How (Un)Helpful is AD Manometry in Children with Orthostatic Intolerance?

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A recent retrospective study (LN Zhang et al. J Pediatr 2019; 205: 133-44) reviewed the records of 103 consecutive children with orthostatic intolerance and gastrointestinal symptoms, all of whom had undergone antroduodenal manometry (ADM). The median age was 17 years with a 3:1 female predominance. The same group has published a smaller study in 2016 with 35 children (A Darbari et al JPGN 2016; 63: 329-35).

In their methods, the authors stated that neurogenic intestinal dysmotility was diagnosed if there was

1. lack of fasting MMC III
2. presence of simultaneous nonpropagative or retrograde phases
3. prolonged >30 min high amplitude clusters in duodenum
4. increase in basal tone >30 mmHg for >3 minutes during phase II MMC in a fasting state
5. lack of conversion from fasting MMC-III to fed MMC-II after meals
6. bursts of nonpropagating phase contractions w/in 30 minutes of meals

Key findings:

  • At baseline, the authors state that 12 (12%) had neurogenic intestinal dysmotility and 8 (8%) had significant antral hypomoility.
  • When ADM was undertaken in conjunction with tilt testing, the authors identified neurogenic intestinal dysmotility in 51 (50%), rumination/regurgitation in 23 (22%), and visceral hyperalgesia in 11 (11%).
  • Abnormalities in ADM did not have any correlation with abnormal gastric emptying studies (GES)s (which were performed in 83 of 103).  For example, among those with abnormal ADM (n=83), 48 (73%) had normal GES. And, among those with normal GES (n=58), 48 (83%) had abnormal ADM.
  • “Analysis of EGD biopsy samples revealed nonspecific esophagitis and/or gastritis in 16 of 103 patients (15%)”

While this research provides some insight into why children with orthostatic intolerance may have gastrointestinal symptoms, I remain skeptical of the usefulness of ADM as a routine study in clinical practice. The authors claim that ADM has ‘potential importance…in its utility in targeting future therapies.’

There are many hurdles, in my view, in making these studies worthwhile clinically:
  1. More uniformity in interpretation of ADM studies.  I do not have specialized neurogastroenterology training, but my understanding is that the difference between normal and abnormal is often blurry.
  2. More effective motility agents including prokinetics and agents to improve visceral hyperalgesia. How helpful is it to identify subtle manometric abnormalities without effective therapeutic agents?
  3. If GI problems are only demonstrated during tilt testing, how important is this?  I suspect that many individuals would have abnormalities if ADM was done while they were on a roller coaster, but I doubt that this would help me determine treatment for GI symptoms induced by this type of stimulus.
My take: This study confirms that EGDs are rarely useful in this setting and suggests that ADM could be.  While the study identifies frequent abnormalities when ADM was combined with tilt testing, it remains uncertain whether this will improve clinical management.
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Cholla Cactus, Joshua Tree National Park
Don’t get too close -often called the ‘jumping cactus’

Toronto Consensus for Perianal Fistulizing Crohn’s Disease

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A recent consensus report (AH Steinhart, R Panaccione et al. Inflamm Bowel Dis 2019; 1-13) provides updated guidelines for the management of perianal fistulizing Crohn’s disease (CD).

As an aside, the article starts off with an extremely lengthy disclosure (of financial interests) –more than 30 lines of extremely small font!

The scope of the problem:

  • About 21% of CD patients have developed perianal fistulizing disease by 10 yrs and 26% after 20 years.
  • This complication leads to significant morbidity/reduced quality of life and about 70% require surgical treatment during long-term followup.

The substance of the article are summarized in Table 4 and Figure 1. The recommendations all are considered to be based on either low quality of evidence or very low quality of evidence:

  • In those with active fistulizing disease, the authors recommend imaging (EUS or MRI)
  • In those with evidence of complicated fistulizing disease, “we suggest surgical consultation.”
  • In those with active fistulizing CD, “we suggest the use of antibiotic therapy for initial management.”
  • In those with active fistulizing CD, “we recommend the use of anti-TNF therapy” for induction and maintenance.
  • In those with active fistulizing CD, “when starting anti-TNF therapy, we suggest it be combined with thiopurine or methotrexate over monotherapy to optimize pharmacokinetic parameters.”
  • In those with active fistulizing CD, surgical management is recommended in those when there is an inadequate response to medical management.

Some additional pointers:

  • Early surgical consultation is recommended in setting of suspected clinical abscess (eg. pain, fever, leukocytosis).
  • The authors’ algorithm suggests that if early surgical intervention is not required, then patients should first receive antibiotics for initial symptom control, followed by imaging, and, if uncomplicated fistulizing disease on imaging, followed by anti-TNF therapy (with either MTX or thiopurine).  If complicated fistulizing disease, then surgical intervention may be needed prior to institution of anti-TNF therapy.
  • “The rate of fistula healing was 43% with medical therapy alone and 53% with combination surgical and medical therapy” based on a systematic review of 8 cohort studies.

My take: This article helps simplify/streamline the approach to this troubling complication.

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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.

 

Shoshone, California

Can Therapeutic Drug Monitoring with Monotherapy Achieve Similar Results as Combination Therapy for IBD?

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A recent retrospective study (S Lega et al. Inflamm Bowel Dis 2019; 25: 134-41) suggests that proactive therapeutic drug monitoring (pTDM) with infliximab (IFX) helps achieve similar outcomes as combination therapy (with immunomodulator) in patients with inflammatory bowel disease.

Before reviewing the key findings, it is important to emphasize a few crucial limitations/methods:

  • The study enrolled 83 patients; only 16 received were in the monotherapy pTDM group.
  • This was a retrospective study
  • The authors utilized TDM at week 10. (week 10 infliximab level). If the IFX level was <20 mcg/mL, the dose and frequency of infliximab were both adjusted. If the level was between 20 & 25, either the frequency was adjusted or no adjustment, and if the level was >25, then no adjustment in dosing was performed.

Key findings:

  • The frequency of infliximab discontinuation with mono therapy in those with pTDM was lower than in those with ‘standard of care’ TDM (P=0.04) but did not differ from patients receiving combination therapy
  • Overall 9 of the 83 patients (11%) discontinued IFX during the 1-year study

In the discussion, the authors suggest that week 14 TDM may be suboptimal as this is the first time patients have an 8-week interval.

My take: The jury is out with regard to whether pTDM can negate the need for combination therapy  –a prospective trial is needed; however, the idea of getting TDM a bit earlier is intriguing, particularly as it has been shown that a high percentage of pediatric patients are receiving an insufficient dose of infliximab (Is Standard Infliximab Dose Tool Low in Pediatrics?)

Key words: 10 weeks, therapeutic drug monitoring, infliximab, trough

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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.

View from Artist’s Drive, Death Valley

“Grateful Patient Programs”

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From NY Times: Hospitals Are Asking Their Own Patients to Donate Money

This article in the NY Times reviews a growing trend of non-profit hospitals asking patients for contributions; sometimes, physicians are asked to help identify potential donors.

An excerpt:

Many hospitals conduct nightly wealth screenings — using software that culls public data such as property records, contributions to political campaigns and other charities — to gauge which patients are most likely to be the source of large donations…

These various tactics, part of a strategy known as “grateful patient programs,” make some people uncomfortable…it could make patients worry that their care might be affected by whether they made a donation.

My take: Should hospitals simplify the process by adding a line on the bill for a tip?

Badwater basin, Death Valley

 

Gastrostomy Complications

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A recent review (RJ Sealock, K Munot. Clin Gastroenterol Hepatol 2018; 16: 1864-69) provides a quick review of some common and rare problems: infection, buried bumper, leakage, bleeding, colonic perforation, tube dislodgment, and nonhealing stoma.

It is a useful reference.  One item (Link to Figure 2) that was interesting was a technique for gastrostomy site closure.  The authors describe passing 2 sutures through a long needle into the stomach around the stoma and using an endoscope/endoscopic biopsy forceps to redirect the sutures back through a catheter to make a loop which can be tied externally.

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Golden Gulch Trail, Death Valley

Lost Boys (& Girls) of Celiac

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The blog post alludes to the ‘lost boys of Sudan.’ Between 1987-2005, there were more than 20,000 Sudanese boys displaced by the civil wars in Sudan.

With regard to Celiac disease (CD), the problem is no where near as dire.  However, the authors of a recent abstract note poor follow-up for pediatric celiac disease and speculate that this could lead to worsened outcomes (NAPSGHAN Annual Meeting 2018; abstract 105 cited in gastroendonews.com: Clinicians Fumbling Follow-up For Celiac Kids).  Those without followup may have suboptimally-treated CD which could lead to vitamin deficiencies, and autoimmune diseases.

Key finding:

  • “We lost 25% in the first year and half within three years.”  Patients were considered lost to follow-up if they did not attend a visit with a celiac specialist for 18 months.

There has been data documenting even higher rates of poor follow-up among adults with celiac disease: Closer followup for Celiac disease & pediatric guidelines (2012)

My take: Celiac disease may have higher rates of poor follow-up than other GI conditions since symptoms may be minimal in many; however, poor followup is commonplace throughout medicine and contributes to worsened outcomes

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Highway near Death Valley

Management of Acute Severe Colitis

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A recent review (KG Whatley, MJ Rosen. Inflamm Bowel Dis 2019; 25: 56-66) succinctly summarizes the contemporary medical management of acute severe ulcerative colitis (ASUC).

Figure 1 provides a useful initial checklist which includes the following:

  • PUCAI score
  • Labs/Imaging: CBC/d, CMP, CRP/ESR, Stool studies (culture/C diff), AXR
  • Pre-salvage labs: TB screen, Hep B serology, VZV serology if needing anit-TNF, TPMT if contemplating thiopurine, lipids if contemplating calcineurin inhibitor
  • Endoscopy: Consider Flex Sig (unsedated) with tissue for CMV PCR if not responding to 3 days of IV steroids
  • Thromboembolism prophylaxis: Low molecular weight heparin (adults, & high-risk pediatric patients), pneumatic compression (low-risk pediatric)
  • Nutrition plan
  • Corticosteroids: methylprednisolone 1-15. mg/kg (to max of 40-60 mg daily)

Each of these recommendations is discussed. For the flex sig recommendation, the authors note that a “full colonoscopy is not recommended due to risk of perforation.” With regard to CMV, the authors acknowledge the low quality of evidence to support antiviral treatment of CMV in this setting.  In addition, the authors suggest PCP prophylaxis in those who receive triple immunosuppression or in those receiving calcineurin inhibitors.

Figure 2 provides a handy algorithm for infliximab salvage therapy in the setting of ASUC:

  • If salvage therapy with infliximab is indicated (day 3-5 of IV steroids), the authors recommend 10 mg/kg dosing.  If there is no response after 3-5 days, repeat dosing is recommended.  If there is no response after an additional 3-5 days, colectomy is recommended.
  • If there is a response to infliximab, the algorithm recommends outpatient management. At time of the 3rd dose (week 5-6), the authors obtain an IFX level.  In those with a level <15, then dosing at 4 week maintenance is recommended; whereas in those 15 and above, every 8 week maintenance is recommended.

The authors discuss some potential emerging treatments. Recommendations from the authors with regard to surgery:

  • Most patients are best served with a subtotal colectomy/end ileostomy in preparation for future ileal pouch anal anastomosis
  • “Surgery should not be delayed to enhance nutrition or taper steroids.”

My take: This article summarizes current approaches with emphasis on not waiting a long time for salvage therapies and using early therapeutic drug monitoring to assist in dosing frequency.

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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.

Death Valley

 

Experimental Use of FMT for Ulcerative Colitis

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In a recent randomized, double-blind study (SP Costello et al. JAMA. 2019;321(2):156-164. doi:10.1001/jama.2018.20046), the use of fecal microbiota transplantation (FMT) was effective in 32% in inducing remission in adult patients with ulcerative colitis (UC).

Key Finding:  In this randomized clinical trial that included 73 adults with mild to moderately active ulcerative colitis, the proportion achieving steroid-free remission at 8 weeks was 32% with donor FMT vs 9% with autologous FMT, a significant difference

Abstract:

Importance  High-intensity, aerobically prepared fecal microbiota transplantation (FMT) has demonstrated efficacy in treating active ulcerative colitis (UC). FMT protocols involving anaerobic stool processing methods may enhance microbial viability and allow efficacy with a lower treatment intensity.

Objective  To assess the efficacy of a short duration of FMT therapy to induce remission in UC using anaerobically prepared stool.

Design, Setting, and Participants  A total of 73 adults with mild to moderately active UC were enrolled in a multicenter, randomized, double-blind clinical trial in 3 Australian tertiary referral centers between June 2013 and June 2016, with 12-month follow-up until June 2017.

Interventions  Patients were randomized to receive either anaerobically prepared pooled donor FMT (n = 38) or autologous FMT (n = 35) via colonoscopy followed by 2 enemas over 7 days. Open-label therapy was offered to autologous FMT participants at 8 weeks and they were followed up for 12 months.

Main Outcomes and Measures  The primary outcome was steroid-free remission of UC, defined as a total Mayo score of ≤2 with an endoscopic Mayo score of 1 or less at week 8. Total Mayo score ranges from 0 to 12 (0 = no disease and 12 = most severe disease). Steroid-free remission of UC was reassessed at 12 months. Secondary clinical outcomes included adverse events.

Results  Among 73 patients who were randomized (mean age, 39 years; women, 33 [45%]), 69 (95%) completed the trial. The primary outcome was achieved in 12 of the 38 participants (32%) receiving pooled donor FMT compared with 3 of the 35 (9%) receiving autologous FMT (difference, 23% [95% CI, 4%-42%]; odds ratio, 5.0 [95% CI, 1.2-20.1]; P = .03). Five of the 12 participants (42%) who achieved the primary end point at week 8 following donor FMT maintained remission at 12 months. There were 3 serious adverse events in the donor FMT group and 2 in the autologous FMT group.

Conclusions and Relevance  In this preliminary study of adults with mild to moderate UC, 1-week treatment with anaerobically prepared donor FMT compared with autologous FMT resulted in a higher likelihood of remission at 8 weeks. Further research is needed to assess longer-term maintenance of remission and safety.

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Golden Gulch Trail, Death Valley

 

Fecal Microbioata Transplantation for Recurrent Clostridium difficile — Position Paper

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A recent position paper (ZH Davidovics et al. JPGN 2019; 68: 130-43) from NASPGHAN/ESPGHAN on Fecal Microbioata Transplantation (FMT) for Recurrent Clostridium difficile infection (CDI) provides a pretty good review. Though, I think a summary table of recommendations would have made this publication much more helpful.

Here is a full-text link: Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection and Other Conditions in Children: A Joint Position Paper

A couple key points/excerpts:

In general, we concur with current adult guidelines  when considering FMT for the treatment of rCDI in children and propose FMT be considered in children with one of the following:
1. rCDI (recurrence of symptoms within 8 weeks of treatment for CDI) (either a or b)
a. At least 3 episodes of mild to moderate CDI and failure of a 6- to 8-week taper with vancomycin with or without an alternative antibiotic (eg, rifaximin, nitazoxanide).
b. At least 2 episodes of severe CDI resulting in hospitalization and associated with significant morbidity.

2. Moderate CDI not responding to standard therapy (including vancomycin) for at least 1 week. We recommend caution, however, in such cases, with repeated testing for etiologies other than CDI such as IBD.

3. Severe CDI or fulminant C difficile colitis with no response to standard therapy after 48 hours.

My take:  I think the IDSA 2017 guidelines are more useful: Clostridium difficile Guidelines (2017 IDSA/SHEA)

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ESPGHAN Position Paper: Biosimilars in Pediatric Inflammatory Bowel Disease

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A recent position paper from ESPGHAN/Porto Group:

Full text: Use of Biosimilars in Pediatric Inflammatory Bowel Disease: An Updated Position Statement of the Pediatric IBD Porto Group of ESPGHAN. L de Riddler et al. JPGN 2019; 68: 144-53

Key points:

  • There are sufficient data (by extrapolation from different indications, adult data and limited pediatric data) to state that in children with IBD who are indicated for IFX treatment, CT-P13 is a safe and efficacious alternative to the originator IFX for
    induction, and maintenance, of remission. 97% agreement
  • A switch from the originator infliximab to CT-P13 may be considered in children with IBD in clinical remission, following at least 3 induction infusions. 84% agreement
  • Multiple switches (>1 switch) between biosimilars and reference drug or various biosimilars are not recommended in children with IBD, as data on interchangeability is limited and traceability of the drugs in case of loss of efficacy and/or safety signals may be compromised. 97% agreement
  • Physicians/institutions should keep records of brands and batch numbers of all biological medicines (including biosimilars) administered. 89% agreement

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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.