RISK Study Abstract: Prediction of complicated disease course for children newly diagnosed with Crohn’s disease: a multicentre inception cohort study (S Kugathasan et al. Lancet 2017; 389: 17108. DOI: http://dx.doi.org/10.1016/S0140-6736(17)30317-3)

Key findings:

  • Early TNF therapy reduced the likelihood of penetrating (B3) but not stricturing (B2) disease
  • Based on analysis of genetic expression at baseline, individuals who are likely to develop B2 or B3 disease can be identified. This assay may be available clinically in a few years

Jahnavi Srinivasan -Multi-Disciplinary Approach to IBD A Surgical Perspective

  • Teeuwen PH et al study spans a long period and there have been many changes since that time. The study’s 9% 30-day mortality rate is very high (current Whipple 30-day mortality ~2%)
  • 3-stage surgery most common now for ulcerative colitis due to sicker patients who now need operation
  • Harder to differentiate UC and CD
  • Try to get patients off steroids; this is a key factor in surgical complications. Nutritional support may be helpful though some effects may be mediated by helping with steroid tapering

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) and changes in diet should be confirmed by prescribing physician.  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.

CCFA: Updates in Inflammatory Bowel Disease 2017 (part 2)

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Douglas Wolf -New Treatments and New Strategies

  • More proactive approach is recommended; this leads to less surgery, less hospitalization, and less antibodies to infliximab
  • Risk assessment should guide treatment; higher risk indicates a need for more aggressive therapy
  • Higher doses of anti-TNFs appropriate in some cases (eg weekly Humira)
  • For distal colitis/proctitis, budesonide foam is an alternative to cortifoam
  • Azathioprine monotherapy has a low response rate
  • Combination therapy may not be needed if good IFX levels obtained.  Though, it is possible that development of antibodies precludes achieving good levels; thus, combination therapy may increase likelihood of good levels by reducing antibody formation, particularly earlier in course
  • Vedolizumab can be shortened to q4weeks if not improving.
  • CALM study: symptom based management compared to management based treat-to-target relying on CRP, and calprotectin. Improved outcomes with treatment based on CRP, calprotectin in addition to symptoms.
  • Tofacitinib –will be available in 2018 for ulcerative colitis

Chiristina Ha -Treatment Strategies in the Elderly

Dr. Ha referenced Dr. Sandborn who recently stated that combination therapy should be first-line therapy in moderate-to-severe disease –though this may be different in elderly patients.

  • Older age –increases mortality risk
  • Immunosenescence -relative immunodeficiency state associated with aging
  • Pharmokinetic changes with aging
  • Increased susceptibility to drug toxicity (eg. Renal, hepatic)
  • Older patients usually excluded from therapeutic trials
  • Polypharmacy is more common

Treatment:

  • Frequent strategy in elderly has been using 5-ASAs and steroids, even in moderate-to-severe disease. This has been due to increased fear of adverse events with IMM and anti-TNFs.  However, using data from rheumatoid arthritis, older patients’ biggest risk is steroids.
  • Thiopurines have unfavorable risk profile in the elderly.
  • Anti-TNFs are not as effective in the elderly
  • Preliminary data on vedolizumab -very limited data, may work better in older patients
  • Most common infections by be reduced considerably by immunizations. (eg.  ,bacterial pneumonia, herpes zoster)
  • Correct anemia, nutritional deficiencies

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) and changes in diet should be confirmed by prescribing physician.  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.