It Hurts Here and Here and Here

A recent study (below) reminded me of a joke. First the joke (better with the visual effect):

A guy goes to his doctor. The patient says, “Doctor when I touch here on my shoulder (with index finger) it hurts, when I touch here on my leg (with index finger) it hurts, and when I touch here on my stomach (with index finger) it hurts.”

The doctor says: “Your finger is broken.”

BP Chumpitazi et al. J Pediatr 2021; 236; 131-136. Multisite Pain Is Highly Prevalent in Children with Functional Abdominal Pain Disorders and Is Associated with Increased Morbidity

In this cross-sectional study of 7-17 year olds (n=406) with Rome III functional abdominal pain disorder (FAPD), the authors examined the frequency of pain outside GI tract over a 2 week study period. Patients were recruited from both a large academic pediatric GI practice and general pediatric offices in same hospital system.

Key findings:

  • In total, 295 (73%) children endorsed at least 1 co-occurring nonabdominal pain, thus, were categorized as having multisite pain with the following symptoms: 172 (42%) headaches, 143 (35%) chest pain, 134 (33%) muscle soreness, 110 (27%) back pain, 94 (23%) joint pain, and 87 (21%) extremity (arms and legs) pain
  • In addition, 200 children (49%) endorsed 2 or more nonabdominal pain symptoms
  • Participants with (vs without) multisite pain had significantly higher abdominal pain frequency (P < .001) and severity (P = .03), anxiety (P < .001), and depression (P < .001). Similarly, children with multisite pain (vs without) had significantly worse functional disability (P < .001) and health-related quality of life scores (P < .001).

The authors note that due to the design of their study, they cannot establish a causal association between pain symptoms and psychosocial functioning.

My take: A lot of kids with stomach pain have multisite pain as well as anxiety and depression. This study reminds us to ask about them.

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More Pictures From Atlanta Beltline West End

Colorectal Cancer in Patients Up to Age to 25 Years

In a nationwide retrospective cohort from The Netherlands (pop. ~17 million), a recent study (RM de Voer et al. Clin Gastroenterol Hepatol 2021; 19: 1642-1651. Full Text: Clinical, Pathology, Genetic, and Molecular Features of Colorectal Tumors in Adolescents and Adults 25 Years or Younger) characterizes the clinical and genetic features of colorectal cancer (CRC) in individuals <26 years of age (aka AYA group) from 2000-2017.

Key findings:

  • There were 139 patients in the AYA group identified: 9 (ages 10-15), 26 (ages 16-20), and 104 (ages 21-25)
  • Overall, the AYA group represents 0.1% of all CRC cases. However, AYA cases were much more likely to be at an advanced stage at diagnosis (66% at stage 3 or 4 compared with 46% of adults with CRC in The Netherlands).
  • Negative predictors for outcomes included age <16 yrs, signet ring cell carcinoma histology, and advanced stage at diagnosis.
  • Genetic tumor risk syndromes were identified in 39% and IBD was noted in 8.4% of the AYA group. The genetic risk is underestimated as the authors did not test for all CRC-predisposing genes. Lynch syndrome was the most common genetic disorder (identified in 22 patients) followed by familial adenomatous polyposis (identified in 5 patients)

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Lots of Room to Improve with H pylori Treatment

Briefly noted: A recent survey study (N Du et al. JPGN Reports: 2021; 2: p e033. doi: 10.1097/PG9.0000000000000033. Full Text: Assessment of Community Pediatric Providers’ Approach to Children With Helicobacter pylori) found that pediatric providers had poor knowledge and/or adherence to pediatric H pylori guidelines.

Key findings:

  • Over a third of the respondents reported incorrectly testing patients for H. pylori while they were taking proton pump inhibitors.
  • 17% (n=17) incorrectly preferred blood serology as testing modality
  • 63% (n=64) relied on symptom resolution as indication of cure

My take: It would be interesting to compare pediatric gastroenterology provider responses to general pediatric providers. It is likely that a much higher percentage would be following established guidelines. One area of the guidelines that I think should be changed would be encouraging increased use of quadruple therapy in children, especially if resistance testing is not performed; this change would better align with adult guidelines. In adults, quadruple therapy has been associated with increased cure rates.

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Canadian Pediatric Guidelines for Crohn’s Disease

DR Mack et al. Gastroenterol 2019; 157: 320-48Full Text: Canadian Association of Gastroenterology Clinical Practice Guideline for the Medical Management of Pediatric Luminal Crohn’s Disease

“When the consensus group met in October 2017, the most recent consensus guidelines for the treatment of CD in pediatric patients were those from” ESPGHAN/ECCO in 2014 with data from June 2013. Thus, the guideline attempts to provide more updated information and recommendations based on incorporating the latest studies.

The authors provide 25 consensus statements.  Here are a few of interest:

  • Recommendation 9: In patients with CD, we suggest exclusive enteral nutrition to induce clinical remission (Recommendation 6 recommends steroids as a treatment for clinical remission; adult Canadian guidelines recommended against using exclusive enteral nutrition)
  • Recommendation 11: In patients with CD in remission, we suggest that if partial enteral nutrition is used it should be combined with other medications to maintain clinical remission.
  • Recommendation 20: When starting infliximab in males, we suggest against using it in combination with a thiopurine.
  • Recommendation 24: In patients with moderate to severe CD who fail to achieve or maintain clinical remission with anti-TNF–based therapy, we suggest ustekinumab to induce and maintain clinical remission.
  • Recommendation 25: In patients with CD, we recommend against cannabis or derivatives to induce or maintain remission.

In addition, the authors provide 13 statements with no recommendations -here are two of them:

  • No consensus J: When starting infliximab in females, the consensus group does not make a recommendation (for or against) regarding combining it with a thiopurine to maintain a durable clinical remission.
  • No consensus L: In patients with CD who have achieved a clinical remission with anti-TNF therapy, the consensus group does not make a recommendation (for or against) regarding assessment for mucosal healing within the first year to determine the need to modify therapy.

Crater Lake, OR

New Hepatitis B Treatment Guidelines

Link to full article: Updated Hepatitis B Treatment Guidelines from AASLD

With regard to pediatrics:

9A. The AASLD suggests antiviral therapy in HBeAg-positive children (ages 2 to <18 years) with both elevated ALT and measurable HBV DNA levels, with the goal of achieving sustained HBeAg seroconversion.

“Most studies required ALT elevation (>1.3 times ULN) for at least 6 months with HBV DNA elevations for inclusion. Given that HBV DNA levels are typically very high during childhood (>106 IU/mL), there is no basis for a recommendation for a lower-limit value with respect to treatment. However, if a level <104 IU/mL is observed, therapy might be deferred until other causes of liver disease and spontaneous HBeAg seroconversion are excluded.”

“Duration of treatment with oral antivirals that has been studied is 1-4 years. It may be prudent to use HBeAg seroconversion as a therapeutic endpoint when oral antivirals are used, continuing treatment for an additional 12 months of consolidation, as recommended in adults. It is currently unknown whether a longer duration of consolidation would reduce rates of virological relapse.”

“Children who stop antiviral therapy should be monitored every 3 months for at least 1 year for recurrent viremia, ALT flares, and clinical decompensation.”

9B. The AASLD recommends against use of antiviral therapy in HBeAg-positive children (ages 2 to <18 years) with persistently normal ALT, regardless of HBV DNA level.

Another nice summary of current treatment recommendations: P Martin et al. Clin Gastroenterol Hepatol 2015; 13: 2071-87.  Table 5 lists recommendations for treatment of HBeAg-positive.

  • The main group needing treatment (entecavir, tenofovir, or PEGinterferon alfa-2a) are those with HBV DNA >2000 IU/mL and elevated ALT.  Table 6 lists recommendations for those with HBeAg-negative.  Main group needing treatment are the same (HBV DNA >2000 IU/mL and elevated ALT).
  • With both groups (HBe-Ag negative and positive), “consider liver biopsy or transient elastography” if elevated HBV DNA >2000 and normal ALT.  If histologic disease present, consider treatment.
  • One point the authors make about therapy regards duration: “Historically, HBeAg seroconversion was considered a durable response, and discontinuation of antiviral therapy was recommended after a period of consolidation therapy of 6-12 months from the time of HBeAg seroconversion. However, patients who discontinue therapy …can experience recurrent viremia and ALT flares.  Thus, long-term therapy is justified.”
  • For HBeAg negative patients who have compensated liver disease, loss of HBsAg for 6-12 months may be discontinued from therapy.

Pediatric Entecavir Data

While entecavir and tenofovir have been in use for many years in adult hepatology for hepatitis B virus (HBV) infection, a well-designed study supporting their use in pediatrics has been lacking until now.  Recently, a study (M Jonas et al. Hepatology 2015; DOI: 10.1002/hep.28015)  has shown that entecavir is effective for pediatric HBV

Link to full study. Randomized Controlled Trial of Entecavir Versus Placebo in Children with HBeAg-positive Chronic Hepatitis B

Here’s the abstract:

This ongoing, randomized phase III study assesses the safety and efficacy of entecavir versus placebo in nucleos(t)ide-naive children (2 to <18 years) with HBeAg-positive chronic hepatitis B (CHB). Blinded treatment was administered for a minimum of 48 weeks. After Week 48, patients with HBeAg seroconversion continued blinded treatment; those without, switched to open-label entecavir. The primary endpoint was HBeAg seroconversion and HBV DNA <50 IU/mL at Week 48. A total of 180 patients were randomized (2:1) and treated. Baseline median age was 12 years, with approximately 50% of children aged >12 to <18, and 25% each aged ≥2 to ≤6 and >6 to ≤12. Rates for the primary endpoint at Week 48 were significantly higher with entecavir than placebo (24.2% [29/120] versus 3.3% [2/60]; P=0.0008). Furthermore, higher response rates were observed with entecavir compared with placebo for the key Week 48 secondary endpoints: HBV DNA <50 IU/mL (49.2% [59/120] versus 3.3% [2/60]; P < 0.0001), alanine aminotransferase normalization (67.5% [81/120] versus 23.3% [14/60]; P < 0.0001), and HBeAg seroconversion (24.2% [29/120] versus 10.0% [6/60]; P = 0.0210). Among entecavir-randomized patients there was an increase in all efficacy endpoints between Weeks 48 and 96, including an increase from 49% to 64% in virologic suppression. The cumulative probability of emergent entecavir resistance through Years 1 and 2 of entecavir was 0.6 and 2.6%, respectively. Entecavir was well tolerated with no observed differences in adverse events or changes in growth compared with placebo. Conclusion: In childhood CHB, entecavir demonstrated superior antiviral efficacy to placebo with a favorable safety profile. These results support the use of entecavir as a therapeutic option in children and adolescents with CHB.

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From Brooklyn Bridge

From Brooklyn Bridge

 

NASPGHAN “Best Practices Cleanout Regimens”

The authors of a recent report (JPGN 2014; 59: 409-16) acknowledge that “bowel regimens vary significantly” and “few clinical studies in pediatrics have evaluated the use of various bowel preparation regimens.” Furthermore, “pediatric studies did not have a common efficacy measure.”

Nevertheless, they provide a “NASPGHAN best practices cleanout regimens.”  According to Table 7:

  • Option 1: PEG-3350 (eg. Miralax) -1-day cleanout:  If less than 50 kg, then 4 g/kg/day + bisacodyl 5 mg.  If >50 kg, then 238 g in 1.5 L sports drink + bisacodyl 10 mg.   PEG-3350 administered over 4-6 hours.
  • Option 2: PEG-3350 -2-day cleanout: If <50 kg, then 2 g/kg/day + bisacodyl 5 mg; if >50 kg, then 2 g/kg/day + bisacodyl 10 mg.
  • Option 3: NG cleanout: PEG-ELS (eg. Nulytely) 25 mL/kg/h (max 450 mL/h).  NG cleanouts mainly in those with history of failed preps or other adherence problems (eg. vomiting).
  • Option 4: non-PEG cleanout: Magnesium citrate 4-6 mL/kg/day + bisacodyl 5-10 mg.

My personal opinion is that Table 7 could drop the words “best practices” since the report states “alternative dosing regimens may be entirely reasonable” and the data are quite limited.

With regard to split dosing preparations which are now recommended in adults, their role in pediatrics is a “potential area for future research.” For adults, the U.S. Multi-Society Task Force Consensus Statement on Adequate Bowel Cleansing for Colonoscopy (Johnson DA et al. Optimizing Adequacy of Bowel Cleansing for Colonoscopy: Recommendations from the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology 2014; 147(4):903-924) recommends:

  • Use of a split-dose bowel cleansing regimen is strongly recommended for elective colonoscopy, meaning roughly half of the bowel cleansing dose is given the day of the colonoscopy.
  • The second dose of split preparation ideally should begin four to six hours before the time of colonoscopy with completion of the last dose at least two hours before the procedure time.
  • During a split-dose bowel cleansing regimen, diet recommendations can include either low-residue or full liquids until the evening on the day before colonoscopy. 

Take-home message: This NASPGHAN report summarizes the literature and provides recommendations for effective bowel preparations.

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