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Quality improvement and better outcomes in Pediatric Inflammatory Bowel Disease

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More information on outcomes and quality improvement (QI) efforts are available from Cincinnati Children’s Hospital (JPGN 2012; 55: 679-88).  The QI efforts at Cincinnati are part of a broader effort in QI in pediatric IBD that has been discussed on a previous post (see below).

Our group has rejoined Improve Care Now (ICN) and I look forward to gaining more first hand experience.  Some of the ICN target goals:

  • 80% remission rate among each center and sustained remission rate of 45%
  • 76% steroid-free remission
  • 90% checking TPMT if using thiopurine
  • 95% checking PPD/chest xray if using biologic therapy
  • 95% using accepted methotrexate dosing

As I look at these goals, I wonder whether the remission rate is feasible and about the variation in different centers. For example, among the groups with >75% enrollment of their patients, one center reports a 89% remission rate and another center 64% remission rate.  Given the limited number of therapeutic agents, how could there be such a difference?  Some explanations could include variation in the use of more potent biologic agents as well as capturing/assuring followup of more patients who are doing well.

Given this backdrop, I looked at this most recent publication to learn how their QI practices could translate into better care for my patients.

In this retrospective chart review study of 505 patients, who were followed from 2007-2010 at the IBD center, the remission rate increased from 59% to 76%.  The data were captured prospectively.  This corresponded to improved patient global assessment (>7) from 69% to 80%.  Repeated steroid use dropped from 17% to 10%.  Vitamin D (25-OH D) improved and this also correlated with quiescent disease.

Remission rates were defined by a pediatric Crohn clinical disease index, the sPCDAI, or PUCAI for Ulcerative colitis.

Key observations:

  • There was a trend towards increased use of anti-TNFα therapy (along with decreased use of 6-mercaptopurine) during the study period, but this did not reach statistical significance. No statistical difference was identified in the use of any major IBD medication class.
  • Despite target goals, the only drug class with a statistically significant change in dosing was 5-ASA (from 42 mg/kg to 50 mg/kg).
  • Fecal calprotectin monitoring increased.  The QI team recommended that IBD patients with ‘inactive’ disease have a fecal calprotectin measured every 6 months.  Those with elevated values had therapeutic drug monitoring implemented.  “Fecal calprotectin >400 μg/g is associated with a higher chance of relapse in a pediatric cohort.”
  • Starting in 2009, increased vitamin D monitoring was implemented (every 6 months).  In patients with a serum 25-OHD level < 30 ng/mL, treatment with 50,000 units weekly (for 6-8 weeks) was recommended (8000 units if weight <20 kg).  Once serum 25-OHD was >30 ng/mL, patients were maintained on monthly dosing.
  • Preclinic planning also increased and corresponded to improved remission rates which were 67% in 2009 and 76% in 2010.
  • The authors conclude: “Our results show that significant improvement in patient outcomes were achieved following QI efforts that did not rely on new medications or therapies, rather through initiating novel care processes and standardization of care.”

I think this conclusion is misleading.  First of all, as the authors point out, they did change their therapeutic approach.  They started vitamin D in more patients, used anti-TNFα therapy in more patients, and increased dosing of 5-ASA agents.  Other gains in remission rate could have been related to improved followup of patients who were doing well.

Despite my skepticism about the conclusion, I think the overall achievements are laudable.  Decreasing variation of care and assuring that all patients receive the best care possible with our diagnostic tests and current therapies is certainly worthwhile.  When patient care is studied carefully, this makes sure that “standard” practice like checking TPMT status before thiopurine use, checking PPDs before anti-TNFα therapy, and using optimal drug dosing occur in virtually all patients.

Developing a checklist for each patient can help assure that best practices occur.  For those with electronic medical records, this may mean putting in more “hard stops.”  A hard stop means the physician cannot sign out of a chart without paying attention to a specific detail.  For example, if a physician orders methotrexate, a “hard stop” could come up if the dosing was not in the typical target range.

Useful link:

Link for disease classification (quiescent, mild, moderate, severe):

http://links.lww.com/MPG/A129

Related blog entries:

Another option for line locks

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A pediatric study from London with 19 patients demonstrates the utility of taurolidine line locks (JPGN 2012; 55: 403-7).

Taurolidine has broad antimicrobial activity against Gram-positive and Gram-negative bacteria in addition to antifungal properties.  Also, taurolidine prevents biofilm formation which can help minimize colonization of catheters.  It acts by binding to the cell walls of organisms; this results in the prevention of bacterial adhesion to biological surfaces. TauroLock™ | TauroLock™

15 of the 19 patients had a history of recurrent central catheter infections and 4 were started on the line locks empirically.  At the completion of the parenteral nutrition, 0.7 to 1 mL of the taurolidine solution was instilled and left for at least 12 hours.

Taurolidine-treated patients had 1.1 episodes per 100 catheter days of CVL infections; this compared with a rate of 8.6 episodes per 1000 catheter days for heparin control.  Furthermore, 74% (14) had no infections for up to 33 months after changing to taurolidine.  No reports of mulitresistant organisms or adverse effects were reported.  Taurolidine is nontoxic for humans and rapidly metabolized to taurine, carbon dioxide, and water.

To my knowledge, taurolidine is not available in the U.S.  Nevertheless, the data on line locks indicate that antimicrobial line locks are associated with reductions in catheter infections.

Related blog entries:

Additional reference:

Best strategy for dose escalation of infliximab

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At least 50% of patients with long-term infliximab therapy require dose escalation.  However, dose escalation can mean doubling the dose or shortening the infusion interval.  So which strategy is best?  A recent article provides some insight into this question (Inflamm Bowel Dis 2012; 18: 2026-33).

In this multicenter retrospective study of 168 Crohn’s disease (CD) patients, the outcome of patients who had dose-doubling (n=112) to 10 mg/kg/dose/8 weeks was compared with patients whose infusion intervals were halved to 5 mg/kg/dose/4 weeks (n=56).  The entire cohort had a mean age of 25 years and a mean disease duration of 12 years.  39% had a history of previous intestinal surgery.  Concurrent use of thiopurines was noted in 68% and concurrent use of methotrexate in 4%.

Sustained response at 1 year to dose-doubling strategy was 50% compared with 39% in the interval-halving group.  Favorable factors included nonsmoking status, normal C-reactive protein, and CD diagnosis between 16-40 years of age.

It is noted that a subsequent dose escalation was experienced by 28 of the 87 patients who had loss of response after first dose escalation.  Regained response occurred in 9 (32%) of this cohort.

The authors indicate that increasing the dose to 10 mg/kg/8 weeks is likely preferable due to convenience and cost.  At the same time, it is apparent that shortening the infusion interval is not likely to be more effective than dose doubling.

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Does bone density improve with IBD therapy?

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Long term followup is needed to determine the significance of low bone mineral density (BMD) in children and adolescence with IBD; data with 2 year followup is available (JPGN 2012; 55: 511-18).

In this study from Sweden, 144 patients with IBD were enrolled and 126 were available at 2-year followup (2003-2005).  Among the 144 patients, there were 93 males and 83 with UC. Low BMD was noted in children with both UC and CD for the lumbar spine at baseline and no improvement was noted at 2 years.  Only boys had lower BMD z scores for the lumbar spine (LS) (-1.1); girls had normal LS z scores (0).

While the investigators could not demonstrate catch up in bone mineral density, they note that gains in BMD may accrue beyond late adolescence into early adulthood; this takes place after completion of linear growth.  In the subgroup of subjects in early adulthood, there was improvement in BMD:

  • For boys: from -1.7 at baseline (age 17.9) to -0.5 at followup (age 20.0)
  • For girls: from -0.4 at baseline (age 17.1) to 0.4 at followup (age 19.2)

With greater use of biologic therapy, these data are likely to change.  Among medical treatments, only biologic therapies have been shown to improve bone formation and improve catchup growth.

Related blog entry:

Additional references:

  • -JPGN 2011;53: 361. Similar prevalence of low Vitamin D as general population –58% with less than 32.
  • -JPGN 2011; 53: 11. Guidelines for low bone mineral density in IBD.
  • -JPGN 2009; 48: 538. Need to adjust bone density for bone age.
  • -Gastroenterol 2009; 136: 123. Longitudinal bone health study. Steroids did NOT adversely affect bones. n=78.
  • -Clin Gastro & Hep 2008; 6: 1378. IFX improves biomarkers of bone formation.
  • -J Pediatr 2008; 153: 454, 484. Use of biomarkers of bone turnover in Crohn dz; even when controlling for other factors like delayed bone age, delayed puberty, etc, still evidence of decrease bone formation and increased resorption.
  • -JPGN 2007; 45: 538. Ca/Vit D supplements -no change in BMD in IBD patients over 12 months.
  • -Clin Gastro & Hep 2007; 5: 721. DXA may not predict risk well.
  • -IBD 2007; 4: 416. Inflammation, not steroids, is key factor in bone mineral density.
  • -IBD 2006; 13: 42. Natural hx of bone mineral density in IBD; steroid dose did not correlate with BMD. Children did not have “catch up” bone density.
  • -JPGN 2006; 43: 597. Crohn’s patients had similar rate of fractures as siblings w/o IBD.
  • -Clin Gastro & Hep 2006; 4: 152. Osteoporosis in IBD.
  • -IBD 2006; 12: 797. Review of bone mineral density with IBD
  • -Clin Gastro & Hepatol 2005; 3: 113-121, 122-132 & editorial 110. In 1st article, budesonide better for bones than other steroids. In 2nd article, unable to show benefit of addition of etidronate to Ca++/Vit D.
  • -NEJM 2002; 351: 868. Intermittent steroids in nephrotic syndrome did NOT change bone mineral density.
  • -Gastro 2001; 121: 1485-88. Tanning bed Rx of vitamin D deficiency.
  • -Gastro 2000; 119: 639-46. Alendronate increases BMD in pts c Crohn’s
  • -NEJM 1998; 339: 292-9/ J Bone Miner Res 2000; 15: 1006-13. Bisphosphonates effective in steroid-induced bone disease

False-positive serology for Celiac disease

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It is prudent to exercise caution in establishing a diagnosis of Celiac disease (CD) in young asymptomatic children who are identified with screening serology (J Pediatr 2012; 161: 980-14).

In this Italian study, a nationwide, multicenter, prospective intervention trial was established to assess the role of age at gluten introduction on development of CD.  Subjects were recruited at birth who were at increased risk for CD; they had at least one first-degree relative with CD.

In their cohort, 96 children were identified.  In addition to having an affected first-degree relative, all children had positive serology (21 with positive tissue transglutaminase IgA antibody [tTG] and 1 with IgA deficiency/positive gliadin IgG antibody) and results of a small intestinal antibody.

While 72 had definitive CD, 24 were considered potential CD (serology positive/Marsh 0-1 histology) and asymptomatic.  The fascinating part of this study was the followup of the potential CD cases –21/24 continued on a regular diet.  Only 1 developed overt CD. 18 (86%) developed normal serology and 2/21 had fluctuating antibody levels after two years.

Based on their findings as well as consensus guidelines, the authors propose that asymptomatic young patients with abnormal serology should be followed for at least 3-6 months as long as tTG < 11 times ULN.

Other findings:

  1. Breastfeeding may have a protective role; individuals with overt CD had a shorter mean duration of breastfeeding than the potential CD group (4.2 months compared with 5.1 months).
  2. Gluten introduction at age 6 months did not increase risk of overt CD (compared to potential CD) relative to introduction at 12 months.

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How to dissolve a bezoar

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Some bezoars, like lactobezoars, can resolve quite easily often with intravenous fluids.  Trichobezoars often require surgery.  Phytobezoars can dissolve with  diet coke and cellulase (Gastroenterol Hepatol 2012; 8: 770-72).

A phytobezoar, which is the most common type, is composed of indigestible fruit and vegetable fibers and occur in the setting of impaired gastric motility.  In the three cases presented, the combination of diet coke and an over-the-counter cellulase (Enzymedica Digest Gold) which contains 3000 units of cellulase per capsule was successful at dissolution of the phytobezoars over a 6-8 week period.

The role of the diet coke is less certain.  The sodium bicarbonate in sodas and the penetration of carbon dioxide bubbles may have facilitated dissolution.  Additionally, the acidic pH (2.6) of Coca-Cola along with the phosphoric and carbonic acids may have been beneficial.  While Coca-Cola and Diet Coke have the same potential mechanism of action, Diet Coke is easier to administer in diabetic patients.

Additional references:

One year later

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It has been one year and 300 posts since I’ve started this blog.  I’ve enjoyed putting together my thoughts about recent articles.  In addition, I like being able to search for previous blogs for information that I find helpful.

Currently there are close to ~35 hits per day in addition to the email/wordpress followers (about 30).  This number has been increasing and it is fascinating to see that people from all over the world will sometimes stumble across this blog.

If you have suggestions for topics, articles or other ways to improve this pediatric GI blog, please send me an email at jjhochman@gmail.com.

Predicting Necrotizing Enterocolitis with Fecal Biomarker

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A recent study has shown some promise in detecting necrotizing enterocolitis (NEC) with a fecal biomarker, S100A12 (J Pediatr 2012; 161: 1059-64).

In this prospective study of 145 preterm infants with a birth weight <1500 g, stool samples were collected on alternated days for 4 weeks.  Fecal S100A12 and calprotectin were measured.  Calprotectin in previous studies has been shown to be a poor marker for NEC.

Fecal S100A12, also called calgranulin C, belongs to a novel group of proinflammatory molecules. It is released by activated or damaged cells under conditions of cell stress and indicates phagocyte-specific damage.

18 (12.4%) developed NEC.  Fecal S100A12 levels were elevated in severe NEC and also at 4-10 days beforehand.  The sensitivity, specificity, positive predictive values, and negative predictive values were 70%, 68%. 37%, and 89% respectively.  Thus, there is limited utility of this stool test due to the limited sensitivity/specificity.  There is substantial overlap between control patients and patients who developed NEC.  Furthermore, fecal S100A12 levels are age-dependent.  Generally, they are higher early in life, likely due to increased mucosal permeability.

Calprotectin levels were elevated at the onset of NEC (median 349 mg/kg) and 48 hours before onset (median 83 mg/kg).  The difference at 48 hours prior to onset did not reach statistical significance.

Congenital Sucrase Isomaltase Deficiency

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Congenital Sucrase Isomaltase Deficiency (CSID) has an extensive review in a recent JPGN supplement (JPGN 2012; supplement 2: S1-47).

A concise update of the clinical aspects is provided by William Treem (S7-S13).   Specific points that he makes includes the following:

  • CSID was first described in 1960 by Weijers and colleagues
  • Sucrase-isomaltase gene (3q25-26) identified in 1992; now more than 55 mutations have been described.  At least one of the four most common mutations are identified in about 80% of affected individuals.
  • Prevalence: estimates range from 1 in 500 to 1 in 2000 in caucasians; the prevalence is lower in other populations.  Some patients suspected of having CSID may be heterozygotes with low enzyme activity (but not truly deficient).
  • Clinical features determined by degree of enzyme deficiency and amount of sugar and starch consumed.  In the U.S. typically 60% of calories consumed are derived from carbohydrates and 30% from sucrose.  A typical U.S. adult consumes 150 lb of sugar per year.
  • Classical presentation: severe watery diarrhea and poor weight gain in a 9- to 18-month old after exposure to juices, baby foods/fruits, and other starches.
  • Other symptoms: gas/bloating, abdominal pain, irritable bowel syndrome
  • Diagnosis: intestinal biopsy analysis.  A potential pitfall includes mishandling of biopsy specimens. An alternative means of diagnosis is the 13-C sucrose breath test.
  • Treatment: 1. dietary avoidance results in improvement in many, though only 10% respond fully to diet. 2. enzymatic treatment. Baker’s yeast (Saccharomyces cerevisiae) contains a sucrase.  Development of sacrosidase (Sucraid) from Baker’s yeast has allowed 81% of patients to consume an unrestricted diet.  Dosing: 1 mL with meals/snacks if <15 kg and 2 mL if >15 kg.
  • Despite sacrosidase treatment, 27% of patients required strict sucrose restriction with either mild or strict starch restriction to maintain acceptable suppression of symptoms.
  • What is not noted in this summary–cost information: sucraid may cost as much as $3700 per month.  A similar product in Europe costs about $400 per month

Multiple other articles in this supplement address related subjects.

On page S31, information is given from parent support group.  This parent support group (CSIDinfo.com) offers dietary advice specific for each phenotype (A,B,C,D and F) which is based on their disaccharidase levels, ability to outgrow symptoms, and tolerance of starch and maltodextrins.

On page S34, the major genetic mutations are discussed.  Use of genetic testing will detect the majority with CSID which could become an alternative means of diagnosing CSID in this population.

Additional Information

Norovirus -now more important than rotavirus

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Norovirus has become more important than rotavirus.  This is evident based on a recent review (NEJM 2012; 367: 2126-32).

Key points:

  • Noroviruses are the most common cause of acute gastroenteritis requiring hospital ER evaluation in U.S. adults.  It is predicted to become the most common cause of diarrhea in all age groups worldwide once rotavirus infection is controlled through vaccination.
  • Noroviruses are small nonenveloped single-stranded RNA viruses from the Calciviridae family.  There are six major genogroups.
  • Exposure can occur from other individuals, contaminated food/water, and environment sources, including nosocomial.
  • Chronic infection is common in immunocompromised hosts, perhaps 15-20% of some immunocompromised populations.  Evolution of the norovirus genome in patients infected for extended periods is relatively rapid (3.3% amino acid substitutions per year).
  • In normal hosts, viral shedding lasts 20-40 days; in the immunocompromised, shedding can occur for years.
  • Can be detected readily with RT-PCR assays.
  • There are no vaccines or specific viral agents available that have proven efficacy.  Passive antibody therapies have been given in individual cases.
  • Hand-washing is crucial, especially in the hospital.  In one study, 80% of hospital surfaces were contaminated with multiple norovirus strains—this study was done in a unit for children with immunodeficiencies.

Additional References:

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