Category Archives: Uncategorized

Vedozlizumab -Detectable in Breastmilk

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A recent correspondence (M Julsgaard et al.Gastroenterol 2018; 154: 752-65) shows that vedolizumab is detectable in varying concentrations in breastmilk.  The authors collected samples from 5 mothers who were receiving vedolizumab (VDZ) for inflammatory bowel disease.

Key findings:

  • Peak VDZ concentration in breastmilk was 0.318 mcg/mL which was 1/179th of the corresponding concentration of the maternal serum levels.
  • The authors calculated a maximum oral dose of 0.048 mg/kg/day for breastfed infants based on this peak level. “This minute quantity is furthermore anticipated to undergo proteolysis in the stomach” and be bound/excreted in GI tract.
  • VDZ was detectable in all samples for 30 minutes prior to infusion (trough) through 14 days.

This study is in agreement with another study showing that levels in the breastmilk were minute (~1/100) of serum levels (A Lahat et al. J Crohns Colitis. 2018 Jan 5;12(1):120-123).

My take: These are low levels of VDZ –nevertheless further monitoring of infants to determine conclusively whether VDZ enterally causes any adverse effects is warranted.

Views from Mike O’Callahan -Pat Tillman Bridge

 

Pediatric Home and Office Biologic Infusions -What is Needed

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A recent clinical report (E Barfield et al. JPGN 2018; 66: 680-86) will be influential.  This guideline is from the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.  Congratulations to my partner, Chelly Dykes, who is one of the coauthors.

Full text: Assuring Quality for Non-Hospital Based Biologic Infusions in Pediatric Inflammatory Bowel Disease: A Clinical Report from the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition

For many years, our office has had an office-based infusion center which has provided infusions in a safe and cost-effective manner.  Recently, there have been some situations in which home-based infusions have been proposed either to lower costs and/or for convenience.  This report succinctly describes the hurdles that need to be addressed before recommending this treatment pathway. As noted below, patient safety encompasses a great deal more than infusion reactions. Delays in infusions (which can increase risk of loss of response) due to reactions and lapses in communication are additional issues.

Recommendation 1: Home- or office-based infusions should ensure safe administration of the biologic infusion, provide reliable execution of infusion-related orders (eg, laboratories for therapeutic drug monitoring, dose optimization protocols, etc), and be equipped to recognize and respond to potential complications.

  • Infusion reactions:  ” Infusion reactions associated with infliximab and vedolizumab can range from mild reactions such as fever and chills, dyspnea, pruritus, or urticaria (in approximately 5%–10%), to severe reactions including anaphylaxis, convulsions, and hypotension (<1%)”
  • Emergencies: “In the event of an urgent or emergent reaction during home- or office-based infusions, the in-home services agency (IHSA) nurse needs to be able to contact the appropriate ordering medical team member expeditiously by phone or pager to review/clarify specific concerns or needs to have an established clear policy on how to proceed with managing the reaction.” 
  • Communication: “We identified the lack or inconsistency of on-call coverage by the primary medical team when home- or office-based infusions occur as a significant barrier to safely initiating or continuing home- or office-based infusion programs. Difficulty in reaching a knowledgeable team member is a breach in reliable care and represents serious patient risk.”
  • Related work: “In addition to administering the biologic infusion, executing all other infusion-related orders is an important safety consideration. Implementing unique home infusion protocols is linked to treatment efficacy.”  

Recommendation 2: Pediatric home- or office-based infusions, particularly for patients 12 years and younger, should be staffed by a pediatric nurse professional with Pediatric Advanced Life Support (PALS) certification and clinical experience with pediatric patients.

Recommendation 3: Evidence-based standard of care for biologic therapy maximizing effectiveness and treatment sustainability should be established before initiating home or office-based infusions.

Recommendation 4: Home- or office-based infusion pathways that decrease opportunity loss for patients and families and deliver high-quality, patient-centered care should be supported and reproduced.

Recommendation 5: Pediatric gastroenterologists should ensure appropriate shared liability with IHSAs to deliver high-quality care in home-based infusions for children by executing pragmatic steps as outlined below:

  1. “Document discussion with the patient and family about the indication, risks, and adverse event management …
  2. Refer the patient to an accredited, licensed IHSA based on patient’s insurance coverage. If no accredited, licensed IHSA for the pediatric patient exists, this is grounds for not initiating home- or office-based infusions…
  3. & 4. Use an infusion protocol… with clear directives on recognition of signs/symptoms of reactions and administration of reaction medications and use of EMS or parent transport to an emergency room.
  4. Maintain accurate documentation and communication of therapy type, dose, and frequency.
  5. Provide a reliable communication mechanism for the IHSA to notify provider of changes or infusion-related events
  6. Regularly reviewing ongoing IHSA performance with regard to delivery of services, accurate laboratory ordering and turnaround time, safety and quality concerns and timely redressal of these issues.
  7. Switch to another IHSA if the performance reliability is unsatisfactory. …we acknowledge that changing IHSAs may be difficult.”

Recommendation 6: A more equitable division of labor should be established to offset increased administrative burden placed on the pediatric gastroenterologist and medical team to effectively facilitate and maintain home- or office-based infusions, especially when driven by payer-mandated policies.

Recommendation 7: …Among patients receiving home- or office-based infusions, unreliable follow-up care with the provider as scheduled is grounds for discontinuation of home- or office-based biologic therapy.

Recommendation 8: A proper appeals process should be in place to prevent cost transference from payer to patient in payer-mandated decisions for home- or office-based infusions.

Our office practice:

  • Emergencies: In our office, there is always one physician dedicated to being available to assess patients who are receiving infusions.  This helps insure safety and in addition, helps to make sure that minor medical problems do not needlessly postpone important treatment.
  • Documentation: With our office-based infusions, each infusion is documented by the administering nurse.  This documentation along with labs are embedded in the medical record (EPIC) to help modify treatment.
  • Communication: In our office, prior to each infusion, each patient’s chart is reviewed and specific orders are given.  This assures that needed blood tests/imaging, additional treatments (eg. iron infusion), insurance authorizations, necessary followup, and personalized adjustments are made.  This type of communication needs to be replicated for home-based infusions; hence, the use of home-based infusions could result in a huge increase in uncompensated work for the treating physician.

My take: In my experience, office-based infusions can be provided safely and in a cost-effective manner.  While the convenience of home-based infusion is desirable, before implementing broadly, issues regarding communication, safety protocols, and documentation to allow modifications in therapy need to be proactively addressed. Families may not realize some of the complexities involved in managing infusions and how these issues could affect their child’s long-term response to biologic therapy.

Related blog posts:

The following image relates to another convenience-related health trend:

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.

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.

Related blog post:

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.

Related blog posts:

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.

Related blog posts:

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.

Related blog posts:

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.