Category Archives: Pediatric Gastroenterology Intestinal Disorder

Acid Suppression/C difficile and Adrenal Suppression/Topical Steroids

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Briefly noted:

J Jimenez et al. (JPGN 2015; 61: 208-11) provide more data that gastric acid suppression is associated with an increase risk of Clostridium difficile infection (CDI). This was a retrospective case-control study with 138 children with CDI and 276 controls. After adjustment, acid-suppression therapy had a 1.8 Odds Ratio association with CDI.

S Harel et al. (JPGN 2015; 61: 190-3) in this retrospective ‘pilot’ study of  patients receiving topical budesonide for eosinophilic esophagitis, 6 of 14 (43%) had mild biochemical evidence of adrenal suppression, as measured by ACTH testing. Bottomline: a prospective study is likely needed to confirm or refute these findings. In the meanwhile, stress steroid coverage could be considered in patients on prolonged budesonide.

Improving ER Performance for Suspected Constipation

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While the ultimate goal would be for most constipation to be prevented or managed by primary care physicians, the reality is that a lot of children are seen in the ER setting.  Particularly in the hospital setting, many practitioner’s have relied on abdominal xrays (AXRs) and this practice has been criticized previously (What’s Wrong with Ordering an AXR for Constipation in the …).

It is gratifying that efforts are underway to reverse this tendency.  A recent study (J Kurowski et al. J Pediatr 2015; 167: 706-10) document the effect that a 10 minute training session can have.

In this retrospective chart review, the researchers examined a 2 month baseline period and then a 2 month period after institution of a 10-min educational module for ER healthcare providers.  The module included the following:

  1. Rome III criteria for constipation  -at least 2 criteria weekly for >2 months:
    • ≤2 defecations in the toilet per week
    • at least 1 episode of fecal incontinence per week
    • history of retentive posturing or excessive volitional stool retention
    • history of painful or hard bowel movements
    • presence of a large fecal mass in the rectum
    • history of large stools which may obstruct toilet
  2. Review of the lack of utility of abdominal radiographs
  3. Use of rectal exam

Patients were identified who were discharged from the ER (without hospital admission)  with a diagnosis of constipation and with a chief complaint of abdominal pain.  In the baseline period, there were 105 patients and in the followup period, there were 91 patients.

Key findings:

  • Digital exams increased: 22.9% —>47.3%
  • AXR decreased: 69.5% –>26.4%

This study has numerous limitations; these include retrospective study and patient selection. Nevertheless, it makes several useful points.  If constipation is suspected, better care at a lower cost can be achieved by including a digital exam.  The authors note that “there is no strong evidence to support the utility of radiographs for this diagnosis [constipation] or even reliable standards to evaluate the normal stool burden across different ages.”

My take: The lessons from this study are applicable to primary care physicians and gastroenterologists as well as to ER physicians.  While this educational module is a good start, if I were designing a module, I would include information on irritable bowel syndrome which is often confused with isolated constipation.

Related blog posts:

Overdiagnosis of Clostridium difficile with PCR Assays

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A recent study (JAMA Intern Med. Published online September 08, 2015. doi:10.1001/jamainternmed.2015.4114) indicates that use of PCR assays to detect C diff results in overdiagnosis and overtreatment.  Perhaps, a more selective approach to using C diff PCR assay is needed and returning to use of toxin immunoassays is worthwhile.  

 

ABSTRACT:

Importance  Clostridium difficile is a major cause of health care–associated infection, but disagreement between diagnostic tests is an ongoing barrier to clinical decision-making and public health reporting. Molecular tests are increasingly used to diagnose C difficile infection (CDI), but many molecular test-positive patients lack toxins that historically defined disease, making it unclear if they need treatment.

Objective  To determine the natural history and need for treatment of patients who are toxin immunoassay negative and polymerase chain reaction (PCR) positive (Tox−/PCR+) for CDI.

Design, Setting, and Participants  Prospective observational cohort study at a single academic medical center among 1416 hospitalized adults tested for C difficile toxins 72 hours or longer after admission between December 1, 2010, and October 20, 2012. The analysis was conducted in stages with revisions from April 27, 2013, to January 13, 2015.

Main Outcomes and Measures  Patients undergoing C difficile testing were grouped by US Food and Drug Administration–approved toxin and PCR tests as Tox+/PCR+, Tox−/PCR+, or Tox−/PCR−. Toxin results were reported clinically. Polymerase chain reaction results were not reported. The main study outcomes were duration of diarrhea during up to 14 days of treatment, rate of CDI-related complications (ie, colectomy, megacolon, or intensive care unit care) and CDI-related death within 30 days.

Results  Twenty-one percent (293 of 1416) of hospitalized adults tested for C difficile were positive by PCR, but 44.7% (131 of 293) had toxins detected by the clinical toxin test. At baseline, Tox−/PCR+ patients had lower C difficile bacterial load and less antibiotic exposure, fecal inflammation, and diarrhea than Tox+/PCR+ patients (P < .001 for all). The median duration of diarrhea was shorter in Tox−/PCR+ patients (2 days; interquartile range, 1-4 days) than in Tox+/PCR+ patients (3 days; interquartile range, 1-6 days) (P = .003) and was similar to that in Tox−/PCR− patients (2 days; interquartile range, 1-3 days), despite minimal empirical treatment of Tox−/PCR+ patients. No CDI-related complications occurred in Tox−/PCR+ patients vs 10 complications in Tox+/PCR+ patients (0% vs 7.6%, P < .001). One Tox−/PCR+ patient had recurrent CDI as a contributing factor to death within 30 days vs 11 CDI-related deaths in Tox+/PCR+ patients (0.6% vs 8.4%, P = .001).

Conclusions and Relevance  Among hospitalized adults with suspected CDI, virtually all CDI-related complications and deaths occurred in patients with positive toxin immunoassay test results. Patients with a positive molecular test result and a negative toxin immunoassay test result had outcomes that were comparable to patients without C difficile by either method. Exclusive reliance on molecular tests for CDI diagnosis without tests for toxins or host response is likely to result in overdiagnosis, overtreatment, and increased health care costs.

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Celiac Update September 2015

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A useful review (CP Kelly et al. Gastroenterol 2015; 148: 1175-86) summarizes the ‘state of the art” information regarding celiac disease presentation and management. The review notes that some expert organization consensus state that intestinal biopsy is mandatory whereas some do not under certain conditions.

According to ESPGHAN, if anti-TTG >10-fold elevated, anti-EMA positive in separate sample, and +HLA typing, then a biopsy may not be required.  For the WGO (World Gastroenterologic Organization), the exception focuses on available local resources.

The article recommends the following for monitoring:

  • Clinical evaluation -annually or if recurrent symptoms
  • Serology & Nutritional evaluation -every 3-6 months until normal, then every 1-2 years.  Common nutrient deficiencies: iron, vitamin D, vitamin B12, folate, and zinc
  • Bone density -once within first 2 years.  (Some recommend checking after 1 year on gluten free diet)
  • Liver transaminase levels & Thyroid function tests -at diagnosis, then every 1-2 years.  Autoimmune thyroid disorders are “found in approximately 15-20% of adults with celiac disease”

A second retrospective indicates that ESPGHAN criteria for avoiding biopsy in children and adolescents with high titers for anti-TTG (>10-fold) along with positive EMA, and HLA-DQ2/DQ8.are reasonable.  Here’s the abstract:

Are ESPGHAN “Biopsy-Sparing” Guidelines for Celiac Disease also Suitable for Asymptomatic Patients?

CM Trovato, et al.The American Journal of Gastroenterology , (15 September 2015) | doi:10.1038/ajg.2015.285

OBJECTIVES:

In 2012, European Society of Pediatric Gastroenterology, Hepatology, and Nutrition published novel guidelines on celiac disease (CD) diagnosis. Symptomatic children with serum anti-transglutaminase (anti-tTG) antibody levels ≥10 times upper limit of normal (ULN) could avoid duodenal biopsies after positive HLA test and serum anti-endomysial antibodies (EMAs). So far, both asymptomatic and symptomatic patients with anti-tTG titer <10 times ULN should undergo upper endoscopy with duodenal biopsies to confirm diagnosis. The aim of this study was to assess the accuracy of serological tests to diagnose CD in asymptomatic patients.

METHODS:

We retrospectively reviewed data of 286 patients (age range: 10 months to 17 years) with CD diagnosis based on elevated titer of anti-tTG, EMA positivity, and histology. All patients were distinguished between symptomatic and asymptomatic; histological lesions were graded according to the Marsh–Oberhuber (MO) criteria. Fisher exact test was applied to analyze both groups in terms of diagnostic reliability of serological markers.

RESULTS:

A total of 196 patients (68.53%) had anti-tTG titers ≥10 times ULN. Among them, a group of 156 patients (79.59%) also had symptoms suggestive of CD (“high-titer” symptomatic); of these, 142 patients (91.02%) showed severe lesion degree (3a, 3b, 3c MO). Conversely, 40 out of 196 patients (20.40%) were asymptomatic (“high-titer” asymptomatic) and 37 patients (92.5%) of them showed severe lesion degree (3a, 3b, 3c MO). No difference in histological damage was found between “high-titer” symptomatic and “high-titer” asymptomatic children (Fisher exact test, P=1.000).

CONCLUSIONS:

If confirmed in large multicenter prospective studies, the “biopsy-sparing” protocol seems to be applicable to both symptomatic and asymptomatic patients with anti-tTG titer ≥10 times ULN, positive EMA, and HLA-DQ2/DQ8.

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Celiac Disease: “Ten Things That Every Gastroenterologist Should Know”

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Turns out that a recent review (AS Oxentenko, JA Murray. Clin Gastroenterol Hepatol 2015; 13: 1396-1404) is a succinct summary on celiac disease with questions focused on diagnosis, endoscopy, genetics/HLA typing, at risk groups, management, adherence, non responsive celiac patient, and refractory patients.  Most of these topics have been addressed previously on this blog.

However, here are a few pointers:

  • “Histologic improvement is slow in adults…Mucosal recovery, defined by a villous:crypt ratio of 3:1, was present in 34% at 2 years and 66% at 5 years, with healing complete in 90% by 9 years.”
  • “Mucosal recovery is faster and more complete in children, with 95% recovery in 2 years and 100% recovery long-term in children following a GFD.”
  • With nonresponsive celiac disease, “defined as a lack of response to 6 months on a GFD or a recurrence of celiac-related features despite compliance,” the authors recommend reviewing serology and biopsies.  Other etiologies to consider include bacterial overgrowth, autoimmune enteropathy, tropical sprue, Crohn’s disease, combined variable immunodeficiency, collagenous sprue, and eosinophilic gastroenteritis.
  • For refractory celiac disease with ongoing villous atrophy, this “should prompt immunophenotyping and T-cell rearrangement studies” of duodenal biopsies.

Briefly noted: ET Jensen et al. Clin Gastroenterol Hepatol 2015; 13: 1426-31.  The authors examined 88,517 patients who had undergone both esophageal and duodenal biopsies.  “Odds of EoE (eosinophilic esophagitis) were 26% higher in patients with celiac disease than in patients without celiac disease” (adjusted odds ratio 1.26).

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From the High Line, NYC

From the High Line, NYC

Parenteral Nutrition and False Positive Newborn Screens, Plus One

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Briefly noted:

“Stopping Parenteral Nutrition for 3 Hours Reduces False Positives in Newborn Screening” T Tim-Aroon et al. J Pediatr 2015; 167: 312-6. By stopping parenteral nutrition (PN), the authors reduced false-positive results for amino acid disorders among newborn screenings. In patients receiving PN, holding PN (and using IVFs) was associated with a false-positive rate of 2/65 compared with 29/245 who continued PN (3.1% vs. 11.8%; P=.037)

“Age at Weaning and Infant Growth: Primary Analysis and Systemic Review” B Vail et al. J Pediatr 2015; 167: 317-24. UK prospective study with n=571 singletons along with systemic review which identified two trials. Conclusion: “In high-income countries, weaning between 3 and 6 months appears to have a neutral effect on infant growth.  Inverse associations are likely related to reverse causality.”

 

 

Desperate Measures in Refractory IBD

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The often cited, ‘desperate times call for desperate measures,’ resonates in the setting of refractory inflammatory bowel disease (IBD).  [Of course, this saying could be used to justify about anything you want to do.]  For IBD, two recent studies point out potential remedies:

  • SA Merkley, et al. Inflamm Bowel Dis 2015; 21: 1854-59.
  • M Lazzerini, et al. Inflamm Bowel Dis 2015; 21: 1739-49, with editorial by A Bousvaros (1750-51)

In the first study, the authors retrospectively analyzed date from 24 IBD patients who were treated with intravenous immunoglobulin (IVIG) at a dose of 0.4 g/kg/day for 3 days, then 0.4 g/kg once a month. Key findings: 16 (67%) had a response and 3 (12.5%) obtained remission. Measures of improvement included CRP, ESR, Simple Endoscopic Score for Crohn’s disease, and the Harvery-Bradshaw Index. The researchers speculate that IVIG has anti-inflammatory and immunomodulator effects.  In addition, they note that IVIG can be given with concurrent infections.

In the second study, the authors studied thalidomide(1.5-2.5 mg/kg/day) in a double-blind, placebo-controlled randomized pediatric clinical trial in children with refractory active ulcerative colitis. Key findings: at week 8, clinical remission was achieved in 10/12 (83%) of thalidomide arm compared with 2/11 (19%) of control patients.  Then, among control patients who were switched, 8 of 11 (72%) reached remission as well. Peripheral neuropathy and amenorrhea were reported adverse effects. In the accompanying editorial, Dr. Bousvaros notes that there has been some data to suggest thalidomide efficacy in ulcerative colitis since 1979.  However, due to widespread bad publicity related to thalidomide-induced teratogenicity (eg. phocomelia) and side effects including neuropathy, it has not been used with much frequency. He notes that this study, as well, requires replication and speculates that “the primary focus on drug development will focus on newer small molecules and biologics, and this potentially useful medication may be left on the sidelines.” It is worth noting that the authors response (pg 1752) to this editorial was that the stigma of thalidomide is unwarranted and that teratogenicity can be avoided. “No case was observed out of 124,000 patients enrolled in the thalidomide distribution risk management program for more than 6 years.”

Bottomline: Both thalidomide and IVIG may be beneficial to desperate patients (and desperate doctors).  While small trials appear promising, larger trials are needed.  Don’t hold your breath waiting … will they ever happen?

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Another Look at “Step-up” IBD Therapy

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Whether and how long to continue immunomodulators in patients who have undergone a “step-up” treatment to anti-tumor necrosis factor (anti-TNF) therapy remains murky.  This is due to conflicting data from different patient cohorts, changing treatment trends, (e.g. use of drug monitoring to enhance anti-TNF therapy), and different endpoints. With regard to the latter, dual therapy has been clearly more effective in some landmark studies (eg. SONIC, UC SUCCESS); however, there have been ongoing concerns regarding long-term outcomes and adverse effects.

Will more studies help resolve this question? Perhaps, but not today.

A recent study (MT Osterman et al. Clin Gastroenterol Hepatol 2015; 13: 1293-1301) examined a retrospective cohort of new users of anti-TNF therapy for Crohn’s disease in Medicare recipients.  The authors matched 381 combination with infliximab (ie. dual therapy) with 912 users of monotherapy. In addition, the authors did the same with adalimumab with 196 combination users and 505 monotherapy users. In their cohort, combination therapy occurred primarily as a “step-up” treatment after institution of thiopurine therapy.

Results:

  • Key outcome measures were unchanged: rates of surgery (hazard ratio [HR] 1.2, hospitalization HR 0.82, discontinuation of anti-TNF therapy or surgery HR 1.09, and serious infection HR 0.93
  • Opportunistic infections were increased in combination therapy with HR 2.64 and herpes zoster infection was increased with HR 3.16

Take-home message: This study suggests, at least in this elderly population, that once remission is achieved with anti-TNF therapy, discontinuation of thiopurine therapy or use of an alternative immunomodulator therapy may be worthwhile.  At the same time, definitive answers to these type of questions await carefully designed randomized trials.

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Identifying Anastomotic Ulcers with Capsule Endoscopy

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A retrospective review (LM Bass et al. JPGN 2015; 61: 215-9) showed that capsule endoscopy (CE) can be helpful in identifying anastomotic ulcers among patients with short bowel syndrome and chronic GI blood loss.

This study of 4 patients (& 6 CE procedures) indicated that two of these patients underwent surgery after identifying anastomotic ulcers.  The other common treatment was antibiotics. In the suggested evaluation CE was used after upper/lower endoscopy. The recommended role for patency capsule/small bowel imaging is not clearly spelled out, but should be carefully considered due to the risk of strictures.

“The decision to perform CE is made in conjunction with medical and surgical teams so that, although every effort is made to avoid a situation that may result in a retained capsule, both parents and care teams are prepared.”

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Changing Practice Patterns with Pediatric Pancreatitis

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A recent study (FK Szabo et al. J Pediatr 2015; 167: 397-402) supports the practice of early enteral nutrition and aggressive fluid administration with acute pancreatitis. Starting in January 2014, Cincinnati Children’s began using high rates of intravenous fluid and resuming enteral nutrition within 48 hours for children presenting with acute pancreatitis.  This retrospective study assessed this practice in 201 patients and compared with prior experience dating back to 2009. To be included, patients had to have mild acute pancreatitis based on the Atlanta criteria (Gut 2013; 62: 102-11). Exclusion criteria:

  • Severe acute pancreatitis: multiorgan failure, systemic inflammatory response, local pancreatic complications (eg. necrosis, hemorrhage, pseudocyst), or respiratory complications
  • Pancreatitis due to trauma, gallstones or postsurgical

With regard to enteral nutrition (EN), nasoenteric tubes were not placed during the first 48 hours, but preexisting enteral tubes were used. So, most patients were orally fed. With regard to IV fluids, 62% received 1.5-2 times the maintenance IVF during the first 24 hours of admission.  More than 90% of cases received dextrose 5% normal saline. Key Findings:

  • Length of stay was 2.9 days in the early EN group compared with 4.4 days in the NPO group (P <.0001).  It is noted that the NPO group did include 24% with severe acute pancreatitis compared with 6% in the early EN group.
  • The authors did not identify any change in measured outcomes based on high or low volume IVF.

From the discussion:

  • “EN remains an integral part of management which has been associated with a lower incidence of infection, multiorgan failure, lower mortality rates, and a shorter hospital stay in adult patients with AP [acute pancreatitis]”
  • “Our study shows that oral feeds represent a safe and a feasible strategy in mild AP.” There was not an increase in readmission rates within 72 hours of discharge, either.

Because this is a retrospective study, this limits the interpretation of these findings; there could be an element of reverse causation with regard to the outcomes.

My take: Increasing evidence supports the practice of early enteral feedings in mild acute pancreatitis.  The exact IV fluids to use remain unclear, though my preference is lactated ringer’s based on ERCP-induced pancreatitis studies.

Related blog posts:

  • Why an ERCP Study Matters to Pediatric Care | gutsandgrowth This post explains why LR may be best.
  • Nutrition University / gutsandgrowth What are the nutritional management recommendations for acute pancreatitis? Justine Turner indicated that too many centers continue to rely on parenteral nutrition.  Yet, guidelines recommend the use of enteral nutrition due to lower risk of poor outcomes (eg. infections when NPO and on parenteral nutrition). ‘Resting pancreas is not helpful.’ With acute pancreatitis, enzyme secretion is reduced.  Her approach is to start nasogastric (NG) feedings at about 24 hours after presentation, as long as hemodynamically stable.  She indicated that nasojejunal (NJ) feedings can be done if NG is not well-tolerated.  NJ feedings are effective at reducing enzyme secretion.  However, Praveen Goday stated that his practice was often starting with NJ feeds.  “Sometimes there is only one shot” before the ICU team starts HAL.  Both physicians indicated that polymeric formulas were probably acceptable; however, starting with semi-elemental or elemental feedings are often done, again as a practical matter to minimize the likelihood of reverting to parenteral nutrition.
Artist Point, Yellowstone

Artist Point, Yellowstone