Plasma miR-1290 -Specific Biomarker for Necrotizing Enterocolitis

Briefly noted: P Cheung, et al. J Pediatr 2019; 205: 83-90.  This study showed that a plasma biomarker for necrotizing enterocolitis (NEC), miR-1290, was very useful in a cohort of 301 neonates.

  • Of 20 infants with miR-1290 > 650 copies/microliter, 15 were diagnosed with NEC.
  • In those with intermediate values (220-650 copies/microliter) adding CRP (>1.58 mg/dL) allowed for a sensitivity of 0.83, specificity of 0.96, a positive predictive value of 0.75, and a negative predictive value of 0.98.
  • The authors state that 7 of 36 infants had NEC diagnosed earlier by 8-32 hrs based on the availability of miR-1290 testing.

My take: Biomarkers are helping us identify serious diseases more quickly and changing how we practice.  Hopefully, work in this area will help us identify NEC sooner and improve outcomes.

Below is a visual abstract indicating that transfusion for platelet count less than 25 K was associated with a lower rate of death/major bleeding that a platelet count threshold of 50 K.

Visual abstract indicates that most preterm infants do not need platelet transfusions as long as the platelet count is >25 K.

Oral Antibiotics For Refractory Inflammatory Bowel Disease

A recent retrospective study (J Breton et al. Inflamm Bowel Dis 2019; https://doi.org/10.1093/ibd/izz006) currently available online in advance of publication is likely to influence current practice in children with refractory inflammatory bowel disease (IBD). Thanks to Ben Gold for sharing this reference.

Link to abstract: Efficacy of Combination Antibiotic Therapy for Refractory Pediatric Inflammatory Bowel Disease

Here are some of the details:

  • There were 63 patients who met inclusion criteria.
  • 27 (43%) with colonic (n=18) or ileocolonic (n=9) Crohn’s disease (CD)
  • 23 (36.5%) with ulcerative colitis
  • 13 (21% classified with IBD-U.
  • 34 (54%) were corticosteroid-refractory or dependent
  • 62/63 with previous or present loss of response or primary nonresponse to anti-tumor necrosis factor (anti-TNF) therapy
  • 48 (76.2%) were receiving anti-TNF therapy at time of antibiotic initiation
  • Of the 37 with available anti-TNF trough, 23 (62.%) were considered therapeutic  (IFX ≥5, or ADA ≥7.5)
  • Medical refractoriness “was defined by corticosteroid resistance, as shown by no or partial response to more than 7 days of hgih-dose corticosteroids (≥ 1 mg/kg/day prednisone equivalent) or primary nonresponse or loss of response to a biologic”

Antibiotic regimens: A=Amoxicillin, D =Doxycycline, M =Metronidazole, C= Ciprofloxacin, V= vancomycin. Antibiotic therapy was based on previous study which used ADM. A =50 mg/kg/day divided TID to max 500 mg/dose; D =4 mg/kg/day divided BID to max 100 mg/dose; M 15 mg/kg/day divided TID to max of 250 mg/dose. In children <8 yrs, C =20 mg/kg/day divided BID to max of 250 mg.  Vancomycin 125 mg/dose QID in <8 y and 250 mg/dose QID in ≥8 yo could be added as a 4th drug and Gentamicin cold be substituted in those with a drug allergy.

  • 45% ADM
  • 8% ADMV
  • 8% CMV
  • 8% AMV
  • 8% ACM
  • 6% ADV
  • 17% Other

Improvement with Regimen:

  • Median PUCAI dropped from 55 at baseline to 10 (P<0.0001) by 3 weeks ± 1 week after antibiotic initiation
  • 40 (63.5%) experienced a clinical response with a change in PUCAI of ≥20 points
  • 25 (39.7%) entered clinical remission, including 6 who achieved corticosteroid-free remission
  • Other markers of improvement: increased median hemoglobin (10.7–>11.6), Improved median CRP (1.1 –> 0), improved median ESR (38 –>21)
  • Use of doxycycline (OR 0.25) and high PUCAI ≥ 65 (OR 0.2) were both associated with a much lower odds of clinical remission

Outcomes:

  • Among the 25 entering clinical remission, 13 (65%) had successful rescue of current anti-TNF therapy, 6 were transitioned to another biologic (vedolizumab or ustekinumab)
  • No serious adverse drug-related toxicities were evident.  No cases of Clostridium difficile. One patient had a vaginal yeast infection

Implications:

  • The authors interpret their findings as indicating that antibiotics could serve as an effective rescue therapy in some and potentially rescue anti-TNF therapy in patients with refractory disease.
  • The discussion speculates that improvement is related to microbial modulation as dysbiosis “may play a causative role in perpetuating inflammation”
  • In those placed on antibiotics, the authors state that “clinical response should be assessed frequently and therapy discontinued if no improvement is documented within 1 week”

Safety and Antibiotic Choice:

  • While there were no safety signals evident in this study over 1 year, the long-term risks of using antibiotics is uncertain. For example, with ciprofloxacin, a fluoroquinolone, there is a well-recognized risk of permanent damage to tendons/joints (link to FDA update) and fluoroquniolones increase the risk of aortic tear/rupture.  Because aortic rupture is rare, this increased risk represents a very low absolute risk.
  • The authors indicate that doxycycline, used in 45%, had a much lower response rate.  This makes the choice of antibiotic regimen uncertain –none of the other regimens were used in more than 8%.
  • Given the retrospective nature, it is unclear whether some of the improvement could be related to additional time for the adjunctive/non-antibiotic treatments to work. Though, the authors found that the effect of antibiotics seemed to be independent of therapy optimization.

My take: This is an important study for children with limited treatment options in the setting of refractory disease and may act to salvage current anti-TNF treatment or facilitate a bridge to an alternative treatment.  Though, the optimal antibiotic regimen in this setting is unclear.

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.

Heart-shaped Cactus, Joshua Tree National Park

Joshua Tree National Park. This image selected since this article discusses a ‘bridge’ therapy,

 

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

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

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.

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.

 

Shoshone, California

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

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.  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?)

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.

View from Artist’s Drive, Death Valley

Gastrostomy Complications

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

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

Related blog posts:

Highway near Death Valley