Monthly Archives: March 2016

Eosinophilic Esophagitis: the Limits of “Clinical Remission”

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Among patients with eosinophilic esophagitis (EoE), two issues are particularly vexing for families:

  • The recommendation to use endoscopy to assess response to treatment.
  • Using proton pump inhibitor (PPI) therapy as first line treatment when other therapies have higher response rates

To some extent, these issues are intertwined because PPI therapy works in less than half of patients and to determine this conclusively, an endoscopy is needed.  Clearly, a reliable noninvasive biomarker would be quite helpful.

In the meantime, another study (CE Kuehni et al. Gastroenterol 2016; 150: 581-90, editorial 547-48) has shown that “clinical remission” has modest accuracy in detecting endoscopic and histologic remission in EoE.

This prospective observational study, performed between 2011-14, recruited 269 consecutive adults in Switzerland and U.S.. 67% male median age 39 years.

Key finding:

Of 111 who were in clinical remission (41.3%), only 79 (72%) and 75 (68%) were in endoscopic and histologic (<20 eos/mm2 which corresponds to <5 eos/median hpf) remission respectively.

My take (borrowed): “Physicians cannot rely on lack of symptoms to make assumptions about lack of biologic disease activity in adult EoE patients.”

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Gibbs Gardens

Gibbs Gardens

Guidelines on Functional Heartburn

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How to diagnose and manage adults with functional heartburn: C Hachem, NJ Shaheen Am J Gastroenterol 2016; 111-53-61 (thanks to Ben Gold for reference).

Functional heartburn is defined as chronic symptoms of heartburn without objective evidence of reflux.  The authors algorithm (Figure 2) recommends endoscopy for patients who have had heartburn that is unresponsive to a 2 month trial of PPI.  If endoscopy is normal, pH-impedance study is recommended.  If abnormal, impedance indicates nonerosive reflux disease.  If normal and there is symptom correlation, this suggests esophageal hypersensitivity.  If normal and there is no symptom correlation, this suggests functional heartburn (though authors note a role for motility testing in this circumstance in their algorithm).

Their conclusions:

  • Functional heartburn (FH) responds poorly to PPI therapy
  • The pathophysiology of FH is unknown but it is often associated with visceral hypersensitivity
  • Modulation of pain perception and alternative therapies (melatonin, TCA, SSRI, biofeedback, acupuncture, or hypnotherapy) may be helpful

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Flamenco Beach -Not the Best Day for the Beach

Flamenco Beach -Not the Best Day for the Beach

Which kids who aspirate need a gastrostomy tube?

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While some may think all children who aspirate should have a gastrostomy tube, a recent study (ME McSweeney et al. J Pediatr 2016; 170: 79-84) indicates a more selective approach is appropriate.

This retrospective review of 114 patients (2006-2013) compared patients fed by gastrostomy tube (g-tube) and those who were fed orally.  In their introduction, the authors note, “there has been a practice shift at many institutions away from g-tube placement and more toward continuing to feed children with aspiration orally.”  All patients in the study had aspiration and/or penetration with thin liquids and/or nectar thick liquids on a videofluoroscopic swallow study (VFSS).

There were 61 who aspirated only thin liquids and 53 who aspirated thin and nectar thick liquids.  All patients were divided into two groups: a g-tube group which did not have a preoperative trial of thickened feeds and an orally-fed group.  Patients who had a fundoplication or post-pyloric feeds were excluded from this study.

Key findings:

  • There were no significant differences in admissions among those who aspirated thins compared with those that aspirated thin & nectar thick liquids.
  • Patients fed by gastrostomy were hospitalized more frequently (median 2 times compared to once with orally-fed) and for longer duration (median 24 days compared with median 2 days for orally-fed)
  • No differences in total pulmonary admissions were noted between gastrostomy-fed and orally-fed group

The authors advocate a trial of oral feeding in all children cleared to take nectar or honey thick liquids prior to g-tube placement.

 

While the authors note that g-tube placement did not result in fewer pulmonary admissions, in their discussion, they also reviewed studies which showed that fundoplication (with g-tube) was not associated with a reduced risk of respiratory complications and in fact, had higher rehospitalizations.

This current study, and previous studies, are limited by their design.  Patients were not randomized and g-tube-fed patients may have had more comorbidities, biasing the results.  The authors note that there were 11 children who failed oral thickening trials and needed g-tube placement.  At the same time, there are substantial numbers of children whose swallow function improve.  Also, the authors note that thickening agents have not been shown to lead to dehydration risk.

My take: the widespread availability of swallow studies has likely led to some children undergoing g-tube placement who may have been fine with ongoing orally-thickened feeds.  Avoiding g-tube placement for children who can tolerate and thrive on thickened feeds is worthwhile.

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Walnut Street Bridge & Tennessee River

Walnut Street Bridge & Tennessee River

Super cool and its effects on the microbiome

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A terrific review (ED Rosen. NEJM 2016; 374: 885-7) explains how cool temperature can alter the microbiome and the implications of this finding.

Background: mammals have at least two types of adipose tissue: “the familiar (and all too abundant) white fat that stores calories, and brown adipose tissue that dissipates energy…studies of mice have identified several drivers of the appearance of beige fat cells in white fat pads, a process known as ‘browning.'”

Reviewed study: Chevalier et al. Cell 2015; 163: 1360-74.

“This new work shows that cold exposure, like dietary change, provokes alterations in the gut microbiota of mice.  Moreover, when cold-adapted flora are transferred to a germ-free animal, the recipient mouse loses fat mass and has improved insulin sensitivity…[they] are better able to defend their body temperature on being placed in the cold.”

  • “This new work shows that prolonged cold exposure induces a massive increase in the absorptive surface of the gut…cold causes a profound increase in the ratio of Firmicutes to Bacteroidetes”
  • “A companion article from the same group suggests that antibiotic therapy, which depletes gut microbiota, also induces browning and weight loss.”

My take: In totality, these studies demonstrate how multiple organs (in this case: adipose tissue and the gut) work together to face an environmental challenge.  Furthermore, changes in the gut microbiome may be important for therapeutic advantage in many disease states including obesity, type 2 diabetes, short bowel syndrome, irritable bowel syndrome and many others.  Now, that is cool.

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View from Walnut Street Bridge, Chattanooga

View from Walnut Street Bridge, Chattanooga

Hepatitis B Vaccine Protects for Up to 30 Years

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From summary at GI & Hepatology News: Hepatitis B vaccine protection lasts 30 years

An excerpt:

  • Ninety percent of patients in a 1981 hepatitis B vaccine trial still had evidence of immune protection 30 years later, according to a study in the Journal of Infectious Diseases…
  • 243 members of the original cohort who responded to the original primary vaccine series but received no subsequent doses during the 30-year period…
  • Of the patients tested, 125 (51%) had anti-HBs levels greater than or equal to 10 mIU/mL. Among participants with anti-HBs levels below 10 mIU/mL who were available for follow-up, 75 of 85 (88%) responded to a booster dose with an anti-HBs level greater than or equal to 10 mIU/mL at 30 days.
  • Read the full study in the Journal of Infectious Diseases (J Infect Dis. 2016 Jan 21. doi: 10.1093/infdis/jiv748).

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Bell Tower, Univ Mich

Bell Tower, Univ Mich

 

LEAP-ON Study: Early Peanuts Prevent Allergies

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A followup study to the LEAP study (The Peanut Story -From NEJM Blog | gutsandgrowth) shows that early peanut exposure produces a durable protection from peanut allergies. NPR summary: Peanut Mush in Infancy Cuts Allergy Risk

Here’s an excerpt:

Researchers followed the kids for one additional year. The kids were between 5 and 6 years old during this follow-up period. It turned out, these high-risk kids’ tolerance to peanuts held up even if they stopped eating peanuts.

“A 12-month period of peanut avoidance was not associated with an increase in the prevalence of peanut allergy,” the authors write in the paper.

This is an important finding, because it wasn’t known whether the kids would need to maintain regular weekly consumption of peanuts in order to stave off developing an allergy…

But that doesn’t mean all parents should just rush in with the peanut mush. The guidance recommends that “infants with eczema or egg allergy in the first 4 to 6 months of life might benefit from evaluation by an allergist” — before they’re introduced to peanut-based foods.

Fajardo, Puerto Rico

Fajardo, Puerto Rico

Pharmaceutical Prescription Practices Tied to Pharmaceutical Payments to Doctors

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A recent buzz has developed regarding a ProPublica study showing an association between the amount of money physicians receive from pharmaceutical companies and their likelihood of recommending brand (rather than generic) prescription drugs.

Here’s a link to the full story: Now There’s Proof: Docs Who Take Company Cash Tend to Prescribe More Brand-Name Meds

“The more money doctors receive from drug and medical device companies, the more brand-name drugs they tend to prescribe, a new ProPublica analysis shows. Even a meal can make a difference.”

Here’s a link to NPR’s summary:  Drug-Company Payments Mirror Doctors’ Brand-Name Prescribing  An excerpt:

“A ProPublica analysis has found that doctors who receive payments from the medical industry do indeed prescribe drugs differently on average than their colleagues who don’t. And the more money they receive, the more brand-name medications they tend to prescribe.

We matched records on payments from pharmaceutical and medical device makers in 2014 with corresponding data on doctors’ medication choices in Medicare’s prescription drug program.

Doctors who got money from drug and device makers prescribed a higher percentage of brand-name drugs overall than doctors who didn’t, our analysis showed. Even those who simply got meals from companies prescribed more brand-name drugs, on average.”

My take: Prescription patterns vary widely among physicians and often for good reason.  At the same time, it is likely that in many cases variation in prescription patterns is influenced by frequent contact with pharmaceutical companies.  As a consequence, this has the potential to make patients question whether their physician always has their best interest in mind and the potential to increase healthcare costs.

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Law Library Ceiling, Univ Michigan

Law Library Ceiling, Univ Michigan

Is Intestinal Function in Children with Autism Different?

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There has been a lot of concern that abnormal GI function contributes to both behavioral and gastrointestinal symptoms in children with autism.  To categorize some of these problems, the term ‘leaky gut’ has been used.

An upcoming study (RI Kushak et al. JPGN DOI: 10.1097/MPG.0000000000001174) (thanks to Ben Gold for forwarding this reference) examines this issue. Using a case-control design, pediatric patients with autism spectrum disorder (ASD) (n=61) were compared with 50 children with normal development.

Workup:

  • Endoscopy (EGD and colonoscopy) with histologic analysis
  • Disaccharidase analysis
  • Intestinal permeability studies with lactulose and rhamnose
  • Fecal biomarkers: calprotectin and lactoferrin

According to the authors, all of the study subjects underwent endoscopy and “all had clinical indications for diagnostic endoscopy.”  Most common indications were parental reports of abdominal pain and diarrhea.

Key findings:

  • Disaccharidase activity levels were not significantly different between the groups. In agreement with prior studies, there was frequent lactase deficiency, with 66% of ASD children in this study with deficient enzyme activity (<15 μmol/min/g).  However, lactase activity in the children with ASD was not lower than the non-ASD children.
  • There were no significant differences in measures of intestinal permeability.  Normative values for lactulose and rhamnose ratio are not definitively established.  However, when using similar cutoff ratios, there were similar results in both groups.

Calprotectin:

  • Intestinal inflammatory markers (calprotectin/lactoferrin) were not significantly different, after the authors excluded the five “neurotypical” children who were diagnosed with inflammatory bowel disease.
  • For calprotectin, the authors considered a level <50 mcg/g to be normal.  In the ASD group, 31of 49 (63%) had abnormal calprotectin compared with 19 of 31 (61%) in the non-ASD group.
  • For calprotectin levels >150 mcg/g, 9 of 49 (18%) reached this level in the ASD group and 8 of 31 (26%) in the non-ASD group.

Histology:

  • Similar levels of GI tract inflammation were noted in both groups –generally mild.
  • In the ASD group, 32 (52%) had inflammation somewhere in their GI tract, “but it was generally mild and non-diagnostic.”  In the ASD group, five had features consistent with GERD, two had eosinophilic esophagitis (EoE).  There were 12 (19%) who had colonic inflammation and 3 (5%) with ileal inflammation.  None had celiac disease or H pylori.
  • In the non-ASD group, four had EoE, four (8%) had ileal inflammation, and nine (18%) had colonic inflammation.  The authors noted Crohn’s disease in three and a total of five children with IBD.

My take:

  1. This study suggests that symptomatic children with autism have similar (and probably not worse) GI problems as neurotypical children.  The idea that children with autism have a more leaky gut than children without autism is quite dubious based on these results.
  2. The biggest problem for GI physicians is not addressed in this study and involves children with and without autism: appropriate selection for evaluation.  While the authors chose children with “clinical indications,” these, in fact, are often subjective and with permissive interpretation could be used to justify endoscopy in 40% of children.
  3. Another huge problem is interpretation of abnormal results.  While the authors report large numbers with intestinal inflammation in both groups, most of this was considered to be insignificant clinically.  How should trivial inflammation be reported in studies?  This problem is not unique to this study and makes it difficult to assess the value of endoscopy more broadly.

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Law Quad, Univ Michigan

Law Quad, Univ Michigan

 

Detrimental Effect of Early Parenteral Nutrition in Critically-ill Children

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Ahead of publication: T Fizez et al. Early versus Late Parenteral Nutrition in Critically Ill Children. DOI: 10.1056/NEJMoa1514762

Link to quick take video summary (<2 minutes) : NEJM Quick Take on Parenteral Nutrition in Children

Abstract:

BACKGROUND

Recent trials have questioned the benefit of early parenteral nutrition in adults. The effect of early parenteral nutrition on clinical outcomes in critically ill children is unclear.

METHODS

We conducted a multicenter, randomized, controlled trial involving 1440 critically ill children to investigate whether withholding parenteral nutrition for 1 week (i.e., providing late parenteral nutrition) in the pediatric intensive care unit (ICU) is clinically superior to providing early parenteral nutrition. Fluid loading was similar in the two groups. The two primary end points were new infection acquired during the ICU stay and the adjusted duration of ICU dependency, as assessed by the number of days in the ICU and as time to discharge alive from ICU. For the 723 patients receiving early parenteral nutrition, parenteral nutrition was initiated within 24 hours after ICU admission, whereas for the 717 patients receiving late parenteral nutrition, parenteral nutrition was not provided until the morning of the 8th day in the ICU. In both groups, enteral nutrition was attempted early and intravenous micronutrients were provided.

RESULTS

Although mortality was similar in the two groups, the percentage of patients with a new infection was 10.7% in the group receiving late parenteral nutrition, as compared with 18.5% in the group receiving early parenteral nutrition (adjusted odds ratio, 0.48; 95% confidence interval [CI], 0.35 to 0.66). The mean (±SE) duration of ICU stay was 6.5±0.4 days in the group receiving late parenteral nutrition, as compared with 9.2±0.8 days in the group receiving early parenteral nutrition; there was also a higher likelihood of an earlier live discharge from the ICU at any time in the late-parenteral-nutrition group (adjusted hazard ratio, 1.23; 95% CI, 1.11 to 1.37). Late parenteral nutrition was associated with a shorter duration of mechanical ventilatory support than was early parenteral nutrition (P=0.001), as well as a smaller proportion of patients receiving renal-replacement therapy (P=0.04) and a shorter duration of hospital stay (P=0.001). Late parenteral nutrition was also associated with lower plasma levels of γ-glutamyltransferase and alkaline phosphatase than was early parenteral nutrition (P=0.001 and P=0.04, respectively), as well as higher levels of bilirubin (P=0.004) and C-reactive protein (P=0.006).

CONCLUSIONS

In critically ill children, withholding parenteral nutrition for 1 week in the ICU was clinically superior to providing early parenteral nutrition. (Funded by the Flemish Agency for Innovation through Science and Technology and others; ClinicalTrials.gov number, NCT01536275.)

More details:

Methods:

  • “In both study groups, enteral nutrition was initiated early and was increased in accordance with local guidelines. Both study groups also received intravenous micronutrients (trace elements, minerals, and vitamins) starting from day 2 and continuing until the enteral nutrition provided reached 80% of the caloric targets. Starting from the morning of day 8 in the pediatric ICU, supplementary parenteral nutrition was provided for patients in both groups who were not yet receiving 80% of the caloric target enterally.”
  • 45% of patients were less than 1 year of age

Discussion:

“Late parenteral nutrition resulted in fewer new infections, a shorter duration of dependency on intensive care, and a shorter hospital stay. The clinical superiority of late parenteral nutrition was shown irrespective of diagnosis, severity of illness, risk of malnutrition, or age of the child.”

My take:  The concept of providing early aggressive nutrition is NOT supported by this study; this study shows that early parenteral nutrition may be detrimental in critically-ill children.  This study echoes the results of a similar study in adults: Early versus late parenteral nutrition in critically ill adults

Springtime in my neighborhood

Springtime in my neighborhood

Torsion of Accessory Spleen

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A case report (PM Guglietta et al. NEJM 2016; 374; 373-82) presents a 9 year-old girl who had repeated episodes of abdominal pain with associated nonbilious vomiting.  These pains started 5 years prior and were often sudden episodes of sharp pain on the left side or epigastric region and were associated with tachycardia.

AXR in Case Report

AXR in Case Report

Ultimately the diagnosis was established with a CT scan.  “Most persons with accessory spleens are asymptomatic, but abdominal pain can occur with torsion.”

While the case report is interesting, one aspect I did not like was the discussants justification of the delay of the diagnosis based on the presumption of constipation.  The radiologist even commented: “a moderate-to-abundant amount of stool distributed in the colon, particularly the ascending colon; these findings are consistent with the clinical history of constipation.”  This and other comments in the case study go against previous expert recommendations to avoid routine radiographs in the diagnosis of constipation and the finding of reviews which have not found a correlation between clinical symptoms and so-called fecal loading on abdominal radiographs.

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Flamenco Beach

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