Category Archives: Pediatric Gastroenterology Intestinal Disorder

Newsflash: constipation frequently causes abdominal pain

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From the following link (forwarded to me by Mike Hart) http://www.dailyrx.com/abdominal-pain-children-emergency-room-was-most-commonly-constipation:

A recent study found that constipation is the most common reason for abdominal pain among children going to one emergency room.

Appendicitis was diagnosed in only about 4 percent of children who went to the ER.

In addition, the researchers did not find any major differences in the treatment or outcomes of children based on their race.

“Call the pediatrician if your child has severe abdominal pain.”

The study, led by Kerry Caperell, MD, of the Department of Pediatrics at the University of Louisville in Kentucky, looked at the outcomes of children who went to the emergency room for abdominal pain.

The researchers investigated the medical records of 9,424 children, aged 1 to 18, who went to the Children’s Hospital of Pittsburgh emergency department for abdominal pain during a two-year period.

More than half of these children, a total of 5,493, ended up receiving multiple diagnoses for their complaints.

The researchers found that 1.9 percent of the African American children and 5.1 percent of the white children who visited the ER were diagnosed with appendicitis. Overall, 4.3 percent of the children had appendicitis.

Appendicitis was less common among younger children, but constipation was commonly diagnosed for all ages.

Almost 20 percent of the children were diagnosed with constipation, and more than 25 percent of the children aged 5 to 12 had constipation.

Constipation, gastroenteritis and urinary tract infections were more common among the African American patients than the white patients.

“Diagnosing causes of abdominal pain in children can often be difficult, especially the younger they are,” said Chris Galloway, MD, a dailyRx expert who specializes in emergency medicine.

“Fortunately common causes are still common and constipation is a frequent diagnosis we make in the ER, and can be quite distressing for your child,” Dr. Galloway said. “Consult your pediatrician if your child has abdominal pain.”

Older children were more likely to remain in the hospital and have an operation related to the reason they went to the ER.

The researchers did not find any differences in children’s outcomes related to their race. This finding means that all the children who went to the ER received similar evaluation and treatment and had similar outcomes regardless of their ethnicity.

The study was published May 20 in the journal Pediatrics. The research did not receive external funding, and the authors declared no conflicts of interest.

Comment: While constipation is a common entity, many of these children have underlying functional problems that are not addressed in the ER setting.

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Overcoming ATIs

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Usually, when antibodies to infliximab (ATI) develop in combination with a loss of clinical response in an individual with inflammatory bowel disease (IBD), this often indicates a need to switch treatments.  A recent study suggests that some patients can eliminate ATIs with the addition of immunomodulators (Clin Gastroenterol Hepatol 2013; 11: 444-47).

In this small retrospective study, 5 patients (18-37 years of age) who developed ATIs were able to continue infliximab therapy after instituting immunomodulator treatment (3 with thiopurines, and 2 with methotrexate).  What makes this report interesting, was that these ATIs (prior to immunomodulator use) were identified multiple times and were associated with undetectable infliximab levels.  None of these patients had dose intensification of infliximab.  After instituting immunomodulator therapy, detectable infliximab was evident and the ATIs disappeared.  According to Figure 1, the timeframe for return of response was about 10 weeks in some of these patients.

The authors note that the addition of immunomodulators can gradually eliminate a preformed memory response to infliximab antigen.  They also note that ATIs can sometimes disappear spontaneously, though this had not been noted to occur previously when mulitple ATIs levels have been identified.

While these observations are important, a larger prospective study is needed to inform how frequently this strategy could be successful.

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Anti-TNF Therapy for Eosinophilic Gastroenteritis

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A recent report highlights the use of anti-TNF therapy (eg. infliximab (IFX) and adalimumab [ADA])  for eosinophilic enterocolitis/eosinophilic gastroenteritis in eight patients who had not responded to other treatments (JPGN 2013; 56: 492-97).

The mean age of these patients was 8 years with a range of 1 to 14 years.  Prior to use of IFX therapy, multiple therapies had been used.  Four patients had been treated with complete elemental diet; medications that were used included montelukast, hydroxyzine, sodium cromogylcate, budesonide, amitriptyline, prednisone, ketotifen, cyproheptadine, thiopurines, and methotrexate (Table 1 in study).

Complete clinical remission was noted to occur in 6 (75%) with IFX induction treatment; this was associated with mucosal healing in 3, mucosal improvement in 2, and unknown in 1 patient.

The six responders were followed for a median of 7 years.  During that timeframe, four of six had secondary loss of response and were switched to ADA.  Three of these four maintained a clinical response with ADA using high doses (80 mg EOW).

Additional References:

  • -Clin Gastroenterol Hepatol 2011; 9: 950.  40% of Eosinophili gastroenteritis resolved.
  • -JPGN 2010; 51: 723. n=91.  Incidental gastric eosinophils does not predict a worse response to fluticasone then isolated EoE.
  • -NEJM 2009; 361: 1387.  Description of a case of eosinophilic gastroenteritis.
  • -Gut 2009; 58: 721-32. Review of primary Eos d/o of GI tract.
  • -JPGN 2008; 47: 234-8.  EGIDs.

More HCV options -phase 3 for Sofosbuvir

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The pace of research for HCV is incredible.  Two months ago phase 2 data for Sofosbuvir were reported and noted on this blog (More options for Hepatitis C | gutsandgrowth).  Now phase 3 data from multiple trials have emerged indicating the effectiveness of sofosbuvir for all HCV genotypes.

In the first study, NEJM 2013; 368: 1867-77, data from two trials (POSITRON and FUSION) of patients with HCV genotypes 2 and 3 are reported.  The POSITRON trial (63 sites, n=278 received treatment) was a blinded placebo-controlled study that evaluated 12 weeks of sofosbuvir/ribavirin compared with placebo in patients who discontinued interferon due to unacceptable adverse events or could not take interferon due to contraindications (most commonly psychiatric disorder or autoimmunity). Results: sustained virological response (SVR) in 78% of treatment group compared with 0% of placebo patients.  In addition, there was “complete concordance (100%) between rates of SVR at 12 weeks and at 24 weeks.”

The FUSION study (67 sites, n=201 received treatment) was a blinded, active-control study in patients who did not respond to a previous interferon-based regimen; one of two treatment regimens were administered: 12 weeks of sofosbuvir/ribavirin followed by placebo or 16 weeks of sofosbuvir/ribavirin. Results: 93% of genotype 2 patients had SVR and 61% of genotype 3 patients had SVR.  Among cirrhotic patients, 61% had SVR (94% of genotype 2, 21% of genotype 3); for those without cirrhosis, there was an 81% SVR (92% with genotype 2, 68% with genotype 3).  Thus, it is easy to conclude that genotype 3 patients with cirrhosis responded much less favorably.

Other important findings: rates of discontinuation among the treatment groups were similar to the placebo groups.  The most common adverse effect was anemia in the treatment groups.

In the second study, NEJM 2013; 368: 1878-87, an additional two phase 2 trials (NEUTRINO and FISSION) are reported from previously untreated chronic HCV patients.  The first trial (NEUTRINO) was an open-label study examining a 12-week regimen of sofosbuvir, peginterferon alfa-2a, and ribavirin in 327 HCV patients (98% genotypes 1 or 4).  Results: SVR noted in 90%. The second trial (FISSION) enrolled 499 patients with genotypes 2 and 3 who randomly received either peginterferon alfa-2a/ribavirin for 24 weeks or sofosbuvir/ribavirin for 12 weeks. Results: SVR noted to be 67% in both groups.  Genotype 2 patients again fared better than genotype 3 among the sofosbuvir/ribavirin group (97% versus 56%).  Some adverse events like fatigue, headache and nausea were common.  Overall, side effects were much lower in those not receiving peginterferon (see Table 3).

Take home message: From the editorial (pg 1931-32 in same issue): “a radical change in clinical practice is imminent…the low incidence of side effects, the relatively short duration of treatment, and the pangenotypic properties of the drugs are strong selling points of a sofosbuvir-ribavirin regimen and will probably lower the threshold for HCV treatment for both patients and physicians.”

Hopefully, we will see pediatric studies soon.

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Simponi (Golimumab) Approved for Ulcerative Colitis

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The U.S. Food and Drug Administration on 5/15/13 approved a new use for Simponi (golimumab) injection to treat adults with moderate to severe ulcerative colitis.

Here’s the link:

FDA approves Simponi to treat ulcerative colitis

From the link:

The U.S. Food and Drug Administration today approved a new use for Simponi (golimumab) injection to treat adults with moderate to severe ulcerative colitis.

Simponi works by blocking tumor necrosis factor (TNF), which plays an important role in causing abnormal inflammatory and immune responses. Previously approved to treat rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis (arthritis affecting the joints in the spine and the pelvis), Simponi is now approved to treat adults with moderate to severe ulcerative colitis that is resistant (refractory) to prior treatment or requires continuous steroid therapy.

Ulcerative colitis is a chronic disease that affects about 620,000 Americans. It causes inflammation and ulcers in the inner lining of the large intestine and is one of two main forms of chronic inflammatory bowel disease. The inflammation can lead to abdominal discomfort, gastrointestinal bleeding, production of pus and diarrhea.

“Simponi is an important new treatment option for patients with moderate to severe ulcerative colitis,” said Andrew E. Mulberg, M.D., deputy director of the Division of Gastroenterology and Inborn Errors Products in the FDA’s Center for Drug Evaluation and Research. “It is critical that patients suffering from the serious and painful symptoms of ulcerative colitis have additional treatment options since patients experience the effects of the disease and respond to treatments differently.”

The safety and effectiveness of Simponi for ulcerative colitis were established in two clinical studies. Evaluations of patients included measures of stool frequency, rectal bleeding, endoscopic findings and a physician’s overall assessment.

In the first study, 513 patients with moderate to severe ulcerative colitis who could not tolerate or failed to respond to other therapies were randomly assigned to receive Simponi or a placebo. Results showed that a greater proportion of Simponi-treated patients achieved clinical response, clinical remission and, as seen during endoscopy, had improved appearance of the colon after six weeks compared with the placebo group.

In the second study, 310 patients with moderate to severe ulcerative colitis who were responders to Simponi were randomly assigned to receive Simponi or placebo. A greater proportion of Simponi-treated patients maintained clinical response through week 54 and had clinical remission at both weeks 30 and 54.  

The most common side effects in patients treated with Simponi are upper respiratory infection and redness at the site of injection. Patients treated with Simponi are at increased risk of developing serious infections, invasive fungal infections, reactivation of Hepatitis B infection, lymphoma, heart failure, nervous system disorders and allergic reactions.

What is the risk with Rifaximin?

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While no one knows how quickly resistance of gut microbes will develop in response to rifaximin, the likelihood of resistance is high and this should temper its usage (J Clin Gastroenterol 2013; 47: 205-11).

Rifaximin, along with other antibiotics, has been shown to relieve symptoms in certain cohorts of irritable bowel syndrome (IBS) patients.  Generally, the results of these studies have been modest (see below); however, because it is a “gut specific” antibiotic with minimal systemic absorption (<1%) and therefore minimal adverse effects, it has been considered a reasonable and safe treatment by many.  It has been useful as well for traveler’s diarrhea, hepatic encephalopathy, and colonic diverticular disease.  With regard to IBS, the major concern is that this is a chronic disorder and repeated usage will result in antimicrobial resistance.

Resistance to rifaximin could result in serious consequences if it provoked a class effect resistance.  Rifaximin belongs to the rifamycin class of antibiotics which treat numerous diseases including tuberculoses, meningococcal disease, Clostridium difficile, and methicillin-resistance Staphylococcus aureus.

Given the limited number of suitable alternatives and emerging resistance patterns, wise stewardship of our current antibiotics is essential, though unlikely.  It is not difficult to foresee a rise in mortality from some infectious problems that are easily treated currently.

Related references:

  • -JPGN 2011; 52: 382.  Double-blind, placebo-controlled study of rifaximin in children with RAP.  n=75.  Not effective in this study.
  • -NEJM 2011; 364: 22 (pg 81-editorial). About 10% improvement over placebo in pts with IBS-D. Effects lasted up to 3 months.
  • -DDW 2010, 475 abstract. Target 1 & Target 2. n=623, n=637. Relief of IBS in ~41% vs ~32% placebo. 550mg TID x 14days.

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Do Enemas Help Nonretentive Encopresis?

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No –according to a recent study (J Pediatr 2013; 162: 1023-7).

In this study, 71 children (76% boys, median age 9 years) with functional nonrententive fecal incontinence (FNRFI) were randomized to receive conventional therapy (control group) or conventional therapy along with daily enemas for 2 weeks.  Conventional therapy was considered education, toilet training, behavioral strategies, and a daily bowel diary with reward system. All children were instructed to defecate on toilet for 5 minutes after each meal.  Treatment success was defined as <2 episodes of fecal incontinence (FI) per month.  Outcomes were measured at 6 weeks, 12 weeks, 6 months, and 12 months after the start of treatment.

Results:

  • At the start, median FI was 6.1 per week and median defecation frequency was 7.0 per week.
  • In both the control group and the treatment group, there was improvement.  After the initial 6 weeks of treatment, FI episodes were 2.0/week in the control group and 1.0/week in the treatment group.
  • The treatment success at long-term followup was 17% for both groups.

In the discussion, the authors note that a longer course of enemas (> 3 months) could be needed to improve long-term outcomes.  They also note a high rate of daytime (31%) and night time (35%) urinary incontinence in these children; “we hypothesize that children with FNRFI not only deny or neglect their urge to defecate but exhibit the same behavior toward micturation.”

Take-home message: Both treatments improved the frequency of FI (and urinary incontinence); however, neither were highly effective.  Short-term use of enemas is not likely to have a meaningful effect.  Better treatment strategies are needed.

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Drug Shortages and Selenium Deficiency

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If you participate in the care of patients who are dependent on parenteral nutrition, then you are familiar with frequent component drug shortages.  Generally, attempts to manage these shortages involve rationing and targeting those with the greatest need.  In one institution, this was not effective in preventing biochemical deficiency of selenium (JPEN 2013; DOI 10.1177/0148607113486005).  Thanks to Kipp Ellsworth for this reference.

The authors describe five pediatric patients who were completely dependent on parenteral nutrition due to intestinal failure.  During a 9-month shortage of intravenous selenium, all five who were previously selenium replete had deficiency identified (level <20 ng/mL).

After these deficiencies were identified, the patients were placed on Multitrace-5 (MTE-5).  This multivitamin contains 20 mcg/mL of selenium.  While patients prior to the shortage typically received 50-75 mcg/day, after instituting MTE-5, they received 10-26 mcg/day.  Nevertheless, this helped prevent any clinical evidence of deficiency.  In patients with selenium deficiency, there is an increased risk of cardiomyopathy, chronic illness, and death.

The authors note that their preference is to individually dose the specific trace elements and that MTE-5 can contribute to elevated levels of manganese and chromium with long-term usage.

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Related references:

  • -Gastroenterol 2009; 137: S61-S69.
  • -J Pediatr 2011; 159: 39.

Overlooking Important Detail$ in Hereditary Angioedema Treatment

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Several approved treatments are now available for Hereditary Angioedema (HAE) attacks. A recent article highlights the effectiveness in 46 children who received 2237 infusions of nanofiltered C1-esterase inhibitor (C1 INH-nf) treatment (J Pediatr 2013; 162: 1017-22).

Background:  HAE prevalence: 1 in 50,000.  Though it is inherited in an autosomal dominant manner, up to 25% of case are de novo. HAE is characterized by recurrent episodic attacks of subcutaneous edema of the skin, GI tract or upper airway.  Symptoms often present between 4 and 11 years of age.  GI tract symptoms are often recurrent colicky abdominal pain. Triggers for attacks may include infections, emotional stress, and trauma (e.g. bodily contact from play).

This manuscript provides data from 4 prospective clinical trials of  C1 INH-nf (Cinryze).  Most children in this study responded within 30 minutes compared with 2 hours for placebo.  Therapy also reduced the rate of attacks.  One interesting aspect of the study was its lack of any mention of cost.

From UptoDate:  “Cost of first-line therapies — All first-line therapies for acute attacks of HAE are costly. In the US, the cost of one treatment with C1INHRP,ecallantide, or icatibant ranged from $5000 to $10,000.”  Hereditary angioedema: Treatment of acute attacks – UpToDate

From a Hereditary Angioedema – RegenceRx website: “As a preventative therapy, C1 esterase inhibitor (Cinryze) is significantly more costly than other formulary alternatives (~$500,000 per year; ~250 times more than danazol). For acute treatment of an HAE attack, C1 esterase inhibitor (Berinert) and ecallantide (Kalbitor) costs approximately $6,000 to $10,000 per attack. Cost may double if re- treatment is needed within 24 hours.”

Additional reference:

  • -Eur J Pediatr 2012; 171: 1339-48.  Consensus of therapeutic strategies for HAE.

Liver Injury from Anti-TNF Agents

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While anti-TNF agents have been associated with drug-induced liver injury (DILI), it has been difficult to get a handle on how much importance to place on this.  A recent study provides more data and some reassurance (Clin Gastroenterol Hepatol 2013; 11: 558-64).

The authors searched the U.S. DILI Network database from 2003 to 2011 and describe 6 cases of anti-TNF DILI; in addition, they searched PubMed for articles related to anti-TNF agent associated hepatotoxicity and identified an additional 28 cases. Other causes of liver disease were excluded in these patients, including reactivation of hepatitis B, and acute viral hepatitis (eg. hepatitis C, hepatitis E).

Results of anti-TNF hepatotoxicity:

  • 26 cases due to infliximab, 4 cases due to etanercept, and 4 due to adalimumab.
  • Based on scoring system, the anti-TNF agent was considered a definite cause of DILI in 1 (3%), very likely in 21 (62%) and probable in 12 (35%).
  • Median latency (duration of therapy before onset of DILI) was 13 weeks with a range of 2-104 weeks.
  • 22 (67%) had positive anti-nuclear and/or smooth muscle antibodies.  15 of 17 of these patients had liver biopsy features consistent with autoimmunity.
  • Among those 22 with autoimmune features, there was a higher peak alanine aminotransferase compared with the 12 without these features (784 vs 528 U/L)
  • Favorable outcome: all but one patient improved after discontinuation of the implicated drug; 12 received corticosteroids. One patient with underlying cirrhosis underwent liver transplantation after infliximab-induced liver injury.

While the authors note the potential for a class effect of anti-TNF agents, in studies from patients with psoriasis, there was a lack of cross-toxicity between etanercept and infliximab.

Take-home messages:

The risk of hepatocellular injury from anti-TNF agents is very low.  DILI due to anti-TNFs often have autoimmune features. The prognosis is favorable, and alternative anti-TNFs can be given after resolution.

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