Category Archives: Uncategorized

Salmonella by mail-order

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Sometimes patients are amazed that hemoccult cards can be sent by mail.  Now, I learned something new: you can mail-order live poultry and thereby spread salmonella far and wide (NEJM 2012; 366: 2065-73).  This study identified 316 cases in 43 states.

Key findings:

  • 36 hospitalized (23%)
  • 38 had chicks as pets (42%); of these, 22 (69%) said the pet owner was a child <5 years
  • Salmonella enterica serotype Montevideo subtype
  • 81% of infections identified as coming from a hatchery in Western U.S.
  • After identification of problem, owners implemented recommendations which lowered salmonella contamination.  After these measures, outbreak strain still detected in 7% of samples
  • Hatcheries mail live poultry to all 50 states –4 million birds are produced annually for this purpose. Approximately 250,000 birds are shipped each week, usually within 24 hours of hatching; each costing about $5 each.

Because only a portion of salmonella infections are identified with laboratory tests, there are likely thousands more infections associated with this outbreak.  Overall, nontyphoidal salmonella infections are estimated to cause 1 million illnesses, 19,000 hospitalizations, and 370 deaths annually.  Most infections are acquired as foodborne illnesses.  Though contact with animals, as this report indicates, is another mechanism.  These birds can appear healthy and intermittently shed salmonella.

Individuals wishing to reduce their risk of illness should practice careful hand hygiene around animals.  See link for helpful advice:

http://www.cdc.gov/healthypets/resources/salmonella-baby-poultry.pdf

The poultry business can help by adhering to sanitary practices, by avoiding artificially coloring chicks (which targets children), and by warning recipients of the danger of salmonella infection.

Food choices, FODMAPs, and gluten haters

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Given the frequency of functional gastrointestinal diseases (FGID), including irritable bowel syndrome (IBS), dietary treatments that may improve symptoms receive a lot of attention.  A recent review of the role of food choices in the development and management of FGIDs is a useful reference (Am J Gastroenterol 2012; 107: 657-66 -thanks to Ben Gold for forwarding this article).

This review details specific dietary advice as well as the following specific physiologic effects of FODMAPs:

  • Osmotic effects
  • Bacterial fermentation
  • Motility effects
  • Prebiotic effects
  • Systemic effects –mild depression, tiredness
In addition, the review looks at other potential foods which could serve as a trigger for IBS symptoms, like gluten & summarizes why some IBS patients are gluten haters.  The authors acknowledge that gluten sensitivity, in the absence of celiac disease, does not have a known mechanism.  Until a reliable marker becomes available, the importance of gluten sensitivity for FGIDs is unknown.
Related posts:

What to make of FODMAPs

Gluten sensitivity without celiac disease

Is a biopsy necessary in Celiac disease?

New caustic danger from detergent pods

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“Brightly colored little packets that combine laundry detergent with other cleaning agents are a new convenience for consumers — and a new danger for kids.”

See more complete story at attached links that follow:

http://www.washingtonpost.com/national/poison-control-centers-field-increased-number-of-calls-of-children-ingesting-detergent-packets/2012/05/24/gJQAaiSZnU_story.html

http://yourlife.usatoday.com/health/healthyperspective/post/2012-05-24/new-kid-danger-swallowing-candy-colored-laundry-packets/701134/1

Does pancreas divisum cause pancreatitis?

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The role of pancreas divisum (PD) as a cause of either acute recurrent or chronic pancreatitis (AR/CP) remains a matter of debate.  A recent study suggests that pancreas divisum serves as a cofactor but does not cause pancreatitis independently (Am J Gastroenterol 2012; 107: 311-17).

PD occurs due to failure of fusion of the dorsal and ventral pancreatic buds during gestation.  The frequency of PD has been estimated to be between 5-10% of the general population based on large post-mortem studies.  There is an increased frequency of PD in patients with idiopathic pancreatitis (12-26%).  The referenced study from France examined the frequency of genetic mutations vis-a-vis relationship with PD.  PD was determined using MRCP.

Findings–percentage with PD among subgroups:

  • 7% of subjects without pancreatic disease, n=45
  • 7% of alcohol-associated pancreatitis patients, n=29
  • 5% of idiopathic pancreatitis patients, n=40
  • 16% of patients with PRSS-1-associated pancreatitis, n=19
  • 16% of patients with SPINK-1-associated pancreatitis, n=25
  • 47% of patients with CFTR-associated pancreatitis, n=30

The study has several limitations.  Overall, the numbers of patients with pancreatitis are fairly low.  In addition, these genetic mutations are not typically examined in individuals without pancreatitis.  As such, the effect of these mutations with PD still is difficult to know in comparison to a larger population.

Additional references:

  • Recurrent pancreatitis and genetic underpinnings (previous blog post)
  • -Clin Gastro & Hep 2009; 7:141.  Review -case of recurrent pancreatitis -suggests checking ANA, Trig, IgG4 (also TTG)
  • – J Pediatr 2008; 152: 106.  Acute pancreatitis in young children; 109 cases.  systemic dz in 29, drugs in 7, gallstones in 3, annular pancreas in 1, trauma in 7, infections in 16, CF in 2, Idiopathic in 15.
  • -NEJM 2006; 354: 2142.  Review of acute pancreatitis mgt.
  • -Clin Gastro & Hep 2006; 4: 455.  Elevated pancreatic enzymes frequently identified in celiac disease.
  • -Clin Gastro & Hep 2007; 5: 1347. Celiac is a risk factor for acute & chronic pancreatitis. n=14,239 & 69,381 reference population (Sweden).
  • -Pediatrics 2005; 115: e463. CF & pancreatitis
  • -JPGN 2003; 37: 5591. Systemic dz 14%, Trauma 14%, drugs 12%, metabolic 6%, structural 5%, infectious 8%, ERCP 6%, Biliary 12%, Familial 3% (but accounted for 20% of episodes) Transplant 8%, idiopathic 8%
  • -Clin Perspectives in Gastro 2002; 5: 73. Pancreas divisum

Quantifying Risk of PML with Natalizumab

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Given the limited number of treatment options for inflammatory bowel disease, when Natalizumab became available, there was a great deal of enthusiasm.  This quickly diminished as reports of progressive multifocal leukoencephalopathy (PML) emerged.  So far, I have not prescribed this agent.

Due to its efficacy for multiple sclerosis and IBD, there has been continued interest in understanding the risk for PML (NEJM 2012; 366: 1870-80, editorial pg 1938-39).

Key findings:

  • 212 cases of PML among 99,571 patients treated with natalizumab (2.1 cases per 1000)
  • Three main risk factors: positive JC-virus antibody, previous use of immunosuppressants, and receiving natalizumab more than 2 years

Patients who were negative for anti-JC virus antibodies had an incidence of 0.09 cases or less per 1000 patients.  Among patients who test positive for anti-JC virus antibodies, the risk remained <1 per 1000 patients if no use of immunosuppressants and 2 per 1000 if prior use of immunosuppressants during the first two years of therapy.  The risks were five-fold higher after 2 years in both groups.

While the risks are becoming more clear, the benefits of natalizumab are fairly well-established for multiple sclerosis.  Natalizumab decreased the annualized rate of relapse among patients with relapsing–remitting multiple sclerosis by 68%.

Additional references:

  • -NEJM 2009; 361: 1067, 1075, 1081.  Asymptomatic detection of JC virus common in urine noted in patients Rx’d with natalizumab (19% baseline to 63% on Rx); actual leukoencephalopathy ~1/1000 patients.
  • -Gastroenterol 2007; 132: 1672.  ENCORE trial.
  • -JPGN 2007; 44: 185. n=31 children/adolescents.  55% response, 29% remission; dosed at 3mg/kg.
  • -IBD 2007; 13: 2.  n=79.  Trial of combination natalizumab & infliximab.
  • -NEJM 2006; 354: 899, 911, 924.  Natalizumab slows progression of MS.  Risk of PML due to JC virus 1:1000 in 18 months of Rx.
  • -NEJM 2005; 353: 1912/1965.  Natalizumab not significantly effective for Crohn’s in this study
  • -NEJM 2005; 353: 362, 369, 375, 414.  3 cases of PML associated with Natalizumab
  • -JPGN 2004; 39: S49 [abstract 0107].  Natalizumab in 38 adolescents was effective (Hyams et al).
  • -Gastroenterol 2004; 126: 1574-81. review.  Natalizumab benefitted subjects with elevated CRP. (dosing 300mg every 4 weeks.)
  • -NEJM 2003; 24-32 & 68.  Natalizumab improved response rates in pts c Crohn’s dz (similar to infliximab).  Drug blocks alpha4 integrins which are required for lymphocytes to enter the intestine.
  • -Gastroenterol 2001; 121: 268-74. Infusion of 3mg/kg decreases CDAI in Crohn’s dz.

Something new for blue (BRBNS)

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A case report describes the use of low-dose sirolimus (rapamycin) for treating blue rubber bleb nevus syndrome (BRBNS).  (Pediatrics 2012; 129: e1080-84). This patient, an 8-year-old girl from Turkey) presented with massive gastrointestinal bleeding had multiple venous malformations all over her body, especially throughout her gastrointestinal tract.

Before instituting sirolimus, patient had failed several agents: prednisolone, interferon-α, propranolol, and aminocaproic acid.  Sirolimus was dosed at 0.05-0.1 mg/kg as an antiangiogenic agent with a goal of maintaining a trough level between 1 and 5 ng/mL.  The lesions decreased in size but did not disappear.  Initially, patient received therapy with propranolol concomitantly.  Dramatic improvements in hemoglobin were noted after starting sirolimus therapy.

Additional references:

  • -Pediatr Blood Cancer 2011; 57: 1018-24.  Use of sirolimus for complicated vascular anomalies in children
  • -Pediatrics 2001; 107: 418.  Case report of BRBNS
  • -JPGN 2001; 33:183-188. Use of octreotide in BRBNS

Diarrhea, GC-C and guanylin

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During my fellowship, I participated in research studying the effects of guanylin and its interaction with the receptor, guanylate cyclase C (GC-C).  So whenever clinical articles demonstrate clinical significance, I am interested.  This month there is evidence that some cases of familial diarrhea are due to mutations which activate the GC-C receptor (NEJM 2012; 366: 1586-95).

The authors describe a novel dominant disease in 32 members of a Norwegian family due  to a mutation in the sequence of GUCYC which encodes GC-C.  Exposure of this mutant receptor to its ligands results in increased cyclic guanosine monophosphate (cGMP).  This in turn likely causes hyperactivation of the cystic fibrosis transmembrance regulator (CFTR)  resulting in diarrhea.  Individuals with this mutation tended to have mild chronic diarrhea with an early onset as well as a susceptibility to inflammatory bowel disease and small bowel obstruction.

While this mutation is rare, there is a larger role for GC-C.  Heat-stable enterotoxins form E. coli bind to this receptor starting a cascade which results in diarrhea.  Since there had to be a role for GC-C other than facilitating development of diarrhea after exposure to pathogens (Why would our body create a receptor for a pathogen?), researchers discovered an endogenous ligand for GC-C, guanylin.   Guanylin acts as an agonist of  GC-C and regulates electrolyte and water transport in intestinal and renal epithelia.  In addition, guanylin and GC-C serve as a model for intestinal gene regulation.  Also, GC-C has been investigated as a predictive marker for colorectal cancer and for a role in renal electrolyte transport in humans; in animals, GC-C and its ligands have been shown to have effects on behavior and satiety.  

Additional references:

  • -Steinbrecher KA, Cohen MB. Transmembrane guanylate cylase in intestinal pathophysiology. Curr Opin Gastroenterol 2011; 27: 139-45.
  • -Gastroenterology 2010; 138: 886.  Linaclotide -a guanylin analog –use for constipation.
  • -Hochman JA, Sciaky D, Whittaker T, Hawkins JA, Witte DP, Cohen MB. “HNF-1 Regulates the Transcriptional Activation of Guanylin” Am. J.  Physiol. 273 (Gastrointest. Liver Physiol. 36): G833-G841, 1997.
  • It’s often elemental  Previous post discusses protracted diarrhea of infancy

Improve Care Now

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Several years ago, “ImproveCareNow” Network was established with a goal of improving the quality of care children with inflammatory bowel disease. https://improvecarenow.org/ (http://www.youtube.com/watch?v=beG2eMROWqg)

Documentation of some outcomes of this effort have now been published (Pediatrics 2012; 129: e1030-e1041).  In this study from six U.S. centers, data from 843 children with Crohn’s disease and Ulcerative Colitis were available.  Centers were eligible to participate if they did not have extensive quality improvement (QI) experience and if they were able to enroll >75% of their IBD patients.  During the course of the study (2007-2010), there were increases in the proportion of patients with measurement of thiopurine methyltransferase (TPMT) before initiation of thiopurines, increased percentage of individuals receiving an appropriate thiopurine dosage, and an increased percentage of patients with inactive disease.  In Crohn’s disease, the number with inactive disease changed from 55% to 68%; in ulcerative colitis, the number increased from 61% to 72%.  

This study shows significant progress in these patients and the potential benefit of a more-structured approach.  However, some of the improvements in these outcomes may not be to process improvements. 

Study limitations:

  • The study does not document the rate of inactive disease in non-participating centers; thus there is not an adequate control population.  Given more widespread use of biologic therapies, this may account for much of the improvement in outcomes.   In fact, the study does not describe the percentage of patients receiving thiopurines or biologic agents.
  • The use of the physician global assessment (PGA) as indicative of disease activity.  The authors acknowledge that “PGA ….is a relatively subjective measure.”  A more reliable measure of disease activity like a stool calprotectin, endoscopy, or imaging study improvement would have been helpful.  
  • Better documentation or better outcomes? It is not clear whether some of the improvement reflects better documentation or improved care delivery.

Despite the limitations of this study, it is a good starting point.  The goal of improving the care of patients is shared by almost all physicians.  One way to start making a difference is measuring specific outcomes and targeting specific goals/checklists. Going forward with QI there are many QI hurdles: 

  • Defining optimal care is nearly impossible, there are few trials comparing efficacy & difficult to judge risk/benefit ratio of many therapies.
  • Difficulty selecting appropriate outcome measures -indications for hospitalization and surgery are not clear-cut in many cases.  Surgery may be an appropriate treatment rather than a negative outcome. 
  • Risk adjustment is an imperfect science.

Goals with Quality Improvement:

  • Plan-Do-Study-Act cycles.
  • Learning from high-performing centers -benchmarking

Warranted vs unwarranted variations:
Unwarranted: selecting inadequate dosing of medications, failure to check for TB before remicade/biologics, failure to consider drug interactions, failure to discuss options with families
Warranted: variation due to differences in disease (eg budesonide for ileitis but not pancolitis), variation driven by patient preferences (eg. using NG instead of corticosteroids)

“When you can measure what you are speaking about and express it in numbers, you know something about it; but when you cannot express it in numbers, your knowledge is of a meagre and unsatisfactory kind” –Lord Kelvin 1883

“Not everything that counts can be counted, and not everything that can be counted counts.” –Albert Einstein

Additional references on quality improvement:

  • Free Self Management Handbook endorsed by ImproveCareNow:

https://improvecarenow.org/patients/self-management-handbook

  • -JPGN 2009; 49: 272.  Review of quality measures/history.
  • -Kohn LT, et al. To Err is Human: Building Safer Health System.  Nat’l Academy Press; 2000
  • -Crossing the quality chasm.  Wash DC: Nat’l Academy Press; 2001.
  • -Clin Gastro & Hep 2010; 8: 709.  Quality indicator sets in cirrhosis.
  • -J Pediatr 2005; 146: 744-50.  Bucuvalas JC et al.  Adjusting calcinerin inhibitor dosing
  • -IBD guidelines: www.cincinnatichildrens.org/svc/alpha/health-policy/ev-based/ibd.htm
  • -JPGN 2009; 49: 297.  Variation in care in pediatric Crohn disease. (Our center participated in this study)
  • -J Pediatr 2009; 154: 582.  Ventilator assoc pneumonia reduced w bundle of hand hygiene, elevated HOB, not changing ventilator circuits except when soiled & mouth care
  • -“The Learning Curve”(Atul Gawande) in The Best American Essays 2003 -some CF ctrs outperform, extending life expectancy ~14yrs.
  • -” A Surgeons Notes on Performance-Atul Gawande
    -NEJM 2007; 357: 2652.  Nice editorial.
  • www.icsi.org
  • www.qualityforum.org
  • www.ambulatoryqualityalliance.org
  • www.ncqa.org
  • www.cms.hhs.gov/hospitalqualityinit

Comments from lead author forwarded to blog:

Thanks for including our recent paper in your blog.  I agree with the study limitations as you mentioned, but wanted to put a couple of things in context.  We actually thought very hard about the issue of a control group, and specifically how to determine what the remission rate would be without the intervention.  We could not come up with a reasonable comparator (very few people/groups outside of ICN even know what the remission rate of their population is).  One very rough measure (which we did not feel was legitimate to include) is the rate of remission for new sites as they are joining the collaborative.  Established sites with complete participation have better outcomes than newer sites or sites that participate less fully, suggesting that at least a significant portion of the effect is due to the QI intervention rather than secular trend.  As far as the objective measures for outcomes, I know you realize that we are not able to mandate specific objective evaluations for a QI/observational research study, so we may never be able to use mucosal healing (for example) as our measure of remission.  However you probably noticed in the paper that we did demonstrate improvements in objective measures including sPCDAI, PUCAI and use of corticosteroids.  Certainly improvements in process measures may have been due in part to better documentation, but it is unlikely that objective outcome measures improved due to documentation. Thanks again for sharing our work with your audience.

Pierre Robin and what else?

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In a large pediatric center, patients with Pierre Robin Sequence (PRS) are routinely seen by genetics and for good reason.  Underlying syndromic features were present in 60% of a recent retrospective review (J Pediatr 2012; 160: 645-50).

Most common syndromes with PRS include the following:

  • Stickler syndrome (22% pf all cases)
  • 22q11.2 deletion syndrome/velocardiofacial syndrome
  • Marshall syndrome
  • Moebious syndrome
  • Cornelia de Lange syndrome
  • Treacher Collins syndrome
  • Fetal alcohol syndrome
  • Van der Woude syndrome
  • Oculo-auricular-vertebral spectrum

For gastroenterologists, the article notes that 43% of the San Diego cohort required tube feeding whereas 79% of the Cleveland cohort needed tube feedings.  Overall, average was 52% needing tube feeds.

Additional references:

  • -J Pediatr 2011; 159: 887.  Feeding problems common in UAO/Robin-like phenotype.
  • -Burstein FD, Williams JK.  Mandibular distraction. Plast Reconstr Surg 2005; 115: 61-7.
  • www.vcfsef.org
  • www.sticklers.org
  • -J Pediatr 2002; 140: 719.  Frequent upper esophageal/oral motor dysfxn (24/28)
  • -J Pediatr 2001; 139: 588. n=117.  descriptive study.  35% c syndrome, 48% isolated, 17% c associated anomalies.
  • -JPGN 2001; 32: 297.  Frequent oroesophageal motor disorders in these patients.  86% required prolonged NG feeds.

Recurrent pancreatitis and genetic underpinnings

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While the absolute number of patients with genetic causes of pancreatitis is small, due to frequent hospitalizations, this remains a significant problem.  This month additional information on genetic predisposition for pancreatitis is available (JPGN 2012; 54: 645-50).

Sultan et al (Milwaukee, WI) reviewed the charts of children <18 years with recurrent acute pancreatitis (RAP) and patients with chronic pancreatitis (CP) from 2000-2009.   RAP was considered if patient had a minimum of two distinct episodes of acute pancreatitis.  Acute pancreatitis was considered the diagnosis if patient had typical symptoms associated with 3-fold elevation of amylase or lipase or imaging changes consistent with acute pancreatitis. CP was defined as a minimum of 2 episodes of acute pancreatitis associated with pancreatic duct abnormalities or pancreatic insufficiency.

Among this cohort of 29 children, 23 (79%) had mutations which have been associated with genetic pancreatitis (GP).  Family history was positive in only five patients.

  • CFTR mutation in 14 (48%): two had homozygous mutations, six heterozygous, and four had 5 T variants.  The importance of a single CFTR mutation in contributing towards pancreatitis is unclear.  However, the Wisconsin population has a carrier frequency of 1:32; the striking difference in frequency  indicates that even a single mutation may be important in the pathogenesis of RAP.
  • SPINK1 (serine protease inhibitor Kazal type 1) in 8 (27%).  SPINK1 mutations occur in 1-3% of the general population.  It is often a modifying factor rather than an isolated causal factor in the development of RAP.  Four of the patients with SPINK1 mutations also had a CFTR mutation.
  • PRSS1 (cationic trypsinogen gene) in 7 (24%).  Individuals with these mutations are considered to have hereditary pancreatitis, an autosomal disease with incomplete penetrance.
  • Only one patient was tested for chymotrypsin C gene (CTRC) –tested negative.

Seven patients with RAP did not undergo genetic testing & were excluded from the study.  These patients had other known causes of RAP: 3 had gallstones, 2 had pancreas divisum, 1 had a metabolic disorder, and 1 had a medication-induced pancreatitis.  The authors note, however, that patients with pancreas divisum have had genetic mutations identified in other studies.

Additional References:

  • www.uni-leipzig.de/pancreasmutation. This link will take you to the hereditary pancreatitis database where you can search for the specific mutation you identified and find articles dealing with a variety of aspects of that particular mutation.
  • 2011 Naspghan Postgraduate Course:
    Pancreatitis Workup
    -1st bout, check U/S, trig
    -if 2nd bout, suggested to check MRI, genetics (SPINK1, PRSS1, CFTR), sweat test, fecal elastase, possibly IgG4/ANA
  • OMIM#167800/276000
  • -Gastroenterology 2006; 131: 1844.  Mouse model w R122H Trypsiongen expression.
  • -Whitcomb DC. Gut 2004; 53: 1710-17. test for PRSS1 (cationic trypsinogen), SPINK1 (Serine protease inhibitor, Kazal Type 1), and CFTR gene.
  • -JPGN 2002; 34: 1A pg 444. n=108 with hereditary or idiopathic pancreatitis. (28% had + fhx)  12 c PRSS1 mutation, 24 c SPINK1 (21 s fhx); 22 had + CFTR mutation.
    -Pancreatology 2001; 1: 405-415.  Consensus guidelines for testing for H. Pancreatitis. PRSS1 gene -cationic trypsinogen
    http://www.pancreas.org/assets/pdfs/Pancreatology/HPgeneTestConsensus.pdf
  •  David Whitcomb’s laboratory at the University of Pittsburgh. The test is commercially available there. Their web site for the forms is:
    http://www.pitt.edu/~whitcomb/HPINFO/MolGenTest.html
  • -JPGN 2011; 52: 262. Review.
  • -J Pediatrics 2011; 158: 612.  Acute pancreatitis can result in diabetes.
  • -Clin Gastro & Hep 2010; 8: 410-416, 417. REVIEW of acute pancreatitis.  Rec NJ generally over TPN.
  • -Clin Gastro Hep 2010; 8: xxii.  Anomalous pancreatobiliary jxn as a cause.
  • -JPGN 2009; 49: 137.  Pancreatitis assoc w celiac
  • -Clin Gastro & Hep 2009; 7: 702.  Harmless Acute pancreatitis score.  Nonsevere when NL hgb, NL creatitine, and no rebound tenderness/guarding
  • -Alim Pharm Ther 2008; 28: 777-781.  Use of a low fat diet helped shorten hospital stay among adult pts with acute pancreatitis.
  • -Clin Gastro & Hep 2008; 6: 1070, 1077.   Fluids and imaging in acute pancreatitis.  With imaging, CT probably best.
  • – J Pediatrics 2008; 152: 106.  Acute pancreatitis in young children

Related blog entry:

Indomethacin to prevent post-ERCP pancreatitis