Category Archives: Uncategorized

Do Acid Blockers Given to Infants Increase the Risk of Allergic Disease?

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A recent retrospective study (Mitre E, et al. JAMA Pediatr. 2018;doi:10.1001/jamapediatrics.2018.0315) suggests that acid blockers, both histamine receptor antagonists and proton pump inhibitors increase the risk of developing allergic disease.  Since this is a retrospective study, this association with allergic diseases has NOT been proven to have a causal relationship; thus, an alternative explanation would be that infants who are likely to develop allergic diseases could be prescribed these agents more frequently due to symptoms attributed to reflux.

Here is an excerpt from a summary of this study (from Healio):  Acid-suppressor, antibiotic use in infancy tied to later allergic disease

Of the 792,130 children included in the study (49.9% female), 7.6% were prescribed a histamine-2 receptor antagonist (H2RA) and 1.7% were prescribed a proton pump inhibitor (PPI) within the first 6 months of life. Antibiotics also were prescribed for 16.6% of infants included in the study during this time. Mitre and colleagues noted that data continued to be collected on these infants for a median of 4.6 years…

When children were prescribed an H2RA, the researchers noted adjusted HRs of 2.18 (95% CI, 2.04-2.33) for food allergy, 1.70 (95% CI, 1.60-1.80) for medication allergy, 1.51 (95% CI, 1.38-1.66) for anaphylaxis, 1.50 (95% CI, 1.46-1.54) for allergic rhinitis and 1.25 (95% CI, 1.21-1.29) for asthma.

Infants who were prescribed PPIs had comparable aHRs, which the researchers observed at 2.59 (95% CI, 2.25-3.00) for food allergy, 1.84 (95% CI, 1.56-2.17) for medication allergy, 1.45 (95% CI, 1.22-1.73) for anaphylaxis and 1.44 (95% CI, 1.36-1.52) for asthma.

Mitre and colleagues also calculated the aHRs related to later allergic disease in children who were prescribed antibiotics within the first 6 months of life. They observed these rates at 2.09 (95% CI, 2.05-2.13) for asthma, 1.75 (95% CI, 1.72-1.78) for allergic rhinitis, 1.51 (95% CI, 1.38-1.66) for anaphylaxis and 1.42 (95% CI, 1.34-1.50) for allergic conjunctivitis.

My take: This study is another reminder that these agents may be more detrimental than beneficial in the vast majority of infants.

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Interchangeability, Immunogenecity and Infliximab Biosimilars

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A recent study (G Fiorino et al. IBD 2018; 24: 601-6, editorial by KH Katsanos et al 465-6) provides more data on “full interchangeability” in regards to infliximab (IFX) and biosimilars CT-P13 and SB2. Full abstract below.

Key finding in study:

  • Antibodies to infliximab (ATI) cross-reacted with any type of IFX or IFX-biosimilar

Points from the editorial:

  • “The landmark NOR-SWITCH randomized controlled trial showed that 1-time switching from RMC [Remicade] to CT-P13 is not inferior to continued treatment with the infliximab originator…there are no data regarding multiple switches…Consequently, cross-switching (switching between 2 biosimilars), reverse switching (switching from biosimilar to its originator) or multiple/repeated switching is not currently recommended.”
  • This study, however, shows that “if you have already developed antibodies to 1 infliximab product, there is no point in switching to another infliximab product.”

Abstract:

Background: Infliximab (IFX) biosimilars CT-P13 and SB2 have comparable efficacy, safety, and immunogenicity to the originator Remicade (RMC). However, concerns about cross-switching patients between the 3 brands were raised in the absence of cross reactivity data between them. We aimed to determine whether antibodies to infliximab (ATI) in inflammatory bowel disease (IBD) patients cross-react with RMC, CT-P13, and SB2.

Methods: Based on previous ATI status, samples from 34 patients participating in the BIOSIM01 study (13 RMC, 9 CT-P13, and 12 switchers) were selected. Patients were treated with either RMC only, or CT-P13 only, or with RMC switched to CT-P13. Additionally, 28 IFX-naïve patients were assayed as controls. In total, 180 samples were analyzed. ATI trough levels were measured in parallel with 3 different bridging Enzyme Linked Immunosorbent Assays constructed using the 3 drugs. Spearman’s coefficient and percentages of agreement were used to study the correlation between each assay.

Results: In total, 76 samples out of 152 IFX-treated patient samples were ATI-positive (30 RMC, 14 CT-P13, and 32 switchers). All resulted ATI-positive when either CT-P13 or SB2 bridging assays were used. The overall percentage of agreement was 100% when compared either with CT-P13 or SB2 assays. No significant differences were found among ATI levels and coefficients (Spearman’s 0.98 to 1.0, P < 0.0001).

Conclusions: ATI of RMC-treated, CT-P13-treated or RMC to CT-P13 switched patients show full cross-reactivity with CT-P13 and SB2. Findings suggest that immunodominant epitopes in the reference and CT-P13 drugs are equally present in SB2. Data support full interchangeability between biosimilars in regard to immunogenicity.

My take: In patients doing well with IFX, switching to a biosimilar is not currently recommended.  In patients naive to IFX, use of IFX or biosimilar is expected to have similar efficacy.

Related study: B Kang et al. IBD 2018; 24: 607-16.  This prospective study of 36 pediatric patients did not identify any significant differences in efficacy…or immunogenicity after switching from IFX to CT-P13.

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Does C-section Increase Risk of Celiac Disease? Probably Not

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Using data from the prospective TEDDY (The Environmental Determinants for Diabetes in the Young) from 2004-2010, a recent study (S Koletzko et al. JPGN 2018; 66: 417-24) has shown that cesarean section is not associated with an increased risk of celiac disease (CD) or celiac disease autoimmunity (CDA). TEDDY participants are at increased risk for CD and type 1 diabetes (T1D) based on HLA-risk genotypes.

Key findings:

  • Of the 6087 singletons, 1600 (26%) were born via C-section
  • C-section was associated with a lower risk for CDA (HR 0.85) and a lower risk of CD (HR 0.75)

My take: While environmental factors are likely to be responsible for increasing incidence of CD, C-section compared to vaginal delivery does not appear to be a risk factor.

Related blog posts:

Amber Cove, Dominican Republic

Eluxadoline and Pancreatitis

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It looks like eluxadoline, recently FDA-approved for IBS-D, is associated with a significant rate of pancreatitis.  The most recent report: AJ Gawron, K Bielefeldt. Clin Gastroenterol Hepatol 2018; 16: 378-84.

The authors extracted reports of eluxadoline adverse events using the Federal Adverse Event Reporting System.

  • Of the 597 reports, 98 (16.4%) were due to pancreatitis; 53 cases required hospitalization.  (The FDA separately reported 120 cases of pancreatitis –https://www.fda.gov/Drugs/DrugSafety/ucm546154.htm)
  • The FDA report, which noted the risk primarily in those with prior cholecystectomy, “listed 1 fatality caused by pancreatitis..which manifested within the first day of therapy.”

My take: This study showing a significant risk of pancreatitis changes the risk-benefit ratio of eluxadoline.  Since pancreatitis can result in hospitalization and even death, alternative therapies for IBS will be favored.

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Autoimmune Hepatitis Associated with Anti-TNF Therapy

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A recent study (A Ricciuto et al. J Pediatr 2018; 194: 128-35) identified an index case of autoimmune hepatitis (AIH) associated with anti-tumor necrosis factor (TNF) therapy and reviewed liver biochemistries in a cohort of 659 children.

Key findings:

  • In the index case, features of autoimmune hepatitis (AIH) on liver biopsy were noted 23 weeks after starting infliximab.   These findings resolved entirely within 4 months after withdrawal of infliximab
  • Overall, 7.7% of cohort had elevations of ALT while receiving anti-TNF therapy.  Most were mild and attributable to other causes than drug toxicity. No other cases of AIH were identified.

The authors recommend a careful investigation in those with elevations >2-3 times ULN which persists >3 months. Livertox (NIH) website notes the following for infliximab:

“The liver injury caused by infliximab is usually mild and rapidly reversed once therapy is stopped.  However, fatal instances of HBV reactivation and induction of autoimmune hepatitis due to infliximab have been reported, and regular monitoring of patients early during the course of infliximab is recommended.”

My take: Serious liver injury related to anti-TNF therapy is rare. A great place to understand the spectrum of liver problems potentially related to infliximab is the livertox website:

Related blog entries:

AIH:

Views from inside Hoover Dam, including Mike O’Callaghan–Pat Tillman Memorial Bridge

2018 Pediatric Gastroesophageal Reflux Clinical Practice Guidelines

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Full text: NASPGHAN Pediatric Gastroesophageal Reflux Clinical Practice Guidelines (R Rosen et al. JPGN 2018; 66: 516-54)

This is a lengthy report with ~50 recommendations/302 references –many with several subrecommendations. I will highlight a few below. Tables 2 defines “red flags” that suggest the need for additional diagnostic tests and Table 3 provides a lengthy differential diagnosis (=everything).

R Rosen et al. JPGN 2018; 66: 516-54

The article reviews several frequent clinical diagnostic/management issues and provides two algorithms with suggested evaluation/treatment for infants and older children.  The older child algorithm (algorithm 2) suggests referral to GI if not improved with acid suppression or unable to wean after course of treatment.  For pediatric GI physicians, this algorithm suggests use of endoscopy if persistent symptoms on PPI or inability to stop PPI; pH-MII or pH-metry recommended if normal-appearing endoscopy.

Key point:

  • For infants: “if excessive irritability and pain is the single manifestation, it is unlikely to be related to GERD.”

Some of the Recommendations -My Top Ten:

  • 3.5 We suggest not to use esophago-gastro-duodenoscopy to diagnose GERD in infants and children.
  • 3.13 We suggest not to use a trial of PPIs as a diagnostic test for GERD in infants.
  • 3.14 We suggest a 4 to 8 week trial of PPIs for typical symptoms (heartburn, retrosternal or epigastric pain) in children as a diagnostic test for GERD
  • 3.15 We suggest not to use a trial of PPIs as a diagnostic test for GERD in patients presenting with extraesophageal symptoms.
  • 5.1 We suggest not to use antacids/alginates for chronic treatment of infants and children with GERD.
  • 5.4 We recommend not to use H2RA or PPI for the treatment of crying/distress in otherwise healthy infants.
  • 5.5 We recommend not to use H2RA or PPI for the treatment of visible regurgitation in otherwise healthy infants
  • 5.7 We suggest not to use H2RAs or PPIs in patients with extraesophageal symptoms (ie, cough, wheezing, asthma), except in the presence of typical GERD symptoms and/or diagnostic testing suggestive of GERD.
  • 5.10 We suggest to consider the use of baclofen prior to surgery in children in whom other pharmacological treatments have failed.
  • 6.4 We suggest to consider the use of transpyloric/jejunal feedings in the treatment of infants and children with GERD refractory to optimal treatment as an alternative of fundoplication.

My take: This is an excellent updated summary of current best clinical practices for evaluation/management of pediatric GERD.

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

 

Note full text link available online identified in Google Search

How to Cultivate Clostridium difficile Infections

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The emergence of more frequent and virulent Clostridium difficile infections (CDIs) has generally been attributed to antibiotic usage.  A recent study (J Collins et al Nature 553, 291–4.  doi:10.1038/nature25178) suggests that changes in our diet are a contributing factor as well.

From Abstract:

Here we show that two epidemic ribotypes (RT027 and RT078) have acquired unique mechanisms to metabolize low concentrations of the disaccharide trehalose. RT027 strains contain a single point mutation in the trehalose repressor that increases the sensitivity of this ribotype to trehalose by more than 500-fold. Furthermore, dietary trehalose increases the virulence of a RT027 strain in a mouse model of infection. RT078 strains acquired a cluster of four genes involved in trehalose metabolism, including a PTS permease that is both necessary and sufficient for growth on low concentrations of trehalose. We propose that the implementation of trehalose as a food additive into the human diet, shortly before the emergence of these two epidemic lineages, helped select for their emergence and contributed to hypervirulence.

From GI & Hepatology News: Food additive makes C difficile more virulent: “Prior to 2000, trehalose was limited by a relatively high cost of production.”  However, with innovations in production, trehalose concentrations in food increased, particularly in ice cream, pasta, and ground beef; “concentration in food skyrocketed form around 2% to 11.25%.”  In addition, the FDA in 2000 noted that trehalose as “generally recognized as safe.”

My take: “On the basis of these observations, we propose that the widespread adoption and use of the disaccharide trehalose in the human diet has played a significant role in the emergence of these epidemic and hypervirulent strains,” Dr. Collins and his colleagues wrote in Nature.

Flower Display in Las Vegas Hotel

For the Next Upper GI Bleed, Azithromycin?

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Earlier this week, I was tasked with helping a teenager with an upper GI bleed.  I was surprised to learn that our hospital did not have IV erythromycin available due to a shortage.  A potential alternative is azithromycin.

The following is a 2017 ACG abstract (D Issa et al): A Comparison of Azithromycin to Erythromycin Infusions in Improving Visualization of Endoscopy for Upper Gastrointestinal Bleeding

Introduction: Several studies show the use of intravenous erythromycin prior to upper endoscopy for upper gastrointestinal bleeding (GIB) improves visualization and decreases the need for second look endoscopy. Erythromycin requires reconstitution delaying administration in emergency procedures. Azithromycin is more readily available as it is part of pneumonia treatment protocols and does not require reconstitution. Physiologic studies show azithromycin produces motility effects similar to that of erythromycin.

Aim: To assess the effect of azithromycin in improving the quality of endoscopic visualization in upper GIB compared to erythromycin.

Methods: We performed a retrospective analysis of patients admitted with acute upper GIB who underwent emergent endoscopy and were ordered either erythromycin or azithromycin before procedure. Primary outcome of the quality of visualization was assessed by two gastroenterologists, blinded to the choice of infusion, using a scoring system ranging from 0 to 8 with a maximum of 2 points assigned to each of the fundus, body, antrum and bulb. Secondary outcomes included time elapsed between administering the infusion and starting the procedure, length of hospital stay, blood transfusions, and procedure-related complications.

Results: The study included 31 patients in the erythromycin group and 18 patients in the azithromycin group. Mean age was 57 years and 68% were male. The overall median visualization score was significantly higher in the azithromycin group compared to that of the erythromycin group {7.0 (1.5) vs. 6.0 (3.0), respectively; P=0.02}. Time between administration of azithromycin and starting the procedure was longer than that of erythromycin but did not meet statistical significance (67 vs 48.5 minutes, respectively; P = 0.92). Length of hospital stay was comparable between the two groups after adjusting for the admission primary diagnosis (6.0 days for azithromycin vs. 7.0 days for erythromycin; P=0.48). Four patients were ordered erythromycin but this was not administered on time whereas all patient who were ordered azithromycin started the infusion prior to the procedure. Procedure immediate complications, need for second look endoscopy and number of transfused blood units did not differ between the groups.

Discussion: Azithromycin infusion before endoscopy for upper GIB was associated with better visualization than that of erythromycin, the current standard of care. Randomized trials are needed to validate these findings.

Here is a link to a summary from Gastro and Endoscopy News: Azithromycin Appears Worthy Stand-In For Erythromycin in Upper GI Bleeding

There have been prior publications showing that azithromycin, like erythromycin, has prokinetic properties: Broad J, Sanger GJ. The antibiotic azithromycin is a motilin receptor agonist in human stomach: comparison with erythromycin. Br J Pharmacol. 2013 Apr;168(8):1859-67.

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

Motility in Duchenne Muscular Dystrophy

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Briefly noted: D Kraus et al J Pediatr 2018; 194: 238-40.  This study of 7 young adults with Duchenne muscular dystrophy (DMD_ showed normal gastrointestinal motility using a wireless motility capsule (WMC).  The study findings are limited by the small sample size and a selection bias of enrolling only patients capable of swallowing a WMC. This study, however, is important as it supports the notion of ‘enteric muscle sparing’ in DMD.

Related blog post: Don’t Let the Chief of Staff Review This Study

Chattahoochee River

IBD Shorts -March 2018

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T Piester et al. Inflamm Bowel Dis 2018; 24: 227-34.  Stanford group published data on 49 patients which highlight the utility of a point of care (mobile) infliximab (IFX) dosing calculator: http://med.stanford.edu/gastroenterology/infliximab-calc/  In their cohort, the IFX calculator recommendations were for IFX dosing escalations in 13% of the 222 calculations.  Overall, the IFX calculator was part of a larger quality initiative (QI) to achieve therapeutic drug levels >5 mcg/mL which occurred in 81% during the QI period.

JC deBruyn et al. JPGN 2018; 66: 268-77. This was a retrospective review of infliximab (IFX) in pediatric Crohn’s disease with 180 children. The authors determined that IFX had good therapeutic durability with 91% remaining on IFX after 2 years of treatment.

FS Macaluso et al. Inflamm Bowel Dis 2018; 24: 394-401. In this 2-year study, among 630 patients, 46 had a modestly-dosed immunomodulator added to anti-TNF therapy due to loss of response (31 to IFX or biosimilar, 10 with adalimumab, and 5 with golimumab).  This resulted in a steroid-free remission in 15 (32.6%) and a clinical response in 6 (13.0%). The immunomodulators were azathioprine in 15, 6-mercaptopurine in 5, methotrexate in 20, and mycophenolate mofetil in 6. The median doses for immunomodulators were 1.64 mg/kg/day, 0.84 mg/kg/day, 15.6 mg/week, and 1500 mg/day respectively.

C Reenaers et al. Clin Gastroenter Hepatol 2018; 16: 234-43. This retrospective study examined 7-year outcomes from a STORI cohort of 115 adults with Crohn’s disease (CD) with combination therapy who had infliximab withdrawal after achieving sustained remission. Among those restarting infliximab, treatment failed in 30.1%; 70.2% “had no failure of de-escalation strategy.” Major complicatins occurred in 18.5% of patients. Risk factors for failure included anemia (Hgb <12.5), increased white blood cell count >5.0, and upper GI location of CD.

VM Merrick et al. JPGN 2018; 66: 274-80.  This UK “real-life” review of 37 centers and 524 patients (429 with Crohn’s disease) found a remarkably poor rate of documentation.  They could determine the remission rates in only 71 of these patients (65% 46 of 71).  Thus, in the real-world, presumably in adults and children, most institutions do not know their remission rates.  While the determination of remission still relies on imperfect measures, the centers who participate in ImproveCareNow have high documentation rates –this is also a real-world experience as more than 29,000 patients and more than 900 pediatric GI doctors participate.