About gutsandgrowth

I am a pediatric gastroenterologist at GI Care for Kids (previously called CCDHC) in Atlanta, Georgia. The goal of my blog is to share some of my reading in my field more broadly. In addition, I wanted to provide my voice to a wide range of topics that often have inaccurate or incomplete information. Before starting this blog in 2011, I would tear out articles from journals and/or keep notes in a palm pilot. This blog helps provide an updated source of information that is easy to access and search, along with links to useful multimedia sources. I was born and raised in Chattanooga. After graduating from the University of Virginia, I attended Baylor College of Medicine. I completed residency and fellowship training at the University of Cincinnati at the Children’s Hospital Medical Center. I received funding from the National Institutes of Health for molecular biology research of the gastrointestinal tract. During my fellowship, I had the opportunity to work with some of the most amazing pediatric gastroenterologists and mentors. Some of these individuals included Mitchell Cohen, William Balistreri, James Heubi, Jorge Bezerra, Colin Rudolph, John Bucuvalas, and Michael Farrell. I am grateful for their teaching and their friendship. During my training with their help, I received a nationwide award for the best research by a GI fellow. I have authored numerous publications/presentations including original research, case reports, review articles, and textbook chapters on various pediatric gastrointestinal problems. In addition, I have been recognized by Atlanta Magazine as a "Top Doctor" in my field multiple times. Currently, I am the vice chair of the section of nutrition for the Georgia Chapter of the American Academy of Pediatrics. In addition, I am an adjunct Associate Clinical Professor of Pediatrics at Emory University School of Medicine. Other society memberships have included the North American Society for Pediatric Gastroenterology Hepatology and Nutrition (NASPGHAN), American Academy of Pediatrics, the Food Allergy Network, the American Gastroenterology Association, the American Association for the Study of Liver Diseases, and the Crohn’s and Colitis Foundation. As part of a national pediatric GI organization called NASPGHAN (and its affiliated website GIKids), I have helped develop educational materials on a wide-range of gastrointestinal and liver diseases which are used across the country. Also, I have been an invited speaker for national campaigns to improve the evaluation and treatment of gastroesophageal reflux disease, celiac disease, eosinophilic esophagitis, hepatitis C, and inflammatory bowel disease (IBD). Some information on these topics has been posted at my work website, www.gicareforkids.com, which has links to multiple other useful resources. I am fortunate to work at GI Care For Kids. Our group has 17 terrific physicians with a wide range of subspecialization, including liver diseases, feeding disorders, eosinophilic diseases, inflammatory bowel disease, cystic fibrosis, DiGeorge/22q, celiac disease, and motility disorders. Many of our physicians are recognized nationally for their achievements. Our group of physicians have worked closely together for many years. None of the physicians in our group have ever left to join other groups. I have also worked with the same nurse (Bernadette) since I moved to Atlanta in 1997. For many families, more practical matters about our office include the following: – 14 office/satellite locations – physicians who speak Spanish – cutting edge research – on-site nutritionists – on-site psychology support for abdominal pain and feeding disorders – participation in ImproveCareNow to better the outcomes for children with inflammatory bowel disease – office endoscopy suite (lower costs and easier scheduling) – office infusion center (lower costs and easier for families) – easy access to nursing advice (each physician has at least one nurse) I am married and have two sons (both adults). I like to read, walk/hike, bike, swim, and play tennis with my free time. I do not have any financial relationships with pharmaceutical companies or other financial relationships to disclose. I have helped enroll patients in industry-sponsored research studies.

Early Look At Entyvio (Vedolizumab) in Pediatrics

Posted on May 30, 2015 by gutsandgrowth

From DDW 2015 and HealioGastro: Entyvio shows promise in pediatric patients

First study, abstract 321:

Namita Singh, MD, of Cedars Sinai Medical Center in New York, … presented results of a prospective observational study in which they initiated Entyvio (vedolizumab, Takeda; 6 mg/kg, maximum 300 mg) — off label — via intravenous infusion in pediatric patients…The primary clinical outcomes was clinical remission at week 6 (PUCAI ≤ 10; PCDAI ≤ 10).

The study looked at 23 patients (15 with Crohn’s; eight with ulcerative colitis) enrolled between June 2014 and October 2014; median age of vedolizumab initiation was 14 years.

At 88%, the patients with ulcerative colitis had a higher rate of remission than those with Crohn’s who were at 40% [at week 6]. This trend sustained at week 14 and Singh said all patients with ulcerative colitis were in remission at week 14.

Week 6 and week 14 remission rates overall were 46.6% and 54.5%, respectively, and week 6 remission predicted week 14 remission (P < .05).

“Week 6 remission is associated with week 14 remission,” Singh said. “This suggests that we can determine early in therapy whether a patient will be a primary responder to therapy. If not, then perhaps we should move on to another therapy.”

“Longer duration from last anti-TNF exposure is associated with higher remission rates,” Singh said.

Second study, abstract 322:

Ronen Stein, MD, from the Perelman School of Medicine at the University of Pennsylvania, also presented data on vedolizumab therapy in patients with severe pediatric IBD…In this single center, prospective observational cohort study, the primary endpoint was a decrease in PCDAI/PUCAI from baseline to weeks 6, 14 and 22 and secondary endpoints were changes in albumin, hematocrit and CRP as well as remission at the same time points.

Patients received vedolizumab infusions (300 mg) at weeks 0, 2 and 6 for induction and maintenance through week 22.

The researchers included children aged 13 years to 21 years (n = 17) with IBD who weighed 40 kg or more and had a past failure on TNF-alpha inhibitor therapy. Of these patients, 15 had Crohn’s disease and two had unclassified IBD (IBD-U).

More than three-quarters started on systemic corticosteroids at baseline; more than one quarter were on immunomodulators. Seven patients had previous abdominal surgery and 59% of patients had failed more than one biologic therapy…

At each time point in question, this study saw improvement of PCDAI (P < .001 at week 6; P < .05 at week 14; P < .0001 at week 22).

“Starting at week 6, there was a significant decrease in PCDAI that was sustained for weeks 14 and 22.”

Five patients reached remission at week 6.

“There really is no pattern to tell us which patients will be in remission at week 6. They have pretty different characteristics,” Stein said.

Briefly noted:

Link: Case description/images of 9 year old with gastric Crohn’s

Related blog posts:

I love Ria’s Bluebird –the best pancakes ever!

Do You Know How Long to Use Antibiotics for Intraabdominal Infections?

Posted on May 29, 2015 by gutsandgrowth

Since 2010, there have been published guidelines for complicated intraabdominal infections which recommend a treatment course of 4 to 7 days. These include guidelines from the Surgical Infection Society (SIS) and the Infectious Diseases Society of America (IDSA). Now, a new study (Sawyer RG et al. NEJM 2015; 372: 1996-2005, editorial 2062-63) provides additional support for a short course of antibiotics when there is adequate source control. The study termed “Study to Optimize Peritoneal Infection Therapy” or STOP-IT included 23 institutions from the U.S. and Canada.

Video Summary (1:33): Trial of Short-Course Antimicrobials

Rationale: While traditional therapy of 10-14 days has been based on the premise that ongoing fever and leukocytosis indicate ongoing infection, “more recent experimental data, however, suggest that a prolonged SIRS [systemic inflammatory response syndrome] may be more a reflection of host immune activity than an indication of the presence of viable microorganisms.”

Design: 518 patients were randomly assigned to either a fixed 4-day course of antibiotics or to a control group that received antibiotics for 2 days after resolution of fever, leukocytosis, and ileus (max of 10 days). The median number of days in the control group was 8 days.

Study characteristics:

Mean age 52 years
34% of the infections originated in colon/rectum, 14% in small bowel, and 14% in the appendix
11% had cancer, 10% had inflammatory bowel disease

Source-control procedures: “defined as procedures that eliminate infectious foci, control factors that promote ongoing infection, and correct or control anatomical derangements to restore normal physiological function”

Percutaneous drainage 33.1%
Resection and anastomosis or closure 26.5%
Surgical drainage alone 21.2%
Resection and proximal diversion 10.4%
Simple closure 7.7%
Surgical drainage and diversion 1.2%

Results:

Surgical site infection, recurrent intraabdominal infection, or death occurred in 21.8% of the experimental 4-day group compared with 22.3% of the control group. Death occurred in 3 experimental patients and 2 control patients.
No significant differences were found between the two groups in terms of primary or secondary outcomes.

Limitations:

18% of the experimental group and 27% of the control group deviated from the protocol. In the control group, this included 26 patients who received less than 10 days of therapy but more than 2 days longer than the resolution of the physiological findings.
Patients without adequate source control were excluded

The editorial notes that if these findings are incorporated into clinical practice, more than $97 million would be saved on antibiotic costs alone; in addition, there would be less diarrhea and phlebitis. The editorial suggests that the reason why more than 20% of both groups had complications is likely related to source control. If inadequate course of antibiotics was the culprit, “we would have expected still more complications after treatment in the short-course therapy group.”

(From editorial): “We have encouraging data from the STOP-IT trial that suggest cost savings and improved safety.”

Take-home message Because of years of practice patterns, it is going to be difficult to stop antibiotics at 4 days when patients are still having fevers, especially since 20% will not have resolution of their infection. These data should, however, make it easier to shorten antibiotic courses.

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Zoo Atlanta

Something Bad is Going to Happen

Posted on May 28, 2015 by gutsandgrowth

A recent commentary (Sonnenberg A, Clin Gastroenterol Hepatol 2015; 13: 820-23) discusses the statistical inevitability of adverse events. As such, despite our efforts to provide the best care, we should consider how we look at bad outcomes. This article highlights a few common issues in adult gastroenterology, failing to identify colorectal cancer and adverse events at the time of endoscopy. Using statistical models, the author notes that avoiding all adverse events is nearly impossible.

The broader points for pediatric gastroenterologists/all physicians:

Using simple statistics, “adverse events can be expected to occur with a high probability. Their occurrence is a function of the number of patient encounters and the probability of making mistakes.”
“It is a statistical misconception to believe that their rare occurrence would make it possible for an individual gastroenterologist to dodge the bullet.”
“It is another statistical misconception to assume that by exerting extreme caution a gastroenterologist also could avert adverse events. The only means to truly reduce adverse events is to avoid patient encounters.”
“The physician rarely is given credit for innumerous other patient encounters with good outcomes. The bad outcome is considered potentially reflective of professional failure or flawed performance. The process ultimately is geared toward showing avoidable mistakes and assigning guilt. The occurrence of an error, even at its lowest rate, generally is not accepted as a viable reason, although under different circumstances the same reviewers would be willing to accept the less-than-perfect sensitivity or specificity of all diagnostic tests.”
“We have to …free ourselves from the illusion that perfection will become achievable through limitless quality assurance.”
“Highlighting the statistical nature of adverse events is not meant to belittle the need for continued efforts at improving patient safety and increasing the quality of health care delivery…In a ‘just culture’ of safety and accountability, the occurrence of any error would become an opportunity for learning and improvement rather than retribution or punishment.”

As a personal aside, I took some solace in reading this article and previously in reading the book “Complications: A Surgeon’s Notes on an Imperfect Science” (Complications | Atul Gawande). I clearly remember a few terrible situations that from time to time still fill me with sadness and regret. I feel better knowing that the mistakes that I have made were not due to a lack of effort or due to a lack of caring.

Take-home message: If you practice medicine, something bad is going to happen. Can we forgive ourselves if our judgement contributed to an adverse event?

Zoo Atlanta

Does it really cost $2.6 billion to bring a new drug to market?

Posted on May 27, 2015 by gutsandgrowth

A recent editorial (Avorn J. NEJM 2015; 372: 1877-79) helps provide some perspective on a recent unpublished study that “it costs pharmaceutical companies $2.6 billion to develop a new drug.” (http://csdd.tufts.edu/files/uploads/cost_study_backgrounder.pdf)

Dr. Avorn notes that when this study is published scrutiny over the methods is needed; however, the authors of the study note that their methods are unchanged from a previous 2003 study (NEJM 2015; 372: 1972). Apparently the analysis was based on data from 10 drug makers regarding compounds that they had ‘self-originated.’

Some preliminary criticisms:

Nearly half the costs were attributed to the cost of capitol rather than direct spending. This cost indicates that the money being used for drug development was not available for other purposes (“opportunity costs”); however, the capital costs were assessed at a very generous 10.6% per year, compounded.
The analysis did not include the large public subsidies provided to pharmaceutical companies in the form of research-and-development tax credits.
Pharmaceutical companies remain highly profitable and only spend a small fraction of their revenues on truly innovative research.
Many of the drugs brought to market are not “self-originated.”
Many drug costs are borne by the public via research at university-affiliated centers with the pharmaceutical companies taking the new discovery the last mile. “Gilead Sciences did not invent its blockbuster treatment for hepatitis C, sofosbuvir (Sovaldi)…it acquired the product from a small company founded by the drug’s inventor, a faculty member at Emory University, much of whose work on the usefulness of nucleoside viral inhibitors was federally-funded.”

Bottomline: While pharmaceutical companies invest heavily in new drug development, the huge numbers often attributed to research costs may be overestimates; these type of analysis likely underestimate how much taxpayers have paid in subsidizing the foundation for new treatments.

Related blog post: The Difficulty with Drug Development | gutsandgrowth

How to Improve Food Selection at Schools

Posted on May 26, 2015 by gutsandgrowth

A recent study (Cohen JFW et al. JAMA Pediatr 2015; 169: 431-7; thanks to Ben Gold for this reference) showed both the short-term and long-term effects of targeted interventions to improve food selection at schools.

The Modifying Eating and Lifestyles at School Study (MEALS study) was a randomized trial in 2 urban, low-income school districts in Massachusetts. After a one month baseline, there was an initial 3 month randomization period in which there were 4 “chef” schools and 10 control schools. As you may have guessed, the “chef” schools were assigned a chef to improve food palatability and to teach the cafeteria staff.

The recipes are available at the following link: www. projectbread.org/reusable-components/accordions/download-files/school-food-cookbook.pdf. The recipes in this cookbook are great if you need to put together meals serving 100. Recipes include Cachupa, Quinoa, Squash, and Kale.

During the next study period of 4 months, both groups were further divided into schools with “smart cafe” design or control design. The smart cafes encouraged both vegetable and fruit selection/healthy food selection:

Veggies offered at beginning of lunch line
Fruits placed in attractive containers
Fruit options placed by cashier
Improved signage and images promoting fruits and veggies
White milk placed in front of sugar-sweetened milk (eg. chocolate milk)

Did these interventions work? Yes, pretty much.

After 3 months, vegetable selection increased in chef schools with odds ratio (OR) of 1.75
At conclusion of study, vegetable selection increased in the chef (OR 2.54), smart cafe (OR 1.91) and chef plus smart cafe (OR 7.38)
At conclusion of study, fruit selection increase in the chef (OR 3.08), smart cafe (OR 1.45) and chef plus smart cafe (OR 3.10)
Actual consumption (not just selection) increase in chef and chef plus smart cafe schools but there was no lasting effect of smart cafe by itself. The amount of vegetable intake approximately doubled in the chef or chef plus smart cafe, consuming an additional 0.75 cups of vegetables per week.

Conclusions (from the authors): “While using choice architecture [i.e. smart cafe design] “may be a good short-term strategy to increase healthier food consumption, it does not appear to be a successful long-term strategy…This study also reaffirms that a chef intervention focusing on school food quality, palatability, and variety is an effective method …over time…This study also confirms the importance of repeated exposures to new school foods.”

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Kori Bustard, Zoo Atlanta

Vitamin D in Preterm Infants

Posted on May 25, 2015 by gutsandgrowth

Vitamin D has garnered a great deal of attention due to concerns that deficiency worsens the outcomes in so many different conditions, including respiratory tract infections, inflammatory bowel disease, diabetes mellitus (type 1), multiple sclerosis, colorectal cancer, schizophrenia, depression, cardiovascular disease, hepatocellular carcinoma and other conditions. However, evidence of causation is typically inconclusive.

For preterm infants, a study (Onwuneme C, et al. J Pediatr 2015; 166: 1175-80) notes an association between 25-hydroxy vitamin D (25OHD) levels drawn at 24 hours of life and acute respiratory morbidity.

In this study, levels were also drawn at the time of discharge in the 94 preterm infants. In addition, maternal 25OHD) levels were checked 24 hours after delivery. These preterm infants were either <32 weeks gestation or <1.5 kg. The study population was predominantly Caucasian.

Key findings:

92% had 25OHD ≤20 ng/mL (=”<20 group”)
64% had 25OHD ≤12 ng/mL (=”<12 group”)
Levels of 25OHD ≤12 ng/mL were associated with increased oxygen requirement (P=.008) and greater need for assisted ventilation (P=.013). The odds of requiring assisted ventilation were approximately 3-fold higher.
The authors state that the baseline characteristics for the <12 group were similar to the <20 group.
There was statistical difference in the rate of NEC (Bell stage ≥1) based on the 25OHD levels (P=.048)

The authors note in their discussion that they favor supplementation with 400 IU/day which is in agreement with the American Academy of Pediatrics. Previous ESPGHAN recommendations were 800-1000 IU/day for infants.

The authors note that 25OHD did not affect sepsis outcome. In addition, antibiotics during labor was virtually identical between the two groups. However, no data on CRP values were provided.

Bottomline: This study shows an association between 25OHD values and several important neonatal outcomes. Whether 25OHD is a marker (eg. epiphenomenon) for these outcomes or whether low 25OHD contributes to these outcomes remains unclear.

Short Take on Understanding Bias

Posted on May 24, 2015 by gutsandgrowth

A recent commentary (Rosenbaum L. NEJM 2015; 372: 1959-63) adds a couple of new terms to my lexicon regarding bias.

The author notes that there have been multiple concerns regarding industry-sponsored studies. For example:

Industry-sponsored studies are more likely than government-sponsored ones to have positive results
Physicians who attend symposia funded by the pharmaceutical companies subsequently prescribe the featured drugs at a higher rate

While the Physician Payment Sunshine Act requires drug and device companies to disclose payments over $10, she notes that the long-term effects of this transparency are unclear. With increased transparency, there could be a “phenomenon called ‘moral licensing’: once disclosure gets off your chest, you feel liberated and may feel licensed to behave immorally. A corollary concern” for the audience, is that this disclosure may be interpreted as a sign of honesty or a sign of expertise rather than as a warning of potential bias.

Two new terms for me:

“‘Self-serving bias’: when we stand to gain from reaching a certain conclusion, we unwittingly assimilate evidence in a way that favors the conclusion.”
“Bias blind spot“: “Studies suggest that we’re far more likely to think that drug promotions influence our colleagues than that they affect our own behavior.”

The author cautions that anti-industry bias could be detrimental as well. If having ties to industry lessens the opportunity for individuals to voice their support (or opposition) for new drugs or devices, it could bolster individuals who may “overstate the risks and understate the benefits of these new treatments.”

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Zoo Atlanta

IBD Shorts -Skin, Adalimumab Kinetics

Posted on May 23, 2015 by gutsandgrowth

From the IMAgINE study with 192 pediatric patients (Sharma S et al. Inflamm Bowel Dis 2015; 21: 783-92), the authors determined levels for adalimumab, that at week 52, were associated with remission and response. A cutoff level of 3.6 mcg/mL had a sensitivity of 32.7% and specificity of 88.6% for predicting remission; the same cutoff had a sensitivity of 46.2% and specificity of 83% for predicting a response. Overall, the authors noted dose proportionality with patients who received higher (or more frequent) doses with higher serum levels.

“Concomitant Use of Azathioprine/6-Mercaptopurine Decreases the Risk of Anti-TNF-Induced Skin Lesions” (Soh JS et al. Inflamm Bowel Dis 2015; 21: 832-9). Among a cohort of 500 Korean patients, the incidence of psoriaform and eczematiform lesions was 6.2%. Concomitant use of a thiopurine was associated with a hazard ratio of 0.452 (lower risk) for developing these adverse skin reactions.

Helicobacter Pylori: Relationship to Cancer and Dubious Beneficial Claims

Posted on May 22, 2015 by gutsandgrowth

I found a recent review (Gastroenterol 2015; 148: 719-31) regarding Helicobacter pylori (HP) of interest. David Graham explores the issue of HP eradication with regard to cancer and whether there are benefits to the infection that result in detrimental effects with HP eradication.

The potential mechanisms in which HP infection can increase the risk of gastric cancer are depicted in Figure 2; the most important:

Inflammation induced by infection
Genetic/epigenetic changes –> genetic instability in gastric epithelial cells

Lessons regarding eradication therapy:

Sequential therapy has been shown in some studies to be effective/superior (in Italy) yet inferior in others (eg. Korea). “The results are explained entirely by differences in patterns of drug resistance, which typically were not assessed before studies were initiated.”
Findings from many studies cannot be applied to other populations without resistance data.

Does HP infection reduce the risk of obesity or childhood asthma? Probably not.

“Any claim that a major human pathogen also might provide a meaningful health benefit, and that plans to eradicate it should be reconsidered, is guaranteed to elicit interest from the press.”
As a counter example, Dr. Graham notes “because 2 events are associated does not mean that one causes the other. For example, one study reported a correlation between the number of storks in Brandenburg, Germany, and the birth rate in Berlin.” [Backen MB. Harm. In: Bracken MB. Risk, chance, and causation. New Haven: Yale University Press, 2013; 108-09.]
He notes that HP can both promote or inhibit acid secretion/acid reflux. Increased acid secretion with resultant esophageal disease could increase the risk of adenocarcinoma of the esophagus; however, “the risk of developing adenocarcinoma of the stomach remains higher than the risk of adenocarcinoma of the esophagus.” This indicates that if there is an increased esophageal cancer risk, eradication would still be favorable by lowering gastric cancer risk.
Asthma: “overall, the studies do not support the hypotheses that increases in childhood asthma were related to the absence of H pylori.”
Obesity: “A meaningful causative association between H pylori and obesity is unlikely.”

Screen Shot

Take-home message: H pylori is a pathogen and should be treated as such.

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University of Chicago

An “Ally” For Hepatitis C Genotype 3

Posted on May 21, 2015 by gutsandgrowth

A new study (Hepatology 2015; 61: 1127-35) shows that an all-oral 12 week treatment of daclatasvir (DCV) with sofosbuvir (SOF) is effective in the difficult-to-treat Hepatitis C virus (HCV) genotype 3 patients. In this study, the “Ally-3” phase III study, 101 treatment-naïve and 51 treatment experienced patients were treated with a daily regimen of DCV 60 mg and SOF 400 mg.

Key findings:

SVR12 was 90% in treatment-naïve, and 86% among in treatment experienced.
Among patients without cirrhosis, the SVR12 was 96%, compared with 63% of those with cirrhosis (based on FibroTest scores)

Related blog posts:

Bottomline: This new regimen is a promising addition to the new crop of HCV drugs which will be affordable when?

A second study (Hepatology 2015; 61: 1174-82) examined the minimum target pricing for direct-acting antivirals (DAA) for HCV. Using data on manufacturing costs, derived in large part from experience with HIV antivirals, the authors calculate that a minimum cost for a 12-week course of combination DAA could be US $171-360 per person without genotyping and the drug costs alone from US $122-192 per person. Of course, these costs are completely theoretical and complete fantasy, at least until 2027 when some of the patents expire.

Briefly noted: Hepatology 2015; 61: 1261-68. N=986 Koreans with HBsAg carrier status and 40 years of age or older. FIB-4 is highly predictive of hepatocellular carcinoma (HCC) risk in those with chronic hepatitis B. FIB-4 was defined based on age x AST , PLTS, and ALT. Since a high FIB-4 reflects liver fibrosis, it is not unexpected that high levels were associated with HCC. A FIB-4 >/= 2.4 showed an adjusted Hazard Ratio of 21.34.