Category Archives: Pediatric Gastroenterology Intestinal Disorder

Abstract Only: Mucosal Healing in Pediatric Inflammatory Bowel Disease

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This post provides the full abstract from today’s earlier post.

 

A retrospective study (Inflamm Bowel Dis 2017; 23: 1447-53) describes assessment of mucosal healing in pediatric patients with inflammatory bowel disease.

Here is abstract:

Background: Mucosal healing (MH) is associated with improved clinical outcomes in patients with Crohn’s disease (CD) and ulcerative colitis (UC). MH as a target for treatment has been suggested, although there is little pediatric data. The goal of this study was to evaluate MH in clinical practice in pediatric patients with inflammatory bowel disease in clinical remission.

Methods: A retrospective review of electronic health record data was performed on all patients with CD or UC who underwent at least 2 colonoscopies from 2010 through 2016. Only patients in clinical remission undergoing a scope for MH were included in our study. The incidence of MH and histologic healing (HH) was analyzed, along with cumulative rates of MH in each group. MH was defined by both physician assessment of MH and an endoscopic score of zero for CD and UC.

Results: A total of 76 patients with CD and 28 patients with UC underwent at least one MH scope while in clinical remission. Of the 76 patients with CD, 51 patients (67%) demonstrated MH by physician assessment, 34 patients (45%) demonstrated MH by a simple endoscopic score for CD of zero, and 35 patients (46%) demonstrated HH. Of the 28 patients with UC, 20 patients (71%) demonstrated MH by physician assessment, 10 patients (36%) demonstrated MH by a Mayo score of zero, and 10 patients (36%) demonstrated HH. Nineteen patients underwent a second MH scope and 11 (58%) demonstrated MH by physician assessment, 7 patients (37%) demonstrated MH by simple endoscopic score for CD or Mayo scores of zero, and 5 patients (26%) demonstrated HH. Of those patients with active disease, 21 of 25 patients with CD underwent escalation of therapy, whereas 8 of 8 patients with UC underwent escalation of therapy. Cumulative rates of MH when defined by physician assessment were 79% (60 of 76 patients) in CD and 79% (22 of 28 patients) in UC.

Conclusions: MH is feasible in pediatric CD and UC, and rates of cumulative MH in pediatric patients are similar to previously published adult data. In children with inflammatory bowel disease in clinical remission, approximately one-third demonstrate active disease at endoscopy.

Pediatric IBD: Treating to Target

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In 2014, an influential study by Sandborn et al (Clin Gastroenterol Hepatol 2014; 12: 978-85) described the importance of mucosal healing in a strategy termed “treating to target.”  The main findings (reviewed in a previous post Treating to Target) were the following:

  • Only half of the patients achieved MH.  “After a median follow-up of 62 weeks, 50.7% had MH and 61.1% had endoscopic improvement.”  79% of those who underwent adjustments achieved MH.
  • Clinical symptoms do not correlate with MH. “40.9% of patients experienced clinical symptoms despite MH and 18.8% of patients without clinical symptoms had significant endoscopic lesions.”
  • Biomarkers may be effective at predicting MH. “None of the patients with MH had an increased concentration of CRP.”
  • Adjusting treatment is needed if abnormal endoscopy; this is inherent in the philosophy of treating-to-target.

Now, my colleagues at Emory have published a single-center experience on mucosal healing (MH) (SL Santha, PR Shankar, A Pan, B Schoen, S Kugasthasan, CG Sauer. Inflamm Bowel Dis 2017; 23: 1447-53).  While this study has the typical limitations of a retrospective study, it makes several useful points.  It takes a little extra effort to interpret their findings as they describe their results based only on the 104 patients with clinical remission rather than based on the total of 182 patients who had at least two colonoscopies.  78 were excluded due to ‘acute GI symptoms.’

Of the 104 patients considered to be in clinical remission, 76 had Crohn’s disease and 28 patients had ulcerative colitis.

Key findings:

  • For patients with ulcerative colitis (UC) who were in clinical remission, 20 (71%) had MH per physician assessment, though only 10 patients (36%) had MH based on Mayo score of zero.  10 patients (36%) demonstrated histologic healing.
  • For patients with Crohn’s disease (CD) who were in clinical remission, 51 (67%) had MH per physician assessment, 34 (45%) had MH base on simple endoscopic score for CD, and 35 (46%) had histologic healing.
  • 21 of 25 CD patients and 8 of 8 patients with UC underwent escalation of therapy based on endoscopic evaluation. 9 patients underwent dose optimization of their biologic as the modification in their therapy; this step is now routinely done in pediatrics without followup endoscopy.

The discrepancy in MH rates based on physician assessment, endoscopic scores, and histologic healing is explained.  Generally, MH based on physician assessment would include normal and those with very mild mucosal disease.  “For CD, this included small and rare aphthous ulcers, and for UC, this included mild Mayo 1 erythema in only one segment of bowel.”

Questions about the approach to ‘treating to target:’

  • This study does not describe other alternative modalities to assess for mucosal healing. Is it feasible to use a biomarker like an abnormal calprotectin to target those in need of further evaluation? In those with abnormal biomarkers, dose escalation would not require a repeat scope.
  • The Emory group has used MRE extensively, but does not report MRE findings in this population.  Would MRE (which does not require sedation) be more useful in some patients?

As in adult patients, this study does show the need for objective markers in pediatric inflammatory bowel disease; 30% of patients who were considered to be in clinical remission had active disease with further investigation.  This finding has implications for ImproveCareNow which uses physician global assessment in tracking remission rates for pediatric IBD.

In their discussion, the authors state that “changes in medical therapy can increase the MH rate to nearly 80%, which could be even higher with additional changes in those who did not demonstrate MH on a second endoscopy.”  This sentence needs to be carefully interpreted.  The authors were able to show MH based on physician assessment in 82 of 104 patients (79%) who were in clinical remission.  This rate would be MUCH lower if the entire cohort of 182 were included, possibly no greater than 50%.

The authors conclude with “endoscopy should be considered in pediatric patients with IBD in clinical remission to identify those without MH who may require medication escalation despite the absence of clinical symptoms.”

My take: I agree with the authors that objective markers of clinical remission need to be obtained to assess the effectiveness of therapy.  However, I am not convinced that endoscopy is needed in every patient who is doing well on therapy; other biomarkers and imaging may be more beneficial.

Related blog posts:

Sign at Pisgah Fish Camp Restaurant: “On this site in 1897 nothing happened.”

 

 

Something Useful for Apparent Life-Threatening Events (ALTEs)

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In many cases of Apparent Life-Threatening Events (ALTEs) (also called Brief Resolved Unexplained Events, BRUEs) in infants, the exact reasons are unclear.  Sometimes these events are blamed on reflux despite studies indicating this is unlikely in the vast majority (see links at bottom of post).

A recent study (DR Duncan, J Amirault, PD Mitchell, K Larson, RL Rosen. JPGN 2017; 65: 168-73) finds that oropharyngeal dysphagia is correlated with ALTEs.

In this retrospective study which took place between 2012-15, the authors reviewed all patients admitted with ALTE.  They excluded infants with underlying diseases that included known neurologic impairment, congenital heart disease, and other congenital anomalies.

Demographics:

  • Median age 49 days
  • Color change: blue 65%, pale 8%, red 10%, none 17%
  • URI symptoms: 23%
  • Relationship to feeds: during 20%, after 35%, none 45%
  • Appeared well in ED 86%

Key findings:

  • Video fluoroscopic swallow study (VFSS) [also called oropharyngeal motility swallow study] was obtained in 29%.  In this group, 73% (n=40) had evidence of aspiration or penetration.
  • 26% of patients who had clinical feeding evaluation and VFSS were ascribed as having no oropharyngeal dysphagia prior to detecting aspiration on VFSS.
  • “Of all of the diagnostic tests ordered on patients with  ALTEs, the VFSS had the highest rate of abnormalities.”

Conclusion (from authors): “Oropharyngeal dysphagia with aspiration is the most common diagnosis identified in infants presenting with ALTEs.  The algorithm for ALTE should be revised to include an assessment of VFSS as clinical feeding evaluations are inadequate to assess for aspiration.”

Related blog post: What to do with ALTEs

Also, an except and link from NASPGHAN Consensus guidelines on GERD (2009)

  • In premature infants, a relationship between GER (i.e. reflux) and pathologic apnea and/or bradycardia has not been established. Despite a lack of convincing evidence, if pathological apnea occurs in the face of pre- existing reflux, then the following two statements are the most common features:
  • Although reflux causes physiologic apnea, it causes pathologic apneic episodes in only a very small number of newborns and infants.
  • When reflux causes pathological apnea, the infant is more likely to be awake and the apnea is more likely to be obstructive in nature.
  • A diagnosis of an acute life-threatening event (ALTE) warrants consideration of causes other than GER (i.e. reflux).Reflux of gastric acid seems to be related to ALTEs (episodes of combinations of apnea, color change, change in muscle tone, choking, and gagging) in < 5 % of infants with ALTE. 
  • Link: Gastroesophageal Reflux Disease in the Pediatric … – NASPGHAN.o

Dry Falls, Highlands, NC

Surgery as Placebo

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A recent summary by 538 website details how surgery can be a powerful placebo: Surgery Is One Hell of a Placebo

Here’s an excerpt:

“expectations matter, and we know they matter because of a bizarre research technique called sham surgery. In these fake operations, patients are led to believe that they are having a real surgical procedure…

A 2014 review of 53 trials that compared elective surgical procedures to placebos found that sham surgeries provided some benefit in 74 percent of the trials and worked as well as the real deal in about half.1 Consider the middle-aged guy going in for surgery to treat his knee pain. Arthroscopic knee surgery has been a common orthopedic procedure in the United States, with about 692,000 of them performed in 2010,2 but the procedure has proven no better than a sham when done to address degenerative wear and tear, particularly on the meniscus…

Even without a robust placebo effect, an ineffective surgery may seemhelpful. Chronic pain often peaks and wanes, which means that if a patient sought treatment when the pain was at its worst, the improvement of symptoms after surgery could be the result of a condition’s natural course, rather than the treatment. That softening of symptoms from an extreme measure of pain is an example of the statistical concept of regression to the mean.

My take: Both with medicine and surgery, sometimes improvement occurs even when the treatment itself is not effective.

Dupont Forest, NC

CHAPLE Syndrome: Early-Onset Protein-Losing Enteropathy

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With more widespread use of whole exome sequencing, new diseases are being uncovered.  CHAPLE syndrome has recently been described: A Ozen et al. NEJM 2017; 377: 52-61.

CHAPLE syndrome comprises CD55 (decay-acclerating factor) deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy (PLE).

  • In this report of 11 patients, 8 presented before 2 years of life.
  • Disease manifestations included chronic diarrhea in 8, abdominal pain in 4, vomiting in 6.
  • PLE features included hypoalbuminemia in 10 of 11, hypogammaglobulinemia in all 11, and primary intestinal lymphangiectasia (or Waldmann’s disease) in 5.
  • Thrombotic disease: 3 with thrombosis, 2 with thrombocytosis
  • Endoscopic findings (2 patients did not have endoscopy): mucosal ulcer in 4, lymphoid infiltrates in mucosa in 6
  • Other features: recurrent lung infections in 5, hypothyroidism in 3, arthritis/arthralgia in 2, and clubbing in 5
  • Patents’ T lymphocytes showed increased complement activation; cytokine modulation by CD55 were defective
  • Treatment: Genetic reconstitution of CD55 or treatment with a complement-inhibitory therapeutic antibody reversed abnormal complement activation

In a related letter to the editor (NEJM 2017; 377: 87-9), Kurolap et al show that eculizimab therapy was helpful in a family with CHAPLE syndrome, reducing PLE and bowel movements within 100 days of initiation.

My take: CHAPLE syndrome needs to be considered in young patients with PLE (& primary intestinal lymphangiectasia).

Shem Creek, SC

Good Safety Data on Infliximab vis a vis Malignancy and Hemophagocytic Lymphohistiocytosis

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Using data from 5766 pediatric participants with inflammatory bowel disease in a prospective DEVELOP study (JS Hyams, MC Dubinsky et al. Gastroenterol 2017; 152: 1901-14) provide more reassurance regarding the safety of infliximab.  This study took place between 2007 to 2016 and accounted for 24,543 patient-years of followup.  While the study examined rates of malignancy, the SEER database does not include non-melanoma skin cancer; thus, the authors did not have a suitable comparator for this outcome; there were two cases of basal cell carcinoma in the study population.  This article’s abstract was published on this blog previously: Infliximab Not Associated with Malignancy

Key findings:

  • There was NO increased risk of malignancy or hemophagocytic lymphohistiocytosis (HLH) in patients exposed to infliximab as monotherapy.
  • Malignancy risk was 0.46 per 1000 patient-years in patients with infliximab exposure compared with 1.12/1000 patient-years in patients who had no exposure to biologics.
  • HLH risk was 0 in those with infliximab monotherapy compared with 0.56 per 1000 patient-years in those who had no exposure to biologics.
  • Patients exposed to thiopurines with or without biologics did have increased risks of malignancy compared with comparative populations. 13 of 15 patients who developed a malignancy and all 5 patients who developed HLH had thiopurine exposure.
  • Thiopurine exposed patients had 0.75 malignancy events per 1000 patient-years compared to 0.27 malignancy events per 1000 patient-years for patients who had no thiopurine exposure
  • Thiopurine exposed patients had 0.29 HLH events per 1000 patient-years compared to 0 HLH events per 1000 patient-years for patients who had no thiopurine exposure
  • In their discussion, the authors note that after discontinuation of thiopurine therapy for 1 or more years, the standardized incidence ratio (SIR) for malignancy approached the non-exposed group (1.48 compared to 1.30); whereas ongoing or recent thiopurine exposure had SIR of 4.45.

Limitations: Study duration (<10 years). Hard to detect changes in rare malignancies

My take: In this largest prospective pediatric cohort to date, there is NO increased risk of malignancy (excluding non-melanoma skin cancer) or HLH with infliximab therapy; however, there is a trend towards increased risk among those with thiopurine exposure. Nevertheless, as malignancy is a rare event, very low increased risk of malignancy with infliximab cannot be entirely excluded.

Related blog posts:

For HLH:

 

Hazardous Toys: Jarts and Magnets

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I had completely forgotten about Jarts until reading a recent editorial by Athos Bousvaros (J Pediatr 2017; 186: 6-7). He succinctly describes how these lawn darts were ultimately removed from the market primarily due to the advocacy of a father who became a strong advocate after the death of his daughter.

A more complete description of the effort to remove Jarts -from Mental Floss website: How One Grieving Father Got Lawn Darts Banned

Dr. Bousvaros, in commentary on a study on high-powered (neodymium) magnets (Rosenfeld D et al. J Pediatr 2017; 186: 78-81) describes the similarities between these magnets and the jarts.  Both have caused catastrophic injuries and death.  However, the recent removal of these magnets from the market was overturned.  There is no national tracking system for magnet ingestions in U.S. or Canada.  However, the referenced study demonstrated a dramatic reduction  in medical/surgical procedures in 2014-2015 (n=10) when a ban was placed compared to 2011-2012 (n=29).

For U.S physicians, all we can do currently is to report to the CPSC (Consumer Product Safety Commission) all magnet-related injuries and to publicize the dangers of these hazardous products.  To report: go to CPSC website (link: CPSC website) and “report an unsafe product” on the right side of the page.

Related blog posts:

Is there a link between Eosinophilic Esophagitis and Celiac Disease?

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Probably most pediatric gastroenterologists have seen patients who underwent endoscopy for celiac disease and found out that the patient had both celiac disease and esophageal eosinophilia.  Whether the esophageal eosinophilia should be classified as eosinophilic esophagitis (EoE) is based in part on whether one concludes that the EoE is a separate disorder and unrelated to the celiac disease.

One useful retrospective study on this topic (S Hommeida et al. JPGN 2017; 65: 58-63) examines the association between celiac disease and EoE.   Key findings:

  • Among a cohort of 10,201 children seen at the Mayo clinic, 595 were considered to have EoE and 546 had celiac disease.
  • Only 10 patients had both celiac disease and EoE.
  • The risk of EoE was not increased in children with celiac disease compared to those without celiac disease (odds ratio 0.29).  The prevalence of EoE in children with celiac disease was 1.8% whereas the prevalence among all children undergoing endoscopy was 5.8%.
  • 4 of 10 children treated only with GFD clinically improved (no followup histology)

Limitations:

  • The diagnosis of EoE was not clear in this study.  As noted in the associated editorial (pg 1-2), “the use of a high-dose proton pump inhibitor at the time of initial diagnosis is not mentioned.”
  • Overall, the number of patients with both EoE and celiac disease was small.  Thus, a much larger study could be necessary to prove the lack of an association.

My take: This study suggests that there is not an association between EoE and celiac disease. Some patients with both disorders will respond to a gluten free diet, whereas some will require additional treatment directed at EoE.

Related study: T Wallach et al. JPGN 2017; 65: 64-8. This retrospective study showed poor adherence to biopsy guidelines in EoE and celiac disease.  Among 9171 children, 8% were biopsied in accordance with 2007 AGA EoE consensus recommendations and 35% in accordance with  2006 AGA celiac guidelines.  Higher detection rates were observed among patients who had higher adherence to diagnostic guidelines. With both diseases, obtaining sufficient number of biopsies is key; and with celiac disease, obtaining biopsies from duodenal bulb as well as distal duodenum is recommended.

Chattahoochee River, Sandy Springs

Use of Antidepressant Medications to Treat Recurrent Abdominal Pain

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A recent study (C AM Zar-Kessler et al. JPGN 2017; 65: 16-21) retrospectively reviewed a single center’s 8 year experience (2005-2013) using antidepressant medications to treat nonorganic abdominal pain. Of 531 cases, 192 initiated treatment with either a selective serotonin reuptake inhibitor (SSRI) or a tricyclic antidepressant (TCA).

Key findings:

  • 63 of 84 (75%) of SSRI-treated patients improved; 56 of 92 (61%) of TCA-treated patients improved.  The higher response rate to SSRIs persisted after control for psychiatric factors.
  • A much higher percentage of SSRI-treated patients, compared to TCA-treated patients, had anxiety (49% vs 22%); an additional 15% and 5%, respectively, had combined anxiety/depression.
  • The most common SSRI in this study was citalopram with median dose of 10 mg (range 5-60 mg).
  • The most common TCA in this study was nortriptyline with median dose of 20 mg (range 10-50).
  • Similar numbers of patients in each group had adverse effects, include 21 (25%) of SSRI-treated patients and 20 (22%) of TCA-treated patients.  14% of SRRI-treated patients discontinue medication due to adverse effects, compared with 17% of TCA-treated patients.
  • Mood disturbances were higher in this study among TCA-treated patients: 14% compared with 6% of SSRI-treated patients
  • TCAs were prescribed by gastroenterologists in 88% of cases; with SSRIs, only 39% of prescriptions were from gastroenterologists.

In the discussion, the authors note that “all patients who experienced GI adverse effect were prescribed medications that would worsen their underlying bowel complaint…these issues may have been mitigated if more attention was paid” to this.  “Specifically, TCAs should be used cautiously in those with constipation, whereas SSRIs should be avoided in those with diarrhea.”

My take: This study shows that both classes of antidepressants were associated with improvement.  The conclusions about effectiveness are limited as this is a retrospective study and could not control/evaluate many variables. That being said, particularly if there is coexisting anxiety, as was frequent in this study population, a SSRI may be more effective.

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.

Tynn Church, Prague