Category Archives: Pediatric Gastroenterology Intestinal Disorder

Reporting Bias: Infections with TNF Inhibitors

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A recent article (Clin Infect Dis 2013; 57: 1318-30 -thanks to Jeff Lewis for this reference) summarized the pediatric literature on infectious complications associated with tumor necrosis factor-α (TNF) inhibitors for both Juvenile Idiopathic Arthritis (JIA) and Inflammatory Bowel Disease (IBD).

In total 33 studies for JIA were included and 39 studies for IBD.  Many others were excluded due to overlapping cohorts or lack of sufficient data.

For JIA, the authors identified 296 infliximab (IFX) patients, 2465 etanercept patients, and 242 adalimumab patients.  Most infectious were mild and mainly viral etiology.  For example, 1016 upper respiratory illnesses with etanercept were reported.  However there were a significant number of more serious infections which included lower respiratory infections (n=37), cellulitis/abscess (n=15), histoplasmosis (n=2), and meningitis (n=4). Four patients had infectious fatalities.

Similarly, for IBD, most patients had mild infections.  Among 1407 IFX patients and 241 adalimumab (ADA) patients, there were 105 URIs noted.  Again, more serious infectious were noted in many.  Four fatalities were reported; 1 was due to disseminated CMV, 1 due to bacterial sepsis, and 2 were due to central line infections.

When examining this report, the question of reporting bias cannot be avoided. The various reports that were summarized included 30 prospective studies, 23 retrospective studies, and 19 various reports (case reports, case series, and FDA reports).  The composite, in my view, likely overestimates the risk of serious infections.  In addition, many of the infections may have been due to concurrent immunosuppressive therapy, but the details for this are lacking.

With regard to microbiology:

  • 5 JIA patients had tuberculosis; there were no tuberculosis cases reported in the IBD cohort
  • Varicella/zoster was the most frequent viral infection and was frequently severe.  In JIA cohort, there were 39 VZV cases (11 severe); among IBD cohort, there were 16 VZV cases (3 severe).

Bottomline: Given the frequent use of anti-TNF agents, better prospective pediatric data are needed.  In addition, careful analysis of the data is needed for better attribution; the risk for many of these infections is likely due to concurrent medications like corticosteroids.

Also Noted:

Clin Gastroenterol Hepatol 2013; 11: 826-31.  In a prospective cohort of 200 anti-TNF-naive adult patients (100 treated with IFX and 100 with ADA), the effectiveness was similar for IFX and ADA at both 1 and 2 year followup.  Improved efficacy was noted when these agents were combined with immunomodulators, though this was statistically significant for IFX. The total patient response was 63.5% at 1 year and 45% at 2 years.

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Rehabilitation for Short Bowel Syndrome

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As noted in several blog posts, there have been some important advances in the care of short bowel syndrome (SBS)/intestinal failure (IF) patients which have resulted in improved outcomes.  A recent review of 28 children with ≤20 cm of small bowel has been published (J Pediatr 2013; 163: 1361-6, editorial 1243) and provides tangible evidence of these changes.

This retrospective study reviewed the charts of these children managed at Omaha’s intestinal rehabilitation program.  7 patients had NEC, 6 intestinal atresia, 6 had gastroschisis, 3 omphalocele, 5 had malrotation, and 1 patient had vascular disease.

Key results:

  • 27 survived (96%)
  • 14 (50%) had at least one lengthening procedure; in this cohort, bowel lengthening was not associated with a greater rate of adaptation than native bowel.
  • 13/27 (48%) achieved parenteral nutrition independence (“nutritional autonomy”) with their native bowel.
  • Predictors of “successfully rehabilitated” patients: intact colon and ileocecal valve
  • All patients had improvements in lowering PN requirements, total bilirubin, and growth z-scores.
  • Serum transaminase levels did not improve in the nonrehabilitated patients

The main medical treatments at IRP include use of agents for control of bacterial overgrowth, reducing gastric acid production, lipid minimization, promotility and antimotility agents (eg. loperamide), and ethanol locks.  The editorial comments on the “poor results” for surgical intervention, “particularly among those with ultra-short bowel.” This may be due to ‘marginal motility, ischemia, severe wall thickening, or due to adhesions.’

With regard to ethanol locks, the editorial supports them but states, “the main factor in prevention [of line infections] has been maintaining a consistent and strict protocol for catheter care.”

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How Birth Can Affect Your GI Tract

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A recent review (JPGN 2013; 57: 543-49) provides information about the relationship between neonatal environment and subsequent inflammatory gastrointestinal disease.

While most of the review, focuses on physiology and pathophysiology, the most interesting part is the assertions (with references) in Table 1 which include the following:

  • Breastfeeding reduces risk of IBD
  • Cesarean section increases the risk of celiac disease, cow’s milk allergy, and other IgE-mediated food allergies
  • Many chronic adult diseases have been shown to have origins in neonatal life, particularly cardiovascular disease/metabolic syndrome

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Primary Enteric Nervous System Disorders

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If you are wondering what these are, you may want to review a recent consensus statement (JPGN 2013; 57: 677-86).

This ‘practical guide’ discusses Hirschsprung’s disease, intestinal neuronal dysplasia, chronic intestinal pseudo-obstruction, ultrashort segment Hirschsprung’s disease, hypoganglionosis, and ganglioneuromatosis in MEN 2B.

Most of the focus is on Hirschsprung’s disease including the intricacies of diagnosis, clinical presentation, and genetics.  While the authors do mention the PHOX2B gene and others, there is not a discussion of Ondine’s curse (Congenital central hypoventilation syndrome and Hirschsprung’s …).  One point that I think is important (but not discussed in the above reference) in patients who have Ondine’s curse and Hirschsprung’s is determining whether a family member may have a milder phenotype that could still place them at risk for sudden death (eg. after a simple sedation procedure).

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What is calretinin? | gutsandgrowth

Explaining the Vitamin D Paradox

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For a long time, there has not been a satisfying explanation for the fact that blacks have higher bone mineral density but lower 25-hydroxy-vitamin D levels than whites.  New research (NEJM 2013; 369: 1991-2000, editorial 22047-48) helps explain this paradox.

This study examined a community cohort of 2085 individuals in the “Healthy Aging in Neighborhoods of Diversity across the Life Span” study.

Key Findings:

  • Blacks had higher bone mineral density and lower 25-hydroxy-vitamin D levels than whites
  • The calculated bioavailable levels of 25-hydroxy-vitamin D were similar to whites.

The editorial notes that the similar bioavailability is due to differences in the vitamin D-binding protein (aka GC-globulin).  “GC1F is the most abundant form in persons of African ancestry whereas GC1S is most abundant in European populations.”  Thus, it has been hypothesized that the vitamin D-binding protein in blacks has “increased affinity for vitamin D3, and thus able to transport vitamin D3 more efficiently from the skin to the liver for its metabolism to 25-hydroxy-vitamin D.”

Bottomline: This research in vitamin D metabolism may impact on how we determine vitamin D deficiency.  The measurement of vitamin D-binding protein may need to be incorporated into the assessment.

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Reclassifying Biliary Atresia -Three Subtypes

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Using a large prospective multicenter cohort (ChiLREN study group), a recent study examined 289 infants and identified three subtypes of biliary atresia (BA) enrolled in PROBE (Hepatology 2013; 58: 1724-31).

Previously, BA has been considered to have two presentations:

  • Acquired/nonsyndromic ~90%
  • Embryonic/syndromic ~10%

However, this study suggests the following:

  • Group 1 -nonsyndromic, isolated BA. n=242 (84%)
  • Group 2 -BA with major malformation but without laterality defect. n=17 (6%)
  • Group 3 -syndromic, with laterality defect. n=30 (10%)

Group 3 BA defects included splenic abnormalities (eg. asplenia, polysplenia, right-sided spleen), cardiovascular anomalies (eg. dextrocardia, TAPVR, interrupted IVC) and gastrointestinal anomalies (eg. “abdominal heterotaxy,” malrotation, annular pancreas).

In contrast, Group 2 BA had frequent genitourinary problems (cystic kidney and hydronephrosis) along with different cardiovascular anomalies and gastrointestinal anomalies which included esophageal/duodenal/jejunal atresia and imperforate anus.

Other points:

  • The frequency of cardiac problems is particularly important to recognize as this could make differentiation from Alagille syndrome more difficult.
  • One other interesting finding was the high incidence of autoimmunity in first-degree relatives of all BA groups (~44%).

Bottomline: there are at least 3 subtypes of BA.

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Long-term Outcomes with Pediatric PEG Placement

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As noted about a week ago in this blog, gastrostomy tube (gtube) placement in children is much different from gtube placement in adults.

A retrospective study from Boston Children’s followed 138 patients who had PEG tube placed between 1999-2000 (JPGN 2013; 57: 663-67).  The median followup was approximately 5 years.

Results:

  • Median time to elective tube removal was 10.2 years.
  • ~50% of patients continued with gastrostomy tube 10 years after placement.
  • 11% (n=15) had at least 1 major complication related to gastrostomy placement.  Major complication was defined as any unplanned adverse events requiring hospitalization, surgery (eg. fundoplication) or interventional radiology (eg. gastrojejunal tube placement). Most major complications occurred during the first 6-12 months following placement with the most common being cellulitis (n=10).
  • 18% of the cohort died during the 10-year study period because of non-gastrostomy-related issues.  No deaths were attributed to gastrostomy tube placement.

Bottomline: The need for gastrostomy tube placement is associated with frequent comorbidities.  A significant number of patients undergoing gastrostomy tube placement experience major complications.

Also noted:

JPGN 2013; 57: 659-62. This prospective study of 69 patients showed that early reintroduction of feedings after gastrostomy placement, 4 hours postoperatively, was safe and compared favorably to those fed 12 hours postoperatively.  Early feedings were associated with hospital duration, on average, of 6.7 hours. At this center, prophylactic antibiotics were not administered without apparent increase in infections.

JPGN 2013; 57: 668-72. This retrospective study of 77 children with feeding disorders showed that inpatient behavioral interventions are effective in transitioning children from gastrostomy tube feeding to oral feeding.

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Microscopic, Lymphocytic and Collagenous Colitis

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Microscopic Colitis (MC) is a rare pediatric problems and occurs when chronic diarrhea occurs in the presence of a normal-appearing endoscopic exam but with abnormal histology.  In adult populations, microscopic colitis is seen more frequently and can be confused with irritable bowel syndrome.  The two subtypes:

  • Lymphocytic Colitis (LC):  >20 intraepithelial lymphocytes/100 colonocytes
  • Collagenous Colitis (CC): thickened subeptihelial collagen band in addition to changes seen with LC

In a recent study (JPGN 2013; 57: 557-61), 27 MC cases were identified from a pathology database between 1995-2011.  5 were excluded due to an enteric infection.  Among the 22 other cases, 19 had LC and 3 had CC.  Association with celiac disease was evident in 4 patients and many had preceding drug exposures.

Treatment included steroids, melamine, an bismuth.

Additional references:

  • -JPGN 2011; 53: 579. lymphocytic colitis case report
  • -Clincal Gastro & Hep 2011; 9: 13.  Celaic with persistent symptoms: consider poor adherence**, SBBO*, pancreatic insufficiency*, refractory celiac (rare), PLE, giardia, malignancy, lactose intolerance, functional d/o*, microscopic colitis, Crohn’s*, NSAIDs
  • -Gut 2009; 58: 68-72. Collagenous colitis: Budesonide at 6mg/day maintained remission in ~25%.
  • Gastro 2008; 135: 1510.  Budesonide effective for collagenous colitis; n=48, 9mg/day.
  • -Gastro 2011; 140: 1155. Review of microscopic colitis/collagenous colitis.
  • -Am J Gastroenterol 2010; 105: 859-865.  n=466 & 451 controls.  Microscopic colitis present in 1.5% of IBS patients.  IBS pts with lower incidence of adenomas (7.7.% vs 26%).  9% had diverticulosis (lower).
  • -Clin Gastro & hep 2009; 7: 1210. 4.3% of pts w microscopic colitis had celiac. 44/1009.

Family Resource for IBD

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In cooperation with ImproveCareNow, EmpoweredByKids.com, which was started by a group of parents, developed ‘The Book of Hope.’ This book “contains stories of hope and inspiration from parents and patients of Inflammatory Bowel Disease.  These are encouraging stories to let families know someone else has been there too and you are not alone.”

You can download a copy of the IBD Book of Hope here.

I read through the downloaded version.  In my view, the general theme was of perseverance.  Given some of the difficulties shared in the book, this book might be best when someone is hospitalized and/or very sick rather than at the onset of diagnosis.

What do you think?

Additional family resource:

Free Self Management Handbook endorsed by ImproveCareNow:

https://improvecarenow.org/patients/self-management-handbook

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Predicting Remission in Pediatric Ulcerative Colitis

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Trying to offer realistic information to families on the long-term success of infliximab (Remicade) for pediatric ulcerative colitis has been difficult due to a limited amount of data.  In addition, many studies have a number of limitations which can make it difficult to extrapolate to a less-selected population (According to the study which you would never qualify for …).

A recent post hoc analysis (Clin Gastroenterol Hepatol 2013; 11: 1460-65) from 51 children (age 6-17 years) provides some insight into this issue.  The authors used data collected prospectively during the T72 clinical trial (Clin Gastroenterol Hepatol; 10: 391-99 -reviewed in blog post: Infliximab for children with Ulcerative Colitis | gutsandgrowth).

Results:

  • Week 8 PUCAI scores best predicted which patients would be in steroid-free remission after 1 year of treatment: 9 of 17 (53%) with scores <10 points were in sustained remission compare with 4 of 20 (25%) with scores ≥10.
  • Week 8 PUCAI outperformed mucosal healing in predicting remission.

Key points:

  • PUCAI may have outperformed mucosal healing because the latter can lag behind clinical response.  Furthermore, mucosal healing is more subjective with less interobserver reliability.
  • In patients with known inflammatory bowel disease, endoscopic assessment remains important in several situations: condition or reason for symptoms is in question (eg. exclude irritable bowel symptoms or medication-induced symptoms), acute severe colitis not responding to 3-day treatment with intravenous steroids to exclude superinfection, and to assess mucosa before major treatment changes “such as when starting or stopping biologics and before referral for colectomy.”

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