Category Archives: Pediatrics

Diagnosing hemophagocytic lymphohistiocytosis (HLH)

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HLH is difficult to diagnose –patients without HLH can meet the established criteria (see links below); and, especially early in the disease, patients with HLH may not meet the established criteria.  A study which will help with this difficulty has been published (J Pediatr 2012; 160: 984-90 and summary pg A1).  For pediatric gastroenterologists, HLH is important because some of our IBD patients may develop HLH and because some patients presenting with liver disease have HLH.

This study examined 756 consecutive patients with fever in Hematology/Oncology unit of China’s Children’s Hospital of Zhejiang between 2005-2010.  Three control groups also were studied: hematology-oncology patients without fever (n=202), healthy children (n=100), and previously-healthy children with bacterial sepsis (n=85).

A highly discriminating cytokine pattern was identified in 71 episodes of HLH.

  • Highly elevated IFN-γ : 94% sensitivity, 97% specificity for HLH using a cutoff of 100 pg/mL
  • Highly elevated IL-10
  • Modestly elevated IL -6
  • Combined use of IFN-γ (>75 pg/mL) & IL-10 (>60 pg/mL) had sensitivity of 93% and specificity of 99% for HLH

Using these cytokines may help establish a more rapid diagnosis of HLH and allow institution of critical therapy while avoiding implementation of the wrong treatment in patients who have other conditions.  In other studies (see below), there are other useful markers that have been identified.

Additional references:

  • -J Pediatr 2011; 159: 808.  HLH increased with Crohn’s Rx.  If fever >5days, can screen for HLH with ferritin (>500mcg/L) & lymphopenia.  Need to discontinue immunosuppression.  100-fold increase risk of HLH.  Diagnostic criteria for HLH pg 809. Newer criteria: molecular, low/absent NK activity & soluble CD-25 (ie. soluble IL-2 receptor) >2400 U/mL.
  • Hemophagocytic Syndrome  Link with powerpoint case presentation including diagnostic criteria for primary and secondary HLH.
  • Hemophagocytic lymphohistiocytosis (HLH) and related disorders  Link with review article by leader in field (A Filipovich, 2009).
  • -J Peds 2006; 149: 134-7.  Aftrican-american infants c HLH often have a specific defect in perforin gene -50delT-PRF1
  • -NEJM 2004; 351: 1120. case of twins c FELS. Impaired NK cell activity is key with absence of NK intracytoplasmic perforin in 20-40%.
  • -JPGN 2002; 34: 3A (pg 433.)  Liver failure with HLH.  mortality 84%, n=25.

Why “therapeutic dose” of codeine can kill

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While this blog has described some of the huge problems with the overuse of narcotics (Deadly consequences of pain management), another danger with narcotics occurs especially with codeine due to its metabolism via the CYP2D6 pathway; codeine is particularly risky in young children.  A reminder of this is a recent case report (Pediatrics 2012; 129: e1343-1347).

During my training, I was told by an ENT doctor that he never prescribed codeine in children less than 6 years of age due to safety concerns.  While he could not explain the mechanism, this case report does.  This case report describes three children with severe cases (two were fatal) from North America.  In the two fatal cases, gene duplications encoding Cytochrome P450 2D6 (CYP2D6) caused a significantly greater production of morphine from its parent drug, codeine.  This risk of respiratory depression may be enhanced in ENT cases especially in children with obstructive sleep apnea.

The risk from codeine involves individuals who are ‘ultra-metabolizers’ of CYP2D6; this is because the metabolized drug in this case, morphine, is more potent than the parent drug, codeine.  Other opioids that are similar to codeine, like hydrocodone and oxycodone, may have additional risk as well.  Ultra-metabolizers include up to 7% of all caucasians.  In addition, 5-10% of caucasians are poor-metabolizers which would result in a lack of therapeutic effect with codeine.

While ultra-metabolizers of CYP2D6 function are prone to codeine toxicity, poor-metabolizer individuals will have an exaggerated response when the parent drug is more potent than its metabolites.  In addition, there are numerous drugs (not metabolized by CYP2D6) which interact to inhibit the function of CYP2D6 (eg. diphenhydramine).  Thus, these drugs can potentiate the effect of CYP2D6 on its substrates.

Other drugs commonly used by gastroenterologists and metabolized by CYP2D6 include tricyclic antidepressants, most SSRIs, metoclopropramide, ondansetron, and promethazine.  In ultra-metabolizer individuals, many of these drugs will not work because the quickly-produced metabolites, unlike the parent substrate, do not have therapeutic effects.

Additional references:

  • N Engl J Med 2004; 351: 2827-31.  Codeine Intoxication Associated with Ultrarapid CYP2D6 Metabolism. 62 year old: “12 hours after the last dose of codeine, the blood level of morphine was 20 to 80 times as high as the blood level that would have been expected on the basis of measurements in healthy persons ” due to ultrametabolism of CYP2D6 in combination with inhibition of CYP3A4 activity by other medications
  • CYP2D6 – Wikipedia, the free encyclopedia
  • Drug and Alcohol Dependence 89 (2007) 190–194. Association of CYP2D6 ultrarapid metabolizer genotype with deficient patient satisfaction regarding methadone maintenance treatment
  • What happens when codeine is used with drugs – WorstPills.org –

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.

Diseases peculiar to children

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In celebration of NEJM’s 200th anniversary, a special series of articles is being published.  A recent one, titled “What we don’t see” makes some useful observations about the history and trajectory of the field of pediatrics (NEJM 2012; 366: 1328-34).

According to the author, most physicians did not consider children as a distinct medical population in the early part of the 19th century.

  • In 1789 Benjamin Rush at the Univ of Pennsylvania gave lectures called “diseases peculiar to children.”
  • William Osler introduced the term “pediatrics” in 1880.
  • While advances in genetics, surgery, neonatology, oncology, and many other disciplines have been very important, infectious diseases have remained the predominant cause of childhood death both in the past and currently.
  • In 2008, causes of childhood death worldwide:  pneumonia 19%, diarrhea 15%, malaria 8%, other infections 26%.  Diarrhea and pneumonia each killed more than 1 million children.
  • Neonatal deaths comprised 41% of all deaths in the first 5 years of life.

Stimulants for constipation

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Overall, 12-19% of Americans are affected by chronic constipation (Am J Gastroenterol 2004; 9: 750-59).  Despite the fact that constipation problems are widespread, the amount of useful research available to guide treatment is quite limited.  Two recent articles do offer some information:

  • Clin Gastroenterol Hepatol 2011; 9: 577-83.
  • Gut 2011; 60: 209-18.

The first reference examined the use of bisacodyl in a randomized, double-blind placebo-controlled study in the UK.  During the 4-week treatment period, patients receiving 10mg/day bisacodyl (n=247) had increased stools, from 1.1 per week to 5.2 per week.  Stool frequency also increased to 1.9 per week in the placebo group (n=121).  All secondary endpoints including constipation-associated symptoms (eg. quality of life indices, physical discomfort) improved significantly compared to placebo.  Average age of patients in this study was 55 years.  The main adverse effect was diarrhea –mainly during the 1st week of therapy.

A selected summary in Gastroenterology (Gastroenterology 2012; 142: 402-404) reviews the first study and makes several useful points:

  • Stimulant laxative use has been hindered by myths & misconceptions along with lack of supporting data.  Most recent studies do not support a role of stimulant use in causing enteric neuropathies, a cathartic colon or increasing the risk of colon cancer
  • Osmotic laxatives have been favored in guidelines but this has not been bolstered by supporting data
  • Only recently have two large randomized controlled studies proven the efficacy and safety of stimulant laxatives over the short-term
  • Long-term prospective studies are not available on the use of stimulant laxatives.

The second reference is a systematic review and meta-analysis of randomized controlled trials (RCTs) of pharmacologic therapy for chronic idiopathic constipation.  Twenty one eligible RCTs were identified: eight laxative studies (n=1411), seven prucalopride studies (n=2639), three lubiprostone (n=610), and three linactolide trials (n=1582).  All of these studies showed treatment was superior to placebo. These studies involved subjects who were mainly adults (>90% older than 16 years).

The results showed benefit from both stimulant and osmotic laxatives.  Overall, the osmotic and stimulant laxative studies showed higher response than the pharmacologic agents like prucalopride, lubiprostone, and linaclotide.  Nevertheless, between 50% and 85% of patients did not fulfill criteria for response to therapy.

Additional references:

  • -J Clin Gastro 2003; 36: 386-389.  Safety of stimulants for long-term use.
  • -Am J Gastro 2005; 100: 232-242.  Myths about constipation.  Stimulants have not been proven to cause a “cathartic colon”
  • -J Pediatr 2009; 154: 258.  Constipation associated w 3-fold increase in health utilization/cost.
  • -Clin Gastro  Hep 2009; 7: 20.  Review of complications assoc c constipation in adults.
  • -Pediatrics 2008; 121: e1334.  Behavioral therapy ineffective in treating childhood constipation.
  • -NEJM 2008; 358: 2332, 2344.  Use of methylnatrexone for opioid-induced constipation & trial of n=620 of prucalopride for severe constipation.  Both drugs were helpful.
  • -Gastroenterology 2004; 126: S33. Review of pediatric incontinence.
  • -J Pediatr 2004; 145: 253-4.  Prevalence of encopresis 15% /constipation 23% in obese children  (n=80).  Questionnaire administered to 80 consecutive obese children.
  • -Gastroenterology 2003; 125: 357.  Longterm constipation followup.  one-third with persistent constipation; 60% better at 1 year.  (tertiary referral group)
  • -Pediatrics 2004; 113: 1753 & e520.  When constipation & toileting difficulties both occur, constipation usually precedes toileting problems

Pediatric pharmaceutical poisoning

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Overdosing and taking a bad mix of medications is not just a problem in adults.  This remains a big problem in pediatrics (J Pediatr 2012; 160: 190-192, 265-70).  The study and accompanying editorial discuss the ongoing impact of pediatric pharmaceutical poisoning and what can be done to improve the situation.  This study involved 453,559 children (<5yrs) who had ingestion of a single product (55% prescription, 45% OTC).  Child self-exposure was responsible for 95%.  Between 2001-2008, these exposures led to 248,023 health care visits, 41,847 admissions, and 18,191 significant injuries.  This data likely underestimates the full extent as the data was collected ‘passively’ by the National Poison Data System (from the U.S. Poison Control Centers).

Although the number of ingestions has been increasing, the number of deaths declined marginally from 2001-2004 to 2005-2008, mainly due to a decline in pediatric acetaminophen deaths.  The authors conclude the problem is getting worse, not better.

What can be done to decrease this burden?

1. Packaging.  Since the poison prevention packaging act was passed in 1970, it has been recognized that the child-resistant closure (CRC) is not sufficient.  The main problem has been that once the vial is open, the entire contents of the vial are available for ingestion.

Options: insertion of needleless syringe for liquid medicines, requiring pressure to be applied to bottle to express medicine & blister packs (inside CRC container) for pills.

2. Targeting interventions for the highest risk medications.  Opioids, cardiovascular agents, and sedatives.

3. Healthy People 2020.  A collaborative approach to this problem is underway.

In our patient populations, we need to remember that the medications we prescribe may be inadvertently ingested by our patients (overdose) or by their siblings.  A word of precaution may save a life.

Additional references:

  • -Pediatrics 2011; 127: e1597-9. Preventing medication overdoses in young children.
  • -Ann Emerg Med 2009; 47: 348-54. Unrecognized toll of opioid abuse on young children.
  • -NEJM 2009; 361: 2105. Changes in FDA labeling of analgesics. ~30,000 hospitalizations  each year due to acetaminophen overdose in U.S. –1/2 inadvertent overdose.
  • -Hepatology 2007; 46: 966. AASLD public policy re: acetaminophen. It is leading cause of acute liver failure in U.S.  500 deaths annually. 10% of cases may occur in those receiving the proper doses.
  • -JAMA 2006; 296: 87-93. Prospective study of daily 4gm acetaminophen in healthy volunteers. (stayed at research facility). ALT >3 ULN in 38%. Resolved over 6 days.
  • http://www.healthypeople.gov/2020/topicsobjectives2020/objectiveslist.aspx?topicId+27

Protecting the most vulnerable

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Although pediatric gastroenterologists are not on the front lines of the vaccine controversies, we should add our voices to support immunizations.  Some of our immunocompromised patients are among the most vulnerable and rely on herd immunity to lessen their chances of serious infection.  When healthy children and adults do not receive their immunizations, this does not only increase their risk of infections but the risk to others.

A perfect example of this is highlighted in NEJM 2012; 366: 391-92.  In 2010, California reported over 9000 cases of pertusis; of these cases, 89% occurred in infants less than 6 months.  This population is too young to be adequately immunized.  Ten of these infants died.

The author recommends trying to persuade those who are hesitant to proceed with immunizations.  Parents who are opposed based on personal beliefs will not be persuaded.

  • Remove socioeconomic barriers to vaccination
  • Enforce school entry requirements; it should not be easier to opt out of immunizations than to receive them
  • Aggressively address misinformation
  • Learn to use persuasion effectively: http://www.cdc.gov/vaccines/conversations

Additional references:

  • -NEJM 2011; 365: 1108. RV vaccine resulted in 64,000 less hospitalizations in US between 2007-2009.
  • -NEJM 2010; 362: 289, 299, & 358. Rotavirus vaccines lowering death rate in Africa & Mexico.
  • -NEJM 2011; 364: 2283. Rotavirus vaccine: risk of intussception ~1:50,000-1:70,000; thus could cause ~96 cases per year. Vaccine at same time prevented 80,000 hospitalizations & 1300 deaths in Brazil & Mexico.
  • -Gastroenterology 2007; 132: 1287. Two decades of HBV vaccination in Taiwan
  • -NEJM 2007; 16: 1275, 1278, 1281.  Medical evidence refuting Thimersol toxicity; yet many vaccine cases in litigation
  • -Liver Transplant 2008; 14: 1389.  Vaccine policies:  MMR/Varicella can be given as early as 6 months of age. Must give 3-4weeks before Tx. Can give inactivated ~6-12 mo p-OLT. Except for oral polio, good idea for contacts to get all their immunizations.
  • -Inflamm Bowel Dis 2009;15:1410–1416.  Vaccination Strategies for Patients with Inflammatory Bowel Disease on immunomodulators and biologics

Live Virus Vaccines, Generally Contraindicated in Patients Receiving Immune-Suppressive Therapy:

Anthrax vaccine
Intranasal influenza
Measles-mumps-rubella (MMR)
Polio live oral vaccine (OPV)
Rotavirus
Smallpox vaccine
Tuberculosis BCG vaccine
Typhoid live oral vaccine
Varicella
Yellow fever

Unexplained chest pain

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Not surprisingly -unexplained pediatric chest pain has a high association with anxiety/psychiatric disorders (J Pediatr 2012; 160: 320).  In this study, the authors compared patients (8-17 years) with chest pain (n=100) to a cohort referred with innocent heart murmur (n=80).  In addition to cardiology evaluation, patients had a structured interview and a child health questionnaire to assess for psychiatric disorders; also, the investigators interviewed the parent(s).

Based on DSM-IV criteria, 70% of chest pain patients had an anxiety disorder and 9% had depression.  In contrast, 33% of heart murmur patients had an anxiety disorder and none were depressed.  Among the chest pain subjects, 26% had abdominal pain and 26% had headaches -both higher than the control group, 9% and 10% respectively.  Also, 90% of patients with chest pain had psychiatric disorders which preceded the chest pain.

For pediatric gastroenterologists, a take home message from this article is that chest pain is quite similar to abdominal pain (see references below); it might be interesting to discuss with cardiologists.

  • Do cardiologists experience the same reluctance from families to seek help from mental health?
  • How much testing is required before a functional diagnosis is accepted?
  • Do they follow patients with functional chest pain or send back promptly to primary care physician?

This article does not examine parental mental health issues.  This would be interesting.  In functional abdominal pain, maternal anxiety has been ascribed as the most consistent predictor of outcome (Acta Paediatr 2007; 96: 697-701).  Another factor that would be of interest would be level of activity; exercise helps reduce symptoms of irritable bowel/abdominal pain.

At the same time, the issue of reflux is not addressed by this article and not infrequently the issue of whether reflux is causing chest pain needs to be considered.  An article (Gut 2011; 60: 1473-78) regarding chest pain in adults indicates that patients with pH-probe (or endoscopic) proven GERD often respond partially (>50% reduction in symptoms) to PPI use.  This study reviewed RCTs involving chest pain and PPIs -six met inclusion criteria.  The RR of therapeutic gain for PPI usage was 4.3 for those with proven reflux and 0.4 for those with pH-probe (or endoscopic) negative chest pain.  Interestingly, in this study, heartburn was not predictive of whether chest pain was due to GERD on pH study.

Additional references:

  • -Pediatr Emerg Care 2010; 26: 830-6.  Psychopathology among children presenting to ER with unexplained chest pain.
  • -Clin Gastro 2008; 6: 329-32.  Depressive symptoms common in RAP -45%
  • -Pediatrics 2004; 113: 817.  Anxiety & depression commonly associated with RAP.  anxiety in ~79%, depression ~43%; anxiety often precedes RAP.
  • -JPGN 2011; 53: 200. n=98. 79% of FAP responded to low dose tricyclics
  • -Gastroenterology 2009; 137: 1261, 1207– Editorial.  Amitriptyline helped in 66% vs 58% with placebo. n=90. dose 10mg <35kg, 20mg >35kg. 89% had failed Rx prior to study. ‘Inability to use placebo.. in practice may justify amitriptyline’ Rx. Consider hypnotherapy/CBT first.
  • -Gut 2011; 60: 1473-78. PPI use in unexplained chest pain.
  • -Pain 2006; 122: 43-52. (Walker LS et al), J Pain 2006; 7: 319-26.  Distraction/ignoring important.
  • -J Pediatr 2009; 154: 313 (editorial), 322. Prospective school study. n=237. Weekly prevalence of abd pain was 38%. 18% with persistence for >12 weeks.
  • -Clin Gastro Hepatol 2008; 6: 329-32.  FAP persists into adulthood in 1/3 to 1/2 of cases.
  • -Gastroenterol 2006; 130: 1459-1465.  Functional esophageal d/o.
  • -Clin Gastro & Hep 2006; 4: 558. Review.
  • -Ann Heart J 2000; 40: 367-372.  Sertraline decreased chest pain independent of mood alteration/psychological scores.